Facile biocatalytic syntheses of optically active 4-hydroxycyclohex-2-enone and 4-benzylthiacyclopent-2-enone

Article abstract of DOI:10.1016/j.tetasy.2004.07.042

Novozyme 435 (Candida antarctica Lipase B) effects the kinetic resolution of both 3-benzylthia-4-hydroxycyclopentanone and its six-membered ring analogue, providing a novel route to both enantiomers of 4-benzylthiacyclopent-2-enone and the two enantiomers of 4-hydroxycyclohex-2- enone, all in a state of very high optical purity.

Full text of DOI:10.1016/j.tetasy.2004.07.042

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2807–2809
Facile biocatalytic syntheses of optically active
4-hydroxycyclohex-2-enone and 4-benzylthiacyclopent-2-enone
a
Ben S. Morgan, Dorothee Hoenner, Paul Evans and Stanley M. Roberts
a
b
a,
*
´
aDepartment of Chemistry, Liverpool University, Liverpool, L69 7ZD, United Kingdom
bDepartment of Chemistry, Trinity College, Dublin 2, Ireland
Received 1 June 2004; accepted 2 July 2004
Available online 11 September 2004
Abstract—Novozyme 435Ò (Candida antarctica Lipase B) effects the kinetic resolution of both 3-benzylthia-4-hydroxycyclopenta-
none and its six-membered ring analogue, providing a novel route to both enantiomers of 4-benzylthiacyclopent-2-enone and the
two enantiomers of 4-hydroxycyclohex-2-enone, all in a state of very high optical purity.
Ó 2004 Elsevier Ltd. All rights reserved.
O
OH
1. Introduction
O
H
O
steps
[H]
The diverse synthetic utility of optically active 4-
H
hydroxycyclohex-2-enone
and
cyclohex-2-ene-1,4-
O
O
O
O
O
O
diols has been summarised by Figueredo et al.1 Not
surprisingly, therefore, compounds such as (4R)- and
(4S)-4-hydroxycyclohex-2-enone 1 have been the focus
of a number of synthetic endeavours. For example,
(4S)-1 is available in six steps from a member of the chi-
ral pool [(D)-quinic acid].2 Both enantiomers of the hyd-
roxy ketone 1 are available by a protocol using a chiral
auxiliary3 or by a pathway involving a stereoselective
deprotonation of 4-benzyloxycyclohexanone using a chi-
ral lithium amide reagent.4 One of the most recently
reported methods utilises a chiral derivative of 1,4-ben-
zoquinone;1 unfortunately the partial reduction of 2 to
afford the enone 3 is difficult to control, with over-reduc-
tion to the saturated ketone occurring readily (Scheme
1).5
Ph
Ph
Ph
Ph
(S)-1
4
2
3
Scheme 1.
A better enzymatic method involves the kinetic resolu-
tion of 6-acetoxy-3-methoxycyclohex-2-enone;7 finally
desymmetrisation of cis-1,4-diacetoxycyclohex-2-ene
using Pseudomonas cepacia lipase provided a three step
pathway to (4R)-1;8 unfortunately in both these cases
the starting materials are not readily available on a large
scale.
There are three routes to optically active 1 involving bio-
transformations described in the literature. The first
method describes the BakersÕ yeast reduction of the
meso-diketone 4 to give the hydroxy ketone, followed
by a retro-Diels–Alder reaction.6 However, the yield of
the reduction process is low (32%) and the enantiomeric
excess of the desired product is only ca. 67%.
2. Results and Discussion
In contrast, racemic 4-hydroxycyclohex-2-enone is very
easy to make from anisole 5 (Scheme 2).9 While we con-
sidered that the enzyme-catalysed kinetic resolution of 6
would not be easy (vide infra: attempted resolution of
the five-membered ring analogue) we recognised that a
simple reversible Michael-type derivatisation of 6 would
serve temporarily to distinguish the topology around the
carbon atoms at positions 3 and 5. Thus to investigate
this strategy enone 6 was first reacted with benzylthiol
to give the cis-substituted compound 7 in 84% yield.
*
Corresponding author. Tel.: +44 0151 794 3501; fax: +44 0151 794
2304; e-mail: smrsm@liv.ac.uk
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.042

2808
B. S. Morgan et al. / Tetrahedron: Asymmetry 15 (2004) 2807–2809
OMe
O
O
O
O
O
ref. 10
i
ref. 6
i
OH
PhH2CS
OH
PhH2CS
OH
OH
OH
11
12
10
5
6
7
ii
ii
O
O
O
O
O
O
iii
iii
SCH2Ph
PhH2CS
PhH2CS
OH
(S,S)-12
PhH2CS
PhH2CS
(R)-13
(S)-13
OAc
OH
OH
(-)-8
(+)-7
(-)-1
Scheme 3. Reagents and conditions: (i) PhCH2SH (1equiv), Et3N
(1equiv), CH2Cl2, rt, 16h, 86%; (ii) a. vinyl acetate (5equiv),
Novozyme 435Ò, DIPE, 30°C, 16h, b. Et3N (1equiv), 1h; (iii) Ac2O
in pyridine, Et3N (2equiv) rt, 6h, 87%.
O
O
iii
iv
OAc
OH
(+)-9
(+)-1
vinyl acetate in the presence of Novozyme 435Ò then
base gave recovered (3S,4S)-alcohol (ꢀ)-12 (49% yield;
>99% ee) and 4(R)-benzylthiacyclopent-2-enone (R)-13
(43% yield; >99% ee), E >200. The (S,S)-alcohol 12
was converted into (4S)-benzylthiacyclopent-2-enone
(S)-1317 in 87% yield using acetic anhydride in pyridine.
Scheme 2. Reagents and conditions: (i) PhCH2SH (1equiv), Et3N
(0.1equiv), CH2Cl2, rt, 16h; (ii) vinyl acetate (5equiv), Novozyme
435Ò, diisopropyl ether (DIPE), 30°C, 16h; (iii) DBU (2equiv),
CH2Cl2, rt, 24h; (iv) K2CO3, MeOH, rt, 15min.
The racemic hydroxy ketone 7 was enantioselectively
esterified employing Novozyme 435Ò and vinyl acetate
to furnish optically active alcohol (+)-7 (44% yield;
>99% ee, CHPLC)10 and the ester (ꢀ)-8 (48% yield;
>99% ee),11 enantioselectivity, E >200,12 which were
readily separated by flash column chromatography.
Desulfurisation of (+)-7 was effected using 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) to give the (S)-alcohol
(S)-1 [a]D = ꢀ120 (c 1.68, CHCl3); lit.5 [a]D = ꢀ92.3 (c
1.3, CHCl3). Similarly the acetate (ꢀ)-8 was converted
into the (R)-acetoxy enone (R)-9 and thence by a litera-
ture procedure into the (R)-hydroxy enone (R)-1.4
The absolute configuration of compounds 12 and 13 was
confirmed by deprotection then thiolation of commer-
cially available (4R)-tert-butyldimethylsilyloxycyclo-
pent-2-enone 14 (Scheme 4).18
O
O
O
ii
i
OSiMe2tBu
OH
(R)-11
PhH2CS
OH
14
(R,R)-12
Scheme 4. Reagents and conditions: (i) AcOH/THF/H2O (3:1:1), rt,
48h, 75%; (ii) PhCH2SH (1equiv), Et3N (0.1equiv), CH2Cl2, rt, 16h,
88%.
We have used a related strategy to prepare both enantio-
mers of 4-benzylthiacyclopent-2-enone 13. The simplic-
ity of the protocol suggests it would be the method of
choice for the synthesis of other 4-thiacyclopent-2-
enones.
Note that in connection with this study, attempts made
to resolve racemic 11 by lipase-catalysed kinetic resolu-
tion were generally unfruitful: in our hands Aspergillus
melleus lipase-catalysed esterification of ( )-11 gave
the best, but still modest, enantioselectivity (E = 15,
conversion = 47%).
While optically active 4-hydroxy and 4-alkoxycyclopent-
2-enone (and its silylated derivatives) are well-known
intermediates (e.g., in prostaglandin synthesis),13 the
preparation of optically active 4-alkylthiacyclopent-2-
enone is much more obscure. Indeed, to our knowledge,
there is only one paper detailing the isolation of an opti-
cally active 4-thiacyclopent-2-enone (a derivative of
(1S)-10-mercaptoisoborneol).14 Even in this paper the
formation of the 4-thiacyclopent-2-enone was incidental
to the main thrust of the study.
3. Conclusion
In summary, in this study we have used Novozyme 435Ò
to perform kinetic resolutions on racemic 3-benzylthia-
4-hydroxycyclopentanone 12 and its six-membered ring
homologue 7 to afford access to both enantiomers of
4-benzylthiacyclopent-2-enone 13 and both enantiomers
of 4-hydroxycyclohex-2-enone 1, respectively. We have
also proved the concept of Michael-type addition to
4-hydroxycyclopent-2-enone and 4-hydroxycyclohex-2-
enone in order to aid kinetic resolution by altering the
substitution pattern alpha to the hydroxy group.
In order to establish a general route to the latter com-
pounds, racemic 4-hydroxycyclopent-2-enone 11 was
prepared from furfuryl alcohol 10 (Scheme 3).15
Treatment of the enone 11 with benzylthiol produced
only trans-3-benzylthia-4-hydroxycyclopentanone 12
(86% yield).16 Reaction of this racemic compound with

B. S. Morgan et al. / Tetrahedron: Asymmetry 15 (2004) 2807–2809
2809
Suzuki, J.; Noyori, R. J. Org. Chem. 1989, 54, 1785;
Dauvergne, J.; Happe, A. M.; Roberts, S. M. Tetrahedron
2004, 60, 2557; Dauvergne, J.; Happe, A. M.; Roberts, S.
M.; Jadhav, V.; Justice, D.; Matos, M. C.; McCormack, P.
J.; Pitts, M. R.; Singh, S. K.; Snape, T. J.; Whittall, J.
Tetrahedron 2004, 60, 2559.
Acknowledgements
We thank the Pro-Bio Faraday Partnership for a stu-
dentship to Ben Morgan.
References
14. Eschler, B. M.; Haynes, R. K.; Ironside, M. D.; Kremmy-
das, S.; Ridley, D. D.; Hambley, T. W. J. Org. Chem.
1991, 56, 4760.
1. Alibes, R.; de March, P.; Figueredo, M.; Font, J.;
Marjanet, G. Tetrahedron: Asymmetry 2004, 15, 1151.
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Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738.
3. Carredo, M. C.; Ruano, J. L. G.; Garrido, M.; Ruiz, M.
P.; Solladie, G. Tetrahedron Lett. 1990, 31, 6653.
4. Suzuki, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem.
2001, 66, 1494.
5. de March, P.; Escoda, M.; Figueredo, M.; Font, J.;
Garcia-Garcia, E.; Rodriguez, S. Tetrahedron: Asymmetry
2000, 11, 4473.
6. Marchand, A. P.; Xing, D.; Wang, Y.; Bott, S. G.
Tetrahedron: Asymmetry 1995, 6, 2709.
15. Typical laboratory procedure for preparation of ( )-4-
hydroxycyclopent-2-enone 11: A 3L five-necked round
bottomed flask, equipped with long air condenser, ther-
mometer pocket and a bubbler, was charged with furfuryl
alcohol (25g, 0.255mol), potassium dihydrogen ortho-
phosphate (6.3g, 0.022mol) and distilled water (1.5L).
The reaction was purged with a slow stream of nitrogen
along with paddle stirring. It was heated to 99°C for 48h.
The solution developed brown insoluble impurities during
the reaction. It was cooled to room temperature and then
washed twice with ethyl acetate. The aqueous layer was
concentrated to almost dryness under reduced pressure.
The residue was then thoroughly extracted with ethyl
acetate. The combined organic extracts were dried over
anhydrous magnesium sulfate and concentrated under
vacuum. The residue was distilled under high vacuum
using a fractionating column. Enone 11 was obtained as a
pale yellow coloured oil distilling at 95–100°C at
0.5mmHg (10.0g, 40% yield).
7. Demir, A. S.; Sesenoglu, O. Org. Lett. 2002, 4, 2021.
8. Harris, K. J.; Shih, Y.-E.; Girdaukas, G.; Sih, C. J.
Tetrahedron Lett. 1991, 32, 3941; Kazlauskas, R. J.;
Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A.
J. Org. Chem. 1991, 56, 2656.
9. Pour, M.; Negishi, E. Tetrahedron Lett. 1996, 37, 4679.
10. For compound 7: 1H NMR (400MHz, CDCl3) d 1.67–
1.77 (1H, m, CHAHB), 2.19 (1H, dddd, J = 2.0, 3.0, 7.0,
14.5Hz, CHAHB), 2.29 (1H, dddd, J = 3.0, 4.0, 7.5,
14.0Hz, CHAHB), 2.39 (1H, dddd, J = 0.75, 2.0, 5.0,
14.5Hz, CHAHB), 2.57 (1H, dd, J = 12.75, 14.5Hz,
CHAHB), 2.62–2.71 (2H, m, CHAHB and OH), 3.23 (1H,
ddd, J = 2.5, 5.0, 12.75Hz, CH), 3.74 (1H, d, J = 13.5Hz,
CHAHB), 3.81 (1H, d, J = 13.5Hz, CHAHB), 3.97–4.01
(1H, m, CH), 7.26–7.33 (5H, m, ArH); 13C NMR
(100MHz, CDCl3) 30.5 (CH2), 35.5 (CH2), 35.6 (CH2),
42.6 (CH2), 48.8 (CH), 65.2 (CH), 127.8 (CH), 129.0 (CH),
16. For compound 12: 1H NMR (400MHz, CDCl3) d 2.18
(1H, ddd, J = 1.5, 12.0, 18.5Hz, CH2), 2.27 (1H, dd,
J = 4.5, 18.5Hz, CH2), 2.39 (1H, ddd, J = 1.0, 8.0, 18.5Hz,
CH2), 2.50 (1H, dd, J = 1.25, 18.5Hz, CH2), 2.70 (1H, s,
OH), 3.28 (1H, ddd, J = 3.5, 8.25, 11.75Hz, CH), 3.76
(1H, d, J = 13.75Hz, CHAHB), 3.82(1H, d, J = 13.75Hz,
CHAHB), 4.16 (1H, apparent t, J = 3.85Hz, CH) 7.25–7.36
(5H, m, ArH). 13C NMR (100MHz, CDCl3) 213.4 (C@O),
137.7 (C), 128.9 (CH), 128.6 (CH), 127.7 (CH), 68.0 (CH),
47.1 (CH2), 46.5 (CH2), 40.3 (CH2), 35.5 (CH2). IR mmax
(neat, cmꢀ1) 3478, 3055, 2985, 2921, 2305, 1748, 1602,
1264, 735. HRMS calcd for: C12H18NO2S (CI, MNHþ4 )
requires 240.1058. Found 240.1058. White solid, mp 50–
52°C. Anal. Calcd for C12H14O2S: C, 64.86; H, 6.31.
Found: C, 64.60; H, 6.31. [a]D = ꢀ60 (S,S)-12 (c 1.0,
CHCl3).
129.2 (CH), 137.7 (C), 208.4 (CO); IR mmax (neat, cmꢀ1
3450, 3027, 2926, 1701, 1601, 1083; HRMS calcd for:
C13H20SO2N (CI, MNHþ4 ) requires 254.1215. Found
254.1217. [a]D = +5.5 (R,S)-7 (c 1.65, CHCl3).
)
11. For compound 8: 1H NMR (400MHz, CDCl3) d 1.75–
1.86 (1H, m, CHAHB), 2.15 (3H, s, CH3), 2.24–2.33 (2H,
m, CH2), 2.24–2.67 (5H, 2m, CH2), 3.00 (1H, ddd, J = 2.5,
5.0, 12.0Hz, CH), 3.75 (1H, d, J = 13.5Hz, CHAHB), 3.81
(1H, d, J = 13.5Hz, CHAHB) 5.31–5.37 (1H, m, CH),
7.21–7.33 (5H, m, ArH). 13C NMR (100MHz, CDCl3)
207.0 (C@O), 170.1 (C@O ester), 137.3 (C), 128.8 (CH),
128.6 (CH), 127.3 (CH), 68.2 (CH), 44.8 (CH), 43.3 (CH2),
35.8 (CH2), 35.4 (CH2), 28.5 (CH2), 20.9 (CH3). IR mmax
(neat, cmꢀ1) 3061, 2964, 1731, 1601, 1238; HRMS calcd
for: C14H22SO3N (CI, MNH4þ) 296.1321. Found 296.1316.
[a]D = ꢀ31.9 (S,R)-8 (c 1.074, CHCl3).
17. For compound 13: 1H NMR (400MHz, CDCl3) d 2.3 (1H,
ddd, apparent dt, J = 2.25, 19.0Hz, CH2), 2.72 (1H, ddd,
J = 2.25, 6.5, 19.0Hz, CH2), 3.76 (1H, d, J = 13.5Hz,
CHAHB), 3.82(1H, d, J = 13.5Hz, CHAHB), 3.88–3.95
(1H, m, CHS), 6.15–6.21 (1H, m, CHolefinic) 7.21–7.38 (5H,
m, ArH), 7.41–7.44 (1H, m, CHolefinic). 13C NMR
(100MHz, CDCl3) 207.5 (C@O), 163.6 (C@C), 137.9
(C), 134.9 (CH), 129.3 (CH), 129.2 (CH), 127.9 (C@C),
43.7 (CH), 43.0 (CH2), 36.0 (CH2). IR mmax (neat, cmꢀ1
)
3059, 3027, 2918, 1950, 1713, 1658, 1581, 699. HRMS
calcd for: C12H13SO (CI, M+) requires 205.06873. Found
205.06852. Compound (S)-13 [a]D = +178 (c 1.0, CHCl3);
(R)-13 [a]D = ꢀ178 (c 1.0, CHCl3).
12. Chen, C.-S.; Fujimoto, G.; Sih, C. J. J. Am. Chem. Soc.
1982, 104, 7294.
13. Noyori, R.; Suzuki, M. Angew. Chem., Int. Ed. Engl. 1984,
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18. The silyl compound 14 is available from StylaCats Ltd,
Runcorn, U.K.