AN EFFICIENT PREPARATION OF OPTICALLY ACTIVE (E)-γ-HYDROXY-α,β-UNSATURATED PHENYL SULFONES USING LIPASE-MEDIATED ACYLATIONS

Article abstract of DOI:10.1016/S0040-4039(00)93455-5

(E)-γ-Hydroxy-α,β-unsaturated phenyl sulfones have been efficiently resolved via irreversible enzymatic acylation with Lipase PS (Pseudomonas cepacia) and vinyl acetate.This process has been applied to the synthesis of the aggregation pheromone (-)-(3S,4S)-4-methyl-3-heptanol.

Full text of DOI:10.1016/S0040-4039(00)93455-5

Tetr~hedron Letters, Vo1.32, No.38, pp 5159-5162, 1991
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Pergamon Press plc
AN EFFICIENT P R E P A R A T I O N OF O P T I C A L L Y ACTIVE (E)-Y-HYDROXY-a,I]-UNSATURATED
P H E N Y L S U L F O N E S U S I N G LIPASE-MEDIATED A C Y L A T I O N B
Esteban DomfnguezI, Juan Carlos Carretero1*, Alfonso Fern~tndez-Mayoralas z
and Santiago Conde3.
tDepartamento de Qufrnica (C-I). Facultad de Ciencias. Universidad Aut6noma. Cantoblanco.
28049-Madrid. Spain. z I n s t i t u t o de Qufmica Orgz~nica. CSIC. Juan de la Cierva 3. 28006
Madrid. 3Instituto de Qufmica Medica. CSIC. Juan de la Cierva 3. 28006 Madrid. Spain.
Abstract: (E)-Y-Hydroxy-a,13-unsaturated
phenyl sulfones have been efficiently resolved
via irreversible enzymatic acylation with lipase PS (pseudomonas cepacia) and vinyl
acetate. This process has been applied to the synthesis of the aggregation
(-)-(3S,4S)-4-meth yl-3-heptanol.
pheromone
The a,13-unsaturated sulfonyl moiety is a very versatile functionality 1 that allows
the formation of two C-C bonds by Dials-Aider reaction or by conjugated addition followed
by alkylation (or acylation) of the resulting a-sulfonylcarbanion. The sulfonyl group can
be furthermore removed either through
a reductive procedure or by elimination. In
particular Y-hydroxy-a,8-unsaturated sulfones have an array of functionality which can
be potentially used in many synthetic ways. Thus, the stereoselective conjugated addition
of organometallics to cyclic and acyclic derivatives of Y-hydroxy-a,B-unsaturated sulfones
has been widely studied by Fuchs'z and Isobe's3 groups respectively and it has been
applied to the synthesis of natural products. Hence, methods for the preparation of these
hydroxysulfones in enantiomerically pure form are of great importance in asymmetric
synthesis. These methods are mainly the Paterson olefination with homochiral a-
alkoxyaldehydes4 and the enantioselective reduction of B-sulfonylenoness.
Recently, we have reported a practical method to the synthesis of racemic (E)-Y-
hyd roxy-a,g-u nsatu rated
phenyl
sulfones
(2)
by
condensation
of
p-tolylsulfinyl
phenylsulfonyl methane (1) with enotizable aldehydes°. However, attempts to obtain
enantiomerically pure compounds 2 from homochiral sulfoxide (S)-I failedeb (scheme 1). We
report herein that racemic alcohols 2 can be efficiently resolved via irreversible lipase-
mediated acylation7 in organic media8,
OH
P h S O 2 ~ S ~ T o I Jr
(S)-I
R
v C H O
~
P h S 0 2 ~ / ~ " - R
7 0 - 8 8 %
2
Scheme 1
(ref. 6b)
e.e. =10-50'%
5159

5160
Screening experiments were made with ( E ) - 4 - p h e n y l s u l f o n y l - 3 - b u t e n - 2 - o l (2a, R=Me)
u s i n g d i f f e r e n t lipases and acylating reagents. Out of the e i g h t commercially available
lipases9 and the t h r e e acylating reagents (2-chloroethyl butyrate, b u t y r i c a n h y d r i d e and
v i n y l acetate) tested, the combination of lipase PS (pseudomonas cepacia, Amano) and
v i n y l acetate gave the best results. When u s i n g d i i s o p r o p y l e t h e r as solvent, this lipase
(25 m g / m l ) catalyzed in 5.5 h o u r s the enantioselective acylation of 2a (50 mM) by v i n y l
acetate (5 equiv.). The presence in the reaction of molecular sieves is essential in o r d e r
to reach the 50% conversion10. The r e s u l t i n g acetate and the unreacted alcohol were
readily separated
by flash chromatography o b t a i n i n g both
in 47% and 46% yield
respectively. The absolute stereochemistry (S) and the optical p u r i t y of the unreacted
alcohol 2a (>98% e.e.) was determined by 1H-NMR analysis of its Mosher e s t e r (MTPA)
derivative 11, whereas the enantiomeric excess of the acetate 3a (>95% e.e.) was determined
by 1H-NMR u s i n g Pr(hfc)3 as c h i r a l s h i f t reagent. Therefore the enantiomeric ratio (E)~z
of this lipase-mediated acylation was excellent (E >100).
OH
OH
OAc
"R
PhSO 2
R
PhSO 2
R
Jr
PhSO2"
v
A c O f ~ , iPr20~
2
(S)
-
2
(R)
-
3
Table 1
Unreacted alcohols
2
( c o n f . )
Product acetates
3
( c o n f . )
Entry
R
time (h)a
e.e.%b yield%c [a]~o
n
e.e.%e
yield%c [a]~o
d
Ef
a
b
c
Me
Et
5.5
3.5
62
2a >98 (S)
2b >98 (S)
46
49
46
48
48
+42.9
+45.3
+48.9
+44.4
-3.8
3a >95 (R)
3b >95 (R)
3c >95 (R)
3d >95 (R)
3e >95 (R)
47
49
48
47
47
+17.5
+16.7
+10.1
+5.7
>100
>i0 n
>100
>100
>100
iPr
2c
2d >98 (S)
2e 88 (S)
94 (S)
d
e
n-Hex
10
BnOCHzCHz 169
+11.2
a
All reactions were performed at 50 mmol concentration of substrates 2, at r . t . , u s i n g
25 mg/ml ~ f the enzyme, e q u i v , of v i n y l acetate and 50 mg/ml of powdered molecular
sieves (4A). Determined by IH-NMR analysis of the Mosher e s t e r (MTPA) d e r i v a t i v e 11.
In pure product a f t e r f l a s h chromatography, c=I, CHCI3. Determined by IH-NMR using
0 . 1 - 0 . 3 e q u i v , of P r ( h f c ) 3 . Enantiomeric r a t i o calculated according to ref. 12. Due
to the poor s o l u b i l i t y of 2e in i p r 2 0 the reaction was run in toluene.
5
b
c
d
•
f
9
In
a
next stage, these optimized enzymatic acylation c o n d i t i o n s were applied to
o t h e r substrates in o r d e r to explore the scope of the resolution of Y-hydroxy-o,13-
unsaturated p h e n y l sulfones by lipase PS. These results are shown in table 1. it is
h i g h l y noteworthy that with the five s t u d i e d alcohols
high enantioselectivity (E values >100), excellent y i e l d s and reasonable rates, the (R)
enantiomer being much more reactive in all cases11. The high enantiomeric p u r i t i e s
and b) and long linear c h a i n s (entries and e),
resolution c o u l d be applied to wide r a n g e of
a-branched chain ( e n t r y c, R=iPr) has
2 the process o c c u r s with very
achieved, with both s h o r t (entries
suggest that this lipase-mediated
a
R
d
a
substrates 2. Thus, even compound 2c with
a
R

5161
been satisfactorily resolved13 (E >100). E n t r y
e
is particularly important because the
functionalized chain in the resolved alcohol (S)-2e or in the acetate (R)-3e could be
R
easily manipulated to elaborate complex side chains for
applications.
a
wide range of synthetic
A
chemical correlation from enantiomerically pure alcohol (S)-2b to the aggregation
pheromone (-)-(3S,4S)-4-methyl-3-heptano114
(6) was made (scheme 2) in o r d e r to p r o v e
unequivocally the (S)-stereochemistry of the unreacted alcohols 2. This stereochemistry
had been initially established from the 1H-NNR data of t h e i r Mosher's esters11 and by
comparation with the optical rotation values of related homochiral hydroxysulfonesSb,i
The alcohol 2b was initially converted into the corresponding methoxymethyl ether, which
was metallated with n-BuLl in THF at -78°(3 and then silylated (TNSCl) to give
overall yield TM. Compound was readily transformed into sulfone 5 (9296 yield) via highly
syn-stereoselective conjugated addition of NeLl in Et20 at -78oc (syn:anti= >98:2)TM and
f u r t h e r desilylation with KF. Finally, afforded the enantiomerically pure aggregation
4 in 8096
4
5
pheromone (-)-616, in 7096 yield, by the straightforward t h r e e s t e p s sequence: ethylation
of the a-sulfonylcarbanion of 5 (n-BuLl, then IEt), acidic hydrolysis of the acetal moiety
and reductive elimination of phenylsulfonyl g r o u p (Na-Hg, NEON).
OH
TMS
OMOM
OMOM
OH
( S ) - Z b
4
5
8
®=PhS02
S c h e m e
2
a
CHz(ONe)2, Pz05, r.t., 2h.
b
n-BuLl (I.1 eq.), THF, -78°C, 30 min,
KF (10 eq.), NeOH, r.t., lb.
(1.1 eq.), T H F - H M P A , -78°C, 30 rain; then Etl (4 eq.), r.t., 12h. HOt (6N), NeOH-HzO, r.t.,
5h. Na(Hg) 696, Na2HP04, NEON, r.t., 22h.
then T M S C l (4 eq.),
-78°C, 2h.
¢
NeLl (1.1 eq.), Et20, -78°C, 30 rain.
e
e
n-BuLi
f
s
In summary, the lipase-catalyzed acylation of racemic Y-hydroxy-a,13-unsaturated
phenyl sulfones (2) with v i n y l acetate, in diisopropyl ether, in the presence of lipase PS
(pseudomonas cepacia) occurs with very high enantioselectivity and excellent yields.
F u r t h e r experiments for the determination of the scope and limitations of this reaction
and applications of (S)-2 and (R)-3, as chiral building blocks, in asymmetric synthesis are
now in progress.
Typical procedure for the lipase-mediated acylation of compounds 2:4.60 ml of v i n y l
acetate (5 eq.),
to solution of 2.26
shaken at r.t. and monitored by G.C. A f t e r 3.5
enzyme. The solvent was evaporated and the residue was then chromatographed (hexane-
ethyl acetate 3:1). 1.13 (4996) of (S)-2b and 1.34 (4996) of (R)-3b were obtained.
5
g
of lipase PS and 10
of racemic 2b in 200 ml of iPr~3. The resulting suspension was
the reaction was stopped by filtering
g of powdered molecular sieves (4A) were added
a
g
h
g
g
Acknowledgement. Support of this research by Rh6ne-Poulenc Farma S.A.E. was greatfully
acknowledged.

5162
References and notes
1.- For
a
recent review ~ee "The chemistry of Vinylsulphones", Simpkins N.S. Tetrahedron
1990, 46, 6951.
2.- a) Hamann, P.R.; Fuchs, P.L.J. Org. Chem. 1983, 48, 914. b) Burkholder, T.P.; Fuchs, P.L.
J. Am. Chem. Soc. 1990, 119, 9601 and references cited therein.
3.- Isobe, H; Perspectives ~n the Organic Chemistry of Sulfur, (ed. by Zwanembourg, 8. and
Klande, A,J.H.) Studies in Organic Chemistry 1987, 28, 209 and references cited therein.
4.- Isobe, N; Ichikawa, Y; M!o, S.; Gore, T. Tetrahedron 1986, 42, 2863.
5.- a) Trost, B.M.; Seoane, P.; Hignani, S.; Acemoglu, N. J. Am. Chem. Soc. 1989, 111, 7487.
b) Corey, E.J.; Bakshi, R.K. Petrahedron Lett. 1990, 31, 611.
6.- a) Dom~nguez, E.; Carr~tero, J.C.
Tetrahedron Lett., 1990, 31, 2487. b) Domfnguez, E.;
Carretero, J.C. Tetrahedron/1990, 46, 7197.
t
7.- An example of a p a r t i ~ enzymatic-catalyzed resolution of
aryl sulfone, mediated porcine pancreatic lipase (PPL), has been recently reported:
Chinchilla, R.; Najera, Yus, M. Tetrahedron Asymmetry 1990, 1, 575.
a
Y-hydroxy-a,B-unsaturated
~
~
8.- For a recent review see "Asymmetric Transformations Catalyzed by Enzymes in Organic
Solvents", Klibanov, A.M. Acc. Chem. Re& 1990, 23, 114.
9.- Tested lipases were described as follows: porcine pancratin lipase (PPL, Sigma), candida
ci/indracea lipase (CCL, Sigma), mucor miehei lipase (Amano), geotrictium candidum lipase
(lipase GC, Amano), rhizopus arrhizus lipase (Fluka), penici/lium roqueforti lipase (lipase R,
Amano), candida cilindracea lipase (lipase AY, Amano) and pseudomonas cepacia lipase (lipase
PS, Amano).
10.- The use of molecular sieves in lipase-mediated resolutions of alcohols has been
previously reported. For instance see: Burgess, K; Jennings, L.D. J. Am. Chem. Soc. 1990,
112, 7434.
11.- Dale, J.A.; Nosher, M.S. J. Am. Chem. Soc. 1973, 95, 512. According to this reference,
the chemical shifts (values in CDCI3) of both olefinic protons in the diastereomeric pair of
(R)-MTPA esters derived from alcohols
2 have been used as a criterium for sterochemical
assignment. Diestereomer R,R: 6=6.92-6.95 (S-C=CH) and 6.30-6.39 ppm (S-CH=C). Diastereomer
S,R: 5= 6.87-6.89 (S-C=CH) and 6.11-6.14 ppm (S-CH=C).
12.- Chen, C.S.; Fufimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294.
13.- This result is in contrast with the recently reported in the enzymatic resolution of
Y-hydroxy-e,B-unsaturated methyl esters mediated by pseudomonas K-IO (Burgess, K.;
Henderson, I. Tetrahedron: Asymmetry 1990, 1, 57). These authors noticed that when R is ~Pr
the enantioselectivity of the process was poor (E=1.6) and reversed (S enantiomer more
reacti re).
14.- (-)-4-Methylhepten-3-ol (6) is
a
beetle-produced pheromone responsible for the
aggregation of the smaller european elm bark beetle, Scolytus hfultistriatus hfarsham. For
previous syntheses see: a) Mori, K. Tetrahedron 1977, 33, 289. b) Hori, K.; Iwasawa H.
Tetrahedron 1980, 36, 2209.
15.- Alcaraz, C.; Carretero, J.C.; Domfnguez, E. Tetrahedron Lett. 1991, 32, 1385.
16.- lit14. [a]~0=-21.7 (n-hexane); found [a]~o=-23.0 (n-hexane, c=1). All spectral data were
identical.
(Received in UK 17 May 1991)