Stereodivergent synthesis of carbasugars from D-mannose. Syntheses of 5a-carba-α-D-allose, β-L-talose, and α-L-gulose pentaacetates

Article abstract of DOI:10.1055/s-2002-31900

A stereodivergent entry to 5a-carba-D- and L-pyranoses from a single precursor is described. The approach is based on the selective deoxygenation of polyoxygenated methylcyclohexane intermediates, readily available from radical cyclization of D-mannose de

Full text of DOI:10.1055/s-2002-31900

LETTER
891
Stereodivergent Synthesis of Carbasugars from D-Mannose. Syntheses of
5a-Carba- -D-allose, -L-Talose, and -L-Gulose Pentaacetates
S
tereodivergent Sy
n
nthesisof
C
a
a
rbasugars from
D
M
-
Mannose . Gómez,* Eduardo Moreno, Serafín Valverde, J. Cristóbal López*
Instituto de Química Orgánica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
Fax +34(91)5644853; E-mail: clopez@iqog.csic.es
Received 15 April 2002
termediates 4 and 5 (Scheme 2) readily obtained by radi-
cal cyclization of a D-mannose derivative precursor, 3.
Our strategy, outlined in Scheme 3, is based on the selec-
tive deoxygenation of a polyoxygenated intermediate10
Abstract: A stereodivergent entry to 5a-carba-D- and L-pyranoses
from a single precursor is described. The approach is based on the
selective deoxygenation of polyoxygenated methylcyclohexane in-
termediates, readily available from radical cyclization of D-man-
nose derivatives. This strategy has been applied to the preparation (e.g. 6, Scheme 3) at C-4 or at C-5a to afford either a 5a-
of 5a-carba- -D-allo-, 5a-carba- -L-talo-, and 5a-carba- -L-gulopy-
ranose pentaacetates.
carba-L-sugar derivative, 7, or a 5a-carba-D-sugar deriva-
tive 8, respectively.
Key words: stereodivergent synthesis, carbasugars, radical cycli-
The synthetic route takes further advantage from the fact
zation, stereoselective synthesis
that the relative ratio of compounds 4 and 5 can be modu-
lated upon changes in the nature of the substituent at C-1
The term ‘carbasugar’ is used to describe monosaccharide
Ph
Ph
O
Ph
analogues in which the oxygen ring has been replaced by
a methylene group.1 Many of these substances, owing to
their close resemblance to carbohydrates,2 are endowed
with an interesting range of biological activities3 which
has triggered the development of different synthetic ap-
proaches for their preparation.1,4,5 As part of an ongoing
program in our laboratory aimed at the preparation of car-
bocycles from carbohydrates6,7 we have recently reported
two synthetic strategies for such an approach.8,9 These
methods, based on radical cyclizations of monosaccharide
derivatives, were designed to directly correlate a given
carbohydrate, 1, with its corresponding 5a-carba-D-pyra-
nose analogue, 2 (Scheme 1).8,9 However a direct correla-
tion method for the preparation of ‘rare’ carbasugars, or
those corresponding to the L-series, would present prob-
lems related with the availability of the starting monosac-
charides.
PhO
O
O
O
O
O
S
4
O
O
5
5
OR
OR
HSnBu3
OR
1
+
AIBN
ref 9
O
O
O
O
O
3
4
5
4 steps
from D-mannose
a) R= OTBS; b) R=OC(O)OEt; c) R= H
Scheme 2 6-Exo-dig radical cyclization of a D-mannose derivative9
HO
HO
5a
OH
Deoxygenation
at C-5a
1
HO
OH
HO
HO
OH
5a
7
5
O
O
O
O
5a-carba-
D
-sugar
O
OH
4
5
5
1
OH
OH
1
1
HO
OH
HO
OH
O
O
O
O
6
OH
4
Deoxygenation
at C-4
1
2
1
D-mannopyranose
5a-carba-D-mannopyranose
HO
HO
Scheme 1 Direct correlation of carbohydrates with carbasugars
HO
HO
In this communication we disclose a novel, stereodiver-
gent, approach for the synthesis of D- and L-carbasugars
from a single precursor which has been illustrated with the
syntheses of 5a-carba- -L-gulo, 13, 5a-carba- -D-allo, 19,
and 5a-carba- -L-talopyranose, 23, pentaacetates from in-
4
OH
1
HO
OH
8
5a-carba-L-sugar
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,0891,0894,ftx,en;D07802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
Scheme 3 Stereodivergent synthesis of carbasugars from polyoxy-
genated intermediates

892
A. M. Gómez et al.
LETTER
(Table). Cyclization of 3c yields a 1:4.2 mixture of trans- C-4, then in 17, via the corresponding phenyl thionocar-
and cis-dioxa-decalines 4c and 5c, compared to a 1:1.5 bonate, paved the way to D-allo-derivative 18, which upon
ratio when the protecting group at C-1 is a tert-butyldime- conventional deprotection steps and acetylation led to
21
thylsilyl group.
5a-carba- -D-allose 1911–13. {[ ]D +36.0 (c 1.0, CHCl3,
mp 95–98 °C). Lit. ref.12 [ ]D +78.7 (c 1.5, CHCl3, mp
21
Table Influence of the Nature of the Substituent at C-1 in the Stere-
ochemical Outcome of the Radical Cyclization
96–97 °C}.
HSnBu3
AcOH
THF
H2O
O
O
OR
O
HO
HO
OBn
OBn
+
5
4
3
AIBN
1) O3, Me2S
OR
1
5c
Entry
Substrate
Ratio (4:5)
1:1.5
Yield (%)
2) NaBH4, CeCl3
62%
(4:2:1)
95%
O
HO
OH
i
3a
3b
3c
95
75
51
16
14 R= H
ii
iii
1:3.3
NaH, BnBr
70%
15 R= Bn
1:4.2
1) ClTBDPS
TPSO
TPSO
HO
OBn
OBn
OBn
OBn
Imidazol
DMAP
1) ClC(S)OPh
Pyridine
Accordingly, compound 5c was transformed into carba-
sugars of the L-gulo- and D-allo-series by deoxygenation
at C-5a and C-4 respectively. Protection of the 1-OH
group in 5c led to 9 (Scheme 4), which upon ozonolysis
and reduction of the resulting carbonyl group afforded
compounds 10, as a 1:1 epimeric mixture. Deoxygenation
at C-5a in the latter, via the corresponding epimeric xan-
thates, 11, furnished L-gulo derivative 12. Routine trans-
formations in 12, then led to 5a-carba- -L-gulose
4
4
2) HSnBu3
AIBN
OMe
O
O
O
O
pTsOH,
2)
59%
17
18
45%
AcO
1) Bu4NF.3H2O
2) H2 Pd/C
OAc
OAc
OAc
AcO
AcO
AcO
4
4
OAc
OAc
21
pentaacetate 1311,12. {[ ]D –34.0 (c 0.32, CHCl3). Lit.
3) AcOH/THF/H2O
(4:2:1)
ref.11 [ ]D21 –29.5 (c 1.5, CHCl3}.
AcO
4) Ac2O, pyridine
19
86%
Ph
O
Scheme 5 Synthesis of 5a-carba- -L-talose pentaacetate 19
O
O
OR
O
1) O3, Me2S
5a
NaH, BnBr
73%
O
OBn
1
OBn
5c
Compound 20, obtained by ozonolysis and reduction of
4a (Scheme 6), was treated with phenylchlorothionofor-
mate in the presence of pyridine to afford thiocarbonate
21, in which an unexpected rearrangement of the trans
4,6-O-isopropylidene group to a cis-5a,6-O-isopropy-
lidene ring had taken place prior to activation of the hy-
droxyl group at C-4. Compound 22, which was obtained
by treatment of 21 with tri-n-butyltin hydride in toluene,
was then transformed into 5a-carba- -L-talose pentaace-
tate 2314 {[ ]D21 +5.2 (c 0.4, CHCl3), mp 135–138 °C}.
2) NaBH4, CeCl3
64%
O
O
O
9
10 R= H
NaH, CS2, MeI
70%
11 R= C(S)SMe
1) H2 Pd/C
2) AcOH/THF/H2O
OBn
(4:2:1)
O
AcO
AcO
AcO
5a
O
HSnBu3
OAc
3) Ac2O, pyridine
70%
AIBN
75%
In summary, we have reported a stereodivergent strategy
for the preparation of carbasugars based on the selective
deoxygenation of polyoxygenated intermediates readily
available from D-mannose upon radical cyclization. We
have illustrated the synthetic potential of this approach
with the preparation of carbasugars 13, 19, and 23 from
synthetic intermediates 4 and 5. The scope of this strategy
can still be greatly enhanced by modifying the stereo-
centers at C-5, C-5a and C-1 in the latter compounds,
while maintaining the stereochemical integrity, at posi-
tions C-2, C-3 and C-4, arising from D-mannose, or by uti-
lizing a different monosaccharide starting material. Use of
the above strategy for the preparation of additional carba-
sugars and derivatives thereof is underway in our labora-
tory and will be described in due course.
O
O
OAc
12
13
Scheme 4 Synthesis of 5a-carba- -L-gulose pentaacetate 13
The synthetic process for the deoxygenation at C-4 of
compound 5c (Scheme 5), involved ozonolysis of the lat-
ter followed by reduction of the resulting carbonyl group
to yield diol 14, which upon benzylation afforded diace-
tonide 15. Deprotection of the acid labile isopropylidene
groups in 15 resulted in the formation of tetraol 16. Com-
pound 17, in which the 4-OH group was now differentiat-
ed, was prepared from 16 through a reactions sequence
which involved regioselective silylation at the primary
hydroxyl group followed by selective protection of the cis
diol moiety as O-isopropylidene acetal. Deoxygenation at
Synlett 2002, No. 6, 891–894 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Stereodivergent Synthesis of Carbasugars from D-Mannose
893
Hz, 1 H, H5aeq). 13C NMR (75 MHz, CDCl3): (ppm) = 170.8,
170.1, 170.0, 169.8, 169.6, 69.0, 68.9, 68.7, 66.1, 63.0, 29.7, 23.5,
26.8 ( 2), 20.7, 20.6, 20.5. Anal. Calcd for C17H24O10: C, 52.57; H,
6.23. Found: C, 52.71; H, 6.43.
O
O
OH
O
5a
1) O3, methanol
OTBS ClC(S)OPh
4
4a
2) BH3.SMe2
60%
Pyridine
70%
O
Acknowledgement
20
This work was supported by grants from the Dirección General de
Enseñanza (grants PB96-0822 and PB97-1244). EM Thanks
Janssen-Cilag and C.S.I.C. for a fellowship.
O
O
1) Bu4NF.3H2O
PhO
O
O
O
2) AcOH/THF/H2O
(4:2:1)
OTBS
HSnBu3
S
5a
4
5a
4
O
OTBS
AIBN
90%
References
3) Ac2O, pyridine
(1) Suami, T.; Ogawa, S. Adv. Carbohydr. Chem. Biochem.
1990, 48, 21.
O
O
O
80%
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257; and references cited therein.
21
22
OAc
4
OAc
OAc
5a
4
5a
AcO
OAc
OAc
OAc
OAc
AcO
AcO
23
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2001, 42, 7663. (b) Gravier-Pelletier, C.; Maton, W.;
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2000, 41, 7663. (e) Arjona, O.; Iradier, F.; Medel, R.;
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Scheme 6 Synthesis of 5a-carba- -L-talose pentaacetate 23
General Procedure for Radical Cyclization
A thoroughly degassed (argon) solution of thiocarbonate in toluene
(0.02 M) was heated to 85 °C under argon. A solution of Bu3SnH
(1.6 equiv) and AIBN (0.1 equiv) in toluene (5 mL/mmol) was then
added and the reaction mixture was kept at that temperature over 12
h. After cooling, the organic solvent was evaporated and the residue
was purified by flash chromatography.
Data for selected compounds:
1,2,3,4,6-penta-O-Acetyl-5a-carba- -l-gulopyranose 13. (39 mg,
21
1
70% overall): [ ]D –34.1 (c 0.3, CHCl3) H NMR (300 MHz,
C6D6): (ppm) = 5.83 (dd, J = 3.2, 6.5 Hz, 1 H, H3), 5.72 (m, 2 H,
H2 y H4), 5.61 (dt, J = 3.0, 6.7 Hz, 1 H, H1), 4.24 (dd, J = 7.0, 10.8
Hz, 1 H, H6), 4.02 (dd, J = 6.7, 10.8 Hz, 1 H, H6), 2.76 (m, 1 H,
H5), 1.96 (m, 2 H, 2H5a), 1.97 (s, 3 H), 1.91(s, 3 H), 1.90 (s, 3 H);
1.89 (s, 3 H), 1.80 (s, 3 H). 13C NMR (75 MHz, CDCl3): (ppm) =
169.8, 169.7, 169.5, 169.4, 169.3, 69.1, 68.3, 67.5, 62.9, 53.3, 30.2,
26.9, 20.5, 20.3, 20.2, 20.0, 18.5. MS: m/z = 411.2 [M + Na+]. Anal.
Calcd for C17H24O10: C, 52.57; H, 6.23. Found: C, 52.81; H, 6.51.
1,2,3,4,6-penta-O-Acetyl-5a-carba- -d-allopyranose 19. (43 mg,
86% overall): mp 95–98 °C, [ ]D21 +36.0 (c 1.0, CHCl3) 1H NMR
(300 MHz, C6D6): (ppm) = 5.54 (t, J = 3.1 Hz, 1 H, H3), 5.38 (m,
1 H, H1), 4.96 (t, J = 3.1 Hz, 1 H, H2), 4.89 (dd J = 3.1, 11.3 Hz, 1
H, H4), 4.18 (dd, J = 4.7, 11.3 Hz, 1 H, H6), 4.00 (dd, J = 2.9, 11.3
Hz, 1 H, H6), 2.56 (m, 1 H, H5), 2.14 (s, 3 H), 2.11 (s, 3 H), 2.10 (s,
3 H), 2.02 (s, 3 H), 2.01 (m, 1 H, H5aax), 2.00 (s, 3 H), 1.71 (dt,
J = 3, 14 Hz, 1 H, H5aeq). 13C NMR (75 MHz, CDCl3): (ppm) =
170.8, 170.1, 170.0, 169.7, 169.6, 69.3, 68.9, 68.5, 67.1, 63.0, 30.7,
29.3, 20.9, 20.8, 20.7, 20.6, 20.5. Anal. Calcd for C17H24O10: C,
52.57; H, 6.23. Found: C, 52.76; H, 6.51.
1,2,3,4,6-penta-O-Acetyl-5a-carba- -l-talopyranose 23. (84 mg,
21
1
80%): mp 135–138 °C, [ ]D +5.2 (c 0.4, CHCl3) H NMR (500
MHz, CDCl3): (ppm) = 5.49 (t, J = 3.1 Hz, 1 H, H2), 5.38 (t,
J = 2.9 Hz, 1 H, H4), 4.39 (m, 2 H, H1, H3), 4.05 (dd, J = 8.8, 11.1
Hz, 1 H, H6ax), 3.91 (dd, J = 6.3, 11.1 Hz, 1 H, H6eq), 2.20–2.10 (m,
1 H, H5), 2.11 (s, 3 H), 2.07 (s, 3 H), 2.02 (s, 3 H), 1.99 (s, 3 H),
1.96 (s, 3 H), 1.88 (q, J = 12.5 Hz, 1 H, H5aax), 1.69 (dt, J = 4, 12.5
Synlett 2002, No. 6, 891–894 ISSN 0936-5214 © Thieme Stuttgart · New York

894
A. M. Gómez et al.
LETTER
(10) Selected synthesis of related compounds: (a) Ogawa, S.;
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(13) Enantiopure D form: See ref.11
(14) DL mixture: Ogawa, S.; Kobayashi, N.; Nakamura, K.;
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Synlett 2002, No. 6, 891–894 ISSN 0936-5214 © Thieme Stuttgart · New York