A general stereodivergent strategy for the preparation of carbasugars. Syntheses of 5a-carba-α-D-glucose, α-D-galactose, and β-L-gulose pentaacetates from D-mannose

Article abstract of DOI:10.1016/S0040-4039(02)01121-8

A stereodivergent approach to 5a-carba-D- and L-pyranoses has been applied to the preparation of 5a-carba-α-D-gluco-, 5a-carba-α-D-galacto-, and 5a-carba-β-L-gulopyranose pentaacetates. The strategy, by which a single precursor can be transformed into thr

Full text of DOI:10.1016/S0040-4039(02)01121-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5559–5562
A general stereodivergent strategy for the preparation of
carbasugars. Syntheses of 5a-carba-a- -glucose, a- -galactose,
and b- -gulose pentaacetates from -mannose
D
D
L
D
Ana M. Go´mez,* Eduardo Moreno, Seraf´ın Valverde and J. Cristo´bal Lo´pez*
Instituto de Qu´ımica Orga´nica General, C.S.I.C., Juan de la Cierva 3, 28006 Madrid, Spain
Received 24 May 2002; accepted 13 June 2002
Abstract—A stereodivergent approach to 5a-carba-
5a-carba-a- -galacto-, and 5a-carba-b- -gulopyranose pentaacetates. The strategy, by which a single precursor can be trans-
formed into three different carbasugars, features a stereoselective reduction followed by deoxygenation of a key polyoxygenated
D
- and
L
-pyranoses has been applied to the preparation of 5a-carba-a-D-gluco-,
D
L
methylcyclohexanone intermediate. The latter is readily available by 6-exo-dig radical cyclization of a
D-mannose derivative.
© 2002 Elsevier Science Ltd. All rights reserved.
More than 30 years ago McCasland and coworkers
synthesized the first sugar in which a methylene group
replaced the oxygen ring.1 Owing to their close resem-
blance to the parent carbohydrate,1 many of these
substances, now termed carbasugars,2 were found to
possess an interesting range of biological activities,3
which has triggered the development of different syn-
thetic approaches for their preparation.1,4,5 In this con-
text we have recently reported two synthetic strategies
for such an approach.6–8 These methods, based on
radical cyclizations of monosaccharide derivatives,9
were designed to directly correlate a given carbohy-
drate, 1, with its corresponding carbasugar, 2 (Scheme
1).
tion of
intermediate. In this communication, we disclose the
syntheses of 5a-carba-a- -galacto 21, 5a-carba-b-
gulo, 24, and 5a-carba-a- -glucopyranose, 30, penta-
D- and L-carbasugars from a single carbocyclic
D
L-
D
acetates from a polyoxygenated methyl cyclohexanone,
e.g. 6 (Scheme 2b). The latter is readily available by
ozonation of a methylenecyclohexene, e.g. 5, prepared
by 6-exo-dig radical cyclization of a
precursor 3 (Scheme 2a).
D-mannose derived
Our approach takes advantage of the observation that
selective deoxygenation of polyoxygenated
intermediate10 (e.g. 7, Scheme 3) at C-4 or at C-5a
could afford either a 5a-carba- -sugar derivative, 8, or
a 5a-carba- -sugar derivative 9, respectively.
a
L
D
More recently, unlike in our previous work,6,7 we have
focused on a stereodivergent strategy for the prepara-
When the above-mentioned deoxygenation is combined
with the stereoselective reduction of a carbonyl group
in a polyoxygenated cyclohexanone, e.g. 10, the latter
can be correlated with up to three different carbasugars
(Scheme 4). Accordingly, ketone 10, could be trans-
formed into epimeric polyols 11 and 12, which upon
deoxygenation either at C-5a or at C-4 would afford
carbapyranoses 13, 14 and 15.
O
O
O
O
O
5
5
OH
OH
1
1
ref 7
O
O
O
O
2
Along these lines, carbonate 5 (Scheme 5) was treated
with potassium carbonate in methanol to afford alkene
16, which upon ozonolysis and reduction at C-5a
afforded diol 17. Compound 19, in which the 4-OH had
already been differentiated, was prepared by benzyla-
tion of 16 followed by chemoselective acetal hydrolysis
and regioselective silylation at the primary hydroxyl
1
D-mannopyranose
5a-carba-D-mannose
Scheme 1.
* Corresponding authors. Tel.: +34 91 5622900; fax: +34 91 5644853;
e-mail: anago@iqog.csic.es; clopez@iqog.csic.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01121-8

5560
A. M. Go´mez et al. / Tetrahedron Letters 43 (2002) 5559–5562
OPh
O
O
O
O
S
O
O
5
O
5
OR
OR
HSnBu3
4
a)
OR
+
1
AIBN
74%
O
O
O
O
O
O
(2 : 1)
3
4
5
four steps
from D-mannose
R= COOEt
O
O
O
O
5a
5a
OR'
O
OR'
b)
ozonation
O
O
O
O
5
6
Scheme 2.
group. Deoxygenation at C-4, was carried out via the
corresponding xanthate by treatment with tri-n-butyltin
hydride,11 and led to 5a-carba-galactose derivative 20.
Deprotection steps, followed by acetylation yielded 5a-
imentation was carried out on the reduction of cyclo-
hexanones 25a and 25b, which showed a preferred
facial approach of the incoming reducing agent
carba-a-
-galactose pentaacetate 2112–14 ([h]D21 +35.8 (c
D
0.4, CHCl3), Lit. Ref. 13a ([h]2D0 +35.2 (c 1.77, CHCl3).
HO
O
5a
Compound 16 was benzylated at 1-OH and submitted
to ozonation and reduction of the ensuing carbonyl
group to afford 22 (Scheme 6) in 40% yield (its C-5a
HO
OH
1
HO
OH
epimer
was
also
obtained
(3:1
mixture)).
10
Deoxygenation11 of 22 yielded gulose-derivative 23
which was submitted to routine deprotection steps and
Reduction
of C-5a
acetylation to yield 5a-carba-b-L-gulose pentaacetate
2415 ([h]D21 +18.7 (c 0.4, CHCl3), Lit. Ref. 15a ([h]2D0
+20.5 (c 1.0, CHCl3).
HO
HO
HO
OH
OH
5a
5a
4
HO
4
OH HO
OH
The synthetic process for the preparation of 5a-carba-
1
1
D
-glucose implied: (a) preparation of an equatorial
HO
OH
OH
5a-OH, rather than an axial one as in 17, and (b)
deoxygenation at C-4 (as in Scheme 4). Extensive exper-
11
12
Deox
C-4
Deox
C-5a
Deox
C-4
HO
HO
HO
OH
OH
HO
HO
HO
OH
OH
5a
Deoxygenation
at C-5a
OH
5a
4
OH
1
4
OH
OH
HO
OH
HO
HO
OH
HO
HO
OH
5a
HO
HO
OH
OH
8
5
14
β-L-gulo
5a-carba-L-sugar
4
OH
HO
HO
HO
OH
HO
1
HO
HO
HO
OH
4
4
4
OH
OH
HO
OH
4
1
1
7
Deoxygenation
at C-4
HO
13
α-D-galacto
OH
HO
HO
HO
OH
15
9
α-D-gluco
5a-carba-D-sugar
Scheme 3.
Scheme 4.

A. M. Go´mez et al. / Tetrahedron Letters 43 (2002) 5559–5562
5561
preferred
O
O
O
O
OH
1) O3,
Me2S
O
O
O
5a
O
OR
O
5a
OH
OH
BnBr
1
Reduction
OR
K2CO3
70%
O 4
O
4
O
O
OH
5
NaH
72%
O
O
O
O
2) NaBH4,
CeCl3
75%
25
a) R= H, b) R= Bn
17 R= H
16
OBn
OBn
17
22 R= Bn
1) NaH,
CS2,
MeI
1) PPTS
Major isomer
O
O
O
TBSO
OBn
OBn
CH2Cl2
(85%)
Scheme 7.
4
HO
2) HSnBu3,
AIBN
2) TBSCl
Imidazol
(90%)
O
O
O
carbonyl group led to the desired isomer, 29, as the
70%
major isomer (2.5:1 ratio). Conventional deprotection
18
19
steps on 29, and acetylation led to 5a-carba-a-D-glucose
OAc
pentaacetate 3014c,16,17 ([h]D21 +32.1 (c 0.4, CHCl3), Lit.
Ref. 16a ([h]2D1 +37 (c 0.90, CHCl3), Ref. 16b ([h]2D1 +57
(c 0.90, CHCl3).
OTBS
OAc
1) Bu4NF
2) H2,
Pd/C
OBn
OAc
OAc
OAc
4
AcO
OAc
OAc
4
OBn
4
3) AcOH,
THF
H2O
4) Ac2O
pyridine
In summary, we have reported a stereodivergent strat-
egy for the preparation of carbasugars based on the
combination of a stereoselective reduction and a site-
selective deoxygenation of a polyoxygenated intermedi-
AcO
O
O
OAc
20
21
ate. The latter is readily available from
D-mannose
50%
upon 6-exo-dig radical cyclization. We have illustrated
the synthetic potential of this approach with the prepa-
ration of three carbasugars 21, 24, and 30 from a single
synthetic intermediate, 5. Similar chemistry carried out
with major isomer 4 (Scheme 2), might have led to
Scheme 5.
O
O
OH
1) NaH,
CS2,
MeI (80%)
1) NaH, BnBr
2) O3, Me2S
5a
5a-carbasugars of the a-
D
-allo-, a-
L
-gulo-, and a-
D-gulo
OBn
series. The scope of this strategy can still be enhanced
16
3) NaBH4, CeCl3
40%
2) HSnBu3,
AIBN
O
O
OTPS
O
O
(70%)
22
1) PPTS
CH2Cl2
NaH,
BnBr
OBn
1
O
O
1
4
HO
OBn
AcO
AcO
16
1) H2, Pd/C
O
O
5a
80%
2) ClTPS
Imidazol
5a
OBn
O
O
OAc
OAc
2) AcOH/THF/H2O
(4:2:1)
78%
26
O
O
AcO
27
OTPS
OH
3) Ac2O, pyridine
70%
OTPS
23
24
1) NaH, CS2,
MeI
5a
1) O3, Me2S
Scheme 6.
OBn
4
OBn
2) HSnBu3
AIBN
54%
2) NaBH4,
CeCl3
O
O
O
O
60%
(Scheme 7) leading to axial C-5a derivatives. Finally,
removal of the isopropylidene acetals and deoxygena-
tion at C-4 prior to reduction of the carbonyl group
allowed us to obtain the desired 5a-OH epimer as a
major isomer (vide infra).
29
28
AcO
AcO
1) Bu4NF AcO
2) H2, Pd/C
OAc
5a
4
4
5a
OAc
OAc
OAc
OAc
3) AcOH/THF/H2O
(4:2:1)
Chemoselective deprotection of the acid labile primary
isopropylidene acetal in 26 (Scheme 8), followed by
regioselective protection of 6-OH afforded compound
27, in which the 4-OH group was now differentiated.
Deoxygenation via the corresponding xanthate, as
above, resulted in the formation of olefin 28. Ozonation
of the latter, followed by reduction of the resulting
AcO
AcO
4) Ac2O, pyridine
56%
30
Scheme 8.

5562
A. M. Go´mez et al. / Tetrahedron Letters 43 (2002) 5559–5562
by the use of different monosaccharide starting materi-
als, or by the use of carbocyclic key intermediates with
different stereocenters at C-5, and C-1, while maintain-
ing the stereochemical integrity, at positions C-2, C-3
6. Go´mez, A. M.; Danelo´n, G. O.; Valverde, S.; Lo´pez, J.
C. J. Org. Chem. 1998, 63, 9626.
7. Go´mez, A. M.; Danelo´n, G. O.; Moreno, E.; Valverde,
S.; Lo´pez, J. C. Chem. Commun. 1999, 175.
8. For reviews on the preparation of carbocycles from car-
bohydrates see: (a) Ferrier, R. J.; Middleton, S. Chem.
Rev. 1993, 93, 2779. (b) Fraser-Reid, B.; Tsang, R. In
Strategies and Tactics in Organic Synthesis; Academic
Press: New York, 1989; Vol. 2, Chapter 4.
and C-4, in derivatives arising from D
-mannose.7 Use of
the above strategy for the preparation of additional
carbasugars and derivatives thereof is underway in our
laboratory and will be described in due course.
9. For the first references on radical cyclization of carbohy-
drate derivatives leading to carbasugars see: (a) Schmid,
W.; Whitesides, G. M. J. Am. Chem. Soc. 1990, 112,
9670; (b) Andersson, F. O.; Classon, B.; Samuelsson, B.
J. Org. Chem. 1990, 55, 4699.
10. Selected synthesis of related compounds: (a) Ogawa, S.;
Ohno, M.; Ohhira, T. Heterocycles 1999, 50, 57; (b)
Takahashi, H.; Iimori, T.; Ikegami, S. Tetrahedron Lett.
1998, 39, 6939; (c) Riley, A. M.; Guedat, P.; Schlewer,
G.; Spiess, B.; Potter, B. V. L. J. Org. Chem. 1998, 63,
295; (d) McDevitt, R. E.; Fraser-Reid, B. J. Org. Chem.
1994, 59, 3250.
Acknowledgements
This research was supported with funds from the Direc-
cio´n General de Ensen˜anza Superior (Grants No.
PB97-1244, PPQ2000-1330, and BQU2001-0582). E.M.
thanks Janssen-Cilag S.A. and C.S.I.C. for a fellowship.
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