Syntheses of gabosine A, B, D, and E from allyl sulfide derived from (-)-quinic acid

Article abstract of DOI:10.1055/s-2002-32985

An efficient conversion of allyl sulfide 6 prepared from (-)-quinic acid (5) to gabosines was achieved by a series of sequential reactions: i) Mislow-Evans rearrangement, ii) SeO₂ oxidation, iii) conjugate addition of sodium hydroxide or sodium

Full text of DOI:10.1055/s-2002-32985

LETTER
1341
Syntheses of Gabosine A, B, D, and E from Allyl Sulfide Derived from
(–)-Quinic Acid
S
ynthese
s
of Ga
e
bosine
A
,
t
B,
D
,
an
s
d
E
uro Shinada,* Toshiyuki Fuji, Yasuhiro Ohtani, Yasutaka Yoshida, Yasufumi Ohfune*
Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
Fax +81(6)66053153; E-mail: shinada@sci.osaka-cu.ac.jp; E-mail: ohfune@sci.osaka-cu.ac.jp
Received 15 May 2002
BBA
O
OH
5
BBA
O
O
Abstract: An efficient conversion of allyl sulfide 6 prepared from
(–)-quinic acid (5) to gabosines was achieved by a series of sequen-
tial reactions: i) Mislow–Evans rearrangement, ii) SeO2 oxidation,
iii) conjugate addition of sodium hydroxide or sodium acetate, and
iv) elimination of the methoxymethyloxy group.
O
Pummerer
reaction
HO
6
OH
4
OTBS
OTBS
ref. 3
ref. 3
OH
COOH
CHO
O
SPh
allylic
oxidation
6
7
(-)-Quinic acid (5)
Key words: gabosine, cyclitol, allyl sulfide, quinic acid, conjugate
addition
i)
BBA
O
O
BBA
O
BBA
O
O
OTBS
OTBS
iii)
iv)
OTBS
OP
ii)
Gabosines isolated from Streptomyces strains are a class
of carba-sugars bearing 2-methylcyclohexane as their
common carbon skeleton (Scheme 1).1 Gabosines and
their related natural products are known to exhibit a vari-
ety of biological activities such as antiprotozoal activity,
DNA binding properties, and inhibition of glyoxalase-I
and glycosidases.1 Their diverse activities and highly ox-
ygenated structures have prompted extensive synthetic
studies focusing on preparative efficiency and regio- and
stereoselective construction of the concomitant hydroxy
groups onto the 2-methylcyclohexane framework.2 We
wish to report herein a new and efficient entry to the syn-
theses of gabosine A and B, and enantiomers of gabosine
D and E starting with allyl sulfide 6 derived from (–)-
quinic acid in a highly stereoselective manner.
O
OP
O
A
B
Nu = OH,
OAc or H
C
Nu
Nu
i) Mislow-Evans rearrangement
ii) Allylic oxidation
iii) Conjugate addition
iv) β-Elimination
Me
Me
OMe
MeO
BBA =
P = protecting group
OH
OH
OH
OH
5
HO
O
OH
HO
O
OH HO
O
OH
HO
O
OH
5
4
6
4
6
OR
OR
ent-1 R = Ac
ent-2 R = H
Gabosine A (3) Gabosine B (4)
Gabosine D (1) R = Ac
Gabosine E (2) R = H
Scheme 1
Novel features of the present work are the use of allyl sul-
fide 63 as a common synthetic precursor in which consec-
utive trihydroxy groups at C4, C5, and C6 corresponding
to gabosines are already installed. Consequently, the key
step to the present syntheses focused on the conversion of
the allyl sulfide moiety into conjugated , -unsaturated
cyclohexenone C, a plausible precursor common to ga-
bosines. Preliminary experiment was conversion of 6 or 7
to the key intermediate C. However, the allylic oxidation
of 6 with SeO2 was unsuccessful, giving an undesired al-
dehyde 7 in poor yield. Similarly, allylic oxidation of 7
prepared by Pummerer reaction from 63 resulted in recov-
ery of the starting material. These facts prompted us to ex-
amine a stepwise approach to the desired C which
involves: i) conversion to exo-methylene alcohol A by
Mislow–Evans rearrangement,4 ii) allylic oxidation lead-
ing to B,5 and iii) conjugate addition of a nucleophile such
as hydride, hydroxide, or acetate to B, iv) -elimination of
the OP group to produce C.
Initially, we examined the conversion of 6 to exo-methyl-
ene compound 12 which corresponds to B in Scheme 2.
Oxidation of allyl sulfide 6 with mCPBA afforded a 1:1
mixture of sulfoxide 8 which, upon thermolysis in the
presence of (EtO)3P, provided allyl alcohol 9 as a single
diastereomer in 98% yield.6,7 Allyl alcohol 9 was protect-
ed with a methoxymethyl (MOM) group to give MOM
ether 10. Allylic oxidation of 10 using SeO2 in the pres-
ence of pyridine N-oxide as a co-oxidant gave a mixture
of , -unsaturated ketone 12,8 and alcohols 11a and 11b.7
Yields and ratios of the above allylic oxidation varied ac-
cording to the amount of SeO2 and pyridine N-oxide. As a
result, the best total yields (81%) of , -unsaturated ke-
tone 12 and the mixture of 11a and 11b were obtained un-
der the optimized conditions (1 equiv of SeO2 and 0.5
equiv of pyridine N-oxide in dioxane). A mixture of alco-
hols 11a and 11b was smoothly oxidized to the ketone 12
by the Albright–Goldman oxidation.9
Our next attempts were the conversion of the unsaturated
ketone 12 into the enantiomers of gabosine D (1) and E
(2), respectively, via a conjugate addition of water or ace-
tate followed by -elimination of the methoxymethyloxy
(MOMoxy) group at C3 (Scheme 2). Conjugate addition
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1341,1343,ftx,en;Y07002ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1342
T. Shinada et al.
LETTER
BBA
O
involving: i) catalytic hydrogenation of the exo-olefin
group of 11a and 11b, ii) oxidation to ketone 15, and iii)
-elimination of the MOMoxy group (Scheme 3). Hydro-
genation of the mixture of 11a and 11b followed by oxi-
dation using Dess–Martin periodinane afforded ketone
15, whose exposure to aqueous sodium hydroxide effect-
ed elimination of the MOMoxy group to give the desired
unsaturated ketone 16. Removal of the protecting groups
with TFA gave gabosine A (3). It has been reported that
hydrogenation of 3 gave 4 in only 22% yield.1c We repeat-
ed the same procedure and found that the reaction gave a
mixture of 4 and its -Me isomer (1:1) in poor yield. From
these results, we considered that protected 16 would be an
appropriate precursor for this conversion in view of the
stereoselectivity and the product yield. Protected 16 was
subjected to the hydrogenation, leading to a mixture of
17a and 17b in 80% yield. However, the ratio was 1:1.
O
BBA
O
BBA
O
O
O
OTBS
OTBS
OTBS
OR
a
b
d
6
HO
OMOM
PhS
11a: α-OH
11b: β-OH
O
9: R = H
10: R = MOM
c
8
e
BBA
O
BBA
O
OH
O
OTBS
HO
OH
O
OTBS
h
3
O
OMOM
O
O
RO
RO
f
12
13a R = H
13b R = Ac
ent-2 from 13a R = H (59%)
ent-1 from 13b R = Ac (64%)
g
Scheme 2 Conditions: a) 1.4 equiv mCPBA, CH2Cl2, 20 min (90%).
b) (EtO)3P, EtOH, reflux, 16 h (98%). c) MOMCl, 2 equiv i-Pr2NEt,
CH2Cl2, 16 h (90%). d) 1 equiv SeO2, 0.5 equiv pyridine N-oxide, 1,4-
dioxane, reflux, 16 h (11a, 11b (1:1 3:2), 54%; 12, 27%). e) Ac2O, Since the -methyl group of 17b is placed in an axial ori-
DMSO (3:2), 18 h (65%). f) 0.1 N NaOH, THF (1:9), 40 min (68%).
g) 5 equiv AcONa, AcOH, 110 °C, 2.5 h (71%). h) TFA–H2O (1:20),
CH2Cl2, 2–4 h.
entation on the conformationally rigid bicyclic ring, we
assumed that 17a would be epimerized to -isomer 17a.
As expected, 17b underwent epimerization by treatment
with DBU to give the desired 17a, which, upon deprotec-
tion with TFA, gave gabosine B (4). The spectroscopic
data and optical rotation of the synthetic 3 and 4 were
identical in all respects with those of the natural prod-
ucts.1c,2d,10
of H2O in the presence of a weak base such as DABCO
was unsuccessful, resulting in recovery of 12 even at ele-
vated temperature (~100 °C). On the other hand, the use
of 0.1 N sodium hydroxide afforded the desired allyl alco-
hol 13a in 68% yield. Similarly, an acetoxy group was in-
troduced to 12 using sodium acetate in acetic acid to
afford acetate 13b in 71% yield. The protecting groups of
13a and 13b were removed with TFA to give ent-2 and
ent-1, respectively. The spectroscopic data of the synthet-
ic ent-2 and ent-1 were identical in all respects with those
of the natural products, respectively, except for the sign of
optical rotation.1c
In conclusion, we have demonstrated an efficient conver-
sion of allyl sulfide 6 to gabosines A, B, ent-D, and ent-E
in a highly regio- and steroselective manner. The present
synthesis involves several stereoselective transformations
on the cyclohexane ring as exemplified by Mislow–Evans
rearrangement and epimerization of 17b to 17a. These re-
sults would provide new insight into the syntheses of car-
ba-sugars and other cyclitols via allyl sulfide 6 as the
useful synthetic precursor.
BBA
O
BBA
O
BBA
O
O
O
O
OTBS
OTBS
OTBS
11a
and
11b
b
a
c
Acknowledgement
60%
O
O
OMOM
a
HO
OMOM
This study was supported by a grant from the Research for the Fu-
ture Program from the Japan Society for the Promotion of Science
(JSPS) and SUNBOR Grant.
15
16
14
0.5 h,
90%
d
80%
(1:1)
BBA
OH
OH
O
HO
OH
HO
OH
O
OTBS
References
O
O
O
(1) Isolation and biological activity of gabosines: (a) Tatsuta,
K.; Tsuchiya, T.; Mikami, N.; Umezawa, S.; Umezawa, H.
J. Antibiot. 1974, 27, 579. (b) Muller, A.; Keller-Schierlein,
W.; Bielecki, J.; Rak, G.; Stumpfel, J.; Zahner, H. Helv.
Chim. Acta 1986, 69, 1829. (c) Bach, G.; Breiding-Mack,
S.; Grabley, S.; Hammann, P.; Hutter, K.; Thiericke, R.;
Hermann, U.; Wink, J.; Zeeck, A. Liebigs Ann. Chem. 1993,
241. (d) Tang, Y.-Q.; Maul, C.; Hofs, R.; Sattler, I.; Grabley,
S.; Feng, X.-Z.; Zeeck, A.; Thiericke, R. Eur. J. Org. Chem.
2000, 149.
(2) For recent synthetic studies: (a) Tatsuta, K.; Yasuda, S.;
Araki, N.; Takahashi, M.; Kamiya, Y. Tetrahedron Lett.
1998, 39, 401. (b) Lubineau, A.; Billaut, I. J. Org. Chem.
1998, 63, 5668. (c) Frederick, C.; Huntley, M.; Wood, H. B.;
Ganem, B. Tetrahedron Lett. 2000, 41, 2031. (d)Mehta, G.;
Lakshminath, S. Tetrahedron Lett. 2000, 41, 3509.
d
17a: β-Me
17b: α-Me
Gabosine B (4)
Gabosine A (3)
e
17 h, 68%
Scheme 3 Conditions: a) 10% Pd–C (50% w/w), H2, MeOH, 6 h. b)
1.2 equiv Dess–Martin periodinane, CH2Cl2 (67%), 4.5 h. c) 0.1 N
NaOH, THF, 3 h (81%). d) TFA, H2O (1:20), CH2Cl2. e) 0.5 equiv
DBU, C6H6, reflux, 16 h (89%).
It was envisioned that the addition of hydride to 12 would
provide a common intermediate 16 for the syntheses of
gabosines A (3) and B (4). However, several attempts for
the 1,4-conjugate reduction, using the Wilkinson catalyst/
H2, CuCl/PhMe2SiH, or Pd(OAc)2/Et3SiH were unsuc-
cessful, giving the starting 12 as the major product. There-
fore, we examined an alternative approach to 16
Synlett 2002, No. 8, 1341–1343 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Syntheses of Gabosine A, B, D, and E
1343
(3) (a) Shinada, T.; Yoshida, Y.; Ohfune, Y. Tetrahedron Lett.
1998, 39, 6027. (b) The allyl sulfide can be prepared in a
large scale (>20 g) from (–)-quinic acid via
(6) The exclusive diastereofacial rearrangement would be
induced by the steric repulsion of the bulky allylic silyloxy
group which lies on the -face of the cyclohexane ring.
(7) Structures of 9, 11a, and 11b were confirmed by their
conversions into conduritols A and C. Full details of these
results will be reported in due course.
tributylphosphine–diphenyldisulfide-assistedregioselective
dehydration and phenylthiolation of an exomethylene 1,2-
diol intermediate.
(4) For a review: Evans, D. A.; Andrews, G. C. Acc. Chem. Res.
1974, 7, 147.
(8) Kiegiel, J.; Wovkulich, P. M.; Uskokovic, M. R.
Tetrahedron Lett. 1991, 32, 6057.
(5) It was presumed that the allylic oxidation of A would
facilitate its conversion to B in comparison with that from 6
or 8 according to the related example: Bamba, M.;
Nishikawa, T.; Isobe, M. Synlett 1998, 371.
(9) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89,
2416.
(10) Yields on the deprotection step to gabosines were good to
moderate (>59%) due probably to the prolonged reaction
period leading to the undesired acid-catalyzed
decomposition.
Synlett 2002, No. 8, 1341–1343 ISSN 0936-5214 © Thieme Stuttgart · New York