Catalytic Enantioselective C–C Bond-Forming Reactions of

Article Cite This: J. Org. Chem. 2018, 83, 12071−12085

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Catalytic Enantioselective C−C Bond-Forming Reactions of Deconjugated Butyrolactams: Michael Addition to α,β-Unsaturated Aldehydes and Ketones Soumya Jyoti Singha Roy and Santanu Mukherjee* Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India

J. Org. Chem. 2018.83:12071-12085. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 10/05/18. For personal use only.

S Supporting Information *

ABSTRACT: Nucleophilic reactivity of deconjugated butyrolactams has been demonstrated for enantioselective Michael additions to α,β-unsaturated aldehydes and ketones. These reactions are catalyzed by diphenylprolinol silyl ether and trans-1,2diaminocyclohexane-derived bifunctional primary aminothiourea, respectively, producing the Michael adducts with moderate diastereoselectivities and good to excellent enantioselectivities (up to 99:1 er). Unlike in the case of structurally related deconjugated butenolides where vinylogous addition is prevalent, an exclusive α-addition is observed for deconjugated butyrolactams.

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INTRODUCTION Scaffold hopping is one of the popular tools in rational drug design process.1 This technique involves the search of structurally novel molecules starting from known bioactive compounds by modifying their core structure. Oxindole is considered among the popular scaffolds in medicinal chemistry. A number of molecular entities based on the oxindole moiety show a broad spectrum of biological activities and became either marketed drug candidates or occupies a position in the drug development pipeline.2 Current consensus calls for the endeavor in developing chiral drugs preferably through sustainable chemistry. In this respect, catalytic enantioselective transformations have proved their potential. Libraries of bioactive molecules have been generated based on the oxindole core through its catalytic enantioselective modifications.3 A cursory glance on β,γ-unsaturated butyrolactam (deconjugated butyrolactam) 1 makes it apparent that this species may be considered as a truncated oxindole (Figure 1). Chemical modification, especially enantioselective functionalization of 1, would provide novel modular three-dimensional chemical space, which in turn

could generate oxindole analogs with a unique intellectual property (IP) space. Despite these attractive features, deconjugated butyrolactams (1) have rarely received due attention in asymmetric catalysis. The first example of the utilization of deconjugated butyrolactam in asymmetric synthesis was described by Dixon et al., where it was used as an in situ generated iminium precursor in a Brønsted acid-catalyzed Pictet−Spengler cyclization through the generation of N-acyliminium salts.4 The groups of Gallagher and Zhang developed a catalytic hydrogenation of deconjugated butyrolactams leading to enantioenriched γ-lactams.5 Structurally related deconjugated butenolides (2 in Scheme 1), on the other hand, are a very popular class of nucleophiles due to their ease of enolization driven by aromatic dienolate formation. Direct vinylogous addition of deconjugated butenolides (2) to a variety of electrophiles has been studied quite extensively during the past few years to produce γ,γdisubstituted α,β-unsaturated butenolides.6 For instance, Michael addition of 2 to enals and enones under iminium catalysis is known to produce vinylogous addition products 3 (Scheme 1A).7 The corresponding α,β-unsaturated (conjugated) butyrolactams (4) are also known to show a vinylogous reactivity pattern.6 For example, on Michael addition to enals and enones, 4 produces vinylogous addition product 5 (Scheme 1A).8 Notably, enantioselective Michael additions of oxindoles to enals and enones have also been reported.9

Figure 1. Deconjugated butyrolactam as a scaffold hopping framework of oxindoles. © 2018 American Chemical Society

Received: August 8, 2018 Published: September 4, 2018 12071

DOI: 10.1021/acs.joc.8b02051 J. Org. Chem. 2018, 83, 12071−12085

Article

The Journal of Organic Chemistry Scheme 1. Enantioselective Addition of γ-Lactones and γLactams to α,β-Unsaturated Carbonyl Compounds

Scheme 2. Effect of Amine Catalyst on the Regioselectivity

butyrolactam 4, where the addition takes place exclusively through the γ-position (Scheme 1),7,8 the Michael addition of 1a proceeded exclusively in an α-selective manner. Although with pyrrolidine as the catalyst, the Knoevenagel condensation product 7 was obtained exclusively, utilization of pyrrolidine-based enantiopure diphenylprolinol silyl ether (I) could channelize the reaction predominantly toward the desired 1,4-addition pathway (Table 1). Once again, the reaction was found to be completely α-selective, and the Michael adduct 8aa was obtained in 74% isolated yield with 2.5:1 dr (entry 1). The major and the minor diastereomers were formed with 94:6 and 84:16 er, respectively. Under these conditions, formation of only a trace amount of the Knoevenagel condensation product 7 was observed by TLC. To address the modest diastereoselectivity of this reaction, different solvents were screened. A marked variation in enantioselectivities was observed as a function of reaction medium; however, little or no change in diastereoselectivity resulted (Table 1, entries 1−6). The optimum solvent turned out to be 1,4-dioxane, which furnished the product with 2.5:1 dr and both of the diastereomers at 96:4 er (entry 6). Various secondary amine catalysts were then screened mainly with the objective of improving the diastereoselectivity of the reaction (entries 7−13). Surprisingly, bis[3,5-bis(trifluoromethyl)phenyl]prolinol silyl ether (II) and diphenylprolinol (VIII) itself turned out to be completely inactive (entries 7 and 13). Among the different silyl ethers screened (V−VII), TBDMS protected diphenylprolinol (VI) turned out to be the best, affording the product with 3:1 dr and excellent enantioselectivity for each of the diastereomers (entry 11). At this point, a few Brønsted acids (A1−A3 and PhCO2H) were screened as cocatalyst (entries 14−17). While a marked increase in reaction rate was observed in the presence of some of these additives, no improvement in diastereoselectivity was observed. In fact, in each of these cases, the product was formed with reduced er. After a careful review of the results of the optimization studies, the reaction in the presence of catalyst VI in 1,4dioxane without any cocatalyst (Table 1, entry 11) was deemed as the optimum and selected for demonstrating the scope and limitations of this protocol. As shown in Table 2A, the optimized reaction conditions were found to be amenable to a collection of α,β-unsaturated aldehydes having β-substituents of varied steric and electronic nature (6a−j). These include both aromatic, heteroaromatic, and aliphatic substituents at the β-position. In all the cases, Michael adducts (8aa−aj) were obtained in moderate to good yields with good to excellent enantioselectivities for both of the

Deconjugated butyrolactams, due to their structural resemblance to deconjugated butenolides, can be expected to be easily enolizable. Yet, the nucleophilic potential of deconjugated butyrolactams has remained untapped until recently. In 2017, Maruoka and co-workers described the vinylogous Michael reaction of a mixture of conjugated and deconjugated butyrolactams to methyl vinyl ketone using a phase-transfer catalyst (Scheme 1A).10 Soon after this report, we demonstrated the α-selective nucleophilic reactivity of functionally rich and structurally diverse deconjugated butyrolactams for catalytic enantioselective carbon−heteroatom bond formation.11 During the preparation of this article, Kalaitzakis, Vassilikogiannakis, and co-workers developed a [3 + 2]-annulation involving deconjugated butyrolactams for the enantioselective synthesis of bicyclic lactams.12 Herein, we report a catalytic asymmetric α-selective Michael addition of deconjugated butyrolactams to α,β-unsaturated aldehydes and ketones (Scheme 1B).

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RESULTS AND DISCUSSION For the purpose of catalyst identification and reaction conditions optimization, deconjugated butyrolactam 1a and cinnamaldehyde (6a) were chosen as model substrates (Scheme 2). Although pyrrolidine is known to promote iminium catalysis, no Michael addition took place in the presence of 10 mol % of pyrrolidine in CH2Cl2 at 25 °C. Instead, a Knoevenagel condensation product 7 was obtained in 81% yield. Clearly, pyrrolidine favors 1,2-addition of 1a to the iminium-activated enal instead of the desired 1,4-addition. We speculated that the use of a more sterically encumbered secondary amine catalyst would suppress the unwanted 1,2addition and promote the expected 1,4-addition. Gratifyingly, a shift in regioselectivity was indeed observed using diisobutylamine as the catalyst, and the Michael adduct (rac-8aa) was isolated in 84% yield after reductive quenching of the reaction with NaBH4 (Scheme 2). It is noteworthy that, unlike the corresponding deconjugated butenolides 2 or conjugated 12072

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Table 1. Catalyst Screening and Reaction Conditions Optimization for the Michael Addition of Deconjugated Butyrolactam 1a to Cinnamaldehyde 6aa

entry

catalyst

cocatalyst

solvent

t (h)

conv (%)b,c

drb

erd

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

I I I I I I II III IV V VI VII VIII VI VI VI VI

A1 A2 A3 PhCO2H

toluene CH2Cl2 DMF 2-MeTHF TBME 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane

48 14 36 36 36 48 60 48 48 48 48 48 60 48 16 36 30

>95 (74) >95 >95 >95 >95 >95 95 >95 >95 >95 (76) >95 95 >95 >95 >95

2.5:1 2.5:1 2:1 3:1 3:1 2.5:1 n.d. 2.5:1 2.5:1 2.5:1 3:1 2:1 n.d. 2.5:1 2.2:1 2.5:1 2:1

94:6/84:16 95:5/95:5 87.5:12.5/77:23 95:5/93:7 94.5:5.5/94:6 96:4/96:4 n.d. 93.5:6.5/82.5:17.5 90:10/87:13 95:5/89.5:10.5 98:2/98.5:1.5 97:3/97:3 n.d. 95:5/88:12 94.5:5.5/89:11 92:8/73:27 75:25/81:19

a

Reactions were performed on a 0.05 mmol scale using 1.0 equiv of 1a and 1.2 equiv of 6a. bConversion and diastereomeric ratio (dr) as determined by 1H NMR analysis of the crude reaction mixture. cValues in parentheses indicate isolated yield of the product as a combination of both of the diastereomers. dEnantiomeric ratio (er) was determined by HPLC analysis using a stationary phase chiral column. n.d. = not determined.

diastereomers. While all β-aryl-substituted enals displayed comparable dr and er, a relatively poor dr was obtained for βalkyl-substituted enal crotonaldehyde (6j). Nevertheless, both the diastereomers of the product (8aj) were formed with high er. In addition to α,β-unsaturated aldehydes, the compatibility of deconjugated butyrolactams with respect to substituents on C-5, nitrogen, and ester (R1−R3, Table 2) was also tested. The results are summarized in Table 2B. Both aliphatic and aromatic substituents at C-5 of butyrolactam (6b−d,g) could be used, and the products were obtained with comparable dr and er. Similarly, N-substituents could be varied from benzyl to p-methoxybenzyl (PMB) and p-methoxyphenyl (PMP) without any deleterious effect on the reaction outcome. Besides ethyl ester, bulkier benzyl ester was also tolerated under the optimized reaction conditions, and the corresponding product (8hb) was formed with nearly equal efficacy. Unfortunately, attempts to separate the diastereomers through column chromatography were futile for all the products, and a mixture of two diastereomers was isolated in each case. Intrigued by the similar level of dr obtained for nearly all the products, we wondered whether the observed drs reflect the thermodynamic ratio instead of the desired catalyst-controlled kinetic outcome. The reason behind this hypothesis is the

presence of an enolizable proton α- to carbonyl in the products. To test this hypothesis, the reduced Michael adduct 8ab (with 3:1 dr) was treated with various bases in different reaction media (Table 3). Neither erosion nor enrichment in dr was observed in any of the cases. In addition, on subjecting the product 8aa with a dr of 2:1 to basic conditions (Na2CO3 in EtOH), the dr improved to 3:1 (Scheme 3). Interestingly, this dr is the same as that obtained under catalytic reaction conditions (8aa in Table 2A). These observations tentatively suggest that the Michael adducts (8) are formed with a thermodynamic diastereomeric ratio. Besides reductive quenching, the enantioselective Michael addition reactions can be quenched under oxidation conditions. Thus, the reaction mixture, upon completion of the Michael addition (TLC), when subjected to Pinnick oxidation conditions13 led to the formation of the corresponding acid derivative 9ab in comparable yield and dr (Scheme 4). Similarly, the Michael reaction can be coupled with Wittig olefination. Addition of stabilized Wittig ylides to the reaction mixture after completion of the Michael addition produced densely functionalized homologated α,β-unsaturated esters 10 maintaining the same level of dr and er (Scheme 4). Since the products of the Michael addition-reduction sequence (8) are densely functionalized, their manipulation 12073

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The Journal of Organic Chemistry Table 3. Control Experiments with Product 8aba

Table 2. Scope of the Michael Addition to α,β-Unsaturated Aldehydesa

entry

base

solvent

t (h)

drb

1 2 3 4 5 6

Na2CO3 (0.1 equiv) K2CO3 (0.1 equiv) DBU (0.1 equiv) DBU (0.1 equiv) DMAP (0.1 equiv) basic alumina

EtOH EtOH EtOH CH2Cl2 CH2Cl2 EtOH

48 48 14 36 36 48

3:1 n.d.c n.d.c n.d.c 3:1 3:1

a

Studies were performed on a 0.05 mmol scale of 8ab. Diastereomeric ratio (dr) was determined by 1H NMR analysis of the crude reaction mixture after stipulated time period. cDecomposition of 8ab was observed. b

Scheme 3. Product Epimerization under Basic Conditions

Scheme 4. One-Pot Michael Addition/Pinnick Oxidation and One-Pot Michael Addition/Wittig Olefination

a

Reactions were carried out on a 0.2 mmol scale. Yields correspond to the isolated combined yield of two diastereomers. Diastereomeric ratio (dr) was determined by 1H NMR analysis of the crude reaction mixture. Enantiomeric ratio (er) was determined by HPLC analysis using a stationary phase chiral column (see the Supporting Information). PMB = p-methoxybenzyl. PMP = p-methoxyphenyl.

can give rise to diverse molecular frameworks. This scenario is exemplified by the conversion of the product alcohol 8ab to a novel tetrahydropyranopyrrole framework 12a through the corresponding mesylate derivative 11a (Scheme 5A). The structure and absolute configuration of 12a were unambiguously determined by single-crystal X-ray diffraction analysis. This transformation could be performed in a one-pot manner without the isolation of the mesylate intermediate (11), with yield and enantioselectivity comparable to that of the stepwise process. This was illustrated for two alcohols (8ab and 8ae) for the synthesis of the corresponding tetrahydropyranopyrroles 12a and 12b, respectively (Scheme 5B). During this transformation, both diastereomers of the starting material (8) led to the formation of the same product enantiomer (12) with preservation of the enantiopurity. These results indicate that the diastereomers of 8ab (and 8ae) are epimeric at α- to the carbonyl of butyrolactam and not at the stereogenic center derived from the electrophilic aldehydes. Another stereoconvergent molecular rearrangement leading to an azaspirobicyclic framework (13) was observed during an

attempted azidation of the mesylate 11a under open air conditions at 90 °C (Scheme 6). This azaspirobicyclic framework is somewhat similar to the core structure of the amathaspiramide class of natural products.14 On performing the reaction under a mixed atmosphere of air and argon at a relatively lower temperature (70 °C), a similar rearrangement took place, generating a diazoester (14) having contiguous quaternary and tertiary stereocenters (Scheme 6). During these rearrangements, enantiopurity of the starting material was conserved in the products. Both the products (13 12074

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tosyl, nosyl, thiocarbamate, etc.) met with failure, presumably due to their isolation as a diastereomeric mixture. However, while the enantioenriched mesyl derivative 11a (with 3:1 dr) did not produce diffraction-quality crystals, the corresponding racemic mesyl derivative (rac-11a) could be crystallized as a single diastereomer from a 3:1 petroleum ether/Et2O mixture (Figure 2). Comparison of NMR spectra of these crystals with that of the diastereomeric mixture (with 3:1 dr) of 11a confirmed that the crystals are of the major diastereomer of rac-11a.

Scheme 5. Synthetic Elaboration of Michael Adducts to Tetrahydropyranopyrroles

Figure 2. Relative configuration of the major diastereomer of rac-11a and its X-ray structure.

The crystal structure of the major diastereomer of rac-11a allowed us to assign its relative configuration and hence that of the major diastereomer of 8ab. The relative configuration of other alcohols (8 in Table 2) was assigned as the same by analogy. As described above, the three derivatives (12a, 13, and 14) of 8ab were synthesized through the corresponding mesylate 11a. The absolute configuration at the carbon center attached to 4-chlorophenyl substituent was found to be the same in all of these compounds (Schemes 5A and 6). As these reactions proceed with complete stereochemical fidelity, it is reasonable to assume that the configuration at this carbon center in both diastereomers of the alcohols (vide supra) is the same as that of 12a, 13, and 14. This observation allowed us to unambiguously assign the absolute configuration of the stereocenter outside the butyrolactam ring in mesylate 11a. In analogy, the relative and absolute configurations of both of the alcohol (8) diastereomers were assigned. Having successfully accomplished the enantioselective Michael addition of the deconjugated butyrolactams to α,βunsaturated aldehydes, we looked to explore the possibility of using α,β-unsaturated ketones (enones) as Michael acceptor. We surmised that iminium activation might be applicable for the Michael addition to enones as well. However, when the deconjugated butyrolactam 1a and benzylideneacetone 15a were subjected to the standard reaction conditions optimized for α,β-unsaturated aldehydes, no product formation could be detected, even at 80 °C (Scheme 7). This observation was not particularly surprising in light of the known reluctance of secondary amines (such as VI) in forming iminium ions with acyclic α,β-unsaturated ketones. Therefore, we decided to use primary amines as catalyst considering their ease of formation of iminium with various types of ketones.16 Michael addition of deconjugated butyrolactam 1a to benzylideneacetone 15a was selected for optimizing the catalyst and reaction conditions (Table 4). In the presence of 10 mol % of cinchonine-derived primary amine IX in

Scheme 6. Molecular Rearrangements Involving Mesylate 11a

and 14) could be recrystallized to obtain essentially enantiopure crystals. The structure and absolute configuration of these products were established by single-crystal X-ray diffraction analysis (Scheme 6). These two mechanistically enigmatic rearrangements are an interesting addition to a large array of unique reactivities already known for organic azides,15 even though the reaction mechanisms are not clear at this stage. Our attempts to obtain diffraction-quality crystals of either the products of the Michael addition-reduction sequence (8) or their derivatives (e.g., 4-bromobenzoate, 4-nitrobenzoate, 12075

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reaction rate was curtailed considerably (entry 11). Under these conditions, the major product diastereomer was isolated in 59% yield with 98.5:1.5 er. A little improvement in the yield was observed when 1.5 equiv of the enone 15a was used (entry 12). The reaction on a larger (0.2 mmol) scale under these conditions did not show any adverse effect on the reaction outcome (entry 13). The optimum catalyst and reaction conditions (Table 4, entry 13) were then extended to other α,β-unsaturated ketones (Table 5). A number of arylidene and heteroarylidene acetones (15b−j) were employed as electrophile for reaction with 1a, and the products (16ab−aj) were formed in high yields with excellent enantioselectivities and a useful level of diastereoselectivity (entries 2−10). Importantly, in almost all of the cases, the diastereomers were separable by column chromatography, and the major diastereomer was obtained in moderate to good yields. When (E)-styryl-substituted enone 15k was used as the electrophile, no 1,6-addition product could be detected, and only the 1,4-addition product was isolated as a mixture of inseparable diastereomers. However, enantioselectivities for both of the diastereomers were found to be excellent (entry 11). No product formation was observed when alkylidene acetones were used as the electrophile, which marks a limitation of our protocol.

Scheme 7. Preliminary Experiment on the Michael Addition of Deconjugated Butyrolactam to α,β-Unsaturated Ketones

toluene at 25 °C, the reaction was indeed found to take place with decent conversion and diastereoselectivity but with poor enantioselectivity (entry 2). Initial screening of a small collection of primary amines (X−XII) led to the identification of (R,R)-1,2-diaminocyclohexane-based bifunctional primary aminothiourea XII as the most promising catalyst (entries 3− 5). Brønsted acid cocatalysts were found to play a very important role in this reaction. More specifically, in the presence of 20 mol % of benzoic acid, complete conversion was observed within 36 h, and the major diastereomer of the product 16aa was obtained with 98:2 er (entry 6). Among the various acid cocatalysts screened, 2-fluoro benzoic acid (2FC6H4CO2H) turned out to be the best and furnished 16aa with 5:1 dr and 98.5:1.5 er (entry 8). At this point, a number of primary amine catalysts were screened in an attempt to improve the diastereoselectivity of the reaction. However, primary aminothiourea XII prevailed. Use of mesitylene as the solvent instead of toluene led to a slight improvement in dr (to 6:1) without affecting the enantioselectivity, although the

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CONCLUSION Nucleophilic reactivity of deconjugated butyrolactams has been demonstrated through amine-catalyzed enantioselective Michael additions to α,β-unsaturated aldehydes and ketones.

Table 4. Catalyst Screening and Reaction Conditions Optimization for the Michael Addition of Deconjugated Butyrolactam 1a to Benzylideneacetone 15aa

entry

catalyst

cocatalyst

solvent

t (h)

conv (%)b,c

drb

erd

1 2 3 4 5 6 7 8 9e 10 11 12f 13g

IX X XI XII XII XII XII XII XIII XII XII XII

PhCO2H CF3CO2H 2-FC6H4CO2H 2-FC6H4CO2H 2-FC6H4CO2H 2-FC6H4CO2H 2-FC6H4CO2H 2-FC6H4CO2H

toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene mesitylene mesitylene mesitylene

48 48 48 48 72 36 48 72 72 72 120 120 120

95 >95 >95 >95 95 >95 25 >95 (59) >95 (62) >95 (64)

4:1 4:1 4:1 4:1 4:1 5:1 4:1 n.d. 6:1 6:1 6:1

66:34 84:16 86:14 89:11 98:2 98.5:1.5 97.5:2.5 n.d. 98.5:1.5 98.5:1.5 98.5:1.5

a

Unless stated otherwise, reactions were carried out on a 0.05 mmol scale using 1.0 equiv of 1a and 1.4 equiv of 15a. bCoversion and diastereomeric ratio (dr) as determined by 1H NMR analysis of the crude reaction mixture. cValues in parentheses indicate isolated yield of the major product diastereomer. dEnantiomeric ratio (er) of the major diastereomer as determined by HPLC analysis using a stationary phase chiral column. eUsing 10 mol % cocatalyst. fReaction with 1.5 equiv of 15a. gReaction using 1.5 equiv of 15a on a 0.2 mmol scale. n.d. = not determined. 12076

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NMR and CDCl3 δ 77.00 for 13C NMR). For 1H NMR, data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, dt = doublet of triplets, m = multiplet), coupling constants (Hz), and integration. High-resolution mass spectrometry was performed on a Micromass Q-TOF Micro instrument. Optical rotations were measured on a JASCO P-2000 polarimeter. Melting points were measured using ANALAB μ-Thermocal 10 melting point apparatus. All melting points were measured in open glass capillary, and values are uncorrected. Enantiomeric ratios were determined by a Shimadzu LC-20AD HPLC instrument and SPD-20A UV/vis detector using stationary phase chiral columns (25 cm × 0.46 cm) in comparison with authentic racemic compounds. Unless stated otherwise, all reactions were carried out with distilled and dried solvents under an atmosphere of argon in oven (120 °C)dried glassware with standard vacuum line techniques. Organic solvents used for carrying out reactions were dried using standard methods. All workup and purification were carried out with reagent grade solvents in air. Thin layer chromatography was performed using Merck silica gel 60 F254 precoated plates (0.25 mm). Column chromatography was performed using silica gel (230−400 or 100− 200 mesh). CCDC 1558826−1558829 contain the supplementary crystallographic data for this Article. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033. General Procedure for Catalytic Enantioselective Michael Addition of Deconjugated Butyrolactams (1) to α,β-Unsaturated Aldehydes (6). In a reaction tube fitted with a magnetic stir bar, catalyst VI (7.4 mg, 0.02 mmol, 0.1 equiv) was taken along with α,β-unsaturated aldehyde 6 (0.24 mmol, 1.2 equiv) in 0.5 mL of 1,4dioxane under a positive argon pressure. The resulting solution was cooled to 0 °C. A solution of butyrolactam 1 (0.20 mmol, 1.0 equiv) in 0.5 mL of 1,4-dioxane was added. The resulting mixture was stirred at 25 °C until complete consumption of 1 (followed by TLC). The reaction mixture was diluted with EtOAc (2.0 mL), cooled to 0 °C, and NaBH4 (23 mg, 0.60 mmol, 3.0 equiv) was added. The cooling bath was removed, and the heterogeneous mixture was stirred vigorously for 20 min at 25 °C. The reaction was quenched with satd aqueous NH4Cl solution (5 mL) and extracted with EtOAc (30 mL). The organic layer was washed with brine (5 mL), dried over anhyd Na2SO4 and concentrated under reduced pressure to obtain a semisolid residue, which was purified by silica gel (230−400 mesh) column chromatography to obtain the desired product 8. Compound 8aa. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% EtOAc in petroleum ether) afforded 8aa as a colorless thick oil (60 mg, 0.152 mmol, 76% yield). Rf = 0.25 (40% EtOAc in petroleum ether). FT-IR (neat): 3448 (br), 2922 (w), 1688 (s), 1685 (m), 1451 (m), 1390 (m), 1212 (m), 1056 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.18− 7.26 (m, 4H), 7.07−7.08 (m, 4H), 6.67−6.69 (m, 2H), 4.66 (d, J = 16.2 Hz, 1H), 4.23−4.41 (m, 3H), 3.66−3.87 (m, 4H), 2.43−2.61 (m, 2H), 2.03 (d, J = 1.5 Hz, 3H), 1.68 (br, 1H), 1.35 (t, J = 7.1 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 7.29−7.48 (m, 4H), 4.74 (d, J = 16.2 Hz, 1H), 3.52−3.59 (m, 2H), 2.14−2.21 (m, 2H), 2.12 (d, J = 1.1 Hz, 3H), 1.36 (br, 1H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.7, 164.3, 153.8, 139.5, 136.9, 128.6, 128.3, 128.0, 127.2, 126.8, 126.3, 106.8, 61.1, 59.8, 50.7, 42.9, 41.4, 34.1, 14.5, 12.5; representative signals corresponding to the minor diastereomer, 177.9, 164.9, 154.2, 140.0, 136.0, 128.8, 128.7, 128.1, 126.9, 126.3, 107.0, 61.2, 60.0, 51.9, 44.4, 43.1, 35.5, 14.4, 12.7. HRMS (ESI+): calcd for C24H27NO4Na ([M + Na]+), 416.1838; found, 416.1836. Optical rotation: [α]22D −26.4 (c 1.0, CHCl3) for an enantiomerically enriched sample with 98:2 er for the major diastereomer and 98.5:1.5 er for the minor diastereomer (dr 3:1). The enantiomeric ratio was determined by HPLC analysis using Phenomenex Cellulose-2 column

Table 5. Scope of the Michael Addition to α,β-Unsaturated Ketonesa

a

Reactions were carried out on a 0.2 mmol scale. bYields correspond to the combined yield of the diastereomers after column chromatography. Values in the parentheses represent isolated yield of the major diastereomer. cDiastereomeric ratio (dr) was determined by 1H NMR analysis of the crude reaction mixture. dEnantiomeric ratio (er) was determined by HPLC analysis using a stationary phase chiral column and is shown for the major diastereomer except for entry 11.

Unlike in the case of structurally related deconjugated butenolides where vinylogous addition is prevalent, an exclusive α-addition was observed for the deconjugated butyrolactams. In the case of α,β-unsaturated aldehydes, diphenylprolinol TBDMS ether was used as the catalyst, and the Michael adducts were isolated after in situ reduction to the corresponding alcohols in good yields with modest diastereoselectivities and excellent enantioselectivities. The utility of the products was demonstrated through synthetic manipulations leading to interesting heterocyclic scaffolds. Additionally, the Michael adducts could either be oxidized in situ to obtain carboxylic acid derivatives or homologated to the corresponding alkenyl esters through in situ Wittig olefination. With α,β-unsaturated ketones as the electrophile, using a bifunctional primary aminothiourea as the catalyst, the Michael adducts were obtained in high yield. Although the diastereoselectivity of this reaction is moderate, in nearly all cases the diastereomers were separable by column chromatography, and the major diastereomers were isolated with excellent enantioselectivities. With the nucleophilic potential of deconjugated butyrolactams as well as their regiochemical preference established, their enantioselective reactions with other classes of electrophiles are certain to appear in the near future.

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EXPERIMENTAL SECTION

General Information. Infrared (FT-IR) spectra were recorded on a PerkinElmer Spectrum BX spectrophotometer and Bruker alfa FTIR, νmax in cm−1. NMR spectra were recorded on a Bruker Ultrashield spectrometer at 400 MHz (for 1H NMR) and 100 MHz (for 13C NMR). Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as internal standard (CDCl3 δ 7.26 for 1H 12077

DOI: 10.1021/acs.joc.8b02051 J. Org. Chem. 2018, 83, 12071−12085

Article

The Journal of Organic Chemistry (80:20 n-hexane/EtOH, 1.0 mL/min, 20 °C, 210 nm; for minor diastereomer τmajor = 19.3 min, τminor = 36.9 min, and for major diastereomer τminor = 23.3 min, τmajor = 32.9 min). Compound 8ab. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% EtOAc in petroleum ether) afforded 8ab as a colorless thick oil (63 mg, 0.147 mmol, 73% yield). Rf = 0.25 (40% EtOAc in petroleum ether). FT-IR (neat): 3426 (br), 2928 (w), 1695 (s), 1627 (m), 1492 (m), 1391 (m), 1220 (s), 1112 (m), 1018 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.19−7.26 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.64−6.68 (m, 2H), 4.74 (d, J = 16.1 Hz, 1H), 4.21−4.38 (m, 3H), 3.79−3.84 (m, 2H), 3.49−3.71 (m, 2H), 2.39−2.57 (m, 1H), 2.01−2.23 (m, 1H), 2.07 (s, 3H), 1.79 (bs, 1H), 1.35 (t, J = 7.1 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 7.25−7.26 (m, 3H), 4.80 (d, J = 16.1 Hz, 1H), 3.49−3.55 (m, 2H), 2.14 (s, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.4, 164.2, 154.0, 138.1, 135.7, 132.5, 129.8, 128.7, 128.2, 127.4, 126.3, 106.5, 60.8, 59.9, 50.5, 43.0, 40.6, 34.0, 14.5, 12.7; representative signals corresponding to the minor diastereomer, δ 164.8, 154.4, 138.6, 130.2, 128.7, 128.2, 106.8, 60.9, 60.1, 51.6, 43.2, 14.4, 12.8. HRMS (ESI+): calcd for C24H26NO4ClNa ([M + Na]+), 450.1448; found, 450.1444. Optical rotation: [α]21D −29.8 (c 2.0, CHCl3) for an enantiomerically enriched sample with 96:4 er for each of the diastereomers (dr 3:1). The enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, 20 °C, n-hexane/IPA = 75:25, 1.0 mL min−1; for major diastereomer τmajor = 11.8 min, τminor = 17.5 min, and for minor diastereomer τminor = 14.5 min, τmajor = 27.3 min). Compound 8ac. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% EtOAc in petroleum ether) afforded 8ac as a colorless thick oil (60 mg, 0.141 mmol, 70% yield). Rf = 0.25 (50% EtOAc in petroleum ether). FT-IR (neat): 3447 (br), 2936 (w), 1688 (s), 1622 (m), 1511 (m), 1389 (m), 1247 (s), 1061 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.13−7.18 (m, 3H), 6.97−6.99 (m, 2H), 6.70−6.72 (m, 2H), 6.62−6.64 (m, 2H), 4.72 (d, J = 16.2 Hz, 1H), 4.20−4.36 (m, 3H), 3.61−3.75 (m, 3H), 3.79−3.84 (m, 1H), 3.76 (s, 3H), 2.40−2.56 (m, 2H), 2.13−2.17 (m, 1H), 2.04 (d, J = 2.0 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 7.10−7.12 (m, 2H), 6.76−6.79 (m, 2H), 4.78 (d, J = 16.2 Hz, 1H), 3.78 (s, 3H), 3.50− 3.58 (m, 1H), 2.10 (d, J = 2.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.7, 164.3, 158.4, 153.8, 136.0, 131.5, 129.4, 128.5, 127.3, 126.34, 113.4, 106.9, 61.1, 59.8, 55.0, 50.9, 42.9, 40.5, 34.4, 14.5, 12.6; representative signals corresponding to the minor diastereomer, δ 178.0, 165.0, 158.5, 154.2, 129.8, 126.3, 113.3, 107.0, 61.3, 60.0, 52.0, 43.9, 43.1, 36.0, 14.4, 12.7. HRMS (ESI+): calcd for C25H29NO5Na ([M + Na]+), 446.1943; found, 446.1945. Optical rotation: [α]21D −33.8 (c 2.0, CHCl3) for an enantiomerically enriched sample with 95.5:4.5 er for the major diastereomer and 94.5:5.5 er for the minor diastereomer (dr 3.5:1). The enantiomeric ratios were determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, 20 °C, n-hexane/ EtOH = 80:20, 1.0 mL min−1; for major diastereomer τmajor = 12.4 min, τminor = 16.0 min, and for minor diastereomer τminor = 17.4 min, τmajor = 23.4 min). Compound 8ad. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 50% EtOAc in petroleum ether) afforded 8ad as a colorless thick oil (68.5 mg, 0.156 mmol, 78% yield). Rf = 0.20 (50% EtOAc in petroleum ether). FT-IR (neat): 3425 (br), 2930 (w), 1689 (s), 1610 (m), 1519 (s), 1390 (m), 1345 (s) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.96−7.98 (m, 2H), 7.15−7.29 (m, 5H), 6.75−6.77 (m, 2H), 4.68 (d, J = 15.9 Hz, 1H), 4.22−4.39 (m, 3H), 3.97−4.02 (m, 1H), 3.81−3.89 (m, 1H), 3.65− 3.74 (m, 2H), 2.56−2.65 (m, 1H), 2.38−2.47 (m, 1H), 2.12 (d, J = 1.9 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 8.07−8.09 (d, J = 8.5 Hz, 2H), 6.84−6.86 (d, J = 6.8 Hz, 2H), 4.74 (d, J = 15.8 Hz, 1H), 3.45−

3.53 (m, 1H), 2.22 (d, J = 1.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.1, 164.1, 154.1, 147.7, 146.9, 135.6, 129.2, 128.6, 127.8, 126.7, 123.1, 106.2, 60.6, 60.1, 50.1, 43.2, 41.1, 33.8, 14.5, 12.7; representative signals corresponding to the minor diastereomer, δ 177.5, 164.6, 154.5, 148.3, 147.0, 129.7, 128.7, 127.8, 126.7, 123.2, 106.5, 60.5, 60.2, 51.3, 43.4, 34.5, 14.4, 12.9. HRMS (ESI+): calcd for C24H26N2O6Na ([M + Na]+), 461.1689; found, 461.1686. Optical rotation: [α]21D −31.6 (c 2.0, CHCl3) for an enantiomerically enriched sample with 98:2 er for each of the diastereomers (dr 3.3:1). The enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak AD-H column, 254 nm, 20 °C, n-hexane/EtOH = 80:20, 1.0 mL min−1; for major diastereomer τmajor = 13.1 min, τminor = 20.1 min, and for minor diastereomer τminor = 22.5 min, τmajor = 35.8 min). Compound 8ae. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% EtOAc in petroleum ether) afforded 8ae as a colorless thick oil (65 mg, 0.138 mmol, 69% yield). Rf = 0.25 (40% EtOAc in petroleum ether). FT-IR (neat): 3428 (br), 2925 (m), 1686 (s), 1625 (m), 1388 (m), 1059 (m), 1019 (s) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.25−7.30 (m, 1H), 7.21−7.23 (m, 1H), 7.10−7.17 (m, 3H), 6.92−6.97 (m, 2H), 6.66− 6.73 (m, 2H), 4.64 (d, J = 16.2 Hz, 1H), 4.30−4.38 (m, 1H), 4.15− 4.26 (m, 2H), 3.69−3.80 (m, 2H), 3.54−3.64 (m, 2H), 2.30−3.46 (m, 2H), 2.32−2.52 (m, 1H), 1.92−2.15 (m, 1H), 1.98 (d, J = 1.8 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 7.36−7.38 (m, 1H), 7.01−7.05 (m, 2H), 6.35−6.36 (m, 2H), 4.70 (d, J = 16.1 Hz, 1H), 3.25−3.33 (m, 2H), 2.09 (s, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.1, 164.0, 153.8, 142.1, 135.7, 131.0, 129.6, 129.3, 128.5, 127.1, 126.9, 126.0, 121.8, 106.3, 60.3, 59.7, 50.3, 42.7, 40.7, 33.6, 14.2, 12.4; representative signals corresponding to the minor diastereomer, δ 177.6, 164.4, 154.0, 142.7, 135.7, 131.5, 129.7, 129.4, 127.15, 127.13, 126.1, 121.8, 106.6, 60.1, 59.8, 51.3, 43.2, 43.0, 34.9, 14.1, 12.5. HRMS (ESI+): calcd for C24H26NO4BrNa ([M + Na]+), 496.0943; found, 496.0948. Optical rotation: [α]21D −29.0 (c 1.0, CHCl3) for an enantiomerically enriched sample with 98.5:1.5 er for each of the diastereomers (dr 3:1). The enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, 20 °C, n-hexane/IPA = 80:20, 1.0 mL min−1; for major diastereomer τmajor = 14.9 min, τminor = 21.0 min, and for minor diastereomer τminor = 24.0 min, τmajor = 27.5 min). Compound 8af. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% EtOAc in petroleum ether) afforded 8af as a colorless thick oil (51 mg, 0.108 mmol, 54% yield). Rf = 0.25 (40% EtOAc in petroleum ether). FT-IR (neat): 3440 (br), 2961 (m), 1688 (s), 1614 (m), 1514 (m), 1245 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.36−7.38 (m, 3H), 7.01−7.05 (m, 3H), 6.72− 6.74 (m, 2H), 6.64−6.67 (m, 1H), 4.59 (d, J = 15.9 Hz, 1H), 4.22− 4.37 (m, 3H), 3.80−3.87 (m, 2H), 3.64−3.75 (m, 2H), 2.43−2.62 (m, 1H), 2.11−2.22 (m, 2H), 2.05 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 4.67 (d, J = 15.9 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.52−3.60 (m, 1H), 3.77−3.79 (m, 3H), 2.15 (s, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.6, 164.3, 153.9, 137.3, 135.7, 133.2, 128.3, 128.0, 127.5, 127.0, 125.9, 125.6, 125.5, 114.0, 106.8, 59.7, 55.2, 50.6, 42.4, 41.5, 34.3, 14.5, 12.6; representative signals corresponding to the minor diastereomer, δ 178.0, 165.0, 154.2, 137.6, 135.7, 132.5, 125.5, 107.1, 59.9, 55.2, 51.8, 44.3, 42.6, 35.9, 14.4, 12.7. HRMS (ESI+): calcd for C24H28NO4BrNa ([M + Na]+), 496.1099; found, 496.1099. Optical rotation: [α]22D −17.2 (c 1.0, CHCl3) for an enantiomerically enriched sample with 96:4 er for each of the diastereomers (dr 3.5:1). The enantiomeric ratio was determined by HPLC analysis using a Daicel Chiralpak IC column (80:20 n-hexane/EtOH, 1.0 mL/min, 20 °C, 200 nm; for minor diastereomer τmajor = 19.3 min, τminor = 27.6 min, and for major diastereomer τmajor = 22.5 min, τminor = 31.1 min). Compound 8ag. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% 12078

DOI: 10.1021/acs.joc.8b02051 J. Org. Chem. 2018, 83, 12071−12085

Article

The Journal of Organic Chemistry

the major diastereomer, δ 177.3, 164.1, 154.5, 142.5, 136.0, 128.6, 127.2, 126.3, 124.7, 123.3, 106.7, 60.8, 59.8, 50.6, 43.0, 36.7, 35.6, 14.4, 12.6; representative signals corresponding to the minor diastereomer, δ 177.7, 164.7, 154.9, 134.2, 136.0, 128.6, 127.3, 126.2, 125.8, 124.0, 106.7, 60.0, 51.8, 43.2, 40.0, 37.9, 14.3, 12.8. HRMS (ESI+): calcd for C22H25NO4SNa ([M + Na]+), 422.1435; found, 422.1439. Optical rotation: [α]22D −7.5 (c 1.0, CHCl3) for an enantiomerically enriched sample with 97.5:2.5 er for each of the diastereomers (dr 3:1). The enantiomeric ratio was determined by HPLC analysis (Phenomenex Cellulose-2 column, 254 nm, 20 °C, nhexane/EtOH = 80:20, 1.0 mL min−1; for major diastereomer τmajor = 22.9 min, τminor = 39.7 min, and for minor diastereomer τminor = 26.9 min, τmajor = 35.0 min). Compound 8aj. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% EtOAc in petroleum ether) afforded 8aj as a colorless oil (45 mg, 0.136 mmol, 68% yield). Rf = 0.20 (50% EtOAc in petroleum ether). FT-IR (neat): 3430 (br), 2930 (m), 1689 (s), 1624 (m), 1389 (m), 1226 (m), 1060 (m) cm−1. 1H NMR (400 MHz, CDCl3): both diastereomers together, δ 7.27−7.35 (m, 6H), 7.20−7.22 (m, 4H), 4.66−4.85 (m, 4H), 4.14−4.28 (m, 4H), 4.66−4.85 (m, 4H), 4.14−4.28 (m, 4H), 3.85−3.91 (m, 1H), 3.70−3.81 (m, 2H), 3.60−3.66 (m, 1H), 3.53− 3.55 (m, 1H), 3.40−3.41 (m, 1H), 2.52−2.64 (m, 2H), 2.35−2.37 (m, 6H), 2.05−2.14 (m, 2H), 1.83−1.92 (m, 2H), 1.56−1.64 (m, 1H), 1.37−1.46 (m, 1H), 1.27−1.32 (m, 7H), 1.17 (d, J = 6.9 Hz, 3H), 0.81 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): both diastereomers together, δ 178.6, 178.4, 164.5, 164.2, 154.0, 153.8, 136.61, 136.55, 128.8, 127.7, 127.0, 126.9, 107.6, 107.0, 61.2, 61.0, 59.8, 51.5, 49.7, 43.4, 43.3, 36.5, 35.3, 31.4, 30.5, 17.0, 15.1, 14.3, 14.3, 12.84, 12.77. HRMS (ESI+): calcd for C19H25NO4Na ([M + Na]+), 354.1681; found, 354.1682. Optical rotation: [α]22D −7.9 (c 2.0, CHCl3) for an enantiomerically enriched sample with 96:4 er for one diastereomer and 95.5:4.5 er for the other diastereomer (dr 1.1:1). The enantiomeric ratio was determined by HPLC analysis (Phenomenex Cellulose-2 column, 254 nm, 20 °C, n-hexane/IPA = 80:20, 0.7 mL min−1; for one diastereomer τminor = 26.6 min, τmajor = 34.8 min, and for the other diastereomer τmajor = 49.6 min, τminor = 58.3 min). Compound 8bb. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 45% EtOAc in petroleum ether) afforded 8bb as a colorless thick oil (72 mg, 0.148 mmol; 74% yield). Rf = 0.20 (50% EtOAc in petroleum ether). FT-IR (neat): 3424 (br), 2961 (m), 1687 (s), 1614 (m), 1514 (m), 1245 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.14 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 8.3 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 4.54 (d, J = 15.8 Hz, 1H), 4.37 (d, J = 15.8 Hz, 1H), 4.21−4.32 (m, 2H), 3.78 (s, 3H), 3.77−3.86 (m, 2H), 3.65−3.73 (m, 2H), 2.31−2.59 (m, 3H), 1.80−1.91 (m, 1H), 1.67 (br, 1H), 1.35 (t, J = 7.1 Hz, 3H), 0.88−1.20 (m, 2H), 0.73 (t, J = 7.3 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 7.20 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 2H), 4.67 (d, J = 15.7 Hz, 1H), 3.77 (s, 3H), 3.53−3.60 (m, 2H), 2.00−2.23 (m, 3H), 0.80 (d, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.8, 163.9, 158.9, 158.4, 138.5, 132.5, 130.2, 129.8, 128.2, 127.8, 114.0, 106.3, 60.9, 59.8, 55.2, 50.2, 42.6, 40.8, 33.9, 28.0, 21.7, 14.4, 13.9; representative signals corresponding to the minor diastereomer, δ 178.2, 158.9, 158.8, 138.2, 132.7, 128.2, 127.7, 113.8, 106.4, 61.0, 60.0, 51.4, 44.1, 42.8, 35.8, 28.3, 21.8, 14.3, 14.1. HRMS (ESI+): calcd for C27H32NO5ClH ([M + H]+), 486.2047; found, 486.2046. Optical rotation: [α]22D −6.6 (c 1.0, CHCl3) for an enantiomerically enriched sample with 98:2 er for each of the diastereomers (dr 2.5:1). The enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, 20 °C, n-hexane/IPA = 80:20, 1.0 mL min−1; for major diastereomer τmajor = 17.4 min, τminor = 23.2 min, and for minor diastereomer τminor = 21.1 min, τmajor = 40.4 min). Compound 8cb. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% EtOAc in petroleum ether) afforded 8cb as a colorless thick oil (78 mg, 0.142

EtOAc in petroleum ether) afforded 8ag as a colorless thick oil (63 mg, 0.142 mmol, 71% yield). Rf = 0.30 (40% EtOAc in petroleum ether). FT-IR (neat): 3422 (br), 2928 (m), 1687 (s), 1624 (m), 1389 (m), 1062 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.78−7.83 (m, 1H), 7.70−7.76 (m, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 7.42−7.49 (m, 2H), 7.20−7.22 (m, 1H), 6.97−7.03 (m, 1H), 6.70−6.77 (m, 2H), 6.45 (d, J = 7.7 Hz, 2H), 4.72 (d, J = 16.1 Hz, 1H), 4.25−4.39 (m, 3H), 4.00−4.05 (m, 1H), 3.83−3.90 (m, 1H), 3.66−3.78 (m, 2H), 2.57−2.72 (m, 2H), 1.96 (d, J = 1.9 Hz, 3H), 1.60 (br, 1H), 1.39 (t, J = 7.1 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 7.33−7.36 (m, 1H), 4.80 (d, J = 16.2 Hz, 1H), 3.55−3.61 (m, 1H), 2.21−2.31 (m, 2H), 2.07 (d, J = 1.7 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.6, 164.3, 153.9, 137.3, 135.6, 133.2, 132.5, 128.3, 128.0, 127.5, 127.0, 126.9, 126.0, 125.6, 125.5, 106.8, 61.1, 59.8, 50.9, 42.9, 41.3, 34.3, 14.5, 12.7; representative signals corresponding to the minor diastereomer, δ 178.0, 165.0, 154.2, 137.6, 135.7, 133.3, 132.6, 128.3, 127.9, 127.5, 127.1, 126.6, 125.9, 125.8, 125.6, 107.1, 61.2, 60.0, 52.0, 44.8, 43.1, 35.9, 14.4, 12.8. HRMS (ESI+): calcd for C28H29NO4Na ([M + Na]+), 466.1994; found, 466.1995. Optical rotation: [α]22D −53.9 (c 2.0, CHCl3) for an enantiomerically enriched sample with 97:3 er for the major diastereomer and 98:2 er for the minor diastereomer (dr 3:1). The enantiomeric ratio was determined by HPLC analysis using a Daicel Chiralpak IC column (80:20 n-hexane/IPA, 1.0 mL/min, 20 °C, 254 nm; for major diastereomer τmajor = 20.6 min, τminor = 32.3 min, and for minor diastereomer τminor = 29.5 min, τmajor = 62.0 min). Compound 8ah. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% EtOAc in petroleum ether) afforded 8ah as a colorless thick oil (50 mg, 0.114 mmol, 57% yield). Rf = 0.25 (40% EtOAc in petroleum ether). FT-IR (neat): 3426 (br), 2924 (m), 1686 (s), 1623 (m), 1492 (m), 1389 (m), 1236 (m), 1039 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.20− 7.23 (m, 3H), 6.70−6.77 (m, 3H), 6.62 (s, 1H), 6.52−6.54 (m, 1H), 5.90−5.92 (m, 2H), 4.79 (d, J = 16.4 Hz, 1H), 4.38 (d, J = 16.2 Hz, 1H), 4.20−4.33 (m, 2H), 3.60−3.85 (m, 4H), 2.37−2.54 (m, 2H), 2.09 (d, J = 1.4 Hz, 3H), 1.67 (br, 1H), 1.35 (t, J = 7.1 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 6.64 (s, 1H), 4.40 (d, J = 16.0 Hz, 1H), 3.51−3.57 (m, 1H), 2.17 (d, J = 2.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.7, 164.3, 153.9, 147.3, 146.3, 136.1, 133.6, 128.6, 127.3, 126.3, 121.6, 108.7, 107.8, 106.8, 100.7, 61.1, 59.8, 50.8, 43.0, 41.0, 34.6, 14.5, 12.7; representative signals corresponding to the minor diastereomer, δ 177.9, 164.8, 152.2, 147.3, 146.4, 136.1, 134.0, 128.6, 127.4, 126.4, 122.0, 109.0, 107.9, 107.9, 107.0, 100.8, 61.1, 60.0, 52.1, 44.0, 43.2, 35.8, 14.4, 12.8. HRMS (ESI+): calcd for C25H27NO6Na ([M + Na]+), 460.1736; found, 460.1735. Optical rotation: [α]22D −41.9 (c 2.0, CHCl3) for an enantiomerically enriched sample with 95:5 er for each of the diastereomers (dr 3.5:1). The enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, 20 °C, nhexane/EtOH = 80:20, 1.0 mL min−1; for major diastereomer τmajor = 15.1 min, τminor = 20.7 min, and for minor diastereomer τmajor = 25.1 min, τminor = 28.1 min). Compound 8ai. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% EtOAc in petroleum ether) afforded 8ai as a yellow thick oil (60 mg, 0.150 mmol, 75% yield). Rf = 0.25 (40% EtOAc in petroleum ether). FT-IR (neat): 3442 (br), 2961 (m), 1684 (s), 1618 (m), 1532 (m), 1242 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.17−7.21 (m, 3H), 7.06−7.08 (m, 1H), 6.71− 6.90 (m, 4H), 4.71 (d, J = 16.2 Hz, 1H), 4.40 (d, J = 16.2 Hz, 1H), 4.20−4.35 (m, 2H), 4.12−4.18 (m, 1H), 3.67−3.88 (m, 3H), 2.44− 2.60 (m, 1H), 2.28−2.29 (m, 1H), 2.11 (d, J = 2.2 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 7.12−7.14 (m, 1H), 4.80 (d, J = 16.0 Hz, 1H), 4.02− 4.06 (m, 1H), 3.53−3.59 (m, 1H), 2.01−2.09 (m, 1H), 2.16 (d, J = 2.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to 12079

DOI: 10.1021/acs.joc.8b02051 J. Org. Chem. 2018, 83, 12071−12085

Article

The Journal of Organic Chemistry

signals corresponding to the minor diastereomer, δ 177.9, 164.9, 154.3, 140.1, 128.7, 128.2, 128.1, 127.8, 126.8, 114.0, 107.0, 61.2, 59.9, 55.2, 51.8, 44.3, 42.6, 35.5, 14.4, 12.7; HRMS (ESI+): calcd for C25H29NO5Na ([M + Na]+), 446.1943; found, 446.1945. Optical rotation: [α]22D −19.2 (c 2.0, CHCl3) for an enantiomerically enriched sample with 99:1 er for the major diastereomer and 95.5:4.5 er for the minor diastereomer (dr 2:1). The enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, 20 °C, n-hexane/IPA = 80:20, 1.0 mL min−1; for major diastereomer τmajor = 29.1 min, τminor = 43.9 min, and for minor diastereomer τminor = 39.3 min, τmajor = 62.1 min). Compound 8fa. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 45% EtOAc in petroleum ether) afforded 8fa as a colorless oil (71 mg, 0.154 mmol, 77% yield). Rf = 0.20 (50% EtOAc in petroleum ether). FT-IR (neat): 3427 (br), 2927 (m), 1688 (s), 1513 (s), 1380 (m), 1248 (s) cm−1. 1 H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.11−7.28 (m, 5H), 6.84−6.92 (m, 2H), 6.52−6.60 (m, 2H), 4.26−4.41 (m, 2H), 3.78−3.86 (m, 5H), 3.52−3.74 (m, 2H), 2.05−2.58 (m, 3H), 1.88 (d, J = 1.8 Hz, 3H), 1.40 (d, J = 7.1 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 1.97 (d, J = 1.7 Hz, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.4, 164.3, 159.6, 154.2, 139.5, 128.9, 128.4, 127.8, 126.9, 126.0, 114.6, 106.9, 61.1, 59.8, 55.4, 50.6, 42.3, 33.6, 14.5, 13.0; representative signals corresponding to the minor diastereomer, δ 177.8, 165.0, 160.4, 154.8, 139.4, 129.0, 128.8, 127.8, 127.0, 126.1, 106.8, 61.2, 60.0, 51.8, 45.5, 35.4, 14.4, 13.3. HRMS (ESI+): calcd for C24H27NO5Na ([M + Na]+), 432.1787; found, 432.1787. Optical rotation: [α]22D −39.2 (c 2.0, CHCl3) for an enantiomerically enriched sample with 97.5:2.5 er for both of the diastereomers (dr 3:1). The enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, 20 °C, n-hexane/IPA = 50:50, 1.0 mL min−1; for major diastereomer τmajor = 13.2 min, τminor = 20.8 min, and for minor diastereomer τminor = 17.6 min, τmajor = 42.5 min). Compound 8gb. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% EtOAc in petroleum ether) afforded 8gb as a colorless oil (66 mg, 0.134 mmol, 67% yield). Rf = 0.20 (40% EtOAc in petroleum ether). FT-IR (neat): 3429 (br), 2926 (m), 1695 (s), 1491 (m), 1377 (m), 1123 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.30−7.35 (m, 1H), 7.21−7.26 (m, 3H), 7.08−7.17 (m, 5H), 7.03−7.06 (m, 3H), 6.48−6.50 (m, 2H), 4.37 (d, J = 15.3 Hz, 1H), 4.17 (d, J = 15.3 Hz, 1H), 3.82−4.04 (m, 4H), 3.68−3.74 (m, 1H), 2.55−2.64 (m, 1H), 2.26−2.48 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 6.34−6.36 (m, 2H), 4.52 (d, J = 15.6 Hz, 1H), 4.08 (d, J = 15.6 Hz, 1H), 3.57−3.63 (m, 1H), 2.06−2.14 (m, 1H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.5, 163.3, 154.8, 138.1, 135.8, 132.6, 130.2, 129.7, 129.2, 128.1, 128.0, 127.8, 127.5, 127.2, 127.1, 108.6, 60.8, 59.7, 50.5, 43.9, 41.1, 33.7, 13.8; representative signals corresponding to the minor diastereomer, δ 177.9, 164.2, 155.1, 138.3, 132.8, 130.0, 129.9, 128.1, 127.8, 108.8, 60.9, 59.9, 51.7, 44.4, 44.0, 35.8, 13.6. HRMS (ESI+): calcd for C29H28ClNO4Na ([M + Na]+), 512.1605; found, 512.1606. Optical rotation: [α]21D −47.3 (c 2.0, CHCl3) for an enantiomerically enriched sample with 96:4 er for each of the diastereomers (dr 2:1). The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IC column (80:20 n-hexane/ EtOH, 1.0 mL/min, 20 °C, 200 nm; for minor diastereomer τmajor = 19.3 min, τminor = 27.6 min, and for major diastereomer τmajor = 22.5 min, τminor = 31.1 min). Compound 8hb. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 45% EtOAc in petroleum ether) afforded 8hb as a colorless oil (74 mg, 0.142 mmol, 71% yield). Rf = 0.20 (50% EtOAc in petroleum ether). FT-IR (neat): 3424 (br), 2929 (m), 1688 (s), 1619 (m), 1512 (m), 1390 (m), 1051 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 6.72−6.74 (m, 2H), 6.64−6.67 (m, 2H), 4.59 (d, J = 15.9 Hz, 1H), 4.22−4.37 (m, 3H),

mmol, 71% yield). Rf = 0.25 (40% EtOAc in petroleum ether). FT-IR (neat): 3427 (br), 2929 (m), 1691 (s), 1611 (m), 1513 (m), 1247 (s) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.14−7.28 (m, 5H), 7.05 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 7.3 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 6.60 (d, J = 8.5 Hz, 2H), 4.46 (d, J = 15.9 Hz, 1H), 4.25−4.39 (m, 2H), 4.18 (d, J = 15.9 Hz, 1H), 3.83−3.88 (m, 2H), 3.78 (s, 3H), 3.70−3.74 (m, 2H), 2.84−2.91 (m, 1H), 2.39−2.67 (m, 3H), 2.05−2.12 (m, 2H), 1.76 (br, 1H), 1.38 (t, J = 7.1 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 6.95 (d, J = 7.1 Hz, 2H), 4.62 (d, J = 16.1 Hz, 1H), 3.53−3.59 (m, 1H), 2.16−2.22 (m, 2H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.7, 163.7, 159.0, 157.9, 140.3, 138.2, 132.7, 129.9, 128.5, 128.2, 128.1, 127.9, 126.40, 114.1, 106.6, 61.0, 60.0, 55.3, 50.4, 42.5, 40.7, 34.4, 34.0, 28.6, 14.6; representative signals corresponding to the minor diastereomer, δ 128.3, 128.0, 127.8, 126.4, 61.1, 60.2, 51.6, 44.2, 42.7, 36.0, 34.4, 28.8, 14.5. HRMS (ESI+): calcd for C32H34NO5ClNa ([M + Na]+), 570.2023; found, 570.2025. Optical rotation: [α]22D −32.1 (c 2.0, CHCl3) for an enantiomerically enriched sample with 98:2 er for the major diastereomer and 97.5:2.5 er for the minor diastereomer (dr 2:1). The enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, 20 °C, n-hexane/IPA = 80:20, 1.0 mL min−1; for major diastereomer τmajor = 16.7 min, τminor = 24.9 min, and for minor diastereomer τminor = 19.9 min, τmajor = 43.7 min). Compound 8db. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 45% EtOAc in petroleum ether) afforded 8db as a colorless oil (71 mg, 0.142 mmol, 71% yield). Rf = 0.20 (50% EtOAc in petroleum ether). FT-IR (neat): 3430 (br), 2929 (m), 1688 (s), 1614 (m), 1514 (m), 1247 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 6.77 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.5 Hz, 2H), 5.48−5.66 (m, 1H), 4.82−4.94 (m, 2H), 4.59 (d, J = 15.8 Hz, 1H), 4.22−4.37 (m, 3H), 3.81−3.88 (m, 2H), 3.78 (s, 3H), 3.67−3.73 (m, 2H), 2.64−2.71 (m, 1H), 2.51−2.60 (m, 1H), 2.36− 2.49 (m, 1H), 1.82−2.09 (m, 2H), 1.58−1.68 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 7.22 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 4.72 (d, J = 15.9 Hz, 1H), 3.78 (s, 3H), 3.52−3.58 (m, 1H), 2.13− 2.22 (m, 1H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.7, 163.8, 158.9, 157.7, 138.2, 136.3, 132.6, 129.8, 128.1, 128.0, 127.9, 115.6, 114.0, 106.6, 60.8, 59.9, 55.2, 50.3, 42.6, 40.7, 33.9, 32.0, 25.7, 14.4; representative signals corresponding to the minor diastereomer, δ 178.2, 164.5, 158.9, 158.0, 138.5, 136.4, 130.2, 128.2, 127.8, 115.7, 106.8, 60.9, 60.1, 51.4, 44.0, 42.8, 35.8, 32.1, 26.0, 14.3. HRMS (ESI+): calcd for C28H32NO5ClNa ([M + Na]+), 520.1867; found, 520.1868. Optical rotation: [α]22D −15.0 (c 1.0, CHCl3) for an enantiomerically enriched sample with 98:2 er for the major diastereomer and 97.5:2.5 er for the minor diastereomer (dr 2:1). The enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, 20 °C, n-hexane/IPA = 80:20, 1.0 mL min−1; for major diastereomer τmajor = 16.6 min, τminor = 22.6 min, and for minor diastereomer τminor = 19.9 min, τmajor = 38.9 min). Compound 8ea. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 50% EtOAc in petroleum ether) afforded 8ea as a colorless oil (64 mg, 0.151 mmol, 75% yield). Rf = 0.20 (50% EtOAc in petroleum ether). FT-IR (neat): 3428 (br), 2931 (m), 1687 (s), 1618 (m), 1513 (m), 1389 (m), 1247 (m), 1061 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 6.72−6.74 (m, 2H), 6.64−6.67 (m, 2H), 4.59 (d, J = 15.9 Hz, 1H), 4.22−4.37 (m, 3H), 3.80−3.87 (m, 2H), 3.78 (s, 3H), 3.64−3.75 (m, 2H), 2.43−2.62 (m, 1H), 2.11−2.22 (m, 2H), 2.05 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 4.67 (d, J = 15.9 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.52−3.60 (m, 1H), 3.77−3.79 (m, 3H), 2.15 (s, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.7, 164.3, 158.7, 153.9, 139.6, 128.3, 128.1, 128.9, 127.8, 126.7, 114.0, 106.8, 61.1, 59.7, 55.2, 50.6, 42.4, 41.5, 34.1, 14.4, 12.5; representative 12080

DOI: 10.1021/acs.joc.8b02051 J. Org. Chem. 2018, 83, 12071−12085

Article

The Journal of Organic Chemistry

Compound 10a. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether/5% EtOAc in petroleum ether) afforded 10a as a yellow oil (93 mg, 0.166 mmol, 83% yield). Rf = 0.40 (30% EtOAc in petroleum ether). FT-IR (neat): 2930 (w), 1719 (s), 1714 (s), 1625 (m), 1494 (m), 1389 (m), 1152 (m) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.32− 7.36 (m, 5H), 7.21−7.22 (m, 5H), 7.16 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 6.59−6.61 (m, 2H), 6.09 (d, J = 15.7 Hz, 1H), 5.16 (s, 2H), 4.76 (d, J = 16.2 Hz, 1H), 4.26−4.32 (m, 3H), 3.79−3.84 (m, 1H), 3.58−3.59 (m, 1H), 3.29−3.37 (m, 1H), 3.02−3.09 (m, 1H), 2.08 (d, J = 1.9 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 176.7, 166.0, 164.0, 154.5, 147.2, 137.2, 136.0, 135.6, 132.8, 129.7, 128.6, 128.4, 128.2, 128.1, 128.1, 127.4, 126.1, 123.2, 106.0, 66.0, 59.9, 50.1, 42.9, 42.5, 33.7, 14.4, 12.6. HRMS (ESI+): calcd for C33H32NO5ClNa ([M + Na]+), 580.1867; found, 580.1866. Optical rotation: [α]22D −26.1 (c 1.0, CHCl3) for an enantiomerically enriched sample with 96:4 er for each of the diastereomers (dr 3:1). The enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak IE column, 220 nm, 20 °C, nhexane/IPA = 80:20, 1.0 mL min−1; for major diastereomer τminor = 35.7 min, τmajor = 46.3 min, and for minor diastereomer τmajor = 50.6 min, τminor = 58.4 min). Compound 10b. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether/4% EtOAc in petroleum ether) afforded 10b as a yellow oil (93 mg, 0.178 mmol, 89% yield) having 3:1 diastereomeric mixture. Slow column chromatographic purification provided a diastereomerically enriched 10b (54 mg, 0.103 mmol, 51% yield, 13:1 dr). Rf = 0.20 (10% EtOAc in petroleum ether). FT-IR (neat): 2977 (w), 1696 (s), 1693 (s), 1627 (m), 1390 (m), 1150 (s) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.20−7.22 (m, 3H), 7.16 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 8.3 Hz, 2H), 6.83−6.90 (m, 1H), 6.57−6.58 (m, 2H), 5.96 (d, J = 15.7 Hz, 1H), 4.74−4.78 (m, 1H), 4.22−4.36 (m, 3H), 3.76−3.81 (m, 1H), 3.58−3.60 (m, 1H), 3.28−3.36 (m, 1H), 2.93−2.99 (m, 1H), 2.08 (s, 3H), 1.46 (s, 9H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 176.8, 165.8, 164.1, 154.6, 145.2, 137.4, 135.7, 132.8, 129.7, 128.7, 128.3, 127.4, 126.2, 125.3, 106.1, 80.1, 59.9, 50.0, 42.9, 42.6, 33.5, 28.1, 14.5, 12.6. HRMS (ESI+): calcd for C30H34NO5ClNa ([M + Na]+), 546.2023; found, 546.2027. Optical rotation: [α]22D −30.3 (c 1.0, CHCl3) for a sample with 13:1 dr and 96.5:3.5 er. Enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak AD-H column, 220 nm, n-hexane/IPA = 97:3, 1.0 mL min−1, τmajor = 26.0 min, τminor = 33.1 min). Synthesis of Tetrahydropyranopyrrole (12). Conversion of 8ab to Mesyl Intermediate 11a. In a 10 mL round-bottom flask was dissolved 8ab (286 mg, 0.67 mmol, 1.0 equiv) in dry CH2Cl2 (6 mL). At 0 °C, MsCl (62 μL, 0.80 mmol, 1.2 equiv) was added dropwise to this solution followed by dropwise addition of Et3N (140 μL, 1.0 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 2 h by which time all 8ab was consumed (TLC). The reaction mixture was concentrated under reduced pressure to obtain a yellow oil, which was dissolved in 50 mL of CH2Cl2. The solution was washed with (2 × 10 mL) aq 1 N HCl solution, followed by satd aq NaHCO3 (10 mL) and brine (10 mL); the organic layer was dried over anhyd Na2SO4 and concentrated under reduced pressure to obtain a yellow oil. This was purified by silica gel (230− 400 mesh) column chromatography (gradient elution: 25−40% EtOAc/petroleum ether) to obtain 11a as a yellow oil (318 mg, 0.67 mmol, 94% yield). Rf = 0.10 (50% EtOAc in petroleum ether). FT-IR (thin film): 1687 (s), 1627 (s), 1493 (m), 1352 (s), 1173 (s) cm−1. 1 H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.20−7.24 (m, 3H), 7.14−7.16 (m, 2H), 6.99 (d, J = 8.2 Hz, 2H), 6.66−6.69 (m, 2H), 4.75 (d, J = 16.1 Hz, 1H), 4.12− 4.38 (m, 5H), 3.85−3.90 (m, 1H), 3.55−3.57 (m, 1H), 2.94 (s, 3H), 2.63−2.82 (m, 2H), 2.08 (s, 3H), 1.35−1.38 (m, 3H); representative signals corresponding to the minor diastereomer, δ 7.28−7.37 (m, 2H), 7.13−7.16 (m, 2H), 4.82 (d, J = 16.0 Hz, 1H), 3.99−4.06 (m, 1H), 3.68−3.71 (m, 1H), 3.63−3.64 (m, 1H), 2.92 (s, 3H), 2.24− 2.37 (m, 1H), 1.35−1.37 (m, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 176.8, 163.8,

3.80−3.87 (m, 2H), 3.78 (s, 3H), 3.64−3.75 (m, 2H), 2.43−2.62 (m, 1H), 2.11−2.22 (m, 2H), 2.05 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 4.67 (d, J = 15.9 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.52−3.60 (m, 1H), 3.77−3.79 (m, 3H), 2.15 (s, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.7, 164.3, 158.7, 153.9, 139.6, 128.3, 128.1, 127.9, 127.8, 114.0, 106.3, 66.7, 59.9, 55.2, 50.5, 42.4, 41.5, 34.0, 12.9; representative signals corresponding to the minor diastereomer, δ 177.3, 163.8, 154.8, 138.0, 128.7, 128.2, 128.1, 127.6, 106.0, 66.0, 60.7, 51.5, 44.3, 42.6, 35.5, 12.7. HRMS (ESI+): calcd for C30H30NO5ClNa ([M + Na]+), 542.1710; found, 542.1710. Optical rotation: [α]22D −39.2 (c 2.0, CHCl3) for an enantiomerically enriched sample with 98:2 er for each of the diastereomers (dr 2:1). The enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, 20 °C, nhexane/IPA = 80:20, 1.0 mL min−1; for major diastereomer τmajor = 20.5 min, τminor = 26.3 min, and for minor diastereomer τminor = 23.7 min, τmajor = 39.6 min). Procedure for One-Pot Michael Addition/Pinnick Oxidation: Synthesis of Compound 9ab. In a reaction tube fitted with a magnetic stir bar were taken catalyst VI (7.4 mg, 0.02 mmol, 0.1 equiv) along with α,β-unsaturated aldehyde 6b (0.24 mmol, 1.2 equiv) in 0.5 mL of 1,4-dioxane under a positive argon pressure. At 0 °C, a solution of butyrolactam 1a (0.20 mmol, 1.0 equiv) in 0.5 mL of 1,4-dioxane was added. The resulting mixture was stirred at 25 °C until complete consumption of lactam 1a (followed by TLC). At this point, 2-methyl-2-butene (0.8 mL) and tert-butanol (0.7 mL) were added. The resulting mixture was cooled to 0 °C. A solution of NaClO2 (50 mg, 0.4 mmol, 2.0 equiv) and NaH2PO4·2H2O (48 mg, 0.4 mmol, 2.0 equiv) in 0.5 mL of water was added dropwise. The reaction mixture was allowed to attain ambient temperature, and vigorous stirring was continued for 18 h. The reaction mixture was diluted with 40 mL of EtOAc. The organic layer was washed with 10 mL of brine, dried over anhyd Na2SO4, and concentrated under reduced pressure to obtain a yellow oil. Purification by silica gel (230−400 mess) column chromatography (gradient elution: CH2Cl2 to 10% THF in CH2Cl2) afforded 9ab as colorless oil (71 mg, 0.160 mmol, 80% yield). Rf = 0.30 (10% THF in CH2Cl2). FT-IR (neat): 3218 (br), 2924 (w), 1698 (s), 1644 (m), 1557 (m), 1377 (s) cm−1. 1 H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.19−7.22 (m, 3H), 7.13 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.62−6.64 (m, 2H), 4.75 (d, J = 16.0 Hz, 1H), 4.26− 4.34 (m, 3H), 4.14−4.19 (m, 1H), 3.68−3.69 (m, 1H), 3.47 (dd, J = 8.0, 16.7 Hz, 1H), 3.20 (dd, J = 8.0, 16.7 Hz, 1H), 2.08 (d, J = 2.0 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 6.66−6.68 (m, 2H), 4.01−4.06 (m, 1H), 3.78−3.79 (m, 1H), 3.00 (dd, J = 8.3, 16.6 Hz, 1H), 2.81 (dd, J = 8.3, 16.6 Hz, 1H), 2.14 (d, J = 2.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 177.1, 164.0, 154.5, 137.0, 135.6, 132.9, 129.9, 129.4, 128.6, 128.3, 127.5, 126.3, 106.2, 60.0, 50.3, 43.0, 39.6, 35.7, 14.4, 12.5; representative signals corresponding to the minor diastereomer, δ 177.0, 164.7, 155.2, 137.6, 135.7, 133.0, 128.7, 128.3, 127.5, 126.3, 60.2, 51.0, 43.3, 42.4, 14.3, 12.8. HRMS (ESI+): calcd for C24H24NO5ClNa ([M + Na]+), 464.1241; found, 464.1243. Optical rotation: [α]23D −31.9 (c 1.0, CHCl3) for a sample with 3:1 dr. Procedure for One-Pot Michael Addition/Wittig Olefination: Synthesis of Compound 10. In a reaction tube fitted with a magnetic stir bar were taken catalyst VI (7.4 mg, 0.02 mmol, 0.1 equiv) along with α,β-unsaturated aldehyde 6b (0.24 mmol, 1.2 equiv) in 0.5 mL of 1,4-dioxane under a positive argon pressure. At 0 °C, a solution of butyrolactam 1a (0.20 mmol, 1.0 equiv) in 0.5 mL of 1,4-dioxane was added. The resulting mixture was stirred at 25 °C until complete consumption of lactam 1a (followed by TLC). Wittig ylide (0.24 mmol, 1.2 equiv) was then added, and stirring was continued until full consumption of the Michael adduct (followed by TLC). Solvent was evaporated under reduced pressure, and the resulting oil was purified by silica gel column chromatography to obtain α,β-unsaturated esters 10. 12081

DOI: 10.1021/acs.joc.8b02051 J. Org. Chem. 2018, 83, 12071−12085

Article

The Journal of Organic Chemistry 154.2, 136.6, 135.6, 132.9, 129.6, 128.5, 128.4, 126.2, 105.9, 68.0, 59.8, 50.4, 42.9, 39.8, 37.1, 30.6, 14.5, 12.5; representative signals corresponding to the minor diastereomer, δ 177.1, 164.4, 154.7, 137.2, 135.7, 133.1, 130.1, 128.6, 128.3, 126.2, 106.1, 67.7, 60.0, 51.3, 43.1, 37.1, 32.3, 14.3, 12.7. HRMS (ESI + ): calcd for C25H28NO6ClSNa ([M + Na]+), 528.1224; found, 528.1222. Optical rotation: [α]22D +11.6 (c 1.0, CHCl3) for a sample with 3:1 dr. Racemic mesylate (rac-11a) was prepared following the same procedure as above and crystallized from 3:1 petroleum ether/Et2O at 0 °C to obtain X-ray diffraction quality crystals of the major diastereomer (40% recovery). Melting point of the major diastereomer of rac-11a: 102 °C. Conversion of 11a to 12a. In a 50 mL round-bottom flask was dissolved 11a (102 mg, 0.20 mmol, 1.0 equiv) in 1.0 mL of absolute toluene. A solution of DBU (32 μL, 0.22 mmol, 1.1 equiv) in 1.0 mL of toluene was added. The resulting solution was heated at 60 °C and stirred for 2 h. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting yellow oil was purified by silica gel (230−400 mesh) column chromatography (gradient elution: 1−10% EtOAc/petroleum ether) to obtain 12a as a white solid (55 mg, 0.134 mmol, 67% yield). Rf = 0.50 (10% EtOAc in petroleum ether). Recrystallized from 4:1 nhexane/Et2O at −20 °C affording diffraction quality crystals. mp 119−120 °C. FT-IR (KBr): 2919 (m), 1684 (s), 1608 (m), 1535 (m), 1476 (m), 1405 (s), 1361 (m), 1264 (m), 1231 (m), 1089 (s) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.32−7.36 (m, 2H), 7.21−7.29 (m, 3H), 7.07−7.11 (m, 4H), 4.97−5.06 (m, 2H), 4.31−4.33 (m, 2H), 4.15−4.19 (m, 1H), 3.89−3.97 (m, 4H), 2.43 (s, 3H), 2.34− 2.41 (m, 1H), 1.80−1.86 (m, 1H), 0.89 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 165.7, 146.0, 142.9, 137.3, 131.2, 129.2, 129.1, 128.8, 128.0, 127.4, 126.3, 107.7, 94.7, 64.6, 58.8, 44.8, 35.9, 32.7, 14.0, 10.8. HRMS (ESI+): calcd for C24H24NO3ClNa ([M + Na]+), 432.1342; found, 432.1346. Optical rotation: [α]21D +23.41 (c 0.5, CHCl3) for a sample with >99.9:0.1 er, obtained after column chromatography followed by a single recrystallization. The compound 12a was obtained after column chromatography with 96:4 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak IB column, 240 nm, n-hexane/IPA = 98:2, 1.0 mL min−1, τmajor = 12.5 min, τminor = 13.9 min). Typical Procedure for One-Pot Conversion of 8 to 12. In a 10 mL round-bottom flask was dissolved 8ae (110 mg, 0.232 mmol, 1.0 equiv) in absolute CH2Cl2 (4 mL). MsCl (22 μL, 0.278 mmol, 1.2 equiv) was added at 0 °C followed by dropwise addition of Et3N (49 μL, 0.35 mmol, 1.5 equiv). The resulting mixture was stirred at 25 °C for 2 h by which time 8ae was consumed, producing the mesyl intermediate (TLC). The resulting solution was concentrated under reduced pressure to obtain a yellow oil. This oil was dissolved in dry toluene (2 mL), and DBU (38 μL, 0.255 mmol, 1.1 equiv) was added. The resulting solution was heated at 60 °C and stirred for 2 h at that temperature. After being cooled to ambient temperature, the reaction mixture was concentrated under reduced pressure to obtain a yellow oil. This was purified by silica gel (230−400 mesh) column chromatography (gradient elution: 1−10% EtOAc/petroleum ether) to obtain pure 12b as a yellow oil (62 mg, 0.136 mmol, 59% yield). Rf = 0.50 (10% EtOAc in petroleum ether). FT-IR (thin film): 2932 (m), 2105 (m), 1678 (s), 1629 (m), 1520 (m), 1412 (m), 1264 (m) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.25−7.36 (m, 5H), 7.07−7.15 (m, 4H), 5.04 (d, J = 16.4 Hz, 1H), 4.99 (d, J = 16.4 Hz, 1H), 4.30− 4.32 (m, 1H), 4.15−4.19 (m, 1H), 3.87−4.00 (m, 3H), 2.43 (s, 3H), 2.33−2.42 (m, 1H), 1.82−1.88 (m, 1H), 0.90 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 165.7, 150.0, 143.0, 137.2, 131.0, 129.5, 129.3, 128.8, 128.7, 127.4, 126.5, 126.2, 122.2, 107.6, 94.4, 64.5, 58.8, 44.8, 36.2, 32.6, 13.9, 10.8. HRMS (ESI+): calcd for C24H24NO3BrNa ([M + Na]+), 476.0837; found, 476.0836. Optical rotation: [α]21D +22.9 (c 1.0, CHCl3) for a sample with 98.5:1.5 er obtained after column chromatography. Enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, n-hexane/IPA = 95:5, 1.0 mL min−1, τmajor = 8.2 min, τminor = 10.1 min). Procedure for Rearrangements of Mesyl Alcohol 11a. Synthesis of 13. In a 50 mL round-bottom flask was taken 11a

(181 mg, 0.36 mmol, 1.0 equiv) in 3 mL of DMF, and NaN3 (117 mg, 1.8 mmol; 5.0 equiv) was added. The resulting heterogeneous mixture was heated and stirred at 90 °C for 12 h under open air. After being cooled to ambient temperature, the reaction mixture was diluted with water (25 mL) and extracted with Et2O (4 × 20 mL). The organic layer was dried over anhyd Na2SO4 and concentrated under reduced pressure to obtain a yellow oil, which was purified by silica gel (230− 400 mesh) column chromatography (gradient elution: 25−90% EtOAc/petroleum ether) to obtain 13 as an off-white solid (57 mg, 0.14 mmol, 39% yield). Rf = 0.20 (80% EtOAc in petroleum ether). Recrystallized from 4:1 n-hexane/CHCl3 (by slow diffusion to a toluene-filled closed chamber) afforded diffraction quality crystals. mp 212−214 °C. FT-IR (KBr): 3224 (m), 2895 (br), 1717 (s), 1684 (s), 1639 (s), 1489 (m), 1395 (s), 1345 (s), 1161 (s), 1007 (m), 950 (s) cm−1. 1H NMR (400 MHz, CDCl3): δ 11.09 (s, 1H), 7.22−7.27 (m, 1H), 7.16−7.19 (m, 2H), 7.00 (d, J = 5.5, 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 7.5 Hz, 2H), 4.53 (s, 2H), 3.99−4.03 (m, 1H), 3.85−3.94 (m, 2H), 2.93−3.05 (m, 1H), 2.25−2.31 (m, 1H), 2.11 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 173.1, 169.8, 169.1, 160.3, 134.5, 134.2, 131.4, 129.3, 129.0, 28.5, 127.7, 69.1, 53.2, 47.7, 42.2, 29.4, 21.4. HRMS (ESI+): calcd for C22H20N3O3ClNa ([M + Na]+), 432.1091; found, 432.1093. Optical rotation: [α]21D −52.38 (c 1.0, CHCl3) for a sample with >99.9:0.1 er, obtained after column chromatography followed by a single recrystallization. Compound 13 was obtained after column chromatography with 96:4 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak IE column, 210 nm, n-hexane/IPA = 75:25, 1.0 mL min−1, τminor = 29.9 min, τmajor = 43.4 min). Synthesis of 14. In a 50 mL round-bottom flask was taken 11a (172 mg, 0.34 mmol, 1.0 equiv) in 3 mL of DMF, and NaN3 (111 mg, 1.70 mmol, 5.0 equiv) was added. Without degassing, an argon balloon was introduced. The resulting heterogeneous mixture was heated and stirred at 70 °C for 3 h under an atmosphere of air and argon mixture. After being cooled to ambient temperature, the reaction mixture was diluted with water (25 mL) and extracted with Et2O (3 × 25 mL). The organic layer was dried over anhyd Na2SO4 and concentrated under reduced pressure to obtain a yellow oil, which was purified by silica gel (230−400 mesh) column chromatography (gradient elution: 25−70% EtOAc/petroleum ether) to give 14 as an off-white solid (59 mg, 0.126 mmol, 37% yield). Rf = 0.10 (50% EtOAc in petroleum ether). Recrystallized from 4:1 n-hexane/CHCl3 (by slow diffusion to a toluene-filled closed chamber) afforded diffraction quality crystals. mp 145−146 °C. FT-IR (KBr): 2932 (m), 2105 (m), 1678 (s), 1629 (m), 1520 (m), 1412 (m), 1264 (m) cm−1. 1 H NMR (400 MHz, CDCl3): δ 7.26−7.33 (m, 3H), 7.18−7.20 (m, 2H), 7.10−7.11 (m, 2H), 7.02−7.04 (m, 2H), 5.94 (t, J = 5.2 Hz, 1H), 4.58 (dd, J = 13.3, 6 Hz, 1H), 4.13−4.28 (m, 3H), 3.99 (dd, J = 14.5, 5 Hz, 1H), 3.80−3.91 (m, 2H), 2.33−2.45 (m, 1H), 2.13−2.17 (m, 1H), 2.11 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 170.4, 166.5, 165.7, 137.3, 134.6, 133.6, 129.4, 128.7, 128.4, 128.1, 127.6, 73.5, 61.1, 60.6, 48.3, 47.9, 44.1, 27.6, 23.0, 14.3. HRMS (ESI+): calcd for C24H25N4O4ClNa ([M + Na]+), 491.1462; found, 491.1465. Optical rotation: [α]21D +13.05 (c 1.0, CHCl3) for a sample with >99.9:0.1 er, obtained after column chromatography followed by a single recrystallization. The compound 14 was obtained after column chromatography with 96:4 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak AD-H column, 254 nm, n-hexane/EtOH = 95:5, 1.0 mL min−1, τmajor = 23.7 min, τminor = 27.5 min). General Procedure for Catalytic Enantioselective Michael Addition of Deconjugated Butyrolactams (1) to α,β-Unsaturated Ketones (15). In a reaction tube fitted with a magnetic stir bar were taken catalyst XII (7.7 mg, 0.02 mmol, 0.1 equiv) and 2-fluoro benzoic acid (5.6 mg, 0.04 mmol, 0.2 equiv) in 0.8 mL of mesitylene, which was stirred at 25 °C for 10 min. α,β-Unsaturated ketone 15 (0.3 mmol, 1.5 equiv) was added, and stirring was continued for 15 min. Butyrolactam 1a (0.20 mmol, 1.0 equiv) was added at 0 °C, and the resulting mixture was stirred at room temperature until complete conversion (followed by TLC). The reaction mixture was purified by silica gel column chromatography to obtain the desired product 16. 12082

DOI: 10.1021/acs.joc.8b02051 J. Org. Chem. 2018, 83, 12071−12085

Article

The Journal of Organic Chemistry Compound 16aa. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 10% EtOAc in petroleum ether) afforded the major diastereomer of 16aa as a colorless oil (52 mg, 0.128 mmol, 64% yield). Combined yield of the diastereomers was 91% (74 mg, 0.182 mmol). Rf = 0.25 (30% EtOAc in petroleum ether). FT-IR (neat): 1719 (s), 1694 (s), 1630 (w), 1377 (m), 1252 (m), 1232 (m) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.14−7.23 (m, 6H), 7.04−7.05 (m, 2H), 6.69−6.70 (m, 2H), 4.66 (d, J = 16.1 Hz, 1H), 4.39 (d, J = 16.1 Hz, 1H), 4.22−4.36 (m, 3H), 3.64−3.77 (m, 2H), 3.23 (dd, J = 6.5, 17.7 Hz, 1H), 2.20 (s, 3H), 2.03 (d, J = 2.1 Hz, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 206.7, 177.3, 164.0, 154.2, 138.4, 135.7, 131.2, 129.8, 128.7, 127.5, 126.3, 120.8, 106.5, 59.9, 50.1, 44.6, 43.0, 38.7, 30.5, 14.5, 12.5. HRMS (ESI+): calcd for C25H27NO4Na ([M + Na]+), 428.1838; found, 428.1839. Optical rotation: [α]22D +27.3 (c 1.0, CHCl3) for an enantiomerically enriched sample with 98.5:1.5 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, n-hexane/EtOH = 90:10, 1.0 mL min−1, τminor = 11.8 min, τmajor = 13.5 min). Compound 16ab. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 10% EtOAc in petroleum ether) afforded the major diastereomer of 16ab as a colorless oil (38 mg, 0.091 mmol, 45% yield). Combined yield of the diastereomers was 85% (72 mg, 0.171 mmol). Rf = 0.3 (30% EtOAc in petroleum ether). FT-IR (neat): 2924 (m), 1717 (s), 1693 (s), 1626 (m), 1386 (m), 1217 (w), 1065 (m) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.21−7.23 (m, 3H), 7.12−7.14 (m, 1H), 7.05−7.06 (m, 2H), 6.87−6.93 (m, 3H), 4.68 (d, J = 16.0 Hz, 1H), 4.54 (d, J = 16.0 Hz, 1H), 4.47−4.50 (m, 1H), 4.15−4.28 (m, 2H), 3.68−3.71 (m, 1H), 3.53 (dd, J = 7.5, 17.7 Hz, 1H), 3.19 (dd, J = 7.3, 17.7 Hz, 1H), 2.27 (s, 3H), 2.14 (s, 3H), 2.07 (d, J = 2.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 207.3, 178.4, 164.3, 154.0, 138.5, 136.9, 136.1, 130.5, 128.8, 127.5, 126.8, 126.7, 126.5, 125.9, 107.0, 59.9, 50.4, 46.5, 43.2, 35.1, 30.6, 19.4, 14.3, 12.5. HRMS (ESI+): calcd for C26H29NO4Na ([M + Na]+), 442.1994; found, 442.1994. Optical rotation: [α]22D +22.2 (c 1.0, CHCl3) for an enantiomerically enriched sample with 97:3 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak IC column, 220 nm, n-hexane/EtOH = 95:5, 1.0 mL min−1, τminor = 24.5 min, τmajor = 28.8 min). Compound 16ac. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 35% Et2O in petroleum ether) afforded the major diastereomer of 16ac as a colorless oil (41 mg, 0.094 mmol, 47% yield). Combined yield of the diastereomers was 89% (78 mg, 0.178 mmol). Rf = 0.20 (50% Et2O in petroleum ether). FT-IR (neat): 1716 (s), 1689 (s), 1627 (m), 1388 (m), 1352 (m), 1221 (m), 1020 (m) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.18−7.22 (m, 3H), 7.08 (t, J = 7.9 Hz, 1H), 6.71−6.76 (m, 3H), 6.62−6.65 (m, 2H), 4.72 (d, J = 16.2 Hz, 1H), 4.22−4.42 (m, 4H), 3.65−3.73 (m, 2H), 3.67 (s, 3H), 3.22 (dd, J = 6.5, 17.7 Hz, 1H), 2.21 (s, 3H), 2.05 (d, J = 2.2 Hz, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 207.2, 177.6, 164.2, 159.3, 154.0, 141.1, 136.1, 129.1, 128.7, 127.4, 126.3, 120.4, 113.5, 112.9, 106.9, 59.8, 55.0, 50.1, 44.8, 43.0, 39.5, 30.6, 14.6, 12.5. HRMS (ESI+): calcd for C26H29NO5Na ([M + Na]+), 458.1943; found, 458.1943. Optical rotation: [α]22D +22.2 (c 1.0, CHCl3) for an enantiomerically enriched sample with 98.5:1.5 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak AS-H column, 254 nm, nhexane/IPA = 90:10, 1.0 mL min−1, τminor = 15.1 min, τmajor = 21.9 min). Compound 16ad. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% Et2O in petroleum ether) afforded the major diastereomer of 16ad as a colorless oil (45 mg, 0.097 mmol, 48% yield). Combined yield of the diastereomers was 85% (79 mg, 0.170 mmol). Rf = 0.20 (50% Et2O in petroleum ether). FT-IR (neat): 1719 (s), 1690 (s), 1624 (m), 1388 (m), 1351 (m), 1280 (m) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.4 Hz, 2H), 7.15−7.23 (m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 6.73−6.75 (m, 2H), 4.63 (d, J = 16.1 Hz, 1H), 4.41 (d, J = 16.1 Hz, 1H), 4.24−4.37 (m, 3H), 3.91 (s, 3H), 3.66−3.72 (m, 2H), 3.28 (dd,

J = 6.9, 18.0 Hz, 1H), 2.20 (s, 3H), 2.05 (d, J = 2.2 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 206.8, 177.4, 166.9, 164.0, 154.2, 144.9, 135.8, 129.4, 128.9, 128.7, 128.1, 127.6, 126.5, 106.5, 60.0, 52.1, 49.9, 44.5, 43.1, 39.4, 30.6, 14.5, 12.5. HRMS (ESI+): calcd for C27H29NO6Na ([M + Na]+), 486.1893; found, 486.1891. Optical rotation: [α]22D +37.9 (c 1.0, CHCl3) for an enantiomerically enriched sample with 98.5:1.5 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak AD-H column, 230 nm, n-hexane/IPA = 90:10, 1.0 mL min−1, τminor = 31.4 min, τmajor = 35.0 min). Compound 16ae. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 8% EtOAc in petroleum ether) afforded the major diastereomer of 16ae as a colorless oil (46 mg, 0.097 mmol, 48% yield). Combined yield of the diastereomers was 85% (81 mg, 0.171 mmol). Rf = 0.25 (20% EtOAc in petroleum ether). FT-IR (neat): 1718 (s), 1691 (s), 1625 (m), 1390 (m), 1326 (s), 1220 (m), 1017 (s) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 8.1 Hz, 2H), 7.17−7.24 (m, 3H) 7.14 (d, J = 8.1 Hz, 2H), 6.73−6.75 (m, 2H), 4.72 (d, J = 16.1 Hz, 1H), 4.24−4.39 (m, 4H), 3.65−3.71 (m, 2H), 3.29 (dd, J = 7.1, 18.1 Hz, 1H), 2.20 (s, 3H), 2.08 (d, J = 2.2 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 206.6, 177.4, 164.0, 154.3, 143.7, 135.7, 129.1 (q, J = 32 Hz), 128.7, 128.5, 127.6, 126.5, 125.1 (q, J = 4 Hz), 124.1 (q, J = 272 Hz), 106.4, 60.0, 50.0, 44.6, 43.1, 39.1, 30.6, 14.5, 12.6. HRMS (ESI+): calcd for C26H26NO4F3Na ([M + Na]+), 496.1712; found, 496.1715. Optical rotation: [α]22D +23.1 (c 1.0, CHCl3) for an enantiomerically enriched sample with 98.5:1.5 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak AD-H column, 220 nm, n-hexane/IPA = 90:10, 1.0 mL min−1, τminor = 12.9 min, τmajor = 17.2 min). Compound 16af. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 10% EtOAc in petroleum ether) afforded the major diastereomer of 16af as a colorless oil (44 mg, 0.093 mmol, 46% yield). Combined yield of the diastereomers was 80% (76 mg, 0.16 mmol). Rf = 0.25 (30% EtOAc in petroleum ether). FT-IR (neat): 1717 (s), 1690 (s), 1626 (m), 1389 (m), 1352 (m), 1224 (m) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.18−7.25 (m, 5H), 6.84−6.87 (m, 1H), 6.73−6.75 (m, 2H), 4.76 (d, J = 16.1 Hz, 1H), 4.38 (d, J = 16.1 Hz, 1H), 3.59−3.65 (m, 2H), 4.22−4.35 (m, 3H), 3.26 (dd, J = 7.1, 18.2 Hz, 1H), 2.20 (s, 3H), 2.10 (d, J = 2.0 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 206.4, 177.2, 164.0, 154.4, 140.0, 135.8, 132.2, 131.0, 130.0, 129.9, 128.8, 127.7, 127.6, 126.3, 106.3, 60.0, 50.0, 44.6, 43.1, 38.5, 30.5, 14.5, 12.6. HRMS (ESI+): calcd for C25H25NO4Cl2Na ([M + Na]+), 496.1058; found, 496.1060. Optical rotation: [α]22D +26.7 (c 0.75, CHCl3) for an enantiomerically enriched sample with 99:1 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak IC column, 230 nm, n-hexane/EtOH = 90:10, 1.0 mL min−1, τminor = 15.0 min, τmajor = 17.1 min). Compound 16ag. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 8% THF in petroleum ether) afforded the major diastereomer of 16ag as a colorless oil (48 mg, 0.0.085 mmol, 42% yield). Combined yield of the diastereomers was 90% (101 mg, 0.18 mmol). Rf = 0.40 (20% THF in petroleum ether). FT-IR (neat): 1715 (s), 1688 (s), 1630 (m), 1382 (m), 1354 (m), 1224 (w), 1019 (s) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.51−7.53 (m, 1H), 7.28−7.30 (m, 2H), 7.22−7.26 (m, 1H), 7.17−7.18 (m, 2H), 6.84−6.86 (m, 2H), 4.70 (d, J = 16.3 Hz, 1H), 4.50 (d, J = 16.3 Hz, 1H), 4.31 (t, J = 7.1, 18.2 Hz, 2H), 4.21−4.26 (m, 1H), 3.61−3.68 (m, 2H), 3.22 (dd, J = 6.9, 18.2 Hz, 1H), 2.23 (s, 3H), 2.10 (d, J = 2.2 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 206.3, 177.2, 163.9, 154.4, 143.9, 135.9, 132.7, 129.9, 129.0, 127.6, 126.3, 122.6, 106.3, 60.1, 49.8, 44.4, 43.2, 38.7, 30.5, 14.6, 12.7. HRMS (ESI+): calcd for C25H25Br2NO4Na ([M + Na]+), 584.0048; found, 584.0051. Optical rotation: [α]23D +24.9 (c 0.85, CHCl3) for an enantiomerically enriched sample with 99:1 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak IC column, 210 nm, n-hexane/EtOH = 95:5, 1.0 mL min−1, τminor = 16.6 min, τmajor = 18.2 min). 12083

DOI: 10.1021/acs.joc.8b02051 J. Org. Chem. 2018, 83, 12071−12085

Article

The Journal of Organic Chemistry Compound 16ah. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 10% EtOAc in petroleum ether) afforded major diastereomer of 18ai as a colorless oil (50 mg, 0.121 mmol, 60% yield). Combined yield of the diastereomers was 80% (66 mg, 0.16 mmol). Rf = 0.25 (20% EtOAc in petroleum ether). FT-IR (neat): 1717 (s), 1690 (s), 1626 (w), 1377 (m), 1352 (m), 1223 (m) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.18−7.21 (m, 3H), 7.07−7.08 (m, 1H), 6.85−6.87 (m, 1H), 6.72− 6.75 (m, 3H), 4.72 (d, J = 16.1 Hz, 1H), 4.54−4.59 (m, 1H), 4.44 (d, J = 16.1 Hz, 1H), 4.32−4.38 (m, 1H), 4.22−4.31 (m, 1H), 3.72 (dd, J = 8.1, 17.9 Hz, 1H), 3.64−3.66 (m, 1H), 3.27 (dd, J = 6.6, 17.9 Hz, 1H), 2.23 (s, 3H), 2.14 (d, J = 2.2 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 206.7, 177.4, 164.0, 154.8, 142.2, 136.0, 128.7, 127.4, 126.5, 126.4, 124.7, 123.5, 106.7, 59.9, 50.2, 45.9, 43.1, 34.9, 30.5, 14.5, 12.6. HRMS (ESI+): calcd for C23H25SNO4Na ([M + Na]+), 434.1402; found, 434.1404. Optical rotation: [α]23D +21.3 (c 1.0, CHCl3) for an enantiomerically enriched sample with 98.5:1.5 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak AD-H column, 230 nm, n-hexane/IPA = 90:10, 1.0 mL min−1, τminor = 23.7 min, τmajor = 37.3 min). Compound 16ai. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% Et2O in petroleum ether) afforded major diastereomer of 16ai as a colorless oil (60 mg, 0.152 mmol, 76% yield). Combined yield of the diastereomers was 91% (72 mg, 0.182 mmol). Rf = 0.30 (60% Et2O in petroleum ether). FT-IR (neat): 1718 (s), 1691 (s), 1630 (m), 1494 (w), 1392 (m), 1232 (m) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.27−7.29 (m, 1H), 7.23−7.25 (m, 2H), 7.13−7.14 (m, 1H), 6.96− 6.98 (m, 2H), 6.17−6.19 (m, 1H), 5.91 (d, J = 3.1 Hz, 1H), 4.80 (d, J = 16.1 Hz, 1H), 4.46 (d, J = 16.1 Hz, 1H), 4.38−4.43 (m, 1H), 4.28− 4.35 (m, 1H), 4.18−4.25 (m, 1H), 3.59−3.62 (m, 1H), 3.55 (dd, J = 7.9, 18.1 Hz, 1H), 3.19 (dd, J = 7.0, 18.1 Hz, 1H), 2.21 (s, 3H), 2.18 (d, J = 2.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 206.9, 177.4, 164.0, 154.2, 154.0, 141.3, 136.2, 128.7, 127.5, 126.8, 109.9, 106.8, 106.3, 59.8, 48.6, 43.3, 43.1, 33.8, 30.4, 14.5, 12.5.HRMS (ESI+): calcd for C23H25NO5Na ([M + Na]+), 418.0630; found, 418.0626. Optical rotation: [α]22D +28.6 (c 1.0, CHCl3) for an enantiomerically enriched sample with 98:2 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak IE column, 254 nm, n-hexane/IPA = 90:10, 1.0 mL min−1, τminor = 45.7 min, τmajor = 49.1 min). Compound 16aj. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 40% Et2O in petroleum ether) afforded the major diastereomer of 16aj as a colorless oil (47 mg, 0.104 mmol, 52% yield). Combined yield of the diastereomers was 84% (76 mg, 0.169 mmol). Rf = 0.25 (60% Et2O in petroleum ether). FT-IR (neat): 1714 (s), 1689 (s), 1627 (w), 1493 (m), 1385 (m), 1220 (s) cm−1. 1H NMR (400 MHz, CDCl3): δ 7.19−7.23 (m, 3H), 6.76−6.78 (m, 2H), 6.58−6.62 (m, 2H), 6.51− 6.53 (m, 1H), 5.89 (s, 2H), 4.77 (d, J = 16.2 Hz, 1H), 4.40 (d, J = 16.2 Hz, 1H), 4.23−4.36 (m, 2H), 4.17−4.22 (m, 1H), 3.57−3.64 (m, 2H), 3.21 (dd, J = 7.0, 17.7 Hz, 1H), 2.19 (s, 3H), 2.10 (d, J = 2.2 Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 207.2, 177.6, 164.2, 154.1, 147.3, 146.4, 136.1, 133.3, 128.6, 127.4, 126.4, 121.3, 108.5, 107.9, 106.8, 100.8, 59.9, 50.4, 45.3, 43.0, 39.1, 30.6, 14.5, 12.6. HRMS (ESI+): calcd for C26H27NO6Na ([M + Na]+), 472.1736; found, 472.1732. Optical rotation: [α]22D +34.2 (c 1.0, CHCl3) for an enantiomerically enriched sample with 97.5:2.5 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak AD-H column, 240 nm, n-hexane/IPA = 90:10, 1.0 mL min−1, τmajor = 37.2 min, τminor = 45.8 min). Compound 16ak. Purification by silica gel (230−400 mesh) column chromatography (gradient elution: petroleum ether to 10% EtOAc in petroleum ether) afforded the mixture of diastereomers (dr 3.5:1) of 16ak as a yellow oil (71 mg, 0.164 mmol, 82% yield). Rf = 0.45 (30% EtOAc in petroleum ether). FT-IR (neat): 1716 (s), 1690 (s), 1626 (m), 1389 (m), 1352 (w), 1221 (m), 1018 (m) cm−1. 1H NMR (400 MHz, CDCl3): signals corresponding to the major diastereomer, δ 7.03−7.37 (m, 10H), 6.37 (d, J = 15.8 Hz, 1H), 4.85−5.91 (m, 1H), 4.98 (d, J = 16.1 Hz, 1H), 4.46 (d, J = 16.0 Hz,

1H), 4.19−4.37 (m, 2H), 3.79−3.86 (m, 1H), 3.55−3.56 (m, 1H), 3.35 (dd, J = 7.4, 17.4 Hz, 1H), 3.04 (dd, J = 7.0, 17.4 Hz, 1H), 2.27 (d, J = 2.1 Hz, 3H), 2.24 (s, 3H), 1.38 (t, J = 7.0 Hz, 3H); representative signals corresponding to the minor diastereomer, δ 6.54 (d, J = 15.9 Hz, 1H), 6.30−6.36 (m, 1H), 4.92 (d, J = 15.9 Hz, 1H), 4.57 (d, J = 16.1 Hz, 1H), 3.65−3.72 (m, 1H), 3.62−3.63 (m, 1H), 2.32 (d, J = 2.0 Hz, 3H), 2.11 (s, 3H). 13C NMR (100 MHz, CDCl3): signals corresponding to the major diastereomer, δ 206.3, 176.6, 163.1, 153.3, 135.7, 135.16, 131.5, 127.8, 127.4, 126.3, 126.0, 125.8, 125.4, 125.3, 105.7, 58.8, 48.5, 43.9, 42.1, 36.7, 29.6, 13.4, 11.6; representative signals corresponding to the minor diastereomer, δ 205.7, 176.7, 163.3, 153.7, 135.8, 135.2, 131.1, 127.8, 127.7, 127.4, 126.6, 126.39, 126.35, 125.4, 105.0, 59.0, 49.7, 44.3, 42.4, 39.1, 29.4, 13.4, 11.9. HRMS (ESI+): calcd for C27H29NO4Na ([M + Na]+), 454.1994; found, 454.1996. Optical rotation: [α]22D +28.5 (c 1.0, CHCl3) for an enantiomerically enriched sample with 97.5:2.5 er for the major diastereomer and 98:2 er for the minor diastereomer (dr 3.5:1). The enantiomeric ratio was determined by HPLC analysis (Daicel Chiralpak IC column, 254 nm, n-hexane/EtOH = 90:10, 1.0 mL min−1; for the major diastereomer τminor = 17.5 min, τmajor = 22.3 min, and for the minor diastereomer τmajor = 31.6 min, τminor = 53.9 min).

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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.8b02051. Copies of 1H and 13C NMR spectra of products, HPLC chromatogram of products, and X-ray crystallographic data (ORTEP) of 11a, 12a, 13, and 14 (PDF) X-ray crystallographic data of 11a (CIF) X-ray crystallographic data of 12a (CIF) X-ray crystallographic data of 13 (CIF) X-ray crystallographic data of 14 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Santanu Mukherjee: 0000-0001-9651-6228 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research is funded by the Council of Scientific and Industrial Research (CSIR), New Delhi [grant no. 02(0207)/ 14/EMR-II]. S.J.S.R. thanks CSIR, New Delhi, for a doctoral fellowship. Our special thanks are due to Mr. Prodip Howlader and Mr. Rupak Saha (Department of Inorganic and Physical Chemistry, IISc, Bangalore) for their help with the X-ray diffraction analysis.

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REFERENCES

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DOI: 10.1021/acs.joc.8b02051 J. Org. Chem. 2018, 83, 12071−12085

Article

The Journal of Organic Chemistry

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DOI: 10.1021/acs.joc.8b02051 J. Org. Chem. 2018, 83, 12071−12085