Efficient kinetic resolution of (±)-4-methyl-Hajos-Parrish ketone by baker's yeast reduction

Article abstract of DOI:10.1016/S0957-4166(00)00010-0

Kinetic resolution of (±)-4-methyl-Hajos-Parrish ketone (±)-2a using baker's yeast reduction was investigated. The reaction rate and enantiomeric purity depended on the concentration of substrate and yeast. Under concentrated conditions, (-)-2a and the alcohol (+)-3 were obtained in high enantiomeric excess. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00010-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 829–834
Efficient kinetic resolution of (±)-4-methyl-Hajos–Parrish ketone
by baker’s yeast reduction
Hideaki Hioki, Takefumi Hashimoto and Mitsuaki Kodama ∗
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
Received 26 November 1999; accepted 14 December 1999
Abstract
Kinetic resolution of (±)-4-methyl-Hajos–Parrish ketone (±)-2a using baker’s yeast reduction was investigated.
The reaction rate and enantiomeric purity depended on the concentration of substrate and yeast. Under concentrated
conditions, (−)-2a and the alcohol (+)-3 were obtained in high enantiomeric excess. © 2000 Elsevier Science Ltd.
All rights reserved.
1. Introduction
Optically active Hajos–Parrish ketone 2a and its derivatives have been widely used as intermediates
for natural product syntheses. (+)-2a is generally prepared using L-proline catalyzed aldol reaction of 1
followed by dehydration in good chemical yield and enantiomeric excess.1 As part of a program directed
towards the synthesis of trinervitane diterpenes, e.g. 4,2 we required its 4-methyl derivative (−)-2b in
enantiomerically pure form. However, Paquette et al. reported that amino acid catalyzed asymmetric
reaction to afford (+)-2b did not exceed 75% enantiomeric excess under their most favorable conditions.3c
Recently, Hagiwara et al. prepared enantiomerically pure (+)-2b using stoichiometric L-phenylalanine
followed by recrystallization in 45% chemical yield.3e To apply this method to the preparation of (−)-
2b, expensive D-phenylalanine is required stoichiometrically. We envisioned that the requisite compound
could be prepared on a large scale by kinetic resolution of (±)-2b using baker’s yeast reduction,4,5 which
has been successfully utilized in the asymmetric reduction of α-hydroxy ketones in our laboratory.6
∗
Corresponding author. E-mail: kodama@ph.bunri-u.ac.jp
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00010-0
tetasy 3233

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H. Hioki et al. / Tetrahedron: Asymmetry 11 (2000) 829–834
2. Results
The kinetic resolution of (±)-2b under various conditions is summarized in Table 1. At first the
reduction was run under the standard conditions used for α-hydroxy ketones.6 After 24 h, 20% of 2b
was reduced and (+)-3b was obtained preferentially, but its enantiomeric excess was only 72% ee (entry
1). The absolute stereochemistry of (−)-2b was determined by the comparison with the reported sign
of specific rotation for (+)-2b.3a,b Complete diastereoselectivity was observed in the reduction and the
relative stereochemistry was determined as cis because the spectroscopic data of (+)-3b were identical to
those for the compound produced by NaBH4 reduction of (−)-2b.3d,e Ethanol did not affect the efficiency
of the reduction (entry 1 vs entry 2). To improve the enantioselectivity, the substrate concentration was
varied. At high concentration of substrate and baker’s yeast, the reaction rate and enantiomeric excess
(ee) were dramatically increased (entry 3). This result indicated that several enzymes participated in
the reduction.7 Thus, a high concentration of substrate (entry 4) improved the ee of (−)-2b but not the
reaction rate. Further high concentration of baker’s yeast led to the reduction proceeding smoothly and
enantiomerically pure (−)-2b was recovered (entry 5). Next we investigated the yield and ee under a
variety of reaction times (entries 5–9). After 3 h (+)-3b was isolated in 93% ee and 42% yield (entry 6).
Recovering enantiomerically pure (+)-2b require 18 h under the same reaction conditions (entries 6–9).
Thus, both (−)-2b and (+)-3b were found to be obtained in good chemical yield and enantiomeric excess
by changing reaction time.
Finally this reduction was applied to Hajos–Parrish ketone (±)-2a and Wieland–Miecher ketone (±)-5
(Scheme 1). Kinetic behavior of (±)-2a was almost the same as (±)-2b. (+)-3a was obtained in 94% ee
and 42% yield after 3 h, and (−)-2a with 99.5% ee was recovered in 42% yield after 18 h.8 In contrast to
(±)-2, the reduction of Wieland–Miecher ketone (±)-59 was very slow, although almost enantiomerically
pure (+)-6a was obtained in 32% yield along with the ketone (−)-5 with 59% ee after 24 h.10 A small
amount of (−)-5 was also reduced from the same face as (+)-5 to afford (−)-6b in 88% ee.

H. Hioki et al. / Tetrahedron: Asymmetry 11 (2000) 829–834
831
Table 1
Kinetic resolution of (±)-4-methyl-Hajos–Parrish ketone (±)-2b by baker’s yeast reduction
Scheme 1. Kinetic resolution of (±)-Hajos–Parrish ketone (±)-2a and (±)-Wieland–Miecher ketone (±)-5

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H. Hioki et al. / Tetrahedron: Asymmetry 11 (2000) 829–834
Further work toward the synthesis of trinervitane diterpenes using (−)-2b obtained by this kinetic
resolution is currently underway and will be reported in due course.
3. Experimental
3.1. General
Melting points (uncorrected) were determined by using a Yanagimoto micro melting point apparatus.
Optical rotations were measured on a JASCO DIP-1000 digital polarimeter using sodium light (D line,
589.3 nm) and are recorded in degrees; concentrations (c) are recorded in g/100 mL. Substrates (±)-2a,11
(±)-2b3b and (±)-512 were prepared according to literature procedures. Baker’s yeast was purchased
from Kyowa Hakko Co., Ltd (Japan).
3.2. Determination of enantiomeric purity by gas chromatography
Enantiomeric purity analyses were carried out with both racemic and enantioenriched compounds.
Enantiomeric purity was determined by gas chromatography (Shimadzu GC-14B gas chromatograph
equipped with a flame ionization detector) using a chiral capillary column. Analytical conditions for
each compound are as follows:
2a: Column: SPELCO gamma-DEX™ 225; oven temp.: 190°C; retention time: (+)-2a: 9.6 min. (−)-2a:
10.1 min.
3a: Column: SPELCO beta-DEX™ 120; oven temp.: 200°C; retention time: (+)-3a: 10.6 min. (−)-3b:
10.9 min.
2b: Column: SPELCO gamma-DEX™ 225; oven temp.: 190°C; retention time: (+)-2b: 10.2 min. (−)-
2b: 10.9 min.
3b: Column: SPELCO beta-DEX™ 120; oven temp.: 180°C; retention time: (+)-3b: 20.8 min. (−)-3b:
21.5 min.
5: Column: SPELCO gamma-DEX™ 225; oven temp.: 210°C; retention time: (+)-5: 8.4 min. (−)-5: 8.8
min.
6: Column: SPELCO beta-DEXrm 225; oven temp.: 180°C; retention time: (+)-6a: 31.7 min. (−)-6a:
32.8 min. (+)-6b: 36.2 min. (−)-6b: 35.4 min.
3.3. Representative procedure for baker’s yeast reduction
3.3.1. Kinetic resolution of 4,7a-dimethyl-2,3,7,7a-tetrahydro-6H-indene-1,5-dione 2b (Table 1 entry 9)
A mixture of 9.0 g of baker’s yeast, 3.5 g of glucose and 2 mL of H2O was incubated for 0.5 h. The
mixture was added to (±)-2b (104.3 mg, 0.585 mmol). After stirring for 18 h at room temperature, 10 g
of Celite and 30 mL of AcOEt were added and stirred for 1 h. The mixture was filtered through Celite,
which was washed with AcOEt. The combined filtrates were concentrated under reduced pressure. The
crude product (211.4 mg) was analyzed by gas chromatography to determine the enantiomeric purity of
2b and 3b. Flash chromatography of crude product on silica gel (4:1 hexane:EtOAc to 1:1 hexane:EtOAc)
gave 46.4 mg (0.257 mmol, 44%) of (−)-2b and 53.0 mg (0.294 mmol, 50%) of (+)-3b.
In the case of the reduction of solid substrate ((±)-2a and (±)-5), the substrate was dissolved in a small
amount of ethanol (100 mg of 2a or 5 in 0.2 mL of ethanol).

H. Hioki et al. / Tetrahedron: Asymmetry 11 (2000) 829–834
833
25
3.4. (−)-(7aR)-7a-Methyl-2,3,7,7a-tetrahydro-6H-indene-1,5-dione (−)-2a
25
Colorless needles: mp 65–66°C (lit.1 64–66°C); [α] −355 (c 1.0, toluene) (lit.1 for (−)-2a [α]
D
D
+347.5–349 (c 1.0, toluene)).
3.5. (+)-(1S,7aS)-1-Hydroxy-7a-methyl-1,2,3,6,7,7a-hexahydro-inden-5-one (+)-3a
20
1
Colorless needles: mp 47–48°C; [α] +82.5 (c 1.1, CHCl3); IR (KBr) 3383, 1640 cm−1; H NMR
D
(300 MHz, CDCl3) δ 5.79 (1H, brs), 3.86 (1H, ddd, J=5.8, 7.4, 10.4 Hz), 2.71 (1H, tdd, J=2.2, 11.8,
19.8 Hz), 2.33–2.61 (3H, m), 2.06–2.20 (2H, m), 1.71–1.98 (3H, m), 1.15 (3H, s); 13C NMR (75 MHz,
CDCl3) δ 15.1, 26.4, 29.2, 33.3, 34.1, 45.2, 80.7, 123.5, 174.8, 199.1; MS (EI) 109 (base), 166 (M+);
HRMS (EI) calcd for C10H14O2 (M+) 166.0993, found 166.0996. The spectroscopic data were identical
to those for the compound produced by NaBH4 reduction of (−)-2a.8
3.6. (−)-(7aR)-4,7a-Dimethyl-2,3,7,7a-tetrahydro-6H-indene-1,5-dione (−)-2b
21
25
Colorless needles: mp 43–44°C; [α] −328 (c 1.1, CHCl3) (lit.3b [α] −337 (c no description,
D
D
CHCl3)).
3.7. (+)-(1S,7aS)-1-Hydroxy-4,7a-dimethyl-1,2,3,6,7,7a-hexahydro-inden-5-one (+)-3b
25
94% ee: Colorless oil. [α] +68.7 (c 1.1, CHCl3); IR (film) 3416, 1642 cm−1; 1H NMR (300 MHz,
D
CDCl3) δ 3.84 (1H, dd, J=7.4, 10.4 Hz), 2.50–2.62 (2H, m), 2.34–2.46 (2H, m), 2.28 (1H, brs), 1.72–1.92
(2H, m), 1.66 (3H, s), 1. 12 (3H, s); 13C NMR (75 MHz, CDCl3) δ 10.7, 15.2, 25.6, 29.5, 33.3, 34.0, 45.0,
80.9, 128.9, 167.9, 198.8; MS (EI) 123, 180 (M+, base); HRMS (EI) calcd for C11H16O2 (M+) 180.1149,
found 180.1139. The spectroscopic data were identical to those for the compound produced by NaBH4
reduction of (−)-2b.3d,e
3.8. (−)-(8aR)-8a-Methyl-3,4,8,8a-tetrahydro-2H,7H-naphthalene-1,6-dione (−)-5
21
76% ee: Colorless solid: mp 45–49°C (lit.10a 49–50°C); [α] −72.4 (c 1.1, toluene) (lit.10a for (+)-5
D
[α]25 +97.3 (c 1.0, toluene)).
D
3.9. (+)-(4aS,5S)-5-Hydroxy-4a-methyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one (+)-6a
20
26
Colorless needles: mp 42–43°C (lit.10b 45–48°C); [α] +202 (c 0.72, benzene) (lit.10b [α] +198.5
D
D
(c 0.93, benzene)). The spectroscopic data were identical to those for the compound produced by NaBH4
reduction of (−)-5.10b
3.10. (−)-(4aR,5S)-5-Hydroxy-4a-methyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one (−)-6b
20
25
88% ee: Colorless solid: mp 93–94°C (lit.9 94–95°C); [α] −90.0 (c 1.0, benzene) (lit.9 [α] −111
D
D
(c 1.3, benzene)). IR (KBr) 3434, 1644 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.86 (1H, brs), 3.66 (1H,
brs), 2.58 (1H, m), 2.36–2.50 (3H, m), 2.04 (1H, m), 1.64–1.86 (4H, m), 1.51 (1H, td, J=4.4, 12.1 Hz),
1.25 (3H, s); 13C NMR (75 MHz, CDCl3) δ 19.8, 21.8, 28.7, 30.7, 31.7, 34.0, 40.9, 75.3, 126.9, 167.8,
199.4; MS (EI) 162 (base), 180 (M+); HRMS (EI) calcd for Cl1H16O2 (M+) 180.1149, found 180.1126.

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H. Hioki et al. / Tetrahedron: Asymmetry 11 (2000) 829–834
Acknowledgements
We are grateful to Spelco Japan, Ltd for a special gift of capillary column for the analyses of
enantiomeric purity. This work was supported in part by a Grant-in-Aid for Scientific Research from
the Ministry of Education and Culture of Japan (No. 11672132).
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