- Email: [email protected]
Lipase catalyzed kinetic resolution of aryl β-hydroxy ketones
Tetrahedron: Asymmetry 11 (2000) 2049±2052
Lipase catalyzed kinetic resolution of aryl b-hydroxy ketones Mangalam S. Nair* and S. Joly Organic Chemistry Division, Regional Research Laboratory (CSIR), Thiruvananthapuram-695 019, India Received 5 April 2000; accepted 18 April 2000
Abstract Enzymatic kinetic resolution of racemic aryl b-hydroxy ketones in organic media catalyzed by Candida cylindracea lipase is reported. # 2000 Elsevier Science Ltd. All rights reserved.
Chiral aryl b-hydroxy ketones (aldols) are important building blocks in synthetic organic chemistry. The aldol product has two useful functional groups which can serve as reaction sites for further synthetic transformations. Chirality of the hydroxyl group can also be used for controlling/ generating stereochemistry at other sites. Acyclic b-hydroxy ketones are useful in the synthesis of syn- and anti-1,3-diols1 as well as syn-1,3-aminoalcohols2 which are important functional groups found in many biologically active compounds. Several methods for obtaining optically active aldols have been reported: viz. (i) using stoichiometric amounts of chiral auxiliaries;3 (ii) using transition metal based catalysts;4 (iii) enzymatic transformations, etc.5 Among the latter are baker's yeast reduction of 1,3-diketones5 and the use of aldolase antibodies.6 Enzymatic transesteri®cation has been used successfully for the resolution of a-hydroxy ketones by Adam et al.7 The use of Amano PS as catalyst for resolution of aryl homoallyl alcohols and their use in the synthesis of biologically active compounds like ¯uoxetine have been reported.8 Based on our previous experience in enzymatic kinetic resolutions,9 we searched the repertoire of readily available enzymes to identify the one that would resolve aryl substituted b-hydroxy ketones. Our special interest was in the resolution of 4-(30 ,40 -dichlorophenyl)-4-hydroxy-2butanone which would ®nd use in the synthesis of sertraline10 (one of the most widely used antidepressants) type compounds. We investigated the eect of several lipases (CCL, PPL, Amano PS) on aryl substituted aldols and found that Candida cylindracea lipase (700±1500 U/mg) very eciently provides the kinetic resolution. In this paper, we describe the enzymatic resolution of acetone aldol products of various substituted benzaldehydes and naphthaldehydes 1a±8a. The racemic starting materials were prepared either by Wacker oxidation11 of the corresponding homoallyl alcohol (which was in turn obtained from the corresponding aldehyde using Zn, * Corresponding author. E-mail: [email protected] 0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0957-4166(00)00159-2
2050
M. S. Nair, S. Joly / Tetrahedron: Asymmetry 11 (2000) 2049±2052
NH4Cl and allyl bromide)12 or by a simple aldol reaction of the corresponding aldehyde with acetone in the presence of base.13 Acetylation was carried out using 1.5±2 mass equivalents of CCL as the catalyst. Vinyl acetate was used as the acyl donor. The reactions were monitored by TLC analysis and terminated when nearly half of the alcohol was consumed. Under these reaction conditions, CCL exhibited high enantioselectivity yielding the acetate with an enantiomeric excess >96%.14 After usual work up, the acetate and alcohol were easily puri®ed by column chromatography and their enantiomeric compositions were measured by 1H NMR analysis using chiral shift reagent Eu(hfc)3. The results are summarised in Table 1. The nature of the substituent on the benzene ring did not aect the outcome of the reaction signi®cantly. It was found that 1naphthyl-b-hydroxy ketone was resistant to bioconversion under these conditions. Even after six days, only negligible conversion was obtained, whereas 2-naphthyl-b-hydroxy ketone showed moderate reactivity.
Table 1 Enzymatic resolution of racemic aldol products
M. S. Nair, S. Joly / Tetrahedron: Asymmetry 11 (2000) 2049±2052
2051
To assign the absolute con®guration enantiomerically pure (S)-1-aryl-1-acetyloxy-3-butene was synthesised using Amano PS lipase as in the literature8 and converted to (+)-1b and (+)-2b by Wacker oxidation. Comparison of the speci®c rotation established the R-con®guration of acetates 1b and 2b and S-con®guration of alcohol. The S-con®guration of resolved alcohol 1a was further con®rmed by comparison with reported data.16 In all cases, the acetates were obtained with high enantiomeric purity and eorts were made to increase the conversion rate. By prolonging the reaction time, the conversion could be improved slightly, but it resulted in the formation of enone through elimination. The addition of molecular sieves 4 AÊ to the reaction mixture also had no eect. To get the alcohol as optically pure, the enantiomerically enriched alcohol 1a was again subjected to acetylation in presence of the same lipase, which aorded the corresponding alcohol with 71% ee. When isopropenyl acetate was used as the acylating agent, negligible conversion was observed. In order to optimise the transesteri®cation of (þ)-6a, we studied the eect of temperature on 6a (Table 2). The best result obtained was at 40 C whereas beyond 40 C, conversion was reduced and enantioselectivity only slightly improved. With three mass equivalents of enzyme, a better result was obtained. Table 2 Eect of temperature on the rate of acetylation of (þ)-6a
The typical procedure used for this enzymatic transesteri®cation is as follows: To a solution of racemic 1a (150 mg, 0.915 mmol) in vinyl acetate (5 ml) was added CCL (225 mg) and stirred at room temperature for 28 h. Then the enzyme was ®ltered o and the solvent was evaporated. The crude product was subjected to column chromatography (pet. ether:EtOAc 10±20%) to give acetate (+)-1b (60 mg, 33%) and alcohol (^)-1a (97 mg, 65%). Compound (+)-1b; 25 D +64.6 16 ^36.1 (c 1.7, CHCl ). All compounds have been characterized using (c 0.71, CHCl3); (^)-1a; 25 3 D IR, 1H NMR, 13C NMR and GC±MS. In conclusion, we have shown that optically active aryl b-hydroxy ketones can be prepared with high ee by kinetic resolution using enzymes. Transesteri®cation proceeded with high E values and in acceptable chemical yield. Acknowledgements S.J. thanks the CSIR for a research fellowship and M.S.N. thanks the Director, Regional Research Laboratory, Trivandrum for providing facilities.
2052
M. S. Nair, S. Joly / Tetrahedron: Asymmetry 11 (2000) 2049±2052
References 1. (a) Narasaka, K.; Pai, F. C. Tetrahedron 1984, 40, 2233. (b) Evans, D. A.; Chapman, K. T.; Carrera, E. M. J. Am. Chem. Soc. 1988, 110, 3560. 2. Haddad, M.; Dorbais, J.; LarcheveÃque, M. Tetrahedron Lett. 1997, 38, 5981. 3. Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1. 4. (a) Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.; Asakawa, K.; Yamamoto, H. J. Am. Chem. Soc. 1997, 119, 9319 and references cited therein. (b) Carreira, E. M.; Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995, 117, 3649. (c) Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J. Am. Chem. Soc. 1997, 119, 10859. (d) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1871. 5. Drauz, K.; Waldman, H. Enzyme Catalysis In Organic Synthesis; VCH: Weinheim, 1995; Vol. I and II. 6. Zhong, G.; Shabat, D.; List, B.; Anderson, J.; Sinha, S. C.; Lerner, R. A.; Barbas III, C. F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2481. 7. Adam, W.; DõÂaz, M. T.; Fell, R. T.; Saha-MoÈller, C. R. Tetrahedron: Asymmetry 1996, 7, 2207. 8. Master, H. E.; Newadkar, R. V.; Rane, R. A.; Kumar, A. Tetrahedron Lett. 1996, 37, 9253. 9. (a) Nair, M. S.; Anilkumar, A. T. Tetrahedron: Asymmetry 1996, 7, 511. (b) Anilkumar, A. T.; Sudhir, U.; Joly, S.; Nair, M. S. Tetrahedron 2000, 56, 1899. 10. (a) Welch, W. M.; Kraska, A. R.; Sarges, R.; Coe, K. B. J. Med. Chem. 1984, 27, 1508. (b) Coe, B. K.; Weissman, A.; Welch, W. M.; Broune, R. G. J. Pharmacol. Exp. Ther. 1983, 226, 686. 11. Tsuji, J.; Shimizu, I.; Yamamoto, K. Tetrahedron Lett. 1976, 17, 2975. 12. Wilson, S. R.; Guazzaroni, M. E. J. Org. Chem. 1989, 54, 3087. 13. Shokat, K.; Uno, T.; Schultz, P. G. J. Am. Chem. Soc. 1994, 116, 2261. 14. The other isomer is not seen in 300 MHz NMR. Since NMR technique is used for the determination of ee, an accuracy of only >96% is claimed. 15. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294. 16. Boldrini, G. P.; Lodi, L.; Tagliavini, E.; Trombini, C.; Umani-Rochini, A. J. Organomet. Chem. 1987, 336, 23.
Lipase catalyzed kinetic resolution of aryl b-hydroxy ketones Mangalam S. Nair* and S. Joly Organic Chemistry Division, Regional Research Laboratory (CSIR), Thiruvananthapuram-695 019, India Received 5 April 2000; accepted 18 April 2000
Abstract Enzymatic kinetic resolution of racemic aryl b-hydroxy ketones in organic media catalyzed by Candida cylindracea lipase is reported. # 2000 Elsevier Science Ltd. All rights reserved.
Chiral aryl b-hydroxy ketones (aldols) are important building blocks in synthetic organic chemistry. The aldol product has two useful functional groups which can serve as reaction sites for further synthetic transformations. Chirality of the hydroxyl group can also be used for controlling/ generating stereochemistry at other sites. Acyclic b-hydroxy ketones are useful in the synthesis of syn- and anti-1,3-diols1 as well as syn-1,3-aminoalcohols2 which are important functional groups found in many biologically active compounds. Several methods for obtaining optically active aldols have been reported: viz. (i) using stoichiometric amounts of chiral auxiliaries;3 (ii) using transition metal based catalysts;4 (iii) enzymatic transformations, etc.5 Among the latter are baker's yeast reduction of 1,3-diketones5 and the use of aldolase antibodies.6 Enzymatic transesteri®cation has been used successfully for the resolution of a-hydroxy ketones by Adam et al.7 The use of Amano PS as catalyst for resolution of aryl homoallyl alcohols and their use in the synthesis of biologically active compounds like ¯uoxetine have been reported.8 Based on our previous experience in enzymatic kinetic resolutions,9 we searched the repertoire of readily available enzymes to identify the one that would resolve aryl substituted b-hydroxy ketones. Our special interest was in the resolution of 4-(30 ,40 -dichlorophenyl)-4-hydroxy-2butanone which would ®nd use in the synthesis of sertraline10 (one of the most widely used antidepressants) type compounds. We investigated the eect of several lipases (CCL, PPL, Amano PS) on aryl substituted aldols and found that Candida cylindracea lipase (700±1500 U/mg) very eciently provides the kinetic resolution. In this paper, we describe the enzymatic resolution of acetone aldol products of various substituted benzaldehydes and naphthaldehydes 1a±8a. The racemic starting materials were prepared either by Wacker oxidation11 of the corresponding homoallyl alcohol (which was in turn obtained from the corresponding aldehyde using Zn, * Corresponding author. E-mail: [email protected] 0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0957-4166(00)00159-2
2050
M. S. Nair, S. Joly / Tetrahedron: Asymmetry 11 (2000) 2049±2052
NH4Cl and allyl bromide)12 or by a simple aldol reaction of the corresponding aldehyde with acetone in the presence of base.13 Acetylation was carried out using 1.5±2 mass equivalents of CCL as the catalyst. Vinyl acetate was used as the acyl donor. The reactions were monitored by TLC analysis and terminated when nearly half of the alcohol was consumed. Under these reaction conditions, CCL exhibited high enantioselectivity yielding the acetate with an enantiomeric excess >96%.14 After usual work up, the acetate and alcohol were easily puri®ed by column chromatography and their enantiomeric compositions were measured by 1H NMR analysis using chiral shift reagent Eu(hfc)3. The results are summarised in Table 1. The nature of the substituent on the benzene ring did not aect the outcome of the reaction signi®cantly. It was found that 1naphthyl-b-hydroxy ketone was resistant to bioconversion under these conditions. Even after six days, only negligible conversion was obtained, whereas 2-naphthyl-b-hydroxy ketone showed moderate reactivity.
Table 1 Enzymatic resolution of racemic aldol products
M. S. Nair, S. Joly / Tetrahedron: Asymmetry 11 (2000) 2049±2052
2051
To assign the absolute con®guration enantiomerically pure (S)-1-aryl-1-acetyloxy-3-butene was synthesised using Amano PS lipase as in the literature8 and converted to (+)-1b and (+)-2b by Wacker oxidation. Comparison of the speci®c rotation established the R-con®guration of acetates 1b and 2b and S-con®guration of alcohol. The S-con®guration of resolved alcohol 1a was further con®rmed by comparison with reported data.16 In all cases, the acetates were obtained with high enantiomeric purity and eorts were made to increase the conversion rate. By prolonging the reaction time, the conversion could be improved slightly, but it resulted in the formation of enone through elimination. The addition of molecular sieves 4 AÊ to the reaction mixture also had no eect. To get the alcohol as optically pure, the enantiomerically enriched alcohol 1a was again subjected to acetylation in presence of the same lipase, which aorded the corresponding alcohol with 71% ee. When isopropenyl acetate was used as the acylating agent, negligible conversion was observed. In order to optimise the transesteri®cation of (þ)-6a, we studied the eect of temperature on 6a (Table 2). The best result obtained was at 40 C whereas beyond 40 C, conversion was reduced and enantioselectivity only slightly improved. With three mass equivalents of enzyme, a better result was obtained. Table 2 Eect of temperature on the rate of acetylation of (þ)-6a
The typical procedure used for this enzymatic transesteri®cation is as follows: To a solution of racemic 1a (150 mg, 0.915 mmol) in vinyl acetate (5 ml) was added CCL (225 mg) and stirred at room temperature for 28 h. Then the enzyme was ®ltered o and the solvent was evaporated. The crude product was subjected to column chromatography (pet. ether:EtOAc 10±20%) to give acetate (+)-1b (60 mg, 33%) and alcohol (^)-1a (97 mg, 65%). Compound (+)-1b; 25 D +64.6 16 ^36.1 (c 1.7, CHCl ). All compounds have been characterized using (c 0.71, CHCl3); (^)-1a; 25 3 D IR, 1H NMR, 13C NMR and GC±MS. In conclusion, we have shown that optically active aryl b-hydroxy ketones can be prepared with high ee by kinetic resolution using enzymes. Transesteri®cation proceeded with high E values and in acceptable chemical yield. Acknowledgements S.J. thanks the CSIR for a research fellowship and M.S.N. thanks the Director, Regional Research Laboratory, Trivandrum for providing facilities.
2052
M. S. Nair, S. Joly / Tetrahedron: Asymmetry 11 (2000) 2049±2052
References 1. (a) Narasaka, K.; Pai, F. C. Tetrahedron 1984, 40, 2233. (b) Evans, D. A.; Chapman, K. T.; Carrera, E. M. J. Am. Chem. Soc. 1988, 110, 3560. 2. Haddad, M.; Dorbais, J.; LarcheveÃque, M. Tetrahedron Lett. 1997, 38, 5981. 3. Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1. 4. (a) Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.; Asakawa, K.; Yamamoto, H. J. Am. Chem. Soc. 1997, 119, 9319 and references cited therein. (b) Carreira, E. M.; Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995, 117, 3649. (c) Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J. Am. Chem. Soc. 1997, 119, 10859. (d) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1871. 5. Drauz, K.; Waldman, H. Enzyme Catalysis In Organic Synthesis; VCH: Weinheim, 1995; Vol. I and II. 6. Zhong, G.; Shabat, D.; List, B.; Anderson, J.; Sinha, S. C.; Lerner, R. A.; Barbas III, C. F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2481. 7. Adam, W.; DõÂaz, M. T.; Fell, R. T.; Saha-MoÈller, C. R. Tetrahedron: Asymmetry 1996, 7, 2207. 8. Master, H. E.; Newadkar, R. V.; Rane, R. A.; Kumar, A. Tetrahedron Lett. 1996, 37, 9253. 9. (a) Nair, M. S.; Anilkumar, A. T. Tetrahedron: Asymmetry 1996, 7, 511. (b) Anilkumar, A. T.; Sudhir, U.; Joly, S.; Nair, M. S. Tetrahedron 2000, 56, 1899. 10. (a) Welch, W. M.; Kraska, A. R.; Sarges, R.; Coe, K. B. J. Med. Chem. 1984, 27, 1508. (b) Coe, B. K.; Weissman, A.; Welch, W. M.; Broune, R. G. J. Pharmacol. Exp. Ther. 1983, 226, 686. 11. Tsuji, J.; Shimizu, I.; Yamamoto, K. Tetrahedron Lett. 1976, 17, 2975. 12. Wilson, S. R.; Guazzaroni, M. E. J. Org. Chem. 1989, 54, 3087. 13. Shokat, K.; Uno, T.; Schultz, P. G. J. Am. Chem. Soc. 1994, 116, 2261. 14. The other isomer is not seen in 300 MHz NMR. Since NMR technique is used for the determination of ee, an accuracy of only >96% is claimed. 15. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294. 16. Boldrini, G. P.; Lodi, L.; Tagliavini, E.; Trombini, C.; Umani-Rochini, A. J. Organomet. Chem. 1987, 336, 23.