Synthesis of Structurally Diverse 3-, 4-, 5-, and 6-Membered

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Synthesis of Structurally Diverse 3-, 4-, 5- and 6-Membered Heterocycles from Diisopropyl Iminomalonates and Soft C-Nucleophiles Padmanabha V. Kattamuri, Urmibushan Bhakta, Surached Siriwongsup, Doo-Hyun Kwon, Lawrence B. Alemany, Muhammed Yousufuddin, Daniel H. Ess, and László Kürti J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00681 • Publication Date (Web): 22 Apr 2019 Downloaded from http://pubs.acs.org on April 23, 2019

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The Journal of Organic Chemistry

Synthesis of Structurally Diverse 3-, 4-, 5- and 6-Membered Heterocycles from Diisopropyl Iminomalonates and Soft C-Nucleophiles Padmanabha V. Kattamuri,† Urmibhusan Bhakta,† Surached Siriwongsup,† Doo-Hyun Kwon,‡ Lawrence B. Alemany,#† Muhammed Yousufuddin,┴ Daniel H. Ess*,‡ and László Kürti*† †

Department of Chemistry, Rice University, BioScience Research Collaborative, Houston, TX 77005, USA. Shared Equipment Authority, Rice University, 6100 Main Street, Houston, TX 77005, USA. ‡ Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, USA ┴ Life and Health Sciences Department, University of North Texas at Dallas, TX 75241, USA. KEYWORDS. Aziridines, Lactones, Lactams, Asymmetric Synthesis, CBS Reduction, Amino acid building blocks #

ABSTRACT: Herein, we present a general synthetic strategy for the preparation of 3-, 4-, 5- and 6-membered heterocyclic unnatural amino acid derivatives by exploiting facile Mannich-type reactions between readily available N-alkyl- and N-aryl-substituted diisopropyl iminomalonates and a wide range of soft anionic C-nucleophiles without using any catalyst or additive. Fully substituted aziridines were obtained in a single step when enolates of alpha-bromo esters were employed as nucleophiles. Enantiomerically enriched azetidines, γ-lactones and tetrahydroquinolines were obtained via a two-step catalytic asymmetric reduction and cyclization sequence from ketone enolate-derived adducts. Finally, highly substituted γ-lactams were prepared in one-pot from adducts obtained using acetonitrile-derived carbanions. Overall, this work clearly demonstrates the utility of iminomalonates as highly versatile building blocks for the practical and scalable synthesis of structurally diverse heterocycles.

INTRODUCTION We recently reported the convenient preparation of novel Nelectrophilic diisopropyl iminomalonates (2) derived from readily available primary amines and their application for the synthesis of a large number of secondary amines (3) using organometallic C-nucleophiles such as Grignard reagents, alkyl- and aryllithiums (1).1 These hard C-nucleophiles preferentially attacked the nitrogen atom of the imine moiety in the absence of catalysts or additives (Figure 1A). The experimental findings were also supported by DFT computational studies. In the same report we also disclosed the result of adding the lithium enolate of acetophenone (4) to the N-PMP-substituted diisopropyl iminomalonate (5, Figure 1B). Based on routine NMR spectra (1H and 13C) of the major product, we assigned putative structure (6) in which the alpha position of acetophenone was aminated. Subsequent ketone reduction and cyclization afforded presumed compound (7) – this 6-membered lactone structure was also in good agreement with routine NMR spectra. Since the focus of this past work was the unique N-selective addition of hard C-nucleophiles to iminomalonates, no in-depth spectroscopic studies were performed on compound (7) at that time. During the follow-up studies, when we focused our attention on exploring the reactivity of iminomalonates with softer C-nucleophiles such as enolates derived from ketones and esters along with carbanions obtained from acetonitrile derivatives, we performed 1D and 2D NMR studies on presumed compound 7. These studies strongly pointed to the presence of a 5-membered lactone scaffold (9) instead of the originally presumed 6-membered lactone scaffold (7). The only way a 5-membered lactone product (9) could have formed was to have a preferential attack occur at the iminomalonate carbon atom during the enolate addition step to afford compound 8.

Fig. 1. Exploring the reactivity of hard and soft nucleophiles with iminomalonates. This surprising switch in chemoselectivity was in stark contrast with the predominant N-attack of hard C-nucleophiles on a wide variety of N-substituted iminomalonates.1 Even though we originally anticipated predominant N-attack by most C-nucleophiles, based on the demonstrated reactivity pattern by Grignard

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reagents and alkyl/aryl lithium compounds, in-depth computational studies (vide infra) on the reactivity of iminomalonates towards soft C-nucleophiles confirmed our new experimental findings (Figure 1B). We identified three unique structural features of the 5-membered lactone product (9), namely: (a) two stereogenic centers with one being fully substituted; (b) an aminoaryl substituent in the alpha-position of the lactone carbonyl group and (c) the generation of a highly substituted, unnatural cyclic amino acid derivative (Figure 1B). In fact, non-proteinogenic amino acids have become important tools for modern pharmaceutical research.2 While some occur naturally (e.g., Ornithine, from urea cycle), the vast majority of these are chemically synthesized. Owing to their remarkable structural and functional diversity, they are often used as building blocks for drug discovery.2

Fig. 2. Comparison of achievable structural diversity in known Mannich reactions and this study. We also realized that there are only a few reported examples of these highly substituted 5-membered lactone scaffolds and even fewer methods exist for their synthesis.3 A survey of reported Mannich reactions between activated imines (10-14) and aldehydes/ketones is shown in Figure 2. The Mannich reaction is one of the classic methods for the synthesis of β-amino carbonyl compounds.4-9 The versatility of this important carbon−carbon

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(C−C) bond forming reaction lies in its potential to create both functional and structural diversity that generated a lot of interest in the synthetic community. However, the overwhelming majority of reported reactions produces compounds that have limited structural diversity with regard to both the imine and the carbonyl coupling partners.6 Even fewer reports attempted to make use of the initial Mannich adducts and convert these to more elaborated building blocks (i.e., γ-butyrolactones, Figure 2C).10 Of particular concern is the dearth of structural diversity with respect to the substituents on the nitrogen atom as well as in the γ-position of the lactone scaffold. In contrast to known reports, we fully recognized the opportunity to convert our initial iminomalonate/ketone Mannich adducts into γ-butyrolactones (24) in which the nature of the substituents at each position (i.e., α, β and γ), including the substituent on the nitrogen atom, can be widely varied (Figure 2D). This wide variation in the structure of substituents is possible because nearly all primary arylamines can be easily converted to the corresponding N-aryl iminomalonates1 (25) and virtually any enolizable ketone (26) can be coupled to these in the absence of catalysts or additives. We argued that the absolute stereochemistry could be readily controlled in the next step by the well-known and predictable CBS reduction of the carbonyl group (27→28, Figure 3).11

Fig. 3. Proposed synthesis of chiral nonracemic azetidines, tetrahydroquinolines, and lactones from iminomalonates via enantiomerically enriched secondary alcohols (28). Moreover, the resulting enantiomerically enriched secondary alcohols (28) could open up a number of exciting possibilities for the synthesis of densely functionalized N- and O-heterocycles. For instance, activation of the benzylic alcohol moiety by inversion would allow for a subsequent intramolecular nucleophilic (SNi) substitution reaction by the N atom to furnish the corresponding azetidines (30) in which the benzylic stereocenter would retain its original configuration (i.e., double inversion). Alternatively, the aromatic ring attached to the nitrogen could also act as a nucleophile and perform the benzylic substitution with inversion in order to afford tetrahydroquinolines


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(31). A third option is to use the benzylic alcohol OH group as a nucleophile as we have already observed in our recent study (Figure 1B). Thus, an intramolecular nucleophilic acyl substitution reaction (SNAc; i.e., lactonization) is expected to take place with one of the isopropyl ester groups to yield α-aminoaryl γ-lactones (24) either under acid-catalyzed or base-mediated conditions (Figure 3). Additional synthetic possibilities for iminomalonates include a one-pot aza-Darzens-type reaction12 with haloester enolates to form aziridines (33; Figure 4) and also a two-step sequence that involves the addition of nitrile enolates. Reduction of the nitrile to a primary amine followed by intramolecular N-acylation is expected to furnish α-aminoaryl γ-lactams (36; Figure 4).

group. The resulting γ-lactams all feature α-amino acid backbones and these compounds can be utilized as amino acid surrogates. Based on these encouraging initial findings we decided to explore the full synthetic potential of adding soft C-nucleophiles to iminomalonates. Herein we provide the detailed report for the successful synthesis of structurally diverse 3-, 4-, 5- and 6membered heterocycles via sequential Mannich reaction and cyclization. Since these heterocyclic scaffolds are prevalent in a wide variety of natural products and drug molecules (Figure 5), a unified synthetic strategy that exploits readily available and inexpensive iminomalonates1 and enolates as starting materials would be a valuable addition to the toolbox of synthetic as well as medicinal chemists.

Fig. 4. Proposed synthesis of aziridines and lactams from iminomalonates (25). These exciting synthetic possibilities prompted us to investigate the scope of enolates that would also exclusively attack the imine carbon of the iminomalonate substrates (25). Accordingly, we selected readily available esters, ketones and nitriles and carried out the reaction of iminomalonates with their corresponding enolates (32) or alkylnitrile-derived carbanions (34) under a variety of conditions. While simple ester enolates did not react with either N-aryl or N-alkyl iminomalonates, the Lienolate of the non-sterically hindered methyl-bromoacetate quickly furnished the corresponding N-aryl- as well as N-alkylaziridines (33). The mechanism of this process is necessarily similar to an aza-Darzens reaction.12 A thorough literature search revealed that there were very few examples involving the addition of alkylnitrile-derived carbanions (e.g., 34) to activated imines such as α-iminoesters.13 From a synthetic perspective, alkylnitriles are versatile building blocks as they can be readily converted to primary amines, aldehydes, amides and carboxylic acids. Gratifyingly, N-aryl iminomalonates (25) displayed remarkable reactivity towards arylacetonitrile-derived carbanions (34), yielding β-nitriloamines (35). As anticipated, reduction of the nitrile moiety followed by in situ cyclization allowed us to transform these compounds into highly sought-after γ-lactams (36) which are popular targets among medicinal chemists.14 Just like in the case of γ-lactones, a fully substituted α-stereocenter could be generated bearing an aminoaryl and an alkoxycarbonyl

Fig. 5. Natural products and active pharmaceutical ingredients that contain 3-, 4-, 5- and 6-membered heterocycles. RESULTS AND DISCUSSION The catalytic asymmetric synthesis of tetrasubstituted carbon stereocenters remains a significant challenge in organic synthesis.15 The stereoselective Mannich reaction between prochiral ketimines and enolates affords highly substituted chiral amines that are potentially valuable building blocks for further elaboration provided that the activating group, often present on the nitrogen, can be removed.10e Our investigation began with the systematic study of the Mannich-type reaction between nonprochiral (i.e., symmetrical) N-aryl iminomalonates and ketonederived enolates (Figure 3) as this approach would allow the control of absolute stereochemistry in a variety of ways. First, we combined two equivalents of pre-formed acetophenone-derived lithium enolate with one equivalent p-methoxyphenyl iminomalonate (25a; Ar = PMP) at −78 °C in THF. The reaction proceeded well and exclusively furnished the C-addition product 27a in 66% yield (see SI, pages S5 & S6). The nature of the lithium base used for the pre-formation of the ketone enolate in THF was important: LiHMDS afforded the highest isolated yield of 27a (66%) while n-BuLi as well as LDA resulted in reduced yield of the Mannich adduct (54% and 22%, respectively). Next, the impact of the reaction temperature was evaluated in THF as the solvent. Increasing the temperature from −78 °C to first −40 °C and then to −20 °C, led to decreasing yields of 27a (36% and 0%, respectively) and at −20 °C the reaction mixture became too complex.



Switching the solvent from THF to 2-Me-THF significantly lowered the isolated yield (66% → 27%). Other ethereal solvents such as diethyl ether, MTBE, dioxane and DME were inferior compared to THF when LiHMDS was used as the base for the preparation of the pre-formed enolate (see SI, pages S5 & S6). However, when KHMDS was employed as a base first in MTBE and then in DME at −78 °C, the yield of 27a dramatically improved to 61% and 70%, respectively. Subsequently, we examined the effect of the amount of enolate coupling partner on the isolated yield of 27a. Reducing the amount of the enolate from 2 equivalents to 1.1 equivalents decreased the yield slightly (70%→ 63%); however, we found that employing 1.5 equivalents of enolate coupling partner 26 was optimal, as it afforded 27a in 94% isolated yield. Changes in the concentration (0.1 M to 0.3 M) did not have a significant effect on the isolated yield. Thus, the optimal Mannich coupling conditions called for the combination of reactants (i.e., 1:1.5 ratio of iminomalonate/potassium enolate) as a 0.2 M solution in DME at −78 °C (Figure 6).

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We were pleased to find that under the optimized coupling conditions, a variety of N-aryl-substituted iminomalonates (25) smoothly reacted with different aromatic, heteroaromatic and aliphatic ketone enolates (26), and the corresponding bench-stable Mannich adducts (27) were isolated in good to excellent yields. Ultimately, we explored the reactivity of thirteen (13) different ketone enolates with a diverse set of aromatic and heteroaromatic iminomalonates (10 structurally different examples, Figure 6). Simple aromatic and aliphatic ketone-derived enolates afforded the corresponding Mannich adducts (27a−t, Figure 6) in excellent yields. However, in the case of nitrogen-containing heteroaromatic ketone enolates (e.g., pyridines and pyrroles; 27m, 27q−t), the yields were lower compared to oxygen- and sulfurcontaining heteroaromatics (e.g., furans and thiophenes; 27i−k). Surprisingly, N-aliphatic iminomalonates were found to be unreactive with both aromatic and aliphatic ketone-derived enolates. This prompted us to use density functional theory (DFT) calculations to examine the reactivity and selectivity for enolate additions to these iminomalonates.


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In Gaussian 09,26 we used the M06-2X27 functional with def2TZVP28 basis set for final SCF energies and 6-31G(d,p) for geometries and thermochemical analysis. Tetrahydrofuran was used as a substitute for DME in the continuum SMD29 model. We used the N-Bu and N-Ph iminomalonates with methyl ester groups as models. For the enolates, we used the acetophenonederived enolate (Figure 8a) as well as the potassium-oxygen stabilized version (Figure 8b). As expected from the outcome of the reactions presented in Figure 6, enolate addition to the N-Bu and N-Ph iminomalonate carbon is lower in Gibbs free energy (and enthalpy) than attack to the nitrogen. For the unstabilized enolate model, the C-attack transition states are 3−4 kcal/mol lower in energy. Interestingly, using the potassium-stabilized enolate model, the selectivity is much higher: the C-attack transitions states are ~7−12 kcal/mol lower in energy than N-attack transition states, which is consistent with the experimental observation of C-attack products. Our transition states also confirm that the N-Bu iminomalonate is significantly less reactive than the N-Ph derivative. For example, the unstabilized enolate C-attack transition state for N-

Bu iminomalonate requires ΔG‡ = 18.6 kcal/mol, while for the N-Ph derivative ΔG‡ = 13.9 kcal/mol. The potassium-enolate model transition states for C-attack show >7 kcal/mol lower barrier for the N-Ph iminomalonate. Next we proceeded to reduce the carbonyl group of the Mannich adducts utilizing the well-established CBS reduction (Figure 7).11 In order to identify the optimal conditions for the desired highly enantioselective carbonyl reduction (27→28), we carefully evaluated several combinations of chiral oxazaborolidine catalysts and borane reducing agents to obtain the corresponding secondary benzylic alcohols (see SI, pages S35 & S36). A quick temperature study (between 25 °C and −20 °C) revealed that at −15 °C with 15 mol% catalyst loading the highest enanatioselectivity (94% ee) could be achieved. Any further increase in the catalyst loading as well as further lowering of the reaction temperature resulted in inferior isolated yields and significantly longer reaction times (e.g., at −20 °C the reaction took >96 h to go to completion). Ultimately we found that the combination of 15 mol% of (S)−2−methyl oxazaborolidine catalyst, two equivalents of



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Fig. 8. M06-2X/def2-TZVP//M06-2X/6-31G(d,p) transition-state structures and energies (Gibbs energy, enthalpy at 298 K) for a) acetophenone-derived enolate and phenyl isopropyl ketone-derived enolate addition to N-Bu and N-Ph iminomalonates b) potassiumcoordinated enolate addition to N-Bu and N-Ph iminomalonates. Energies are relative to separated reactants and in kcal/mol. Thus, we surmised that our versatile iminomalonates are the BH3.DMS in THF at −15 ˚C were optimal for the efficient rebest precursors for the construction of these important structural duction of ketones (i.e., up to 94% isolated yield). With these moieties via sequential Mannich-type reaction, asymmetric caroptimized conditions in hand, we proceeded with the asymmetbonyl reduction and cyclization. Initially, 1,3-aminoalcohol ric carbonyl reduction of over one dozen Mannich adducts and 28h was treated with mesyl chloride (1.5 equiv) in the presence obtained the corresponding amino alcohols (28a−m, Figure 7) of triethylamine (1.5 equiv) at room temperature with the exin good-to-excellent isolated yields and with very high enantipectation of activating the benzylic alcohol moiety towards the oselectivities (up to 98% ee as in the case of 28f). subsequent intramolecular nucleophilic attack by conversion to Both the isolated yields and enantioselectivities were slightly the corresponding mesylate. While some of the desired cyclized lowered in the case of pyridine-containing substrates (28l and products (30h and 31h) were formed, most of the starting ma28m, Figure 7). The absolute configuration of these chiral 1,3terial remained unreacted even after several hours of stirring aminoalcohols was unambiguously determined to be (R) by (see SI, Table S4, page S23). When the amounts of mesyl chlo16 Mosher-Ester analysis (see SI, page S37). The three Mannich ride and base were both increased (1.5 → 3.0 equiv) and the adducts that were prepared by the addition of α-branched ketemperature was elevated (25→50 °C), complete consumption tone enolates to N-aryl iminomalonates (27n−p, Figure 6) were of the 1,3-aminoalcohol substrate (28h) was observed and the subjected to simple borane reduction (BH3.DMS, no CBS catacorresponding O-mesylate was obtained as the major product. lyst was employed) and the corresponding racemic 1,3-aminoIn this case, the anticipated cyclization was incomplete as only alcohols (28n−p, Figure 7) were obtained as single diastere25% of the O-mesylate intermediate was converted to the prodomers. With the over one dozen enantiomerically enriched 1,3ucts 30h and 31h (obtained as a mixture of 2:1, respectively). aminoalcohols in hand (28a−m), we were in the position to In order to improve the efficiency of the intramolecular cyclizaevaluate two possible intramolecular cyclization pathways to tion step, we decided to alter the nature of the leaving group by either furnish azetidines or tetrahydroquinolines (28 → 29 → converting the benzylic alcohol moiety to the corresponding 2o 30 and 31, Figure 3 and Figure 9). alkyl bromide (29) via inversion of configuration. Two different bromination conditions were explored (PPh3 with either CBr4 or Azetidines are one of the privileged classes of heterocycles in 2,4,5-tribromoimidazole; see Table S4 in SI) and the combinamedicinal chemistry.17 This four-membered and rigid aza-hettion of triphenylphosphine with 2,4,5-tribromoimidazole was erocycle displays higher metabolic stability, ligand efficiency found to be optimal. and physicochemical profiles compared to its higher homologues. Owing to the challenges associated with the formation With this optimized cyclization condition in hand, we examined of this strained four-membered ring, relatively few methods are the further reaction of four representative examples (Figure 9). available for their synthesis.17 Likewise, the tetrahydroquinoWe found that the aromatic substituent on the nitrogen had a line ring system is a common structural motif prevalent in nusignificant impact on both the product distribution (i.e., azetmerous natural products and therapeutic agents.18 Although idine or tetrahydroquinoline) and the stereoselectivity of the cyseveral methods have been developed for the enantioselective clization step. For example, the N-(3-trifluoromethylphenyl)synthesis of 2-substituted tetrahydroquinolines, synthetic routes substituted aminoalcohol (28e) did not furnish the anticipated leading to 3- and 4-substituted derivatives have garnered signiftetrahydroquinoline (31e); only the azetidine product (30e) was icantly less attention despite their industrial importance.19 Reobserved. This suggests that the distribution cently Han et. al. and Ghosh et. al. independently reported the synthesis of malonate-derived azetidines and tetrahydroquinolines by the ring-opening of donor-acceptor cyclopropanes.20


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OH HN

R

Ar CO2iPr

2,4,5-tribromoimidazole (1.1 equiv) PPh3 (2.2 equiv)

CO2iPr CO2iPr

48h-96h

(28c, 28e, 28f, 28h)

Ar HN

R

Toluene, 80 oC

CO2iPr

iPrO

Br

(29c, 29e, 29f, 29h)

SN 2

iPrO

SNi and/or SEAr

2C

R2

2C

N

+

0.2 0.6 mmol scale

CO2iPr

R1

R2

N H

R1

(30c, 30e, 30f, 30h)

CO2iPr

(31c, 31e, 31f, 31h)

Structures of Azetidines and Tetrahydroquinolines (Entry): Compound #; Isolated Yield (%) Br iPrO iPrO

iPrO

2C

2C

72%

(R)

N

iPrO

2C

2C

N

Me

(R)

1:0

1.9 : 1

Me Br

Me

Me

iPrO

(S)

CO2iPr

N H

CO2iPr

iPrO

2C

2C

N

(R)

iPrO

73%

Me

( )-30f er 20:80

Me

CO2iPr

N H

CO2iPr

(+)-31f er 19:81

CO2iPr

N H

CO2iPr

31e Not observed

(R)

71% 4.5 : 1

(S)

(S)

2C

2C

N

Me

1 : 2.8

Me

F3C

CF3

(+)-30e er 37:63

(+)-31c er 92:8

( )-30c er 7:93

iPrO

31%

(+)-30h er 91:9

(S)

CO2iPr

N H

CO2iPr

(+)-31h er 10:90

Fig. 9. Cyclization of chiral alcohols to corresponding azetidines and tetrahydroquinolines. The chiral alcohols obtained by reduction of ketone adducts were subjected to the above mentioned conditions with 0.05M concentration of starting material for cyclization to corresponding azetidines and tetrahydroquinolines considered complete upon the full consumption of the individual chiral alcohols by TLC analysis.

of the electron-density between the nitrogen substituent and the π system of the aryl ring dictates which one of these moieties will perform the nucleophilic displacement of bromine to afford either the azetidine or tetrahydroquinoline as the major product. If π-stacking interaction is possible during the cyclization (e.g., 28f→31f), this secondary interaction can completely switch the product distribution compared to substrates in which such an interaction cannot occur (cf. 28h→30h and 28c→30c, Figure 9). The γ-lactone moiety has attracted great interest in the synthetic organic chemistry community for two main reasons: (a) the molecules that contain this moiety exhibit a diverse range of biological activities and (b) its synthesis presents challenges. In fact, the γ-lactone substructure is present in more than 15,000 natural products and it is also a valuable building block for the preparation of structurally complex molecules as well as active pharmaceutical ingredients.21 While there are a number of efficient synthetic methods available for the preparation of structurally simple γ-lactones, access to highly-substituted members of this family is limited. For example, to the best of our knowledge, there have been only a few reports for the synthesis of α-amino-substituted γ-lactones (see Figure 2C).10 Since our group found that N-aryliminomalonates reacted efficiently with ketone-derived enolates (Figure 6) and the resulting Mannich adducts afforded the corresponding 1,3-aminoalcohols in high enantiomeric excess (Figure 7), the main question was how we could efficiently convert these aminoalcohols (28a-p, Figures 10 & 11) to the corresponding γ-lactones (24)?.

Importantly, when the solution of 1,3-aminoalcohol 28a in toluene was treated with 20 mol% of TsOH.H2O at 50 °C, the lactonization (i.e., between the benzylic alcohol and isopropyl ester moieties) took place in 24 h and the easy-to-separate diastereomeric lactones (24c and 24d) were obtained in a 2:1 ratio. Increasing the reaction temperature (e.g., 70 °C and 110 °C) resulted in significantly faster lactonization − at 70 °C the lactonization was fast (1 h) and had minimal impurities. In order to increase the diastereoselectivity during lactonization, we turned to using chiral Brønsted acid (i.e., phosphoric acid) catalysts.22 It was anticipated that the use of a chiral phosphoric acid catalyst would lead to an efficient cyclization process in a highly stereoselective manner owing to the ability of the chiral phosphate counterion to influence the stereochemistry-determining step. Ultimately, we screened a total of seven chiral Brønsted acid catalysts (e.g., chiral phosphoric acids and camphor sulfonic acids) and identified (R)−3,3′−bis[3,5-bis(trifluoro-methyl)phenyl]-1,1′-binaphthyl-2,2′-diylhydro-genphosphate to be the most efficient, as it afforded the cyclized γ-lactone products 24c and 24d in a 3.3:1 diastereomeric ratio at 100 °C in just 2 h (see SI, pages S57 & S58). All the other combinations of solvent, temperature and Brønsted acid furnished the γ-lactones in about ~2:1 diastereomeric ratio. These results clearly indicated that the presence of a chiral counterion did not significantly improve the diastereoselectivity of the lactonization step (e.g., 2:1 dr → 3.3:1 dr, which represents only a 1.65x increase). Such modest increase in the diasteromeric ratio could not justify the use of an expensive chiral phosphoric acid catalyst. Thus we shifted our focus



towards using cheaper achiral Brønsted acids − p-toluenesulfonic acid monohydrate (TsOH.H2O) was found to be the optimal catalyst in toluene at 70 °C as the reaction proceeded to completion in just one hour. With these optimized acid-catalyzed lactonization conditions in hand, we proceeded to cyclize 14 amino alcohols (Figures 10 & 11). Without exception, each of the isolated γ-lactones were obtained in excellent enantiomeric excess (up to 98:2 er). Surprisingly, the acid-catalyzed cyclization conditions were unsuitable for heterocycle-containing substrates and invariably led to complex reaction mixtures. For these heteroaromatic substrates, base-mediated conditions (e.g., DBU) were found to be optimal, and the desired lactone products were obtained in high isolated yields while the diastereoselectivities varied from 1.2:1 → 1.5:1 (24q, r; 24s, t; and 24u, v; Figures 10 and 11). The modest diastereoselectivity in the lactonization step can be attributed to the lack of substituents at the β-position of the γ-lactone moiety. However, aminoalcohols 28n, 28o and 28p underwent lactonization with complete diastereoselectivity – in all three cases the product γ-lactones were substituted in their β-position (Figure 11). Diversely substituted aziridines are not only valuable synthetic intermediates but they also occur as substructures in natural products and drug-like molecules.12a, 23 Among these diverse family of aziridines, aziridine-2,2-diesters are special (i.e., donor-acceptor aziridines) as they serve as precursors of azomethine ylide intermediates that undergo a variety of cycloaddition reactions.24, 25 The synthesis of fully substituted aziridines remains a significant synthetic challenge.23b Since synthetic access to structurally diverse donor-acceptor aziridines is fairly limited,25 we saw an opportunity to access these valuable building blocks using an aza-Darzens reaction between haloester enolates and N-alkyl as well as N-aryl diisopropyl iminomalonates (Figure 12). We briefly reported earlier about this transformation in our previous publication to show the additional synthetic possibilities from iminomalonates.1 As we briefly mentioned earlier (vide infra), simple ester enolates did not react with iminomalonates but alpha-halogenated ester enolates reacted quickly and efficiently affording the aziridine-2,2,3-triesters as single diastereomers. In fact, DFT calculations showed that the trans-1-phenyl-3-methoxycarbonyl aziridine diastereomer (33a, Figure 12) is favored over the cis-diastereomer by ~4 kcal/mol (see SI, pages S128 & S129). We also carried out DFT calculations on the reaction pathway for aziridine formation. Similar to what we showed in Figure 8, the enolate derived from ester 46 has a lower energy transitions state for C-attack compared to N-attack. The calculated structures along the aziridine reaction pathway are shown in Figure 15. After the C-attack, with a barrier of 17 kcal/mol, the resulting intermediate can then induce intramolecular nucleophilic substitution and bromide ejection with a barrier of 12 kcal/mol. This lower barrier for intramolecular substitution is consistent with the lack of observation of the addition intermediate (29). For the optimization study (see SI, page S80), we have chosen methyl bromoacetate and N-phenyl iminomalonate as coupling partners. Various ethereal solvents and strong bases were screened: when either n-BuLi or NaHMDS were used as bases, a complex reaction mixture was obtained and no desired aziridine product (33a) was isolated. When KHMDS was used, only 3% of product was isolated at −78 °C. Ultimately, LiHMDS was identified as the most suitable base and THF as the best solvent at −41°C (i.e., acetonitrile-dry ice bath); using these conditions,

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33a was isolated in 79% yield. With these optimized conditions in hand, we proceeded to explore the scope and limitations of this transformation (Figure 12). Both aliphatic and aromatic iminomalonates worked well as reaction partners and the aziridines were isolated in moderate to excellent yields. We then studied the reactivity of nitrile-derived carbanions with iminomalonates (Figure 13). For the optimization study, 4fluorophenylacetonitrile (48i) was chosen as the coupling partner. Various solvents and bases were thoroughly screened at −78 °C. A very strong base, such as n-BuLi, only led to decomposition. Weaker bases, such as HMDS-derived bases, were then applied with varying results. LiHMDS and NaHMDS were totally ineffective: the 4-fluorophenylacetonitrile substrate was completely recovered in both THF and DME. With the combination of KHMDS and either THF, Et2O or 1,4dioxane, the product could only be obtained in low yields (811%). However, when the reaction was carried out with KHMDS in DME as the solvent, the yield improved significantly (58%). We also determined that decreasing the amount of carbanion from 1.5 equivalents to 1.35 equivalents made the reaction much cleaner, hence simplifying the purification process. It was observed that the using over 1.5 equivalents of the carbanion generally resulted in more complex reaction mixtures. With the optimized reaction conditions in hand (1.35 equivalents of KHMDS and 1.35 equivalents of nitrile at −78 ° C in DME), we embarked upon exploring the generality of this method with a variety of nitrile coupling partners (Figure 13). The isolated yields of adducts (35) ranged from good to excellent on 1−4 mmol scale. There was no dramatic effect of the substituents on the nitrogen atom of the imine partner on the yields. Imines with both electron withdrawing groups and electron donating groups on the nitrogen atom were tolerated (Figure 13). The structure of the acetonitrile coupling partner was also widely varied. While arylacetonitriles worked well, aliphatic acetonitriles either performed poorly or did not react. The use of very strong bases (e.g., n-BuLi) with these aliphatic acetonitriles only led to their complete decomposition even at −78 ° C. From these results, it is clear that both the stability and reactivity of the acetonitrile-derived anions are important - it can be opined that the nature of the anion from the acetonitrile is of paramount importance as the metal counterion can significantly alter the reactivity pattern. The successful acetonitriles were those that had anion-stabilizing substituents - thus an aromatic ring or a heavier atom such as sulfur in the α-position were found to be critical. We then sought to find a method which would enable us to perform the reduction of the nitrile functionality (35 → 49, Figure 14) and the subsequent cyclization (49 → 36) to the corresponding γ-lactam in one step. After carefully exploring a number of methods, we found that the nickel-mediated hydrogenation of the nitrile addition products afforded the desired lactams in good isolated yields. It is important to note that some of the nitrile addition products, those with a chlorine substituent on their aromatic rings, failed to cyclize to the desired lactams. Presumably, the presence of nickel may have led to the decomposition of these substrates. To address these shortcomings, an alternative reduction method was performed on these substrates. Accordingly, treatment with excess borane was followed by an aqueous quench and subsequent reflux to facilitate a clean lactam formation (Figure 14). Both of these methods (A and B) delivered the γ-lactam products as single diastereomers. This is in contrast to the formation of γ-lactones (Figure 10 and 11) that were formed as a mixture of


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Fig. 15. M06-2X/def2-TZVP//M06-2X/6-31G(d,p) calculated reaction pathway structures and energies (Gibbs free energy, enthalpy at 298 K) for 46-derived enolate addition to N-Ph iminomalonate. fully separable diastereomers. We believe that this difference in diastereoselectivity can be attributed to the presence or absence of substituents in the β−position (i.e., relative to the carbonyl group) of the 5-membered lactam ring. CONCLUSION In summary, we have developed a practical and operationally simple protocol for the synthesis of five different classes of heterocycles (i.e., with ring sizes 3-6) using N-substituted iminomalonates as the common coupling partners. Each heterocycle features an unnatural amino acid backbone. The Mannich adducts, obtained via reaction with soft C-nucleophiles such as enolates of ketones, nitriles and haloesters, were further functionalized (e.g., CBS reduction and cyclization) to afford structurally diverse heterocyclic moieties which are valuable building blocks for the preparation of biologically relevant molecules such as active pharmaceutical ingredients and structural analogs of natural products. The complete switch of chemoselectivity (i.e., predominant N-attack versus exclusive C-attack of the iminomalonate C=N bond) depending on the nature of the Cnucleophile (i.e., hard or soft) is unprecedented in the literature and our experimental findings have been corroborated by detailed DFT calculations. Studies are currently underway in our laboratories to explore the reactivity of iminomalonates with additional soft C-nucleophiles and our findings will be reported in due course. EXPERIMENTAL SECTION General Information Reagents were purchased at the highest quality from commercially available sources and used without

further purification. 1,2-Dimethoxyethane (DME), tetrahydrofuran (THF) and toluene for the reactions were obtained from pure process technology solvent system by passing the previously degassed solvents through an activated alumina column under argon. All reactions were carried out in flame-dried glass ware under an atmosphere of argon with magnetic stirring. All reactions were monitored by either 1H NMR or thin layer chromatography (TLC) carried out on 0.25 mm pre-coated E. Merck silica plates (60F-254), using shortwave UV light as a visualizing agent and KMnO4 or phosphomolybdic acid (PMA) and heat as developing agents. Flash column chromatography was performed using Biotage Isolera One automated chromatograph with pre-packed KP-Sil cartridges. 1D 1H, 13C and DEPT-135 13 C NMR spectra were recorded on Bruker Avance III HD 600 and Bruker Avance III 500 spectrometers operating at 600 MHz and 500 MHz for 1H, 151 MHz and 126 MHz for 13C. The spectra were calibrated using either TMS or the solvent as an internal reference (residual CHCl3: 7.26 ppm 1H NMR; CDCl3: 77.00 ppm 13C NMR). 2D COSY, NOE, HSQC, and HMBC experiments were done on the 500 MHz spectrometer. 19F NMR spectra at 471 MHz were recorded on the 500 MHz spectrometer, and the chemical shifts were relative to CF35Cl3 defined as 0 ppm. For reporting NMR peak multiplicities, the following abbreviations were used: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, hept = heptet, m = multiplet. High-resolution mass spectra (HRMS) were recorded on an Agilent UHPLC TOF mass spectrometer using electrospray ionization time-of-flight (ESI-TOF) or chemical ionization time-offlight (CI-TOF) reflectron experiments. Melting points and


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ranges were recorded on Mettler Toledo MP50 melting point system. General Procedure for the synthesis of Mannich adducts using ketone enolates, Figure 6. In a thick-walled flame dried reaction vial, ketone (1.5 equiv) was dissolved in anhydrous DME (0.4M) under argon and cooled to −78 ˚C using dry ice/acetone bath. To this cooled reaction mixture, commercially available KHMDS (1M solution in THF) (1.6 equiv) was added dropwise and stirred for 45 min. Then iminomalonate (1.0 equiv) dissolved in anhydrous DME (0.4M) was added slowly dropwise over 5 minutes to the enolate solution and continued stirring for 2 h or until the complete consumption of starting material at −78 ˚C. Then the reaction was quenched using saturated NH4Cl solution (5 mL). Workup and purification: After quenching, the reaction mixture was diluted with brine (20 mL) and the organic layer was separated. The aqueous layer was then extracted with EtOAc twice (2 X 30 mL) and the combined organic layers were washed with brine (30 mL) once, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by automated flash column chromatography. Diisopropyl-2-((4-methoxyphenyl)amino)-2-(2-oxo-2-phenylethyl)malonate (27a). The general procedure was followed using Acetophenone (0.72 mL, 1.5 mmol), KHMDS (1M solution in THF) (6.6 mL, 1.6 mmol) and p-methoxyphenyl iminomalonate (1.27 g, 4.1 mmol) as starting materials to afford the ketone adduct as a brown colored waxy solid (1.65 g, 94%). Compound was purified by flash column chromatography (Rf = 0.41 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.85 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 2H), 6.66 (d, J = 8.9 Hz, 2H), 6.60 (d, J = 9.0 Hz, 2H), 5.11 (h, J = 6.3 Hz, 3H), 4.02 (s, 2H), 3.67 (s, 3H), 1.20 (d, J = 6.3 Hz, 6H), 1.15 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 196.3, 168.8, 153.3, 138.0, 136.5, 133.1, 128.4, 127.8, 117.7, 114.4, 70.1, 67.0, 55.4, 40.9, 21.3. HRMS (ESITOF) m/z: [M+H]+ Calcd for C24H30NO6 428.2068; Found 428.2069. Note: The evidence for C-attack by the enolate was the generation of a quaternary aliphatic carbon, as shown by the presence of a signal at δ67.0 in the standard 13C spectrum (p. S53) and the absence of this signal in the DEPT-135 13C spectrum (p. S54). Diisopropyl-2-((3,5-dimethylphenyl)amino)-2-(2-oxo-2-phenylethyl)malonate (27b). The general procedure was followed using Acetophenone (0.40 mL, 3.4 mmol), KHMDS (1M solution in THF) (3.66 mL, 3.6 mmol) and 3,5-dimethylphenyl iminomalonate (0.7 g, 2.2 mmol) as starting materials to afford the ketone adduct as a pale yellow colored viscous oily liquid (0.85 g, 87%). Compound was purified by flash column chromatography (Rf = 0.57 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.89 (d, J = 7.4 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 6.36 (s, 1H), 6.26 (s, 2H), 5.35 (s, 1H), 5.13 (hept, J = 6.2 Hz, 2H), 4.13 (s, 2H), 2.18 (s, 6H), 1.22 (d, J = 6.3 Hz, 6H), 1.15 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 196.2, 168.6, 144.1, 138.4, 136.5, 133.1, 128.3, 127.8, 120.4, 112.5, 70.1, 66.1, 40.8, 21.27, 21.25, 21.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H32NO5 426.2275; Found 426.2275. Diisopropyl-2-(2-(4-bromophenyl)-2-oxoethyl)-2-((3,5-dimethylphenyl)amino)malonate (27c). The general procedure was followed using 4-bromo-acetophenone (0.68 g, 3.4 mmol), KHMDS (1M solution in THF) (3.66 mL, 3.6 mmol) and 3,5dimethylphenyl iminomalonate (0.7 g, 2.2 mmol) as starting

materials to afford the ketone adduct as a pale yellow colored waxy solid (0.92 g, 80%). Compound was purified by flash column chromatography (Rf = 0.57 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.73 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 6.36 (s, 1H), 6.22 (s, 2H), 5.29 (s, 1H), 5.11 (hept, J = 6.1 Hz, 2H), 4.05 (s, 2H), 2.17 (s, 6H), 1.21 (d, J = 6.3 Hz, 6H), 1.14 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 195.5, 168.6, 144.1, 138.6, 135.3, 131.7, 129.5, 128.4, 120.6, 112.6, 70.4, 66.2, 40.8, 21.38, 21.36, 21.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H31BrNO5 504.1380; Found 504.1378. Diisopropyl-2-(benzo[d][1,3]dioxol-5-ylamino)-2-(2-oxo-2phenylethyl)malonate (27d). The general procedure was followed using acetophenone (0.49 mL, 4.2 mmol), KHMDS (1M solution in THF) (4.56 mL, 4.5 mmol) and 3,4-methylenedioxyphenyl iminomalonate (0.91 g, 2.8 mmol) as starting materials to afford the ketone adduct as a yellow colored waxy solid (1.05 g, 84%). Compound was purified by flash column chromatography (Rf = 0.49 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.86 (d, J = 7.3 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.8 Hz, 2H), 6.53 (d, J = 8.3 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 6.06 (dd, J = 8.3, 2.3 Hz, 1H), 5.78 (s, 2H), 5.17 (s, 1H), 5.11 (hept, J = 6.2 Hz, 2H), 4.02 (s, 2H), 1.20 (d, J = 6.3 Hz, 6H), 1.16 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 196.2, 168.7, 148.0, 140.8, 139.3, 136.4, 133.2, 128.4, 127.8, 108.1, 107.9, 100.5, 99.1, 70.2, 66.8, 40.7, 21.3, 21.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H28NO7 442.1860; Found 442.1868. Diisopropyl-2-(2-oxo-2-phenylethyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (27e). The general procedure was followed using acetophenone (0.58 mL, 4.9 mmol), KHMDS (1M solution in THF) (5.32 mL, 5.3 mmol) and 3-trifluoromethylphenyl iminomalonate (1.1 g, 3.3 mmol) as starting materials to afford the ketone adduct as a white colored solid (0.82 g, 53%) (m.p. 132 –134 ˚C). Compound was purified by flash column chromatography (Rf = 0.53 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.89 (d, J = 8.4 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.19 (t, J = 7.9 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.83 (s, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.70 (s, 1H), 5.13 (hept, J = 6.3 Hz, 2H), 4.12 (s, 2H), 1.21 (d, J = 6.3 Hz, 6H), 1.13 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 196.0, 168.2, 144.6, 136.3, 133.4, 131.4 (q, 2 JCF = 31.9 Hz), 129.6, 128.6, 128.0, 124.0 (q, 1JCF = 272.4 Hz), 117.3, 114.9 (q, 3JCF = 3.9 Hz), 110.5 (q, 3JCF = 3.9 Hz), 70.8, 66.0, 40.6, 21.28, 21.22. 19F NMR (471 MHz, CDCl3): δ −62.0 (S). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H27F3NO5 466.1836; found 466.1827. Diisopropyl-2-((3,5-dimethylphenyl)amino)-2-(2-(naphthalen2-yl)-2-oxoethyl)malonate (27f). The general procedure was followed using 2-acetonaphthone (0.48 g, 2.8 mmol), KHMDS (1M solution in THF) (3.01 mL, 3.0 mmol) and 3,5-dimethylphenyl iminomalonate (0.57 g, 1.8 mmol) as starting materials to afford the ketone adduct as a yellowish brown colored viscous gummy oily liquid (0.75 g, 85%). Compound was purified by flash column chromatography (Rf = 0.5 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.37 (s, 1H), 7.95 (dd, J = 8.6, 1.5 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.55 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 6.38 (s, 1H), 6.32 (s, 2H), 5.41 (s, 1H), 5.19 (hept, J = 6.3 Hz, 2H), 4.28 (s, 2H), 2.19 (s, 6H), 1.26 (d, J = 6.3 Hz, 6H), 1.20 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 196.3, 168.7, 144.1, 138.5, 135.4, 133.8, 132.1, 129.8, 129.3, 128.3, 128.1, 127.5, 126.5, 123.3, 120.5, 112.6,

13 ACS Paragon Plus Environment


70.2, 66.3, 40.8, 21.27, 21.21. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H34NO5 476.2431; Found 476.2433. Diisopropyl-2-(2-(naphthalen-1-yl)-2-oxoethyl)-2-(p-tolylamino)malonate (27g). The general procedure was followed using 1-acetonaphthone (0.47 g, 3.0 mmol), KHMDS (1M solution in THF) (3.29 mL, 3.3 mmol) and 4-methylphenyl iminomalonate (0.6 g, 2.0 mmol) as starting materials to afford the ketone adduct as a yellow colored viscous oily liquid (0.61 g, 66%). Compound was purified by flash column chromatography (Rf = 0.53 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.45 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 7.1 Hz, 1H), 7.49 (p, J = 6.1, 5.5 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 5.40 (s, 1H), 5.18 (hept, J = 6.2 Hz, 2H), 4.21 (s, 2H), 2.20 (s, 3H), 1.28 (d, J = 6.3 Hz, 6H), 1.19 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 200.4, 168.8, 141.9, 135.3, 133.6, 132.6, 129.8, 129.5, 128.2, 128.1, 127.7, 127.5, 126.3, 125.5, 124.1, 115.5, 70.2, 66.7, 44.2, 21.37, 21.30, 20.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H32NO5 462.2275; found 462.2277. Diisopropyl-2-(2-oxo-2-phenylethyl)-2-(phenylamino)malonate (27h). The general procedure was followed using acetophenone (0.62 mL, 5.3 mmol), KHMDS (1M solution in THF) (5.68 mL, 5.6 mmol) and phenyl iminomalonate (0.98 g, 3.5 mmol) as starting materials to afford the ketone adduct as a beige colored solid (m.p. 65–68 ˚C) (1.25 g, 89%). Compound was purified by flash column chromatography (Rf = 0.53 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.87 (d, J = 8.2 Hz, 2H), 7.50 (t, J = 6.8 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.10 (t, J = 7.9 Hz, 2H), 6.70 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.1 Hz, 2H), 5.46 (s, 1H), 5.12 (hept, J = 6.2 Hz, 2H), 4.14 (s, 2H), 1.21 (d, J = 6.3 Hz, 6H), 1.12 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 196.2, 168.6, 144.3, 136.5, 133.2, 129.0, 128.4, 127.9, 118.5, 114.5, 70.3, 66.1, 40.8, 21.29, 21.24. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H28NO5 398.1962; Found 398.1958. Diisopropyl 2-(benzo[d][1,3]dioxol-5-ylamino)-2-(2-(furan-2yl)-2-oxoethyl)malonate (27i). The general procedure was followed using 2-acetylfuran (0.33 g, 3.0 mmol), KHMDS (1M solution in THF) (3.23 mL, 3.2 mmol) and 3,4-methylenedioxyphenyl iminomalonate (0.65 g, 2.0 mmol) as starting materials to afford the ketone adduct as a dark brown colored viscous oily liquid (0.66 g, 77%). Compound was purified by flash column chromatography (Rf = 0.27 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.49 (s, 1H), 7.06 (d, J = 3.5 Hz, 1H), 6.53 (d, J = 8.3 Hz, 1H), 6.43 (dd, J = 3.5, 1.7 Hz, 1H), 6.24 (d, J = 2.3 Hz, 1H), 6.05 (dd, J = 8.3, 2.3 Hz, 1H), 5.79 (s, 2H), 5.08 (hept, J = 6.3 Hz, 3H), 3.85 (s, 2H), 1.20 (d, J = 6.3 Hz, 6H), 1.13 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 185.0, 168.4, 152.2, 147.9, 146.5, 140.8, 139.3, 117.5, 112.2, 108.1, 107.8, 100.5, 99.0, 70.3, 66.7, 40.5, 21.29, 21.27. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26NO8 432.1653; found 432.1657. Diisopropyl-2-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)amino)-2-(2-(furan-2-yl)-2-oxoethyl)malonate (27j). The general procedure was followed using 2-acetylfuran (0.27 g, 2.4 mmol), KHMDS (1M solution in THF) (2.64 mL, 2.6 mmol) and ((tert-butyldimethylsilyl)oxy)ethyl)phenyl iminomalonate (0.72 g, 1.6 mmol) as starting materials to afford the ketone adduct as a brown colored viscous oily liquid (0.67 g, 75%). Compound was purified by flash column chromatography (Rf = 0.44 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.45 (s, 1H), 7.02 (d, J = 3.5 Hz, 1H), 6.91 (d, J = 8.3 Hz, 2H), 6.52 (d,

Page 14 of 42

J = 8.4 Hz, 2H), 6.38 (dd, J = 3.6, 1.7 Hz, 1H), 5.25 (s, 1H), 5.08 (h, J = 6.3 Hz, 2H), 3.91 (s, 2H), 3.66 (t, J = 7.1 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 1.20 (d, J = 6.3 Hz, 6H), 1.09 (d, J = 6.3 Hz, 6H), 0.82 (s, 9H), -0.08 (s, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 184.9, 168.4, 152.1, 146.4, 142.4, 129.5, 129.2, 117.3, 114.7, 112.0, 70.2, 66.1, 64.5, 40.4, 38.5, 25.7, 21.2, 21.1, 18.1, -5.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H44NO7Si 546.2882; found 546.2883. Diisopropyl-2-(benzo[d][1,3]dioxol-5-ylamino)-2-(2-oxo-2(thiophen-2-yl)ethyl)malonate (27k). The general procedure was followed using 2-acetylthiophene (0.40 mL, 3.7 mmol), KHMDS (1M solution in THF) (3.98 mL, 3.9 mmol) and 3,4methylenedioxyphenyl iminomalonate (0.8 g, 2.4 mmol) as starting materials to afford the ketone adduct as a dark brownish yellow colored viscous gummy substance (0.84 g, 76%). Compound was purified by flash column chromatography (Rf = 0.38 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.60 (ddd, J = 14.6, 4.3, 0.8 Hz, 2H), 7.04 (dd, J = 4.8, 3.9 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 6.07 (dd, J = 8.3, 2.3 Hz, 1H), 5.80 (s, 2H), 5.15-5.07 (m, 3H), 3.94 (s, 2H), 1.22 (d, J = 6.3 Hz, 6H), 1.17 (s, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 189.1, 168.5, 148.0, 143.8, 140.9, 139.3, 134.1, 132.2, 128.0, 108.2, 107.8, 100.6, 99.1, 70.3, 66.9, 41.2, 21.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26NO7S 448.1424; found 448.1425. Diisopropyl-2-(2-(4-bromophenyl)-2-oxoethyl)-2-(pyridin-3ylamino)malonate (27l). The general procedure was followed using 4-bromo-acetophenone (0.85 g, 4.3 mmol), KHMDS (1M solution in THF) (4.59 mL, 4.5 mmol) and 3-pyridyl iminomalonate (0.8 g, 2.8 mmol) as starting materials to afford the ketone adduct as a reddish brown colored viscous gummy substance (0.97 g, 71%). Compound was purified by flash column chromatography (Rf = 0.16 (30% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.98 (s, 1H), 7.92 – 7.87 (m, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 6.96 – 6.91 (m, 1H), 6.84 (d, J = 7.0 Hz, 1H), 5.47 (s, 1H), 5.04 (hept, J = 6.2 Hz, 2H), 3.99 (s, 2H), 1.12 (d, J = 6.1 Hz, 6H), 1.04 (d, J = 6.1 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 194.7, 167.7, 140.2, 139.9, 137.1, 134.8, 131.7, 129.2, 128.5, 123.2, 120.2, 70.6, 65.6, 40.2, 21.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26BrN2O5 477.1020; found 477.1021. Diisopropyl-2-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)amino)-2-(2-oxo-2-(pyridin-4-yl)ethyl)malonate (27m). The general procedure was followed using 4-acetylpyridine (0.20 mL, 1.8 mmol), KHMDS (1M solution in THF) (1.94 mL, 1.9 mmol) and ((tert-butyldimethylsilyl)oxy)ethyl)phenyl iminomalonate (0.53 g, 1.2 mmol) as starting materials to afford the ketone adduct as a brown colored viscous oily liquid (0.22 g, 34%). Compound was purified by flash column chromatography (Rf = 0.37 (30% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.70 (d, J = 5.9 Hz, 2H), 7.58 (d, J = 5.9 Hz, 2H), 6.92 (d, J = 8.3 Hz, 2H), 6.52 (d, J = 8.3 Hz, 2H), 5.27 (s, 1H), 5.10 (hept, J = 6.1, 5.2 Hz, 2H), 4.05 (s, 2H), 3.66 (t, J = 7.0 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 1.20 (d, J = 6.3 Hz, 6H), 1.12 (d, J = 6.3 Hz, 6H), 0.82 (s, 9H), -0.09 (s, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 196.1, 168.4, 150.7, 142.3, 142.1, 129.8, 129.7, 120.7, 114.9, 70.5, 66.2, 64.6, 40.8, 38.5, 25.8, 21.35, 21.30, 21.2, 18.2, −5.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H45N2O6Si 557.3041; found 557.3041. Diisopropyl-2-((4-methoxyphenyl)amino)-2-(1-oxo-1-phenylpropan-2-yl)malonate (27n). The general procedure was followed using propiophenone (0.42 mL, 3.1 mmol), KHMDS


Page 15 of 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(1M solution in THF) (3.38 mL, 3.3 mmol) and p-methoxyphenyl iminomalonate (0.65 g, 2.1 mmol) as starting materials to afford the ketone adduct as a yellow colored viscous oily liquid (0.65 g, 70%). Compound was purified by flash column chromatography (Rf = 0.36 (15% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ7.84-7.88 (m, 2H, H-2/H-6); 7.49-7.53 (m, 1H, H-4); 7.38-7.42 (m, 2H, H-3/H-5); 6.68 (apparent s, all 4-methoxyphenyl ring protons); 5.19 (s, broad, NH); 4.67 (q, J = 7.2 Hz, 1H, CH next to quaternary aliphatic carbon); 3.69 (s, 3H, methoxy); 1.41 (d, J = 7.2 Hz, 3H, methyl bonded to methine next to quaternary aliphatic carbon); isopropoxy group #1: 5.23 (hept, J = 6.3 Hz, 1H, methine), 1.31 (d, J = 6.3 Hz, 3H, methyl), 1.23 (d, J = 6.3 Hz, 3H, methyl); isopropoxy group #2: 4.99 (hept, J = 6.3 Hz, 1H, methine), 1.14 (d, J = 6.3 Hz, 3H, methyl), 1.01 (d, J = 6.3 Hz, 3H, methyl). 13C{1H} NMR (126 MHz, CDCl3): δ201.7 (ketone carbonyl); isopropoxycarbonyl group #1: 169.3 (carbonyl), 70.2 (CH), 21.6 (methyl), 21.5 (methyl); isopropoxycarbonyl group #2: 168.7 (carbonyl), 70.0 (CH), 21.31 (methyl), 21.29 (methyl); 153.6 (C-4’); 138.3 (C1’); 136.5 (C-1); 133.0 (C-4); 128.5 (C-3/C-5); 128.3 (C-2/C6); 118.7 (C-2’/C-6’); 114.3 (C-3’/C-5’); 71.1 (quaternary aliphatic carbon); 55.5 (methoxy); 43.9 (CH next to quaternary aliphatic carbon); 14.7 (methyl bonded to CH next to quaternary aliphatic carbon). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H32NO6 442.2224; found 442.2219. Note: The evidence for C-attack by the enolate was the generation of a quaternary aliphatic carbon, as shown by the presence of a signal at δ71.1 in the standard 13C spectrum (p. S93) and the absence of this signal in the DEPT-135 13C spectrum (p. S94). Detailed chemical shift assignments could be made through a combination of 1H (p. S92), 13C, DEPT-135 13C and DEPT-90 13C (both optimized for 1JCH = 145 Hz), COSY (p. S96), NOE with a 0.3s mixing time (p. S95), HSQC optimized for 1JCH = 145 Hz (p. S98), and HMBC optimized for 1JCH = 145 Hz and nJCH = 6.25 Hz (p. S97) experiments. Diisopropyl-2-((4-methoxyphenyl)amino)-2-(2-oxocyclohexyl)malonate (27o). The general procedure was followed using cyclohexanone (0.25 mL, 2.4 mmol), KHMDS (1M solution in THF) (2.56 mL, 2.5 mmol) and p-methoxyphenyl iminomalonate (0.49 g, 1.6 mmol) as starting materials to afford the ketone adduct as a brown colored viscous oily liquid (0.46 g, 71%). Compound was purified by flash column chromatography (Rf = 0.37 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ6.66-6.71 (m, AA’BB’ pattern, 4H, aromatic ring protons); isopropoxy group #1: 5.05 (hept, J = 6.3 Hz, 1H, methine), 1.20 (d, J = 6.3 Hz, 3H, methyl), 1.19 (d, J = 6.3 Hz, 3H, methyl); isopropoxy group #2: 4.97 (hept, J = 6.3 Hz, 1H, methine), 1.16 (d, J = 6.3 Hz, 3H, methyl), 0.99 (d, J = 6.3 Hz, 3H, methyl); 4.92 (s, broad, NH); 3.72 (s, 3H, methoxy); 3.51 (ddd, J = 12.6, 5.2, 1.0 Hz, 1H, methine next to ketone carbonyl); 2.55 and 1.86 [m, 2H, ring 3-CH2 (next to ring methine)]; 1.94 and 1.72 (m, 2H, ring 4-CH2); 2.06 and 1.63 (m, 2H, ring 5-CH2); 2.37 and 2.26 [ring 6-CH2 (next to ketone carbonyl)]. 13C{1H} NMR (126 MHz, CDCl3): δ210.1 (ketone carbonyl); isopropoxycarbonyl group #1: 169.2 (carbonyl), 70.0 (CH), 21.44 (methyl), 21.44 (methyl); isopropoxycarbonyl group #2: 168.1 (carbonyl), 69.7 (CH), 21.44 (methyl), 21.19 (methyl); 153.6 (C-4); 139.3 (C-1); 119.1 (C-2/C-6); 114.1 (C-3/C-5); 69.9 (quaternary aliphatic carbon); 56.6 (ring methine carbon); 55.6 (methoxy); 42.5 (ring 6-CH2); 30.4 (ring 3-CH2); 27.5 (ring 5CH2); 25.4 (ring 4-CH2). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H32NO6 406.2224; found 406.2227. The evidence for C-

attack by the enolate was the generation of a quaternary aliphatic carbon, as shown by the presence of a signal at δ69.9 in the standard 13C spectrum (p. S100) and the absence of this signal in the DEPT-135 13C spectrum (p. S101) and the DEPT-90 13 C spectrum. Detailed chemical shift assignments could be made through a combination of 1H (p. S99), 13C, DEPT-135 13C, DEPT-90 13C, COSY (p. S102), HSQC (p. S104), and HMBC (p. S103) experiments (with key parameters the same as for 27n). Diisopropyl-2-(benzo[d][1,3]dioxol-5-ylamino)-2-(1-oxo1,2,3,4-tetrahydronaphthalen-2-yl)malonate (27p). The general procedure was followed using α-tetralone (0.30 mL, 2.2 mmol), KHMDS (1M solution in THF) (2.43 mL, 2.4 mmol) and 3,4-methylenedioxyphenyl iminomalonate (0.49 g, 1.5 mmol) as starting materials to afford the ketone adduct as a brown colored gummy substance (0.61 g, 86%). Compound was purified by flash column chromatography (Rf = 0.37 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.98 – 7.96 (m, 1H), 7.43 (td, J = 7.5, 1.3 Hz, 1H), 7.28 – 7.24 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 2.3 Hz, 1H), 6.21 (dd, J = 8.4, 2.3 Hz, 1H), 5.81 (s, 2H), 5.14 (dq, J = 12.5, 6.6 Hz, 2H), 4.98 (hept, J = 6.2 Hz, 1H), 3.71 (dd, J = 13.5, 4.0 Hz, 1H), 3.11 (td, J = 15.0, 13.1, 4.0 Hz, 1H), 2.99 (dt, J = 16.6, 3.3 Hz, 1H), 2.70 (dq, J = 11.2, 3.9 Hz, 1H), 2.16 (qd, J = 13.0, 4.1 Hz, 1H), 1.24 (d, J = 6.3 Hz, 3H), 1.15 (dd, J = 16.3, 6.3 Hz, 6H), 0.99 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 196.6, 169.1, 167.7, 147.6, 143.5, 140.9, 140.7, 133.4, 132.4, 128.3, 127.3, 126.5, 109.4, 107.8, 100.5, 100.0, 70.7, 70.3, 69.6, 54.3, 29.4, 26.5, 21.37, 21.32, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H30NO7 468.2017; found 468.2016. Diisopropyl-2-(2-(1-methyl-1H-pyrrol-3-yl)-2-oxoethyl)-2-((3(trifluoromethyl)phenyl)amino)malonate (27q). The general procedure was followed using 3-acetyl-1-methyl pyrrole (0.41 mL, 3.4 mmol), KHMDS (1M solution in THF) (3.7 mL, 3.7 mmol) and 3-trifluoromethylphenyl iminomalonate (0.8 g, 2.3 mmol) as starting materials to afford the ketone adduct as a white colored solid (m.p. 160 – 162 ˚C) (0.57 g, 53%). Compound was purified by flash column chromatography (Rf = 0.31 (30% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.18 (t, J = 7.9 Hz, 1H), 7.07 (t, J = 1.7 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 6.78 – 6.73 (m, 1H), 6.53 – 6.44 (m, 2H), 5.66 (s, 1H), 5.12 (hept, J = 6.3 Hz, 2H), 3.82 (s, 2H), 3.58 (s, 3H), 1.23 (d, J = 6.3 Hz, 6H), 1.13 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 190.7, 168.4, 144.9, 131.3 (q, 2JCF = 31.8 Hz), 129.4, 127.0, 125.5, 124.1 (q, 1JCF = 272.3 Hz), 123.4, 117.6, 114.5 (q, 3JCF = 3.9 Hz), 110.4 (q, 3JCF = 3.9 Hz), 109.2, 70.5, 66.1, 41.0, 36.5, 21.33, 21.27. 19F NMR (471 MHz, CDCl3): δ −61.9 (S). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H28F3N2O5 469.1945; found 469.1944. Diisopropyl-2-((3-chlorophenyl)amino)-2-(2-oxo-2-(pyridin-3yl)ethyl)malonate (27r). The general procedure was followed using 3-acetyl pyridine (0.45 mL, 4.1 mmol), KHMDS (1M solution in THF) (4.43 mL, 4.4 mmol) and 3-chlorophenyl iminomalonate (0.86 g, 2.7 mmol) as starting materials to afford the ketone adduct as a viscous gummy oily liquid (0.71 g, 60%). Compound was purified by flash column chromatography (Rf = 0.20 (30% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 9.05 (s, 1H), 8.67 (s, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.32 – 7.27 (m, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 6.44 (d, J = 7.8 Hz, 1H), 5.52 (s, 1H), 5.07 (hept, J = 6.3 Hz, 2H), 4.06 (s, 2H), 1.16 (d, J = 6.2 Hz, 6H), 1.08 (d, J = 6.2 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 195.0, 167.8,



153.6, 149.2, 145.1, 135.0, 134.6, 131.5, 130.0, 123.3, 118.4, 114.0, 112.2, 70.6, 65.6, 40.6, 21.15, 21.11. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26ClN2O5 433.1525; found 433.1525. Diisopropyl-2-((3-chlorophenyl)amino)-2-(2-oxo-2-(pyridin-2yl)ethyl)malonate (27s). The general procedure was followed using 2-acetyl pyridine (0.43 mL, 3.8 mmol), KHMDS (1M solution in THF) (4.10 mL, 4.1 mmol) and 3-chlorophenyl iminomalonate (0.80 g, 2.5 mmol) as starting materials to afford the ketone adduct as a yellow solid (m.p. 110 – 113 ˚C) (0.61 g, 55%). Compound was purified by flash column chromatography (Rf = 0.62 (30% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.68 – 8.55 (m, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.77 (t, J = 7.1 Hz, 1H), 7.48 – 7.36 (m, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 5.57 (s, 1H), 5.13 (hept, J = 6.2 Hz, 2H), 4.43 (s, 2H), 1.23 (d, J = 6.1 Hz, 6H), 1.14 (d, J = 6.1 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 197.6, 168.1, 152.5, 148.7, 145.5, 136.6, 134.4, 129.8, 127.2, 121.4, 118.2, 114.3, 112.5, 70.3, 65.9, 40.0, 21.2, 21.1. HRMS (ESI-TOF)m/z: [M+H]+ Calcd for C22H26ClN2O5 433.1525; found 433.1527. Diisopropyl-2-((4-bromophenyl)amino)-2-(2-oxo-2-(pyridin-3yl)ethyl)malonate (27t). The general procedure was followed using 3-acetyl pyridine (0.37 mL, 3.3 mmol), KHMDS (1M solution in THF) (3.59 mL, 3.5 mmol) and 4-bromophenyl iminomalonate (0.80 g, 2.2 mmol) as starting materials to afford the ketone adduct as a yellow solid (m.p. 127 – 130 ˚C) (0.58 g, 54%). Compound was purified by flash column chromatography (Rf = 0.21 (30% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 9.05 (s, 1H), 8.70 (d, J = 4.1 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 7.8, 4.9 Hz, 1H), 7.15 (d, J = 8.6 Hz, 2H), 6.47 (d, J = 8.6 Hz, 2H), 5.46 (s, 1H), 5.08 (hept, J = 6.2 Hz, 2H), 4.06 (s, 2H), 1.17 (d, J = 6.3 Hz, 6H), 1.10 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 195.1, 168.0, 153.6, 149.3, 143.0, 135.0, 131.8, 131.6, 123.4, 115.9, 110.5, 70.7, 65.8, 40.5, 21.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26BrN2O5 477.1020; Found 477.1017. General procedure for the asymmetric reduction of ketone adducts via CBS reduction, Figure 7. In a thick-walled flame dried reaction vial, Mannich ketone adduct (1.0 equiv) was dissolved in anhydrous THF (0.2M) under argon and cooled to −15 ˚C using a NESLAB CC 100 immersion cooler with isopropanol as bath solvent. To this cooled reaction mixture, (S)-(−)-2-methyl-CBS-oxazaborolidine solution (1M solution in toluene) (0.15 equiv) was added dropwise and stirred for 5 min. Then BH3.DMS solution (2M solution in THF) (2.0 equiv) was added slowly dropwise to the reaction mixture and continued stirring for 75 h at −15 ˚C or until the complete consumption of the starting material ketone. Then the reaction was cooled to 0 ˚C and quenched using saturated NH4Cl solution or methanol (3 mL). Workup and purification: After quenching, the reaction mixture was diluted with brine (10 mL) and the organic layer was separated. The aqueous layer was then extracted with EtOAc twice (2 X 20 mL) and the combined organic layers were washed with brine (20 mL) once, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by automated flash column chromatography. Diisopropyl-(R)-2-(2-hydroxy-2-phenylethyl)-2-((4-methoxyphenyl)amino)malonate (28a). The general procedure was followed using 27a (0.1 g, 0.2 mmol), (S)-(−)-2-methyl-CBSoxazaborolidine solution (1M solution in toluene) (0.035 mL,

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0.03 mmol) and BH3.DMS solution (2M solution in THF) (0.23 mL, 0.4 mmol) as starting materials to afford the alcohol as a beige colored viscous oily liquid (0.075g, 75%). Compound was purified by flash column chromatography (Rf = 0.33 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.35 – 7.31 (m, 4H), 7.28 – 7.24 (m, 1H), 6.82 (d, J = 8.9 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H), 5.16 (s, 1H), 5.11 (hept, J = 6.3 Hz, 1H), 4.95 (hept, J = 6.3 Hz, 1H), 4.85 (d, J = 10.0 Hz, 1H), 3.98 (s, 1H), 3.74 (s, 3H), 2.74 – 2.62 (m, 2H), 1.29 (d, J = 6.3 Hz, 3H), 1.19 (d, J = 6.3 Hz, 3H), 1.13 (d, J = 6.3 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 169.1, 168.4, 154.1, 144.1, 137.5, 128.3, 127.3, 125.5, 118.8, 114.5, 70.9, 70.2, 69.9, 69.0, 55.5, 41.7, 21.5, 21.36, 21.32, 21.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H32NO6 430.2224; found 430.2228. HPLC Analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 13.6 min, tminor = 15.2 min, ee 94%, er 97:3; [α]D20 = +42.3 (C = 1, CHCl3). Determination of absolute configuration of chiral alcohol using Mosher ester analysis. Preparation of (S)- and (R)-MTPA esters: 16 To a stirred solution of the alcohol (28a, 10 mg, 0.023 mmol) and dry pyridine (5.8 µL, 0.07 mmol, 3.1 equiv.) in dry DCM (0.5 mL, 0.046M) at room temperature, S-(+)-MTPA-Cl (8.2 µL, 0.04 mmol, 1.9 equiv) was added. The reaction progress was monitored by thin-layer chromatography (TLC) on silica gel. After 5 hours of stirring at room temperature the reaction mixture was quenched by the addition of water (~ 1mL) and ethyl acetate (~ 3mL). The aqueous layer was extracted with two additional portions of ethyl acetate (~ 3mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to give the R-MTPA ester. 1H NMR (600 MHz, CDCl3): 7.37 (ddd, J = 8.5, 4.0, 2.1 Hz, 1H), 7.34 – 7.28 (m, 7H), 7.26 (s, 2H), 6.70 (d, J = 8.9 Hz, 2H), 6.53 (d, J = 8.9 Hz, 2H), 6.08 (t, J = 6.7 Hz, 1H), 4.87 – 4.80 (m, 2H), 4.64 (dp, J = 12.6, 7.2, 6.3 Hz, 1H), 3.73 (s, 3H), 3.37 (s, 3H), 3.06 (dd, J = 15.5, 7.0 Hz, 1H), 2.94 (dd, J = 15.5, 6.4 Hz, 1H), 1.19 (d, J = 6.3 Hz, 3H), 1.01 (d, J = 5.7 Hz, 6H), 0.95 (d, J = 6.2 Hz, 3H). In an entirely analogous fashion, the S-MTPA ester was prepared using R-(−)-MTPA-Cl. 1H NMR (600 MHz, CDCl3): 7.37 – 7.29 (m, 2H), 7.26 (h, J = 4.6 Hz, 4H), 7.21 (d, J = 7.7 Hz, 2H), 7.18 (dd, J = 7.6, 1.7 Hz, 2H), 6.73 (d, J = 8.9 Hz, 2H), 6.61 (d, J = 8.9 Hz, 2H), 5.95 (t, J = 6.6 Hz, 1H), 4.99 (s, 1H), 4.95 (hept, J = 12.5, 6.3 Hz, 1H), 4.65 (hept, J = 6.3 Hz, 1H), 3.74 (s, 3H), 3.40 (s, 3H), 3.08 (dd, J = 15.6, 7.2 Hz, 1H), 2.91 (dd, J = 15.6, 6.1 Hz, 1H), 1.11 (d, J = 6.3 Hz, 3H), 1.05 (d, J = 6.2 Hz, 3H), 0.98 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 6.2 Hz, 3H). Diisopropyl-(R)-2-((3,5-dimethylphenyl)amino)-2-(2-hydroxy2-phenylethyl)malonate (28b). The general procedure was followed using 27b (0.5 g, 1.18 mmol), (S)-(−)-2-methyl-CBSoxazaborolidine solution (1M solution in toluene) (0.18 mL, 0.18 mmol) and BH3.DMS solution (2M solution in THF) (1.18 mL, 2.3 mmol) as starting materials to afford the alcohol as a brown colored viscous gummy substance (0.42g, 83%). Compound was purified by flash column chromatography (Rf = 0.47 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.36 – 7.30 (m, 4H), 7.29 – 7.23 (m, 1H), 6.49 (s, 1H), 6.42 (s, 2H), 5.35 (s, 1H), 5.09 (hept, J = 6.3 Hz, 1H), 5.02 (hept, J = 6.3 Hz, 1H), 4.84 (t, J = 6.3 Hz, 1H), 3.42 (s, 1H), 2.75 (d, J = 6.4 Hz, 2H), 2.23 (s, 6H), 1.26 (dd, J = 17.6, 6.3 Hz, 6H), 1.11 (d, J = 6.3 Hz, 3H), 1.05 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 169.0, 168.8, 144.24, 144.22, 138.6, 128.2, 127.2,


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125.5, 121.6, 113.8, 70.6, 70.1, 70.0, 68.0, 41.7, 21.5, 21.3, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H34NO5 428.2431; found 428.2431. HPLC Analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 8.8 min, tminor = 9.4 min, ee 97%, er 98.4:1.6; [α]D20 = +32.7 (C = 1, CHCl3). Diisopropyl-(R)-2-(2-(4-bromophenyl)-2-hydroxyethyl)-2((3,5-dimethylphenyl)amino)malonate (28c). The general procedure was followed using 27c (0.27 g, 0.53 mmol), (S)-(−)-2methyl-CBS-oxazaborolidine solution (1M solution in toluene) (0.08 mL, 0.08 mmol) and BH3.DMS solution (2M solution in THF) (0.53 mL, 1.07 mmol) as starting materials to afford the alcohol as a pale yellow colored foamy solid (0.22g, 81%). Compound was purified by flash column chromatography (Rf = 0.55 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.43 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 6.49 (s, 1H), 6.38 (s, 2H), 5.32 (s, 1H), 5.08 (hept, J = 6.2 Hz, 1H), 5.00 (hept, J = 6.2 Hz, 1H), 4.78 (dd, J = 8.3, 3.9 Hz, 1H), 3.60 (s, 1H), 2.74 – 2.63 (m, 2H), 2.22 (s, 6H), 1.27 (d, J = 6.3 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H), 1.11 (d, J = 6.3 Hz, 3H), 1.04 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 168.9, 168.7, 144.0, 143.2, 138.7, 131.3, 127.2, 121.8, 120.9, 113.8, 70.2, 70.1, 70.0, 68.0, 41.6, 21.5, 21.3, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H33BrNO5 506.1537; found 506.1536. HPLC Analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 8.1 min, tminor = 8.7 min, ee 94%, er 97:3; [α]D20 = +26.8 (C = 1, CHCl3). Diisopropyl-(R)-2-(benzo[d][1,3]dioxol-5-ylamino)-2-(2-hydroxy-2-phenylethyl)malonate (28d). The general procedure was followed using 27d (0.32 g, 0.73 mmol), (S)-(−)-2-methylCBS-oxazaborolidine solution (1M solution in toluene) (0.11 mL, 0.11 mmol) and BH3.DMS solution (2M solution in THF) (0.73 mL, 1.46 mmol) as starting materials to afford the alcohol as a pale yellow colored waxy solid (0.28g, 90%). Compound was purified by flash column chromatography (Rf = 0.35 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.26 – 7.20 (m, 4H), 7.19 – 7.14 (m, 1H), 6.54 (d, J = 8.3 Hz, 1H), 6.36 (d, J = 2.2 Hz, 1H), 6.17 (dd, J = 8.3, 2.3 Hz, 1H), 5.77 (s, 2H), 5.12 (s, 1H), 5.00 (hept, J = 6.2 Hz, 1H), 4.91 (hept, J = 6.3 Hz, 1H), 4.74 (dd, J = 9.5, 2.8 Hz, 1H), 3.58 (s, 1H), 2.66 – 2.52 (m, 2H), 1.19 (d, J = 6.3 Hz, 3H), 1.14 (d, J = 6.3 Hz, 3H), 1.05 (d, J = 6.3 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.0, 168.5, 148.0, 144.1, 141.6, 139.0, 128.3, 127.3, 125.5, 109.0, 108.2, 100.7, 99.9, 70.7, 70.2, 70.0, 68.7, 41.5, 21.5, 21.34, 21.30. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H30NO7 444.2017; found 444.2022. HPLC Analysis: Chiralpak IB, 20% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 14.0 min, tminor = 15.3 min, ee 96%, er 98:2; [α]D20 = +36.2 (C = 1, CHCl3). Diisopropyl-(R)-2-(2-hydroxy-2-phenylethyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (28e). The general procedure was followed using 27e (0.40 g, 0.87 mmol), (S)-(−)-2-methylCBS-oxazaborolidine solution (1M solution in toluene) (0.13 mL, 0.13 mmol) and BH3.DMS solution (2M solution in THF) (0.87 mL, 1.75 mmol) as starting materials to afford the alcohol as a colorless viscous gummy substance (0.385g, 94%). Compound was purified by flash column chromatography (Rf = 0.43 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.33 (t, J = 7.3 Hz, 2H), 7.31 – 7.25 (m, 4H), 7.07 (d, J = 7.5 Hz, 1H), 6.99 (s, 1H), 6.88 (d, J = 7.8 Hz, 1H), 5.77 (s, 1H), 5.13 (hept, J = 6.3 Hz, 1H), 5.06 (hept, J = 6.4 Hz, 1H), 4.84 (s, 1H), 2.85 – 2.72 (m, 3H), 1.33 (d, J = 6.2 Hz, 3H), 1.26 (d, J = 6.2 Hz, 3H), 1.17 (d, J = 6.2 Hz, 3H), 1.07 (d, J = 6.2 Hz, 3H). 13C{1H}

NMR (151 MHz, CDCl3): δ 169.0, 168.6, 144.9, 144.0, 131.5 (q, 2JCF = 31.9 Hz), 129.7, 128.4, 127.5, 125.5, 124.0 (q, 1JCF = 272.3 Hz), 117.5, 115.3 (q, 3JCF = 3.6 Hz), 111.5 (q, 3JCF = 3.6 Hz), 70.6, 70.3, 70.2, 67.2, 41.4, 21.33, 21.30, 21.2, 21.1. 19F NMR (471 MHz, CDCl3): δ −61.9 (S). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H29F3NO5 468.1992; found 468.1993. HPLC Analysis: Chiralpak IB, 2% IP/hexanes, continuous flow at 0.4mL/min, 230 nm; tmajor = 21.1 min, tminor = 18.8 min, ee 92%, er 4:96; [α]D20 = +6.2 (C = 1, CHCl3). Diisopropyl-(R)-2-((3,5-dimethylphenyl)amino)-2-(2-hydroxy2-(naphthalen-2-yl)ethyl)malonate (28f). The general procedure was followed using 27f (0.6 g, 1.26 mmol), (S)-(−)-2-methyl-CBS-oxazaborolidine solution (1M solution in toluene) (0.19 mL, 0.19 mmol) and BH3.DMS solution (2M solution in THF) (1.26 mL, 2.52 mmol) as starting materials to afford the alcohol as a pale yellow colored foamy solid (0.44g, 73%). Compound was purified by flash column chromatography (Rf = 0.51 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.87 – 7.75 (m, 4H), 7.51 – 7.44 (m, 2H), 7.41 (dd, J = 8.5, 1.8 Hz, 1H), 6.52 (s, 1H), 6.45 (s, 2H), 5.41 (s, 1H), 5.11 (hept, J = 6.4 Hz, 1H), 5.07 – 4.99 (m, 2H), 3.55 (s, 1H), 2.91 – 2.79 (m, 2H), 2.25 (s, 6H), 1.29 (dd, J = 14.3, 6.3 Hz, 6H), 1.13 (d, J = 6.2 Hz, 3H), 1.07 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.0, 168.9, 144.2, 141.6, 138.7, 133.2, 132.8, 128.0, 127.9, 127.5, 125.9, 125.6, 124.1, 123.9, 121.7, 113.8, 70.7, 70.2, 70.1, 68.1, 41.7, 21.5, 21.4, 21.3, 21.27, 21.21. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H36NO5 478.2588; found 478.2589. HPLC Analysis: Chiralpak IB, 2% IP/hexanes, continuous flow at 0.4mL/min, 230 nm; tmajor = 26.7 min, tminor = 25.4 min, ee 98%, er 1:99; [α]D20 = +18.8 (C = 1, CHCl3). Diisopropyl-(R)-2-(2-hydroxy-2-(naphthalen-1-yl)ethyl)-2-(ptolylamino)malonate (28g). The general procedure was followed using 27g (0.64 g, 1.40 mmol), (S)-(−)-2-methyl-CBSoxazaborolidine solution (1M solution in toluene) (0.21 mL, 0.21 mmol) and BH3.DMS solution (2M solution in THF) (1.40 mL, 2.80 mmol) as starting materials to afford the alcohol as a beige colored solid (m.p. 95 – 98 ˚C) (0.47g, 73%). Compound was purified by flash column chromatography (Rf = 0.48 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.84 (d, J = 8.2 Hz, 1H), 7.75 (t, J = 8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.29 – 7.22 (m, 1H), 7.03 (d, J = 8.1 Hz, 2H), 6.75 (d, J = 8.3 Hz, 2H), 5.68 (d, J = 10.7 Hz, 1H), 5.47 (s, 1H), 5.14 – 5.04 (m, 2H), 3.31 (s, 1H), 3.00 (d, J = 15.4 Hz, 1H), 2.79 (dd, J = 15.4, 10.8 Hz, 1H), 2.31 (s, 3H), 1.29 (dd, J = 15.6, 6.3 Hz, 6H), 1.12 (dd, J = 21.7, 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.3, 141.8, 140.0, 133.5, 129.8, 129.7, 128.8, 128.6, 127.6, 125.5, 125.4, 125.2, 122.9, 122.8, 116.0, 70.2, 70.1, 67.9, 67.2, 40.6, 21.4, 21.36, 21.31, 20.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H34NO5 464.2431; found 464.2434. HPLC Analysis: Chiralpak ID, 91% IP/hexanes, continuous flow at 0.4mL/min, 250 nm; tmajor = 12.8 min, tminor = 11.7 min, ee 83%, er 8.6:91.4; [α]D20 = +28.5 (C = 1, CHCl3). Diisopropyl-(R)-2-(2-hydroxy-2-phenylethyl)-2-(phenylamino)malonate (28h). The general procedure was followed using 27h (0.45 g, 1.13 mmol), (S)-(−)-2-methyl-CBSoxazaborolidine solution (1M solution in toluene) (0.17 mL, 0.17 mmol) and BH3.DMS solution (2M solution in THF) (1.13 mL, 2.27 mmol) as starting materials to afford the alcohol as a colorless viscous oily liquid (0.37g, 82%). Compound was purified by flash column chromatography (Rf = 0.42 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.34 – 7.23



(m, 5H), 7.18 (dd, J = 8.4, 7.5 Hz, 2H), 6.82 (t, J = 7.3 Hz, 1H), 6.77 (d, J = 7.7 Hz, 2H), 6.77 (d, J = 7.7 Hz, 1H), 5.05 (ddt, J = 20.7, 12.6, 6.3 Hz, 2H), 4.84 (dt, J = 6.5, 3.2 Hz, 1H), 3.16 (s, 1H), 2.79 – 2.71 (m, 2H), 1.25 (dd, J = 6.3, 1.9 Hz, 6H), 1.06 (dd, J = 11.3, 6.3 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 169.0, 168.9, 144.3, 144.1, 129.1, 128.3, 127.3, 125.5, 119.6, 115.6, 70.5, 70.2, 67.9, 41.7, 21.5, 21.3, 21.25, 21.22. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H30NO5 400.2118; found 400.2120. HPLC Analysis: Chiralpak IC, 14% IP/hexanes, continuous flow at 0.4mL/min, 250 nm; tmajor = 14.8 min, tminor = 16.3 min, ee 97%, er 98.4:1.6; [α]D20 = +26.2 (C = 1, CHCl3). Diisopropyl-(R)-2-(benzo[d][1,3]dioxol-5-ylamino)-2-(2-(furan-2-yl)-2-hydroxyethyl)malonate (28i). The general procedure was followed using 27i (0.53 g, 1.24 mmol), (S)-(−)-2-methyl-CBS-oxazaborolidine solution (1M solution in toluene) (0.18 mL, 0.18 mmol) and BH3.DMS solution (2M solution in THF) (1.24 mL, 2.48 mmol) as starting materials to afford the alcohol as a pale yellow colored wax (0.39g, 77%). Compound was purified by flash column chromatography (Rf = 0.26 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.33 (dd, J = 1.8, 0.9 Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 6.38 (d, J = 2.3 Hz, 1H), 6.29 (dd, J = 3.1, 1.8 Hz, 1H), 6.24 – 6.16 (m, 2H), 5.83 (s, 2H), 5.14 (s, 1H), 5.00 (ddt, J = 15.7, 12.5, 6.3 Hz, 2H), 4.88 (dd, J = 10.0, 2.6 Hz, 1H), 3.35 (s, 1H), 2.88 – 2.74 (m, 2H), 1.21 (d, J = 6.4 Hz, 6H), 1.08 (dd, J = 16.5, 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 168.8, 168.7, 155.9, 148.0, 141.8, 141.4, 139.0, 110.0, 108.6, 108.2, 105.6, 100.7, 99.6, 70.2, 70.1, 68.1, 64.3, 37.9, 21.36, 21.30, 21.27, 21.25. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H28NO8 434.1809; found 434.1811. HPLC Analysis: Chiralpak IB, 20% IP/hexanes, continuous flow at 0.8mL/min, 250 nm; tmajor = 14.1 min, tminor = 10.3 min, ee 92%, er 4:96; [α]D20 = +12.0 (C = 1, CHCl3). Diisopropyl-(R)-2-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)amino)-2-(2-(furan-2-yl)-2-hydroxyethyl)malonate (28j). The general procedure was followed using 27j (0.55 g, 1.00 mmol), (S)-(−)-2-methyl-CBSoxazaborolidine solution (1M solution in toluene) (0.15 mL, 0.15 mmol) and BH3.DMS solution (2M solution in THF) (1.00 mL, 2.01 mmol) as starting materials to afford the alcohol as a colorless viscous oily liquid (0.40g, 73%). Compound was purified by flash column chromatography (Rf = 0.37 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.33 (s, 1H), 6.98 (d, J = 8.1 Hz, 2H), 6.66 (d, J = 8.1 Hz, 2H), 6.32 – 6.28 (m, 1H), 6.22 (d, J = 2.9 Hz, 1H), 5.28 (s, 1H), 5.01 (pd, J = 6.1, 2.1 Hz, 2H), 4.90 – 4.85 (m, 1H), 3.70 (t, J = 7.1 Hz, 2H), 3.03 (s, 1H), 2.94 – 2.83 (m, 2H), 2.69 (t, J = 7.1 Hz, 2H), 1.22 (dd, J = 10.3, 6.3 Hz, 6H), 1.05 (dd, J = 28.9, 6.2 Hz, 6H), 0.86 (s, 9H), −0.03 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 169.0, 168.9, 155.9, 142.4, 141.8, 130.2, 129.7, 115.7, 110.0, 105.7, 70.3, 70.1, 67.5, 64.7, 64.3, 38.6, 37.9, 25.8, 21.4, 21.3, 21.26, 21.25, 18.2, −5.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H46NO7Si 548.3038; found 548.3040. HPLC Analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 13.7 min, tminor = 8.4 min, ee 94%, er 3:97; [α]D20 = +1.5 (C = 1, CHCl3). Diisopropyl-(R)-2-(benzo[d][1,3]dioxol-5-ylamino)-2-(2-hydroxy-2-(thiophen-2-yl)ethyl)malonate (28k). The general procedure was followed using 27k (0.51 g, 1.15 mmol), (S)-(−)-2methyl-CBS-oxazaborolidine solution (1M solution in toluene) (0.17 mL, 0.17 mmol) and BH3.DMS solution (2M solution in THF) (1.15 mL, 2.31 mmol) as starting materials to afford the alcohol as a dark brown colored foamy gummy substance

Page 18 of 42

(0.39g, 75%). Compound was purified by flash column chromatography (Rf = 0.32 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.22 (dd, J = 5.0, 1.2 Hz, 1H), 6.95 (dd, J = 5.0, 3.5 Hz, 1H), 6.91 (d, J = 3.4 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.24 (dd, J = 8.3, 2.3 Hz, 1H), 5.86 (s, 2H), 5.16 (s, 1H), 5.12 – 5.04 (m, 2H), 4.99 (hept, J = 6.2 Hz, 1H), 3.71 (s, 1H), 2.86 – 2.75 (m, 2H), 1.25 (d, J = 6.3 Hz, 3H), 1.22 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 6.3 Hz, 3H), 1.08 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 168.8, 168.4, 148.1, 148.0, 141.7, 138.8, 126.5, 124.3, 122.9, 109.1, 108.3, 100.8, 99.9, 70.3, 70.2, 68.6, 67.0, 41.7, 21.5, 21.37, 21.33. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H28NO7S 450.1581; found 450.1581. HPLC Analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.8mL/min, 250 nm; tmajor = 12.3 min, tminor = 10.6 min, ee 90%, er 5:95; [α]D20 = +20.3 (C = 1, CHCl3). Diisopropyl-(R)-2-(2-(4-bromophenyl)-2-hydroxyethyl)-2(pyridin-3-ylamino)malonate (28l). The general procedure was followed using 27l (0.53 g, 1.11 mmol), (S)-(−)-2-methyl-CBSoxazaborolidine solution (1M solution in toluene) (0.16 mL, 0.16 mmol) and BH3.DMS solution (2M solution in THF) (1.11 mL, 2.22 mmol) as starting materials to afford the alcohol as a white colored foamy solid (0.37g, 69%). Compound was purified by flash column chromatography (Rf = 0.30 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.04 (s, 1H), 7.91 (d, J = 5.2 Hz, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.19 (dd, J = 8.1, 5.7 Hz, 1H), 7.06 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.2 Hz, 1H), 6.00 (s, 1H), 5.11 (hept, J = 6.3 Hz, 1H), 5.02 (hept, J = 6.4 Hz, 1H), 4.69 (d, J = 9.5 Hz, 1H), 2.70 – 2.48 (m, 4H), 1.29 (d, J = 6.2 Hz, 3H), 1.20 (t, J = 6.3 Hz, 6H), 1.06 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 168.3, 167.6, 142.6, 142.1, 136.9, 134.5, 131.5, 127.1, 125.2, 121.8, 121.4, 71.3, 70.9, 69.4, 66.3, 40.4, 21.3, 21.29, 21.27. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H28BrN2O5 479.1176; found 479.1173. HPLC Analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 11.1 min, tminor = 9.8 min, ee 82%, er 9:91; [α]D20 = −14.7 (C = 1, CHCl3). Diisopropyl-(R)-2-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)amino)-2-(2-hydroxy-2-(pyridin-4yl)ethyl)malonate (28m). The general procedure was followed using 27l (0.5 g, 0.89 mmol), (S)-(−)-2-methyl-CBSoxazaborolidine solution (1M solution in toluene) (0.13 mL, 0.13 mmol) and BH3.DMS solution (2M solution in THF) (0.9 mL, 1.8 mmol) as starting materials to afford the alcohol as a beige colored foamy solid (0.32g, 65%). Compound was purified by flash column chromatography (Rf = 0.20 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.44 (d, J = 6.3 Hz, 2H), 7.33 (d, J = 6.3 Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H), 6.64 (d, J = 8.3 Hz, 2H), 5.30 (s, 1H), 5.08 (hept, J = 6.2 Hz, 1H), 4.97 (hept, J = 6.2 Hz, 1H), 4.88 (d, J = 10.2 Hz, 1H), 4.03 (s, 1H), 3.71 (t, J = 7.0 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H), 2.57 (dd, J = 15.2, 10.6 Hz, 2H), 1.25 (d, J = 6.3 Hz, 3H), 1.20 (d, J = 6.3 Hz, 3H), 1.08 (d, J = 6.3 Hz, 3H), 1.01 (d, J = 6.3 Hz, 3H), 0.85 (s, 9H), −0.03 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 168.5, 168.3, 157.1, 147.1, 141.7, 131.2, 129.9, 121.9, 115.9, 70.65, 70.60, 68.8, 67.8, 64.4, 40.8, 38.5, 25.8, 21.5, 21.28, 21.21, 21.1, 18.2, −5.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H47N2O6Si 559.3198; found 559.3197. HPLC Analysis: Chiralpak IC, 15% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 16.2 min, tminor = 18.2 min, ee 72%, er 86:14; [α]D20 = +5.5 (C = 1, CHCl3).


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General procedure for the synthesis of racemic alcohols from ketone adducts, Figure 7. In a thick-walled flame dried reaction vial, Mannich ketone adduct (1.0 equiv) was dissolved in anhydrous THF (0.2M) under argon. Then BH3.DMS solution (2M solution in THF) (2.0 equiv) was added slowly dropwise to the reaction mixture at room temperature under constant stirring. Then the reaction mixture was heated to 50 ˚C and continued stirring until the complete consumption of the starting material ketone. Then the reaction was cooled to 0 ˚C and quenched using saturated NH4Cl solution or methanol (3 mL). Workup and purification: After quenching, the reaction mixture was diluted with brine (10 mL) and the organic layer was separated. The aqueous layer was then extracted with EtOAc twice (2 X 20 mL) and the combined organic layers were washed with brine (20 mL) once, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by automated flash column chromatography. Diisopropyl-2-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)-2((4-methoxyphenyl)amino)malonate (28n). The general procedure was followed using 28n (0.34 g, 0.77 mmol) and BH3.DMS solution (2M solution in THF) (0.78 mL, 1.55 mmol) as starting materials to afford the alcohol as a dark yellowish brown colored viscous oily liquid (0.21g, 61%). Reaction was finished in 3.5 hours. Compound was purified by flash column chromatography (Rf = 0.39 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.33 (dt, J = 15.3, 7.6 Hz, 4H), 7.22 (t, J = 7.2 Hz, 1H), 6.81 – 6.74 (m, 4H), 5.51 (s, 1H), 5.10 (hept, J = 6.2 Hz, 2H), 4.96 (hept, J = 6.0 Hz, 1H), 3.74 (s, 3H), 3.37 (s, 1H), 2.86 (q, J = 7.0 Hz, 1H), 1.26 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 6.3 Hz, 3H), 0.94 (dd, J = 14.0, 6.7 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.9, 168.5, 153.9, 143.6, 138.4, 127.9, 126.6, 125.5, 118.7, 114.5, 72.3, 71.9, 70.5, 69.8, 55.6, 43.8, 21.5, 21.45, 21.40, 21.1, 7.5. HRMS (ESITOF) m/z: [M+H]+ Calcd for C25H34NO6 444.2381; found 444.2386. HPLC Analysis: Racemic mixture. Diisopropyl-2-((1R,2R)-2-hydroxycyclohexyl)-2-((4-methoxyphenyl)amino)malonate (28o). The general procedure was followed using 28o (0.31 g, 0.77 mmol) and BH3.DMS solution (2M solution in THF) (0.77 mL, 1.54 mmol) as starting materials to afford the alcohol as a yellow colored viscous oily liquid (0.207g, 66%). Reaction was finished in 14 hours. Compound was purified by flash column chromatography (Rf = 0.32 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 6.69 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 8.8 Hz, 2H), 5.03 (hept, J = 5.9 Hz, 1H), 5.03 (hept, J = 5.9 Hz, 2H), 4.26 (s, 1H), 3.69 (s, 3H), 3.10 (s, 1H), 2.50 (d, J = 11.7 Hz, 1H), 1.82 (q, J = 13.0 Hz, 3H), 1.65 (dq, J = 26.3, 12.7, 11.4 Hz, 2H), 1.36 (dt, J = 45.4, 13.8 Hz, 3H), 1.22 (d, J = 6.2 Hz, 3H), 1.14 (d, J = 6.2 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H), 0.91 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.6, 168.8, 153.4, 138.7, 117.5, 114.3, 72.1, 70.1, 69.7, 66.6, 55.5, 45.7, 33.4, 26.4, 23.0, 21.4, 21.3, 21.2, 21.1, 19.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H34NO6 408.2381; found 408.2381. HPLC Analysis: Racemic mixture. Diisopropyl-2-(benzo[d][1,3]dioxol-5-ylamino)-2-((1S,2R)-1hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)malonate (28p). The general procedure was followed using 28p (0.34 g, 0.72 mmol) and BH3.DMS solution (2M solution in THF) (0.72 mL, 1.45 mmol) as starting materials to afford the alcohol as a beige colored foamy solid (0.178g, 52%). Reaction was finished in 12 hours. Compound was purified by flash column chromatography (Rf = 0.27 (20% EtOAc/hexanes). 1H NMR (600 MHz,

CDCl3): δ 7.28 (d, J = 5.9 Hz, 1H), 7.24 (t, J = 6.9 Hz, 1H), 7.21 – 7.16 (m, 2H), 6.60 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 2.1 Hz, 1H), 6.19 (dd, J = 8.3, 2.1 Hz, 1H), 5.85 (d, J = 3.0 Hz, 2H), 5.25 - 5.14 (m, 2H), 5.09 (s, 1H), 5.00 (hept, J = 6.1, 5.6 Hz, 1H), 2.97 (qd, J = 16.8, 15.7, 7.7 Hz, 3H), 2.38 (s, 1H), 2.27 (d, J = 10.3 Hz, 1H), 2.15 – 2.04 (m, 1H), 1.33 (d, J = 6.2 Hz, 3H), 1.29 (d, J = 6.2 Hz, 3H), 1.21 (d, J = 6.2 Hz, 3H), 1.00 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 170.0, 168.3, 148.0, 140.9, 139.8, 137.8, 136.8, 130.3, 128.8, 128.0, 126.0, 108.3, 108.0, 100.6, 99.0, 70.76, 70.72, 69.5, 67.8, 44.6, 30.5, 21.6, 21.46, 21.40, 21.3, 20.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H32NO7 470.2173; found 470.2172. HPLC Analysis: Racemic mixture. General procedure for the cyclization of chiral alcohols to corresponding azetidines and tetrahydroquinolines, Figure 9. This procedure was adopted from the literature procedure.30,31 In a thick-walled flame dried reaction vial, chiral alcohol (1.0 equiv) was dissolved in anhydrous Toluene (0.05 M) under argon. To this reaction mixture, PPh3 (2.2 equiv) was added in one portion followed by the addition of 2,4,5-tribromoimidazole (1.1 equiv) and continued stirring for 48 h or in general until the complete consumption of starting material by heating at 80 ˚C. After confirming the complete consumption of starting material, the heating was stopped and the reaction mixture was brought to room temperature. Workup and purification: After bringing the reaction mixture to room temperature, the solids that were separated out were filtered and the solids were washed with ethyl acetate twice (2 X 5 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by automated flash column chromatography. Note: For the substrates that we made, the reaction times are ranging from 48 hours to 96 hours. Diisopropyl-(R)-4-(4-bromophenyl)-1-(3,5-dimethylphenyl)azetidine-2,2-dicarboxylate (30c) and Diisopropyl(S)-4-(4-bromophenyl)-5,7-dimethyl-3,4-dihydroquinoline2,2(1H)-dicarboxylate (31c). The general procedure was followed using 28c (0.20 g, 0.39 mmol), PPh3 (0.23 g, 0.87 mmol) and 2,4,5-tribromoimidazole (0.13 g, 0.43 mmol) as starting materials to afford azetidine (30c) as white colored wax (0.093 g) (Rf = 0.40 (10% EtOAc/Hexane)) and tetrahydroquinoline (31c) as pale yellow colored viscous oily liquid (0.048 g) (Rf = 0.35 (10% EtOAc/Hexane)) in the ratio of 1.9:1 after isolation ( 0.14 g in total, 72%). Reaction was finished in 48 hours. Compound was purified by column chromatography to separate azetidine and tetrahydroqinoline. Azetidine (30c): 1H NMR (500 MHz, CDCl3): δ 7.49 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 6.46 (s, 1H), 6.32 (s, 2H), 5.27 (hept, J = 6.2 Hz, 1H), 5.11 (t, J = 7.6 Hz, 1H), 5.03 (hept, J = 6.2 Hz, 1H), 3.14 (dd, J = 11.1, 8.4 Hz, 1H), 2.46 (dd, J = 11.2, 7.0 Hz, 1H), 2.17 (s, 6H), 1.36 (t, J = 6.1 Hz, 6H), 1.21 (d, J = 6.2 Hz, 3H), 1.07 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.6, 168.5, 147.0, 141.6, 138.0, 131.8, 127.5, 121.7, 121.4, 111.5, 72.0, 69.7, 69.2, 61.5, 36.3, 21.68, 21.66, 21.64, 21.48, 21.32. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H31BrNO4 488.1431; found 488.1460. HPLC Analysis: Chiralpak IE, 3% IP/hexanes, continuous flow at 0.4mL/min, 250 nm; tmajor = 13.5 min, tminor = 12.9 min, ee 86%, er 7:93; [α]D20 = −23.8 (C = 1, CHCl3). Tetrahydroquinoline (31c): 1H NMR (500 MHz, CDCl3): δ 7.31 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.49 (s, 1H),



6.42 (s, 1H), 5.02 (hept, J = 6.2 Hz, 1H), 4.76 (s, 1H), 4.43 (hept, J = 6.2 Hz, 1H), 4.21 (dd, J = 6.5, 4.2 Hz, 1H), 2.77 – 2.64 (m, 2H), 2.24 (s, 3H), 1.79 (s, 3H), 1.21 (d, J = 6.3 Hz, 6H), 1.06 (d, J = 6.2 Hz, 3H), 0.83 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.5, 168.6, 143.3, 142.8, 137.4, 137.3, 131.1, 130.2, 122.2, 119.8, 116.9, 114.1, 69.8, 69.7, 63.2, 37.5, 35.1, 21.46, 21.42, 21.1, 21.0, 20.9, 19.4. HRMS (ESITOF) m/z: [M+H]+ Calcd for C25H31BrNO4 488.1431; found 488.1455. HPLC Analysis: Chiralpak IF, 5% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 15.7 min, tminor = 16.5 min, ee 84%, er 92:8; [α]D20 = +65.6 (C = 1.04, CHCl3). Diisopropyl-(R)-4-phenyl-1-(3-(trifluoromethyl)phenyl)azetidine-2,2-dicarboxylate (30e). The general procedure was followed using 28e (0.27 g, 0.58 mmol), PPh3 (0.34 g, 1.29 mmol) and 2,4,5-tribromoimidazole (0.19 g, 0.64 mmol) as starting materials to afford only azetidine as beige colored viscous oily liquid (0.084 g, 31%). In this reaction the starting material was not totally consumed even after stirring at 80 ˚C for 62 hours and at 100 ˚C for 34 hours. Compound was purified by flash chromatography (Rf = 0.39 (10% EtOAc/hexanes). Azetidine (30e): 1H NMR (600 MHz, CDCl3): δ 7.47 (d, J = 7.3 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.14 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 5.29 (hept, J = 6.2 Hz, 1H), 5.19 (t, J = 7.7 Hz, 1H), 5.04 (hept, J = 6.2 Hz, 1H), 3.15 (dd, J = 11.3, 8.4 Hz, 1H), 2.67 (dd, J = 11.3, 7.1 Hz, 1H), 1.38 (dd, J = 6.2, 2.1 Hz, 6H), 1.21 (d, J = 6.3 Hz, 3H), 1.07 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.2, 168.2, 147.6, 141.4, 130.8 (q, 2JCF = 31.8 Hz), 129.0, 128.9, 128.1, 125.9, 124.2 (q, 1JCF = 272.3 Hz), 116.5, 115.8 (q, 3JCF = 3.7 Hz), 110.6 (q, 3JCF = 3.7 Hz), 72.2, 70.3, 69.8, 62.7, 36.5, 21.61, 21.60, 21.5, 21.2. 19F NMR (471 MHz, CDCl3): δ −61.86 (t, J = 0.8 Hz). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H27F3NO4 450.1887; found 450.1889. HPLC Analysis: Chiralpak IA, 2% IP/hexanes, continuous flow at 0.4mL/min, 250 nm; tmajor = 11.4 min, tminor = 10.7 min, ee 26%, er 37:63; [α]D20 = +4.0 (C = 1, CHCl3). Diisopropyl-(R)-1-(3,5-dimethylphenyl)-4-(naphthalen-2yl)azetidine-2,2-dicarboxylate (30f) and Diisopropyl-(S)-5,7dimethyl-4-(naphthalen-2-yl)-3,4-dihydroquinoline-2,2(1H)dicarboxylate (31f). The general procedure was followed using 28f (0.10 g, 0.20 mmol), PPh3 (0.12 g, 0.46 mmol) and 2,4,5tribromoimidazole (0.070 g, 0.23 mmol) as starting materials to afford azetidine (30f) as beige colored viscous oily liquid (0.018g) (Rf = 0.33 (10% EtOAc/hexanes) and tetrahydroquinoline (31f) as beige colored foam (0.051 g) (Rf = 0.28 (10% EtOAc/hexanes) in the ratio of 1:2.8 after isolation ( 0.070 g in total, 73%). Reaction took 48 hours to finish. Compound was purified by column chromatography to separate azetidine and tetrahydroqinoline. Azetidine (30f): 1H NMR (600 MHz, CDCl3): δ 7.93 (s, 1H), 7.85 (t, J = 8.7 Hz, 3H), 7.59 (d, J = 8.3 Hz, 1H), 7.51 – 7.44 (m, 2H), 6.44 (s, 1H), 6.39 (s, 2H), 5.29 (dq, J = 18.5, 6.9, 6.0 Hz, 2H), 5.06 (hept, J = 6.0 Hz, 1H), 3.20 (dd, J = 11.0, 8.5 Hz, 1H), 2.57 (dd, J = 11.2, 7.1 Hz, 1H), 2.15 (s, 6H), 1.37 (dd, J = 15.0, 6.2 Hz, 6H), 1.23 (d, J = 6.2 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.8, 168.8, 147.5, 140.1, 138.0, 133.4, 133.1, 128.6, 128.0, 127.7, 126.1, 125.8, 124.5, 123.8, 121.5, 111.6, 72.2, 69.7, 69.2, 62.4, 36.5, 21.76, 21.72, 21.5, 21.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H34NO4 460.2482; found 460.2479. HPLC Analysis: Chiralpak IE, 3% IP/hexanes, continuous flow at 0.4mL/min, 250 nm; tmajor = 17.4 min, tminor = 16.0 min, ee 60%, er 20:80; [α]D20 = −14.7 (C = 1, CHCl3).

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Tetrahydroquinoline (31f): 1H NMR (600 MHz, CDCl3): δ 7.79 – 7.66 (m, 3H), 7.43 – 7.37 (m, 2H), 7.35 (s, 1H), 7.28 (d, J = 7.5 Hz, 1H), 6.56 (s, 1H), 6.45 (s, 1H), 5.04 (hept, J = 5.8 Hz, 1H), 4.83 (s, 1H), 4.43 (t, J = 5.3 Hz, 1H), 4.13 (hept, J = 6.3 Hz, 1H), 2.87 – 2.78 (m, 2H), 2.29 (s, 3H), 1.81 (s, 3H), 1.22 (d, J = 6.2 Hz, 6H), 0.94 (d, J = 6.1 Hz, 3H), 0.48 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.5, 168.8, 143.0, 141.7, 137.7, 137.1, 133.2, 132.1, 127.8, 127.7, 127.3, 126.89, 126.85, 125.7, 125.2, 122.2, 117.5, 114.1, 69.6, 69.5, 63.4, 38.3, 35.4, 21.45, 21.41, 21.0, 20.5, 19.6. HRMS (ESITOF) m/z: [M+H]+ Calcd for C29H34NO4 460.2482; found 460.2486. HPLC Analysis: Chiralpak IA, 20% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 15.8 min, tminor = 9.6 min, ee 62%, er 19:81; [α]D20 = +66.8 (C = 1, CHCl3). Diisopropyl-(R)-1,4-diphenylazetidine-2,2-dicarboxylate (30h) and Diisopropyl-(S)-4-phenyl-3,4-dihydroquinoline-2,2(1H)dicarboxylate (31h). The general procedure was followed using 28h (0.10 g, 0.25 mmol), PPh3 (0.144 g, 0.055 mmol) and 2,4,5tribromoimidazole (0.084 g, 0.27 mmol) as starting materials to afford azetidine (30h) as beige colored viscous oily liquid (0.055g) (Rf = 0.4 (10% EtOAc/hexanes) and tetrahydroquinoline (31h) as yellow colored viscous oily liquid (0.013 g) (Rf = 0.34 (10% EtOAc/hexanes) in the ratio of 4.2:1 after isolation ( 0.070 g in total, 71%). Reaction took 48 hours to finish. Compound was purified by column chromatography to separate azetidine and tetrahydroqinoline. Azetidine (30h): 1H NMR (500 MHz, CDCl3): C-phenyl group: δ7.46-7.49 (m, 2H, H-2/H-6), 7.34-7.38 (m, 2H, H-3/H5), 7.26-7.31 (m, 1H, H-4); N-phenyl group: 7.08-7.13 (m, 2H, H-3’/H-5’), 6.75-6.79 (m, 1H, H-4’), 6.69-6.73 (m, 2H, H-2’/H6’); isopropoxy group #1: 5.26 (hept, J = 6.3 Hz, 1H, methine), 1.35 (d, 3H, methyl), 1.34 (d, 3H, methyl); isopropoxy group #2: 5.00 (hept, J = 6.3 Hz, 1H, methine), 1.20 (d, J = 6.3 Hz, 3H, methyl), 0.99 (d, J = 6.3 Hz, 3H, methyl); 5.15 (dd, 1H, benzylic proton); 3.13 (dd, J = 11.3, 8.3 Hz, 1H, CH2 proton cis to the benzylic proton); 2.56 (dd, J = 11.3, 7.2 Hz, 1H, CH2 proton cis to the adjacent phenyl group). 13C{1H} NMR (126 MHz, CDCl3): δ169.80 (carbonyl); 168.71 (other carbonyl); 147.43 (quaternary aromatic); 142.29 (other quaternary aromatic); C-phenyl group: 128.80 (C-3/C-5), 127.84 (C-4), 125.97 (C-2/C-6); N-phenyl group: 128.52 (C-3’/C-5’), 119.50 (C-4’), 113.75 (C-2’/C-6’); 72.24 (quaternary aliphatic carbon); isopropoxy group #1: 69.37 (methine), 21.71 (methyl correlating with methyl 1H signal at δ1.34 in HSQC spectrum), 21.66 (methyl correlating with methyl 1H signal at δ1.35 in HSQC spectrum); isopropoxy group #2: 69.86 (methine), 21.71 (methyl correlating with methyl 1H signal at δ1.20 in HSQC spectrum), 21.34 (methyl correlating with methyl 1H signal at δ0.99 in HSQC spectrum); 62.43 (benzylic CH), 36.54 (CH2). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H28NO4 382.2013; found 382.2021. HPLC Analysis: Chiralpak IA, 2% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 12.6 min, tminor = 14.7 min, ee 82%, er 91:9; [α]D20 = +14.8 (C = 1, CHCl3). Tetrahydroquinoline (31h): 1H NMR (500 MHz, CDCl3): δ 7.33 (t, J = 7.4 Hz, 2H), 7.28 – 7.25 (m, 1H), 7.21 (d, J = 7.1 Hz, 2H), 7.03 (dt, J = 8.2, 4.1 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 6.60 (q, J = 3.1, 1.9 Hz, 2H), 5.06 (ddq, J = 31.0, 12.5, 6.3 Hz, 2H), 4.91 (s, 1H), 4.13 (dd, J = 11.9, 5.3 Hz, 1H), 2.84 (ddd, J = 13.4, 5.3, 1.5 Hz, 1H), 2.25 (dd, J = 13.3, 12.0 Hz, 1H), 1.38 – 1.12 (m, 12H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.7, 168.9, 144.2, 142.2, 129.0, 128.8, 128.5, 127.3, 126.7, 123.9, 118.4, 114.8, 70.0, 69.6, 64.8, 40.7, 35.6, 21.54, 21.52, 21.47, 21.43. HRMS (ESI-TOF) m/z: Calcd for [M+H]+ C23H28NO4


Page 21 of 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


382.2013; found 382.2034. HPLC Analysis: Chiralpak IF, 3% IP/hexanes, continuous flow at 0.4mL/min, 250 nm; tmajor = 23.7 min, tminor = 22.7 min, ee 80%, er 10:90; [α]D20 = +37.0 (C = 1, CHCl3). Determination of stereochemistry of the azetidines: The stereochemistry of the two phenyl groups was established through a series of experiments. First, a COSY experiment (p. S189) enabled one set of three aromatic 1H signals to be assigned to one phenyl group and the other set of three aromatic signals to be assigned to the other phenyl group. The single-intensity multiplets at δ7.26-7.31 and δ6.75-6.79 clearly resulted from the para protons, each of which exhibits a 3-contour pattern in the HSQC spectrum (at δ127.84 and δ119.50, respectively) from two (equal) ortho J couplings (p. S190). The two other 3-contour patterns in the HSQC spectrum, at δ128.80 and δ128.52, result from two ortho J couplings and clearly are from the two pairs of phenyl C-3/C-5 carbons. The two 2-contour patterns in the HSQC spectrum, at δ125.97 and δ113.75, result from just one ortho J coupling and are clearly from the two pairs of phenyl C-2/C-6 carbons. The HSQC correlations thus establish that the signals from δ7.46-7.49 result from one set of H-2/H-6 protons, that the signals from δ6.69-6.73 result from the other set of H-2/H-6 protons, that the signals from δ7.34-7.38 result from one set of H-3/H-5 protons, and that the signals from δ7.08-7.13 result from the other set of H-3/H-5 protons. With these secure assignments for the phenyl protons closest to the azetidine ring, NOE experiments then enabled the proximity of these phenyl protons to each other and to the benzylic (δ5.15) and CH2 (δ3.13 and δ2.56) protons to be probed. The absence of any NOE between protons on different phenyl rings with a mixing time of 0.10 or 0.20 s (pp. S191 and S192) strongly indicated that the two phenyl rings were not near each other, i.e., they had a trans orientation. If the rings were cis to each other, H-2/H-6 on one ring would be near H-2’/H-6’ on the other ring; H-3/H-5 on one ring would be near H-3’/H-5’ on the other ring; and strong NOE cross peaks would result, even at very short mixing times. A weak NOE between H-2/H-6 and H-2’/H-6’ is detected with a mixing time of 0.40 or 0.70 s (pp. S193 and S194). Increasing the mixing time from 0.10 to 0.20 to 0.40 to 0.70 s results in a steadily increasing NOE between the H-2/H6 protons at δ7.46-7.49 and the CH2 proton at δ2.56. In contrast, the H-2’/H-6’ protons at δ6.69-6.73 do not show an NOE with this CH2 proton at any mixing time. Clearly, the CH2 proton at δ2.56 is cis to the adjacent C-phenyl group and trans to the more remote N-phenyl group. Pictorial representation of NOE correlation in 30h:

N

H

COOiPr H H

COOiPr

30h

General procedure for the cyclization of chiral alcohols to corresponding γ-lactones, Figure 10 &11. Method A: In a thick-walled flame dried reaction vial, chiral alcohol (28) (1.0 equiv) was dissolved in anhydrous Toluene (0.2 M) under argon. To this reaction mixture, TsOH.H2O (0.20 equiv) was added in one portion and continued stirring for 1 h by heating to 70 ˚C. After confirming the complete consumption

of starting material, the reaction was quenched using water (2 mL). Note: This reaction can be heated to 110 ˚C and the reaction will be finished in less than 1 hour without change in the diastereoselectivity. Workup and purification: After quenching, the reaction mixture was diluted with brine (3 mL) and the organic layer was separated. The aqueous layer was then extracted with EtOAc twice (2 X 10 mL) and the combined organic layers were washed with brine (10 mL) once, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by automated flash column chromatography. Method B: In a thick-walled flame dried reaction vial, chiral alcohol (1.0 equiv) was dissolved in anhydrous Toluene (0.1 M) under argon. To this reaction mixture, DBU (1M solution in EtOAc) (1.1 equiv) was added dropwise and continued stirring for 1 hour at room temperature. After confirming the complete consumption of starting material, the reaction was quenched using water (2 mL). Workup and purification: After quenching, the reaction mixture was diluted with brine (2 mL) and the organic layer was separated. The aqueous layer was then extracted with EtOAc twice (2 X 5 mL) and the combined organic layers were washed with brine (10 mL) once, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography. Isopropyl-(3S,5R)-2-oxo-5-phenyl-3-(phenylamino)tetrahydrofuran-3-carboxylate (24a) and Isopropyl-(3R,5R)-2-oxo-5-phenyl-3-(phenylamino)tetrahydrofuran-3-carboxylate (24b). The general procedure (Method A) was followed using 28h (0.29 g, 0.72 mmol) and TsOH•H2O (0.027 g, 0.14 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 2:1, by crude 1HNMR) (0.21 g, 86%) which were separated by using flash column chromatography. 24a: Physical State: White colored solid (m.p. 79 – 81 ˚C). Rf = 0.52 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.45 – 7.39 (m, 4H), 7.39 – 7.35 (m, 1H), 7.18 (t, J = 7.9 Hz, 2H), 6.82 (t, J = 7.3 Hz, 1H), 6.64 (d, J = 8.0 Hz, 2H), 5.77 (dd, J = 10.3, 6.1 Hz, 1H), 5.10 – 5.02 (m, 2H), 3.57 (dd, J = 13.1, 6.1 Hz, 1H), 2.59 (dd, J = 13.0, 10.5 Hz, 1H), 1.27 (d, J = 6.3 Hz, 3H), 1.02 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 171.9, 167.6, 144.2, 137.8, 129.2, 128.9, 128.8, 125.7, 119.6, 114.8, 80.1, 71.1, 67.2, 42.8, 21.4, 21.0. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H21NO4Na 362.1363; found 362.1365. HPLC Analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 13.9 min, tminor = 14.9 min, ee 94%, er 97:3; [α]D20 = −8.2 (C = 1, CHCl3). 24b: Physical State: White colored solid (m.p. 132 – 134 ˚C). Rf = 0.46 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.46 – 7.34 (m, 5H), 7.23 (t, J = 7.7 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H), 6.67 (d, J = 7.9 Hz, 2H), 5.71 (t, J = 7.5 Hz, 1H), 5.01 (hept, J = 6.0 Hz, 1H), 4.81 (s, 1H), 3.14 (dd, J = 13.8, 8.1 Hz, 1H), 3.06 (dd, J = 13.8, 7.0 Hz, 1H), 1.08 (dd, J = 19.6, 6.2 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 172.4, 168.2, 143.7, 138.8, 129.3, 128.6, 128.5, 125.4, 120.0, 115.6, 78.9, 71.0, 66.3, 39.4, 21.1, 21.0. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H21NO4Na 362.1363; found 362.1365. HPLC Analysis: Chiralpak ID, 40% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 16.5 min, tminor = 15.5 min, ee 90%, er 5:95; [α]D20 = −3.7 (C = 1, CHCl3). Isopropyl-(3S,5R)-3-((4-methoxyphenyl)amino)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (24c) and Isopropyl (3R,5R)3-((4-methoxyphenyl)amino)-2-oxo-5-phenyltetrahydrofuran-



3-carboxylate (24d). The general procedure (Method A) was followed using 28a (0.48 g, 1.11 mmol) and TsOH•H2O (0.042 g, 0.22 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 2:1, by crude 1 HNMR) (0.40 g, 98%) which were separated by using flash column chromatography. 24c: Physical State: Beige colored waxy solid; Rf = 0.41 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ7.33-7.42 (m, phenyl, 5H), 6.75 (m, AA’ part of AA’BB’ pattern, 2H, H-3’/H-5’), 6.63 (m, BB’ part of AA’BB’ pattern, 2H, H-2’/H-6’), 5.70 (dd, J = 10.4, 6.1 Hz, 1H, benzylic), 5.04 (hept, J = 6.3 Hz, 1H, isopropoxy methine), 4.77 (s, broad, NH), 3.72 (s, 3H, methoxy), 3.48 (dd, J = 13.0, 6.1 Hz, 1H, one H of CH2), 2.55 (dd, J = 13.0, 10.4 Hz, 1H, other H of CH2), 1.26 (d, J = 6.3 Hz, 3H, one isopropyl methyl), 1.04 (d, J = 6.2 Hz, 3H, other isopropyl methyl); 13C NMR{1H} (126 MHz, CDCl3): 172.3 (ring carbonyl), 167.9 (isopropoxy carbonyl), 153.9 (C-4’ of p-disubstituted aromatic ring), 138.0 (phenyl C-1), 137.8 (C-1’ of p-disubstituted aromatic ring), 129.0 (phenyl C-4, JCH = 161.3 Hz), 128.9 (phenyl C-3/C-5, JCH ≈ 161.3 Hz), 125.9 (phenyl C-2/C-6, JCH = 158.6 Hz), 117.4 (C2’/C-6’ of p-disubstituted aromatic ring, JCH = 157.5 Hz), 114.7 (C-3’/C-5’ of p-disubstituted aromatic ring, JCH = 159.8 Hz), 80.1 (benzylic CH, JCH = 154.9 Hz), 71.2 (isopropyl CH, JCH = 149.5 Hz), 68.1 (quaternary aliphatic carbon), 55.6 (methoxy, JCH = 143.4 Hz), 42.8 (CH2, JCH = 139.3 Hz with 1H at δ3.48, JCH = 134.8 Hz with 1H at δ2.55), 21.5 [isopropyl methyl (correlating with methyl 1H signal at δ1.26 in HSQC spectrum), JCH = 127.1 Hz with 1H at δ1.26], 21.3 [other isopropyl methyl (correlating with methyl 1H signal at δ1.04 in HSQC spectrum), JCH = 127.3 Hz with 1H at δ1.04]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H24NO5 370.1649; found 370.1646; HPLC Analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.7mL/min, 250 nm; tmajor = 12.6 min, tminor = 13.8 min, ee 93%, er 96.5:3.5; [α]D20 = −6.5 (C = 1, CHCl3). The evidence for C-attack by the initial enolate followed by formation of a 5-membered-ring lactone (rather than N-attack by the initial enolate followed by formation of a 6-membered-ring lactone) was the generation of a quaternary aliphatic carbon, as shown by the presence of a signal at δ68.1 in the standard 13C spectrum (p. S205) and the absence of this signal in the DEPT135 13C spectrum (p. S206) and in the DEPT-90 13C spectrum (both optimized for 1JCH = 145 Hz).32 Additional confirmation that the signal at δ68.1 resulted from a quaternary carbon was provided by the absence of this signal in DEPT-135 13C spectra optimized for 1JCH = 125 Hz and 1JCH = 170 Hz and by the absence of a large 1JCH coupling for the signal at δ68.1 in a 1Hcoupled 13C spectrum. (Just two small couplings, each ≈ 4.4 Hz, were observed, apparently from equal 2JCH couplings with the adjacent CH2 protons.) Detailed chemical shift assignments could be made through a combination of 1H (p. S204), 13C (with and without 1H decoupling), DEPT-135 13C, DEPT-90 13C, NOE (pp. S207-S210), HSQC (p. S212), and HMBC (p. S211) experiments (with key parameters the same as for 27n). The stereochemistry of phenyl and H on the benzylic carbon relative to the substituents on the quaternary aliphatic carbon and relative to the two inequivalent CH2 protons was established through NOE experiments with various mixing times (0.2, 0.3, 0.5, 0.7 s). An NOE experiment with a relatively short mixing time will minimize spin diffusion effects (reference below) and thus enable a more secure identification of the interacting protons provided that cross peaks with sufficient signalto-noise are generated. However, even with the longest mixing time, there is no NOE between any of the phenyl protons and

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an isopropyl methyl group, establishing that these protons are not near each other; similarly, there is no NOE between any of the phenyl protons and the more deshielded CH2 proton (δ3.48). In contrast, with the shortest mixing time, NOE is detected between phenyl protons and the more shielded CH2 proton (δ2.55), establishing their cis relationship, and between phenyl protons and the benzylic proton (δ5.70). NOE is also detected between the methoxy protons (δ3.72) and the aromatic protons at δ6.75, while NOE is detected between the aromatic protons at δ6.63 and NH and each of the CH2 protons. These observations enabled secure assignments of the aromatic protons at δ6.75 (H-3’/H-5’) and at δ6.63 (H-2’/H-6’). Pictorial representation of NOE correlation in 24c:

24d: Physical State: Beige colored waxy solid. Rf = 0.36 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ7.33-7.42 (m, phenyl, 5H), 6.81 (m, AA’ part of AA’BB’ pattern, 2H, H-3’/H5’), 6.74 (m, BB’ part of AA’BB’ pattern, 2H, H-2’/H-6’), 5.56 (dd, J ≈ 7.7, 7.6 Hz, 1H, benzylic), 5.02 (hept, J = 6.3 Hz, 1H, isopropoxy methine), 4.50 (s, broad, NH), 3.76 (s, 3H, methoxy), 3.04 (dd, J ≈ 13.8, 7.7 Hz, 1H, one H of CH2), 2.99 (dd, J ≈ 13.8, 7.6 Hz, 1H, other H of CH2), 1.13 (d, J = 6.3 Hz, 3H, one isopropyl methyl), 1.12 (d, J = 6.3 Hz, 3H, other isopropyl methyl). 13C{1H} NMR (126 MHz, CDCl3): 172.9 (ring carbonyl), 168.6 (isopropoxy carbonyl), 154.7 (C-4’ of p-disubstituted aromatic ring), 138.8 (phenyl C-1), 136.9 (C-1’ of p-disubstituted aromatic ring), 128.7 (phenyl C-3/C-5), 128.6 (phenyl C-4), 125.6 (phenyl C-2/C-6), 119.6 (C-2’/C-6’ of p-disubstituted aromatic ring), 114.7 (C-3’/C-5’ of p-disubstituted aromatic ring), 79.1 (benzylic CH), 71.0 (isopropyl CH), 67.5 (quaternary aliphatic carbon), 55.6 (methoxy), 39.6 (CH2), 21.34 [isopropyl methyl (correlating with methyl 1H signal at δ1.13 in HSQC spectrum)], 21.26 [other isopropyl methyl (correlating with methyl 1H signal at δ1.12 in HSQC spectrum)]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H24NO5 370.1649; found 370.1648. HPLC Analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.7mL/min, 250 nm; tmajor = 11.0 min, tminor = 13.9 min, ee 93%, er 3.4:96.6; [α]D20 = −3.7 (C = 1, CHCl3). The evidence for C-attack by the initial enolate followed by formation of a 5-membered-ring lactone (rather than N-attack by the initial enolate followed by formation of a 6-membered-ring lactone) was the generation of a quaternary aliphatic carbon, as shown by the presence of a signal at δ67.5 in the standard 13C spectrum (p. S214) and the absence of this signal in the DEPT135 13C spectrum (p. S215) and in the DEPT-90 13C spectrum (both optimized for 1JCH = 145 Hz). Detailed chemical shift assignments could be made through a combination of 1H (p. S213), 13C, DEPT-135 13C, DEPT-90 13C, NOE (p. S216-S219), HSQC (p. S221), and HMBC (p. S220) experiments (with key parameters the same as for 27n). The stereochemistry of phenyl and H on the benzylic carbon relative to the substituents on the quaternary aliphatic carbon


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and relative to the two inequivalent CH2 protons was established through NOE experiments with various mixing times (0.2, 0.3, 0.5, 0.7 s). Compared to 24c, the critical difference for 24d is that with a mixing time of just 0.3 s, NOE is clearly detected between phenyl protons and an isopropyl methyl group, establishing that these protons can be near each other. With a mixing time of 0.3 s, NOE is also detected between phenyl protons and the more shielded CH2 proton (δ2.99), establishing their cis relationship, and between phenyl protons and the benzylic proton (δ5.56). NOE is also detected between the methoxy protons (δ3.76) and the aromatic protons at δ6.81, while NOE is detected between the aromatic protons at δ6.74 and NH and each of the more deshielded CH2 protons. These observations enabled secure assignments of the aromatic protons at δ6.81 (H-3’/H-5’) and at δ6.74 (H-2’/H-6’). Pictorial representation of NOE correlation in 24d:

Isopropyl-(3S,5R)-3-((3,5-dimethylphenyl)amino)-2-oxo-5phenyltetrahydrofuran-3-carboxylate (24e) and Isopropyl(3R,5R)-3-((3,5-dimethylphenyl)amino)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (24f). The general procedure (Method A) was followed using 28b (0.35 g, 0.82 mmol) and TsOH•H2O (0.031 g, 0.16 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.2:1, by crude 1HNMR) (0.26 g, 86%) which were separated by using flash column chromatography. 24e: Physical State: Beige colored solid (m.p. 106 –108 ˚C). Rf = 0.57 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.46 – 7.41 (m, 4H), 7.38 (ddd, J = 8.5, 5.1, 2.4 Hz, 1H), 6.48 (s, 1H), 6.28 (s, 2H), 5.78 (dd, J = 10.3, 6.3 Hz, 1H), 5.11 (hept, J = 6.2 Hz, 1H), 4.96 (s, 1H), 3.49 (dd, J = 13.2, 6.3 Hz, 1H), 2.64 (dd, J = 13.2, 10.3 Hz, 1H), 2.23 (s, 6H), 1.31 (d, J = 6.3 Hz, 3H), 1.11 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 172.0, 167.7, 143.8, 138.7, 138.0, 128.8.128.7, 125.6, 121.4, 112.8, 79.8, 71.1, 67.1, 42.2, 21.4, 21.2, 21.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26NO4 368.1856; found 368.1859. HPLC Analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 12.9 min, tminor = 15.5 min, ee 96%, er 97.8:2.2; [α]D20 = −6.7 (C = 1, CHCl3). 24f: Physical State: Pale yellow colored waxy solid; Rf = 0.52 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.47-7.41 (m, 4H), 7.39 (ddd, J = 8.5, 5.3, 2.1 Hz, 1H), 6.56 (s, 1H), 6.32 (s, 2H), 5.72 (t, J = 7.6 Hz, 1H), 5.05 (hept, J = 6.3 Hz, 1H), 4.74 (s, 1H), 3.17 (dd, J = 13.8, 8.1 Hz, 1H), 3.08 (dd, J = 13.8, 7.1 Hz, 1H), 2.28 (s, 6H), 1.13 (dd, J = 16.4, 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 172.5, 168.3, 143.6, 138.9, 138.8, 128.6, 128.4, 125.4, 122.0, 113.6, 78.9, 70.9, 66.3, 39.5, 21.4, 21.1, 21.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26NO4 368.1856; found 368.1859; HPLC Analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 14.5 min, tminor = 12.8 min, ee 96%, er 2:98; [α]D20 = −3.3 (C = 1, CHCl3).

Isopropyl-(3S,5R)-3-(benzo[d][1,3]dioxol-5-ylamino)-2-oxo5-phenyltetrahydrofuran-3-carboxylate (24g) and Isopropyl(3R,5R)-3-(benzo[d][1,3]dioxol-5-ylamino)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (24h). The general procedure (Method A) was followed using 28d (0.27 g, 0.61 mmol) and TsOH•H2O (0.023 g, 0.12 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.8:1, by crude 1HNMR) (0.206 g, 87%) which were separated by using flash column chromatography. 24g: Physical State: Beige colored solid (m.p. 91 – 94 ˚C); Rf = 0.39 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.38 (td, J = 12.3, 10.2, 5.2 Hz, 5H), 6.62 (d, J = 8.3 Hz, 1H), 6.29 (d, J = 2.2 Hz, 1H), 6.07 (dd, J = 8.3, 2.2 Hz, 1H), 5.85 (s, 2H), 5.70 (dd, J = 10.3, 6.1 Hz, 1H), 5.06 (hept, J = 6.2 Hz, 1H), 4.79 (s, 1H), 3.49 (dd, J = 13.0, 6.1 Hz, 1H), 2.53 (dd, J = 13.0, 10.4 Hz, 1H), 1.27 (d, J = 6.3 Hz, 3H), 1.09 (d, J = 6.2 Hz, 3H). 13 C{1H} NMR (151 MHz, CDCl3): δ 172.0, 167.6, 148.3, 141.5, 139.3, 137.8, 128.9, 128.8, 125.7, 108.3, 107.5, 100.8, 98.8, 80.0, 71.1, 67.9, 42.8, 21.4, 21.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H22NO6 384.1442; found 384.1440. HPLC Analysis: Chiralpak ID, 80% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 22.5 min, tminor = 21.2 min, ee 96%, er 2:98; [α]D20 = −9.2 (C = 1, CHCl3). 24h: Physical State: Beige colored solid (m.p. 78 – 80 ˚C); Rf = 0.31 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.38 (dq, J = 14.5, 7.5 Hz, 5H), 6.67 (d, J = 8.3 Hz, 1H), 6.38 (d, J = 2.1 Hz, 1H), 6.17 (dd, J = 8.3, 2.1 Hz, 1H), 5.90 (s, 2H), 5.61 (t, J = 7.6 Hz, 1H), 5.02 (hept, J = 6.2 Hz, 1H), 4.53 (s, 1H), 3.12 – 2.93 (m, 2H), 1.12 (d, J = 6.1 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 172.5, 168.3, 148.3, 142.3, 138.7, 138.4, 128.6, 128.5, 125.4, 109.7, 108.3, 100.9, 100.5, 78.9, 71.0, 67.2, 39.5, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H22NO6 384.1442; found 384.1441. HPLC Analysis: Chiralpak ID, 80% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 18.6 min, tminor = 20.02 min, ee 96%, er 98:2; [α]D20 = −4.0 (C = 1, CHCl3). Isopropyl-(3S,5R)-2-oxo-5-phenyl-3-((3-(trifluoromethyl)phenyl)amino)tetrahydrofuran-3-carboxylate (24i) and Isopropyl(3R,5R)-2-oxo-5-phenyl-3-((3-(trifluoromethyl)phenyl)amino)tetrahydrofuran-3-carboxylate (24j). The general procedure (Method A) was followed using 28e (0.35 g, 0.76 mmol) and TsOH•H2O (0.029 g, 0.15 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.7:1, by crude 1HNMR) (0.285 g, 92%) which were separated by using flash column chromatography. 24i: Physical State: White colored solid (m.p. 79 – 81 ˚C). Rf = 0.50 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.45 – 7.35 (m, 5H), 7.31 – 7.23 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.83 (s, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.80 (dd, J = 10.3, 6.2 Hz, 1H), 5.25 (s, 1H), 5.09 (hept, J = 6.2 Hz, 1H), 3.55 (dd, J = 13.1, 6.2 Hz, 1H), 2.56 (dd, J = 13.0, 10.4 Hz, 1H), 1.28 (d, J = 6.3 Hz, 3H), 1.06 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 171.5, 167.2, 144.6, 137.6, 131.6 (q, 2JCF = 32.0 Hz), 129.8, 129.0, 128.9, 125.7, 124.0 (q, 1JCF = 272.4 Hz), 117.9, 116.0 (q, 3JCF = 3.8 Hz), 110.8 (q, 3JCF = 3.8 Hz), 80.2, 71.6, 67.0, 42.6, 21.4, 21.0. 19F NMR (471 MHz, CDCl3): δ −61.9 (S). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H21F3NO4 408.1417; found 408.1420. HPLC Analysis: Chiralpak ID, 10% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 15.8 min, tminor = 14.8 min, ee 93%, er 3.6:96.4; [α]D20 = −7.2 (C = 1, CHCl3). 24j: Physical State: Colorless viscous oily liquid. Rf = 0.40 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.40 (dq, J = 13.3, 6.9 Hz, 5H), 7.31 (d, J = 7.9 Hz, 1H), 7.10



(d, J = 7.6 Hz, 1H), 6.87 (s, 1H), 6.82 (d, J = 8.1 Hz, 1H), 5.74 (t, J = 7.5 Hz, 1H), 5.07 – 4.96 (m, 2H), 3.17 – 3.05 (m, 2H), 1.07 (dd, J = 14.4, 6.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 171.9, 167.8, 144.2, 138.5, 131.6 (q, 2JCF = 32.0 Hz), 129.8, 128.8, 128.7, 125.4, 124.0 (q, 1JCF = 272.4 Hz), 118.2, 116.4 (q, 3JCF = 3.9 Hz), 111.7 (q, 3JCF = 3.9 Hz), 78.9, 71.4, 66.0, 39.7, 21.1, 21.0. 19F NMR (471 MHz, CDCl3): δ −61.9 (S). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H21F3NO4 408.1417; found 408.1420. HPLC Analysis: Chiralpak ID, 15% IP/hexanes, continuous flow at 0.6mL/min, 250 nm; tmajor = 16.1 min, tminor = 12.6 min, ee 93%, er 3.4:96.6; [α]D20 = −4.3 (C = 1, CHCl3). Isopropyl-(3S,5R)-3-((3,5-dimethylphenyl)amino)-5-(naphthalen-2-yl)-2-oxotetrahydrofuran-3-carboxylate (24k) and Isopropyl-(3R,5R)-3-((3,5-dimethylphenyl)amino)-5-(naphthalen2-yl)-2-oxotetrahydrofuran-3-carboxylate (24l). The general procedure (Method A) was followed using 28f (0.32 g, 0.66 mmol) and TsOH•H2O (0.025 g, 0.13 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.8:1, by crude 1HNMR) (0.25 g, 90 %) which were separated by using flash column chromatography. 24k: Physical State: White foamy solid. Rf = 0.42 (15% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.93 – 7.89 (m, 2H), 7.87 (d, J = 6.3 Hz, 2H), 7.55 – 7.51 (m, 2H), 7.50 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 6.30 (s, 2H), 5.94 (dd, J = 10.1, 6.4 Hz, 1H), 5.13 (hept, J = 6.1 Hz, 1H), 4.99 (s, 1H), 3.55 (dd, J = 13.2, 6.3 Hz, 1H), 2.73 (dd, J = 13.1, 10.5 Hz, 1H), 2.22 (s, 6H), 1.34 (d, J = 6.2 Hz, 3H), 1.13 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 172.1, 167.8, 143.9, 138.8, 135.3, 133.3, 133.0, 128.9, 128.0, 127.7, 126.63, 126.60, 125.0, 122.9, 121.5, 112.9, 80.0, 71.2, 67.2, 42.2, 21.5, 21.3, 21.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H28NO4 418.2013; found 418.2007. HPLC Analysis: Chiralpak IB, 10% IP/hexanes, continuous flow at 0.4mL/min, 230 nm; tmajor = 19.3 min, tminor = 22.9 min, ee 95%, er 97.3:2.6; [α]D20 = −14.2 (C = 1, CHCl3). 24l: Physical State: Brown colored viscous gummy liquid. Rf = 0.37 (15% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.92 (d, J = 8.5 Hz, 1H), 7.87 (t, J = 10.0 Hz, 3H), 7.57 – 7.46 (m, 3H), 6.56 (s, 1H), 6.33 (s, 2H), 5.86 (t, J = 7.5 Hz, 1H), 5.02 (hept, J = 6.4 Hz, 1H), 4.77 (s, 1H), 3.22 (dd, J = 13.7, 8.2 Hz, 1H), 3.15 (dd, J = 13.8, 7.1 Hz, 1H), 2.28 (s, 6H), 1.07 (d, J = 6.2 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 172.6, 168.3, 143.6, 138.9, 136.1, 133.1, 132.9, 128.7, 127.9, 127.6, 126.5, 126.4, 124.6, 122.8, 122.0, 113.7, 79.1, 70.9, 66.3, 39.4, 21.4, 21.1, 21.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H28NO4 418.2013; found 418.2017. HPLC Analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 21.3 min, tminor = 17.7 min, ee 95%, er 2.6:97.3; [α]D20 = −8.2 (C = 1, CHCl3). Isopropyl-(3S,5R)-5-(naphthalen-1-yl)-2-oxo-3-(p-tolylamino)tetrahydrofuran-3-carboxylate (24m) and Isopropyl(3R,5R)-5-(naphthalen-1-yl)-2-oxo-3-(p-tolylamino)tetrahydrofuran-3-carboxylate (24n). The general procedure (Method A) was followed using 28g (0.42 g, 0.90 mmol) and TsOH•H2O (0.034 g, 0.18 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.7:1, by crude 1HNMR) (0.333 g, 91 %) which were separated by using flash column chromatography. 24m: Physical State: Yellow colored foamy gummy substance. Rf = 0.55 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.03 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.54 (dt, J = 20.6, 7.6 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 8.3 Hz, 2H), 6.56 (dd,

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J = 10.3, 6.0 Hz, 1H), 5.16 (hept, J = 6.2 Hz, 1H), 5.02 (s, 1H), 3.81 (dd, J = 13.1, 6.0 Hz, 1H), 2.68 (dd, J = 13.0, 10.6 Hz, 1H), 2.26 (s, 3H), 1.37 (d, J = 6.3 Hz, 3H), 1.13 (d, J = 6.2 Hz, 3H). 13 C{1H} NMR (151 MHz, CDCl3): δ 171.9, 167.8, 141.6, 133.5, 129.64, 129.61, 129.0, 128.96, 128.91, 126.6, 125.9, 125.3, 122.2, 121.8, 115.2, 77.4, 71.1, 67.5, 42.2, 21.4, 21.1, 20.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H26NO4 404.1856; found 404.1854. HPLC Analysis: Chiralpak IB, 9% IP/hexanes, continuous flow at 0.4mL/min, 230 nm; tmajor = 21.8 min, tminor = 20.4 min, ee 80%, er 9.7:90.3; [α]D20 = +4.3 (C = 1, CHCl3). 24n: Physical State: Pink colored foamy gummy substance. Rf = 0.48 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.96 – 7.92 (m, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.77 – 7.72 (m, 1H), 7.69 (d, J = 7.0 Hz, 1H), 7.58 – 7.50 (m, 3H), 7.08 (d, J = 7.9 Hz, 2H), 6.67 (d, J = 8.1 Hz, 2H), 6.39 (t, J = 7.3 Hz, 1H), 4.98 (hept, J = 6.3 Hz, 1H), 4.86 (s, 1H), 3.36 (dd, J = 13.7, 8.6 Hz, 1H), 3.09 (dd, J = 13.7, 6.3 Hz, 1H), 2.30 (s, 3H), 1.11 (d, J = 6.2 Hz, 3H), 1.03 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 173.0, 168.3, 141.3, 134.6, 133.8, 130.0, 129.7, 129.33, 129.30, 128.9, 126.7, 126.0, 125.3, 122.5, 122.2, 116.3, 76.8, 71.1, 66.3, 39.3, 21.35, 21.33, 20.58, 20.57. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H26NO4 404.1856; found 404.1857. HPLC Analysis: Chiralpak ID, 85% IP/hexanes, continuous flow at 0.6mL/min, 250 nm; tmajor = 13.4 min, tminor = 12.6 min, ee 80%, er 10:90; [α]D20 = +0.8 (C = 1, CHCl3). Isopropyl-(3S,5R)-5-(4-bromophenyl)-3-((3,5-dimethylphenyl)amino)-2-oxotetrahydrofuran-3-carboxylate (24o) and Isopropyl-(3R,5R)-5-(4-bromophenyl)-3-((3,5-dimethylphenyl)amino)-2-oxotetrahydrofuran-3-carboxylate (24p). The general procedure (Method A) was followed using 28c (0.37 g, 0.72 mmol) and TsOH•H2O (0.027 g, 0.14 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.7:1, by crude 1HNMR) (0.277 g, 85 %) which were separated by using flash column chromatography. 24o: Physical State: White solid (m.p. 120 – 122 ˚C); Rf = 0.59 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.54 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.47 (s, 1H), 6.24 (s, 2H), 5.70 (dd, J = 10.2, 6.3 Hz, 1H), 5.08 (hept, J = 6.2 Hz, 1H), 4.92 (s, 1H), 3.48 (dd, J = 13.2, 6.3 Hz, 1H), 2.55 (dd, J = 13.2, 10.3 Hz, 1H), 2.21 (s, 6H), 1.29 (d, J = 6.3 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 171.8, 167.6, 143.8, 138.8, 137.1, 131.9, 127.3, 122.8, 121.6, 112.9, 79.0, 71.2, 67.1, 42.1, 21.4, 21.3, 21.0. HRMS (ESITOF) m/z: [M+H]+ Calcd for C22H25BrNO4 446.0961; found 446.0961. HPLC Analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 14.4 min, tminor = 17.3 min, ee 94%, er 97:3; [α]D20 = −12.2 (C = 1, CHCl3). 24p: Physical State: Beige colored solid (m.p. 145 – 148 ˚C); Rf = 0.54 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.54 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 6.53 (s, 1H), 6.27 (s, 2H), 5.63 (t, J = 7.5 Hz, 1H), 5.02 (hept, J = 6.2 Hz, 1H), 4.69 (s, 1H), 3.13 (dd, J = 13.8, 8.2 Hz, 1H), 3.00 (dd, J = 13.8, 7.0 Hz, 1H), 2.24 (s, 6H), 1.12 (d, J = 6.3 Hz, 3H), 1.07 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 172.3, 168.2, 143.5, 138.9, 138.0, 131.8, 127.1, 122.4, 122.1, 113.6, 78.2, 71.1, 66.2, 39.4, 21.4, 21.2, 21.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H25BrNO4 446.0961; found 446.0965. HPLC Analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 13.8 min, tminor = 12.4 min, ee 94%, er 3:97; [α]D20 = −5.2 (C = 1, CHCl3). Isopropyl-(3S,5R)-3-(benzo[d][1,3]dioxol-5-ylamino)-5-(furan-2-yl)-2-oxotetrahydrofuran-3-carboxylate (24q) and Isopropyl-(3R,5R)-3-(benzo[d][1,3]dioxol-5-ylamino)-5-(furan-


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2-yl)-2-oxotetrahydrofuran-3-carboxylate (24r). The general procedure (Method B) was followed using 28i (0.073 g, 0.16 mmol) and DBU (1M solution in ethyl acetate) (0.185 mL, 0.18 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.2:1, by crude 1HNMR) (0.054 g, 86 %) which were separated by using flash column chromatography. 24q: Physical State: Brown colored viscous oily liquid; Rf = 0.35 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.48 (d, J = 1.9 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 3.3 Hz, 1H), 6.41 (dd, J = 3.4, 1.8 Hz, 1H), 6.31 (d, J = 2.5 Hz, 1H), 6.08 (dd, J = 8.2, 2.4 Hz, 1H), 5.87 (s, 2H), 5.70 (dd, J = 10.5, 6.3 Hz, 1H), 5.06 (hept, J = 6.4 Hz, 1H), 4.81 (s, 1H), 3.27 (dd, J = 13.1, 6.3 Hz, 1H), 2.96 (dd, J = 13.1, 10.5 Hz, 1H), 1.27 (d, J = 6.3 Hz, 3H), 1.10 (d, J = 6.2 Hz, 3H). 13 C{1H} NMR (151 MHz, CDCl3): δ 171.3, 167.7, 149.0, 148.4, 144.1, 141.4, 139.1, 111.1, 110.7, 108.4, 107.2, 100.8, 98.5, 73.0, 71.3, 67.4, 37.8, 21.5, 21.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H20NO7 374.1234. found 374.1234. HPLC Analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 24.7 min, tminor = 26.8 min, ee 82%, er 91:9; [α]D20 = −7.3 (C = 1, CHCl3). 24r: Physical State: Dark brown colored viscous oily liquid; Rf = 0.29 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.47 (d, J = 1.9 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.52 (d, J = 3.3 Hz, 1H), 6.43 – 6.35 (m, 2H), 6.18 (dd, J = 8.3, 2.3 Hz, 1H), 5.90 (s, 2H), 5.57 (t, J = 7.7 Hz, 1H), 5.07 (hept, J = 6.3 Hz, 1H), 4.48 (s, 1H), 3.35 (dd, J = 13.9, 7.7 Hz, 1H), 2.88 (dd, J = 13.9, 7.8 Hz, 1H), 1.25 (d, J = 6.3 Hz, 3H), 1.16 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 172.0, 168.2, 149.7, 148.3, 143.7, 142.5, 138.3, 110.7, 110.2, 110.1, 108.4, 101.0, 100.8, 72.6, 71.1, 67.2, 35.4, 21.5, 21.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H20NO7 374.1234; found 374.1249. HPLC Analysis: Chiralpak IC, 35% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 24.5 min, tminor = 21.7 min, ee 86%, er 7:93; [α]D20 = −5.2 (C = 1, CHCl3). Isopropyl-(3S,5R)-3-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)amino)-5-(furan-2-yl)-2-oxotetrahydrofuran-3-carboxylate (24s) and Isopropyl-(3R,5R)-3-((4-(2-((tertbutyldimethylsilyl)oxy)ethyl)phenyl)amino)-5-(furan-2-yl)-2oxotetrahydrofuran-3-carboxylate (24t). The general procedure (Method B) was followed using 28j (0.211 g, 0.38 mmol) and DBU (1M solution in ethyl acetate) (0.423 mL, 0.42 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.2:1, by crude 1HNMR) (0.15 g, 80 %) which were separated by using flash column chromatography. 24s: Physical State: Pale yellow colored viscous oily liquid. Rf = 0.58 (20% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3): δ 7.48 (s, 1H), 7.04 (d, J = 8.1 Hz, 2H), 6.58 (d, J = 8.2 Hz, 2H), 6.54 (d, J = 2.9 Hz, 1H), 6.41 (s, 1H), 5.73 (dd, J = 10.4, 6.4 Hz, 1H), 5.05 (hept, J = 7.3, 6.6 Hz, 1H), 4.96 (s, 1H), 3.74 (t, J = 7.1 Hz, 2H), 3.28 (dd, J = 13.2, 6.3 Hz, 1H), 3.03 – 2.95 (m, 1H), 2.72 (t, J = 7.0 Hz, 2H), 1.27 (d, J = 6.2 Hz, 3H), 1.07 (d, J = 6.2 Hz, 3H), 0.88 (s, 9H), −0.00 (s, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 171.3, 167.8, 149.1, 144.1, 142.1, 130.2, 129.9, 114.8, 111.0, 110.7, 72.9, 71.3, 66.9, 64.7, 38.6, 37.6, 25.9, 21.4, 21.2, 18.3, −5.3, −5.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H38NO6Si 488.2463; found 488.2464. HPLC Analysis: Chiralpak IB, 2% IP/hexanes, continuous flow at 0.4mL/min, 230 nm; tmajor = 19.4 min, tminor = 20.9 min, ee 90%, er 95: 5; [α]D20 = −5 (C = 1, CHCl3). 24t: Physical State: Pale yellow colored viscous oily liquid; Rf = 0.52 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.47 (s, 1H), 7.05 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 8.2 Hz, 2H), 6.53 (d, J =

2.7 Hz, 1H), 6.41 (s, 1H), 5.63 (t, J = 7.6 Hz, 1H), 5.05 (hept, J = 6.3 Hz, 1H), 4.65 (s, 1H), 3.74 (t, J = 7.0 Hz, 2H), 3.39 (dd, J = 13.8, 7.4 Hz, 1H), 2.93 (dd, J = 13.8, 8.0 Hz, 1H), 2.73 (t, J = 6.9 Hz, 2H), 1.23 (d, J = 6.2 Hz, 3H), 1.11 (d, J = 6.2 Hz, 3H), 0.87 (s, 9H), −0.01 (s, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 172.0, 168.2, 149.8, 143.6, 141.8, 131.3, 129.9, 116.3, 110.6, 110.0, 72.6, 71.0, 66.4, 64.6, 38.6, 35.3, 25.9. 21.4, 21.2, 18.3, −5.41. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H38NO6Si 488.2463; found 488.2465. HPLC Analysis: Chiralpak ID, 15% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 18.5 min, tminor = 17.2 min, ee 90%, er 5:95; [α]D20 = −4.3 (C = 1, CHCl3). Isopropyl-(3S,5R)-3-(benzo[d][1,3]dioxol-5-ylamino)-2-oxo5-(thiophen-2-yl)tetrahydrofuran-3-carboxylate (24u) and Isopropyl-(3R,5R)-3-(benzo[d][1,3]dioxol-5-ylamino)-2-oxo-5(thiophen-2-yl)tetrahydrofuran-3-carboxylate (24v). The general procedure (Method B) was followed using 28k (0.288 g, 0.64 mmol) and DBU (1M solution in ethyl acetate) (0.704 mL, 0.70 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.5:1, by crude 1 HNMR) (0.237 g, 95 %) which were separated by using flash column chromatography. 24u: Physical State: Yellow colored viscous oily liquid; Rf = 0.33 (20% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3): δ 7.38 (d, J = 4.5 Hz, 1H), 7.17 (d, J = 3.2 Hz, 1H), 7.04 – 7.00 (m, 1H), 6.64 (d, J = 8.3 Hz, 1H), 6.30 (d, J = 2.2 Hz, 1H), 6.07 (dd, J = 8.3, 2.2 Hz, 1H), 5.93 (dd, J = 10.3, 6.1 Hz, 1H), 5.86 (s, 2H), 5.05 (hept, J = 6.2 Hz, 1H), 4.81 (s, 1H), 3.45 (dd, J = 13.1, 6.1 Hz, 1H), 2.74 (dd, J = 13.1, 10.5 Hz, 1H), 1.26 (d, J = 6.3 Hz, 3H), 1.09 (d, J = 6.2 Hz, 3H). 13 C{1H} NMR (151 MHz, CDCl3): δ 171.2, 167.5, 148.3, 141.4, 139.9, 139.0, 127.2, 127.1, 127.0, 108.3, 107.3, 100.8, 98.7, 75.8, 71.2, 67.8, 42.1, 21.4, 21.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H20NO6S 390.1006; found 390.1011. HPLC Analysis: Chiralpak IC, 25% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 21.1 min, tminor = 24.9 min, ee 92%, er 96:4; [α]D20 = −8.7 (C = 1, CHCl3). 24v: Physical State: Beige colored waxy solid; Rf = 0.25 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.37 (d, J = 4.9 Hz, 1H), 7.14 (d, J = 3.2 Hz, 1H), 7.03 – 7.00 (m, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 6.17 (dd, J = 8.2, 2.0 Hz, 1H), 5.89 (s, 2H), 5.80 (t, J = 7.6 Hz, 1H), 5.06 (hept, J = 6.2 Hz, 1H), 4.51 (s, 1H), 3.16 (dd, J = 13.9, 7.6 Hz, 1H), 3.05 (dd, J = 13.9, 7.6 Hz, 1H), 1.21 (d, J = 6.3 Hz, 3H), 1.15 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 171.8, 168.2, 148.3, 142.4, 140.8, 138.2, 126.9, 126.6, 126.4, 110.0, 108.3, 100.9, 100.7, 75.3, 71.1, 67.4, 39.3, 21.3, 21.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H20NO6S 390.1006; found 390.1008. HPLC Analysis: Chiralpak IB, 40% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; tmajor = 16.2 min, tminor = 19.1 min, ee 90%, er 95: 5; [α]D20 = −4.7 (C = 1, CHCl3). Isopropyl-(3S,4S,5R)-3-((4-methoxyphenyl)amino)-4-methyl2-oxo-5-phenyltetrahydrofuran-3-carboxylate (24w). The general procedure (Method A) was followed using 28n (0.18 g, 0.40 mmol) and TsOH•H2O (0.015 g, 0.08 mmol) as starting materials to afford the fully substituted γ-lactone as a single diastereomer 24w (0.13 g, 84%) which was purified by using flash column chromatography. Physical State: Beige colored viscous gummy substance. Rf = 0.51 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ7.31-7.43 (m, phenyl, 5H), 6.75 (m, AA’ part of AA’BB’ pattern, 2H, H-3’/H-5’), 6.57 (m, BB’ part of AA’BB’ pattern, 2H, H-2’/H-6’), 6.00 (d, J = 5.2 Hz, 1H, benzylic H), 4.93 (hept, J = 6.3 Hz, 1H, isopropyl CH), 4.71 (s, broad, NH), 3.78 (qd, J = 7.5, 5.2 Hz, 1H, ring H-C-CH3), 3.73



(s, 3H, methoxy), 1.19 (d, J = 6.3 Hz, 3H, isopropyl CH3), 0.82 (d, J = 6.2 Hz, 3H, other isopropyl CH3), 0.61 (d, J = 7.5 Hz, ring H-C-CH3). 13C{1H} NMR (151 MHz, CDCl3): δ 172.1, 167.1, 153.3, 138.6, 135.5, 128.5, 128.0, 125.2, 115.1, 114.7, 82.5, 71.5, 70.7, 55.5, 43.8, 21.4, 21.0, 9.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26NO5 384.1805; found 384.1808. The stereochemistry of the methyl group on the 5-membered ring was established with two NOE experiments with very short mixing times [0.1 s (p. S281) and 0.2 s (p. S282)]. This methyl group is clearly cis to the adjacent phenyl substituent. With a mixing time of just 0.1 s: •

The benzylic proton (δ6.00) has a significantly stronger NOE with the adjacent methine proton (δ3.78) than with the adjacent methyl group (δ0.61). • NH exhibits NOE with the adjacent methyl group (δ0.61) but not with the adjacent methine proton (δ3.78). • The protons on the monosubstituted phenyl ring (downfield of δ7.3) exhibit a much stronger NOE with the adjacent methyl group (δ0.61) than with the adjacent methine proton (δ3.78). In addition, the very shielded nature of the methyl protons of ring H-C-CH3 is consistent with these observations. With the monosubstituted phenyl ring and the ring methyl group cis to each other, the ring methyl group is nearly above the monosubstituted phenyl ring, which would be expected to result in a shielding effect. NOE is also detected between the methoxy protons (δ3.73) and the aromatic protons at δ6.75 and between the NH proton (δ4.71) and the aromatic protons at δ6.57. These observations enabled secure assignments of the aromatic protons at δ6.75 (H3’/H-5’) and at δ6.57 (H-2’/H-6’). The same observations were made with a mixing time of 0.2 s. Pictorial representation of NOE correlation in 24w:

Isopropyl-(3R,3aR,7aR)-3-((4-methoxyphenyl)amino)-2oxooctahydrobenzofuran-3-carboxylate (24x). The general procedure (Method A) was followed using 28o (0.149 g, 0.36 mmol) and TsOH•H2O (0.014 g, 0.07 mmol) as starting materials to afford the fully substituted γ-lactone as a single diastereomer 24x (0.12 g, 95%) which was purified by using flash column chromatography. Physical State: Pale brown colored viscous oily liquid. Rf = 0.50 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ6.74 (m, AA’ part of AA’BB’ pattern, 2H, H-3’/H-5’), 6.57 (m, BB’ part of AA’BB’ pattern, 2H, H-2’/H6’), 4.88 (m, 1H, bridgehead methine next to oxygen ≡ H-1), 4.87 (hept, J = 6.3 Hz, 1H, isopropyl methine), 4.57 (s, broad, NH), 3.73 (s, 3H, methoxy), 3.29-3.23 (m, 1H, bridgehead methine next to quaternary carbon ≡ H-2), 2.31-2.25 (m, 1H), 1.761.56 (overlapping m, 4H), 1.41-1.18 (overlapping m, 3H), 1.15 (d, J = 6.3 Hz, 3H, isopropyl methine), 0.80 (d, J = 6.2 Hz, 3H, other isopropyl methine). 13C{1H} NMR (126 MHz, CDCl3): δ173.0 (carbonyl), 166.9 (carbonyl), 153.2 (C-4’), 139.0 (C-1’),

Page 26 of 42

115.2 (C-2’/C-6’), 114.8 (C-3’/C-5’), 77.8 (C-1), 72.2 (quaternary aliphatic carbon), 70.4 (isopropyl CH), 55.7 (methoxy), 43.0 (C-2), 27.3 (C-6), 23.0 (C-4), 22.0 (C-3), 21.4 [isopropyl methyl (correlating with methyl 1H signal at δ1.15 in HSQC spectrum)], 21.1 [other isopropyl methyl (correlating with methyl 1H signal at δ0.80 in HSQC spectrum)], 19.4 (C-5). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H26NO5 348.1805; found 348.1804. As with 24y, the key issue for 24x was determining the stereochemistry of the fusion of the 6- and 5-membered rings, i.e., the relative orientation of H-1 and H-2. The severe overlap of the heptet from the isopropyl methine proton and the multiplet from the bridgehead methine proton next to oxygen (H-1) complicates the analysis. However, detailed chemical shift assignments could be made through a combination of 1H (p. S283), 13C (p. S284), COSY (p. S286), NOE (p. S288-S291), and HSQC (p. S287) experiments. Indeed, the pair of diastereotopic protons associated with each methylene carbon could be assigned as follows: C-3 CH2 (next to bridgehead methine next to quaternary carbon): δ1.65 and δ1.27 with δ22.0, C-4 CH2: δ1.73 and δ1.27 with δ23.0, C-5 CH2: δ1.59 and δ1.34 with δ19.4, C-6 CH2 (next to bridgehead methine next to oxygen): δ2.28 and δ1.66 with δ27.3. NOE experiments with various mixing times (0.15, 0.30, 0.50 s) were used to establish the relative orientation of H-1 and H-2. With the shortest mixing time, prominent cross peaks were detected between the multiplet centered at δ4.88 (H-1) and the multiplets centered at δ3.26 (H-2) and δ2.28 (one of the H-6 protons). These multiplets can be differentiated from the cross peaks between the heptet centered at δ4.87 (isopropyl CH) and the doublets centered at δ1.15 and δ0.80 (p. S289). As with 24y, the prominent cross peak between H-1 and H-2 with a very short mixing time indicated cis ring fusion. NOE is also detected between the aromatic protons at δ6.57 and each of H-2 and NH and between the methoxy protons (δ3.73) and the aromatic protons at δ6.74. These observations enabled secure assignments of the aromatic protons at δ6.57 (H-2’/H-6’) and at δ6.74 (H-3’/H-5’). NOE is not detected between H-2’/H-6’ and the more remote H-1, even with a mixing time of 0.50 s. In general, lengthening the mixing time increased the intensity of various cross peaks and simply reinforced the analysis. The NOE experiments also exhibited a cross peak at δ4.57 / δ1.27 indicating spatial proximity between the amine proton at δ4.57 and methylene proton at δ1.27. This is consistent with interaction between the amine proton and one of the H-3 protons; the cross peak becomes noticeably stronger as the mixing time is lengthened from 0.15 s to 0.30 s to 0.50 s and is consistent with a cis relationship of the 3-CH2 group and the -NHC6H4-OCH3 group. The absence of any cross peak between the amine proton and ring junction H-2 at the three mixing times is consistent with a trans relationship of ring junction H-2 and the -NH-C6H4-OCH3 group. Pictorial representation of NOE correlation in 24x:


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Isopropyl-(3R,3aR,9bS)-3-(benzo[d][1,3]dioxol-5-ylamino)-2oxo-2,3,3a,4,5,9b-hexahydronaphtho[1,2-b]furan-3-carboxylate (24y). The general procedure (Method A) was followed using 28p (0.134 g, 0.28 mmol) and TsOH•H2O (0.011 g, 0.05 mmol) as starting materials to afford the fully substituted γ-lactone as a single diastereomer 24y (0.099 g, 85%) which was purified by using flash column chromatography. Physical State: White colored foam. Rf = 0.51 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ7.46 (m, 1H, H-5), 7.26-7.33 (m, 2H, H7 and H-6), 7.18 (m, 1H, H-8), 6.65 (d, J = 8.3 Hz, 1H, H-5’), 6.28 (d, J = 2.4 Hz, 1H, H-2’), 6.05 (dd, J = 8.3, 2.4 Hz, 1H, H6’), 5.88 (d, J = 1.4 Hz, 1H, one H of -OCH2O-), 5.87 (d, J = 1.4 Hz, 1H, other H of -OCH2O-), 5.78 (d, J = 5.0 Hz, 1H, H4), 4.98 (hept, J = 6.3 Hz, 1H, isopropyl methine), 4.70 (s, broad, NH), 3.60 (ddd, J = 13.5, 5.0, 4.7 Hz, 1H, H-3), 2.722.86 (m, 2H, H-1ax, H-1eq), 1.86 (dddd, J ≈ 13.6, 4.7, 3.6, 3.6 Hz, 1H, H-2ax or H-2eq), 1.51 (dddd, J = 13.6, 13.6, 13.5, 4.7 Hz, 1H, H-2eq or H-2ax), 1.21 (d, J = 6.3 Hz, 3H, isopropyl methyl), 0.90 (d, J = 6.2 Hz, 3H, other isopropyl methyl). 13 C{1H} NMR (151 MHz, CDCl3): δ 171.3, 167.2, 148.4, 140.9, 140.4, 137.9, 131.1, 130.0, 129.2, 128.6, 126.6, 108.5, 105.1, 100.7, 96.9, 78.0, 71.3, 70.7, 43.6, 27.8, 21.4, 21.1, 19.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H24NO6 410.1598; found 410.1599. The key issue was determining the stereochemistry of the fusion of the 6- and 5-membered rings, i.e., the relative orientation of H-4 and H-3. H-4 gave a distinctive, deshielded doublet at δ5.78 (p. S292). Detailed 1H chemical shift assignments could be made through COSY (p. S295) and NOE (p. S296-S300) experiments. In particular, COSY confirmed that only the multiplet at δ3.60 correlated with H-4 and thus resulted from H-3. COSY indicated that H-3 also correlated with the protons at δ1.86 and δ1.51, thus confirming their assignments as H-2. NOE experiments with various mixing times (0.15, 0.30, 0.50 s) were used to establish the relative orientation of H-4 and H3. With the shortest mixing time, a cross peak was not detected between the signals at δ5.78 (H-4) and the H-2 proton at δ1.51; a weak cross peak was detected between H-4 and the other H-2 proton (at δ1.86), which established their closer spatial proximity. A significantly stronger cross peak was detected between the signals at δ5.78 (H-4) and δ3.60 (H-3), which strongly suggested a cis relationship and thus cis ring fusion. With this very short mixing time, the cross peak between H-4 and H-3 was stronger than (1) the cross peak between H-4 and the signal at δ7.46 (thus identified as H-5), (2) the cross peak between the other benzylic protons (H-1) and the signal at δ7.18 (thus identified as H-8), (3) the cross peaks between H-3 and the signals at δ6.28 and δ6.05 (consistent with their assignments as H-2’ and H-6’ on the other aromatic ring on the basis of the magnitude of their J values), and (4) the cross peaks between NH and H-2’ and H-6’. Thus, the relatively strong cross peak between H-4 and H-3 with a very short mixing time indicated cis ring fusion. Lengthening the mixing time increased the intensity of various cross peaks and simply reinforced the analysis. With mixing times of 0.30 and 0.50 s, very weak cross peaks were also observed between H-4 (δ5.78) and each of the isopropyl methyl groups (δ1.21 and δ0.90) and between the 2-CH2 protons (δ1.86 and δ1.51) and the amine NH (δ4.70). These cross peaks were also observed with mixing times of 0.70 and 1.00 s. The cross peaks clearly indicate a cis relationship between H-4 and the isopropoxycarbonyl group and a cis relationship between 2-CH2 and the -NH-C6H4-OCH3 group. Pictorial representation of NOE correlation in 24y:

General procedure for the synthesis of aziridine-2,2,3-triesters, Figure 12. To a solution of methyl bromoacetate (2.0 equiv) in anhydrous THF (0.2 M) in a flame-dried reaction vial under argon was added LiHMDS (1 M solution in THF) (2.1 equiv) dropwise over 3 minutes via syringe at −41 ˚C. After stirring for 45 min, a solution of diisopropyl iminomalonate 25 (1.0 equiv) in anhydrous THF (0.2M) was added dropwise via syringe. After stirring for another 2 h at −41 ˚C and confirming the completion of the reaction by thin layer chromatography, the reaction was quenched with saturated aqueous NH4Cl and warmed to room temperature. The reaction mixture was then diluted with brine (10 mL) and extracted with ethyl acetate thrice (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by automated flash column chromatography to afford the N-aryl aziridine. 2,2-diisopropyl-3-methyl-(R)-1-phenylaziridine-2,2,3-tricarboxylate (33a). The general procedure was followed using diisopropyl phenyl iminomalonate (0.3 g, 1.08 mmol), bromomethyl ester (0.206 mL, 2.16 mmol) and LiHMDS (1M solution in THF) (2.27 mL, 2.27 mmol) were used as starting materials to afford aziridine-2,2,3-triester as pale yellow colored viscous oily liquid (0.3 g, 79%). Compound was purified by flash chromatography (Rf = 0.45 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ7.22-7.26 (m, 2H, H-3/H-5), 7.02-7.06 (m, 1H, H-4), 6.95-6.98 (m, 2H, H-2/H-6), 5.22 (hept, J = 6.3 Hz, 1H, isopropyl CH), 4.86 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.81 (s, 4H, methoxy and aziridine ring methine), 1.34 (d, J = 6.3 Hz, 3H, one isopropyl CH3), 1.31 (d, J = 6.3 Hz, 3H, second isopropyl CH3), 1.13 (d, J = 6.3 Hz, 3H, third isopropyl CH3), 0.96 (d, J = 6.3 Hz, 3H, fourth isopropyl CH3). 13 C{1H} NMR (126 MHz, CDCl3): δ166.9 (carbonyl), 163.7 (carbonyl), 162.6 (carbonyl), 146.1 (sp2 C-N), 129.0 (C-2/C-6 or C-3/C-5), 124.1 (C-4), 119.5 (C-3/C-5 or C-2/C-6), 71.0 (isopropyl CH), 70.0 (other isopropyl CH), 53.1 (quaternary aliphatic), 52.8 (methoxy), 45.6 (aziridine ring CH), 21.6 (overlapping signals for two isopropyl CH3), 21.5 (third isopropyl CH3), 21.1 (fourth isopropyl CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H24NO6 350.1598; Found 350.1598. The singlets for the methoxy protons and the aziridine ring proton completely overlap and give a sharp signal with a half-height linewidth of 0.63 Hz. Additional support for this assignment comes from 13C satellites exhibiting 1JCH values that are reasonable for these functional groups; the identification of these satellites is supported by the expected very small, negative, one-bond 13C vs. 12C isotope effect on the 1H chemical shift [1ΔH(13/12C)] that is also observed for each type of proton. One pair of satellites exhibits 1JCH = 148.0 Hz (consistent with methoxy) with 1ΔH(13/12C) = −0.0025 ppm. A weaker pair of satellites exhibits 1JCH = 176.6 Hz (consistent with aziridine ring H) with 1ΔH(13/12C) = −0.0020 ppm.



Comparing the standard and DEPT-135 13C spectra provided a secure assignment of the quaternary aromatic carbon (δ146.1) and of the quaternary aliphatic carbon (δ 53.1) in the aziridine ring (through the absence of these signals in the DEPT-135 13C spectrum). Comparing the DEPT-135 and DEPT-90 13C spectra provided a secure assignment of the methoxy carbon (δ 52.8) and aziridine ring methine carbon (δ45.6), as the methoxy carbon signal appeared in only the DEPT-135 13 C spectrum while the aziridine ring methine carbon signal appeared in both spectra). In principle, two isomers are possible: the phenyl group can be cis or trans to the aziridine ring methine proton. If both isomers are present and inversion about the nitrogen is very fast, just one set of signals (representing the average environment) will be present, as is observed with N-(p-methoxyphenyl)-2,2-dimethylaziridine above the coalescence temperature Tc of −26 ˚C.33 In general, conjugation of the nitrogen lone pair with an aromatic ring system is known to decrease the barrier to inversion about nitrogen.33-35 The electron-donating nature of the p-methoxy substituent (present in 33b) raises the barrier to inversion relative to an unsubstituted phenyl group (as is present in 33a); Tc = −49 ˚C for N-phenyl-2,2-dimethylaziridine.33 The single pair of 1H and 13C spectra of 33a does not indicate whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer of 1 formed when the enolate reacted with the diisopropyl iminomalonate. However, one can reasonably conclude that slow inversion about the nitrogen is not occurring with a mixture of cis and trans isomers of 1, as only one set of 13C signals and only one set of 1H signals are observed. (This aspect will be further considered in the discussion of 33h.) 2,2-diisopropyl-3-methyl-(R)-1-(4-methoxyphenyl)aziridine2,2,3-tricarboxylate (33b). The general procedure was followed using diisopropyl p-methoxyphenyl iminomalonate (1 g, 3.25 mmol), bromomethyl ester (0.618 mL, 6.50 mmol) and LiHMDS (1M solution in THF) (6.8 mL, 6.8 mmol) were used as starting materials to afford aziridine-2,2,3-triester as brown colored viscous oily liquid (0.758 g, 62%). Compound was purified by flash chromatography (Rf = 0.19 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ6.90 (m, AA’ part of AA’BB’ pattern, 2H), 6.77 (m, BB’ part of AA’BB’ pattern, 2H), 5.21 (hept, J = 6.3 Hz, 1H, isopropyl CH), 4.87 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.80 (s, 3H, methoxy), 3.78 (s, 1H, aziridine ring CH), 3.75 (s, 3H, methoxy), 1.34 (d, J = 6.3 Hz, 3H, one isopropyl CH3), 1.30 (d, J = 6.3 Hz, 3H, second isopropyl CH3), 1.14 (d, J = 6.3 Hz, 3H, third isopropyl CH3), 1.02 (d, J = 6.3 Hz, 3H, fourth isopropyl CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 167.0 (carbonyl), 163.8 (carbonyl), 162.6 (carbonyl), 156.4 (sp2 C-O), 139.2 (sp2 C-N), 120.5 (C-2/C-6 or C-/C-5), 114.2 (C-3/C-5 or C-2/C-6), 70.9 (isopropyl CH), 69.9 (other isopropyl CH), 55.4 (methoxy), 53.4 (quaternary aliphatic), 52.8 (methoxy), 45.8 (aziridine ring CH), 21.64 (isopropyl CH3), 21.62 (second isopropyl CH3), 21.5 (third isopropyl CH3), 21.2 (fourth isopropyl CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H26NO7 380.1704; Found 380.1706. Of the five N-aryl aziridines 33a-e, only 33b has two methoxy groups. The methoxy protons in 33a, 33c, 33d, and 33e give signals from δ3.795-3.811 (dilute solutions in CDCl3). Thus, it is reasonable to assign the singlet in 33b at δ3.80 to the ester and the singlet at δ3.75 to the ether. As with 33a, the combination of standard, DEPT-135, and DEPT-90 13C experiments provided a secure assignment of the quaternary aliphatic carbon (δ53.4) in the aziridine ring, the

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aziridine ring methine carbon (δ45.8), and the methoxy carbons (δ55.4 and δ52.8). The methoxy carbon signals can reasonably be assigned to the ether (δ55.4) and ester (δ52.8) functional groups in light of the signal for the ester in 33a, 33c, 33d, and 33e appearing at δ52.8 or δ52.9. The single pair of 1H and 13C spectra of 33b does not indicate whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer of 33b formed when the enolate reacted with the diisopropyl iminomalonate. However, as with 33a, one can reasonably conclude that slow inversion about the nitrogen is not occurring with a mixture of cis and trans isomers of 33b, as only one set of 13C signals and only one set of 1H signals are observed. 2,2-diisopropyl-3-methyl-(R)-1-(benzo[d][1,3]dioxol-5yl)aziridine-2,2,3-tricarboxylate (33c). The general procedure was followed using diisopropyl p-methoxyphenyl iminomalonate (0.45 g, 1.40 mmol), bromomethyl ester (0.266 mL, 2.80 mmol) and LiHMDS (1M solution in THF) (2.9 mL, 2.94 mmol) were used as starting materials to afford aziridine-2,2,3triester as brown colored viscous oily liquid (0.346 g, 63%). Compound was purified by flash chromatography (Rf = 0.23 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ6.66 (dd, 3 J = 8.3 Hz, 5J ~ 0.3 Hz, 1H, H-5), 6.52 (dd, 4J = 2.3 Hz, 5J ~ 0.3 Hz, 1H, H-2), 6.41 (dd, 3J = 8.3 Hz, 4J = 2.3 Hz, 1H, H-6), 5.91 (AB quartet whose protons have virtually identical chemical shifts, J ~ 1.4 Hz, -OCH2O-), 5.20 (hept, J = 6.3 Hz, 1H, isopropyl CH), 4.93 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.79 (s, 3H, methoxy), 3.75 (s, 1H, aziridine ring CH), 1.33 (d, J = 6.3 Hz, 3H, one isopropyl CH3), 1.30 (d, J = 6.3 Hz, 3H, second isopropyl CH3), 1.17 (d, J = 6.2 Hz, 3H, third isopropyl CH3), 1.08 (d, J = 6.3 Hz, 3H, fourth isopropyl CH3). 13C{1H} NMR (126 MHz, CDCl3): δ166.8 (methoxycarbonyl), 163.7 (isopropoxycarbonyl), 162.5 (other isopropoxycarbonyl), 148.0 (C-3 or C-4), 144.3 (C-4 or C-3), 140.8 (C-1), 111.8 (C-6), 108.1 (C-5), 101.5 (C-2), 101.3 (-OCH2O-), 71.0 (isopropyl CH, correlating with methine 1H signal at δ4.93 in HSQC spectrum), 70.0 (other isopropyl CH, correlating with methine 1H signal at δ5.20 in HSQC spectrum), 53.4 (quaternary aliphatic), 52.8 (methoxy), 46.0 (aziridine ring CH), 21.65 (isopropyl CH3, correlating with methyl 1H signal at δ1.17 in HSQC spectrum), 21.61 (second isopropyl CH3, correlating with methyl 1H signal at δ1.30 in HSQC spectrum), 21.5 (third isopropyl CH3, correlating with methyl 1H signal at δ1.33 in HSQC spectrum), 21.3 (fourth isopropyl CH3, correlating with methyl 1H signal at δ1.08 in HSQC spectrum). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H24NO8 394.1496; Found 394.1489. As with 33a, the combination of standard, DEPT-135, and DEPT-90 13C experiments provided a secure assignment of the quaternary aliphatic carbon (δ53.4) in the aziridine ring, the methoxy carbon (δ52.8), and the aziridine ring methine carbon (δ46.0). These experiments also provided a secure assignment of the -OCH2O- carbon (δ101.3), which has a chemical shift very similar to that of one of the aromatic CH carbons (δ101.5). In light of the unambiguous assignments for H-2, H5, and H-6 in the 1D 1H spectrum, the 1H-13C HSQC spectrum immediately provided the C-2, C-5, and C-6 assignments. It also enabled pairwise 1H/13C assignments for each of the two isopropyl CH groups and for each of the four isopropyl CH3 groups (pages S314-S319). The 1H-13C HMBC spectrum (page S310) unambiguously differentiated the two quaternary aromatic carbons bonded to oxygen from the quaternary aromatic carbon bonded to nitrogen. Only the two more deshielded quaternary aromatic carbons (δ148.0 and δ144.3) correlate with the


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-OCH2O- protons at δ5.91, while only the most shielded quaternary aromatic carbon (δ140.8) correlates with the aziridine ring methine proton at δ3.75 (a 3JCH correlation in each case; page S311). In addition, the HMBC experiment indicated that: • the methoxy 1H signal at δ3.79 correlated with the carbonyl signal at δ166.8 (but not with either of the other carbonyl signals), which clearly established that the signal at δ166.8 resulted from the methoxycarbonyl group (page S311). • the more deshielded isopropyl methine 1H signal at δ5.20 correlated with the carbonyl signal at δ163.7 (but not with either of the other carbonyl signals) and that the more shielded isopropyl methine 1H signal at δ4.93 correlated with the carbonyl signal at δ162.5 (but not with either of the other carbonyl signals) (page S311). Each of these seven-contour cross peaks displays a very noticeable tilt resulting from the six 3 JHH couplings experienced by the methine proton.36 Acquiring the spectrum under conditions of high digital resolution in the 13C dimension (0.074 ppm) enables the individual contours to be readily observed. The separation between contours in the 13C dimension = 3JHH; the separation between contours in the 1H dimension = 3JCH. Tilted correlations are also observed for the correlations involving the isopropyl methyl carbons (page S312). Similarly, the relatively large 3 JH-5,H-6 coupling enables tilted correlations to be observed for correlations involving H-5 and H-6. • the two more deshielded isopropyl methyl doublets at δ1.33 and δ1.30 correlated with the more shielded isopropyl methine carbon at δ70.0 (page S381) and that the two more shielded isopropyl methyl doublets at δ1.17 and δ1.08 correlated with the more deshielded isopropyl methine carbon at δ71.0 (page S313) Tilted correlations are again observed, exhibiting 3JHH in the 13 C dimension and 2JCH in the 1H dimension. The single pair of 1H and 13C spectra of 33c does not indicate whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer of 33c formed when the enolate reacted with the diisopropyl iminomalonate. However, as with 33a and 33b, one can reasonably conclude that slow inversion about the nitrogen is not occurring with a mixture of cis and trans isomers of 33c, as only one set of 13C signals and only one set of 1H signals are observed. 2,2-diisopropyl-3-methyl-(R)-1-(4-bromophenyl)aziridine2,2,3-tricarboxylate (33d). The general procedure was followed using diisopropyl p-bromophenyl iminomalonate (0.36 g, 1.01 mmol), bromomethyl ester (0.192 mL, 2.02 mmol) and LiHMDS (1M solution in THF) (2.12 mL, 2.12 mmol) were used as starting materials to afford aziridine-2,2,3-triester as yellow colored viscous oily liquid (0.311 g, 72%). Compound was purified by flash chromatography (Rf = 0.32 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ7.36 (m, AA’ part of AA’BB’ pattern, 2H), 6.85 (m, BB’ part of AA’BB’ pattern, 2H), 5.21 (hept, J = 6.3 Hz, 1H, isopropyl CH), 4.90 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.81 (s, 3H, methoxy), 3.75 (s, 1H, aziridine ring CH), 1.34 (d, J = 6.3 Hz, 3H, one isopropyl CH3), 1.30 (d, J = 6.3 Hz, 3H, second isopropyl CH3),

1.16 (d, J = 6.3 Hz, 3H, third isopropyl CH3), 1.04 (d, J = 6.3 Hz, 3H, fourth isopropyl CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 166.6 (carbonyl), 163.4 (carbonyl), 162.3 (carbonyl), 145.3 (sp2 C-N), 132.0 (C-2/C-6 or C-3/C-5), 121.2 (C-3/C-5 or C-2/C-6), 116.9 (sp2 C-Br), 71.3 (isopropyl CH), 70.2 (other isopropyl CH), 53.0 (quaternary aliphatic), 52.9 (methoxy), 45.7 (aziridine ring CH), 21.7 (isopropyl CH3), 21.6 (second isopropyl CH3), 21.5 (third isopropyl CH3), 21.2 (fourth isopropyl CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H23BrNO6 428.0703; Found 428.0705. As with 33a and 33c the combination of standard, DEPT-135, and DEPT-90 13C experiments provided a secure assignment of the quaternary aliphatic carbon (δ53.0) in the aziridine ring, the methoxy carbon (δ52.9), and the aziridine ring methine carbon (δ45.7). The single pair of 1H and 13C spectra of 33d does not indicate whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer of 33d formed when the enolate reacted with the diisopropyl iminomalonate. However, as with 33a-c, one can reasonably conclude that slow inversion about the nitrogen is not occurring with a mixture of cis and trans isomers of 33d, as only one set of 13C signals and only one set of 1H signals are observed. 2,2-diisopropyl-3-methyl-(R)-1-(3-chlorophenyl)aziridine2,2,3-tricarboxylate (33e). The general procedure was followed using diisopropyl m-chlorophenyl iminomalonate (0.32 g, 1.02 mmol), bromomethyl ester (0.195 mL, 2.05 mmol) and LiHMDS (1M solution in THF) (2.1 mL, 2.15 mmol) were used as starting materials to afford aziridine-2,2,3-triester as pale yellow colored viscous oily liquid (0.297 g, 75%). Compound was purified by flash chromatography (Rf = 0.36 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ7.18 (ddd, 3JH-5,H-4 = 8.0 Hz, 3JH-5,H-6 = 8.0 Hz, 5JH-5,H-2 ~ 0.3 Hz, 1H, H-5), 7.03 (ddd, 3JH4 4 4,H-5 = 8.0 Hz, JH-4,H-2 = 2.0 Hz, JH-4,H-6 ~ 0.95 Hz, 1H, H-4), 4 4 6.97 (ddd, JH-2,H-4 = 2.0 Hz, JH-2,H-6 = 2.0 Hz, 5JH-2,H-5 ~ 0.3 Hz, 1H, H-2), 6.85 (ddd, 3JH-6,H-5 = 8.1 Hz, 4JH-6,H-2 = 2.2 Hz, 4JH-6,H4 ~ 0.93 Hz, 1H, H-6), 5.21 (hept, J = 6.3 Hz, 1H, isopropyl CH), 4.92 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.81 (s, 3H, methoxy), 3.78 (s, 1H, aziridine ring CH), 1.34 (d, J = 6.3 Hz, 3H, one isopropyl CH3), 1.31 (d, J = 6.3 Hz, 3H, second isopropyl CH3), 1.17 (d, J = 6.3 Hz, 3H, third isopropyl CH3), 1.05 (d, J = 6.3 Hz, 3H, fourth isopropyl CH3). 13C{1H} NMR (126 MHz, CDCl3): δ166.5 (carbonyl), 163.4 (carbonyl), 162.3 (carbonyl), 147.5 (sp2 C-N), 134.6 (sp2 C-Cl), 130.1 (C-5), 124.3 (C-4), 119.8 (C-2), 117.8 (C-6), 71.4 (isopropyl CH), 70.2 (other isopropyl CH), 53.0 (quaternary aliphatic), 52.9 (methoxy), 45.7 (aziridine ring CH), 21.64 (isopropyl CH3), 21.59 (second isopropyl CH3), 21.49 (third isopropyl CH3), 21.18 (fourth isopropyl CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H23ClNO6 384.1208; Found 384.1211. While H-2 and H-5 in the aromatic ring have distinctive coupling patterns, H-4 and H-6 have very similar coupling patterns and cannot be confidently differentiated just on the basis of chemical shift. However, literature 13C chemical shift data on 3-chloroaniline,37 3-chloro-N,N-dimethylaniline,38 and a more elaborate 3-chloro-N,N-dialkylaniline39 clearly show that C-6 is considerably more shielded than C-4 (with C-6 ranging from δ113.9-110.4 vs C-4 ranging from δ119.5-115.9), that C-2 is essentially in between (ranging from δ115.8-112.0), and that C5 is much more deshielded (ranging from δ130.1-129.9). 1H chemical shift data were also reported for 3-chloroaniline11 and the elaborate derivative,39 and in both cases, H-6 is more



shielded than H-4, and H-5 is significantly more deshielded than either. An HSQC experiment on 33e gave the following correlations for the four aromatic CH groups: δC130.1 / δH7.18, δC124.3 / δH7.03, δC119.8 / δH6.97, and δC117.8 / δH6.85 (page S326). The δC130.1 / δH7.18 correlation clearly results from C5/H-5. The δC119.8 / δH6.97 correlation clearly results from C2/H-2. In light of the literature chemical shift data,11-13 the δC124.3 / δH7.03 correlation can reasonably be assigned to C4/H-4, and the δC117.8 / δH6.85 correlation (the most shielded aromatic 13C and 1H nuclei) can reasonably be assigned to C6/H-6. Highly expanded plots of the correlations for the two isopropyl CH groups, the methoxy and aziridine CH groups, and the four isopropyl CH3 groups are shown on pages S327S329. As with 33a and 33c, the combination of standard, DEPT-135, and DEPT-90 13C experiments provided a secure assignment of the quaternary aliphatic carbon (δ53.0) in the aziridine ring, the methoxy carbon (δ52.9), and the aziridine ring methine carbon (δ45.7). In the standard 13C spectrum, two signals of different intensity appear for C-Cl (page S324), reflecting the 1Δ13C(37/35Cl) isotope effect (4 ppb shielding upon replacement of 35Cl with 37Cl).40,41 The single pair of 1H and 13C spectra of 33e does not indicate whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer of 33e formed when the enolate reacted with the diisopropyl iminomalonate. However, as with 33a-c, one can reasonably conclude that slow inversion about the nitrogen is not occurring with a mixture of cis and trans isomers of 33e, as only one set of 13C signals and only one set of 1H signals are observed. 2,2-diisopropyl-3-methyl-(R)-1-phenethylaziridine-2,2,3-tricarboxylate (33f). The general procedure was followed using diisopropyl Phenethyl iminomalonate (0.31 g, 1.01 mmol), bromomethyl ester (0.193 mL, 2.03 mmol) and LiHMDS (1M solution in THF) (2.13 mL, 2.13 mmol) were used as starting materials to afford aziridine-2,2,3-triester as pale yellow colored viscous oily liquid (0.194 g, 51%). Compound was purified by flash chromatography (Rf = 0.29 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ7.29-7.16 (m, phenyl, 5H), 5.12 (hept, J = 6.3 Hz, 1H, isopropyl CH), 5.11 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.70 (s, 3H, methoxy), 3.07 (s, 1H, aziridine ring CH), 3.06-2.99 (m, 3H, CH2), 2.87-2.77 (m, 1H, CH2), 1.29 (d, J = 6.3 Hz, 6H, overlapping doublets for two isopropyl CH3), 1.27 (d, J = 6.2 Hz, 3H, third isopropyl CH3), 1.22 (d, J = 6.3 Hz, 3H, fourth isopropyl CH3). 13C{1H} NMR (126 MHz, CDCl3): δ167.5 (carbonyl), 164.1 (carbonyl), 163.6 (carbonyl), 138.9 (C-1), 128.8 (C-2/C-6 or C-3/C-5), 128.4 (C-3/C5 or C-2/C-6), 126.4 (C-4), 71.0 (isopropyl CH), 69.5 (other isopropyl CH), 53.1 (N-CH2), 52.4 (methoxy), 51.8 (quaternary aliphatic), 47.8 (aziridine ring CH), 35.7 (phenyl C-CH2), 21.73 (isopropyl CH3), 21.55 (second isopropyl CH3), 21.54 (third isopropyl CH3), 21.49 (fourth isopropyl CH3). HRMS (ESITOF) m/z: [M+H]+ Calcd for C20H28NO6 378.1911; Found 378.1909. As with 33a and 33c-e, the combination of standard, DEPT-135, and DEPT-90 13C experiments provided a secure assignment of the quaternary aliphatic carbon (δ51.8) in the aziridine ring, the methoxy carbon (δ52.4), and the aziridine ring methine carbon (δ47.8). The presence of inverted signals at δ53.1 and δ35.7 in the DEPT-135 13C spectrum and their absence in the DEPT-90 13C spectrum enabled their identification

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as CH2 signals. Their large chemical shift difference allowed the N-CH2 and phenyl C-CH2 assignments to easily be made. Inversion about the nitrogen is known to be much slower, in general, in N-alkylaziridines than in N-arylaziridines. In contrast to the coalescence temperature Tc = −49 ˚C for N-phenyl-2,2-dimethylaziridine (15 vol % solution in CF2Cl2),42 Tc = +60 ˚C for N-isopropyl-2,2-dimethylaziridine (1M in CDCl3),43 and Tc = +76 ˚C for N-methyl-2,2-dimethylaziridine (1M in CDCl3).43 Solvent has a noticeable effect, as the Tc values for N-isopropyl-2,2-dimethylaziridine and N-methyl-2,2-dimethylaziridine are significantly lower (+38 ˚C and +48 ˚C, respectively) in 1M C6H12. The effect of substituents on the aziridine ring on the rate of inversion see ms to vary widely with the nature of the N-substituent. Relatively little change in Tc occurs with N-phenyl (Tc = −40 ˚C for N-phenylaziridine in CS2),44 but a large increase in Tc occurs with N-methyl (Tc = +108 ˚C for N-methylaziridine, 1M in C6H12). We are not aware of any studies with several much bulkier C-substituents such as are in aziridines 33a-h and therefore do not know their effect on Tc. Tc is the same within experimental error (+95 ˚C) for N-cyclohexylaziridine and N-(2-phenylethyl)aziridine.45 Since the latter compound has the same N-substituent as in 33f, it seems reasonable to conclude that inversion about the nitrogen in 33f is slow at ambient temperature and that a set of signals for each isomer would be observed if both isomers of 33f were present. However, the 1H and 13C spectra of 33f clearly exhibit signals for only one isomer. To confirm that only one isomer is present and undergoing slow inversion about the nitrogen, spectra would have to be obtained at much lower temperatures to determine if only one set of 1H signals and only one set of 13C signals continue to be observed. The N-alkyl substituent in 33f has a noticeable effect on the 1H chemical shifts of the aziridine ring methine proton and the C-substituents on the aziridine ring and on the 13C chemical shifts of the aziridine ring carbons and their substituents, as shown in Table S7 (see SI page No. S25). Not surprisingly, the effect is most noticeable for the nuclei closest to the aziridine N: the two carbons in the aziridine ring and especially for the aziridine ring proton. Even with the aziridine N-substituent apparently cis to one isopropoxycarbonyl group and trans to the other in 33f, the two isopropyl methine protons have nearly the same chemical shift. In contrast, the environments for the two isopropyl methine protons in N-arylaziridines 33a-e are noticeably different, as the isopropyl methine 1H chemical shifts differ by 0.27-0.36 ppm in 33a-e. Still, it does not seem possible to rigorously conclude from the single pair of 1H and 13C spectra for each of 33ae whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer formed when the enolate reacted with the diisopropyl iminomalonate. The N-alkyl substituent also has a striking effect on some of the 13 C linewidths. Four of the signals are much shorter because they are much broader: the most shielded carbonyl, the N-CH2, the aziridine ring methine carbon, and the aziridine ring quaternary carbon (Table S8) (see SI Page No. S26). Indeed, significant signal averaging is required to clearly detect these signals above the baseline noise in the standard, DEPT-135, and DEPT90 13C experiments. In 33f, the signal for the aziridine ring quaternary carbon is significantly sharper (ν1/2 = 1.09 Hz) than the signals for the other two N-C carbons (ν1/2= 4.6 and 6.5 Hz) but is still broader than


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every other signal except for the most shielded carbonyl (ν1/2 = 2.7 Hz). In contrast, in 33a-e: • the signal for the aziridine ring quaternary carbon is very sharp (ν1/2 = 0.34-0.38 Hz, three times narrower than the corresponding signal in 33f), • the signal for the quaternary aromatic carbon bonded to aziridine N is sharp (ν1/2 = 0.55-0.62 Hz, seven times narrower than the corresponding signal in 33f), • the signal for the aziridine ring methine carbon is almost as sharp (ν1/2 = 0.75-0.81 Hz, eight times narrower than the corresponding signal in 33f), and • the signal for the most shielded carbonyl carbon is very sharp (ν1/2 = 0.34-0.37 Hz, seven times narrower than the corresponding signal in 33f). Relaxation of the quadrupolar 14N appears to be significantly faster with the N-alkyl substituent in 33f than with any of the Naryl substituents in 33a-33e. 2,2-diisopropyl-3-methyl-(R)-1-(1-(tert-butoxycarbonyl)piperidin-4-yl)aziridine-2,2,3-tricarboxylate (33g). The general procedure was followed using diisopropyl-1-(tert-butoxycarbonyl)piperidin-4-yl iminomalonate (0.4 g, 1.04 mmol), bromomethyl ester (0.198 mL, 2.08 mmol) and LiHMDS (1M solution in THF) (2.18 mL, 2.18 mmol) were used as starting materials to afford aziridine-2,2,3-triester as pale yellow colored viscous oily liquid (0.183 g, 39%). Compound was purified by flash chromatography (Rf = 0.4 (30% EtOAc/hexanes). 1H (500 MHz, CDCl3): δ5.12 (hept, J = 6.3 Hz, 1H, isopropyl CH), 5.10 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.93 (br s, 2H, a CH2 proton on each N-CH2), 3.72 (s, 3H, methoxy), 3.22 (s, 1H, aziridine ring CH), 3.00 (m, 2H, a CH2 proton on each NCH2), 2.61 (m, 1H, N-CH in 6-membered ring), 1.75-1.50 (m, 4H, -CH2-CH-CH2-), 1.45 (s, 9H, t-butoxy), 1.29 (d, J = 6.3 Hz, 3H, isopropyl CH3), 1.28 (d, J = 6.3 Hz, 3H, second isopropyl CH3), 1.26 (d, J = 6.3 Hz, 3H, third isopropyl CH3), 1.22 (d, J = 6.3 Hz, 3H, fourth isopropyl CH3). 13C{1H} NMR (151 MHz, CDCl3): δ 167.3 (carbonyl), 163.8 (carbonyl), 163.6 (carbonyl), 154.6 (N-Boc carbonyl), 79.2 (t-butoxy quaternary), 70.7 (isopropyl CH), 69.2 (other isopropyl CH), 55.9 (N-CH in 6-membered ring), 52.3 (methoxy), 51.8 (aziridine ring quaternary), 46.4 (aziridine ring CH), 41.6, 41.3, 40.7, and 40.5 (N-CH2), 30.8 (CH-CH2), 28.2 (t-butoxy methyl), 21.37 (isopropyl CH3), 21.34 (second isopropyl CH3), 21.32 (third isopropyl CH3), 21.30 (fourth isopropyl CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H37N2O8 457.2544; Found 457.2548. As with 33a and 33c-f, the combination of standard, DEPT-135, and DEPT-90 13C experiments provided a secure assignment of the t-butoxy quaternary carbon (δ79.2) and the aziridine ring quaternary carbon (δ51.8), the methoxy carbon (δ52.3), and the 6-membered ring methine carbon (δ55.9) and the aziridine ring methine carbon (δ46.4). The presence of inverted signals at δ41.6, 41.3, 40.7, 40.5, and 30.8 in the DEPT135 13C spectrum and their absence in the DEPT-90 13C spectrum enabled their identification as CH2 signals. The large chemical shift differences for signals with the same multiplicity allowed assignments for the pair of quaternary aliphatic carbons, the pair of ring methine carbons, and the pair of methylene carbons to easily be made. The severe broadening of the CH2 signals is obvious. We believe that the four broad signals near 41 ppm result from a combination of two factors: (1) inversion at nitrogen in the 6-

membered ring occurring on a time scale comparable to the reciprocal of the frequency difference (in Hz) between the chemical shift of a given N-CH2 in the conformer with t-Boc equatorial and the chemical shift of that N-CH2 in the conformer with t-Boc axial (2) the presence of two diastereotopic N-CH2 carbons because of the chiral center in the aziridine ring. For the two diastereotopic CH-CH2 carbons, just one broad signal is observed at δ30.8. The much higher sensitivity of the 600 MHz spectrometer’s cryoprobe optimized for 13C detection greatly facilitated detecting these extremely broad CH2 signals. The 13C signals that are so broad in 33f narrow by approximately a factor of two in 33g (Table S8) (see SI page No. S26). In light of the very slow inversion about nitrogen for N-cyclohexylaziridine,45 it seems reasonable to conclude that inversion about the aziridine nitrogen in 33g is slow at ambient temperature and that a set of signals for each isomer would be observed if both isomers of 33g were present. However, as with 6, the 1 H and 13C spectra of 33g clearly exhibit signals for only one isomer. 2,2-diisopropyl-3-methyl-(R)-1-cyclopentylaziridine-2,2,3-tricarboxylate (33h). The general procedure was followed using diisopropyl cyclopentyl iminomalonate (0.27 g, 1.002 mmol), bromomethyl ester (0.190 mL, 2.005 mmol) and LiHMDS (1M solution in THF) (2.11 mL, 2.10 mmol) were used as starting materials to afford aziridine-2,2,3-triester as colorless viscous oily liquid (0.15 g, 44%). Compound was purified by flash chromatography (Rf = 0.15 (10% EtOAc/hexanes). 1H (500 MHz, CDCl3): δ5.12 (hept, J = 6.3 Hz, 1H, isopropyl CH), 5.10 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.72 (s, 3H, methoxy), 3.21 (s, 1H, aziridine ring CH), 2.94 (m, 1H, N-CH in 5-membered ring), 1.94-1.63 (m, 5H, ring CH2 protons), 1.63-1.45 (m, 3H, ring CH2 protons), 1.28 (d, J = 6.3 Hz, 3H, isopropyl CH3), 1.270 (d, J = 6.3 Hz, 3H, second isopropyl CH3), 1.268 (d, J = 6.3 Hz, 3H, third isopropyl CH3), 1.21 (d, J = 6.3 Hz, 3H, fourth isopropyl CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 167.9 (methoxycarbonyl, ν1/2 = 0.51 Hz), 164.3 (isopropoxycarbonyl, ν1/2 = 0.47 Hz), 163.8 (other isopropoxycarbonyl, ν1/2 = 0.93 Hz), 70.6 (isopropyl CH, ν1/2 = 0.89 Hz, correlating with methine 1H signal at δ5.12 in HSQC spectrum), 69.3 (other isopropyl CH, ν1/2 = 0.90 Hz, correlating with methine 1H signal at δ5.10 in HSQC spectrum ), 62.5 (N-CH in 5-membered ring, ν1/2 = 2.2 Hz), 52.8 (aziridine ring quaternary, ν1/2 = 0.48 Hz), 52.4 (methoxy, ν1/2 = 0.87 Hz), 47.8 (aziridine ring CH, ν1/2 = 2.5 Hz), 32.7 (-CH2-CH-CH2-, ν1/2 = 0.63 Hz), 32.3 (-CH2-CHCH2-, ν1/2 = 0.63 Hz), 24.6 (-CH2-CH2-CH-, ν1/2 = 0.51 Hz), 24.5 (-CH-CH2-CH2-, ν1/2 = 0.50 Hz), 21.59 (isopropyl CH3, ν1/2 = 0.63 Hz, correlating with methyl 1H signal at δ1.270 in HSQC spectrum), 21.553 (second isopropyl CH3, correlating with methyl 1H signal at δ1.21 in HSQC spectrum), 21.548 (third isopropyl CH3, correlating with methyl 1H signal at δ1.28 in HSQC spectrum), 21.49 (fourth isopropyl CH3, ν1/2 = 0.65 Hz, correlating with methyl 1H signal at δ1.268 in HSQC spectrum). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H28NO6 342.1911; Found 342.1936. As with the other aziridines, the combination of standard, DEPT-135, and DEPT-90 13C experiments differentiated among the CH3, CH2, CH, and quaternary carbons. A 1H-13C HSQC experiment (page S340) provided secure assignments and critical additional information: •

The correlation at δH3.72 / δC52.4 (page S341) clearly results from methoxy because the 1H singlet at δ3.72 results from three protons and because the 13C signal



at δ52.4 appears in a DEPT-135 13C spectrum but is strongly attenuated in a DEPT-90 13C spectrum. • The correlation at δH3.21 / δC47.8 (page S341) clearly results from the aziridine ring CH because the 1H singlet at δ3.21 results from one proton and because the 13 C signal at δ47.8 is strong in DEPT-135 and DEPT90 13C spectra. • The correlation at δH2.94 / δC62.5 (page S341) clearly results from the cyclopentyl ring CH because the 1H multiplet at δ2.94 results from one proton and because the 13C signal at δ62.5 is strong in DEPT-135 and DEPT-90 13C spectra. • At each of the four different CH2 13C frequencies (δ32.7, 32.3, 24.6, and 24.5), a different pattern of contours appears (page S342). Each CH2 group is clearly different, consistent with the presence of two pairs of diastereotopic CH2 groups because of the chiral center in the aziridine ring. The pattern is consistent with the relative intensities for the CH2 signals in the 1H spectrum: signals for five CH2 protons downfield of δ1.65 and signals for three CH2 protons upfield of δ1.65. There are striking differences in the 13C spectra of 33g and 33h (pages S334 and S337). First, the 13C signals that are relatively broad in 6 are narrow by about a factor of two in 33g continue to narrow in 33h (Table S9) (See SI page No. S26). The CH2 signals greatly sharpen in 33h and have half-height linewidths comparable to many of the other signals. The two methylene carbons adjacent to the methine are diastereotopic because of the chiral center in the aziridine ring and give distinct signals at δ32.7 and δ32.3. The remaining two methylene carbons are diastereotopic for the same reason; because they are further from the chiral center, they exhibit a smaller chemical shift difference (δ24.6 and δ24.5). An alternative explanation for these pairs of CH2 signals seems much less plausible—the presence of two diastereomers: one with the cyclopentyl group cis to the aziridine ring proton, the other with the cyclopentyl group trans to the aziridine ring proton, and very slow interconversion of the diastereomers (through inversion about nitrogen) because of the rigidity of the three-membered ring with an N-alkyl substituent. This explanation seems much less plausible because pairs of signals would then be expected for all carbons, which is clearly not observed. (A previous report50 has clearly shown different 13C chemical shifts for a wide range of cis- and trans-N-alkyl-2,3disubstituted aziridines). Because of the aziridine ring quaternary carbon's proximity to the N-substituent and the 3-methoxycarbonyl substituent and because of the extreme sensitivity of 13C chemical shifts to even remote changes in stereochemistry,46 the chemical shift of the aziridine ring quaternary carbon should be particularly sensitive to the presence of cis and trans isomers. Because the signal for this carbon in 33h is very sharp (ν1/2 = 0.48 Hz with 0.20 Hz of line broadening applied), observing a pair of signals from the aziridine ring quaternary carbon in the two diastereomers—if they were present—should be particularly easy. Such a pair is not seen. Clearly, only one isomer of 33h is present. Note that in N-aryl aziridines 33a-e, the signal for the aziridine ring quaternary carbon is even sharper (with ν1/2 ranging from 0.34-0.38 Hz), which would make observing a

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pair of signals even easier; however, each of 33a-e exhibits just one aziridine ring quaternary carbon signal. Again, as noted earlier, the single pair of 1H and 13C spectra for each of 33a-e does not indicate whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer of 33a-e formed when the enolate reacted with the diisopropyl iminomalonate. The 1H spectra support the presence of only one isomer for each of N-alkyl aziridines 33f-h, as just one methoxy singlet and just one aziridine ring methine 1H singlet are observed (as is also the case for N-aryl aziridines 33a-e. In 33a, these singlets happen to coincide within our ability to measure.) Remarkably, the 1H half-height linewidths of the methoxycarbonyl and aziridine ring methine proton singlets are remarkably similar in 33a-h (Table S9) (see SI page No. S26); the modest broadening in 33g might result from the relatively slow inversion about nitrogen in the 6-membered ring. Still, it does not seem possible to rigorously conclude from the single pair of 1H and 13C spectra for each of 33a-e whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer formed when the enolate reacted with the diisopropyl iminomalonate. We note that the much smaller chemical shift range in 1H NMR and the presence of multiplets for the other signals make 1H NMR a less sensitive probe for the presence of cis and trans isomers. Still, one could reasonably expect the chemical shift of the aziridine ring methine proton to be sensitive to whether it is cis or trans to the adjacent substituent on nitrogen. (For 33a, the probability of the cis and trans isomers both being present and both methoxy 1H singlets and both aziridine ring methine 1 H singlets all occurring at the same frequency in the slow inversion limit seems extraordinarily low.) Indeed, 1H spectra of N-substituted aziridines have been reported with different 1H chemical shifts for the cis and trans isomers.50 Thus, with only one diastereomer of 33h formed when the enolate reacted with the diisopropyl iminomalonate, determining the stereochemistry was the next goal. NOE experiments have been previously used to determine the relative orientation of substituents on N-substituted aziridines.47-49 NOE experiments with mixing times of 0.6 s and 1.0 s (pages S343 and S344) clearly showed NOE between the aziridine ring proton at δ3.21 and the cyclopentyl methine proton at δ2.94. No cross peak was evident between the methoxy protons at δ3.72 and the cyclopentyl methine proton at δ2.94. These observations are consistent with the cyclopentyl ring cis to the aziridine ring proton and trans to the methoxycarbonyl group, which is clearly the sterically less hindered diastereomer. A 1H-13C HMBC experiment (page S339) indicated that: • the methoxy 1H signal at δ3.72 correlated with the carbonyl signal at δ167.9 (but not with either of the other carbonyl signals), which clearly established that the signal at δ167.9 resulted from the methoxycarbonyl group; • the more deshielded isopropyl methine 1H signal at δ5.12 correlated with the carbonyl signal at δ163.8 (but not with either of the other carbonyl signals) and that the more shielded isopropyl methine 1H signal at δ5.10 correlated with the carbonyl signal at δ164.3 (but not with either of the other carbonyl signals);


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The Journal of Organic Chemistry •

the two more shielded isopropyl methyl doublets at δ1.21 and δ1.268 correlated with the more shielded isopropyl methine carbon at δ69.3; and • the two more deshielded isopropyl methyl doublets at δ1.270 and δ1.28 correlated with the more deshielded isopropyl methine carbon at δ70.6. It was not clear which isopropoxycarbonyl group is cis to the aziridine ring proton and which is trans. Finally, we note the sensitivity of the 1H and 13C chemical shifts of various functional groups to the presence of an N-aryl or an N-alkyl substituent on the aziridine (Table S9) (see SI page No. S26). In general, small, but clearly noticeable, differences are observed for the two types of substituents. However, the chemical shift difference is large for the isopropyl methine protons as well as for the aziridine ring methine proton. General procedure for the addition of nitrile carbanions onto iminomalonates, Figure 13. In a thick-walled flame dried 25 mL round bottom flask, the corresponding acetonitrile (1.35 equiv) was dissolved in DME (0.23M) and cooled to −78 ˚C. KHMDS (1.0 M in THF) (1.35 equiv) was added dropwise to this solution. Usually the solution turned yellow and slowly to reddish yellow. After 1 h of stirring, a solution of the iminomalonate (1 equiv) in of DME (0.13M) was added slowly in a dropwise manner. The reaction mixture was stirred for 2 hours. After confirming the complete consumption of starting material by TLC, saturated aqueous solution of ammonium chloride was added (5 mL) to quench the reaction and the reaction mixture was allowed to warm to room temperature. The organic layer was separated. The aqueous layer was extracted twice with diethylether (2 X 20mL). The combined organic layers were dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The crude reaction mixture was purified by automated flash chromatography. Note: For gram scale reaction (for the synthesis of 35a), for acetonitrile derived carbanion generation, the reaction mixture should be stirred for 2 h. After which, the iminomalonate was added and the reaction mixture was stirred for another 3 h. The rest of the workup procedure is same as mentioned in the procedure described above. Diisopropyl-2-(cyano(phenyl)methyl)-2-(phenylamino)malonate (35a). The general procedure was followed using 2-phenylacetonitrile (0.079 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and phenyl iminomalonate (0.138 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored viscous oily liquid (0.107 g, 54%). Compound was purified by flash column chromatography (Rf = 0.24 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.26 (td, J = 6.1, 5.0, 3.1 Hz, 1H), 7.21 (t, J = 7.4 Hz, 2H), 7.19 – 7.16 (m, 2H), 7.12 – 7.08 (m, 2H), 6.74 (t, J = 7.4 Hz, 1H), 6.57 (d, J = 7.8 Hz, 2H), 5.10 (hept, J = 6.2 Hz, 1H), 5.01 (p, J = 6.3 Hz, 1H), 4.93 (s, 1H), 4.87 (s, 1H), 1.39 (d, J = 6.3 Hz, 3H), 1.18 (d, J = 6.3 Hz, 3H), 1.15 (d, J = 6.2 Hz, 3H), 0.95 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 166.7, 166.0, 143.3, 130.7, 129.5, 129.3, 128.9, 128.4, 119.4, 118.8, 114.8, 72.3, 71.2, 70.4, 40.0, 21.6, 21.3, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H27N2O4 395.1965; found 395.1990. Note: For gram scale reaction, the general procedure was followed using 2-phenylacetonitrile (0.808 g, 6.91 mmol), KHMDS (1M solution in THF) (6.91 mL, 6.91 mmol) and phenyl iminomalonate (1.42 g, 5.12 mmol) as starting materials.

The rest of the procedure is same as mentioned in the procedure described above. Diisopropyl-2-(cyano(phenyl)methyl)-2-((4-methoxyphenyl)amino)malonate (35b). The general procedure was followed using 2-phenylacetonitrile (0.079 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and pmethoxyphenyl iminomalonate (0.154 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a bright yellow colored viscous oily liquid (0.140 g, 66%). Compound was purified by flash column chromatography (Rf = 0.35 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.33 – 7.22 (m, 5H), 6.72 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 8.8 Hz, 2H), 5.10 (hept, J = 6.2 Hz, 1H), 5.01 (hept, J = 6.7 Hz, 1H), 4.84 (s, 1H), 4.74 (s, 1H), 3.72 (s, 3H), 1.40 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.16 (d, J = 6.2 Hz, 3H), 1.0 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 166.9, 166.2, 153.5, 137.2, 130.8, 129.7, 129.0, 128.4, 119.1, 117.0, 114.8, 72.1, 71.23, 71.20, 55.6, 40.5, 21.6, 21.4, 21.3, 21.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H29N2O5 425.2100; found 425.2065. Diisopropyl-2-(cyano(4-fluorophenyl)methyl)-2-(phenylamino)malonate (35c). The general procedure was followed using 2-(4-fluorophenyl)acetonitrile (0.091 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and phenyl iminomalonate (0.138 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored viscous oily liquid (0.150 g, 73%). Compound was purified by flash column chromatography (Rf = 0.24 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.22 (dd, J = 8.6, 5.2 Hz, 2H), 7.15 (t, J = 7.9 Hz, 2H), 6.96 (t, J = 8.6 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 7.9 Hz, 2H), 5.15 (hept, J = 6.3 Hz, 1H), 5.05 (hept, J = 6.3 Hz, 1H), 4.99 (s, 1H), 4.92 (s, 1H), 1.44 (d, J = 6.3 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H). 13C{1H} (151 MHz, CDCl3): δ 166.7, 166.0, 163.0 (d, 1JCF = 248.9 Hz), 143.2, 131.4 (d, 3JCF = 8.3 Hz), 129.4, 126.5 (d, 4JCF = 3.4 Hz), 119.7, 118.7, 115. 5 (d, 2JCF = 21.8 Hz), 114.9, 72.5, 71.4, 70.5, 39.4, 21.6, 21.4, 21.3, 21.2. 19 F NMR (471 MHz, CDCl3): δ −111.3 (tt, J = 8.4, 5.1 Hz). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H26FN2O4 413.1832; found 413.1866. Diisopropyl-2-((4-chlorophenyl)(cyano)methyl)-2-(phenylamino)malonate (35d). The general procedure was followed using 2-(4-chlorophenyl)acetonitrile (0.102 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and phenyl iminomalonate (0.138 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored viscous oily liquid (0.131 g, 61%). Compound was purified by flash column chromatography (Rf = 0.24 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.27 (d, J = 8.5 Hz, 2H), 7.18 (dd, J = 17.6, 8.2 Hz, 4H), 6.83 (t, J = 7.3 Hz, 1H), 6.62 (d, J = 7.9 Hz, 2H), 5.17 (hept, J = 6.3 Hz, 1H), 5.08 (hept, J = 6.2 Hz, 1H), 5.01 (s, 1H), 4.93 (s, 1H), 1.46 (d, J = 6.3 Hz, 3H), 1.25 (d, J = 6.3 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.01 (d, J = 6.3 Hz, 3H). 13 C{1H} (151 MHz, CDCl3): δ 166.5, 165.8, 143.1, 135.1, 130.9, 129.4, 129.2, 128.6, 119.6, 118.4, 114.8, 72.5, 71.4, 70.3, 39.4, 21.6, 21.3, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H26ClN2O4 429.1576; found 429.1582. Diisopropyl-2-(cyano(4-fluorophenyl)methyl)-2-((4-methoxyphenyl)amino)malonate (35e). The general procedure was followed using 2-(4-fluorophenyl)acetonitrile (0.091 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and p-methoxyphenyl iminomalonate (0.154 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored viscous oily liquid (0.130 g, 59%). Compound was purified by



flash column chromatography (Rf = 0.35 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.26 (dd, J = 8.2 Hz, 2H), 6.96 (t, J = 8.5 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 5.10 (hept, J = 6.2 Hz, 1H), 5.01 (hept, J = 6.1 Hz, 1H), 4.85 (s, 1H), 4.77 (s, 1H), 3.72 (s, 3H), 1.39 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.16 (d, J = 6.2 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H). 13C{1H} (151 MHz, CDCl3): δ 166.8, 166.1, 163.0 (d, 1JCF = 248.9 Hz), 153.6, 137.0, 131.5 (d, 3JCF = 8.3 Hz), 126.6 (d, 4JCF = 3.3 Hz), 118.9, 117.0, 115.5 (d, 2JCF = 21.9 Hz), 114.7, 72.2, 71.3, 71.1, 55.5, 39.9, 21.6, 21.4, 21.3, 21.2. 19 F NMR (471 MHz, CDCl3): δ −111.3 (tt, J = 8.4, 5.2 Hz). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H28FN2O5 443.1973; found 443.1972. Diisopropyl-2-((4-chloro-2-fluorophenyl)(cyano)methyl)-2((4-methoxyphenyl)amino)malonate (35f). The general procedure was followed using 2-(4-chloro-2-fluorophenyl)acetonitrile (0.114 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and p-methoxyphenyl iminomalonate (0.154 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a bright yellow colored viscous oily liquid (0.167 g, 70%). Compound was purified by flash column chromatography (Rf = 0.35 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.34 (t, J = 8.1 Hz, 1H), 7.08 (ddd, J = 23.2, 9.1, 1.9 Hz, 2H), 6.74 – 6.72 (m, 2H), 6.69 – 6.67 (m, 2H), 5.16 – 5.09 (m, 2H), 4.98 (hept, J = 6.1 Hz, 1H), 4.74 (s, 1H), 3.73 (s, 3H), 1.38 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 6.2 Hz, 3H), 1.00 (d, J = 6.2 Hz, 3H). 13C{1H} (151 MHz, CDCl3): δ 166.5, 166.2, 160.2 (d, 1JCF = 253.2 Hz), 153.9, 137.1, 136.2 (d, 3JCF = 10.5 Hz), 132.2 (d, 4 or 3JCF = 3.4 Hz), 124.9 (d, 3 or 4 JCF = 3.5 Hz), 118.0, 117.6, 117.5 (d, 2JCF = 13.9 Hz), 116.5 (d, 2JCF = 25.8 Hz), 114.6, 72.3, 71.8, 71.2, 55.6, 34.8, 21.5, 21.2, 21.1. 19F NMR (471 MHz, CDCl3): δ −110.4 (t, J = 8.9 Hz). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H27ClFN2O5 477.1594; found 477.1586. Diisopropyl-2-(cyano(phenylthio)methyl)-2-((4-methoxyphenyl)amino)malonate (35g). The general procedure was followed using 2-(phenylthio)acetonitrile (0.100 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and pmethoxyphenyl iminomalonate (0.154 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellowish brown colored viscous oily liquid (0.178 g, 78%). Compound was purified by flash column chromatography (Rf = 0.35 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.44 – 7.38 (m, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.29 (t, J = 7.3 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 6.76 (d, J = 8.9 Hz, 2H), 5.16 (hept, J = 6.2 Hz, 1H), 5.09 (hept, J = 6.2 Hz, 1H), 5.01 (s, 1H), 4.59 (s, 1H), 3.74 (s, 3H), 1.28 (d, J = 6.3 Hz, 3H), 1.25 (d, J = 6.3 Hz, 3H), 1.20 (d, J = 6.3 Hz, 3H), 1.16 (d, J = 6.3 Hz, 3H). 13C{1H} (151 MHz, CDCl3): 166.6, 165.4, 154.6, 136.0, 134.4, 130.7, 129.5, 129.3, 119.6, 117.6, 114.6, 72.1, 71.7, 70.4, 55.5, 42.4, 21.3, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H29N2O5S 457.1785; found 457.1794. Diisopropyl-2-(cyano(phenyl)methyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (35h). The general procedure was followed using 2-phenylacetonitrile (0.079 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and mtrifluoromethylphenyl iminomalonate (0.172 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored viscous oily liquid (0.141 g, 61%). Compound was purified by flash column chromatography (Rf = 0.36 (10% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.28 – 7.14 (m, 6H), 6.95 (d, J = 7.7 Hz, 1H), 6.69 (dd, J = 8.2, 2.1 Hz, 1H), 6.57 (s, 1H), 5.22 (s, 1H), 5.12 (hept, J = 6.5 Hz, 1H), 4.95 (hept, J = 6.3 Hz,

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1H), 4.84 (s, 1H), 1.37 (d, J = 6.3 Hz, 3H), 1.16 (d, J = 6.3 Hz, 3H), 1.14 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.3 Hz, 3H). 13C{1H} (151 MHz, CDCl3): δ 166.0, 165.9, 144.0, 131.6 (q, 2JCF = 32.1 Hz), 130.4, 129.8, 129.7, 129.2, 128.6, 123.9 (q, 1JCF = 272.4 Hz), 118.7, 117.8, 115.9 (q, 3JCF = 3.8 Hz), 111.3 (q, 3JCF = 3.8 Hz), 72.7, 71.8, 70.7, 40.8, 21.6, 21.4, 21.3, 21.1. 19F NMR (471 MHz, CDCl3): δ −61.9 (S). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H26 F3N2O4 463.1823; found 463.1815. Diisopropyl-2-(cyano(4-fluorophenyl)methyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (35i). The general procedure was followed using 2-(4-fluorophenyl)acetonitrile (0.091 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and m-trifluoromethylphenyl iminomalonate (0.172 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored viscous oily liquid (0.146 g, 61%). Compound was purified by flash column chromatography (Rf = 0.36 (10% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.32 (dd, J = 8.4, 5.2 Hz, 2H), 7.22 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 8.5 Hz, 2H), 6.73 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 5.33 (s, 1H), 5.19 (hept, J = 6.2 Hz, 1H), 5.00 (hept, J = 6.1 Hz, 1H), 4.91 (s, 1H), 1.43 (d, J = 6.3 Hz, 3H), 1.22 (d, J = 5.7 Hz, 3H), 1.21 (d, J = 5.7 Hz, 3H), 0.94 (d, J = 6.2 Hz, 3H). 13 C{1H} (151 MHz, CDCl3): δ 165.9, 165.8, 163.2 (d, 1JCF = 249.5 Hz), 144.0, 131.8 (d, 3JCF = 8.4 Hz), 131.7 (q, 2JCF = 32.1 Hz ), 129.7, 126.2 (d, 4JCF = 3.3 Hz), 123.9 (q, 1JCF = 272.4 Hz), 118.5, 118.0, 116.1 (q, 3JCF = 3.9 Hz), 115.8 (d, 2JCF = 21.9 Hz), 111.2 (q, 3JCF = 3.7 Hz), 72.8, 71.9, 70. 7, 40.4, 21.5, 21.3, 21.2, 21.0. 19F NMR (471 MHz, CDCl3): δ −62.04 (S), −110.9 (tt, J = 8.4, 5.2 Hz). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H25F4N2O4 481.1787; found 481.1785. Diisopropyl-2-(cyano(phenyl)methyl)-2-(pyridin-3-ylamino)malonate (35j). The general procedure was followed using 2-phenylacetonitrile (0.079 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and 3-pyridyl iminomalonate (0.139 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored viscous oily liquid (0.126 g, 64%). Compound was purified by flash column chromatography (Rf = 0.32 (40% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.02 (s, 1H), 7.95 (s, 1H), 7.30 – 7.23 (m, 5H), 7.00 (m, 1H), 6.81 (d, J = 7.4 Hz, 1H), 5.14 (s, 1H), 5.13 (hept, J = 6.2 Hz, 1H), 5.00 (hept, J = 6.2 Hz, 1H), 4.85 (s, 1H), 1.39 (d, J = 6.3 Hz, 3H), 1.20 (d, J = 6.3 Hz, 3H), 1.15 (d, J = 6.2 Hz, 3H), 0.96 (d, J = 6.3 Hz, 3H). 13C{1H} (151 MHz, CDCl3): δ 165.9, 165.8, 140.9, 138.3, 130.3, 129.7, 129.2, 128.7, 120.4, 118.7, 72.6, 71.8, 70.6, 40.8, 21.5, 21.4, 21.3, 21.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26N3O4 [M+H]+ 396.2122; found 396.2101. Diisopropyl-2-(cyano(4-fluorophenyl)methyl)-2-(pyridin-3ylamino)malonate (35k). The general procedure was followed using 2-(4-fluorophenyl)acetonitrile (0.091 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and 3pyridyl iminomalonate (0.139 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored viscous oily liquid (0.124 g, 60%). Compound was purified by flash column chromatography (Rf = 0.32 (40% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.05 (d, J = 4.3 Hz, 1H), 8.01 – 7.94 (m, 1H), 7.30 (dd, J = 7.6, 5.6 Hz, 2H), 7.00 (dt, J = 16.8, 5.9 Hz, 3H), 6.82 – 6.74 (m, 1H), 5.18 (s, 1H), 5.12 (hept, J = 6.2 Hz, 1H), 5.01 (hept, J = 6.1 Hz, 1H), 4.86 (s, 1H), 1.40 (d, J = 6.3 Hz, 3H), 1.22 (d, J = 6.2 Hz, 3H), 1.18 (d, J = 6.2 Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 165.8, 165.7, 163.2 (d, 1JCF = 249.7 Hz), 141.1, 139.9, 138.3, 131.6 (d, 3 JCF = 8.4 Hz), 126.2 (d, 4JCF = 3.3 Hz), 123.4, 120.4, 118.5,


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115.8 (d, 2JCF = 21.8 Hz), 72.8, 72.0, 70.7, 40.3, 21.5, 21.4, 21.3, 21.2. 19F NMR (471 MHz, CDCl3): δ −110.6 (tt, J = 8.4, 5.1 Hz). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H25FN3O4 [M+H]+ 414.2034; found 414.2027. Diisopropyl-2-((4-chloro-2-fluorophenyl)(cyano)methyl)-2((3-(trifluoromethyl)phenyl)amino)malonate (35l). The general procedure was followed using 2-(4-chloro-2-fluorophenyl)acetonitrile (0.114 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and m-trifluoromethylphenyl iminomalonate (0.172 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored oily liquid (0.172 g, 67%). Compound was purified by flash column chromatography (Rf = 0.35 (10% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.33 (dd, 3JHH = 8.4 Hz, 4JHF = 7.8 Hz, 1H, H-6’); 7.27 (dd, 3JHH = 8.0 Hz, 3JHH = 7.9 Hz, 1H, H-5); 7.11 (ddd, 3JHH = 8.4 Hz, 4 JHH = 2.1 Hz, 5JHH ≈ 0.7 Hz, 1H, H-5’); 7.065 (m, 1H, H-4); 7.062 (dd, 3JHF = 9.7 Hz, 4JHH = 2.1 Hz, 1H, H-3’); 6.88 (dd, 3 JHH = 8.2 Hz, 4JHH = 2.4 Hz, 1H, H-6); 6.82 (s with unresolved long-range couplings, 1H, H-2); 5.22 (s, broad, NH); 5.16 [d, 5 JHH (with H-5’) ≈ 0.7 Hz, 1H, H-C-CN]; isopropoxy group #1: 5.19 (hept, J = 6.3 Hz, 1H, methine), 1.41 (d, J = 6.3 Hz, 3H, methyl), 1.16 (d, J = 6.3 Hz, 3H, methyl); isopropoxy group #2: 5.03 (hept, J = 6.3 Hz, 1H, methine), 1.24 (d, J = 6.3 Hz, 3H, methyl), 1.01 (d, J = 6.3 Hz, 3H, methyl). 13C{1H} NMR (126 MHz, CDCl3): δ 160.2 (d, 1JCF = 253.4 Hz, C-2’); 143.9 (s, C1); 136.6 (d, 3JCF = 10.5 Hz, C-4’); 132.0 (d, 3JCF = 3.4 Hz, C6’); 131.6 (q, 2JCF = 32.2 Hz, C-3); 129.8 (s, C-5); 125.1 (d, 4JCF = 3.7 Hz, C-5’); 123.9 (q, 1JCF = 272.4 Hz, CF3); 118.1 (q, 5JCF = 1 Hz, C-6); 117.6 (s, nitrile); 117.1 (d, 2JCF = 14.0 Hz, C-1’); 116.6 (d, 2JCF = 25.6 Hz, C-3’); 116.4 (q, 3JCF = 3.9 Hz, C-4); 111.7 (q, 3JCF = 3.9 Hz, C-2); 70.4 (broadened—unresolved long-range JCF coupling, quaternary aliphatic carbon); 34.5 (d, 3 JCF = 1.7 Hz, N≡C-CH); isopropoxy group #1: 165.7 (s, carbonyl), 72.9 [s, CH (correlating with methine 1H signal at δ5.19 in HSQC spectrum)], 21.5 [s, CH3 (correlating with methyl 1H signal at δ1.41 in HSQC spectrum)], 21.23 [s, CH3 (correlating with methyl 1H signal at δ1.16 in HSQC spectrum)]; isopropoxy group #2: 165.9 (s, carbonyl), 72.4 [s, CH (correlating with methine 1H signal at δ5.03 in HSQC spectrum)], 21.22 [d, JCF = 1 Hz, CH3 (correlating with methyl 1H signal at δ1.24 in HSQC spectrum)], 21.1 [s, CH3 (correlating with methyl 1H signal at δ1.01 in HSQC spectrum)]. 19F NMR (471 MHz, CDCl3): δ −62.03 (broad singlet with shoulders from unresolved longrange JHF couplings that are not recognizable in the 1H spectrum, CF3; satellite 1JCF = 272.4 Hz), δ-110.5 [broad dd, J ≈ 8 Hz, J ≈ 8 Hz from 3JHF with H-3’ and 4JHF with H-6’ (see above), ring CF; satellite 1JCF = 253 Hz)]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H24ClF4N2O4 515.1447; found 515.1441. Detailed chemical shift assignments could be made through a combination of 1H (p. S384), 13C (p. S385), DEPT-135 13C (p. S386), COSY (p. S388), HSQC (p. S390-S394), HMBC (p. S389), and 19F (p. S387) spectra. The 1H-13C HSQC spectra also enabled 1H-19F couplings to be readily recognized and the corresponding JHF values to be measured because of the distinctive effect that coupling to a passive spin (19F) has on the appearance of a 1H-13C HSQC spectrum, i.e., splitting the contour into two contours separated by the value of JCF in the 13C dimension and by the value of JHF in the 1H dimension (pp. S393 and S394).51 For example, p. S393 shows a highly expanded plot of part of the aromatic region in the HSQC spectrum and the corresponding regions in the 1D 1H and 13C spectra. The correlations for C-4/H-4 and C-3’/H-3’ are shown. The two contours at δC116.41 separated in the 1H dimension by about 7.2

Hz and centered at δH7.065 result from C-4 and H-4 on the CF3substituted ring. The separation between the contours results from 3J(H-4,H-5). The 1D 13C spectrum (left side) indicates that C-4 is a quartet with 3JCF = 3.9 Hz. This splitting is too small to detect in the HSQC spectrum, where the 13C FID digital resolution is 5.2 Hz (1.3 Hz after zero-filling). The 4JHF splitting is much too small to detect in the 1H dimension, where the 1H digital resolution is 2.1 Hz. In contrast, the 1D 13C spectrum indicates that C-3’ is a doublet at δ116.62 with 2JCF = 25.6 Hz. The corresponding contours in the HSQC spectrum are offset by ±12.8 Hz in the 13C dimension; the separation of the contours in the 13C dimension is 2JCF. The contours in the 1H dimension are centered at δ7.062 and separated by 9.7 Hz (3JHF). The 4JHH coupling between H-3’ and H-5’ (2.1 Hz) is too small to detect in the 1H dimension of the HSQC spectrum. The severely overlapping 1H signals for H-4 and H-3’ in the 1D 1H spectrum (top) make this region difficult to interpret by sight, but the HSQC results enable the four relatively prominent signals to be recognized as a doublet (3JHF) of doublets (4JHH) for H-3’. The same doublet of doublets centered at δ7.062 is observed in a 400 MHz 1 H spectrum, providing further support for the interpretation. p. S394 shows a highly expanded plot of the C-6’/H-6’ correlation in the HSQC spectrum and the corresponding regions in the 1D 1 H and 13C spectra. The 1H spectrum (top) is a doublet of doublets with similar J values that are attributed to 3JHH = 8.4 Hz and 4JHF = 7.8 Hz. Three equidistant contours (separation ≈ 8.3 Hz) are correspondingly observed in the 1H dimension in the HSQC spectrum. In the 13C dimension, the most shielded and the most deshielded contours differ by 3.4 Hz, the value of 3JCF observed for the doublet in the 1D 13C spectrum (left side). There is no detectable 5JHF between H-5’ and the ring fluorine. Thus, the broad doublet of doublets (with the central peaks clearly overlapping) observed for the ring fluorine in the 19F spectrum can be attributed to 3JHF with H-3’ and 4JHF with H-6’. The 1D 13C spectrum exhibited a completely unexpected splitting of one of the isopropyl methyl signals (p. S385) that was also evident on 400 and 600 MHz spectrometers. In contrast, the 1D 13C spectrum of the analogous compound 35o without the ring fluorine (i.e., a 4-chlorophenyl group) exhibits the expected four singlets for the four different isopropyl methyl carbons. Thus, in the 2-fluoro-4-chlorophenyl compound (35l), there is an unexpected coupling between one methyl carbon and the ring fluorine. A 13C-19F J coupling through eight bonds would not be expected. A through-space 13C-19F coupling of a single methyl carbon with the ring fluorine is also hard to explain. Additional work is required to determine the origin of this unexpected 13C-19F interaction in 35l. Diisopropyl-2-(cyano(phenylthio)methyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (35m). The general procedure was followed using 2-(phenylthio)acetonitrile (0.100 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and m-trifluoromethylphenyl iminomalonate (0.172 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored viscous oily liquid (0.180 g, 73%). Compound was purified by flash column chromatography (Rf = 0.36 (10% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.44 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.32 – 7.26 (m, 3H), 7.09 (d, J = 7.7 Hz, 1H), 6.98 (s, 1H), 6.94 (d, J = 8.1 Hz, 1H), 5.50 (s, 1H), 5.19 (hept, J = 6.2 Hz, 1H), 5.15 (hept, J = 6.2 Hz, 1H), 4.68 (s, 1H), 1.32 (d, J = 6.3 Hz, 3H), 1.29 (d, J = 6.3 Hz, 3H), 1.19 (d, J = 6.2 Hz, 3H), 1.17 (d, J = 6.2 Hz, 3H). 13C{1H} (151 MHz, CDCl3): δ 166.0, 165.0, 143.2, 134.4, 132.4, 132.1, 131.7 (q, 2JCF = 32.1 Hz), 130.4, 129.8, 129.7, 129.5, 129.4, 128.9,



123.9 (q, 1JCF = 272.4 Hz), 118.4, 117.3, 116.6 (q, 3JCF = 3.8 Hz), 116.5, 112.7 (q, 3JCF = 3.8 Hz), 72.7, 72.3, 69.7, 41.9, 21.34, 21.32, 21.2, 21.1. 19F NMR (471 MHz, CDCl3): δ −62.0 (S). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H26F3N2O4S 495.1599; found 495.1595. Diisopropyl-2-((4-chloro-2-fluorophenyl)(cyano)methyl)-2(pyridin-3-ylamino)malonate (35n). The general procedure was followed using 2-(4-chloro-2-fluorophenyl)acetonitrile (0.114 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and 3-pyridyl iminomalonate (0.139 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored viscous oily liquid (0.152 g, 68%). Compound was purified by flash column chromatography (Rf = 0.32 (40% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.06 – 8.03 (m, 2H), 7.32 (t, J = 8.1 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.08 – 7.03 (m, 3H), 5.16 (hept, J = 6.2 Hz, 1H), 5.12 (s, 1H), 5.07 (s, 1H), 5.01 (hept, J = 6.3 Hz, 1H), 1.38 (d, J = 6.3 Hz, 3H), 1.22 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 165.7, 165.5, 160.0 (d, 1JCF = 253.2 Hz), 141.3, 139.7, 138.5, 136.5 (d, 3JCF = 10.5 Hz), 131.8 (d, 4 or 3 JCF = 3.3 Hz), 125.1 (d, 3 or 4JCF = 3.5 Hz), 123.3, 120.8, 117.6, 117.0 (d, 2JCF = 13.9 Hz), 116.7 (d, 2 JCF = 25.6 Hz), 72.8, 72.3, 70.2, 34.3, 21.4, 21.2, 21.1. 19F NMR (471 MHz, CDCl3): δ −110.6 (t, J = 8.3 Hz). HRMS (ESITOF) m/z: [M+H]+ Calcd for C22H24ClFN3O4 448.1434; found 448.1438. Diisopropyl-2-((4-chlorophenyl)(cyano)methyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (35o). The general procedure was followed using 2-(4-chlorophenyl)acetonitrile (0.102 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and m-trifluoromethylphenyl iminomalonate (0.172 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellowish grey colored viscous oily liquid (0.149 g, 60%). Compound was purified by flash column chromatography (Rf = 0.36 (10% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.31 – 7.24 (m, 5H), 7.05 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.62 (s, 1H), 5.35 (s, 1H), 5.21 (hept, J = 6.1 Hz, 1H), 5.04 (hept, J = 6.2 Hz, 1H), 4.93 (s, 1H), 1.45 (d, J = 6.3 Hz, 3H), 1.25 (d, J = 6.3 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H). 13C{1H} (151 MHz, CDCl3): δ 165.8, 165.7, 143.9, 135.5, 131.5 (q, 2JCF = 32.1 Hz), 131.1, 129.7, 128.9, 128.8, 123.8 (q, 1JCF = 272.5 Hz), 118.2, 117.9, 116.2 (q, 3JCF = 3.7 Hz), 111.2 (q, 3JCF = 3.7 Hz), 72.9, 71.9, 70.6, 40.4, 21.5, 21.3, 21.2, 21.0. 19F NMR (471 MHz, CDCl3): δ −62.0 (S). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H25ClF3N2O4 497.1480; found 497.1477. Diisopropyl-2-((4-chlorophenyl)(cyano)methyl)-2-((4-methoxyphenyl)amino)malonate (35p). The general procedure was followed using 2-(4-chlorophenyl)acetonitrile (0.102 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and p-methoxyphenyl iminomalonate (0.154 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a dark brown colored viscous oily liquid (0.146 g, 64%). Compound was purified by flash column chromatography (Rf = 0.35 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.27 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 6.60 (d, J = 8.7 Hz, 2H), 5.13 (hept, J = 6.2 Hz, 1H), 5.03 (hept, J = 6.2 Hz, 1H), 4.85 (s, 1H), 4.77 (s, 1H), 3.75 (s, 3H), 1.41 (d, J = 6.2 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.19 (d, J = 6.1 Hz, 3H), 1.02 (d, J = 6.2 Hz, 3H). 13C{1H} (151 MHz, CDCl3): δ 166.7, 166.0, 153.7, 136.9, 135.2, 131.0, 129.3, 128.7, 118.7, 117.0, 114.8, 72.3, 71.4, 71.1, 55.6, 40.0, 21.6, 21.4, 21.3, 21.2.

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HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H28ClN2O5 459.1681; found 459.1674. Diisopropyl-2-((4-chlorophenyl)(cyano)methyl)-2-(pyridin-3ylamino)malonate (35q). The general procedure was followed using 2-(4-chlorophenyl)acetonitrile (0.102 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and 3pyridyl iminomalonate (0.139 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a brown colored viscous oily liquid (0.159 g, 74%). Compound was purified by flash column chromatography (Rf = 0.31 (40% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.06 (d, J = 4.1 Hz, 1H), 8.00 (d, J = 2.8 Hz, 1H), 7.31 – 7.24 (m, 2H), 7.24 – 7.20 (m, 2H), 7.03 (dd, J = 8.3, 4.7 Hz, 1H), 6.82 (ddd, J = 8.4, 2.9, 1.1 Hz, 1H), 5.18 (s, 1H), 5.15 (hept, J = 6.2 Hz, 1H), 5.01 (hept, J = 6.2 Hz, 1H), 4.84 (s, 1H), 1.39 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 6.2 Hz, 1H), 0.98 (d, J = 6.2 Hz, 3H). 13C{1H} (151 MHz, CDCl3): δ 165.6, 165.4, 140.9, 139.7, 138.1, 135.3, 130.9, 128.8, 128.7, 123.3, 120.4, 118.1, 72.6, 71.8, 70.4, 40.2, 21.4, 21.2, 21.1, 21.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H25ClN3O4 430.1671; found 430.1662. General procedure for the cyclization of nitrile addition products to corresponding γ-lactams, Figure 14. Method A: In a thick-walled flame dried 25 mL round bottom flask, the acetonitrile addition product (1 equiv) was dissolved in of anhydrous methanol (0.07 M) at room temperature. Raney Nickel (600 mg), washed with water and ethanol, was added to this. The mixture was then stirred for 3 days under a hydrogen atmosphere (in form of a balloon). After confirming the complete consumption of the starting material by TLC, the reaction was stopped and the mixture was passed through a small pad of celite and the celite pad was rinsed with ethyl acetate (10 mL). All the solvent was removed under reduced pressure followed by automated flash chromatography. Method B: In a thick wall flame dried 25 mL round bottom flask; the acetonitrile addition product (1.0 equiv) was dissolved in of dry THF (0.83 M) at room temperature. BH3.Me2S (10 equiv) was added dropwise in this solution followed by reflux for 1 hour. After confirming the complete consumption of the starting material by TLC, the reaction mixture was brought to room temperature and 1 mL of water was added slowly dropwise to the reaction mixture. Evolution of hydrogen was noticed. The mixture was again refluxed for 6 hours. The reaction mixture was then allowed to cool to room temperature and ethyl acetate (10 mL) was added. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (2 X 10 mL). The combined organic layer was then dried over anhydrous sodium sulphate. All the solvent was removed under reduced pressure followed by automated flash chromatography. Isopropyl-2-oxo-4-phenyl-3-(phenylamino)pyrrolidine-3-carboxylate (36a). The general procedure, Method A was followed using diisopropyl 2-(cyano(phenyl)methyl)-2-(phenylamino)malonate, 35a (0.197 g, 0.5 mmol) to afford the nitrile adduct as a white colored solid (m.p. 198 –203 ˚C) (0.101 g, 60%). Compound was purified by flash column chromatography (Rf = 0.33 (40% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.22 – 7.14 (m, 5H), 7.03 (t, J = 7.9 Hz, 2H), 6.66 (t, J = 7.3 Hz, 1H), 6.50 (d, J = 7.8 Hz, 2H), 6.47 (s, 1H), 4.94 (hept, J = 6.2 Hz, 1H), 4.68 (s, 1H), 4.52 (d, J = 5.9 Hz, 1H), 4.10 (dd, J = 9.7, 6.6 Hz, 1H), 3.50 (d, J = 9.7 Hz, 1H), 1.16 (d, J = 6.3 Hz, 3H), 0.82 (d, J = 6.3 Hz, 3H). 13C{1H} (151 MHz, CDCl3): δ 172.0, 169.4, 145.3, 139.1, 128.6, 128.2, 128.0, 127.4, 118.5, 114.3, 70.2, 69.8, 49.1, 47.6, 21.5, 21.0. HRMS


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(ESI-TOF): calc’d for C20H23N2O3 [M+H]+ 339.1703; found 339.1703. Isopropyl-3-((4-methoxyphenyl)amino)-2-oxo-4-phenylpyrrolidine-3-carboxylate (36b). The general procedure, Method A was followed using diisopropyl 2-(cyano(phenyl)methyl)-2((4-methoxyphenyl)amino)malonate, 35b (0.212 g, 0.5 mmol) to afford the nitrile adduct as a white colored solid (m.p. 185 – 187 ˚C) (0.088 g, 48%). Compound was purified by flash column chromatography (Rf = 0.35 (40% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.23 – 7.15 (m, 5H), 6.76 (s, 1H), 6.63 (d, J = 8.7 Hz, 2H), 6.48 (d, J = 8.7 Hz, 2H), 4.95 (hept, J = 6.1 Hz, 1H), 4.47 (d, J = 5.5 Hz, 1H), 4.43 (s, 1H), 4.04 (dd, J = 9.6, 6.8 Hz, 1H), 3.68 (s, 3H), 3.50 (d, J = 9.7 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H), 0.88 (d, J = 6.2 Hz, 3H). 13C{1H} (151 MHz, CDCl3): δ 172.3, 169.6, 152.8, 139.1, 138.9, 128.2, 128.0, 127.3, 115.9, 114.2, 70.1, 70.0, 55.6, 49.2, 47.4, 21.5, 21.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H25N2O4 369.1809; found 369.1809. Isopropyl-4-(4-fluorophenyl)-2-oxo-3-(phenylamino)pyrrolidine-3-carboxylate (36c). The general procedure, Method A was followed using diisopropyl 2-(cyano(4-fluorophenyl)methyl)-2-(phenylamino)malonate, (35c) (0.206 g, 0.5 mmol) to afford the nitrile adduct as a white colored solid (m.p. 191 –193 ˚C) (0.112 g, 63%). Compound was purified by flash column chromatography (Rf = 0.35 (40% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.16 (AA’ part of AA’BB’X spin system, 2H, H-2’/H-6’), 7.04 (m, 2H, H-3/H-5), 6.85 (BB’ part of AA’BB’X spin system, 2H, H-3’/H-5’), 6.67 (m, 1H, H-4), 6.47 (m, 2H, H-2/H-6), 6.46 (s, br, amide NH), 4.93 (hept, J = 6.3 Hz, 1H, isopropyl methine), 4.71 (s, br, amine NH), 4.53 (d, J = 6.5 Hz, 1H, benzylic H), 4.12 (dd, J = 9.8, 6.6 Hz, 1H, one of the CH2 protons), 3.45 (ddd, J = 9.8, ≈1.7, ≈1.3 Hz, 1H, the other CH2 proton), 1.16 (d, J = 6.3 Hz, 3H, isopropyl methyl), 0.81 (d, J = 6.3 Hz, 3H, other isopropyl methyl). 13C{1H} (126 MHz, CDCl3): δ 171.8 (carbonyl), 169.3 (carbonyl), 161.9 (d, 1 JCF = 245.8 Hz, C-4’), 145.1 (C-1), 135.1 (d, 4JCF = 3.4 Hz, C1’), 129.5 (d, 3JCF = 8.0 Hz, C-2’/C-6’), 128.7 (C-3/C-5), 118.6 (C-4), 115.1 (d, 2JCF = 21.3 Hz, C-3’/C-5’), 114.2 (C-2/C-6), 70.4 (isopropyl methine), 69.7 (d, 6JCF ≈ 0.8 Hz, quaternary aliphatic carbon), 48.2 (s, br, unresolved 5JCF, benzylic CH), 47.9 (CH2), 21.5 [isopropyl methyl (correlating with the methyl 1H signal at δ1.16 in HSQC spectrum)], 21.0 [other isopropyl methyl (correlating with the methyl 1H signal at δ0.81 in HSQC spectrum)]. 19F NMR (471 MHz, CDCl3): δ −114.1 (X part of AA’BB’X spin system: tt, 3JHF = 8.6 Hz, 4JHF = 5.3 Hz). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H22 FN2O3 357.1609; found 357.1628. The COSY spectrum (p. S423) immediately identifies the two pairs of coupled protons (H-2’/H-6’ and H-3’/H-5’) in the pfluorophenyl ring and the three sets of coupled protons (H-2/H6, H-3/H-5, and H-4) in the -NH-phenyl ring. In the cluster of signals centered at δ6.85 (p. S505), the three tallest signals appear to result from splitting the two most prominent peaks of the BB’ part of the AA’BB’ pattern into two doublets (with the central components overlapping) exhibiting the 3JHF = 8.6 Hz separation seen in the 19F spectrum (p. S422). The HSQC spectrum (pp. S504 and S505) shows that the 1H signal at δ6.85 correlates with the 13C doublet centered at δ115.1. This HSQC correlation for H-3’/C-3’ and H-5’/C-5’ exhibits the expected pair of tilted contours that reflect 3JHF in the 1H dimension and 2JCF in the 13C dimension (p. S425). The relatively shielded aromatic carbon adjacent to CF is consistent with the corresponding carbon in 4-fluorotoluene, where C-3/C-5 gives a signal at

δ114.0.52 In the cluster of signals centered at δ7.16 (p. S506), the four tallest signals appear to result from splitting the two most prominent peaks of the AA’ part of the AA’BB’ pattern into two doublets exhibiting the 4JHF = 5.3 Hz separation seen in the 19F spectrum. The HSQC spectrum shows that the 1H signal at δ7.16 correlates with the 13C doublet centered at δ129.5. This HSQC correlation for H-2’/C-2’ and H-6’/C-6’ also exhibits the expected pair of tilted contours that reflect the smaller 4JHF in the 1H dimension and the smaller 3JCF in the 13C dimension (p. S426). The relative intensities of the 1H signals for the three aromatic multiplets of the -NH-phenyl group, the corresponding 13C chemical shifts, and the HSQC spectrum provided unambiguous assignments for these three types of CH groups. The single-intensity 1H multiplet at δ6.67 can result only from H-4, while the very shielded aromatic 13C signal at δ114.2 clearly results from C-2/C-6 in light of 13C chemical shift data for aniline and N-substituted anilines.53 Thus, the HSQC spectrum indicates that C-4 gives the signal at δ118.6, while H-2/H-6 give the double-intensity multiplet at δ6.47. By elimination, H-3/H-5 give the double-intensity multiplet at δ7.04, and C-3/C-5 give the signal at δ128.7. As expected, ordinary (i.e., untilted) contours are observed for the three HSQC correlations in the phenyl group of -NH-phenyl: at δH6.47 / δC114.2 for H-2/C-2 and H-6/C-6, at δH7.04 / δC128.7 for H3/C-3 and H-5/C-5, and at δH6.67 / δC118.6 for H-4/C-4 (pp. S424 and S427). The equal J values (9.8 Hz) exhibited by the multiplets at δ4.12 and δ3.45 indicated that these signals resulted from the CH2 protons; by elimination, the multiplet at δ4.53 resulted from the benzylic CH proton. The additional J coupling for the CH2 proton at δ3.45 (compared to that at δ4.12) results from coupling with the amide proton, as shown by the COSY spectrum. The NOE observed with mixing times of 0.10, 0.20, and 0.40 s (pp. S428-S430) between the -NH-phenyl H2/H-6 protons at δ6.47 and the amine proton at δ4.71 is reasonable. The NOE observed between the -NH-phenyl H-2/H-6 protons at δ6.47 and the benzylic proton at δ4.53 suggests that -NH-phenyl and the benzylic proton have a cis relationship because it would be hard for the phenyl ring to approach the benzylic proton with the other stereochemistry. Similarly, the weak cross peak between the amine proton at δ4.71 and the p-fluorophenyl H-2’/H-6’ protons at δ7.16 suggests that the amine proton and p-fluorophenyl group have a trans relationship. With mixing times of 0.10, 0.20, and 0.40 s, the CH2 proton at δ3.45 exhibits an NOE with the p-fluorophenyl H-2’/H-6’ protons at δ7.16 but not with the phenyl H-2/H-6 protons at δ6.47. Thus, the CH2 proton at δ3.45 appears to be cis to the p-fluorophenyl group and trans to the -NH-phenyl group. Finally, we note the clearly unequal peak heights for the two components of the 1JCF doublet centered at δ161.9 in the standard 13C spectrum (p. S420, 5.77s FID processed with just 0.2 Hz of line broadening). In contrast, the peak heights are essentially the same (at this level of S/N) for the long-range JCF doublets. The unequal peak heights for the two components of the 1JCF doublet apparently result from 13C-19F cross-correlated relaxation, as previously shown for the 1JCF splitting in 1,3-difluorobenzene.54 Pictorial representation of NOE correlation in 36c:



Isopropyl-4-(4-chlorophenyl)-2-oxo-3-(phenylamino)pyrrolidine-3-carboxylate (36d). The general procedure, Method B was followed using diisopropyl 2-((4-chlorophenyl)(cyano)methyl)-2-(phenylamino)malonate, (35d) (0.214 g, 0.5 mmol) and BH3.Me2S (0.380 g, 5 mmol) to afford the nitrile adduct as a white colored solid (m.p. 184 –186 ˚C) (0.069 g, 37%). Compound was purified by flash column chromatography (Rf = 0.35 (40% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.13 (s, 4H, H-2’/H-6’, H-3’/H-5’), 7.05 (m, 2H, H-3/H-5), 6.68 (m, 1H, H-4), 6.47 (m, 2H, H-2/H-6), 6.43 (s, br, amide NH), 4.92 (hept, J = 6.3 Hz, 1H, isopropyl methine), 4.72 (s, br, amine NH), 4.53 (dd, J = 6.5, ≈0.8 Hz, 1H, benzylic H), 4.12 (dd, J = 9.8, 6.6 Hz, 1H, one of the CH2 protons), 3.43 (ddd, J = 9.8, ≈1.7, ≈1.1 Hz, 1H, the other CH2 proton), 1.16 (d, J = 6.3 Hz, 3H, isopropyl methyl), 0.79 (d, J = 6.3 Hz, 3H, other isopropyl methyl). 13C{1H} (126 MHz, CDCl3): δ 171.7 (carbonyl), 169.2 (carbonyl), 145.1 (C-1), 137.9 (C-1’), 133.1 (C-4’), 129.3 (C2’/C-6’ or C-3’/C-5’), 128.8 (C-3/C-5), 128.4 (C-3’/C-5’ or C2’/C-6’), 118.7 (C-4), 114.2 (C-2/C-6), 70.4 (isopropyl methine), 69.7 (quaternary aliphatic carbon), 48.3 (benzylic CH), 47.7 (CH2), 21.5 [isopropyl methyl (correlating with methyl 1H signal at δ1.16 in HSQC spectrum)], 20.9 [other isopropyl methyl (correlating with methyl 1H signal at δ0.79 in HSQC spectrum)]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H22ClN2O3 373.1313; found 373.1309. The 1H spectrum indicated that the p-chlorophenyl ring provided a very unusual example of H-2’/H-6’ and H-3’/H-5’ having the same chemical shift (δ7.13) and thus giving just a singlet55,56 that exhibits no correlations in the COSY spectrum (p. S434). Consequently, an HSQC spectrum (p. S435) indicated that two carbons (δ129.3 and δ128.4) exhibited correlations at this 1H frequency. The equal J values (9.8 Hz) exhibited by the multiplets at δ4.12 and δ3.43 indicated that these signals resulted from the CH2 protons; by elimination, the multiplet at δ4.53 resulted from the benzylic CH proton. The additional J coupling for the CH2 proton at δ3.43 (compared to that at δ4.12) results from coupling with the amide proton, as shown by a COSY spectrum. The relative intensities of the 1H signals for the three aromatic multiplets of the -NH-phenyl group, the corresponding 13C chemical shifts, and the HSQC spectrum provided unambiguous assignments for these three types of CH groups. The single-intensity 1H multiplet at δ6.68 can result only from H-4, while the very shielded aromatic 13C signal at δ114.2 clearly results from C-2/C-6 in light of 13C chemical shift data for aniline and N-substituted anilines (ref. B). Thus, the HSQC spectrum indicates that C-4 gives the signal at δ118.7, while H-2/H-6 give the double-intensity multiplet at δ6.47. By elimination, H-3/H-5 give the double-intensity multiplet at δ7.05, and C-3/C-5 give the signal at δ128.8. Thus, the NOE observed with mixing times of 0.10, 0.20, and 0.40 s (pp. S436-S438) between the -NH-phenyl H-2/H-6 protons at δ6.47 and the amine proton at δ4.72 is reasonable. The NOE observed

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between the -NH-phenyl H-2/H-6 protons at δ6.47 and the benzylic proton at δ4.53 suggests that -NH-phenyl and the benzylic proton have a cis relationship because it would be hard for the phenyl ring to approach the benzylic proton with the other stereochemistry. Similarly, the weak cross peak between the amine proton at δ4.72 and the p-chlorophenyl protons at δ7.13 suggests that the amine proton and p-chlorophenyl group have a trans relationship. With mixing times of 0.10, 0.20, and 0.40 s, the CH2 proton at δ3.43 exhibits an NOE with the p-chlorophenyl protons at δ7.13 but not with the -NH-phenyl H-2/H-6 protons at δ6.47. Thus, the CH2 proton at δ3.43 appears to be cis to the p-chlorophenyl group and trans to the -NH-phenyl group.

ASSOCIATED CONTENT Complete optimization tables, X-ray crystallography data, computational study details, 1H, 13C, DEPT-135 13C, DEPT-90 13C, COSY, NOE, HSQC, HMBC NMR spectra and HPLC chromatograms. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Authors [email protected], [email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT L.K. gratefully acknowledges the generous financial support of Rice University, the National Institutes of Health (R01 GM114609-04), the National Science Foundation (CAREER:SusChEM CHE-1546097), the Robert A. Welch Foundation (grant C-1764), Amgen (2014 Young Investigators’ Award for LK) and Biotage (2015 Young Principal Investigator Award) that are greatly appreciated. D.H.E. thanks BYU and the Fulton Supercomputing Lab. X-Ray crystallographic data was collected at the Center for Nanostructured Materials at the University of Texas at Arlington.

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