Enzymatic resolution of diols derived from p-benzoquinones

Article abstract of DOI:10.1016/S0040-4039(00)02224-3

An efficient enzymatic resolution of racemic 4-acetoxy-2,3-dibromo-5-cyclohexen-1-ol in organic solvent is described. The methodology is extended to the synthesis of a series of highly functionalized enantiopure intermediates derived from various substituted p-benzoquinones.

Full text of DOI:10.1016/S0040-4039(00)02224-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1213–1215
Enzymatic resolution of diols derived from p-benzoquinones
Jianxin Gu, Mary J. Heeg and Carl R. Johnson*
Department of Chemistry, Wayne State University, Detroit, MI 48202, USA
Received 25 October 2000; accepted 5 December 2000
Abstract—An efficient enzymatic resolution of racemic 4-acetoxy-2,3-dibromo-5-cyclohexen-1-ol in organic solvent is described.
The methodology is extended to the synthesis of a series of highly functionalized enantiopure intermediates derived from various
substituted p-benzoquinones. © 2001 Published by Elsevier Science Ltd.
There are many natural products with antibiotic and
antitumor activity whose common feature is a densely
oxygenated cyclohexene core. Representative examples
are molecules such as conduritols,1 valienamine2 and
gabosine3 along with family members possessing
numerous variations at the asymmetric centers such as
bromoxone,4 epofomin,5 epiepoxydon,6 the Strepto-
mycetes metabolite LL-C10037a7 and the manumycins8
which all have a epoxyquinol core. The synthesis of
these compounds has been a topic of considerable
interest.
the presence of Et2O. Nicolosi14 reported an enzymatic
esterification of diol 2 catalyzed by Mucor miehei lipase
(Lipozyme™) in tert-butyl methyl ether.
In this communication we present a more convenient
and efficient way to access these enantiopure com-
pounds. Monoacetate 3 derived from NaOMe-mediated
mono-deacetylation of ( )-1 was subjected to enzymatic
esterification in organic solvent; this approach was
extended to other substituted analogs. The methodol-
ogy offers advantages in terms of resolution process
monitoring and being amenable to large scales. More-
over, differentiation of the acyl groups can be realized
through this process, which should prove useful for
further elaboration of resulting intermediates.
We initiated a program utilizing p-benzoquinone as a
starting material with bioactive epoxyquinol natural
products as targets. Continuation of our efforts has
resulted in the synthesis of enantiomerically pure (+)-
and (−)-bromoxone,9 (+)- and (−)-harveynone, (+)-tri-
cholomenyn A,10 (−)-LL-C100372a11 and a series of
stereochemically defined intermediates with highly func-
tionalized six-membered ring cores.12 The syntheses
started with enzymatic resolution of C2-symmetric diac-
etate 1 using Pseudomonas cepacia lipase (Amano PS-
30) in phosphate buffer at 50°C (Eq. (1)).9 A modified
hydrolytic procedure was reported by Altenbach13 using
porcine pancreatic lipase (PPL) in phosphate buffer in
The monoacetate ( )-3 is readily available through
selective removal of one acetate using a catalytic
amount of NaOMe in methanol at 0°C from ( )-1 (66%
yield). Treatment of monoacetate ( )-3 in hexane/vinyl
acetate (4:1) with Amano PS-30 (20% weight) at rt for
16 h afforded diacetate (−)-1 in 50% yield (]98% ee)
and (−)-3 in 50% yield (92% ee) (Scheme 1). The latter
after recrystallization provided enantiopure material.15
OAc
OH
OAc
P. cepacia
Br
Br
Br
Br
Br
(Amano PS-30)
+
Br
phosphate buffer
(1)
OAc
OAc
OH
(±)-1
(+)-1
26%, >98%ee
(+)-2
47%, 90%ee
* Corresponding author. E-mail: crj@chem.wayne.edu
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(00)02224-3

1214
J. Gu et al. / Tetrahedron Letters 42 (2001) 1213–1215
This approach was extended to the production of struc-
tural analogs ( )-4a,b containing bromo or methyl sub-
stituents (Scheme 2). The less hindered acetate in
( )-4a,b was selectively removed using NaOMe in high
yield. The resulting monoacetate was then subjected to
an enzymatic esterification in hexane with vinyl acetate
as the acyl donor. Enzyme screening suggested that
Amano PS-30 lipase would afford the most satisfactory
results. Resolution of compound 5a with 50% (w/w)
PS-30 provided diacetate (−)-4a in 49% yield (94% ee);
monoacetate (−)-5a was recovered in 50% yield (87%
ee). Both enantiomers furnished, after recrystallization
from hexane–acetone, enantiomerically pure materi-
als.16 Enzymatic esterification of 5b was achieved under
similar conditions as for 5a, with 50% (w/w) PS-30;
diacetate (−)-4b was obtained in 50% yield (87% ee) and
recovered monoacetate (−)-5b in 50% yield (85% ee).
Recrystallization from hexane–acetone raised both
enantiomeric excess to ]98% according to chiral shift
reagent analysis.17
(−)-4b were determined via X-ray analysis. The
monoacetate with the configuration (1R,2S,3S,4R) was
preferentially acetylated (Scheme 2). The results are
consistent with the simple model 6 proposed for Pseu-
domonas cepacia (Amano PS-30) towards secondary
alcohols.18 It is interesting to note that, unlike the
diacetate ( )-1 or diol ( )-2 which can be enzymatically
resolved either by hydrolysis in buffer or esterification
in organic solvent,9,14 neither the diacetate ( )-4a,b, nor
the corresponding diol, are substrates to various lipases
such as CRL (Candida rugosa lipase), Amano PS-30,
PPL, CAL-B (Candida antarctica lipase B, Novo SP-
435). No hydrolysis or esterification could be observed
under various conditions.
Another compound of interest is 7 which can be
quickly obtained in good yield from 2-hydroxy-5-
methoxybenzaldehyde. The less hindered acetate group
is again regioselectively removed by NaOMe to give
monoacetate 8 in 71% yield (Scheme 3). Due to the
presence of a bulky TBS protecting group in compound
8, among many enzymes screened, only lipase from C.
The absolute configuration of diacetates (−)-4a and
OAc
OH
OAc
OH
Br
Br
Br
Br
Br
Br
Amano PS-30 (20% w/w)
Br
Br
NaOMe (0.4 equiv.)
+
MeOH, 0oC, 15 min
66%
Hexane-Vinyl acetate
(4:1), 16 h, rt
OAc
OAc
OAc
OAc
(-)-1
(-)-3
(±)-1
(±)-3
50%, >98%ee
50%, 92%ee
Scheme 1.
OH
OAc
OAc
OH
Br
Br
Br
Br
Br
Br
Amano PS-30 (50% w/w)
a
+
Hexane-Vinyl acetate
(4:1), 24 h, rt
R
Br
Br
R
R
R
OAc
OAc
OAc
OAc
a: R = Br
b: R = Me
(±)-4a,b
(±)-5a,b
(-)-4a
(-)-4b
(-)-5a 50%, 87%ee
(-)-5b 50%, 85%ee
49%, 94%ee
50%, 87%ee
Scheme 2. aFor 4a: NaOMe (0.6 equiv.), MeOH–THF (5:2), 0°C, 30 min, 91%; for 4b: NaOMe (1.2 equiv.), MeOH, 0°C, 45 min,
85%.
OH
OH
OAc
OAc
Br
Br
Br
Br
Br
Br
Br
Br
Novo SP-435 (300% w/w)
NaOMe (1.5 equiv)
MeOH-THF (2:1)
+
Hexane-Vinyl acetate
(4:1), 3 days, rt
0 oC, 71%
OAc
OTBS
OTBS
OTBS
OTBS
OAc
OAc
OAc
(+)-7
(+)-8
(±)-8
(±)-7
47%, >98%ee
SP-435
50%, 92%ee
92%, >98%ee
Scheme 3.

J. Gu et al. / Tetrahedron Letters 42 (2001) 1213–1215
1215
antarctica (Novo SP-435), which has a more flexible
active site showed good activity and enantioselectivity.
With lipase SP-435 (300% weight of its immobilized
form) and vinyl acetate in hexane, after 3 days, diac-
etate (+)-7 was obtained (47% yield, ]98%ee), monoac-
etate (+)-8 was recovered in 50% yield (92% ee). The
enantiomerically enriched monoacetate was resubjected
to enzymatic esterification with 100% (w/w) SP-435 to
bring the ee up to ]98% in 92% yield.19 The overall
production of enantiopure (+)-8 from ( )-8 was 46%
(out of a theoretical 50%).
donald, G.; Wie, X.; Lewis, N. Synthesis 1998, 775 and
references cited therein.
9. Johnson, C. R.; Miller, M. W. J. Org. Chem. 1995, 60,
6674–6675.
10. Miller, M. W.; Johnson, C. R. J. Org. Chem. 1997, 62,
1582–1583.
11. Murphy, S. T.; Bencsik, J. R.; Johnson, C. R. Org. Lett.
1999, 1, 1483–1485.
12. Kohrt, J. T.; Gu, J. X.; Johnson, C. R. J. Org. Chem.
1998, 63, 5088–5093.
13. Block, O.; Klein, G.; Altenbach, H.; Brauer, D. J. J. Org.
Chem. 2000, 65, 716–721. Hydrolysis of racemic diacetate
1 with PPL in phosphate buffer for 4 days in the presence
of Et2O give both (+)-1 and (+)-2 in 38% yield in enan-
tiopure form after recrystallization.
14. Sanfilippo, C.; Patti, A.; Nicolosi, G. Tetrahedron: Asym-
metry 2000, 11, 1043–1045. Diol (−)-2 is obtained in 48%
yield (]98% ee) and diacetate (−)-1 in 10% yield (]98%
ee) along with the corresponding monoacetate (37% yield,
]98% ee).
15. Enantiomerically pure (−)-1: white crystals (hexane/ace-
tone), mp 107–109°C; [h]D=−11.7 (c 1.0, CH2Cl2) [lit.9
mp 107–109°C; [h]D=11.7 (c 1.05, CH2Cl2) for (+)-1];
enantiopure (−)-3: white crystals (hexane/acetone), mp
147–148°C; [h]D=−36.3 (c 1.0, CH2Cl2) [lit.14 mp 147–
148°C, [h]D=25.0 (c 1.6, CHCl3) for (+)-3].
16. The enantiomeric excess was determined by NMR analy-
sis in the presence of Eu(hfc)3. Enantiopure (−)-4a: white
crystals (hexane/acetone), mp 132–133°C; [h]D=−40.0 (c
1.03, CHCl3). Enantiopure (−)-5a: white crystals (hexane/
acetone), mp 138–139°C; [h]D=−39.8 (c 1.02, CHCl3).
17. Enantiopure (−)-4b: white crystals (hexane/acetone), mp
97–99°C; [h]D=−2.64 (c 1.0, CHCl3). Enantiopure (−)-5b:
white crystals (hexane/acetone), mp 102–103°C; [h]D=
−67.2 (c 1.06, CHCl3).
In summary, we have developed an efficient method for
the preparation of a series of enantiopure mono- and
diacetates of 2,3-dibromo-5-cyclohexen-1,4-diol and
their substituted analogs. These highly functionalized
intermediates should prove useful in the synthesis of
various target molecules. As our preliminary study
shows, the bromovinyl functionality in compound (−)-
5a or (−)-4a can participate in Sonogashira or Suzuki
cross coupling reactions.
Acknowledgements
This work was supported by a grant from the National
Science Foundation (CHE-9801679).
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