Synthesis of quaternary-carbon-containing and functionalized enantiopure pentanecarboxylic acids from biocatalytic desymmetrization of meso-cyclopentane-1,3-dicarboxamides.

DOI: 10.1002/asia.201402913

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Biotransformations

Synthesis of Quaternary-Carbon-Containing and Functionalized Enantiopure Pentanecarboxylic Acids from Biocatalytic Desymmetrization of meso-Cyclopentane-1,3-Dicarboxamides Yu-Fei Ao,[a] De-Xian Wang,[a] Liang Zhao,[b] and Mei-Xiang Wang*[b] Dedicated to the 10th Anniversary of the Asian Core Program

boxamide substrates were converted by the 1S enantioselective amidase into quaternary carbon-bearing enantiopure (1S,2R,3R)-3-carbamoylcyclopentanecarboxylic acids in yields up to 94 %. The application of the method was demonstrated by convenient and practical transformations of the resulting (1S,2R,3R)-2-allyl-3-carbamoylcyclopentanecarboxylic acid derivatives into functionalized cyclopentane-fused d-lactam and d-lactone compounds.

Abstract: Catalyzed by Rhodococcus erythropolis AJ270, a nitrile hydratase–amidase containing microbial whole-cell catalyst under mild conditions, enantioselective desymmetrizations of meso-cyclopentane-1,3-dicarbonitriles and cyclopentane-1,3-dicarboxamides were studied. Although the nitrile hydratase was found to exhibit high enzymatic activity, but low 1R enantioselectivity toward dinitriles, a number of 2,2unsymmetrically substituted meso-cyclopentane-1,3-dicar-

Introduction

documented in the literature, one of the most widely used microbial strains is Rhodococcus erythropolis AJ270.[4] The versatility of this nitrile hydratase and amidase containing whole-cell biocatalyst has been demonstrated by enantioselective biotransformations of a large number of structurally diverse racemic nitriles, including functionalized and (hetero)cyclic ones, to produce highly enantiopure carboxylic acid and amide products.[1, 5] In contrast to the plethora of studies on the biotransformations of racemic nitriles and amides,[1–5] there have only been a few investigations into enantioselective desymmetrization of prochiral[6–8] and meso-dinitriles[9] and diamides,[10] although the desymmetrization protocol offers the potential advantages of complete conversion of substrates with a high level of enantiocontrol. Some prochiral 2,2-dialkylated malononitriles and malonamides,[6] as well as 3-substituted glutaronitriles and glutaramides,[7] for instance, have been used as substrates in biocatalytic desymmetrizations. Depending subtly on the nature of the substituents, reactions generate the corresponding enantioenriched monocyano and -amido carboxylic acid products with enantiomeric excess (ee) values varying dramatically from 22 to 99 %.[7] Very disappointing results in terms of catalytic efficiency and enantioselectivity have been reported from the Rhodococcus rhodochrous IFO15564 catalyzed enantioselective desymmetrization of cyclohexane-1,2-dinitrile derivatives.[9a] Recently, we showed that Rh. erythropolis AJ270 was able to catalyze enantioselective desymmetrization of amino-substituted malonamides to yield polyfunctionalized amino acids with ee values up to > 99.5 %.[6g] More remarkably, five-membered meso-N-heterocyclic dicarboxamides underwent highly efficient and practical desymmetrization reactions to produce enantio-

Biocatalytic hydrolyses of nitriles and amides are powerful methods for the preparation of carboxylic acids and derivatives because of high catalytic efficiency, excellent selectivity, and environmentally benign reaction conditions.[1–3] There are two distinct reaction pathways: the nitrilase enzyme catalyzes direct hydrolysis of nitriles to afford carboxylic acids with the release of ammonium, whereas the nitrile hydratase converts the nitriles into carboxamides, which undergo further hydrolysis under the catalysis of the amidase to produce carboxylic acids. Because some nitrilases, nitrile hydratases, and amidases exhibit good enantioselectivity, they have been utilized in the synthesis of enantioenriched carboxylic acids and amide derivatives. It is worth emphasizing that, in comparison with enzymatic ester hydrolysis, one distinct feature for the biocatalysis of nitriles is the straightforward generation of enantiopure amides, which are invaluable compounds in synthetic chemistry, in addition to the formation of enantiopure carboxylic acids.[1–3] Among numerous nitrile-hydrolyzing biocatalysts [a] Y.-F. Ao, Dr. D.-X. Wang Beijing National Laboratory for Molecular Sciences CAS Key Laboratory of Molecular Recognition and Function Institute of Chemistry, Chinese Academy of Sciences Beijing 100190 (P.R. China) [b] Dr. L. Zhao, Prof. Dr. M.-X. Wang Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education) Tsinghua University, Beijing 100084 (P.R. China) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201402913. Chem. Asian J. 2014, 9, 1 – 11

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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Full Paper merically pure carbamoyl-substituted heterocyclic amino acids in almost quantitative yields.[10] As a continuation of our research program, we undertook the current study on the Rh. erythropolis AJ270 whole-cell-catalyzed desymmetrization of meso-cyclopentane-1,3-dicarbonitriles and -dicarboxamides. We discovered that the nitrile hydratase displayed low 1R enantioselectivity, whereas the amidase exhibited high 1S enantioselectivity in desymmetrization reactions of dinitriles and diamides. We report herein the effective biocatalytic synthesis of quaternary-carbon-bearing and functionalized enantiopure 3carbamoylcyclopentanecarboxylic acids that are rarely accessible by other synthetic means. Scheme 3. Synthesis of 14–16. TsCl = p-toluenesulfonyl chloride.

Results and Discussion was obtained. Further optimization for selective synthesis was not attempted because the products were desired substrates for biotransformations, and they were easily separable and isolable. Functional-group transformations of 2-allylated dinitrile 8 allowed the preparation of other substrates (Scheme 3). For instance, ozonolysis of 8 followed by reduction[15] gave rise to the formation of 2-hydroxyethyl-substituted dinitrile 14 in excellent yield. Dehydration[16] of 14 gave a good yield of vinylbearing dinitrile 15, whereas palladium(II)I-effected isomerization[17] of 8 resulted in the formation of 2-E-propenyl-substituted dinitrile 16 almost quantitatively. The meso-cyclopentane-1,3-dicarboxamide substrates 17–20 and 23–24 were prepared by means of hydration of dinitriles in the presence of H2O2 under basic conditions in dimethylsulfoxide (DMSO). 2,2-Dialkyl-substituted meso-cyclopentane-1,3dicarboxamides 21 and 22 were obtained quantitatively from catalytic hydrogenation of 18 and 19, respectively. Interestingly, in the presence of four equivalents of DMSO in methanolcontrolled chemical hydration of dinitrile compounds 8 and 9 allowed us to prepare the respective racemic monocyano amide products 25 and 26 (Figure 1). With all designed substrates in hand, we first tested the biotransformations of meso-dinitriles. Catalyzed by Rh. erythropolis AJ270 whole cells under standard conditions, namely, in neutral aqueous phosphate buffer at 30 8C,[4] monohydration of 2-

To shed light on the effect of the structure of substrates on biocatalysis, a number of 2,2-disubstituted meso-cyclopentane1,3-dicarbonitriles and -dicarboxamides were designed and synthesized. Schemes 1 to 3 show, for example, the preparation of starting cyclopentane-1,3-dinitrile substrates. As illustrated in Scheme 1, 2-methylcyclopentane-1,3-dione (1) underwent reaction with allyl and benzyl bromides under basic conditions to afford alkylated intermediates 2[11] and 3,[12] respectively. Their reaction with Me3SiCN in the presence of BF3·OEt2 led to the formation of mixtures of stereoisomeric cyanohydrins 4 and 5, which were transformed into the corresponding cyclopenta-3,5-diene-1,3-dicarbonitriles 6 and 7 upon treatment with POCl3 in the presence of Py.[13] Compound 7 was reduced by catalytic hydrogenation, whereas the reduction of cyclopentadiene 6 was carried out by using magnesium in methanol[14] (Scheme 2). In both cases, a mixture of stereoisomers

Scheme 1. Synthesis of 6 and 7. Py = pyridine, Bn = benzyl.

Figure 1. The structures and yields of meso-diamides 17–24 and racemic cyano amides 25 and 26.

Scheme 2. Reduction of 6 and 7.

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Full Paper allyl-2-methylcyclopetane-1,3-dinitriles proceeded very rapidly. For example, incubation of 8 with microbial cells for 1 h produced enantioenriched monocyano amide product ()-25 in 92 % yield. When compound 9, a stereoisomer of 8, was used as a substrate, completion of the biocatalytic mononitrile hydration took slightly longer (2.5 h) to afford optically active amide product (+)-26 in nearly quantitative yield. Unfortunately, the nitrile hydratase exhibited low enantioselectivity in the desymmetrization reaction of meso-dinitriles, with ee values for ()-25 and (+)-26 of 29.1 and 45.5 %, respectively (Scheme 4). Notably, although no further biocatalytic reaction was ob-

tivity of nitrile hydratase of the microbial cell was also dramatically influenced by the structure of dinitrile substrates. This has been exemplified by the observation of no reaction when cisbenzylated dinitrile 12 was incubated with cells for a week. Because the nitrile hydratase exhibited low enantioselectivity in desymmetrization of meso-cyclopentane-1,3-dicarbonitriles 8 and 9 (Scheme 4), we then turned our attention to amidasecatalyzed desymmetrization of meso-cyclopentane-1,3-dicarboxdiamides. Acid products 29 were transformed into benzyl esters 30 to facilitate their isolation and measurement of ee values. To our delight, the amidase of Rh. erythropolis AJ270 was highly enantioselective in catalyzing the desymmetrization reaction of meso-diamides. Most of the meso-diamide substrates surveyed were converted into monoamido-substituted cyclopentanecarboxylic acids with ee values higher than 99.5 %. As summarized in Table 1, under the catalysis of Rh. erythropolis AJ270 cells, meso-2-methylcyclopentane-1,3-dicarboxamides 17–19 and 21–22, which contained an extra transconfigured 2-substituent, underwent specific monoamide hydrolysis to afford the corresponding 2,2-unsymmetrically disubstituted (1S,2S,3R)-3-carbamoylcyclopentanecarboxylic acids in excellent yields with > 99.5 % ee (Table 1, entries 1–3, 5, and 6), except for 2-hydroxyethyl-bearing substrate 20, which remained intact after 7 days of interaction with the biocatalyst (Table 1, entry 4). Although the amidase involved in Rh. erythropolis AJ270 displayed exceedingly high enantioselectivity in the desymmetrization of meso-diamides, enzymatic activity varied considerably, depending on the nature of the 2-transorientated substituent. This was reflected, for example, in the reaction velocity in the order of 22 > 21 > 17 (Table 1, entries 1, 5, and 6), and 19 > 18 (Table 1, entries 2 and 3). Clearly, a smaller and more flexible alkyl and alkenyl group at the 2-position of 2-methylcyclopentane-1,3-dicarboxamides appeared to be beneficial for biocatalysis in terms of biotransformation efficiency. The dependence of biocatalytic efficiency on the steric effect of the substrates was further illustrated by the desymmetrical hydrolytic reaction, which employed meso-2-methylcyclopentane-1,3-dicarboxamides substituted by a cis-configured 2-allyl or 2-benzyl group. For instance, in comparison with substrate 17, which underwent complete biocatalytic conversion to give 30 a effectively (Table 1, entry 1), only 21 % yield of enantiopure (1S,2R,3R)-2-ally-3-carbamoyl-2-methylcyclopentanecarboxylic acid (30 g) was obtained from the reaction of meso-diamide 23 in 7 days, along with the recovery of 70 % yield of the reactant (Table 1, entry 7). In the case of the biocatalytic hydrolysis of cis-benzylated diamide 24, biotransformation proceeded even more sluggishly, with less than 20 % of the substrate being converted into enantiopure product 30 h under identical biocatalytic conditions (Table 1, entry 8). In all cases, the conversion was improved greatly when the loading of biocatalyst was doubled (Table 1). The steric effect observed herein was consistent with previous observations in Rh. erythropolis AJ270 catalyzed desymmetrization of N-substituted meso-pyrrolidine-2,5-dicarboxamides.[10] An increase in the steric bulkiness of the N-substituent results in the slowdown of monoamide hydrolysis of five-

Scheme 4. Biocatalytic desymmetrization of meso-dinitriles 8 and 9.

served for (+)-26 in a week, elongated incubation of 8 with microbial cells led to hydrolysis of the resulting amide 25 to form acid 27. Isolation of acid product 27 was facilitated by its complete conversion into ester derivative 28 by using CH2N2. As shown in Scheme 5, the interaction of 8 with the biocatalyst for 2.3 h produced methyl ester ()-28 (43 % yield, 50.2 % ee), along with amide ()-25 (49 % yield, 52.3 % ee). The consecutive biocatalytic conversion of amide into acid in the biotransformation of dinitrile 8 was also proven by kinetic resolution of racemic substrate 25. Catalyzed by the whole-cell catalyst under identical conditions followed by treatment with CH2N2, racemic monocyano amide 25 was resolved into enantioenriched amide ()-25 and ester ()-28. Nearly the same level of enantiocontrol was obtained from the biotransformation of meso-dinitrile 8 and racemic monocyano amide 25 (Scheme 5). Because compounds 25 and 26 are a pair of stereoisomers, in which the allyl group is trans or cis to the amido groups, respectively, drastically different outcomes of the biotransformations reflect the sensitivity of the amidase involved in Rh. erythropolis AJ270 toward the steric effect of the substrates. The ac-

Scheme 5. Biotransformations of meso-dinitrile 8 and racemic monocyano amide 25. Chem. Asian J. 2014, 9, 1 – 11

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Full Paper most probably comprises a deeply buried enantioselective site that is not readily accessible by sterically hindered cyclic and heterocyclic 1,3-dicarboxamides. Furthermore, although the detailed mechanism of biocatalysis remains unknown at the moment, the exclusive formation of the monoamido acid product or blockage of the monoamide hydrolysis step from the biocatalytic reaction of meso-diamides implies specificity of the amidase toward meso-diamide substrates; this is most likely owing to the hydrophobicity of the active site of the amidase that is not favorable to bond to a polar carboxylic acid moiety. Although a relatively longer reaction period was necessary, or in some cases a higher biocatalyst loading was needed, the biocatalytic desymmetrization of meso-cyclopentane-1,3-dicarboxamides allowed the synthesis of highly enantiopure or a single enantiomer of quaternary stereogenic carbon bearing 3-carbamoylcyclopetanecarboxylic acids, which are rarely available by other synthetic methods. The structures of the products were supported by their spectroscopic data and microanalyses. To determine the absolute configuration of products 30, the biotransformed acid products were converted into 4-iodobenzyl or 2-bromobenzyl esters by using 4-iodobenzyl bromide and 2-bromobenzyl bromide, respectively, instead of benzyl bromide (Table 1). Pleasingly, the 4-iodobenzyl ester (30 b’) of the acid derived from 17 and the 2-bromobenzyl ester (30 g’) of the acid from 23 gave high-quality single crystals from slow evaporation of the solvent from its solution in a mixture of hexane and acetone. Xray diffraction analysis revealed unambiguously that the molecular structures of 30 b’ and 30 g’ (Figures 2 and 3) had (1S,2S,3R)- and (1S,2R,3R)-configured stereogenic centers, respectively. The amidase is therefore 1S enantioselective toward meso-2,2-disubstituted cyclopentane-1,3-dicarboxamide substrates irrespective of the orientation of substituents at 2-position.

Table 1. Biocatalytic desymmetrization of meso-cyclopentane-1,3-dicarboxamides.[a]

Entry Substrate

Product (reaction time, yield [%],[b] ee [%][c])

1 17

30 a (96 h, 92, > 99.5)[d] 30 a (42 h, 93, > 99.5)[e]

18

30 b (108 h, 92, > 99.5)[d] 30 b (46 h, 91, > 99.5)[e]

19

30 c (84 h, 94, > 99.5)[d] 30 c (38 h, 92, > 99.5)[e]

20

30 d (7 days, 0, )[d] 30 d (7 days, 0, )[e]

21

30 e (84 h, 90, > 99.5)[d] 30 e (37 h, 92, > 99.5)[e]

22

30 f (72 h, 91, > 99.5)[d] 30 f (30 h, 90, > 99.5)[e]

23

30 g (7 days, 21,[f] > 99.5)[d] 30 g (7 days, 55,[g] > 99.5)[e]

24

30 h (7 days, 18,[h] > 99.5)[d] 30 h (7 days, 39,[i] > 99.5)[e]

2

3

4

5

6

7

8 Figure 2. X-ray molecular structure of 30 b’. Ellipsoids are shown at the 25 % probability level.

[a] Substrate (1 mmol) was incubated with Rh. erythropolis AJ270 cells (2 or 4 g wet weight) in phosphate buffer (pH 7.0, 0.1 m) at 30 8C. [b] Yield of product isolated. [c] Determined by chiral HPLC analysis. [d] Starting diamide 20 was recovered in 95 %. [d] 2 g wet weight cells were used. [e] 4 g wet weight cells were used. [f] Starting diamide 23 was recovered in 70 % yield. [g] Starting diamide 23 was recovered in 36 % yield. [h] Starting diamide 24 was recovered in 76 % yield. [i] Starting diamide 24 was recovered in 55 % yield.

membered N-heterocyclic diamides. The outcomes obtained so far suggest that the amidase involved in the microbial cell &

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Figure 3. X-ray molecular structure of 30 g’. Ellipsoids are shown at the 25 % probability level.

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Full Paper To assign the absolute configuration of cyano-substituted ester product ()-28, which was obtained from biotransformations of meso-dinitrile 8 and racemic 25 (see Scheme 5), the following chemical correlations were performed. The biotransformation of meso-diamide 17 followed by esterification with CH2N2 led to enantiopure methyl ester product (1S,2S,3R)-30 a’ in 93 % yield. The amide group of (1S,2S,3R)-30 a’ underwent a dehydration reaction to afford cyano-bearing ester (1S,2S,3R)()-28 in good yield without any racemization (Scheme 6). Because the same direction of optical rotation was observed for product (1S,2S,3R)-()-28 and compound ()-28, which was obtained from biotransformations of meso-dinitrile 8 and racemic 25 (see Scheme 5), the absolute configuration of the latter compound was assigned as 1S,2S,3R. Monocyano amide ()-25 should have the opposite configuration of 1R,2R,3S because amide ()-25 and acid ()-28 were formed from kinetic resolution. Finally, based on a comparison of its optical rotation to that of (1R,2R,3S)-()-25, 1R,2R,3S was assigned to monocyano amide ()-25 derived from the nitrile hydratase catalyzed desymmetrization of meso-dinitrile 8 (see Scheme 4). The nitrile hydratase involved in Rh. erythropolis AJ270 exhibits, therefore, 1R enantioselectivity toward meso-cyclopentane-1,3-dicarbonitriles, albeit at a low level. The resulting 3-carbamoylcyclopetanecarboxylic acids are conceivably useful chiral intermediates in synthetic organic chemistry. The densely functionalized cyclopentane structures would render them as unique building blocks in the synthesis of various natural products and bioactive compounds. For example, simple and practical chemical manipulations of amide and ester functional groups of 30 would provide straightforward routes to diverse carba-sugar containing nucleoside analogues.[10] To demonstrate the utility of the method, the synthesis of cyclopentane-fused d-lactam 31 and d-lactone 32 was attempted from biotransformation products. As shown in Scheme 7, ozonolysis of 30 a followed consecutively by cyclic condensation[18] and reduction[19] led to the formation of dlactam product 31 in 76 % yield. Cyano-substituted methyl ester ()-28 underwent saponification with LiOH in a mixture of methanol and water, and subsequent iodolactonization under basic conditions to afford d-lactone derivative 32 as nearly the sole product with a diastereomeric ratio of greater than 20:1. The cis configuration of the iodomethyl substituent relative to the methyl group was determined by the NOE (see the Supporting Information). In all chemical transformations, no racemization was observed.

Scheme 7. Synthesis of 31 and 32.

Conclusion We have shown that Rh. erythropolis AJ270, a nitrile hydratase– amidase containing microbial whole-cell catalyst, was able to catalyze the enantioselective desymmetrization of meso-cyclopentane-1,3-dicarbonitriles and 1,3-carboxamides under mild conditions. Although the nitrile hydratase exhibited low enantioselectivity toward meso-dinitriles, the amidase was highly 1S enantioselective in catalyzing monoamide hydrolysis of mesodicarboxamide substrates. The biocatalytic desymmetrization of meso-2,2-unsymmetrically disubstituted cyclopentane-1,3-dicarboxamides provided a unique approach to functionalized enantiopure 3-carbamoylcyclopentanecarboxylic acids that contained a quaternary carbon atom. The resulting chiral products, which are not readily available by other means, are useful synthetic intermediates and their applications are demonstrated by the construction of densely functionalized bicyclic compounds.

Experimental Section Synthesis of 2 and 3 Alkyl bromide (0.33 mol) was added to a stirred mixture of 1 (33.6 g, 0.3 mol) in an aqueous solution of NaOH (1 m, 300 mL) at room temperature. The resulting reaction mixture was stirred at 40 8C overnight. After extraction with ethyl acetate (100 mL 3), the combined organic layers were washed with brine (200 mL) and dried over anhydrous MgSO4. The solvent was then removed, and the residue was purified by column chromatography on silica gel eluted with a mixture of petroleum ether and ethyl acetate (8:1 v/ v) to afford 2 or 3. Compound 2:[11] Colorless oil (32.4 g, 71 %); 1H NMR (300 MHz, CDCl3): d = 5.67–5.53 (m, 1 H), 5.10–5.04 (m, 2 H), 2.80–2.67 (m, 4 H), 2.36 (d, J = 7.5 Hz, 2 H), 1.13 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 216.3, 131.5, 119.9, 56.7, 40.1, 35.4, 18.8 ppm. Compound 3:[12] White solid (31.5 g, 52 %); m.p. 52–53 8C; 1H NMR (300 MHz, CDCl3): d = 7.24–7.22 (m, 3 H), 7.06–7.03 (m, 2 H), 2.97 (s, 2 H), 2.56 (dd, J = 19.2, 6.8 Hz, 2 H), 2.06 (dd, J = 19.2, 6.8 Hz, 2 H), 1.21 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 217.5, 135.8, 129.6, 128.6, 127.2, 58.3, 43.1, 35.8, 20.0 ppm.

Scheme 6. Synthesis of (1S,2S,3R)-methyl 2-allyl-3-cyano-2-methylcyclopentanecarboxylate (()-28). DMF = N,N-dimethylformamide. Chem. Asian J. 2014, 9, 1 – 11

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Full Paper gas release, the mixture was stirred at room temperature for another 10 min. The mixture was filtered through a pad of Celite, and the filtration cake was washed with ethyl acetate (100 mL). The filtrate was then poured into hydrochloric acid (1 m, 200 mL) slowly. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (100 mL 2). The combined organic layers were washed with a saturated solution of sodium bicarbonate (200 mL) and brine (200 mL), and dried over anhydrous MgSO4. After removal of the organic solvent, the residue was purified by column chromatography on silica gel by using a mixture of petroleum ether and ethyl acetate (7:1 v/v) as the mobile phase to afford 8, 9, and 10.

Synthesis of 4 and 5 .

Me3SiCN (41 mL, 0.31 mol) and BF3 OEt2 (37.5 mL, 0.3 mol) were added dropwise consecutively to a solution of 3 or 4 (0.15 mol) in dry CH2Cl2 (500 mL) under argon. After the resulting mixture was heated at reflux for 8 h, the reaction was quenched at 0 8C by adding hydrochloric acid (1 m, 1 L). The organic layer was collected and the aqueous layer was extracted with CH2Cl2 (100 mL 2). The combined organic layers were washed with brine (500 mL), and dried over anhydrous MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel by using a mixture of petroleum ether and ethyl acetate (4:1 v/v) as the mobile phase to give a mixture of stereoisomers of 4 or 5.

Compound 8: Colorless oil (487 mg, 28 %); 1H NMR (300 MHz, CDCl3): d = 5.90–5.76 (m, 1 H), 5.29–5.20 (m, 2 H), 2.68–2.63 (m, 2 H), 2.35 (d, J = 7.5 Hz, 2 H), 2.21–2.10 (m, 4 H), 1.31 ppm (s, 3 H); 13 C NMR (75 MHz, CDCl3): d = 131.2, 121.2, 119.1, 48.1, 42.4, 36.7, 26.5, 19.2 ppm; IR (KBr): n˜ = 2976, 2240 cm1; MS (EI) m/z (%) 174 (5) [M] + , 173 (8), 159 (10), 133 (100), 106 (65), 79 (31); HRMS (TOFMS-EI): m/z calcd for C11H14N2 : 174.1157 [M] + ; found: 174.1155.

Compound 4: Colorless oil (29.4 g, 95 %); 1H NMR (300 MHz, CDCl3): d = 5.97–5.93 (m, 1 H), 5.26–5.17 (m, 2 H), 4.13 (br s, 1 H), 3.65 (br s, 0.5 H), 3.37 (br s, 0.5 H), 2.72–2.09 (m, 6 H), 1.23–1.14 ppm (m, 3 H); 13C NMR (75 MHz, CDCl3): d = 132.3, 131.7, 131.4, 121.4, 121.2, 120.6, 118.9, 118.6, 78.8, 77.7, 56.9, 56.2, 55.4, 40.6, 37.2, 36.6, 36.3, 35.7, 33.7, 21.2, 20.4, 17.0, 13.5 ppm. Compound 5: White solid (34.2 g, 89 %); m.p. 103–108 8C; 1H NMR (300 MHz, CD3COCD3): d = 7.45–7.43 (m, 2 H), 7.28–7.25 (m, 3 H), 4.13 (br s, 1 H), 3.65 (br s, 0.5 H), 3.54–2.88 (m, 2 H), 2.65–2.28 (m, 4 H), 1.11–1.06 ppm (m, 3 H); 13C NMR (75 MHz, CD3COCD3): d = 137.7, 132.2, 128.6, 127.4, 123.0, 120.6, 79.0, 77.6, 56.7, 37.9, 37.5, 36.8, 17.3 ppm.

Compound 9: Colorless oil (331 mg, 19 %); 1H NMR (300 MHz, CDCl3): d = 6.08–5.94 (m, 1 H), 5.37–5.22 (m, 2 H), 2.70–2.62 (m, 2 H), 2.57 (d, J = 7.4 Hz, 2 H), 2.30–2.19 (m, 4 H), 1.23 ppm (s, 3 H); 13 C NMR (75 MHz, CDCl3): d = 132.1, 120.6, 119.3, 47.9, 40.1, 39.6, 27.8, 25.4 ppm; IR (KBr): n˜ = 2975, 2239 cm1; MS (EI): m/z (%): 174 (11) [M] + ,173 (7), 159 (20), 106 (100), 79 (48); HRMS (TOF-MS-EI): m/z calcd for C11H14N2 : 174.1157 [M] + ; found: 174.1159. Compound 10: Colorless oil (800 mg, 46 %); 1H NMR (300 MHz, CDCl3): d = 5.91–5.77 (m, 1 H), 5.28–5.23 (m, 2 H), 2.91–2.76 (m, 2 H), 2.51–2.33 (m, 4 H), 2.15–2.09 (m, 2 H), 1.29 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 131.9, 120.5, 119.7, 119.5, 48.1, 41.5, 39.4, 37.6, 27.6, 27.4, 21.3 ppm; IR (KBr): n˜ = 2978, 2239 cm1; MS (EI): m/z (%): 174 (5) [M] + , 173 (7), 159 (13), 133 (95), 106 (100), 79 (38); HRMS (TOF-MS-EI): m/z calcd for C11H14N2 : 174.1157 [M] + ; found: 174.1159.

Synthesis of 6 and 7 Without separation and purification of stereoisomers, compounds 4 or 5 (0.13 mol) were dissolved in dry Py (250 mL) followed by the addition of POCl3 (70 mL, 0.75 mol) under argon. After heating at 60 8C for 5 h, the reaction mixture was cooled to 0 8C and CH2Cl2 (500 mL) was added. The mixture was then poured into hydrochloric acid (3 m, 1 L) slowly. After filtration through a pad of Celite, the filtration cake was washed with CH2Cl2 (200 mL) and the filtrate was moved into a separating funnel. The organic layer was collected, and the aqueous layer was extracted with CH2Cl2 (200 mL 2). The combined organic layers were washed with a saturated solution of sodium bicarbonate (500 mL) and brine (500 mL), and dried over anhydrous MgSO4. After removal of the organic solvent, the residue was purified by column chromatography on silica gel by using a mixture of petroleum ether and ethyl acetate (8:1 v/v) as the mobile phase to yield pure 6 or 7. Compound 6: Colorless oil (18.8 g, 85 %); 1H NMR (300 MHz, CDCl3): d = 6.99 (s, 2 H), 5.36–5.25 (m, 1 H), 5.12–4.96 (m, 2 H), 2.57 (d, J = 7.2 Hz, 2 H), 1.36 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 141.3, 130.5, 129.5, 120.2, 113.9, 62.1, 39.3, 19.9 ppm; IR (KBr): n˜ = 2980, 2216 cm1; MS (EI): m/z (%): 170 (79) [M] + , 169 (72), 155 (44), 142 (100); HRMS (TOF-MS-EI): m/z calcd for C11H10N2 : 170.0844 [M] + ; found: 170.0842. Compound 7: White solid (23.5 g, 82 %); m.p. 102–103 8C; 1H NMR (300 MHz, CDCl3): d = 7.21–7.13 (m, 2 H), 6.91 (s, 2 H), 3.24 (s, 2 H), 1.55 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 141.7, 133.8, 130.1, 129.2, 128.0, 127.4, 114.3, 63.5, 41.8, 20.6 ppm; IR (KBr): n˜ = 2214, 1450 cm1; MS (EI): m/z (%): 220 (10) [M] + , 149 (8), 91 (100); elemental analysis calcd (%) for C15H12N2 : C 81.79, H 5.49, N 12.72; found: C 81.70, H 5.49, N 12.75.

Catalytic Hydrogenation of 7 Under a hydrogen (balloon) atmosphere, a mixture of 7 (2.20 g, 10 mmol) and Pd/C catalyst (10 %, 200 mg) in dry ethanol (80 mL) was stirred at room temperature for 24 h. The mixture was then filtered through a pad of Celite, and the filtration cake was washed with ethyl acetate (100 mL). After removal of solvent from the filtrate, the residue was purified by column chromatography on silica gel by using a mixture of petroleum ether and ethyl acetate (5:1 v/v) as the mobile phase to give 12 and an inseparable mixture of 11 and 13. Compound 12: White solid (1.32 g, 59 %); m.p. 119–120 8C; 1H NMR (300 MHz, CDCl3): d = 7.38–7.32 (m, 3 H), 7.21–7.18 (m, 2 H), 2.92 (s, 2 H), 2.50–2.43 (m, 2 H), 2.07–2.04 (m, 4 H), 1.39 ppm (s, 3 H); 13 C NMR (75 MHz, CDCl3): d = 134.6, 130.4, 129.0, 127.6, 119.0, 49.0, 42.1, 34.9, 25.4, 19.8 ppm; IR (KBr): n˜ = 2238 cm1; MS (EI): m/z (%): 224 (5) [M] + , 133 (19), 91 (100); HRMS (TOF-MS-EI): m/z calcd for C15H16N2 : 224.1313 [M] + ; found: 224.1316.

Synthesis of 14 A mixture of 8 (1.74 g, 10 mmol) in dry CH2Cl2 (150 mL) was bubbled with oxygen for 10 min at 78 8C. Ozone was bubbled into the mixture until the color of the reaction mixture changed to pale blue, and oxygen was then bubbled into the mixture for 10 min to remove any remaining ozone. After stirring for another 20 min, dimethyl sulfide (2.2 mL, 30 mmol) was added. The temperature was allowed to increase gradually to room temperature overnight, and

Synthesis of 8, 9, and 10 Magnesium power (2.88 g, 0.12 mol) was added to a solution of 6 (1.70 g, 10 mmol) in dry methanol (70 mL). The exothermic reaction proceeded at room temperature with the evolution of gas. After

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Full Paper (100) [M+H] + ; HRMS (FT-MS-ESI): m/z calcd for C11H15N2 : 175.1230 [M+H] + ; found: 175.1227.

the organic solvent was removed by using a rotary evaporator. The residue was dissolved in ethanol (50 mL), and NaBH4 (570 mg, 15 mmol) was added. After stirring at room temperature for 1 h, the reaction was quenched by the addition of a saturated solution of ammonium chloride (100 mL). The mixture was extracted with ethyl acetate (50 mL 3), and the organic phase was dried over anhydrous MgSO4. The organic solvent was removed, and the residue was purified by column chromatography on silica gel by eluting with a mixture of petroleum ether and ethyl acetate (2:1 v/v) to give 14 as a colorless oil (1.63 g, 92 %). 1H NMR (300 MHz, CDCl3): d = 3.87 (t, J = 6.0 Hz, 2 H), 2.93–2.88 (m, 2 H), 2.25–2.08 (m, 4 H), 1.88–1.84 (m, 3 H), 1.31 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 119.7, 58.4, 47.3, 40.4, 38.0, 26.6, 19.1 ppm; IR (KBr): n˜ = 3481, 2240 cm1; MS (ESI): m/z (%): 179 (100) [M+H] + , 161 (49); HRMS (FT-MS-ESI): m/z calcd for C10H15N2O: 179.1179 [M+H] + ; found: 179.1176.

General Procedure for the Preparation of meso-Diamides H2O2 (30 %, 3 mL) was added slowly to a mixture of meso-dinitriles (3 mmol) and anhydrous K2CO3 (138 mg, 1 mmol) in DMSO (9 mL), and the resulting mixture was stirred at room temperature for 8 h. The reaction was quenched by the addition of a saturated aqueous solution of Na2S2O3 (3 mL). The solvent was evaporated with heating (70 8C), and the resulting sticky residue was mixed with methanol. After removal of the insoluble inorganic salt by filtration and removal of the solvent by evaporation under vacuum, the residue was purified by column chromatography on silica gel by eluting with a mixture of acetone and ethyl acetate (3:1 v/v) to give the pure meso-diamides. Compound 17: White solid (472 mg, 75 %); m.p. 164–165 8C; H NMR (300 MHz, CD3OD): d = 6.13–5.99 (m, 1 H), 5.21–5.14 (m, 2 H), 2.63–2.59 (m, 2 H), 2.37 (d, J = 7.3 Hz, 2 H), 2.16–2.05 (m, 2 H), 1.90–1.80 (m, 2 H), 0.98 ppm (s, 3 H); 13C NMR (75 MHz, CD3OD): d = 178.6, 136.0, 119.0, 54.4, 48.8, 46.2, 27.4, 18.8 ppm; IR (KBr): n˜ = 3337, 3194, 1660 cm1; MS (ESI): m/z (%): 233 (100) [M+Na] + ; elemental analysis calcd (%) for C11H18N2O2 : C 62.83, H 8.63, N 13.22; found: C 62.76, H 8.66, N 13.29.

Synthesis of 15

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Py (1.6 mL, 20 mmol) and then TsCl (1.90 g, 10 mmol) were added to a solution of 14 (890 mg, 5 mmol) in dry CH2Cl2 (10 mL). After stirring at room temperature for 48 h, diethyl ether (50 mL) was added, and the resulting mixture was washed with water (15 mL) and hydrochloric acid (1 m; 15 mL 2). The organic layer was separated and then mixed with ammonia (20 mL). The mixture was stirred at room temperature for 1 h until TsCl was consumed. After washing with an aqueous solution of NaOH (1 m, 15 mL) and water (15 mL), the organic phase was dried over anhydrous MgSO4. The tosylate crude product, obtained after removal of the solvent, was then dissolved in dry THF (10 mL) and used for the next step. NaBH4 (190 mg, 5 mmol) was added slowly to a solution of (PhSe)2 (780 mg, 2.5 mmol) in ethanol (15 mL) at 0 8C. After the color of the solution changed from yellow to colorless, the tosylate solution prepared from the last step was added slowly and the mixture was stirred at room temperature for 6 h. The reaction was quenched by adding an aqueous solution of Na2CO3 (5 %, 50 mL) and then it was extracted with diethyl ether (50 mL 3). The combined organic layers were dried over anhydrous MgSO4. After removal of the drying agent and solvent, the residue was dissolved in chloroform (80 mL) and bubbled with O3 at 30 8C for 30 min. Oxygen was bubbled into the mixture for 10 min, and the mixture was heated at reflux overnight. The solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel by eluting with a mixture of petroleum ether and ethyl acetate (4:1 v/v) to afford 15 as a white solid (632 mg, 79 %). m.p. 71– 72 8C; 1H NMR (300 MHz, CDCl3): d = 5.83 (dd, J = 17.2, 10.7 Hz, 1 H), 5.38–5.30 (m, 2 H), 2.76–2.71 (m, 2 H), 2.32–2.15 (m, 4 H), 1.40 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 139.5, 118.7, 116.7, 50.3, 38.8, 26.5, 16.9 ppm; IR (KBr): n˜ = 2980, 2241 cm1; MS (ESI): m/z (%): 161 (100) [M+H] + ; HRMS (FT-MS-ESI): m/z calcd for C10H13N2 : 161.1073 [M+H] + ; found: 161.1070.

Compound 18: White solid (397 mg, 63 %); m.p. 198–199 8C; H NMR (300 MHz, CD3OD): d = 5.66–5.53 (m, 2 H), 2.70–2.64 (m, 2 H), 2.28–2.14 (m, 2 H), 1.88–1.81 (m, 2 H), 1.77 (d, J = 4.9 Hz, 3 H), 0.96 ppm (s, 3 H); 13C NMR (75 MHz, CD3OD): d = 177.0, 140.0, 126.5, 57.2, 51.3, 25.2, 18.3, 14.4 ppm; IR (KBr): n˜ = 3334, 3192, 1659 cm1; MS (ESI): m/z (%): 233 (100) [M+Na] + ; HRMS (FT-MS-ESI): m/z calcd for C11H18N2O2Na: 233.1260 [M+Na] + ; found: 233.1256. 1

Compound 19: White solid (388 mg, 66 %); m.p. 234–235 8C; H NMR (300 MHz, CD3OD): d = 5.98 (dd, J = 17.4, 10.7 Hz, 1 H), 5.22–5.09 (m, 2 H), 2.72–2.68 (m, 2 H), 2.25–2.19 (m, 2 H), 1.89–1.82 (m, 2 H), 0.97 ppm (s, 3 H); 13C NMR (75 MHz, CD3OD): d = 176.7, 147.2, 115.2, 57.0, 52.0, 25.4, 13.6 ppm; IR (KBr): n˜ = 3338, 3195, 1659 cm1; MS (ESI): m/z (%): 219 (100) [M+Na] + ; HRMS (FT-MSESI): m/z calcd for C10H16N2O2Na: 219.1104 [M+Na] + ; found: 219.1103.

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Compound 20: White solid (385 mg, 60 %); m.p. 171–172 8C; H NMR (300 MHz, CD3OD): d = 3.83 (t, J = 5.5 Hz, 2 H), 2.86–2.81 (m, 2 H), 2.18–2.13 (m, 2 H), 1.89 (t, J = 5.5 Hz, 2 H), 1.85–1.78 (m, 2 H), 0.89 ppm (s, 3 H); 13C NMR (75 MHz, CD3OD): d = 178.1, 58.8, 53.5, 48.1, 41.5, 26.0, 19.4 ppm; IR (KBr): n˜ = 3343, 1659 cm1; MS (ESI): m/z (%): 237 (100) [M+Na] + ; HRMS (FT-MS-ESI): m/z calcd for C10H18N2O3Na: 237.1210 [M+Na] + ; found: 237.1207. 1

Compound 23: White solid (409 mg, 65 %); m.p. 214–215 8C; H NMR (300 MHz, CD3OD): d = 5.94–5.80 (m, 1 H), 5.01–4.95 (m, 2 H), 2.54–2.50 (m, 2 H), 2.29 (d, J = 7.3 Hz, 2 H), 2.20–2.16 (m, 2 H), 1.98–1.96 (m, 2 H), 1.25 ppm (s, 3 H); 13C NMR (75 MHz, CD3OD): d = 179.1, 136.7, 117.8, 58.1, 48.7, 38.5, 28.2, 28.0 ppm; IR (KBr): n˜ = 3193, 1649 cm1; MS (ESI): m/z (%): 233 (100) [M+Na] + ; elemental analysis calcd (%) for C11H18N2O2 : C 62.83, H 8.63, N 13.22; found: C 62.99, H 8.63, N 13.36.

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Preparation of 16 A mixture of 8 (870 mg, 5 mmol), [Pd(MeCN)2Cl2] (26 mg, 0.1 mmol), and benzene (15 mL) was heated at 100 8C in a sealed tube for 5 days. After removal of the catalyst and solvent, the residue was purified by column chromatography on silica gel by eluting with a mixture of petroleum ether and ethyl acetate (4:1 v/v) to afford 16 as a colorless oil (826 mg, 95 %). 1H NMR (300 MHz, CDCl3): d = 5.83–5.72 (m, 1 H), 5.46–5.41 (m, 2 H), 2.72–2.66 (m, 2 H), 2.29–2.10 (m, 4 H), 1.76 (d, J = 1.2 Hz, 2 H), 1.36 ppm (s, 3 H); 13 C NMR (75 MHz, CDCl3): d = 132.7, 127.6, 119.0, 49.7, 39.3, 26.4, 18.1, 17.3 ppm; IR (KBr): n˜ = 2976, 2241 cm1; MS (ESI): m/z (%): 175 Chem. Asian J. 2014, 9, 1 – 11

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Compound 24: White solid (476 mg, 61 %); m.p. 137–138 8C; H NMR (300 MHz, CD3OD): d = 7.44–7.41 (m, 2 H), 7.33–7.23 (m, 3 H), 2.97 (s, 2 H), 2.65–2.60 (m, 2 H), 2.08–1.97 (m, 2 H), 1.83–1.73 (m, 2 H), 1.13 ppm (s, 3 H); 13C NMR (75 MHz, CD3OD): d = 178.9, 139.8, 132.3, 129.1, 127.5, 53.6, 49.6, 47.7, 27.9, 19.4 ppm; IR (KBr): n˜ = 3338, 3190, 1661 cm1; MS (ESI): m/z (%): 261 (100) [M+H] + ; HRMS (FT-MS-ESI): m/z calcd for C15H21N2O2 : 261.1598 [M+H] + ; found: 261.1595.

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Full Paper of Celite. For the biotransformation of 8, 9, and 25, the filtration cake was washed consecutively with water (15 mL 3) and ethyl acetate (15 mL 3). The organic phase of the filtrate was separated and the aqueous phase was extracted with ethyl acetate (20 mL 2). The combined organic solvent was dried over anhydrous MgSO4 and removed under vacuum, and the resulting residue was dissolved in methanol (10 mL) and treated with a solution of CH2N2 in ether (10 mL) at 0 8C. After stirring for 0.5 h, the solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel. Elution with a mixture of petroleum ether and ethyl acetate (2:1 v/v) gave the ester product and further elution with ethyl acetate gave the amide product. For the biocatalytic desymmetrization of meso-diamides, the filtration cake was washed consecutively with water (15 mL 3) and methanol (15 mL 3). The combined filtrate was heated at 50 8C under vacuum to remove the solvent; this gave a waxy solid that was a mixture of acid product and salt. The acid product was dissolved in methanol by washing the waxy solid three times with methanol (15 mL 3). After the solvent was removed under vacuum, the residue was dissolved in DMF (5 mL) followed by the addition of K2CO3 (138 mg, 1 mmol) and benzyl bromide (0.24 mL, 2 mmol). The mixture was stirred overnight, and the reaction was then quenched by adding water (20 mL). Extraction with ethyl acetate (15 mL 3) followed by column chromatography on silica gel by using ethyl acetate as the mobile phase gave product 30. In the case of the biotransformation of 20, 23, and 24, the unreacted meso-diamides were recovered from the aqueous phase by removing water under vacuum and subsequent column chromatography on silica gel by eluting with a mixture of acetone and ethyl acetate (3:1 v/v). All products were fully characterized by means of spectroscopic data. The ee values were obtained from HPLC analysis by using columns coated with chiral stationary phases (see the Supporting Information). The same procedure was applied when the biocatalyst loading was doubled.

Preparation of meso-Diamides 21 and 22 Under hydrogen (balloon), a mixture of 17 or 19 (2 mmol), Pd/C catalyst (10 %, 50 mg), and dry ethanol (30 mL) was stirred at room temperature for 12 h. After removal of the catalyst and solvent, the residue was purified by column chromatography on silica gel to give 21 or 22. Compound 21: White solid (422 mg, 99 %); m.p. 184–185 8C; H NMR (300 MHz, CD3OD): d = 2.59–2.55 (m, 2 H), 2.13–2.09 (m, 2 H), 1.89–1.83 (m, 2 H), 1.59–1.45 (m, 4 H), 0.98 (s, 3 H), 0.96 ppm (t, J = 6.6 Hz, 3 H); 13C NMR (75 MHz, CD3OD): d = 179.1, 55.2, 45.1, 27.7, 18.5, 18.3, 15.2 ppm; IR (KBr): n˜ = 3336, 3190, 1659 cm1; MS (ESI): m/z (%): 235 (100) [M+Na] + ; elemental analysis calcd (%) for C11H20N2O2 : C 62.23, H 9.50, N 13.20; found: C 62.25, H 9.68, N 13.25.

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Compound 22: White solid (391 mg, 99 %); m.p. 237–238 8C; H NMR (300 MHz, CD3OD): d = 2.61–2.56 (m, 2 H), 2.17–2.06 (m, 2 H), 1.89–1.81 (m, 2 H), 1.65 (q, J = 7.5 Hz, 2 H), 1.01 (t, J = 7.5 Hz, 3 H), 0.97 ppm (s, 3 H); 13C NMR (75 MHz, CD3OD): d = 179.1, 54.4, 49.4, 34.5, 27.7, 18.4, 8.9 ppm; IR (KBr): n˜ = 1651 cm1; MS (ESI): m/z (%): 221 (100) [M+Na] + ; HRMS (FT-MS-ESI): m/z calcd for C10H18N2O2Na: 221.1261 [M+Na] + ; found: 221.1258. 1

Preparation of Racemic Amides 25 and 26 H2O2 (30 %, 3 mL) was added slowly to a mixture of 8 or 9 (3 mmol) and anhydrous K2CO3 (138 mg, 1 mmol) in methanol (15 mL). DMSO (0.21 mL, 3 mmol) was then added, and resulting mixture was stirred at room temperature for 4 h. The reaction was quenched by adding a saturated aqueous solution of Na2S2O3 (30 mL). The mixture was extracted with ethyl acetate (30 mL 3) and dried over anhydrous MgSO4. The solvent was evaporated under vacuum, and the residue was purified by column chromatography on silica gel column by eluting with ethyl acetate to give 25 or 26.

Compound ()-25: White solid (94 mg, 49 %, 52.3 % ee); m.p. 84– 85 8C; ½a25 D = 23.58 (c = 1.7, CHCl3); identical spectroscopic data to those of racemic 25 were obtained.

Compound 25: White solid (490 mg, 85 %); m.p. 84–85 8C; 1H NMR (300 MHz, CDCl3): d = 5.95–5.84 (m, 1 H), 5.60 (br s, 1 H), 5.41 (br s, 1 H), 5.27–5.20 (m, 2 H), 2.74 (t, J = 9.5 Hz, 1 H), 2.48–2.36 (m, 3 H), 2.33–2.20 (m, 1 H), 2.14–2.04 (m, 2 H), 1.94–1.82 (m, 1 H), 1.14 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 173.7, 133.1, 120.1, 120.1, 50.6, 47.7, 43.0, 38.1, 26.4, 25.3, 18.7 ppm; IR (KBr): n˜ = 3351, 2237, 1667 cm1; MS (ESI): m/z (%): 193 (100) [M+H] + ; HRMS (FT-MS-ESI): m/z calcd for C11H17N2O: 193.1335 [M+H] + ; found: 193.1335.

Compound (+)-26: White solid (184 mg, 96 %, 45.5 % ee); m.p. 77– 78 8C; ½a25 D = + 13.88 (c = 1.7, CHCl3); identical spectroscopic data to those of racemic 26 were obtained. Compound ()-28: Colorless oil (89 mg, 43 %, 50.2 % ee); ½a25 D = 6.98 (c = 0.6, CHCl3); 1H NMR (300 MHz, CDCl3): d = 5.95–5.81 (m, 1 H), 5.24–5.17 (m, 2 H), 3.71 (s, 3 H), 2.76–2.62 (m, 2 H), 2.39–2.21 (m, 3 H), 2.12–1.86 ppm (m, 3 H), 1.06 (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 172.8, 132.5, 120.3, 120.1, 51.8, 49.5, 48.0, 42.3, 37.4, 26.2, 24.6, 18.9 ppm; IR (KBr): n˜ = 2216, 1735 cm1; MS (EI): m/z (%): 207 (3) [M] + ,192 (14), 176 (25), 121 (62), 106 (100), 79 (49); HRMS (TOF-MS-EI): m/z calcd for C12H17NO2 : 207.1259; found: 207.1262.

Compound 26: White solid (449 mg, 78 %); m.p. 77–78 8C; 1H NMR (300 MHz, CDCl3): d = 6.01–5.87 (m, 2 H), 5.60 (br s, 1 H), 5.41 (br s, 1 H), 5.21–5.09 (m, 2 H), 2.64 (t, J = 8.4 Hz, 1 H), 2.41–2.10 (m, 6 H), 2.04–1.95 (m, 1 H), 1.27 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 174.0, 133.6, 120.4, 119.2, 54.9, 47.7, 41.2, 38.3, 27.1, 26.3 ppm; IR (KBr): n˜ = 3346, 2237, 1667 cm1; MS (ESI): m/z (%): 193 (100) [M+H] + ; HRMS (FT-MS-ESI): m/z calcd for C11H17N2O: 193.1335 [M+H] + ; found: 193.1335.

Compound (+)-30 a: Colorless oil (277 mg, 92 %); ½a25 D = + 16.08 (c = 2.0, CHCl3); ee > 99.5 %; 1H NMR (300 MHz, CDCl3): d = 7.40–7.30 (m, 5 H), 6.05–5.91 (m, 1 H), 5.72 (br s, 1 H), 5.52 (br s, 1 H), 5.20–5.09 (m, 4 H), 2.84–2.78 (m, 1 H), 2.57–2.44 (m, 2 H), 2.37–2.11 (m, 3 H), 1.90–1.78 (m, 2 H), 0.87 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 174.6, 173.2, 135.9, 134.6, 128.6, 128.3, 128.3, 119.0, 66.3, 51.7, 50.9, 48.1, 42.8, 25.1, 24.6, 18.6 ppm; IR (KBr): n˜ = 1729, 1671 cm1; MS (ESI): m/z (%): 302 (100) [M+H] + ; HRMS (FT-MS-ESI): m/z calcd for C18H24NO3 : 302.1751 [M+H] + ; found: 302.1748.

General Procedure for Biotransformations A suspension of Rh. erythropolis AJ270 cells[4] (2 g wet weight) in aqueous phosphate buffer (pH 7.0, 0.1 m, 50 mL) was activated at 30 8C for 0.5 h in an Erlenmeyer flask (150 mL) with a screw cap. A solution of dinitrile, diamide, or racemic amide substrates (1 mmol) in acetone (0.5 mL) was added in one portion, and the resulting mixture was incubated at 30 8C with orbital shaking (200 rpm). The reaction progress was monitored by TLC. After a period of time (see discussion in the main text and Table 1), the reaction was quenched by removing microbial cells by filtration through a pad

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Compound ()-30 b: White solid (275 mg, 92 %, > 99.5 % ee); m.p. 1 135–137 8C; ½a25 H NMR (300 MHz, D = 65.18 (c = 1.7, CHCl3); CDCl3): d = 7.34–7.25 (m, 5 H), 5.82 (br s, 1 H), 5.59–5.44 (m, 3 H), 5.07 (dd, J = 64.0, 12.4 Hz, 2 H), 2.81–2.75 (m, 1 H), 2.62–2.56 (m, 1 H), 2.36–2.17 (m, 2 H), 1.94–1.87 (m, 2 H), 1.69 (d, J = 4.8 Hz, 3 H), 0.92 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 175.2, 173.3, 138.0,

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Full Paper (100) [M+H] + (81Br); HRMS (FT-MS-ESI): m/z calcd for C18H23NO3Br: 380.0856 [M+H] + (79Br); found: 380.0849.

135.9, 131.3, 128.6, 128.5, 128.3, 128.2, 126.5, 66.5, 50.2, 50.1, 48.8, 43.9, 25.7, 24.5, 18.9 ppm; IR (KBr): n˜ = 1728, 1668 cm1; MS (ESI): m/z (%): 324 (100) [M+Na] + ; HRMS (FT-MS-ESI): m/z calcd for C18H23NO3Na: 324.1570 [M+Na] + ; found: 324.1562.

Compound (+)-30 h: Colorless oil (63 mg, 18 %, > 99.5 % ee); 1 ½a25 D = + 55.78 (c = 0.9, CHCl3); H NMR (300 MHz, CDCl3): d = 7.37– 7.20 (m, 10 H), 5.65 (br s, 1 H), 5.28 (br s, 1 H), 5.19 (dd, J = 16.8, 12.0 Hz, 2 H), 3.00 (dd, J = 58.5, 13.5 Hz, 2 H), 2.79–2.73 (m, 1 H), 2.51–2.45 (m, 1 H), 2.26–2.15 (m, 1 H), 2.03–1.92 (m, 1 H), 1.79–1.64 (m, 2 H), 1.00 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 175.2, 173.3, 138.0, 135.9, 131.3, 128.6, 128.5, 128.3, 128.2, 126.5, 66.5, 50.2, 50.1, 48.8, 43.9, 25.7, 24.5, 18.9 ppm; IR (KBr): n˜ = 1729, 1671 cm1; MS (ESI): m/z (%): 352 (100) [M+H] + ; HRMS (FT-MS-ESI): m/z calcd for C22H26NO3 : 352.1907 [M+H] + ; found: 352.1905.

Compound ()-30 b’: White solid (388 mg, 91 %); m.p. 85–86 8C; 1 ½a25 D = 68.58 (c = 2.0, CHCl3); H NMR (300 MHz, CDCl3): d = 7.67 (d, J = 8.3 Hz, 2 H), 7.05 (d, J = 8.3 Hz, 2 H), 5.60–5.51 (m, 2 H), 5.46 (br s, 1 H), 5.32 (br s, 1 H), 5.00 (dd, J = 62.6, 12.6 Hz, 2 H), 2.81–2.75 (m, 1 H), 2.63–2.57 (m, 1 H), 2.38–2.19 (m, 2 H), 1.94–1.84 (m, 2 H), 1.71 (d, J = 4.7 Hz, 3 H), 0.91 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 173.5, 172.2, 139.0, 137.6, 135.7, 130.0, 125.9, 93.7, 65.4, 55.7, 55.7, 49.8, 24.0, 23.4, 18.1, 13.7 ppm; IR (KBr): n˜ = 1729, 1668 cm1; MS (ESI): m/z (%): 450 (100) [M+Na] + ; HRMS (FT-MS-ESI): m/z calcd for C18H22NO3NaI: 450.0537 [M+Na] + ; found: 450.0529.

Preparation of Racemic Esters 30

Compound ()-30 c: White solid (269 mg, 94 %, > 99.5 % ee); m.p. 1 H NMR (300 MHz, 126–127 8C; ½a25 D = 66.08 (c = 1.0, CHCl3); CDCl3): d = 7.34–7.25 (m, 5 H), 5.96 (dd, J = 17.4, 10.7 Hz, 1 H), 5.70– 5.45 (m, 2 H), 5.25–5.02 (m, 4 H), 2.87–2.80 (m, 1 H), 2.67–2.61 (m, 1 H), 2.39–2.23 (m, 2 H), 1.97–1.87 (m, 2 H), 0.94 ppm (s, 3 H); 13 C NMR (75 MHz, CDCl3): d = 173.5, 172.2, 146.0, 135.9, 128.4, 128.3, 128.2, 115.3, 66.2, 55.6, 55.5, 50.4, 24.2, 23.6, 13.0 ppm; IR (KBr): n˜ = 1728, 1674 cm1; MS (ESI): m/z (%): 310 (100) [M+Na] + ; HRMS (FT-MS-ESI): m/z calcd for C17H21NO3Na: 310.1413 [M+Na] + ; found: 310.1408.

A mixture of diamide (1 mmol) in hydrochloric acid (6 n, 5 mL) was heated at 95 8C until the starting material was consumed. The solution was basified to pH 5.0 with an aqueous solution of NaOH (1 m). After removal of water, the residue was treated by following the aforementioned procedure for the esterification of acids from biotransformations. The following racemic benzyl esters were obtained and they gave identical spectroscopic data to their enantioenriched ones. ()-30 a: colorless oil (225 mg, 75 %); ()-30 b: white solid (198 mg, 66 %); m.p. 133–136 8C; ()-30 c: white solid (186 mg, 65 %); m.p. 125–127 8C; ()-30 e: colorless oil (211 mg, 70 %); ()-30 f: colorless oil (196 mg, 68 %); ()-30 g: white solid (195 mg, 65 %); m.p. 108–110 8C; ()-30 h: colorless oil (273 mg, 78 %).

Compound ()-30 e: Colorless oil (271 mg, 90 %, > 99.5 % ee); 1 ½a25 D = 8.68 (c = 0.7, CHCl3); H NMR (300 MHz, CDCl3): d = 7.37– 7.25 (m, 5 H), 5.50 (br d, J = 21.0 Hz, 2 H), 5.12 (dd, J = 21.3, 12.3 Hz, 2 H), 2.80–2.74 (m, 1 H), 2.57–2.51 (m, 1 H), 2.22–2.10 (m, 2 H), 1.87– 1.82 (m, 2 H), 1.61–1.32 (m, 4 H), 0.90 (t, J = 7.1 Hz, 3 H), 0.87 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 174.9, 173.7, 136.0, 128.5, 128.3, 128.2, 66.2, 53.1, 51.6, 48.5, 42.2, 26.0, 25.3, 18.5, 17.2, 14.6 ppm; IR (KBr): n˜ = 1730, 1667 cm1; MS (ESI): m/z (%): 304 (100) [M+H] + ; HRMS (FT-MS-ESI): m/z calcd for C18H26NO3 : 304.1907 [M+H] + ; found: 304.1903.

Synthesis of 31 A mixture of (+)-30 a (151 mg, 0.5 mmol) in dry CH2Cl2 (30 mL) at 78 8C was bubbled with oxygen for 10 min followed by O3 until the color of solution became pale blue. After removal of O3 by bubbling with oxygen for 10 min, the mixture was stirred for another 20 min. Dimethyl sulfide (0.11 mL, 1.5 mmol) was added, and the reaction temperature was increased gradually to room temperature overnight. The solvent was removed on a rotary evaporator, and the residue was dissolved in dry CH2Cl2 (6 mL). At 78 8C, Et3SiH (0.12 mL, 0.75 mmol) and BF3·OEt2 (0.16 mL, 1.25 mmol) were added consecutively. The reaction mixture was stirred at 78 8C for 3 h and then at room temperature overnight. The reaction was quenched by adding a saturated solution of NH4Cl (20 mL) and extracted with CH2Cl2 (15 mL 3). The combined organic phase was dried over anhydrous MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel by eluting with ethyl acetate to afford ()-31 as a white solid (109 mg, 76 %, > 99.5 % ee). m.p. 120–122 8C; ½a25 D = 8.08 (c = 1.2, CHCl3); 1H NMR (300 MHz, CDCl3): d = 7.45–7.33 (m, 5 H), 5.15 (dd, J = 19.1, 12.4 Hz, 2 H), 3.37–3.33 (m, 2 H), 2.72 (t, J = 9.2 Hz, 1 H), 2.38 (dd, J = 12.0, 8.0 Hz, 1 H), 2.19–2.10 (m, 3 H), 1.92– 1.75 (m, 4 H), 0.74 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 173.2, 173.0, 137.6, 129.3, 129.2, 128.9, 66.6, 54.7, 53.3, 44.6, 40.4, 35.5, 23.9, 21.7, 14.1 ppm; IR (KBr): n˜ = 1731, 1668 cm1; MS (ESI): m/z (%): 288 (100) [M+H] + ; HRMS (FT-MS-ESI): m/z calcd for C17H22NO3 : 288.1594 [M+H] + ; found: 288.1592.

Compound ()-30 f: Colorless oil (262 mg, 91 %, > 99.5 % ee); 1 ½a25 D = 17.58 (c = 0.6, CHCl3); H NMR (300 MHz, CDCl3): d = 7.37– 7.26 (m, 5 H), 5.47 (br s, 2 H), 5.12 (s, 2 H), 2.80–2.75 (m, 1 H), 2.58– 2.52 (m, 1 H), 2.24–2.11 (m, 2 H), 1.88–1.82 (m, 3 H), 1.73–1.58 (m, 2 H), 0.97 (t, J = 7.4 Hz, 3 H), 0.87 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 174.8, 173.7, 136.0, 128.5, 128.2, 128.2, 66.2, 52.3, 50.8, 48.6, 31.9, 25.9, 25.3, 18.4, 8.3 ppm; IR (KBr): n˜ = 1728, 1664 cm1; MS (ESI): m/z (%): 312 (100) [M+Na] + ; HRMS (FT-MS-ESI): m/z calcd for C17H23NO3Na: 312.1570 [M+Na] + ; found: 312.1563. Compound (+)-30 g: White solid (63 mg, 21 %, > 99.5 % ee); m.p. 1 H NMR (300 MHz, 110–111 8C; ½a25 D = + 10.08 (c = 1.0, CHCl3); CDCl3): d = 7.37–7.30 (m, 5 H), 5.88 (br s, 1 H), 5.78–5.64 (m, 2 H), 5.08 (s, 2 H), 4.95–4.90 (m, 2 H), 2.64–2.58 (m, 1 H), 2.49–2.43 (m, 1 H), 2.27–2.16 (m, 4 H), 1.96–1.91 (m, 2 H), 1.34 ppm (s, 3 H); 13 C NMR (75 MHz, CDCl3): d = 175.0, 173.9, 135.7, 134.3, 128.6, 128.4, 128.3, 117.9, 66.4, 57.8, 54.9, 48.0, 37.0, 27.1, 25.9, 25.4 ppm; IR (KBr): n˜ = 1727, 1667 cm1; MS (ESI): m/z (%): 302 (100) [M+H] + ; HRMS (FT-MS-ESI): m/z calcd for C18H24NO3 : 302.1751 [M+H] + ; found: 302.1749. Compound (+)-30 g’: White solid (76 mg, 20 %); m.p. 118–119 8C; 1 ½a25 D = + 58.58 (c = 1.5, CHCl3); H NMR (300 MHz, CDCl3): d = 7.58 (d, J = 7.9 Hz, 1 H), 7.45–7.42 (m, 1 H), 7.35–7.30 (m, 1 H), 7.23–7.18 (m, 1 H), 5.88–5.64 (m, 3 H), 5.17 (dd, J = 17.6, 12.9 Hz, 2 H), 4.95– 4.90 (m, 2 H), 2.67–2.62 (m, 1 H), 2.50–2.44 (m, 1 H), 2.28–2.19 (m, 4 H), 1.98–1.92 (m, 2 H), 1.37 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 174.9, 173.6, 135.1, 134.3, 132.9, 130.4, 129.9, 127.5, 123.8, 117.9, 66.0, 57.7, 55.0, 48.0, 36.9, 27.0, 25.8, 25.3 ppm; IR (KBr): n˜ = 1728, 1666 cm1; MS (ESI): m/z (%): 380 (100) [M+H] + (79Br), 382 Chem. Asian J. 2014, 9, 1 – 11

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Synthesis of 32 Biotransformation of diamide 17 (210 mg, 1 mmol) followed by esterification with CH2N2 gave crude product 30 a’. Resulting 30 a’ was mixed with DMF (4 mL) and SOCl2 (0.4 mL). After stirring at room temperature for 3 h, water (4 mL) was added, and mixture was extracted with ethyl acetate (5 mL 3). The combined organic

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Full Paper layers were dried over anhydrous MgSO4. After removal of the solvent, the residue was purified by column chromatographed on silica gel by eluting with a mixture of petroleum ether and ethyl acetate (4:1 v/v) to afford ()-28 as a colorless oil (157 mg, 76 % in three steps, > 99.5 % ee). ½a25 D = 13.28 (c = 0.6, CHCl3). A solution of LiOH (24 mg, 1 mmol) in water (1.5 mL) was added to a solution of ()-28 (104 mg, 0.5 mmol) in methanol (6 mL). The resulting mixture was stirred at room temperature overnight. After addition of hydrochloric acid (1 n) until the pH of solution was around 5, the mixture was extracted with ethyl acetate (10 mL 3). The combined organic layers were dried over anhydrous MgSO4 and concentrated under vacuum to give the acid intermediate. The acid was then mixed with acetonitrile (1.5 mL), iodine (190 mg, 1.5 mmol), and NaHCO3 (42 mg, 0.5 mmol). After stirring at room temperature for 8 h, a saturated solution of Na2S2O3 (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL 3). The combined organic solution was dried over anhydrous MgSO4, and concentrated under vacuum. Column chromatography on silica gel by eluting with a mixture of petroleum ether and ethyl acetate (1:1 v/v) gave 32 as a colorless oil (142 mg, 89 %, 1 H NMR (600 MHz, > 99.5 % ee). ½a25 D = + 119.08 (c = 0.5, CHCl3); CDCl3): d = 4.41–4.37 (m, 1 H), 3.39–3.34 (m, 2 H), 2.71 (t, J = 9.1 Hz, 1 H), 2.64 (t, J = 10.0 Hz, 1 H), 2.34–2.27 (m, 2 H), 2.14–2.08 (m, 2 H), 2.01–1.98 (m, 1 H), 1.89–1.85 (m, 1 H), 1.14 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 171.0, 119.2, 75.4, 49.1, 45.1, 40.4, 27.0, 20.4, 20.2, 6.5 ppm; IR (KBr): n˜ = 2237, 1751 cm1; MS (EI): m/z (%): 319 (15) [M] + , 192 (79), 178 (80), 137 (100), 106 (70); HRMS (TOF-MS-EI): m/z calcd for C11H14INO2 : 319.0069 [M] + ; found: 319.0074.

[5]

[6]

[7]

X-ray Diffraction Studies CCDC 1016421 (30 b’) and 1016370 (30 g’) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

[8]

Acknowledgements

[9] [10]

We thank the National Natural Science Foundation of China (21320102002), Tsinghua University, and the Chinese Academy of Sciences for financial support.

[11] [12]

Keywords: biotransformations · cyclopentanes desymmetrization · enantioselectivity · enzymes

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[13] [14]

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Received: August 2, 2014 Published online on && &&, 0000

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Full Paper

FULL PAPER & Biotransformations

As a whole: Rhodococcus erythropolis AJ270, a nitrile hydratase–amidase containing microbial whole-cell catalyst, is able to catalyze enantioselective desymmetrization of meso-cyclopentane-1,3carboxamides under mild conditions to afford enantiopure quaternary carbon atom bearing 3-carbamoylcyclopentanecarboxylic acids that are not readily available by other means (see scheme; Bn = benzyl).

Chem. Asian J. 2014, 9, 1 – 11

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Y.-F. Ao, D.-X. Wang, L. Zhao, M.-X. Wang* && – && Synthesis of Quaternary-CarbonContaining and Functionalized Enantiopure Pentanecarboxylic Acids from Biocatalytic Desymmetrization of meso-Cyclopentane-1,3Dicarboxamides

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