Lipase-catalyzed asymmetrization of diacetate of meso-2-(2-propynyl)cyclohexane-l,2,3-triol toward the total synthesis of aquayamycin

Article abstract of DOI:10.1055/s-2001-17487

The diacetate of meso-2-(2-propynyl)cyclohexane-1,2,3-triol was efficiently asymmetrized by hydrolysis with Candida antarctica lipase to give the corresponding mono-acetate in enantiomerically pure form, which was used as the starting material for the total synthesis of aquayamycin. Application of the protocol to the related cyclohexanetriols is also described.

Full text of DOI:10.1055/s-2001-17487

1650
LETTER
Lipase-Catalyzed Asymmetrization of Diacetate of Meso-2-(2-
Propynyl)cyclohexane-1,2,3-triol toward the Total Synthesis of Aquayamycin
L
ipase-Catalyze
a
d
A
symme
k
trization for
a
Synthesis
o
s
f
A
quayam
h
ycin i Matsumoto,*a Tadayoshi Konegawa,a Hiroki Yamaguchi,a Takeshi Nakamura,a Takeshi Sugai,b
Keisuke Suzukia
a
Department of Chemistry, Tokyo Institute of Technology and CREST, Japan Science and Technology Corporation (JST), Tokyo 152-
8551, Japan
b
Department of Chemistry, Keio University, Yokohama 223-8552, Japan
Fax +81(3)57343531
Received 3 August 2001
followed by the acetonide formation. Reduction of 9 with
Abstract: The diacetate of meso-2-(2-propynyl)cyclohexane-1,2,3-
LiAlH4 quantitatively gave the corresponding diastereo-
triol was efficiently asymmetrized by hydrolysis with Candida ant-
meric alcohols 10 and 10’ in 93:7 ratio, which were easily
arctica lipase to give the corresponding mono-acetate in enantio-
separated by silica-gel chromatography.6 The major iso-
merically pure form, which was used as the starting material for the
total synthesis of aquayamycin. Application of the protocol to the mer 10 was subjected to acid hydrolysis followed by
acetylation to give the diacetate 5.7
related cyclohexanetriols is also described.
Key words: asymmetrization, hydrolysis, enzyme, meso com-
pound, total synthesis
In our recent total synthesis of aquayamycin (1), the com-
pound 2 was needed as the key AB ring intermediate that
is with many oxygen functions including two tertiary al-
cohols.1,2 As a possible access to 2, it occurred to us to use
the “meso trick” by exploiting enzymatic hydrolysis.
Namely, the retrosynthesis involving reduction of the
double bond and the ketone in 2 suggested the precursor
3, and a further two-carbon disconnection at the side chain
moiety led to the early synthetic intermediate 4 with a
pseudo Cs symmetry.3 Thus, our hope was the selective
hydrolysis of one of the two enantiotopic acetates in the
meso compound 5 (Figure 1).4
Although this asymmetrization seemed promising by the
partial glyceride-like structure in 5, there were two addi-
tional concerns, (1) further hydrolysis of the desired
mono-acetate 4 that might increase or decrease its ee, but
obviously reduce the chemical yield and more seriously,
(2) the possible acyl migration in 4 as implied again by its
glyceride-like structure.
Figure 1
Gratifyingly, however, the approach proved to offer a nice
route to obtain 4 in enantiomerically pure form, which is
With the diacetate 5 in hand, we examined its hydrolysis
described in this communication. Also described is the ap-
by using several commercially available lipases with par-
plication of the protocol to the related compounds, provid-
ticular attention to the reactivity and the enantioselectivi-
ing stereo-defined cyclohexanetriol derivatives, 6 and 7
ty. Thus, 50 mg of 5 was treated with the enzymes in pH
(Figure 1), that have potential utility in natural product
7 phosphate buffer (0.1 M) at 30 °C. As shown in Table,
it turned out that three enzymes (PPL, PLE, or CAL) were
synthesis.
As a substrate for the enzymatic hydrolysis, the diacetate
5 was prepared from the known enone 85 derived from 2-
cyclohexenone (Scheme 1). The enone 8 was converted to
the acetonide 9 via the OsO4-mediated dihydroxylation
effective for the asymmetric hydrolysis, thereby giving
the diol (+)-47 in enantiomerically pure form. By contrast,
the reaction was very slow with PFL to give a low enanti-
oselectivity and PCL failed to catalyze the reaction.
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1650,1652,ftx,en;Y15801st.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Lipase-Catalyzed Asymmetrization for Synthesis of Aquayamycin
1651
O
O
a) OsO4
Me3N→O (71%)
lit. 5
b) 2-methoxypropene
8
p-TsOH (99%)
O
HO
c) LiAlH4
d) 0.5 M H2SO4
e) Ac2O
O
O
O
O
5
(99%, 2 steps)
10 (93%)
9
+
diastereomer 10' (7%)
Scheme 1 Conditions: a) acetone, H2O, 2 days; b) benzene, 10 min;
c) THF, –78 °C, 30 min; d) 1,4-dioxane, 3 h; e) DMAP, pyridine, 30
min.
Scheme 2
Table Lipase-Catalyzed Hydrolysis of 5
Scheme 3 shows a 10-g scale reaction by employing 1.8 g
of CAL, thereby giving, after 3 days, (+)-4 in enantiomer-
ically pure form in 94% yield and recovery of 5 (6%).
OH
OH
lipase
AcO
OAc
AcO
OH
pH 7 phosphate buffer
30 °C
OAc
OAc
5 50 mg
(+)-4
>
M
M
L
L
Lipase
Reaction period/ Yield of 4/% ee/%
days
more reactive
OAc
less reactive
PPLa (200 mg)
PLEb (10 mg)
CALc (20 mg)
PFLd (100 mg)
PCLe (100 mg)
4
68f
89
80
15
0
>99
>99
>99
60
0.4
1
OAc
HO
OH
AcO
OAc
5
Figure 2
2
—
a Porcine pancreas lipase, Sigma, Type II.
b Pig liver esterase, Sigma.
It is notable that the over-hydrolysis into the correspond-
ing triol, which potentially causes the kinetic resolution of
4, did not occur under these conditions. Therefore, the ee
value of (+)-4 just reflects the selectivity of the hydrolysis
of the diacetate 5. Furthermore, another concern at the
outset, i.e. the acyl migration, did not occur.
c Candida antarctica lipase, Roche Diagnostics, Chirazyme L-2.
d Pseudomonas fluorescence lipase, Amano, Lipase AK.
e Pseudomonas cepacia lipase, Amano, Lipase PS.
f 32% of 5 was recovered.
The ee of (+)-4 was determined by chiral GC analysis of
the corresponding acetonide (–)-11.8 The absolute config-
uration was determined by X-ray analysis after derivation
to the camphanic acid ester 12 (Scheme 2).9 Thus, the
sense of the stereoselection proved to be in accordance
with the well-known empirical rule for predicting the fa-
vored enantiomer in the lipase-catalyzed hydrolysis of the
esters of chiral secondary alcohols (Figure 2).10
OH
OH
Candida antarctica
lipase (1.8 g)
AcO
OAc
AcO
OH
0.1 M phosphate buffer (pH 7 )
30 °C, 3 days
(+)-4
94% yield, >99% e.e.
5
10.0 g
Scheme 3
For further optimization, we focused on CAL11 consider-
ing the disadvantages of other two enzymes, i.e. slow re-
action rate (PPL) and high price (PLE). Thus, the reaction
conditions with CAL were optimized with particular at-
tention to the catalyst load in the larger-scale reaction by
varying the catalyst/substrate ratio. As the result, it proved
that even when the catalyst was reduced to 18% by
weight, the reaction rate was acceptable without sacrific-
ing the high yield and the complete enantioselectivity.
It is also significant to note that this protocol is applicable
to the related diacetates, 13 and 14,12 thereby giving the
enantiomerically pure diols, 6 and 7 (Scheme 4). Synthet-
ic utility of these compounds seems promising, because
polyhydroxy cyclohexanes containing the stereogenic ter-
tiary alcohol center(s) are abundant as the structural motif
in various natural products, while the availability of the
chiral building block for such structures is limited.
Synlett 2001, No. 10, 1650–1652 ISSN 0936-5214 © Thieme Stuttgart · New York

1652
T. Matsumoto et al.
LETTER
(7) Data for selected compounds follow; 5: Mp 177–178 °C
(colorless needles; hexane–ether); 1H NMR (CDCl3) 4.92
(dd, 2 H, J = 4.6, 11.2 Hz), 2.52 (d, 2 H, J = 2.7 Hz), 2.12 (s,
6 H), 2.05 (t, 1 H, J = 2.7 Hz), 1.5-2.0 (m, 6 H); 13C NMR
(CDCl3) 169.8, 78.5, 74.2, 73.5, 71.6, 25.7, 25.2, 21.1,
19.2; IR (KBr) 3471, 2120, 1738, 1712 cm-1; Anal. calcd for
C13H18O5: C, 61.40; H, 7.14. Found: C, 61.63; H, 7.36. (+)-
4: Mp 98.5–99.0 °C (colorless needles; hexane–ether);
[ ]28D +6.6 (c 1.5, CHCl3); 1H NMR (CDCl3) 4.90 (dd, 1
H, J = 4.6, 11.6 Hz), 3.71 (ddd, 1 H, J = 4.9, 8.1, 11.2 Hz),
2.68 (dd, 1 H, J = 2.6, 16.8 Hz), 2.60 (dd, 1 H, J = 2.6, 16.8
Hz), 2.50 (s, 1 H), 2.38 (d, J = 8.1 Hz), 2.11 (s, 3 H), 2.06 (t,
1 H, J = 2.6 Hz), 1.5-1.9 (m, 6 H); 13C NMR (CDCl3)
170.1, 79.6, 74.7, 74.0, 71.3, 71.0, 29.3, 25.7, 25.0, 21.1,
19.3; IR (KBr) 3466, 2114, 1734, 1706 cm-1; Anal. calcd for
C11H16O4: C, 62.25; H, 7.60. Found: C, 62.39; H, 7.71. (–)-
11: Mp 92.5–93.0 °C (colorless needles; hexane); [ ]27D –41
(c 1.6, CHCl3); 1H NMR (CDCl3) 5.01 (dd, 1 H, J = 3.7,
9.0 Hz), 4.31 (t, 1 H, J = 2.9 Hz), 2.64 (dd, 1 H, J = 2.7, 16.8
Hz), 2.43 (dd, 1 H, J = 2.7, 16.8 Hz), 2.05 (s, 3 H), 1.99 (t, 1
H, J = 2.7 Hz), 1.5-1.9 (m, 6 H), 1.48 (s, 3 H), 1.38 (s, 3 H);
13C NMR (CDCl3) 170.5, 108.7, 79.5, 79.1, 78.5, 71.5,
71.3, 27.4, 26.8, 26.2, 24.1, 23.1, 21.4, 14.9; IR (KBr) 3265,
2118, 1740 cm-1; Anal. calcd for C14H20O4: C, 66.12; H,
7.93. Found: C, 66.24; H, 8.10.
OH
OH
CALa
OAc
AcO
AcO
AcO
OH
30 °C, 24 h
91% yield
(+)-6, >99% e.e.
13
OH
OH
OH
CALa
AcO
OAc
30 °C, 5 h
quant.
(–)-7, >99% e.e.
14
a) 20 wt% based on the substrate.
Scheme 4
References and Notes
(1) (a) Sezaki, M.; Kondo, S.; Maeda, K.; Umezawa, H.; Ohno,
M. Tetrahedron 1970, 26, 5171. (b) See also: Sekizawa, R.;
Inuma, H.; Naganawa, H.; Hamada, M.; Takeuchi, T.;
Yamaizumi, J.; Umezawa, K. J. Antibiot. 1996, 49, 487.
(2) (a) Matsumoto, T.; Yamaguchi, H.; Hamura, T.; Tanabe, M.;
Kuriyama, Y.; Suzuki, K. Tetrahedron Lett. 2000, 41, 8383.
(b) Yamaguchi, H.; Konegawa, T.; Tanabe, M.; Nakamura,
T.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 2000, 41,
8389. (c) Matsumoto, T.; Yamaguchi, H.; Tanabe, M.;
Yasui, Y.; Suzuki, K. Tetrahedron Lett. 2000, 41, 8393.
(3) For a review on enantioselective synthesis through
enzymatic asymmetrization, see: Schoffers, E.;
(8) Column: CP-Chirasil Dex CB (GL Sci. Inc.), 0.32 mm 30
m; Conditions: 130 °C for 5 min then +12.5 °C/min to
140 °C, He 180 kPa; Retention time: 6.2 min for (–)-11 and
6.4 min for (+)-11.
(9) We express deep appreciation to Ms. Sachiyo Kubo, Tokyo
Institute of Technology, for X-ray analysis.
Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52,
3769.
(10) (a) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A.
T.; Cuccia, L. A. J. Org. Chem. 1991, 56, 2656. (b) Cygler,
M.; Grochulski, P.; Kazlauskas, R. J.; Schrag, J. D.;
Bouthillier, F.; Rubin, B.; Serreqi, A. N.; Gupta, A. K. J. Am.
Chem. Soc. 1994, 116, 3180. (c) Bornscheuer, U. T.;
Kazlauskas, R. J. Hydrolyses in Organic Synthesis; Wiley-
VCH: Weinheim, 1999. (d) For examples of the CAL-
mediated reactions of cyclic secondary alcohol derivatives,
see: Johnson, C. R.; Sakaguchi, H. Synlett 1992, 813.
(e) Orrenius, C.; Norin, T.; Hult, K.; Carrea, G. Tetrahedron:
Asymmetry 1995, 3023. (f) See also, ref. 4c.
(11) (a) A review on the application of Candida antarctica lipase
in organic synthesis:Anderson, E. M.; Larsson, K. M.; Kirk,
O. Biocatal. Biotransform. 1998, 16, 181. (b) For an
example of CAL-mediated asymmetrization of meso
compounds, see ref. 4c.
(4) Selected examples of enzymatic hydrolysis of the related
meso compounds: (a) Eberle, M.; Egli, M.; Seebach, D.
Helv. Chim. Acta 1988, 71, 1. (b) Carda, M.; Van der
Eycken, J.; Vandewalle, M. Tetrahedron: Asymmetry 1990,
1, 17. (c) Johnson, C. R.; Bis, S. J. Tetrahedron Lett. 1992,
33, 7287. (d) Renouf P., Poirier J.-M., Duhamel P.; J. Chem.
Soc., Perkin Trans. 1; 1997, 1739.
(5) (a) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.;
Zanirato, V. Tetrahedron Lett. 1984, 25, 4291.
(b) Confalone, P. N.; Baggiolini, E.; Hennessy, B.;
Pizzolato, G.; Uskokovic, M. R. J. Org. Chem. 1981, 46,
4923.
(6) Although LiEt3BH or Li(s-Bu)3BH showed the complete
stereoselectivity, we did not opt for these reagents for the
synthetic purpose. With these reagents, the starting material
9 was not consumed even by using 3 equivalents and the
separation of 9 from the product 10 was not easy.
(12) The diacetate 13 was synthesized from the alcohol 10 in 4
steps [(1) Ac2O, pyridine; (2) H2, Lindlar's catalyst,
quinoline, hexane; (3) 0.5 M H2SO4 aq., 1,4-dioxane; (4)
Ac2O, pyridine (88% yield, overall)]. Attempted
Reduction of 9 with other reagents.
hydrogenations of 5 into 13 with Lindlar's catalyst were
accompanied by the over-hydrogenation. The diacetate 14
was synthesized from 2-methyl-2-cyclohexen-1-one in a
similar manner as Scheme 1.
Reagenta
Conditions
Yield/%
Selectiv-
(recovery of 9) ityb
NaBH4
MeOH/r.t.
no reaction
89 (7)
--
LiEt3BH
THF/-78 °C r.t.
>99:1
>99:1
92:8
Li(s-Bu)3BH THF/-78 °C r.t.
(i-Bu)2AlH THF/-78 °C 0 °C
80 (1)
93 (--)
a Used in three equivalents.
b 10:10’.
Synlett 2001, No. 10, 1650–1652 ISSN 0936-5214 © Thieme Stuttgart · New York