Chemical synthesis of optically active cis-cyclohexa-3,5-diene-1,2-diols and their 5-2H-derivatives

Article abstract of DOI:10.1016/S0040-4039(01)01014-0

A variety of optically active 3-substituted cis-cyclohexane-3,5-dien-1,2-diol acetonides were readily prepared from chiral 5-(tert-butyldimethylsilyloxy)-2-cyclohexenone through a seven-step reaction in good overall yield. The synthesis also allowed prepa

Full text of DOI:10.1016/S0040-4039(01)01014-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5455–5457
Chemical synthesis of optically active
cis-cyclohexa-3,5-diene-1,2-diols and their 5-2H-derivatives
Takeshi Hanazawa, Sentaro Okamoto and Fumie Sato*
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama,
Kanagawa 226-8501, Japan
Received 10 May 2001; accepted 8 June 2001
Abstract—A variety of optically active 3-substituted cis-cyclohexane-3,5-dien-1,2-diol acetonides were readily prepared from chiral
5-(tert-butyldimethylsilyloxy)-2-cyclohexenone through a seven-step reaction in good overall yield. The synthesis also allowed
2
preparation of the acetonide having an H-atom at the 5-position. © 2001 Elsevier Science Ltd. All rights reserved.
Enzymatic dihydroxylation of mono-substituted ben-
zenes affords an efficient and practical method for
preparing optically active cyclohexadienediols of the
type 1 (Scheme 1). The compounds 1 and their
hydroxy-protected derivatives, especially their acetonide
2, have been widely utilized as starting material for
synthesizing biologically active compounds, including
natural products.1 The methodology, however, with
very few exceptions, allows production of only one
enantiomer of 1, and thus that of 2, with the absolute
stereochemistry shown in Scheme 1. We have now
succeeded in developing an efficient and practical chem-
ical synthesis of both enantiomers of 2.2
step reaction sequence in 51% overall yield as shown in
Scheme 2 (via path a).
After the development of this synthesis, we investigated
another approach to 5 starting from optically active
epichlorohydrin (6), because 6 is commercially available
at lower price in comparison with 4 and the enan-
tiomeric excess (ee) of the commercially available 6 is
somewhat higher than that of 4.4 As shown in path b in
Scheme 2, the preparation of 5 from 6 can be readily
carried out by the conventional reaction sequence.
Thus, 6 was treated with vinylmagnesium bromide in
the presence of a catalytic amount of CuCN in THF to
afford 1-chloropent-4-en-2-ol, the chlorine of which
was replaced by CN by reaction with potassium cya-
nide in methanol, and the resulting cyanohydrin was
converted to 5 by acidic ethanolysis of the cyano group
and the following silylation of the hydroxy group. The
olefinic ester 5, the ee of which was determined to be
more than 98%, was conclusively prepared from 6 by a
four-step reaction in 77% overall yield; thus, eventually,
3 was prepared from 6 by a seven-step reaction in 52%
overall yield. As all the reagents used in either method
for synthesizing 3 from 4 or 6 shown in Scheme 2 are
readily available and inexpensive, and the reaction pro-
cedures are operationally simple, 3 can be easily pre-
pared in quantity.
We have recently introduced optically active 5-(tert-
butyldimethylsilyloxy)-2-cyclohexenone (3) as a versa-
tile chiral building block for synthesizing optically
active cyclohexane derivatives.3 The compound 3 was
synthesized from commercially available, optically
active ethyl 3-hydroxy-4-chlorobutyrate (4) via ethyl
3-(tert-butyldimethylsilyloxy)-5-hexenoate (5) by a six-
R
R
R
OMe
OMe
H+
Enzymatic
dihydroxylation
OH
OH
O
O
1
2
Scheme 1.
As a part of our continuing study to apply 3 as a chiral
building block in asymmetric synthesis,3 we have now
found that a variety of optically active cyclohexadiene-
diol acetonide 2 can be readily prepared from 3.
Although we used 3 with (S)-configuration in the
present synthesis, as its antipode (R)-3 is similarly
Keywords: cis-cyclohexane-3,5-dien-1,2-diol; optically active; chemi-
cal synthesis; deuterium.
* Corresponding author. Tel.: +81-45-924-5787; fax: +81-45-924-5826;
e-mail: fsato@bio.titech.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01014-0

5456
T. Hanazawa et al. / Tetrahedron Letters 42 (2001) 5455–5457
1) FeCl3
pyridine, DMF
2) AcONa, MeOH
Ti(O-i-Pr)4
2 i-PrMgCl
ether
O
OH
CO2Et
CO2Et
Cl
3 steps (ref. 3)
path a
76%
90%
TBSO
HO
TBSO
TBSO
5
4
3
75% yield from 4
77% yield from 6
1) vinylmagnesium bromide
CuCN catalyst, THF
2) KCN, MeOH
Cl
3) H2SO4, EtOH
4) TBSCl, imidazole, DMF
O
6
path b
Scheme 2.
preparable because both enantiomers of 4 and 6 are,
respectively, commercially available, the present
method allows access to both enantiomers of 2.
catalyst or with Tf2O/DBU gave a complicated mixture
including the phenol derivative(s). Finally, to our
delight, we were able to find the conditions enabling the
conversion of 10 to 2 by the two-step procedure shown
in Scheme 3; under these conditions, phenol deriva-
tive(s) was produced in less than 2% yield, if any.
The preparation of 2 from 3 was carried out according
to the procedure shown in Scheme 3. Thus, the dihy-
droxylation of 3 with catalytic osmium tetraoxide–
NMO gave 7 exclusively in 80% yield as previously
reported,3e which in turn was converted quantitatively
to the acetonide 8, and the crude of which was used for
the next reaction. Desilylation of 8 with (HF)n-pyridine
and the following mesylation of the resulting hydroxy
group with MsCl and Et3N was accompanied with
b-elimination to furnish enone 95 in 84% overall yield
from 7, thus, eventually, in 67% yield from 3. From 9,
substituted cyclohexadienediol acetonides 2a–d could be
prepared by a three-step reaction which involves 1,2-
addition of the corresponding organolithium reagent to
9, migrative chlorination of the resulting 10 with thio-
nyl chloride, and the following elimination reaction
using Li2CO3/LiCl6 as a base. The yield of 2 from 9 and
their [h]D values are summarized in Table 1. In conclu-
sion, a variety of optically active acetonides 2a–d were
prepared in 41, 47, 50, or 43% overall yield from 3,
respectively.7,8 It is worth mentioning here that, at first,
we were anxious about the successful conversion of 10
to 2 because further elimination of the resulting 2 to the
corresponding phenol derivative was easily conceivable.
Actually, the direct dehydration of 10 to 2 was unsuc-
cessful. For example, treatment of 10 with p-TsOH
As many biologically important compounds have been
prepared by using 2 as a starting material,1 we next
2
attempted to prepare 2 labeled with H, which eventu-
ally allows access to those biologically important com-
2
2
pounds labeled with H. The preparation of 2 with H
at the 5-position was easily carried out as exemplified
by the synthesis 5-2H-2a as shown in Scheme 4. Thus,
Table 1.
2
R
Yield from 9
[h]D Value
(%)
2a7,9 Me
62
[h]2D9 +93 (c 0.27, MeOH)
lit.7a [h]2D9 +93.7 (c 2.98,
MeOH)
2b
n-Bu
70
75
64
[h]2D6 +101 (c 0.50,
CHCl3)
2c7 Ph
[h]2D6 +204 (c 0.12,
CHCl3)
2d
Me3Si·CꢀC
[h]D28 +131 (c 0.32,
CHCl3)
OMe
O
1) (HF)n-pyridine
O
OsO4 catalyst
OMe
p-TsOH catalyst
pyridine
O
O
OH
OH
NMO
acetone
80%
acetonitrile
2) MsCl, Et3N
CH2Cl2
3
CH2Cl2
TBSO
TBSO
8
7
O
R
R
OH
SOCl2
pyridine
Li2CO3
LiCl
O
O
R-Li
ether
O
O
O
2
CH2Cl2
DMF
O
a : R = Me
Cl
9
b : R = n-Bu
c : R = Ph
10
84% from 7
d : R = C≡C-SiMe3
Scheme 3.

T. Hanazawa et al. / Tetrahedron Letters 42 (2001) 5455–5457
5457
tive: Hentemann, M.; Fuchs, P. L. Org. Lett. 1999, 1,
355–357.
Me
O
O
PCC
10
(R = Me)
3. (a) Hikichi, S.; Hareau, G. P.-J.; Sato, F. Tetrahedron
Lett. 1997, 38, 8299–8301; (b) Koiwa, M.; Hareau, G.
P.-J.; Morizono, D.; Sato, F. Tetrahedron Lett. 1999, 40,
4199–4202; (c) Hareau, G.; Hikichi, S.; Sato, F. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2099–2101; (d) Hareau, G.
P.-J.; Koiwa, M.; Hikichi, S.; Sato, F. J. Am. Chem. Soc.
1999, 121, 3640–3650; (e) Hareau, G.; Koiwa, M.;
Hanazawa, T.; Sato, F. Tetrahedron Lett. 1999, 40, 7493–
7496; (f) Hareau, G. P.-J.; Koiwa, M.; Sato, F. Tetra-
hedron Lett. 2000, 41, 2385–2388; (g) Koiwa, M.; Hareau,
G. P.-J.; Sato, F. Tetrahedron Lett. 2000, 41, 2389–2390.
4. Compounds 4 with 97% ee and 6 with >98% ee are
commercially available from Aldrich.
CH2Cl2
O
11
84%
1) NaBD4
MeOH
2) SOCl2
3) Li2CO3
LiCl
68%
Me
O
O
5. [h]D of 9 was [h]2D6 +101 (c 0.22, CHCl3) and the ee was
found to be 97% by GC analysis with the use of a chiral
column (Chirasil-DEX CB, 0.25 mm×25 m, Chrompack).
Landais et al. reported the preparation of non-racemic 9
with [h]2D5 +76.3 (c 0.94, CHCl3) from chlorodimethyl-
phenylsilane in 38% yield through a five-step reaction,
which involves the Sharpless asymmetric dihydroxylation
of 3-(hydroxydimethylsilyl)-1,4-cyclohexadiene: Ange-
laud, R.; Babot, O.; Charvat, T.; Landais, Y. J. Org.
Chem. 1999, 64, 9613–9624.
2H
5-2H-2a
Scheme 4.
PCC-oxidation of 10 (R=Me), derived from 9 and
MeLi, afforded ketone 11 in 84% yield. The reduction
of 11 with NaBD4 and the successive treatment of the
product with thionyl chloride and LiCO3/LiCl afforded
the acetonide of 3-methyl-5-deutero-cyclohexa-3,5-dien-
1,2-diol (5-2H-2a) with more than 93% of deuterium
incorporation10 in 68% overall yield.
6. Boyd, D. R.; Sharma, N. D.; Dalton, H.; Clarke, D. A.
Chem. Commun. 1996, 45–46.
7. Spectral data of 2a and 2c thus prepared were in good
agreement with those reported. For 2a, see: (a) Hudlicky,
T.; Luna, H.; Barbieri, G.; Kwart, L. D. J. Am. Chem.
Soc. 1998, 120, 4735–4741. For 2c, see: (b) Gibson, D. T.;
Roberts, R. L.; Wells, M. C.; Kobal, V. M. Biochem.
Biophys. Res. Commun. 1973, 50, 211–219.
Acknowledgements
1
8. Compound 2b: H NMR l 5.98 (dd, J=5.7, 9.6 Hz, 1H),
The authors would like to thank the Ministry of Educa-
tion, Culture, Sports, Science and Technology (Japan)
for financial support.
5.78 (dd, J=3.9, 9.6 Hz, 1H), 5.71 (d, J=5.7 Hz, 1H),
4.65 (dd, J=3.9, 8.7 Hz, 1H), 4.53 (d, J=8.7 Hz, 1H),
2.14-2.31 (m, 2H), 1.25–1.58 (m, 4H), 1.39 and 1.41 (2s,
each 3H), 0.92 (t, J=7.5 Hz, 3H); 13C NMR l 138.7,
124.8, 122.3, 118.0, 105.2, 73.5, 71.3, 33.3, 29.4, 27.0,
25.2, 22.6, 14.1; IR (neat) 2958, 2878, 1603, 1458, 1369,
1258, 1048, 868, 804 cm−1. Anal. calcd for C13H20O2: C,
74.96; H, 9.68. Found: C, 75.22; H, 9.67%. Compound
References
1. Reviews: (a) Carless, H. A. J. Tetrahedron: Asymmetry
1992, 3, 795–826; (b) Brown, S. M.; Hudlicky, T. In
Organic Synthesis: Theory and Application; Hudlicky, T.,
Ed.; JAI Press: Greenwich, CT, 1993; Vol. 2, pp. 113–
176; (c) Hudlicky, T.; Gonzalez, D.; Gibson, D. T.
Aldrichim. Acta 1999, 32, 35–62; (d) Hudlicky, T.; Reed.
J. W. In Advances in Asymmetric Synthesis; Hassner, A.,
Ed.; JAI Press: Greenwich, CT, 1995; pp. 271–312.
2. One report for the chemical synthesis of optically active
diol of the type 1 recently appeared which involves
asymmetric epoxidation of 2-sulfonylcyclohexa-1,3-diene
and the following three-step conversion of the resulting
epoxide to 3-sulfonylcyclohexa-3,5-diene-1,2-diol deriva-
1
2d: H NMR l 6.35 (d, J=5.7 Hz, 1H), 6.01 (dd, J=5.7,
9.6 Hz, 1H), 5.92 (dd, J=3.3, 9.6 Hz, 1), 4.71 (dd, J=3.3,
8.1 Hz, 1H), 4.54 (d, J=8.1 Hz, 1H), 1.43 and 1.42 (2s,
each 3H), 0.10 (s, 9H); 13C NMR l 130.6, 126.9, 123.3,
119.7, 105.9, 104.2, 98.8, 72.3, 71.4, 26.9, 25.3, 0.10; IR
(neat) 2960, 2142, 1379, 1250, 1034, 844 cm−1. Anal. calcd
for C14H20O2Si: C, 67.70; H, 8.12. Found: C, 67.38; H,
8.49%.
9. Comparison of the [h]D value of 2a thus prepared with
the reported one indicates that no racemization occurred
during conversion of 9 to 2.
1
10. Determined by H NMR analysis.
.