Enzymatic kinetic resolution of 1,1-dioxo-2,3-dihydro-1H-1λ6-thiophen-3-ol via temporary derivatisation

Article abstract of DOI:10.1016/j.tetlet.2006.05.153

Following the thio-conjugate addition of (±)-9, its enantiomers were extremely efficiently discriminated using Novozym 435. The thio-differentiating unit may then be removed either under reductive conditions, using Raney nickel, or following an

Full text of DOI:10.1016/j.tetlet.2006.05.153

Tetrahedron Letters 47 (2006) 5273–5276
Enzymatic kinetic resolution of 1,1-dioxo-2,3-dihydro-
1H-1k6-thiophen-3-ol via temporary derivatisation
Ben S. Morgan,a Stanley M. Robertsb and Paul Evansc,*
aDepartment of Chemistry, Liverpool University, Liverpool L69 7ZD, United Kingdom
bCoEBio3, University of Manchester, Faraday Building, Manchester M60 1QD, United Kingdom
cCentre for Chemical Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,
University College Dublin, Dublin 4, Ireland
Received 4 April 2006; revised 15 May 2006; accepted 24 May 2006
Abstract—Following the thio-conjugate addition of ( )-9, its enantiomers were extremely efficiently discriminated using Novozym
435ꢀ. The thio-differentiating unit may then be removed either under reductive conditions, using Raney nickel, or following an oxi-
dation–elimination sequence. In this manner enantioenriched derivatives of 1,1-dioxo-2,3-dihydro-1H-1k6-thiophen-3-ol 9 may be
accessed.
ꢁ 2006 Elsevier Ltd. All rights reserved.
We have recently reported that cyclic conjugated alke-
nols (of the type 1, where n = 1 or 2) undergo highly effi-
cient enzymatic kinetic resolution once the electron poor
alkene has undergone conjugate addition with a thiol.1
This observation was of interest since reports,2 corrobo-
rated by us,1 indicated that the direct enzymatic kinetic
resolution of this type of cyclic allylic alcohol was not an
efficient process, affording 2 and 3 with low levels of
enantioselectivity. The likely explanation for this
observation is that the sp2 and sp3 hybridised carbon
units flanking the stereogenic centre possess similar
spatial requirements. Thus, following the syn-selective
conjugate addition of benzyl thiol to 4-hydroxycyclo-
pent-2-enone 1, extremely efficient resolution (E >
200) of ( )-4 was realised using Novozym 435ꢀ (Scheme
1).1
O
O
O
O
Novozym 435®
RSH
n
n
n
n
+
enzymatic kinetic
resolution
conjugate
addition
HO
HO
HO
SR
AcO
SR
SR
( )-1
( )-5
( )-4
(+)-4
n = 1, 2 etc.
retro-conjugate
addition
[- RSH]
O
O
O
O
O
+
n
n
n
n
SR
HO
AcO
(+)-6
AcO
HO
2
3
Scheme 1. Temporary derivatisation for the enzymatic kinetic resolution of cyclic alkenols.
Keywords: Enzymatic kinetic resolution; Cyclic sulfone; Temporary derivatisation.
*
Corresponding author. E-mail: paul.evans@ucd.ie
0040-4039/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.153

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B. S. Morgan et al. / Tetrahedron Letters 47 (2006) 5273–5276
O2
S
O2
S
O2
S
O2
S
δ
δ
(a) NBS, H2O;
BnSH, cat. Et3N,
CH2Cl2, 82%
O
H
R
+
O
O
S
H
S
(b) Et3N, THF, 54%
OH
BnS
OH BnS
OH
7
syn:anti; 2:1
( )-9
( )-syn-10
( )-anti-10
O2
S
O2
S
O2
Novozym 435®
Novozym 435®
S
( )-syn-10
( )-9
+
vinyl acetate, MeCN,
vinyl acetate, MeCN,
rt, 16 h
OAc
( )-12, 100%
BnS
OH BnS
OAc
rt, 16 h
(+)-10, 46%
( )-11, 43%
Scheme 2. Enzymatic kinetic resolution of ( )-syn-10.
In this series (n = 1) we were unable to remove the sulfur
unit in a retro-conjugate addition sense to regenerate the
now enantioenriched 4-substituted cyclic compound,
since the elimination of acetic acid, generating (+)-6,
occurred more readily. However, in the six-membered
series (n = 2) we managed to perform this transformation
embodying our temporary tetrahedralisation-enzymatic
resolution concept. The extension of this sequence for
the preparation of both enantioenriched cyclic alkenols
and alkanols possessing a sulfonyl functional group is
the subject of this letter.
The relative stereochemistry of the major diastereo-
isomer, isolated by flash column chromatography, was
confirmed by X-ray crystallography.7 It seems plausible
that the hydroxyl-substituent serves to overcome steric
barriers to this addition process by hydrogen bonding.
This hypothesis was corroborated by the observation
that in polar solvents, capable of perturbing the pro-
posed hydrogen bonding, significantly more of the
anti-diastereomer was observed. For example, when
the reaction was carried out in MeOH/Et3N, a reversal
in stereochemical preference was observed (syn-( )-
10:anti-( )-10; 1:2). The major diastereoisomer ( )-
syn-10 was treated with Novozym 435ꢀ and vinyl ace-
tate (5 equiv) in acetonitrile and after 16 h, the crude
products were separated in good yield following flash
column chromatography.8 Chiral HPLC analysis
indicated that both acetate (ꢀ)-11 and the unreacted
starting material (+)-10 were highly enantioenriched
(ee > 98%). Acetate (ꢀ)-11 was isolated and proved
not to undergo the facile loss of acetic acid (generating
the vinyl sulfone) as observed in the corresponding
cyclopentanone series (see Scheme 1). As a means of
comparison, under the same conditions ( )-9 underwent
complete conversion into the corresponding racemic
acetate ( )-12. This observation contrasts the behaviour
of acyclic hydroxyl-substituted vinyl sulfones, which
have been reported to undergo efficient enzymatic
kinetic resolution.9
Cyclic five-membered sulfones possessing both unsatu-
ration and saturation have been employed as structural
components in target molecules3 and as synthetic build-
ing blocks.4 In a wider sense, the sulfone unit has found
widespread use in the preparation of complex synthetic
targets and many methods for the derivatisation of sulfo-
nyl-containing molecules exist.5
The synthesis of ( )-9 was accomplished following a
literature method involving the conversion of butadiene
sulfone 7 into bromohydrin 8 (see Scheme 4), which was
then subjected to base mediated dehydrobromination
using triethylamine (Scheme 2).6 This compound under-
went syn-selective conjugate addition, albeit with less
stereoselectivity than in the corresponding ketone
series,1 affording the diastereomeric conjugate adducts 10.
O2
S
O2
S
O2
S
O2
S
NaIO4
Raney Ni,
LiOH(aq),
EtOH, 88%
EtOH, 96%
THF, 94%
BnS
OAc
OAc
OH
OAc
(+)-12
( )-11
( )-13
( )-14
H2, Pd/C, EtOH, 100%
O2
S
O2
S
O2
S
O2
S
Raney Ni,
EtOH, 95%
Ac2O, pyr,
100%
Ac2O, pyr,
100%
BnS
OH
OH
(+)-14
OAc
(+)-13
BnS
OAc
(+)-11
(+)-10
[α]D +15.1 (c 1.12, CHCl3);
ref. 12 [α]D +14.2 (c 1.12, CHCl3)
Scheme 3. Desulfurisation of the enantioenriched conjugate adducts (+)-10 and (ꢀ)-11.

B. S. Morgan et al. / Tetrahedron Letters 47 (2006) 5273–5276
5275
References and notes
(a) Novozym 435®,
vinyl acetate, MeCN;
O2
S
O2
S
O2
S
+
1. Morgan, B. S.; Hoenner, D.; Evans, P.; Roberts, S. M.
Tetrahedron: Asymmetry 2004, 15, 2807; Bickley, J.; Meek,
A.; Morgan, B. S.; Evans, P.; Roberts, S. M. Tetrahedron:
Asymmetry 2006, 17, 355.
Br
OH
OH
( )-9, 47%
OAc
(+)-12, 46%
(b) Et3N, THF
( )-8
2. Ghorpade, S. R.; Bastawade, K. B.; Gokhale, D. V.;
Shinde, P. D.; Mahajan, V. A.; Kalkote, U. R.; Ravindra-
nathan, T. Tetrahedron: Asymmetry 1999, 10, 4115.
3. (a) Ghosh, A. K.; Kincaid, J. F.; Cho, W.; Walters, D. E.;
Krishnan, K.; Hussain, K. A.; Koo, Y.; Rudall, C.;
Holland, L.; Buthod, J. Bioorg. Med. Chem. Lett. 1998, 8,
687; (b) Ghosh, A. K.; Kincaid, J. F.; Walters, D. E.;
Chen, Y.; Chauduri, N. C.; Thompson, W. J.; Culberson,
C.; Fitzgerald, P. M. D.; Lee, H. Y.; Munson, P. M.;
Duong, T. T.; Darke, P. L.; Schlief, W. A.; Axel, M. G.;
Lin, J.; Huff, J. R. J. Med. Chem. 1996, 39, 3278.
4. (a) Martin, S. F.; Anderson, B. G.; Daniel, D.; Gaucher,
A. Tetrahedron 1997, 53, 8997; (b) Martin, S. F.; Daniel,
D. Tetrahedron Lett. 1993, 34, 4218; (c) Nicolaou, K. C.;
Vassilikogiannakis, G.; Ma¨gerlein, W.; Kranich, R.
Angew. Chem. Int. Ed. 2001, 40, 2482; (d) Nicolaou, K.
C.; Vassilikogiannakis, G.; Ma¨gerlein, W.; Kranich, R.
Chem. Eur. J. 2001, 7, 5359.
Scheme 4. Kinetic enzymatic resolution of bromohydrin ( )-8.
We then sought methods to remove the thiol unit. In this
context two strategies were investigated; namely, the
reductive Raney nickel cleavage of the sulfide bond in
the presence of the sulfonyl moiety,10 and the oxidative
Cope-type elimination of sulfenic acid.11 For example,
(ꢀ)-11 was converted into vinyl sulfone (+)-12 in one-
pot following treatment with NaIO4. Pleasingly, the
sulfide unit was also effectively removed using Raney
nickel, in this instance generating the saturated sulfone
(ꢀ)-13. The enantiomeric series may be accessed in a
similar fashion, and opposite optical rotations were
observed (Scheme 3).
5. Simpkins, N. S. Sulphones in Organic Chemistry; Perga-
mon Press: Oxford, 1993.
6. Sammes, P. G.; Ellis, F. J. Chem. Soc., Perkin Trans. 1
1972, 2866.
The absolute configuration of (+)-14 was confirmed by
comparison of the optical rotation value with that of
the identical compound accessed from the chiral pool.12
This also served to prove the sense of stereoselectivity
for the enzymatic step—which, gratifyingly, is the same
as that observed for the cyclopentanone series using
Novozym 435ꢀ.1
7. CCDC reference number 603497.
8. In a 100 mL conical flask a mixture of ( )-syn-10 (0.234 g,
0.85 mmol, 1 equiv), Novozym 435ꢀ (0.234 g, 1:1 w/w
enzyme:substrate), vinyl acetate (0.39 mL, 4.23 mmol,
5 equiv) and acetonitrile (25 mL) was shaken for 16 h
(200 rpm, 30 ꢂC). The reaction was decanted and the
enzyme rinsed with acetonitrile (6 · 20 mL). The com-
bined MeCN washings were concentrated under reduced
pressure and the residue purified by column chromato-
graphy (1% MeOH in CH2Cl2) to give (ꢀ)-11 (0.11 g, 43%,
Rf = 0.4) and (+)-10 (0.105 g, 46%, Rf = 0.1). Data for
compound (+)-10 1H NMR (400 MHz, CDCl3) d 2.73
(1H, s, OH), 3.09–3.20 (3H, m, 3 · CHAHB), 3.38 (1H, d,
J = 14.0 Hz, CHAHB), 3.46 (1H, ddd, J = 2.75, 7.5,
12.5 Hz, CHS), 3.80 (1H, d, J = 13.75 Hz, CHAHB), 3.85
(1H, d, J = 13.75 Hz, CHAHB), 4.19–4.24 (1H, m,
CHOH), 7.29–7.39 (5H, m, ArH). 13C NMR (100 MHz,
CDCl3) 137.2 (C), 129.2 (CH), 128.9 (CH), 128.5 (CH),
68.9 (CHOH), 59.9 (CH2), 53.0 (CH2), 46.9 (CHS), 36.2
(CH2). IR mmax (neat/cmꢀ1) 3454, 1453, 1311, 1123, 90þ6,
Following these successful studies, a more expedient
method, utilising the same concept, was investigated
for the two-step preparation of enantioenriched (ꢀ)-9
and (+)-12 (Scheme 4). Thus, ( )-8 was treated with
the lipase enzyme under identical conditions described.8
After 16 h, NMR spectroscopic analysis indicated
approximately 50% conversion (this value did not alter
significantly after five days). The crude materials were
then filtered and MeCN was exchanged for THF before
treatment with base to effect dehydrobromination. Thus,
the enantioenriched vinyl sulfones were separated fol-
lowing flash column chromatography.
731. HRMS calcd for: C11H18O3S2N (CI, M þ NH4
)
In summary, using our temporary-tetrahedralisation
concept, we have accessed efficiently both enantiomers
of a group of interesting sulfonyl-containing hetero-
cycles that have been used as building blocks and struc-
tural components of pharmacologically useful molecules.
For example, (+)-14 has been used as a structural com-
ponent in a nanomolar HIV-protease inhibitor related
to amprenavir.3a Previous syntheses of this type of enan-
tioenriched compound have followed lengthy synthetic
sequences from the chiral pool,12,13 or from a novel
desymmetrisation.14 The latter approach, however, cur-
rently suffers from low enantiomeric excesses.
requires 276.07281: found 276.07253. [a]D +25.5 c 1.12,
1
CHCl3. Data for compound (ꢀ)-11 H NMR (400 MHz,
CDCl3) d 2.16 (3H, s, CH3), 3.16 (2H, d, J = 10.0 Hz,
CHACHB), 3.32 (2H, m, CHACHB), 3.43 (1H, ddd,
J = 3.5, 10.0, 13.5 Hz, CHS), 3.78 (1H, d, J = 13.5 Hz,
CHAHB), 3.83 (1H, d, J = 13.5 Hz, CHACHB), 5.50–5.54
(1H, m, CHOAc), 7.28–7.37 (5H, m, ArH). 13C NMR
(100 MHz, CDCl3) 170.0 (CO), 137.1 (C), 129.4 (CH),
129.1 (CH), 128.3 (CH), 71.4 (CHOAc), 59.2 (CH2), 54.8
(CH2), 44.1 (CHS), 36.7 (CH2), 21.1 (CH3). IR mmax (neat/
cmꢀ1) 3054, 1749, 1421, 1265, 1125, 896, 738, þ704. HRMS
calcd for: C13H20O4S2N (CI, M þ NH4
) requires
318.08337: found 318.08356. [a]D ꢀ41.1 c 1.12, CHCl3.
HPLC analysis; Daicel AD (B 0.46 cm · 0.25 cm, UV
254 nm), 100% EtOH, 0.3 mL/min; (ꢀ)-11 tr = 20.59 min
(>98% ee); (+)-10 tr = 41.7 min (>98% ee).
Acknowledgements
´
9. Domınguez, E.; Carretero, J. C. J. Org. Chem. 1992, 57,
We wish to acknowledge the receipt of a ProBio scholar-
ship (B.M.) and to thank Dr. Tom McCabe (Trinity
College, Dublin) for X-ray crystallography.
3867.
10. For a review of the use of Raney nickel in desulfurisation
reactions, see: Pettit, G.; van Tamelen, E. E. Org. React.

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B. S. Morgan et al. / Tetrahedron Letters 47 (2006) 5273–5276
`
1962, 12, 356; For the reduction of a sulfonyl group using
Raney nickel, see: Brimble, M. A.; Rush, C. J. J. Chem.
Soc., Perkin Trans. 1 1994, 497.
13. Arcelli, A.; Cere, V.; Peri, F.; Pollicino, S.; Sabatino, P.
Tetrahedron: Asymmetry 2000, 11, 1389.
14. (a) Horcajada, R.; Groombridge, H. J.; Mandalia, R.;
Motevalli, M.; Utley, J. H. P.; Wyatt, P. B. Chem.
Commun. 2004, 412; (b) Alonso, A. M.; Horcajada, R.;
Motevalli, M.; Utley, J. H. P.; Wyatt, P. B. Org. Biomol.
Chem. 2005, 3, 2842.
11. (a) Oppolzer, W. A.; Snowden, R. L.; Briner, P. H. Helv.
Chim. Acta 1981, 64, 2022; (b) Bartlett, P. A. J. Am. Chem.
Soc. 1976, 98, 3305.
12. Kielbasinski, P.; Albrycht, M.; Mikolajczyk, M.; Wiecz-
orek, M. W.; Majzner, W. R.; Filipczak, A.; Ciolkiewicz,
P. Heteroatom Chem. 2005, 16, 93.