Control of the enantioselectivity of the bioreduction with immobilized bakers' yeast in a hexane solvent system

摘要

J. C'HFM soc'. PERKIN TRANS. I 1992 Control of the Enantioselectivity of the Bioreduction with Immobilized Bakers' Yeast in a Hexane Solvent System Yoshinobu Naoshima," Jusei Maeda and Yoshihito Munakata Department of Biological Chemistry, Faculty of Science, Oka yama University of Science, I -I Ridai-cbo, Oka yama 700,Japan Enantioselective reduction of P-keto esters with immobilized bakers' yeast in hexane was either controlled or changed by additives such as acetamide, or adenine, instead of glucose. In recent years, bakers' yeast has been used for enantioselective reductions of P-keto esters, keto acids, or $-unsaturated carbonyl compounds. ' Several ways for controlling the stereo- chemistry of aqueous bakers' yeast reductions have been adopted such as modification of substrate structure,' immobili- zation of the bakers' yeast,3 or with additives such as allyl alcohol and metal salts.4 More recently we reported that immobilized bakers' yeast (IBY) entrapped in calcium alginate beads functioned both in hexane and water systems, IBY- mediated reductions in the former, using alcohols as an energy source or additive, giving chemical and optical yields similar to those with analogous reductions using gl~cose.~ In continuance of our work on IBY reactions, we found that enantioselective reduction of certain P-keto esters, 1-3, in hexane, could be con- trolled by additives such as alcohols, Me'SO, thioacetamide, or adenine, instead of glucose.For 4-chloro-3-oxobutanoate 1, each reduction in hexane, using thioacetamide, Me,SO, and saturated alcohols (e.g.methanol, butan-2-01, and 2,2,2-trifluoroethanoI), gave the cor- responding chiral hydroxy esters R(L)-la with an enantiomeric purity of 21-43',,,. In contrast, for analogous reductions of 1 with allyl alcohol and quinine the stereochemistry of la was largely shifted to the D-isomer, S(D)-la of 55 ee being pro- duced in the presence of the former additive. Both reductions of the keto ester 2, using thioacetamide and adenine, yielded S(L)- 2a with 55", ee, while that of 2 with ally1 alcohol gave R(~)-2a with 64',, ee. Similar reductions with saturated alcohols were also carried out, and resulted in S(~)-2a with an enantiomeric saturated and unsaturated alcohols, Me,SO, thio-R (L)-la S (~)-2a S (L)-3a t 1 2 3 1 S (D)-l a R (D)-2a R (D)-3a Scheme 1 Reactions in the presence of IBY, hexane and additives purity of 1846. For substrate 3, the stereochemistry of the product (R)-3a obtained for reductions in the presence of several additives including saturated alcohols shifted towards the L-isomer, relative to that produced for the reduction using glucose; in contrast, the stereochemistry in Me,SO and allyl alcohol systems was shifted more to the D-isomer than that in glucose system (see Table 1).A combination of DMSO and glucose was a particularly Table 1 Enantioselectivity of the reduction of keto esters 1-3 with immobilized bakers' yeast." la 2a 3a Additive yc, Yield Ee Config.d 7;Yield :(,Ee Config.d "/, Yield 7;Ee ' Config.d Methanol 54 25 45 18 13 38 Ethanol 64 21 35 41 10 62 Propan-2-01 65 28 37 39 11 47 Butan-! -01 70 30 10 33 5 46 Butan-2-01 70 35 42 42 1 42 Trifluoroethanol 70 37 40 46 3 39 Et hy 1 ch loroacet a te 56 26 4 51 3 -f Me,SO 37 32 26 10 8 78 Thioacetamide 52 43 21 55 Adenine 66 23 22 55 16 51 MezSO + gluco~e" 20 8 20 4 31 99 Quinine 51 36 39 -1 36 63 Ally1 alcohol 51 55 6 64 6 95 Glucose 34 4 45 23 35 67 None 30 35 30 22 10 64 ('Reactions were run in the presence of an additive (I g).Determined by HPLC analysis of the MTPA ester derived from la GL Science Lichrosorb SI-100, diethyl ether -hexane (1 :20), 1.0 cm3 min-', 254 nm.Determined by HPLC analysis of the benzoate esters derived from 2a and 3a Daicel Chiralcel OB, propan-2-01 -hexane (I :9),0.7 cm3 min-', 220 nm. Both the stereochemical designations of RS and DL were used to show clearly the direction of stereochernistry. " Me,SO (10g) and glucose (1 g) were used. Racemic. satisfactory additive, the enantiomeric purity. of the product R(~)-3areaching 99. It is interesting to note that the degree of the change of these enantioselectivities varies, depending on the keto ester involved, whereas the direction of the selectivity is controllable by selecting the appropriate additive. In re-ductions using thioacetamide, adenine, and saturated alcohols including butan-2-01 and trifluoroethanol, for example, the stereochemistry of la-3a was generally shifted to the L-isomer.All of these additives can be classified as being L-selective (or L-directing). Since with ally1 alcohol, the stereochemistry was exclusively shifted to the D-isomer, this additive can be classified as being D-selective (or D-directing). Although the present stereochemical control system on IBY- mediated reductions in hexane has not been optimized these results indicate that the enantioselective reductions with bakers' yeast may be controlled in both aqueous and organic solvent systems (particularly in hexane), by using appropriate L-selective or D-selective additives. Experimental Immobilized bakers' yeast entrapped in calcium alginate beads, ca.1.5 mm diam., was prepared according to the procedure described previo~sly.~~ a,, Values were recorded in lo-' deg cm2 g-'. IBY Reduction qf 1-3 in the Presence of Adenine.-IBY prepared from free bakers' yeast (10 g) was added to a solution containing the appropriate keto ester, 1-3 (1 g), adenine (1 g) and hexane (200 cm3). Each mixture was shaken at 3amp;35 "Cfor a different period: 4 h for 1,52 h for 2 and 50 h for 3. The reaction J. CHEM. SOC. PERKIN TRANS. I 1992 mixture was then filtered, and IBY beads were well washed with water; the filtrate and washings were combined and extracted with diethyl ether. Work-up of the extract gave a crude product, which was purified by column chromatography (silica gel and hexane-ethyl acetate) and microvacuum distillation to yield a chiral hydroxy ester; 0.668 g of la, zh2 +5.22 (c 6.12, CHCI,), 0.223 g of 2a, Cali2 +20.64 (c 3.85, CHCI,) and 0.166 g of 3a, zh2 -11.91 (c 4.24, CHCI,), were obtained, respectively.Each hydroxy ester was fully characterized by IR and 'H NMR spectroscopy. References 1 P. Gramatica, Chim. Oggi, 1988, 17; S. Servi, Synthesis, 1990, 1. 2 T. Fujisawa, E. Kojima, T. Itoh and T. Sato, Chem. Left., 1985, 1751; A. Manzocchi, A. Fiecchi and E. Santaniello, J. Org. Chem., 1988,53, 4405. 3 T. Sakai, T. Nakamura, K. Fukuda, E. Amano, M. Utaka and A. Takeda, Bull. Chem. SOC. Jpn., 1986. 59, 3185; K. Nakamura, K. Inoue, K. Ushio, S. Oka and A. Ohno, J. Org. Chem., 1988,53,2589. 4 K. Nakamura, Y. Kawai, S. Oka and A. Ohno, Bull. Chem. SOC.Jpn., 1989, 62,875; K. Nakamura, Y. Kawai and A. Ohno, Tetrahedron Lett., 1990, 31, 267; K. Nakamura and A. Ohno, Yuki Gosei Kagaku Kyokaishi, 1991,49, 110. 5 (a) Y. Naoshima, 3. Maeda, Y. Munakata, T. Nishiyama, M. Kamezawa and H. Tachibana, J. Chem. Soc., Chem. Commun., 1990, 964; (b) Y. Naoshima, Y. Munakata, T. Nishiyama, J. Maeda, M. Kamezawa, T. Haramaki and H. Tachibana, World J. Microhiol. Biotechnol., 1991,7, 219. Paper 2/00191H Received 14th January 1992 Accepted 14th January 1992