Catalytic, Enantioselective Î²-Protonation through a ... - ACS Publications

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Catalytic, Enantioselective β‑Protonation through a Cooperative Activation Strategy Michael H. Wang,† David Barsoum,† C. Benjamin Schwamb,† Daniel T. Cohen,† Brian C. Goess,‡ Matthias Riedrich,† Audrey Chan,† Brooks E. Maki,† Rama K. Mishra,† and Karl A. Scheidt*,† †

Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Northwestern University, Silverman Hall, Evanston, Illinois 60208, United States ‡ Department of Chemistry, Furman University, Greenville, South Carolina 29613, United States S Supporting Information *

ABSTRACT: The NHC-catalyzed transformation of unsaturated aldehydes into saturated esters through an organocatalytic homoenolate process has been thoroughly studied. Leveraging a unique “Umpolung”mediated β-protonation, this process has evolved from a test bed for homoenolate reactivity to a broader platform for asymmetric catalysis. Inspired by our success in using the β-protonation process to generate enals from ynals with good E/Z selectivity, our early studies found that an asymmetric variation of this reaction was not only feasible, but also adaptable to a kinetic resolution of secondary alcohols through NHC-catalyzed acylation. In-depth analysis of this process determined that careful catalyst and solvent pairing is critical for optimal yield and selectivity; proper choice of nonpolar solvent provided improved yield through suppression of an oxidative side reaction, while employment of a cooperative catalytic approach through inclusion of a hydrogen bond donor cocatalyst significantly improved enantioselectivity.

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INTRODUCTION Discovering enabling catalytic processes that transform inexpensive and abundant achiral molecules into high-value chiral materials remains a major goal for chemical synthesis. Over the last few decades, N-heterocyclic carbene (NHC) catalysis has risen to the forefront of stereoselective synthesis.1−4 These versatile small organocatalysts participate in novel, Umpolung reactivity as well as normal polarity-based transformations.5−8 Our initial efforts to develop and study a new reactive intermediate, a catalytic homoenolate, led to the development of the β-protonation of enals.9 In seeking to expand upon the applications of this internal redox process, our subsequent work has focused on the development of an asymmetric variant. Pursuit of this challenging goal revealed critical solvent effects on mechanistic pathways and enantioselectivities, as well as useful insights beyond β-protonation and into general homoenolate reactivity.10,11 Importantly, we found that catalyst and substrate modification produced marginal improvements in levels of enantioselectivity. In contrast to a single-catalyst system, cooperative catalysis has recently emerged as a powerful strategy that employs two catalysts to achieve high levels of efficiency and stereoselectivity.12−17 Taking inspiration from nature, we have implemented a cooperative catalytic system in which separate organocatalytic species operate cooperatively to achieve high yield and selectivity for the first highly enantioselective β-protonation of α,β-unsaturated aldehydes.18 We have leveraged the development of the asymmetric β-protonation reaction as both an opportunity to address a challenging synthetic © 2017 American Chemical Society

transformation as well as a platform for studying NHCgenerated homoenolate intermediates. A hydrogen substituent is effectively the simplest functional group in chemistry, and the manipulation of this versatile and ubiquitous atom is the basis of many modern catalytic processes.19,20 Nonetheless, it is still difficult to control stereoselectivity when installing a hydrogen at a prochiral face of an achiral molecule. Significant effort has been directed toward asymmetric reductions,21,22 including transfer hydrogenation processes, which have emerged as the industry standard.23,24 By comparison, asymmetric protonations have only recently been examined as a potential avenue for asymmetric catalysis.25,26 Methods for installing this small synthetic handle via asymmetric protonation would provide an atom-economical way to access tertiary stereocenters. Many natural products and biologically active compounds contain carbonyl groups with α-stereocenters (Figure 1).25 With the prevalence of these tertiary centers, it is not surprising that enantioselective protonation is found in biological syntheses.27−29 Translating this fundamental process to laboratory settings poses several challenges.25,30 The various Lewis and Brønsted basic entities in a reaction can promote rapid proton exchange, which makes controlling the delivery of a proton problematic. Additionally, the conditions employed to promote enolate formation must be mild and exclusively selective for the substrate, because the same reagents used to generate the prochiral enolate can also racemize the product. Finally, the Received: February 11, 2017 Published: April 25, 2017 4689

DOI: 10.1021/acs.joc.7b00334 J. Org. Chem. 2017, 82, 4689−4702

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The Journal of Organic Chemistry

imparting significant enantioinduction at a remote site from the carbonyl.

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RESULTS AND DISCUSSION Early in our NHC catalysis investigations with acylsilanes for carbonyl anion generation,49−53 we began exploring methods of generating homoenolates9 and reacting these unique intermediates with the simplest electrophile, a proton. Alcohols were envisaged as an ideal reagent, functioning as both the proton source and a nucleophile for catalyst regeneration. Initial screening focused on the use of a single alcohol (Table 1). Even Table 1. Initial Screen for β-Protonation

Figure 1. Natural products and bioactive molecules with αstereocenters.

generation of the nucleophile can be complicated by the enolate geometry, as Z- and E- enolates give rise to enantiodivergent adducts. Early attempts at asymmetric protonation gave moderate yields, even at cryogenic temperatures.31,32 In recent decades, several research groups have developed various procedures for asymmetric protonation of carbanions in the α-position relative to a carbonyl. Common to these different methods is the necessity to generate an enol or enolate intermediate, and numerous innovations have addressed ways to generate such nucleophiles,33,34 including cleaving silyl enol ethers,35,36 decarboxylation,37−39 addition to ketenes,40 and conjugate additions.41,42 Asymmetric α-protonations have also been studied through the lens of NHC catalysis. Rovis and coworkers found that exposing α,α-dihaloaldehydes to chiral NHCs could provide enantioenriched aryl esters43 or acids.44 Glorius and co-workers have accessed similar prochiral enolate intermediates through a Stetter reaction.45 Ye and co-workers have utilized NHCs as acylation catalysts to generate enolates from ketenes, which undergo asymmetric protonations in high yields and good enantioselectivities.46 Shortly thereafter, Smith and co-workers published a similar reaction to the Ye report, which used lower catalyst loadings and milder conditions.47 Recently, Chi and co-workers have demonstrated an efficient method of enriching α,α-disubstituted esters via an NHCcatalyzed dynamic kinetic resolution.48 While asymmetric α-protonation has been well studied, the analogous process of asymmetric β-protonation (Scheme 1) has

entry

ROH

1 2 3 4 5 6 7 8

EtOH CF3CH2OH PhOH 4-NO2-PhOH BnOH BnOH BnOH BnOH

pKa(H2O) catalyst (mol %) 16 12 10 7 15 15 15 15

A (30 mol %) A (30 mol %) A (30 mol %) A (30 mol %) A (30 mol %) B (10 mol %) C (20 mol %) C (5 mol %)

additive

yield (%)

PhOH PhOH PhOH PhOH

30 17 42 0 58 47 82 83

at 100 °C in toluene, the reaction only produced ethyl hydrocinnamate in low yield (entry 1). It was hypothesized that employing more acidic alcohols such as 4-nitrophenol or trifluoroethanol (entries 2−4) would further promote the protonation process. However, what we observed was that these alcohols actually led to decreased yields, presumably due to an inadequate degree of nucleophilicity for the regeneration of the catalyst. Additionally, the alcohol’s higher acidity could suppress the amount of carbene generated in situ. During this solvent screen, it was discovered that a significant amount of ethyl hydrocinnamate was formed alongside the expected phenolic ester when the reaction was conducted in chloroform (Scheme 2). Because the ethyl ester was only Scheme 2. Fortuitous Results

Scheme 1. α-Protonation versus β-Protonation

observed when the solvent was purified by passing through a column of alumina rather than by distillation, this led to the hypothesis that the ethanol stabilizer in chloroform was a competing alcohol. Further experiments verified that the proton source and acylation/regeneration substrates could be distinct chemical entities. With this fortuitous discovery, the optimization of reaction conditions and exploration of substrate scope proceeded rapidly (Table 1).9 A catalyst screen first identified benzimidazolium precatalyst C, which gave the

received much less attention, presumably due to the lack of mild methods to access homoenolates prior to 2004.30 Many groups have successfully addressed the challenges associated with α-protonation and have achieved high enantioselectivity in the ketone products, but β-protonation remains especially difficult due to two significant challenges that are distinct from the analogous α-protonation process: (1) generating the required homoenolate under catalytic conditions and (2) 4690


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The Journal of Organic Chemistry highest yield and could be used in as low as 5 mol % loading without impact on yield (entry 8). With these conditions in hand, we then explored the range of alcohols compatible with β-protonation (Table 2). The reaction

Table 3. Compatibility of Sterically Hindered Phenols

Table 2. Survey of Alcohols

Scheme 3. Kinetic Resolution of Secondary Alcohols

tolerated primary and secondary alcohols (entries 1−4). When using chiral secondary alcohols, racemization of neither the alcohol starting material nor the ester product was observed (entries 5 and 6). Use of bulkier nucleophiles, such as tertbutanol, gave only the phenolic ester product (entry 7). Overall, benzyl alcohol gave the saturated ester product in the highest yield (entry 3). We generally observed higher levels of phenolic ester byproduct when sterically hindered alcohols were employed (e.g., cyclohexanol). In efforts to disfavor this side reaction while maintaining proton donors with similar acidity, we explored more sterically hindered phenols (Table 3). Gratifyingly, we found that 2,6-substitution minimized phenol incorporation (entry 2). Further increasing the size of the substituents, as for 2,6-di-tert-butyl-4-methylphenol (BHT), resulted in complete suppression of the side reaction (entry 3). The tolerance of the β-protonation reaction to secondary alcohols also raised the possibility for a kinetic resolution of chiral secondary alcohols through the use of chiral NHC precatalysts. Indeed, when chiral catalyst D was employed, phenylethanol could be isolated with a selectivity of s = 4.8 (Scheme 3). This result demonstrates the influence of the NHC on the acyl azolium intermediate just prior to the final acylation/turnover step (vide infra). This marks one of the first examples of an NHC-catalyzed kinetic resolution of alcohols.54−61 After establishing alcohols as compatible acylation reagents, we next explored the use of other turnover reagents. Many amine nucleophiles such as anilines, sulfonamides, amides, carbamates, morpholinones, and maleimides were examined (Scheme 4). As NHC-catalyzed amide formation is not commonly reported in the literature, we were not surprised that only the β-amino alkylidene malonate 20 delivered the

Scheme 4. Amines as Turnover Reagents

amide product. The remaining amines produced only their corresponding phenyl esters. In those cases, attempts to suppress ester formation by removing the phenol additive led to no reaction. With optimized conditions in hand, we explored the range of enals compatible with our system (Table 4). The reaction tolerated many aromatic enals, including electron-rich and electron-deficient cinnamaldehydes (entries 1−3), as well as an aliphatic β-substituent (entry 4). Furthermore, dienyl substrates also gave esters in good yields (entry 5). Employing α-methyl cinnamaldehyde as a substrate required extended periods for completion of the reaction, approximately 48 h as compared to 2−6 h for all other substrates (entry 6). This is presumably due to the allylic strain caused by the α-substituent, which hinders formation of a fully conjugated system, and thus nucleophilic character at the β-position.62 Finally, we explored β4691


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The Journal of Organic Chemistry Table 4. Optimized NHC-Catalyzed β-Protonation

Scheme 5. Proposed Mechanism for β-Protonation

entry

R

R1

R2

yield (%)

1 2 3 4 5 6 7 8 9

Ph 4-MeO-Ph 4-Cl-Ph n-propyl H3C(CHCH) Ph Ph 4-Cl-Ph CH3

H H H H H H Ph Ph CH3

H H H H H CH3 H H H

82 76 71 90 70 82 82 86 NR

disubstituted compounds. While aldehydes with aryl substituents were competent substrates (entries 7 and 8), aldehydes with β,β-dialkyl substitution were unreactive (entry 9). We also explored the possibility of applying a similar set of reaction conditions to the β-protonation of ynals (Table 5).10 We began investigating an asymmetric β-protonation of homoenolates by incorporating various chiral NHC catalysts and/or reagents.10 Our initial studies indicated that chiral benzimidazolium salts (e.g., D or F) generated the desired product in moderate yield, but as a racemic mixture (Scheme 6). Switching to imidazolidinium salts gave no product at all (G

Table 5. β-Protonation of Ynals

entry

R

NHC

yield (%)

E/Z

1 2 3 4 5 6

Ph Ph 4-Cl-Ph 4-Cl-Ph 4-MeO-Ph TBSO(CH2CH2)

C E C E C C

65 67 56 59 10 0

3:1 >20:1 3:1 >20:1 4:1

Scheme 6. Exploration of Chiral NHCs for Asymmetric βProtonation

By using IMes (E) and employing BHT as the proton source, we were able to generate unsaturated esters with high E/Z selectivity and in good yields. While these results agree with those of Zeitler,63 we believe that the use of BHT as an additive serves as an acidic proton source and allows us to obtain similar yield in the same time frame with lower reaction temperatures. Aryl ynals were found to be suitable substrates for the transformation; however, aliphatic ynals yielded no product. In comparison, the conditions developed by Zeitler do tolerate aliphatic ynals, which convert in good yields to the corresponding aliphatic enals, presumably due to the use of a weaker base.63 A plausible mechanism for β-protonation is as follows (Scheme 5): carbene 23 (generated in situ) addition to enal 1 generates tetrahedral intermediate 24, and subsequent proton transfer yields extended Breslow intermediate 25. Protonation of the homoenolate and then tautomerization generates acyl azolium 27, whereupon acylation of the alcohol delivers the desired product 5 and regenerates the catalyst. This early methodology was key in demonstrating the ability to extend NHC Umpolung reactivity to new reactions and substrate classes. Homoenolates could be generated and trapped with a simple proton electrophile. Most interestingly, β,β-disubstituted enals can be protonated, thus raising the possibility of developing an enantioselective variant.

or H), underscoring the marked difference in reactivity between benzimidazolium and imidazolium-derived NHCs. We also explored an alternative approach to asymmetric protonation whereby we attempted to introduce asymmetry via the acidic additive, rather than by the NHC precatalyst structure. The use of optically active alcohols such as BINOL and TADDOL in place of BHT with NHC precatalyst C led to only trace amounts of product, even after allowing the reaction to proceed over several days. Given this low reactivity, we were curious as to the origin of the proton in the asymmetric protonation step. We proposed that neither BINOL nor TADDOL additives were operative as asymmetric proton sources under our reaction conditions. 4692


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The Journal of Organic Chemistry Consequently, benzyl alcohol or the conjugate acid of the base (DBU) could likely be involved in promoting protonation of the NHC-bound homoenolate. Indeed, when these additives were omitted from our standard reaction conditions, we observed similarly low conversion (Scheme 7a). To test the

Table 6. Asymmetric Protonation of Homoenolate Equivalents

Scheme 7. Control Experiments

hypothesis that the conjugate acid of the base is a proton source, we used free carbene I (Scheme 7b), which eliminated the necessity of adding base to generate the carbene in situ from the precatalyst. No reaction was observed under these conditions, which suggested that the conjugate acid of the base used to generate the NHC may contribute to the asymmetric protonation step. With this pathway of protonation in mind, we hypothesized that the use of chiral bases might open a potential avenue for asymmetric protonation of NHC-bound homoenolates. However, upon surveying a variety of chiral bases, including alkylated Simpkins’ base derivatives, sparteine, and cinchona alkaloid derivatives, we found that all furnished racemic products. We then returned our focus toward exploring the role of the NHC catalyst on the enantioselectivity of β-protonation by modifying the structure of the chiral NHC precatalysts employed. We surveyed catalysts that were more likely to project toward the remote β-reaction site when bound to the intermediate homoenolate, thereby inducing substrate-controlled selectivity in the protonation step. Gratifyingly, amino alcohol derived azolium salts were able to catalyze the reaction under milder conditions, giving moderate enantioselectivities (Table 6). Increasing the size of the substituent at the asymmetric center of the NHC (α to the azolium core) also increased the level of enantioselectivity observed in the reaction (entries 1, 4, and 5). This trend offers some illumination as to why other NHC substructures we had previously screened failed to impart any facial bias on the homoenolate protonation. When geminal substitution was introduced adjacent to the NHC side chain, we observed an increase in selectivity as well (entries 2−4). We hypothesize that steric congestion at this site helps to hinder free rotation of the side chain, resulting in more effective projection toward the β-position. Ultimately, tryptophan derived M was found to furnish β-protonation product with the highest enantioselectivity (entry 5). Saturated ester products (31) were generated along with their corresponding unsaturated esters 32 as inseparable byproducts of the reaction. These oxidized products are thought to be derived from a Tischenko-like reaction pathway (Scheme 8).64−68 As opposed to the desired proton transfer pathway to generate extended Breslow intermediate 24, collapse of tetrahedral intermediate 33 can generate a hydride

entry

azolium salt

yield (%) of 31 + 32

er of 31

1 2 3 4 5 6 7

I J K L M N O

51 trace trace 58 45 0 0

67:33 55:45 62:38 78:22 80:20

Scheme 8. Proposed Mechanism for Oxidative Pathway

equivalent, which reduces another equivalent of the starting material. Oxidized unsaturated acyl azolium 35 then acylates the alcohol to furnish byproduct 32 with concomitant catalyst regeneration. The divergent pathways of β-protonation and oxidation are evidently both possible under the same reaction conditions, which posed a significant challenge for further reaction development. With the proposed mechanisms for β-protonation and oxidation in mind, we hypothesized that solvent effects would have the greatest impact on reactivity. Although we had determined that the polarity of the reaction solvent had minimal impact on β-protonation in our initial studies, we proposed that the oxidative pathway would be more sensitive to this factor due to the generation of charged species in the hydride donation pathway (i.e., the acyl azolium and the reduced alkoxide). Presumably, greater solvent polarity would promote better solvation of the charged intermediates, while nonpolar solvents should correspondingly disfavor the oxidative pathway. These predictions were examined both experimentally and computationally,11 and the agreement of the data obtained confirmed that the use of a nonpolar solvent such as toluene 4693


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The Journal of Organic Chemistry could give predominantly the desired β-protonation product in good yield with minimal impact on enantioselectivity (Table 7).

Table 9. Catalyst Screen

Table 7. Solvent Effect on β-Protonation

entry

solvent

yield (%, 31 + 32)

ratio 31:32

er of 31

1 2

THF toluene

58 81

3:1 13:1

78:22 77:23

Although encouraging progress had been made in the area of NHC-catalyzed asymmetric β-protonation, the methodology still stood to benefit from improvements in yield and selectivity. Further survey of base and solvent combinations revealed that dichloroethane (DCE) and Hünig’s base were optimal for favoring the β-protonation pathway, while avoiding the undesired oxidative pathway (Table 8). These conditions delivered higher levels of enantioselectivity, but we still observed moderate yields (entry 1). We did observe tolerance for cyclic substitution on the cinnamaldehyde substrate (entry 2), as well as electron-rich (entry 4) and electron-deficient substituents (entries 5−6). While the enantioselectivity of the β-protonation could be further improved by conducting the reactions at 0 °C, they did not go to completion even after 4 days (not shown). All of the β,β-disubstituted enal substrates we had tried up to this point had possessed either aryl/aryl, aryl/alkyl, or alkyl/ alkyl substitution. The enantioselective protonation reactions were conducted at 23 °C but did not achieve total conversion of substrate, even after extended reaction times of 96 h. The only β-protonation conditions that proceeded to completion in shorter time periods were the nonenantioselective variants first disclosed in 2004, and these reactions had been heated to 100 °C.9,69 As expected, attempts at improving conversion under the newly developed protocol by increasing the temperature of the reaction led to lower observed enantioselectivity. It was hypothesized that the homoenolate is likely a high-energy intermediate, and therefore lowering the energy of this intermediate by introducing electron-withdrawing groups at its β-position should lead to a faster, more efficient reaction. To test this hypothesis, we synthesized oxobutenoate substrate 36 and exposed it to our β-protonation conditions (Table 9). After examining a variety of conditions, we were

entry

NHC

er

time (h)

conversion (%)

1 2 3 4 5 6

M L K I Q R

55:45 58:42 66:34 57:43 58:42 75:25

18 12 2 12 18 18

100 100 100 100 100 100

pleased to observe 100% conversion (as determined by 1H NMR) in under 18 h and high isolated yield (entry 1). Despite low observed selectivity (55:45 er), we decided to explore this potential substrate further due to its high reactivity. A quick survey of catalysts revealed an intriguing trend: as the NHC side chain decreased in steric bulk, the enantioselectivity of the reaction increased (entries 2−3). This observation was in agreement with our prior studies on solvent effects, which revealed that a phenyl side chain gave greater selectivity than indole.11 Our current understanding is that the combination of side chain and the vicinal geminal pair (Ph or Me) must be of a certain size for high selectivity: too small and there is little facial bias for protonation, while too large pushes the side chain out of optimal position. Interestingly, the more rigid aminoindanol catalysts (I and Q), relative standbys in NHC catalysis, gave lower levels of enantioselectivity (entry 4 and 5). When we tried the more sterically encumbered analogue, R, we observed an increase in enantioselectivity, as expected (entry 6). Despite the higher er, the lengthy synthesis of R and the lack of improved reaction time made catalyst K the more attractive and viable option for reaction development.70 These results further support our belief that the orientation of the side arm is as important as its size. We next turned our attention to optimizing the base used in the oxobutenoate version of the β-protonation reaction.

Table 8. New Solvent for Asymmetric β-Protonation

entry

R1

R2

NHC

base

solvent

yield (%)

er

1 2 3 4 5 6

Ph Ph Ph 4-MeO-Ph 4-CF3-Ph 2-F-Ph

Me −CH2CH2O− i-Pr Me Me Me

P L L L M L

i-Pr2NEt i-Pr2NEt K3PO4 i-Pr2NEt K3PO4 i-Pr2NEt

DCE DCE EtOAc DCE EtOAc DCE

48 66 51 30 39 43

92:8 85:15 78:22 85:15 80:20 68:32

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this process. These small molecule organocatalysts have been used for a wide array of reaction types, including aldol, Diels− Alder, Mannich, Friedel−Crafts addition, and conjugate addition reactions.71 Within this class, chiral thioureas have emerged as powerful HBD catalysts due to their high acidity (which promotes stronger binding), low Lewis basicity (which prevents oligomerization), and versatility (they are easily synthesized and modified from the chiral pool).72 The use of NHC/HBD cooperative catalysis entails challenges similar to those associated with the use of Brønsted acid cocatalysts, those principally being undesired quenching of the base prior to azolium deprotonation, or, alternatively, protonation of the free carbene rendering the catalyst ineffective. Moreover, if the general acid catalyst is too weak, the additive is ineffective, and the original reaction takes place without the benefit of cooperative catalysis. With these considerations in mind, we surveyed a range of HBD catalysts (Table 12). Chiral phosphoric acids provided

Experiments with chiral amine bases and achiral NHCs did not produce any selectivity, indicating that the conjugate acid of the base is likely participating in the asymmetric protonation step, analogous to our observations on the β-protonation of cinnamaldehyde derivatives. With these factors in mind, we screened a variety of amine bases (Table 10) and found that Table 10. Base Screen

Table 12. Effects of HBD Additives

tertiary amines gave the highest levels of enantioselectivity as compared to secondary amine bases (not shown) and inorganic bases (e.g., NaOAc, Cs2CO3, not shown). Chiral amines did not have any impact on selectivity as evidenced by identical enantioselectivities delivered by 45 and 46, and increased steric bulk of the amine substituents was also associated with decreased selectivity. While the reaction was somewhat insensitive to changes in the structure of the tertiary conjugate acid, it is probable that overall steric bulk does have some impact based on the general proficiency of tertiary amines to facilitate the reaction versus their secondary counterparts. Exhaustive optimization of the reaction variables led to only moderate improvements in observed enantioselectivity. As such, we sought to apply a cooperative catalysis strategy to this reaction, in hopes of increasing both its yield and its selectivity.18 A survey of Lewis acids, including the most generally effective activators of carbonyl systems (Ti(IV) and Mg(II)), generated similar levels of selectivity but with the cost of lengthened reaction times (Table 11). In a majority of reports on NHC/cooperative catalyst systems, the cocatalyst activates an electrophile through carbonyl activation. In particular, hydrogen-bond donor (HBD) catalysis has been shown to be extremely effective in

virtually no improvement in selectivity but required longer reaction times. It is important to note that there was slow conversion ( 0), nucleophilic addition of the NHC into the α,β-unsaturated aldehyde I is the rate-limiting step. This is

Figure 2. DFT calculations of extended Breslow intermediate.

through 1D NOESY where the methylene protons of 36 exhibited an NOE with the ortho-aryl-hydrogens of the thiourea 50 (see the Supporting Information). Combining the DFT calculations, observed NOE, knowledge of NHC catalysis, and the known activation modes of HBDs, intermediate 84 (Figure 3) emerges as the working stereochemical model for activation

Figure 3. Enantioinduction model.

and enantioinduction. The coordination of the HBD presumably increases the steric interaction proximal to the βposition of the homoenolate and allows for more selective protonation. This hypothesis is further supported by our substrate scope, which demonstrated increased enantioselectivity as the β-ester increased in steric size (Table 17) and decreased enantioselectivity when there were competing sites for hydrogen bonding (Table 16). A Hammett plot was constructed to further probe this NHC/HBD cooperative approach for β-protonation. For substrates bearing electron-donating groups (X = p-OMe, pMe) on their β-aryl substitutent, we observed a decrease in rate with respect to the unsubstituted β-phenyl analogue. Interestingly, we also observed a decrease in rate (albeit

Figure 4. Hammett plot and proposed mechanism. 4699


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transformations that do not operate efficiently with a single catalyst. While careful tuning of the catalysts may be required, as observed in our case, the operational simplicity of combining readily available catalysts facilitates rapid reaction development. This expansive study has important implications for the field of carbene catalysis. Base selection is one of the crucial determinants between enolate and homoenolate reactivity. Solvent polarity is often underappreciated in NHC catalysis, but it can clearly play a crucial part in promoting or suppressing reaction pathways. Other knowledge we have gained, such as selectivity trends in catalyst structure, reminds us that the NHC field is still an ever-evolving area of research and that many more exciting discoveries are destined to be uncovered. This cooperative system leverages distinct modes of reactivity to finally enable a challenging bond-forming reaction. It is anticipated that it will serve as one example of many to come of the continuum in reaction discovery and development.

consistent with previous mechanistic work by Bode et al., which shows that H-migration of the NHC-enal adduct II to form the Breslow intermediate III has a lower activation barrier than nucleophilic addition when the NHC bears an N-mesityl group.91 For electron-poor substrates (ρ < 0), the aromatic group is able to stabilize the anionic character of IV. This decreases the nucleophilicity of III/IV, suggesting C−H bond formation is the rate-limiting step. Alternatively, inductive effects may play a role in stabilizing the hemiacetal VII, making elimination and catalyst turnover rate limiting. Further mechanistic investigation is ongoing to understand the intricacies of the β-protonation pathway. On the basis of these mechanisitic studies, we propose the following reaction pathway (Scheme 11): initial deprotonation Scheme 11. Proposed Reaction Pathway

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EXPERIMENTAL SECTION

General procedures and analytical data for compounds 1−20,9 21− 35,10,11 and 36−8718 matched those found in the literature. General Information. All reactions were carried out under a nitrogen atmosphere in oven-dried glassware with magnetic stirring. THF, toluene, and DMF were purified by passage through a bed of activated alumina. Reagents were purified prior to use unless otherwise stated. 1,2-Dichloroethane (DCE) was distilled from CaH2 . Purification of reaction products was carried out by flash chromatography using EM Reagent silica gel 60 (230−400 mesh). Analytical thin layer chromatography was performed on EM Reagent 0.25 mm silica gel 60-F plates. Visualization was accomplished with UV light and ceric ammonium nitrate stain or potassium permanganate stain followed by heating. Infrared spectra were recorded on a Bruker Tensor 37 FT-IR spectrometer. 1H NMR spectra were recorded on AVANCE III 500 MHz with direct cryoprobe (500 MHz) spectrometer and are reported in ppm using solvent as an internal standard (CDCl3 at 7.26 ppm). Data are reported as ap = apparent, s = singlet, d = doublet, t = apparent triplet, q = quartet, m = multiplet, b = broad; coupling constant(s) in Hz; integration. Proton-decoupled 13C NMR spectra were recorded on an AVANCE III 500 MHz with direct cryoprobe (125 MHz) spectrometer and are reported in ppm using solvent as an internal standard (CDCl3 at 77.16 ppm). 19F NMR spectra were acquired at 26 °C on a 400 MHz Agilent 400MR-DD2 spectrometer equipped with a OneNMR probe and a 7600AS autosampler; this system was funded by NSF CRIF grant CHE-104873. Optical rotations were measured on a PerkinElmer model 341 polarimeter with a sodium lamp. Mass spectra were obtained on a WATERS Acquity-H UPLC-MS with a single quad detector (ESI) or on a Varian 1200 Quadrupole mass spectrometer and Micromass Quadro II spectrometer (ESI). Synthesis of Azolium Salt R. To an oven-dried round-bottom flask were added (1S,2R)-1-amino-7-methyl-2,3-dihydro-1H-inden-2ol (1.28 g, 7.84 mmol) and THF (Volume: 52.3 mL), and the resulting suspension was cooled to 0 °C. Sodium hydride (0.345 g, 8.63 mmol) was added, followed by dropwise addition of ethyl 2-chloroacetate (1.007 mL, 9.41 mmol). The reaction was warmed to room temperature and stirred for 16 h. Water was added, and the mixture was extracted with EtOAc (3×), washed with brine, dried over MgSO4, and concentrated to yield a white solid. The solid was dissolved in MeOH and dry-loaded onto silica gel. A Biotage column was run, and the product spots were isolated to give (4aS,9aR)-5-methyl-4,4a,9,9atetrahydroindeno[2,1-b][1,4]oxazin-3(2H)-one as a white solid (821 mg, 52% yield). Next, to a flame-dried Schlenk flask equipped with stirbar and septum was added (4aS,9aR)-5-methyl-4,4a,9,9atetrahydroindeno[2,1-b][1,4]oxazin-3(2H)-one (160 mg, 0.787 mmol). Dry CH2Cl2 (ratio 1.667, volume 2.5 mL) then was added, followed by trimethyloxonium tetrafluoroborate (128 mg, 0.866 mmol), and the resulting solution was stirred under static nitrogen for 18 h. Under positive nitrogen pressure, mesitylhydrazine (130 mg,

of the azolium salt gives the active catalyst species, the free carbene (85). Following addition of 85 to enal 36, a formal [1,2] proton shift gives extended Breslow intermediate (84). Squaramide 57 coordinates to the ester, providing additional steric interactions near the β-position, and enhances facial selectivity of the homoenolate addition. A subsequent protonation and tautomerization affords acyl azolium 86. Catalyst turnover can be enhanced by acyl transfer catalyst DMAP, which forms N-acylpyridinium 87 and regenerates the NHC catalyst. Finally, acylation of the alcohol regenerates DMAP and furnishes chiral succinate 37.

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CONCLUSION Emerging from a long journey of catalyst synthesis and reaction design, we have achieved a high yielding, highly enantioselective NHC-catalyzed β-protonation using a cooperative catalysis approach. This new cooperative process is a metal-free route to succinic esters, and the strategy of deploying multiple catalysts in unison expands upon the conceptual utility of organocatalysis while providing another avenue of research for 4700


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(18) Wang, M. H.; Cohen, D. T.; Schwamb, C. B.; Mishra, R. K.; Scheidt, K. A. J. Am. Chem. Soc. 2015, 137, 5891. (19) Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999. (20) C-H Activation; Yu, J.-Q., Shi, Z., Eds.; Springer Berlin Heidelberg: Berlin, 2010; Vol. 292. (21) Cho, B. T. Tetrahedron 2006, 62, 7621. (22) Cho, B. T. Chem. Soc. Rev. 2009, 38, 443. (23) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226. (24) Magano, J.; Dunetz, J. R. Org. Process Res. Dev. 2012, 16, 1156. (25) Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Nat. Chem. 2009, 1, 359. (26) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539. (27) Miyamoto, K.; Ohta, H. J. Am. Chem. Soc. 1990, 112, 4077. (28) Matsumoto, K.; Tsutsumi, S.; Ihori, T.; Ohta, H. J. Am. Chem. Soc. 1990, 112, 9614. (29) Matoishi, K.; Ueda, M.; Miyamoto, K.; Ohta, H. J. Mol. Catal. B: Enzym. 2004, 27, 161. (30) Oudeyer, S.; Brière, J.-F.; Levacher, V. Eur. J. Org. Chem. 2014, 2014, 6103. (31) Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9. (32) Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415. (33) Vedejs, E.; Kruger, A. W.; Lee, N.; Sakata, S. T.; Stec, M.; Suna, E. J. Am. Chem. Soc. 2000, 122, 4602. (34) Fehr, C. Angew. Chem., Int. Ed. 2007, 46, 7119. (35) Poisson, T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer, S.; Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090. (36) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246. (37) Brunner, H.; Baur, Markus A. Eur. J. Org. Chem. 2003, 2003, 2854. (38) Amere, M.; Lasne, M.-C.; Rouden, J. Org. Lett. 2007, 9, 2621. (39) Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039. (40) Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637. (41) Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159. (42) Nishimura, T.; Hirabayashi, S.; Yasuhara, Y.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 2556. (43) Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 16406. (44) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 2860. (45) Jousseaume, T.; Wurz, N. E.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1410. (46) Wang, X.-N.; Lv, H.; Huang, X.-L.; Ye, S. Org. Biomol. Chem. 2009, 7, 346. (47) Concellón, C.; Duguet, N.; Smith, A. D. Adv. Synth. Catal. 2009, 351, 3001. (48) Chen, X.; Fong, J. Z. M.; Xu, J.; Mou, C.; Lu, Y.; Yang, S.; Song, B.-A.; Chi, Y. R. J. Am. Chem. Soc. 2016, 138, 7212. (49) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314. (50) Mattson, A. E.; Scheidt, K. A. Org. Lett. 2004, 6, 4363. (51) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4932. (52) Mattson, A. E.; Bharadwaj, A. R.; Zuhl, A. M.; Scheidt, K. A. J. Org. Chem. 2006, 71, 5715. (53) Mattson, A. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 4508. (54) Suzuki, Y.; Yamauchi, K.; Muramatsu, K.; Sato, M. Chem. Commun. 2004, 2770. (55) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347. (56) De Sarkar, S.; Biswas, A.; Song, C. H.; Studer, A. Synthesis 2011, 2011, 1974. (57) Kuwano, S.; Harada, S.; Kang, B.; Oriez, R.; Yamaoka, Y.; Takasu, K.; Yamada, K.-i. J. Am. Chem. Soc. 2013, 135, 11485. (58) Lu, S.; Poh, S. B.; Siau, W.-Y.; Zhao, Y. Angew. Chem., Int. Ed. 2013, 52, 1731. (59) De Sarkar, S.; Biswas, A.; Samanta, R. C.; Studer, A. Chem. - Eur. J. 2013, 19, 4664.

0.866 mmol) was then added through the ground glass joint, the septum was replaced, and the resulting bright red solution was stirred under static nitrogen for 3 h. The solvent was removed slowly in vacuo. An oven-dried vacuum adapter was attatched. Chlorobenzene (ratio 1.000, volume 1.5 mL) was then added through the reflux condenser, followed by freshly distilled triethoxymethane (0.917 mL, 5.51 mmol), and the resulting solution was refluxed under nitrogen at 110 °C for 16 h. Purification by a 25 g Biotage column (50% EtOAc/ hex, Rf = 0.4) gave azolium salt R as a tan powder (215 mg, 63% yield). 1H NMR (500 MHz, CDCl3): δ 10.23 (s, 1H), 7.25 (s, 1H), 7.21−7.12 (m, 2H), 6.99 (s, 2H), 6.02 (d, J = 3.9 Hz, 1H), 5.02 (dd, J = 4.2, 1.5 Hz, 3H), 3.14−3.07 (m, 2H), 2.36 (d, J = 16.7 Hz, 6H), 2.04 (s, 6H), 1.63 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 150.1, 143.5, 141.9, 138.3, 137.0, 135.5, 131.2, 130.6, 129.9, 125.4, 124.4, 77.8, 62.2, 60.4, 37.1, 21.4, 21.3, 17.2. LRMS (ESI): mass calcd for C22H24N3O [M − BF4]+, 346; found, 346.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00334. Experimental procedures, spectral data, and crystallographic data (PDF) X-ray data for compound C19H19BrO4 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Karl A. Scheidt: 0000-0003-4856-3569 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support was provided by the NIH NIGMS (GM073072). REFERENCES

(1) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511. (2) Izquierdo, J.; Hutson, G. E.; Cohen, D. T.; Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 11686. (3) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014, 510, 485. (4) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307. (5) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res. 2014, 47, 696. (6) Yetra, S. R.; Patra, A.; Biju, A. T. Synthesis 2015, 47, 1357. (7) Menon, R. S.; Biju, A. T.; Nair, V. Chem. Soc. Rev. 2015, 44, 5040. (8) Menon, R. S.; Biju, A. T.; Nair, V. Beilstein J. Org. Chem. 2016, 12, 444. (9) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905. (10) Maki, B. E.; Chan, A.; Scheidt, K. A. Synthesis 2008, 2008, 1306. (11) Maki, B. E.; Patterson, E. V.; Cramer, C. J.; Scheidt, K. A. Org. Lett. 2009, 11, 3942. (12) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. Rev. 2004, 33, 302. (13) Berkessel, A.; Groger, H. Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis; Blackwell Science Publishers: Oxford, 2005. (14) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633. (15) Cohen, D. T.; Scheidt, K. A. Chem. Sci. 2012, 3, 53. (16) Inamdar, S. M.; Shinde, V. S.; Patil, N. T. Org. Biomol. Chem. 2015, 13, 8116. (17) Wang, M. H.; Scheidt, K. A. Angew. Chem., Int. Ed. 2016, 55, 14912. 4701


Article

The Journal of Organic Chemistry (60) Lu, S.; Poh, S. B.; Zhao, Y. Angew. Chem., Int. Ed. 2014, 53, 11041. (61) Kuwano, S.; Masuda, T. Synthesis 2016, 48, 573. (62) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873. (63) Zeitler, K. Org. Lett. 2006, 8, 637. (64) Castells, J.; Llitjos, H.; Moreno-Mañas, M. Tetrahedron Lett. 1977, 18, 205. (65) Inoue, H.; Higashiura, K. J. Chem. Soc., Chem. Commun. 1980, 549. (66) Miyashita, A.; Suzuki, Y.; Nagasaki, I.; Ishiguro, C.; Iwamoto, K.i.; Higashino, T. Chem. Pharm. Bull. 1997, 45, 1254. (67) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4558. (68) Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Org. Lett. 2007, 9, 371. (69) 2004 Natural Products Gordon Research Conference (Tilton, NH) on Thursday, July 29, 2004. (70) Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 5906. (71) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (72) Connon, S. J. Chem. - Eur. J. 2006, 12, 5418. (73) Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5846. (74) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146. (75) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217. (76) Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.; Schreiner, P. R. Org. Lett. 2012, 14, 1724. (77) Lippert, K. M.; Hof, K.; Gerbig, D.; Ley, D.; Hausmann, H.; Guenther, S.; Schreiner, P. R. Eur. J. Org. Chem. 2012, 2012, 5919. (78) Mamedov, V. A.; Zhukova, N. A.; Balandina, A. A.; Kharlamov, S. V.; Beschastnova, T. y. N.; Rizvanov, I. d. K.; Latypov, S. K. Tetrahedron 2012, 68, 7363. (79) Ian Storer, R.; Aciro, C.; Jones, L. H. Chem. Soc. Rev. 2011, 40, 2330. (80) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416. (81) Levin, E.; Ivry, E.; Diesendruck, C. E.; Lemcoff, N. G. Chem. Rev. 2015, 115, 4607. (82) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686. (83) Amendola, V.; Fabbrizzi, L.; Mosca, L. Chem. Soc. Rev. 2010, 39, 3889. (84) White, J. D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1997, 62, 5250. (85) Burk, M. J.; Bienewald, F.; Harris, M.; Zanotti-Gerosa, A. Angew. Chem., Int. Ed. 1998, 37, 1931. (86) Enantioselective Synthesis of β-Amino Acids, 2nd ed.; Blackwell Science Publishers: Oxford, 2005. (87) Arason, K. M.; Bergmeier, S. C. Org. Prep. Proced. Int. 2002, 34, 337. (88) Freskos, J. N.; Laneman, S. A.; Reilly, M. L.; Ripin, D. H. Tetrahedron Lett. 1994, 35, 835. (89) Nakao, Y.; Chen, J.; Imanaka, H.; Hiyama, T.; Ichikawa, Y.; Duan, W.-L.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 9137. (90) Huang, T.-S.; Li, C.-J. Chem. Commun. 2001, 2348. (91) Mahatthananchai, J.; Bode, J. W. Chem. Sci. 2012, 3, 192.

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