Enantioconvergent access to the enantiomerically pure building blocks (+)-or (-)-4-hydroxy-3-methyl-2-cyclohexenone using a chemoenzymatic process

Article abstract of DOI:10.1055/s-2006-926258

A convenient chemoenzymatic enantioconvergent access to enantiomerically pure (+)- or (-)-4-hydroxy-3-methyl-2-cyclohexenone is described using a one-pot two-step kinetic resolution-stereoinversion protocol followed by hydrolysis. The key step of the sequ

Full text of DOI:10.1055/s-2006-926258

LETTER
403
Enantioconvergent Access to the Enantiomerically Pure Building Blocks (+)-
or (–)-4-Hydroxy-3-methyl-2-cyclohexenone Using a Chemoenzymatic Process
S
ynthesis of (+)
l
-
or (–)
i
-4-Hyd
e
roxy-3-methyl-2-
P
cyclohexenon
a
e
lombo, Gérard Audran,* Honoré Monti*
Laboratoire de Réactivité Organique Sélective, U.M.R. 6180 ‘Chirotechnologies: catalyse et biocatalyse’, Université Paul Cézanne,
Aix-Marseille III, 13397 Marseille Cedex 20, France
Fax +33(4)91288862; E-mail: g.audran@univ.u-3mrs.fr; E-mail: honore.monti@univ.u-3mrs.fr
Received 7 December 2005
O
Abstract: A convenient chemoenzymatic enantioconvergent ac-
cess to enantiomerically pure (+)- or (–)-4-hydroxy-3-methyl-2-cy-
clohexenone is described using a one-pot two-step kinetic
resolution–stereoinversion protocol followed by hydrolysis. The
key step of the sequence is the spontaneous elimination of an undes-
ired stereocenter. The choice between enzymatic acyl transfer or es-
ter alcoholysis of the corresponding racemic starting material,
together with the selectivity of a lipase, determines the absolute
configuration of the desired single enantiomer.
O
O
HO
HO
O
OH
H
chapinolin
elegansidiol
O
Key words: enantioconvergence, biocatalysis, kinetic resolution,
stereoinversion, chiral building blocks
A great variety of natural products contain structural units
related to 4-hydroxy-3-methyl-2-cyclohexenone (1,
Figure 1). Some examples are chapinolin,1 elegansidiol,2
cordiaquinone C3 or pouosides.4
O
O
cordiaquinone C
R1
In the course of our work directed towards the enantiose-
lective synthesis of natural products or their intermediates
containing such a scaffold,5 we described the enzymatic
kinetic resolution of racemic 1,5a which was the key build-
ing block of our approaches (Scheme 1).
GalβO
O
OR2
OAc
HO
pouosides
In spite of its efficiency, the most striking limitations of
this procedure were the maximum theorical yield of 50%
of each enantiomer and chromatographic separation of the
intermediate resolution products. Moreover, in kinetic
resolutions,6,7 half of the starting material has the wrong
absolute configuration for certain purposes. In order to
circumvent these drawbacks, approaches have been de-
veloped which render an enantioconvergent process de-
livering a single enantiomeric product in 100% theoretical
yield.8 Among them, one of the widely employed is the in
situ selective inversion of one enantiomer via a chemoen-
zymatic protocol.8b,e,g,9 Using this technique, both deriva-
tives must be obtained at a maximum of enantiomeric
excess and the point to stop the kinetic resolution has to be
carefully chosen. Depending on the enantioselectivity, the
latter is usually close to or slightly beyond 50%.10 We
therefore decided to reinvestigate our resolution proce-
dure to determine if a more efficient kinetic resolution fol-
lowed by a stereoinversion could be employed in order to
obtain 100% of the desired isomer. Lipases distinguish
between enantiomeric secondary alcohols primarily by
HO
O
R
S
O
(+)-1
( )-1
Figure 1
comparing the size of the two substituents,6,11 so we
intended to increase the enantioselectivity of the lipase-
catalyzed deracemization described in Scheme 1 by mod-
ifying the substrate to increase the size of one substituent.
For this purpose, the starting material was ( )-cis-3,4-di-
hydroxy-3-methyl-cyclohexanone (2) obtained in 80%
yield by standard osmylation (cat. OsO4, NMO, t-BuOH–
H2O, 9:2) of readily available 3-methyl-3-cyclohexenone
(m-methylanisole, Birch reduction).12
Our strategy is described in Scheme 2. A one-pot reaction
sequence could be envisaged wherein a highly enantio-
selective kinetic resolution of racemic diol 2 (or mono-
acetate 3 for the final reverse enantioselectivity) would be
followed by an efficient MsCl/Et3N-mediated in situ me-
sylation–spontaneous elimination of the tertiary hydroxyl
group to afford 4 and 5 with opposite configurations.
SYNLETT 2006, No. 3, pp 0403–0406
1
5.
0
2.
2
0
0
6
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-926258; Art ID: G37205ST
© Georg Thieme Verlag Stuttgart · New York

404
E. Palombo et al.
LETTER
(30 mL) in the presence of PFL (Amano AK lipase, 250
mg),15 which gave the excellent results outlined in
Scheme 3 (path a). The reaction ended by itself after 96
hours to bring about clear-cut enantiotopical discrimina-
tion giving rise to the alcohol 2 and the acetate 3 as a 1:1
mixture with >98% ee each. Both the progress of the reac-
tion and the enantiomeric excess (ee) were determined by
the ratio of the peak areas obtained by GC separation us-
ing the same chiral MEGADEX DETTBSb fused silica
column. The enantiomers of the remaining alcohol and
those of the produced acetate were perfectly separated.
After the biocatalytic deracemization protocol was termi-
nated at 50% conversion, the active enzyme was recov-
ered for reuse by filtration. The mixture of remaining
unreacted (3R,4S)-diol 2 and formed (3S,4R)-hydroxy ac-
etate 3 was concentrated under reduced pressure and treat-
ed with MsCl/Et3N (3.0/4.0 equiv) in CH2Cl2 (30 mL) at
0 °C to effect one-pot two-step mesylation with retention
of configuration and elimination to afford (S)-4 and (R)-5,
respectively. The solvent was evaporated and the reaction
mixture extracted with Et2O. Concentration under re-
duced pressure and stirring with AcOCs (2 equiv) in DMF
(30 mL) at room temperature effected the SN2 reaction on
(S)-4 with the desired inversion of configuration to yield
(R)-5 in >98% ee and 85% overall yield from the racemic
starting diol. Hydrolysis of (R)-5 with Na2CO3/MeOH
afforded the target molecule (+)-1 in 88% yield.5a,16
HO
O
(±)-1
RML
48 h
vinyl acetate
HO
AcO
O
O
59% yield
66% ee
34% yield
96% ee
Na2CO3 MeOH
RML
vinyl acetate
7 d
HO
S
HO
R
O
O
(+)-1
( )-1
40% yield
>98% ee
30% yield
96% ee
Scheme 1 Kinetic resolution of racemic 1
HO
4
HO
4
In order to provide access to the mirror image enantiomer
(–)-1, kinetic resolution in the reverse direction via bu-
tanolysis of rac-3 (synthesized in 91% yield by standard
monoacylation of rac-2)12 was performed. In this case,
the enantioselectivity of PFL was considerably lower
(Table 1, entry 1) and screening experiments were made.
The resolution procedure was as follows: a mixture of ( )-
3 (50 mg), lipase (50 mg) and n-BuOH (245 mL, 10 equiv)
in i-Pr2O (3 mL) was stirred at room temperature. The re-
action progress was monitored as before by direct chiral
GC (see supra) and the reaction was stopped at the conver-
sion rate indicated in Table 1. The outcome of the screen-
ing test indicated that with CAL-B (entry 4) the lipase-
mediated butanolysis reached 50% conversion in 24 hours
with a molecular recognition of >98% ee both for the re-
maining acetate and the produced alcohol. Consequently,
a large-scale enzymatic resolution of ( )-3 (1 g) was per-
formed using a mixture of that lipase (250 mg), n-BuOH
(5 mL), i-Pr2O (40 mL) and gave the results outlined in
Scheme 3 (path b). After 96 hours (50% conversion) the
active enzyme was recovered for reuse by filtration and
the reaction mixture was treated exactly like previously
(see above) except that complete removal of n-BuOH un-
der reduced pressure had to be ensured carefully. Hydrol-
ysis of (S)-5 afforded the target molecule (–)-1 with 71%
overall yield.5a
HO
AcO
3
3
Ac2O
Py, CH2Cl2
O
O
rac-2
(cis)
rac-3
1) kinetic resolution
2) MsCl, Et3N
MsO
AcO
4
4
+
O
O
5
4
AcOCs (inversion)
hydrolysis
(retention)
HO
4
O
1
Scheme 2 Strategic plan for the synthesis of 1
Following this methodology, the undesired stereocenter
C-3 would be discarded. Treating the mixture with
AcOCs would convert the mesylate to the acetate13 while
inverting the configuration to give 5.14 As a consequence,
a single enantiomeric sec-alcohol 1 would be formed as
the sole product after hydrolysis.
In conclusion, the presented methodology provides a very
simple and practical tool for synthesizing the enantiomers
of the versatile building block 4-hydroxy-3-methyl-2-cy-
clohexenone (1) in enantiomerically pure form and a
theorical 100% yield. The efficiency of our approach
Proof-of-principle was provided through treatment of ra-
cemic 2 (1 g) with vinyl acetate as acyl donor and solvent
Synlett 2006, No. 3, 403–406 © Thieme Stuttgart · New York

LETTER
Synthesis of (+)- or (–)-4-Hydroxy-3-methyl-2-cyclohexenone
405
path a
HO
MsCl/Et3N
in situ
Na2CO3
MeOH
PFL
R
rac-2
(S)-4
in situ
AcOCs, DMF
+
(R)-5
(3R,4S)-2 + (3S,4R)-3
vinyl acetate
1 : 1
O
>98% ee
(+)-1
>98% ee
path b
HO
MsCl/Et3N
in situ
Na2CO3
MeOH
CAL-B
S
rac-3
(3S,4R)-2 + (3R,4S)-3
1 : 1
(R)-4
in situ
AcOCs, DMF
+
(S)-5
n-BuOH
i-Pr2O
O
>98% ee >98% ee
(–)-1
Scheme 3 Synthesis of building blocks (+)-1 and (–)-1 involving biocatalytic deracemization combined with in situ inversion
Table 1 Kinetic Resolution of Racemic 3 via Butanolysis
Entry
Lipasea
Reaction time (d)
Conversion
(%)b
Remaining acetate
Produced alcohol
(3R,4S)-3 ee (%)b
(3S,4R)-2 ee (%)b
1
2
3
4
PFL
7
7
7
1
14
0
35
–
>98
–
PCL
RML
CAL-B
27
50
69
>98
>98
>98
a PFL (Pseudomonas fluorescens, Amano AK); PCL (Pseudomonas cepacia, Amano PS); RML (Mucor miehei, Lipozyme RM IM, Novo Nor-
disk A/S); CAL-B (Candida antarctica B, Novozyme 435, Novo Nordisk A/S).
b Measured by GC on a MEGADEX DETTBSb fused silica column (30 m × 0.25 mm i.d.; N2 carrier gas: 70 kPa).
Waldmann, H., Eds.; Wiley-VCH: Weinheim, 2002.
(e) Faber, K. Biotransformations in Organic Chemistry, 5th
ed.; Springer-Verlag: Berlin, 2004. (f) Bommarius, A. S.;
Riebel, B. R. Biocatalysis; Wiley-VCH: Weinheim, 2004.
(7) Recent reviews: (a) Roberts, S. M. J. Chem. Soc., Perkin
Trans. 1 2001, 1475. (b) Zaks, A. Curr. Opin. Chem. Biol.
2001, 5, 130. (c) Koeller, K. M.; Wong, C.-H. Nature
(London) 2001, 409, 232. (d) Klibanov, A. M. Nature
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Nagarajan, V. Trends Biotechnol. 2002, 20, 238.
leans on the ‘ideal’ kinetic resolution of the racemic sub-
strate, as the enzymatic reaction stopped spontaneously at
50% conversion when one enantiomer was completely
consummated, both in the acyl-transfer or ester butanoly-
sis pathways.
References and Notes
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Synlett 2006, No. 3, 403–406 © Thieme Stuttgart · New York

406
E. Palombo et al.
LETTER
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MHz, CDCl3): d = 5.00 (dd, J = 8.8, 4.1 Hz, 1 H), 2.54 and
2.40 (ABX, J = 14.6, 1.7 Hz, 2 H), 2.36 (m, 2 H), 2.18–2.05
(partially overlapped m, 1 H), 2.08 (s, 3 H), 1.97 (m, 1 H),
1.20 (s, 3 H). 13C NMR (75 MHz, CDCl3): d = 207.7 (C),
170.4 (C), 75.0 (CH), 73.7 (C), 51.7 (CH2), 37.4 (CH2), 26.3
(CH3), 25.3 (CH2), 20.9 (CH3). Anal. Calcd for C9H14O4: C,
58.05; H, 7.58. Found: C, 57.89; H, 7.60.
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Schmidt, S. E.; Jung, K. W. Org. Lett. 1999, 1, 1893.
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L.; Prieto, J. A. Synth. Commun. 2003, 33, 3211; and
references cited therein.
(11) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappoport, A. T.;
Cuccia, L. A. J. Org. Chem. 1991, 56, 2656.
(12) Characterization of Compound 2: white solid; mp 62 °C.
IR (KBr): n = 3412, 1728, 1211, 1159 cm–1. 1H NMR (300
MHz, CDCl3): d = 3.80 (dd, J = 7.2, 3.6 Hz, 1 H), 3.07 (s, 2
OH), 2.66 and 2.35 (ABX, J = 14.0, 1.5 Hz, 2 H), 2.49
(dddd, J = 14.2, 7.9, 6.2, 1.7 Hz, 1 H), 2.25 (dddd, J = 14.2,
7.2, 6.0, 1.1 Hz, 1 H), 2.05 (dtd, J = 13.6, 7.2, 6.2 Hz, 1 H),
(15) CAL-B and RML lipases also showed high enantio-
selectivity, but with a slightly lower ee.
(16) Using commercially available AD-mix-a or AD-mix-b, the
Sharpless AD reaction applied to 3-methyl-3-cyclohexen-
one, also afforded directly the target molecule 1 by an in situ
elimination of the tertiary hydroxyl group in 2 (64% yield),
but in the racemic form, see: Sharpless, K. B.; Amberg, W.;
Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.;
Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang,
X.-L. J. Org. Chem. 1992, 57, 2768.
1.93 (dddd, J = 13.6, 7.9, 6.0, 3.6 Hz, 1 H), 1.24 (s, 3 H). 13
C
NMR (75 MHz, CDCl3): d = 209.8 (C), 75.0 (C), 72.8 (CH),
51.3 (CH2), 36.8 (CH2), 28.1 (CH2), 26.1 (CH3). Anal. Calcd
for C7H12O3: C, 58.32; H, 8.39. Found: C, 58.21; H, 8.43.
Characterization of Compound 3: white solid; mp 106 °C.
IR (KBr): n = 3391, 1757, 1723, 1148 cm–1. 1H NMR (300
Synlett 2006, No. 3, 403–406 © Thieme Stuttgart · New York