Ex Situ Enantioconvergent Approaches for the Effective Use of Undesired­ Isomers: Stereochemical Convergence of a Substrate with Multiple Chiral Centers and Recycling of a Decarboxylated Byproduct

Abstract

Enzyme-mediated kinetic resolution of racemic starting materials is a valuable and convenient tool for the preparation of enantioenriched compounds. To overcome the 50% yield limitation in conventional kinetic resolution, diverse enantioconvergent approaches have been developed. After a brief introduction of the recently developed ‘in situ deracemization’ and ‘ex situ enantioconvergent approach’, we present unique ex situ enantioconvergent approaches to solve two difficult cases: 1) In the synthesis of ethyl (3R,4S,5R)-shikimate, a diastereomeric (3R*,4S*,5S*)-substrate containing multiple chiral centers was applied in an enzyme-catalyzed acetylation, and both the enzyme-catalyzed product and unreacted substrate converted into ethyl (3R,4S,5R)-shikimate via partial stereochemical inversions. 2) The enzyme-catalyzed kinetic resolution of a ranirestat precursor and the regeneration of the racemic substrate from a decarboxylated byproduct are described in detail. Since in the latter study, the products spontaneously decarboxylated after hydrolysis of the ester groups, the in situ regeneration of the racemic substrates was of significant difficulty. We successfully installed an ethoxycarbonyl group on the byproduct by ex situ sequential derivatization to overcome the 50% yield limitation.

1 Short Review of Enantioconvergent Approaches

2 Resolution of a Substrate with Multiple Chiral Centers

3 Resolution Based on Enzyme-Mediated Hydrolysis Accompanied by Nonenzymatic C–C Bond Cleavage

4 Conclusions

Biographical Sketches

Yasunobu Yamashita (A) graduated from the Faculty of Pharmacy, Keio University in 2012. He is currently a PhD student in the Graduate School of Pharmaceutical Sciences, Keio University and is expected to complete his PhD in March 2017.

Tohru Kurihara (B) graduated from the Graduate School of Pharmaceutical Sciences, Keio University in 2012.

Takanobu Horiguchi (C) graduated from the Faculty of Pharmacy, Keio University in 2014.

Atsushi Miki (D) graduated from the Faculty of Pharmacy, Keio University in 2015 and is currently a student in the Graduate School of Pharmaceutical Sciences, Keio University.

Mitsuru Shoji (E) received his PhD in 1999 from Tohoku University under the supervision of Prof. Masahiro Hirama. From 1999 to 2001, he worked in the research group of Prof. K. C. Nicolaou as a Postdoctoral Fellow at The Scripps Research Institute, USA. In 2001, he became an Assistant Professor at Tokyo University of Science, while working with Prof. Yujiro Hayashi. He was promoted to a Lecturer position in the laboratory of Prof. Minoru Ueda at Tohoku University in 2006. In 2009, he moved to Keio University as an Associate Professor. His research interests include the total synthesis of natural products and the innovation of synthetic methodologies.

Takeshi Sugai (F) graduated from the Faculty of Agriculture, University of Tokyo in 1981. He quit the PhD course of the Graduate School of the University of Tokyo in 1984, where he became an Assistant in 1984 and received his PhD degree in 1987 under the supervision of Prof. Kenji Mori. He then became an Instructor in the laboratory of Prof. Hiromichi Ohta at the Faculty of Science and Technology, Keio University, and was promoted to Associate Professor in the laboratory of Prof. Shigeru Nishiyama from 1988 to 2008. From 1991 to 1992, he worked in the research group of Prof. C.-H. Wong as a Research Associate at The Scripps Research Institute, USA. In 2008, he moved to the Faculty of Pharmacy, Keio University as a Full Professor. His research interests include preparative bioorganic chemistry.

Kengo Hanaya (G) received his PhD in 2012 from the Graduate School of Pharmaceutical Sciences, Tokyo University of Science under the supervision of Prof. Shin Aoki. In 2012, he became an Assistant Professor at Keio University. His research interests include the development of tools for bioorganic chemistry, enzyme-mediated organic synthesis, and the preparation of novel enzymes.

Short Review of Enantioconvergent Approaches

Enzyme-mediated kinetic resolution is a valuable and convenient tool for the preparation of enantiomerically enriched compounds on both laboratory and industrial preparative scales if the racemic precursors are readily available. The principle of conventional kinetic resolution is briefly illustrated in Scheme [1] (a). In the conventional kinetic resolution of a racemate, the yield of the required enantiomer is limited to a maximum of 50%. To overcome this inevitable constraint, in situ deracemization approaches in which the product is converted into a single enantiomer have been intensively studied.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] These approaches are classified into three types: dynamic kinetic resolution (Scheme [1, b]), in situ stereoinversion (Scheme [1, c]), and enantioconvergent (Scheme [1, d]).[20] Interestingly, it has recently been reported that sulfatases and epoxide hydrolases can be applied in an in situ enantioconvergent approach, resulting in the convergence of racemic sulfate esters and epoxides into the corresponding enantioenriched alcohols and diols, respectively.[20]

The ex situ inversion of the stereochemistry in an undesired stereoisomer after the completion of a kinetic resolution is another possible method to overcome the 50% yield limitation. In lipase-catalyzed kinetic resolutions starting from both esters and alcohols, the convergence of products into a single enantiomer of the esters or alcohols can be accomplished via the introduction of a leaving group and successive stereoinversion (Scheme [2]).

Herein, we present resolution, ex situ enantioconvergent approaches to overcome the 50% yield limitation in two difficult cases where the above-mentioned deracemization approach cannot be successfully applied. The first case is the convergence of a racemate containing multiple chiral centers into a single product via several partial stereoinversions (Section 2). The second case involves nonenzymatic C–C bond cleavage in the product, via decarboxylation, immediately after the enzyme-catalyzed hydrolysis (Section 3).

Resolution of a Substrate with Multiple Chiral Centers

Ethyl shikimate [(3R,4S,5R)-1a], an important intermediate for the synthesis of oseltamivir phosphate, has three chiral centers. Therefore, the above-mentioned deracemization approaches including a simple stereoinversion at a specific secondary alcohol afford only the diastereomer of the desired stereoisomer, not the single enantiomer. We designed a secondary alcohol (3R*,4S*,5S*)-(±)-2a, having a diastereomeric relationship with ethyl shikimate, as a substrate for lipase-mediated kinetic resolution.[21] Alcohol (3R*,4S*,5S*)-(±)-2a was prepared on a large scale by the Diels–Alder reaction of furan with acryloyl chloride and the subsequent introduction of oxygen functional groups.

Among the three commercially available lipases [Burkholderia cepacia lipase (Amano, PS-IM), Candida antarctica lipase B (Novozym 435), and Candida rugosa lipase (Meito OF)], the use of B. cepacia lipase resulted in an excellent E value (>200) and robust catalytic activity under the reaction conditions. Both products obtained from the B. cepacia lipase-catalyzed resolution, alcohol (3R,4S,5S)-2a and acetate (3S,4S,5R)-2b, were merged into (3R,4S,5R)-1a via (3R,4S,5R)-2a and (3R,4R,5R)-2c, respectively, thus establishing a new ex situ enantioconvergent route, as shown in Scheme [3].[21]

Resolution Based on Enzyme-Mediated Hydrolysis Accompanied by Nonenzymatic C–C Bond Cleavage

In the enzyme-mediated hydrolysis of esters bearing adjacent electron-withdrawing groups, such as in β-oxo esters, subsequent decarboxylation can occur during the progress of the enzyme-mediated hydrolysis. The sequential reaction can be advantageous for the desymmetrization approach from 3a to 4 [22] (Scheme [4]).

On the other hand, in kinetic resolution, in situ decarboxylation is disadvantageous for maximum yield; the decarboxylated products are difficult to reconvert in situ into the racemic substrates by the above-mentioned deracemization approaches. In the typical examples shown in Scheme [5,]α-nitro ester 5a [23] and oxo ester 6a [24] were hydrolyzed and subsequently decarboxylated, producing nitroalkane (±)-7 and ketone (±)-8, respectively. Because only slow enantiomers are available for the subsequent synthesis, the fast enantiomer-derived products were generally discarded.

For the effective use of a waste decarboxylated product, the regeneration of the racemic substrate by introducing the lost functional groups after the kinetic resolution is a powerful approach. In the preparation of the synthetic precursor of ranirestat (AS-3201, Scheme [6]), enzymes were screened, and the substrate structure was optimized in the kinetic resolution. Finally, the undesired products in the kinetic resolution were recycled. These results are now described in detail.

Ranirestat has been developed as a drug for the treatment of diabetic neuropathy,[25] a complication of diabetes, by Sumitomo Dainippon Pharma Co., Ltd. It is a highly potent aldose reductase inhibitor that suppresses the accumulation of sorbitol in neural tissues.[25a] [b] Ranirestat has a unique stereocenter on its succinimide ring; the nitrogen atom of a pyrrole ring is directly attached to the tetrasubstituted stereogenic center. The (R)-isomer of ranirestat shows 10 times more potent inhibitory activity against aldose reductase in vitro and 500 times more potent in vivo inhibitory activity than the (S)-isomer.[25a] Thus, enantiomerically enriched 2,2-disubstituted succinimide (R)-9a (Scheme [6]) is crucial for the synthesis of (R)-ranirestat.[25a]

To access (R)-9a with a high enantiomeric excess, Negoro and co-workers prepared enantioenriched (R)-10a, the precursor of (R)-9a, by recrystallization of the cinchonidine salt.[25a] Owing to the high therapeutic potency of ranirestat, more practical synthetic methods were needed, and alternative asymmetric syntheses of (R)-9a have been developed. Shibasaki and co-workers reported the asymmetric amination of a succinimide derivative with a lanthanum-based ternary catalyst.[26] Seki and Kawase reported the asymmetric alkylation of an α-cyano ester using a phase-transfer catalyst.[27] On the other hand, Kudo and Yamada accomplished the kinetic resolution of 10a by pig liver esterase (PLE)-mediated hydrolysis (Scheme [7]), in which (S)-10a (the fast enantiomer) was hydrolyzed more rapidly than (R)-10a (the slow enantiomer), and a moderate E value of 16.6 was obtained.[28] Although (R)-10a was obtained in 98.8% ee, no data exist for (S)-10b. This compound may have spontaneously decarboxylated to afford (±)-11 under the reaction conditions.

Because the pyrrole ring in 9a is smaller than the Cbz group in 10a,[28] reducing the steric repulsion between 9a and enzymes, an improvement in the reactivity and enantioselectivity of the kinetic resolution of 9a was expected. First, the synthesis of racemic substrate (±)-9a and the kinetic resolution of 9a with several enzymes were investigated. Second, the effects of the size of the ester moiety on the enantioselectivity and reaction rate were studied. Finally, the chemical regeneration of (±)-9a from the undesired (S)-isomer by ex situ convergence via the ethoxycarbonylation of (±)-12a was investigated (Scheme [8]).

The racemic substrate 9a used for the kinetic resolution was prepared as shown in Scheme [9]. Malonate 13b, prepared by the Clauson-Kaas reaction of diethyl amino­malonate (13a),[25a] was alkylated with bromoacetonitrile, providing nitrile 13c. Palladium-catalyzed hydration of the cyano group with acetamide[29] afforded amide 13d. Using our procedure, amide 13d can be prepared in two steps, one step shorter than the method used by Negoro and co-workers.[25a] Finally, the subsequent base-mediated intramolecular cyclization of 13d afforded succinimide (±)-9a. Compared to previous reports on the syntheses of kinetic resolution substrates, succinimide (±)-9a can be prepared from commercially available diethyl aminomalonate (13a) in fewer steps; the total yield was >60% over four steps. Moreover, all the reactions are easy to manipulate, indicating suitability for large-scale synthesis.

The enzyme-mediated kinetic resolutions of (±)-9a were conducted under hydrolytic conditions (Table [1]). In all cases, (S)-9a was hydrolyzed preferentially, as in the case of (S)-10a, affording 12a via the spontaneous decarboxylation of (S)-9b. The stereochemistry of the slow enantiomer, (R)-9a, was confirmed by comparing optical rotation values [(R)-9a: [α]_D ²⁵ –56.4 (Lit.[25a] [α]_D ²⁶ –59.5)]. When (±)-9a was treated with PLE, the E value (11.3) was slightly lower than that of 10a, contrary to our expectations. The hydrolysis of 9a proceeded faster than that of 10a, indicating that the reactivity of the (R)-isomer increased by more than that of the (S)-isomer upon replacing the NHCbz group by the pyrrole ring. Thus, three other enzymes, C. antarctica lipase B (Novozym 435), B. cepacia lipase (Amano, PS-IM), and Aspergillus melleus protease (Nagase, XP-488), were applied. The two lipases are solid-supported enzymes that are highly stable in aqueous and organic solvents and can be easily removed from reaction mixtures by simple filtration. A. melleus protease has been developed for the modification of food properties by Nagase ChemteX Corporation (Japan) and applied in the kinetic resolution of ethyl tetrahydrofurancarboxylate and dihydropyridine derivatives,[30] which are structurally similar to 9a. In contrast to the sluggish hydrolysis of 9a with the two lipases, A. melleus protease showed a fast reaction rate and excellent enantioselectivity (E > 200).

Table 1 Kinetic Resolution of (±)-9a by Enzyme-Mediated Hydrolysis

Enzyme	Time (h)	Conv. (%)	E
Pig liver esterase (PLE, Sigma)	1.0	62.6	11.3
C. antarctica lipase B (Novozym 435)	24	0	NDa
B. cepacia lipase (Amano, PS-IM)	24	0	NDa
A. melleus protease (Nagase, XP-488)	1.5	50.0	>200

^a ND: not determined.

To further establish the relationship between the reactivity, selectivity, and substrate structures in A. melleus protease-mediated kinetic resolution, other substrates with a more hindered ester group, such as isobutyl and isopropyl, were used (Table [2]). It was expected that the reaction rate of the slow enantiomers would decrease owing to the steric hindrance of their alkoxy moieties, thus improving the enantioselectivity. Substrates 9c and 9d were prepared by the Ti(Oi-Pr)₄-catalyzed transesterification of 9a with the corresponding alcohols.[31] In the case of isobutyl ester 9c, the enantioselectivity seemed to be slightly lower than that of ethyl ester 9a based on a simple calculation of the data. The bulkier isopropyl ester group in 9d significantly decreased both the enantioselectivity (E = 5.4) and reactivity. The fast enantiomer was more affected by the steric hindrance of the ester moiety than the slow enantiomer. These results proved that (±)-9a is a better substrate for A. melleus protease-mediated kinetic resolution in terms of both synthetic accessibility and enantioselectivity.

As noted above, the kinetic resolution of (±)-9a (E > 200) was successfully carried out using A. melleus protease, affording (R)-9a in 50% yield and with 98.6% ee. While (R)-9a was used for the synthesis of (R)-ranirestat, undesired (±)-12a would normally be discarded. Therefore, for the effective use of undesired product (±)-12a and to overcome the 50% yield limitation, the regeneration of racemic substrate (±)-9a from (±)-12a was investigated. Our regeneration strategy for (±)-9a was as follows: protection of the imide nitrogen in (±)-12a; subsequent ethoxycarbonylation at the C-3 position and deprotection to afford (±)-9a.

Table 2 Effect of the Structure of the Ester Moiety on Kinetic Resolution

Substrate	R	Time (h)	Conv. (%)	E
9a	Et	1.5	50.0	>200
9c	i-Bu	2.0	47.8	>200
9d	i-Pr	2.0	29.8	5.4

Because the acidic proton of the imide nitrogen would interfere with deprotonation of the C-3 position in the ethoxycarbonylation step, a Boc group was introduced on the imide nitrogen, affording 12b (Scheme [10, a]). The imide ring in 12b was expected to be unstable owing to the electron-withdrawing properties of the Boc group; thus, 12b was used in the subsequent ethoxycarbonylation step without further purification. The reaction conditions were adopted from a procedure developed by Crider and co-workers,[32] in which a similar compound bearing a cyclic imide group and an aromatic ring was used. Unfortunately, this resulted in decomposition of the imide ring by the nucleo­philic attack of ethoxide anion. This result indicated that electron-withdrawing groups such as carbamate-type protecting groups are not suitable as protecting groups for the imide nitrogen, and that bulky bases should be used for the ethoxycarbonylation.

Next, various protecting groups, such as a tert-butyl, p-methoxyphenyl, p-methoxybenzyl, or allyl group, were introduced on the nitrogen atom of the imide ring. Disappointingly, the removal of these groups was difficult owing to the high sensitivity of the pyrrole ring under various reaction conditions, including acidic, oxidative, and transition-metal-mediated conditions. These findings prompted us to use the benzyloxymethyl (BOM) group, which can be removed by hydrogenolysis; BOM imide 12c was prepared from 12a in a high yield (Scheme [10, b]). When weakly nucleophilic bases such as NaH and KH were used with 12c, ethoxycarbonylated compound was obtained in negligible amounts. Finally, the reaction was accomplished using potassium hexamethyldisilazide and diethyl dicarbonate, affording 14b as a 3:1 inseparable mixture with regioisomer 15 in a moderate yield.

For the removal of the BOM group, initially, hydrogenolysis conditions were applied by using a palladium catalyst adsorbed on carbon (Table [3], entries 1 and 2) or synthetic polymers[33] (entries 3 and 4). These attempts, however, resulted in reduction of the pyrrole ring, producing the undesired pyrrolidine 16 as the major product. To suppress the reduction of the pyrrole ring, palladium on Diaion^® CR11 polymer[34] bearing an iminodiacetate-chelating group was used; however, imide 9a was not obtained at all (Table [3], entry 5). The addition of Et₃N[35] suppressed the reduction of the pyrrole ring, affording (±)-9a (Table [3], entry 6). After further investigation of the reaction conditions, a combination of Pd(OH)₂ and Et₃N was found to be a superior catalyst for the selective hydrogenolytic cleavage of the BOM group (Table [3], entry 7). The inseparable impurity (±)-15 was also reduced under these conditions, and the reduced compound could be separated in this step. Using this method, the ex situ convergence of (±)-12a into (±)-9a was accomplished. The overall yield was 25% over three steps, and the cycle for the effective use of the undesired isomer was completed.

Table 3 Hydrogenolysis of the BOM Group in 14b

Entry	Catalyst (wt%)	Et3N (mol%)	Ratio 9a/16 a	Yield (%) of 9a
1	10% Pd/C (50)	–	1:2	NDb
2	20% Pd(OH)2/C (50)	–	1:5	NDb
3	ASCA-2®c (200)	–	1:2	NDb
4	10% Pd/HP20d (80)	–	1:2	NDb
5	8% Pd/CR11e (80)	–	0:1	NDb
6	10% Pd/C (116)	80	NDb	56
7	20% Pd(OH)2/C (213)	60	NDb	63

^a Determined from the ¹H NMR spectrum of the crude mixture.

^b ND: not determined.

^c N.E. CHEMCAT Ltd.

^d Pd on Diaion^® HP20 polymer (Mitsubishi Chemical Co. Ltd., on polystyrene–polyvinylbenzene-based synthetic adsorbent).

^e Pd on Diaion^® CR11 polymer (Mitsubishi Chemical Co. Ltd., on iminodiacetate-based chelating resin).

Conclusions

In this study, we have attempted to solve difficult cases of kinetic resolutions where in situ deracemization approaches cannot be applied to overcome the 50% yield limitation. These examples prove that not only in situ deracemization, but also ex situ synthetic derivatization after kinetic resolution, namely a ex situ enantioconvergent approach, can play an important role in the efficient chemoenzymatic transformation of organic compounds. In Section 2 we described the enzyme-catalyzed kinetic resolution of a ‘dia­stereomeric substrate’ bearing multiple chiral centers and chemical convergence to the desired stereoisomer. The design of a racemic substrate having a diastereomeric relationship with ethyl shikimate was the key for the success of the enantioconvergent approach. In Section 3 we described the regeneration of the racemic substrate from a decarboxylated product in an enzyme-catalyzed hydrolytic kinetic resolution. Although the total yield of this regeneration sequence was as low as 25%, for the first time the lost functional group was reintroduced into the undesired product derived from the fast enantiomer, which would normally be discarded.

We hope that our findings will inspire chemists and more unique chemoenzymatic transformations are developed, thus not waiting for the development of better enzymes by enzymologists.

Melting points were recorded on a Yanaco MP-J3 micro melting point apparatus and are uncorrected. IR spectra were measured as ATR on a Jeol FT-IR SPX60 spectrometer. ¹H NMR spectra were measured at 400 MHz on a Varian 400-MR or at 500 MHz on an Agilent Inova-500 spectrometer, and ¹³C NMR spectra were measured at 100 MHz on a Varian 400-MR or at 125 MHz on an Agilent Inova-500 spectrometer. High-resolution mass spectra were recorded on a Jeol JMS-T100LP AccuTOF spectrometer. HPLC data were recorded using Jasco MD-2010 multichannel detectors and a Shimadzu SPD-20A diode array detector. Optical rotation values were recorded on a Jasco P-1010 polarimeter. Merck silica gel 60 F₂₅₄ thin-layer plates (1.05744, 0.5-mm thickness) were used for preparative TLC. Silica gel 60 (spherical and neutral; 100–210 μm, 37560-79) from Kanto Chemical Co. and SNAP silica gel cartridges and an Isolera One flash purification system from Biotage (Sweden) were used for column chromatography. Aspergillus melleus protease (XP-488), Candida antarctica lipase B (Novozym 435), and Burkholderia cepacia lipase (PS-IM) were gifts from Nagase & Co., Novozymes Japan, and Amano Enzyme Inc., respectively.

Diethyl 2-(Cyanomethyl)-2-(1H-pyrrol-1-yl)malonate (13c)

To a stirred suspension of NaH (252 mg, 10.5 mmol) in anhydrous DMF (7.0 mL) was added ester 13b [25a] (2.00 g, 8.88 mmol) at 0 °C, and the mixture was stirred for 1 h at r.t. Then, to the mixture was added dropwise bromoacetonitrile (700 μL, 10.0 mmol) at 0 °C, and the mixture was further stirred at r.t. for 4 h. The reaction was quenched with saturated aq NH₄Cl solution, and the organic materials were extracted with EtOAc (3 ×). The combined organic layer was washed with H₂O and brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel column chromatography (100 g; hexane/EtOAc, 5:1) to afford 13c (2.15 g, 92%) as a colorless oil.

IR (ATR): 2985, 1741, 1250, 721 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 1.31 (t, J = 7.1 Hz, 6 H), 3.35 (s, 2 H), 4.35 (q, J = 7.1 Hz, 2 H), 4.36 (q, J = 7.1 Hz, 2 H), 6.25 (dd, J = 2.1, 2.3 Hz, 2 H), 6.81 (dd, J = 2.1, 2.3 Hz, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 13.8, 26.2, 63.8, 68.9, 110.0, 115.0, 120.0, 165.2.

Anal. Calcd for C₁₃H₁₆N₂O₄: C, 59.08; H, 6.10; N, 10.60. Found: C, 59.08; H, 6.11; N, 10.59.

Diethyl 2-(Carbamoylmethyl)-2-(1H-pyrrol-1-yl)malonate (13d)

A solution of 13c (500 mg, 1.89 mmol), PdCl₂ (42 mg, 0.24 mmol), and acetamide (1.12 g, 19.0 mmol) in a mixture of THF and H₂O (1:1, 15 mL) was stirred at r.t. for 24 h. The mixture was filtered through a short column of Celite^® and the column was washed with EtOAc. The combined filtrate and washings was washed with H₂O and brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel column chromatography (4 g; hexane/EtOAc, 5:1) to afford 13d (468 mg, 88%) as a colorless solid; mp 94.0–95.0 °C.

¹H NMR (400 MHz, CDCl₃): δ = 1.27 (t, J = 7.2 Hz, 6 H), 3.33 (s, 2 H), 4.29 (q, J = 7.2 Hz, 2 H), 4.30 (q, J = 7.2 Hz, 2 H), 5.34 (br s, 1 H), 5.56 (br s, 1 H), 6.17 (dd, J = 2.2, 2.4 Hz, 2 H), 6.84 (dd, J = 2.2, 2.4 Hz, 2 H); the ¹H NMR spectrum was identical with that reported previously.[25a]

Ethyl 2,5-Dioxo-3-(1H-pyrrol-1-yl)pyrrolidine-3-carboxylate (9a)

To a stirred solution of 13d (500 mg, 1.77 mmol) in acetone (7.5 mL) was added K₂CO₃ (25 mg, 0.18 mmol), and the mixture was refluxed for 24 h. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed with saturated aq NH₄Cl solution, H₂O, and brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (2.5 g; hexane/EtOAc, 5:1) to afford 9a (400 mg, 96%) as a colorless oil.

(±)-9a: HPLC [Daicel Chiralpak AY-H, 0.46 cm × 25 cm; hexane/i-PrOH (5:1), 0.5 mL/min; detected at 206 nm]: t _R (min) = 21.1 [(S)-9a], 25.0 [(R)-9a].

¹H NMR (400 MHz, CDCl₃): δ = 1.26 (t, J = 7.2 Hz, 3 H), 3.35 (d, J = 17.9 Hz, 1 H), 3.61 (d, J = 17.9 Hz, 1 H), 4.28 (q, J = 7.2 Hz, 2 H), 6.27 (dd, J = 2.1, 2.2 Hz, 2 H), 6.93 (dd, J = 2.1, 2.2 Hz, 2 H), 8.10 (br s, 1 H); the ¹H NMR spectrum was identical with that reported previously.[25a]

Isobutyl 2,5-Dioxo-3-(1H-pyrrol-1-yl)pyrrolidine-3-carboxylate (9c)

To a stirred solution of ethyl ester 9a (200 mg, 0.85 mmol) in i-BuOH (2.0 mL) was added Ti(Oi-Pr)₄ (110 μL, 0.37 mmol), and the mixture was refluxed for 2.5 h. After cooling, the mixture was filtered through a short column of Celite^® and the column was washed with EtOAc. The combined filtrate and washings was concentrated in vacuo. The residue was dissolved in EtOAc, washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1.5 g; hexane/EtOAc, 10:1) to afford 9c (164 mg, 73%) as a colorless solid; mp 69.0–70.0 °C.

(±)-9c: HPLC [under the same conditions as for (±)-9a]: t _R (min) = 19.5 [(S)-9c], 25.7 [(R)-9c].

IR (ATR): 3209, 3082, 2962, 2873, 2779, 1716 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 0.85 (d, J = 6.7 Hz, 6 H), 1.90 (ddqq, J = 6.4, 6.8, 6.7, 6.7 Hz, 1 H), 3.37 (d, J = 18.0 Hz, 1 H), 3.62 (d, J = 18.0 Hz, 1 H), 3.97 (dd, J = 6.8, 10.8 Hz, 1 H), 4.00 (dd, J = 6.4, 10.8 Hz, 1 H), 6.28 (dd, J = 2.0, 2.5 Hz, 2 H), 6.95 (dd, J = 2.0, 2.5 Hz, 2 H), 8.49 (br s, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 18.6, 27.5, 41.9, 68.6, 73.4, 110.0, 120.1, 167.0, 170.6, 172.8.

Anal. Calcd for C₁₃H₁₆N₂O₄: C, 59.08; H, 6.10; N, 10.60. Found: C, 59.18; H, 6.14; N, 10.48.

Isopropyl 2,5-Dioxo-3-(1H-pyrrol-1-yl)pyrrolidine-3-carboxylate (9d)

In the same manner as described for 9c, 9a (300 mg, 1.28 mmol) was treated with Ti(Oi-Pr)₄ (140 μL, 0.47 mmol) in i-PrOH (3.0 mL) at reflux for 2.5 h. After a similar workup, the residue was purified by silica gel column chromatography (2 g; hexane/EtOAc, 10:1) to afford 9d (256 mg, 80%) as a colorless solid; mp 94.0–94.5 °C.

(±)-9d: HPLC [under the same conditions as for (±)-9a]: t _R (min) = 15.5 [(S)-9d], 18.6 [(R)-9d].

IR (ATR): 3240, 3101, 2987, 1708 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 1.22 (d, J = 6.2 Hz, 3 H), 1.25 (d, J = 6.2 Hz, 3 H), 3.34 (d, J = 18.0 Hz, 1 H), 3.55 (d, J = 18.0 Hz, 1 H), 5.08 (qq, J = 6.2, 6.2 Hz, 1 H), 6.25 (dd, J = 2.0, 2.2 Hz, 2 H), 6.92 (dd, J = 2.0, 2.2 Hz, 2 H), 8.73 (br s, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 21.3, 21.4, 41.9, 68.7, 72.3, 110.1, 120.0, 166.2, 170.4, 172.5.

Anal. Calcd for C₁₂H₁₄N₂O₄: C, 57.59; H, 5.64; N, 11.19. Found: C, 57.70; H, 5.66; N, 11.04.

PLE-Catalyzed Hydrolysis of (±)-9a

To a solution of (±)-9a (20.9 mg, 88.5 μmol) in a mixture of phosphate buffer (0.1 M, pH 7.0; 200 μL) and acetone (50 μL), PLE (Sigma, E2884; 50 μL) was added, and the mixture was stirred for 1 h at 30 °C. The progress of the reaction was monitored by TLC analysis [silica gel, hexane/EtOAc (1:1), by the detection of the deethoxycarbonylated product 12a (R_f = 0.38)]. The reaction was quenched with 2 M HCl to pH 2, and the organic materials were extracted with EtOAc (3 ×). The combined extract was dried over Na₂SO₄ and concentrated in vacuo. The residue (16.7 mg) was purified by preparative TLC (hexane/EtOAc, 1:1) to afford (R)-9a (7.8 mg, 33 μmol, 37.3%) and 12a (9.1 mg, 55 μmol, 62.6%).

(R)-9a: [α]_D ²⁵ –56.4 (c 0.32, MeOH) [Lit.[25a] [α]_D ²⁶ –59.5 (c 1.0, MeOH), for (R)-9a].

HPLC: t _R (min) = 22.5 [(S)-9a, 3.3%], 26.1 [(R)-9a, 96.7%]; 93.4% ee.

The ¹H NMR spectrum of (R)-9a was identical with that of (±)-9a.

Identification of 12a

An authentic sample of 12a was prepared in the following manner: Ester 9a (289 mg, 1.23 mmol) was dissolved in THF (2 mL). After cooling to 0 °C, aq NaOH solution (2.0 M; 700 μL, 1.40 mmol) was added, and the mixture was stirred for 27 h at 0 °C. The reaction was quenched with saturated aq NH₄Cl solution, and the organic materials were extracted with EtOAc (3 ×). The combined extract was washed with H₂O and brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel column chromatography (15 g; hexane/EtOAc, 3:1) to afford 12a (129 mg, 64%).

IR (ATR): 3240, 3095, 1785, 1702, 1172 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 3.00 (dd, J = 5.7, 18.6 Hz, 1 H), 3.34 (dd, J = 9.6, 18.6 Hz, 1 H), 5.08 (dd, J = 5.7, 9.6 Hz, 1 H), 6.25 (dd, J = 2.1, 2.2 Hz, 2 H), 6.92 (dd, J = 2.1, 2.2 Hz, 2 H), 8.19 (br s, 1 H); the ¹H NMR spectrum of the sample derived from the PLE-catalyzed hydrolysis was identical with that of this authentic sample.

¹³C NMR (125 MHz, CDCl₃): δ = 37.8, 57.7, 110.3, 119.5, 173.1, 173.6.

Anal. Calcd for C₈H₈N₂O₂: C, 58.53; H, 4.91; N, 17.06. Found: C, 58.65; H, 4.99; N, 16.85.

Comparison with Other Hydrolytic Enzymes

A 2-mL sample tube was charged with (±)-9a (20 mg), phosphate buffer (0.1 M, pH 7.0; 0.20 mL), and acetone (50 μL). To this, a 20-mg portion of one of the hydrolytic enzymes, A. melleus protease (Nagase, XP-488), C. antarctica lipase B (Novozymes, Novozym 435), or B. cepacia lipase PS (Amano, PS-IM), was added, and the mixture was stirred for 24 h at 30 °C. The reaction was monitored by TLC analysis, as described above. Of the three enzymes tested, only A. melleus protease showed a certain progress of the hydrolysis.

A. melleus Protease-Catalyzed Hydrolysis of (±)-9a

In a similar manner as described for the hydrolysis with PLE, to a solution of (±)-9a (21.4 mg, 90.6 μmol) in a mixture of phosphate buffer (0.1 M, pH 7.0; 200 μL) and acetone (50 μL), A. melleus protease (20 mg) was added. The mixture was stirred for 1.5 h at 30 °C. By the same workup and purification, ester (R)-9a (10.7 mg, 45.3 μmol, 50%) and 12a (8.1 mg, 49.3 μmol, quant.) were obtained.

(R)-9a: [α]_D ²⁵ –61.5 (c 0.38, MeOH).

HPLC: t _R (min) = 22.3 [(S)-9a, 0.7%], 26.1 [(R)-9a, 99.3%]; 98.6% ee.

A. melleus Protease-Catalyzed Hydrolysis of (±)-9c

In a similar manner, by the treatment of (±)-9c (20.3 mg, 76.8 μmol) with A. melleus protease for 2.0 h, (R)-9c (10.6 mg, 40.1 μmol, 52.2%) was obtained.

(R)-9c: [α]_D ²⁶ –42.9 (c 0.48, MeOH).

HPLC: t _R (min) = 18.6 [(S)-9c, 4.2%], 24.3 [(R)-9c, 95.8%]; 91.6% ee.

A. melleus Protease-Catalyzed Hydrolysis of (±)-9d

In a similar manner, by the treatment of (±)-9d (19.8 mg, 79.1 μmol) with A. melleus protease for 2 h, (R)-9d (13.9 mg, 58.8 μmol, 55.5%) was obtained.

(R)-9d: [α]_D ²⁶ –16.2 (c 0.53, MeOH).

HPLC: t _R (min) = 16.3 [(S)-9d, 37.0%], 19.6 [(R)-9d, 63.0%]; 26.0% ee.

1-(tert-Butoxycarbonyl)-3-(1H-pyrrol-1-yl)pyrrolidine-2,5-dione (12b)

A solution of 12a (12 mg, 0.074 mmol), Boc₂O (40 μL, 0.154 mmol), and DIPEA (40 μL, 0.23 mmol) in THF (100 μL) was stirred for 20 h at 40 °C. The reaction was quenched with H₂O, and the organic materials were extracted with EtOAc (3 ×). The combined extract was washed with H₂O and brine, dried over Na₂SO₄, and concentrated in vacuo to give 12b.

¹H NMR (400 MHz, CDCl₃): δ = 1.56 (s, 9 H), 3.03 (dd, J = 6.4, 18.5 Hz, 1 H), 3.35 (dd, J = 9.5, 18.5 Hz, 1 H), 5.06 (dd, J = 6.4, 9.5 Hz, 1 H), 6.24 (dd, J = 2.0, 2.2 Hz, 2 H), 6.70 (dd, J = 2.0, 2.2 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 27.6, 36.8, 56.7, 87.1, 110.3, 119.6, 145.7, 146.7, 169.1, 169.6.

1-(Benzyloxymethyl)-3-(1H-pyrrol-1-yl)pyrrolidine-2,5-dione (12c)

To a solution of 12a (602 mg, 3.67 mmol) and DIPEA (959 μL, 5.51 mmol) in CH₂Cl₂ (15 mL) was added dropwise benzyl chloromethyl ether (554 μL, 4.03 mmol) over 15 min at 0 °C, and the mixture was stirred for 30 min at 0 °C. Then, the mixture was washed with aq NH₄Cl­ solution, H₂O, and brine (20 mL each). The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (SNAP Ultra, 25 g; hexane/ EtOAc, 9:1 to 0:1) to afford 12c (1000 mg, 96%) as a colorless solid.

IR (ATR): 3128, 3008, 2945, 2926, 2879, 1794, 1757, 1716, 1387, 1365, 1323, 1194, 1072 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 2.86 (dd, J = 18.5, 5.8 Hz, 1 H), 3.17 (dd, J = 18.5, 9.5 Hz, 1 H), 4.64 (d, J = 12.8 Hz, 1 H), 4.68 (d, J = 12.8 Hz, 1 H), 4.81 (dd, J = 9.5, 5.8 Hz, 1 H), 5.11 (s, 2 H), 6.23 (dd, J = 2.1, 2.2 Hz, 2 H), 6.60 (dd, J = 2.1, 2.2 Hz, 2 H), 7.29–7.38 (m, 5 H).

¹³C NMR (125 MHz, CDCl₃): δ = 36.6, 56.5, 68.2, 72.5, 110.2, 119.5, 127.6, 128.0, 128.5, 137.4, 173.1, 173.4.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₆H₁₆N₂NaO₃: 307.1059; found: 307.1074.

Ethyl 1-(Benzyloxymethyl)-2,5-dioxo-3-(1H-pyrrol-1-yl)pyrrolidine-3-carboxylate (14b) and Ethyl 1-(Benzyloxymethyl)-2,5-dioxo-4-(1H-pyrrol-1-yl)pyrrolidine-3-carboxylate (15)

To a solution of 12c (352 mg, 1.24 mmol) in anhydrous toluene (10 mL) was added KHMDS solution in toluene (0.5 M; 2.73 mL, 1.36 mmol), and the mixture was stirred at r.t. for 5 min. To the reaction mixture was added diethyl dicarbonate (206 μL, 1.42 mmol), and the mixture was stirred at r.t. for 20 min. The mixture was then diluted with EtOAc (30 mL), and the solution was washed with aq NH₄Cl solution, H₂O, and brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (15 g; hexane/EtOAc, 10:1 to 5:1) to afford an inseparable mixture of 14b and 15 (3:1) as a yellow oil (262 mg, 59%).

IR (ATR): 3027, 2981, 2939, 2908, 2871, 1797, 1759, 1716, 1344, 1325, 1227, 1086, 1076 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ (signals attributed to 14b) = 1.23 (t, J = 7.2 Hz, 3 H), 3.23 (d, J = 7.8 Hz, 1 H), 3.56 (d, J = 7.8 Hz, 1 H), 4.26 (q, J = 7.2 Hz, 2 H), 4.61 (s, 2 H), 5.10 (d, J = 10.6 Hz, 1 H), 5.43 (d, J = 6.6 Hz, 1 H), 6.28 (dd, J = 2.2, 2.1 Hz, 2 H), 6.95 (dd, J = 2.2, 2.1 Hz, 2 H), 7.27–7.38 (m, 5 H).

¹H NMR (400 MHz, CDCl₃): δ (signals attributed to 15) = 1.34 (t, J = 7.2 Hz, 3 H), 3.82 (d, J = 6.6 Hz, 1 H), 4.28 (q, J = 7.2 Hz, 2 H), 4.65 (d, J = 13.2 Hz, 1 H), 4.68 (d, J = 13.2 Hz, 1 H), 5.09 (d, J = 10.6 Hz, 1 H), 5.14 (d, J = 10.6 Hz, 1 H), 5.43 (d, J = 6.6 Hz, 1 H), 6.28 (dd, J = 2.3, 2.2 Hz, 2 H), 6.95 (dd, J = 2.3, 2.2 Hz, 2 H), 7.27–7.38 (m, 5 H).

Regeneration of (±)-9a

To a solution of 14b and 15 (75 mg) in EtOH (1 mL) was added 20% Pd(OH)₂/C (50% in H₂O, 61 mg) and Et₃N (6 μL, 0.042 mmol). The mixture was stirred for 3.5 h at r.t. under hydrogen atmosphere, and then was filtered. The filtrate and washings were concentrated in vacuo, and the residue was dissolved in EtOH (1 mL). To the solution was again added 20% Pd(OH)₂/C (50% in H₂O, 114 mg) and Et₃N (12 μL, 0.084 mmol), and the resulting mixture was stirred for a further 7.5 h under hydrogen atmosphere. The mixture was filtered, and the combined filtrate and washings was concentrated. The residue was purified by silica gel column chromatography (4 g; hexane/EtOAc, 5:1) to afford (±)-9a (23 mg, 63%) as a colorless oil.

The ¹H NMR spectrum was identical with that of authentic 9a.

Acknowledgment

This study was supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Ministry of Education, Culture, Sports, Science (MEXT) and Japan Agency for Medical Research and Development (AMED) and Keio Gijuku Academic Development Funds and The Science Research Promotion Fund from Promotion and Mutual Aid Corporation for Private Schools of Japan. We thank Drs. Masahiro Takeda and Naoki Shirasaka of Nagase & Co. Ltd. for the gift of A. melleus protease XP-488, Dr. Yoichi Suzuki of Novozymes Japan for C. antarctica lipase B Novozym 435, Dr. Yoshihiko Hirose­ of Amano Enzyme Inc. for B. cepacia lipase PS-IM, Mr. Hiroyuki Uchiyama of Meito Sangyo Co. Ltd. for C. rugosa lipase Meito OF, and Profs. Hironao Sajiki and Yasunari Monguchi of Gifu Pharmaceutical University for hydrogenation catalysts and helpful suggestions. We also thank Prof. Masaya Ikunaka of Yasuda Women’s University for discussion and encouragement, and Mr. Yuuki Tatsumi for his efforts in the early phase of this study.

• References

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• References

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  Thieme Connect
• 2 Azerad R, Buisson D. Curr. Opin. Biotechnol. 2000; 11: 565
  CrossrefSearch in Google Scholar
• 3 Faber K. Chem. Eur. J. 2001; 7: 5004
  CrossrefSearch in Google Scholar
• 4 May O, Verseck S, Bommarius A, Drauz K. Org. Process Res. Dev. 2002; 6: 452
  CrossrefSearch in Google Scholar
• 5 Pálmies O, Bäckvall J.-E. Chem. Rev. 2003; 103: 3247
  CrossrefPubMedSearch in Google Scholar
• 6 Burton SG, Dorrington RA. Tetrahedron: Asymmetry 2004; 15: 2737
  CrossrefSearch in Google Scholar
• 7 Turner NJ. Curr. Opin. Chem. Biol. 2004; 8: 114
  CrossrefPubMedSearch in Google Scholar
• 8 Gruber CC, Lavandera I, Faber K, Kroutil W. Adv. Synth. Catal. 2006; 348: 1789
  CrossrefSearch in Google Scholar
• 9 Ahn Y, Ko S.-B, Kim M.-J, Park J. Coord. Chem. Rev. 2008; 252: 647
  CrossrefSearch in Google Scholar
• 10 Kamal A, Azhar MM, Krishnaji T, Malik MS, Azeeza S. Coord. Chem. Rev. 2008; 252: 569
  CrossrefSearch in Google Scholar
• 11 Pellissier H. Tetrahedron 2008; 64: 1563
  CrossrefPubMedSearch in Google Scholar
• 12 Holt J, Hanefeld U. Curr. Org. Synth. 2009; 6: 15
  CrossrefSearch in Google Scholar
• 13 Lee JH, Han K, Kim M.-J, Park J. Eur. J. Org. Chem. 2010; 999
• 14 Ahmed M, Kelly T, Ghanem A. Tetrahedron 2012; 68: 6781
  CrossrefSearch in Google Scholar
• 15 Marcos R, Martín-Matute B. Isr. J. Chem. 2012; 52: 639
  CrossrefSearch in Google Scholar
• 16 Rachwalski M, Vermue N, Rutjes FP. J. T. Chem. Soc. Rev. 2013; 42: 9268
  CrossrefPubMedSearch in Google Scholar
• 17 Akai S. Chem. Lett. 2014; 43: 746
  CrossrefSearch in Google Scholar
• 18 de Miranda AS, Miranda LS. M, de Souza RO. M. A. Biotechnol. Adv. 2015; 33: 372
  CrossrefPubMedSearch in Google Scholar
• 19 Verho O, Bäckvall J.-E. J. Am. Chem. Soc. 2015; 137: 3996
  CrossrefSearch in Google Scholar
• 20 Schober M, Faber K. Trends Biotechnol. 2013; 31: 468
  CrossrefSearch in Google Scholar
• 21 Yamashita Y, Hanaya K, Sugai T, Mizushima T, Shoji M. Tetrahedron 2013; 69: 6527
  CrossrefSearch in Google Scholar
• 22a Node M, Nakamura S, Nakamura D, Katoh T, Nishide K. Tetrahedron Lett. 1999; 40: 5357
  CrossrefSearch in Google Scholar
• 22b Katoh T, Kakiya K, Nakai T, Nakamura S, Nishide K, Node M. Tetrahedron: Asymmetry 2002; 13: 2351
  CrossrefSearch in Google Scholar
• 23 Laronde JJ, Bergbrieter DE, Wong C.-H. J. Org. Chem. 1988; 53: 2323
  CrossrefSearch in Google Scholar
• 24 Westerman B, Scharmann HG, Kortman I. Tetrahedron: Asymmetry 1993; 4: 2119
  CrossrefSearch in Google Scholar
• 25a Negoro T, Murata M, Ueda S, Fujitani B, Ono Y, Kuromiya A, Komiya M, Suzuki K, Matsumoto J. J. Med. Chem. 1998; 41: 4118
  CrossrefPubMedSearch in Google Scholar
• 25b Bril V, Buchanan R. Diabetes Care 2004; 27: 2369
  CrossrefSearch in Google Scholar
• 25c Bril V, Buchanan R. Diabetes Care 2006; 29: 68
  CrossrefSearch in Google Scholar
• 25d Matsumoto T, Ono Y, Kuromiya A, Toyosawa K, Ueda Y, Bril V. J. Pharmacol. Sci. 2008; 107: 340
  CrossrefSearch in Google Scholar
• 25e Matsumoto T, Ono Y, Kurono M, Kuromiya A, Nakamura K, Bril V. J. Pharmacol. Sci. 2008; 107: 231
  CrossrefSearch in Google Scholar
• 25f Ota A, Kakehashi A, Toyoda F, Kinoshita N, Shinmura M, Takano H, Obata H, Matsumoto T, Tsuji J, Dobashi Y, Fujimoto WY, Kawakami M, Kanazawa Y. J. Diabetes Res. 2013; 2013: 1
  Search in Google Scholar
• 26 Mashiko T, Kumagai N, Shibasaki M. Org. Lett. 2008; 10: 2725
  CrossrefSearch in Google Scholar
• 27 Seki M, Kawase Y. WO 2009/051216 A1, 2009
• 28 Kudo Y, Yamada O. WO 2008/035735 A1, 2008
• 29 Maffioli SI, Marzorati E, Marazzi A. Org. Lett. 2005; 7: 5237
  CrossrefPubMedSearch in Google Scholar
• 30 Chikusa Y, Hirayama Y, Ikunaka M, Inoue T, Kamiyama S, Moriwaki M, Nishimoto Y, Nomoto F, Ogawa K, Ohno T, Otsuka K, Sakota K, Shirasaka N, Uzura A, Uzura K. Org. Process Res. Dev. 2003; 7: 289
  CrossrefSearch in Google Scholar
• 31 Ballatore C, Brunden KR, Piscitelli F, Piscitelli F, James MJ, Crowe A, Yao Y, Hyde E, Trojanowski JQ, Lee VM.-Y, Smith III AB. J. Med. Chem. 2010; 53: 3739
  CrossrefSearch in Google Scholar
• 32 Crider AM, Sylvestri SC, Tschappat KD, Dick RM, Leader WG. J. Heterocycl. Chem. 1988; 25: 1407
  CrossrefSearch in Google Scholar
• 33 Monguchi Y, Fujita Y, Endo K, Takao S, Yoshimura M, Takagi Y, Maegawa T, Sajiki H. Chem. Eur. J. 2009; 15: 834
  CrossrefSearch in Google Scholar
• 34 Monguchi Y, Ichikawa T, Nozaki K, Kihara K, Yamada Y, Miyake Y, Sawama Y, Sajiki H. Tetrahedron 2015; 71: 6499
  CrossrefSearch in Google Scholar
• 35 Monguchi Y, Kume A, Hattori K, Maegawa T, Sajiki H. Tetrahedron 2006; 62: 7926
  CrossrefSearch in Google Scholar

• Supplementary Material