A novel entry to 5a-carba-hexopyranoses from carbohydrates based on a 6-exo-dig radical cyclization: Synthesis of 5a-carba-β-D-mannopyranose pentaacetate

Article abstract of DOI:10.1039/a808848i

Carbohydrate-derived 2,3:4,6-diacetonides which are homologated at C-1 by reaction with phenyl acetylide undergo a 6-exo-dig radical cyclization, from a radical located at C-5, to yield highly functionalized cyclohexanes that are correlated with carba-sugars.

Full text of DOI:10.1039/a808848i

A novel entry to 5a-carba-hexopyranoses from carbohydrates based on a
6-exo-dig radical cyclization: synthesis of 5a-carba-b- -mannopyranose
D
pentaacetate
Ana M. Gómez,* Gerardo O. Danelón, Eduardo Moreno, Serafín Valverde and J. Cristóbal López*
Instituto de Química Orgánica General (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
E-mail: clopez@cc.csic.es
Received (in Cambridge, UK) 12th November 1998, Accepted 24th November 1998
Carbohydrate-derived 2,3:4,6-diacetonides which are homo-
logated at C-1 by reaction with phenyl acetylide undergo a
6-exo-dig radical cyclization, from a radical located at C-5,
to yield highly functionalized cyclohexanes that are corre-
lated with carba-sugars.
isomer, diol 5 in 65% isolated yield.† Chemoselective protec-
tion of the prop-2-ynylic hydroxy group could be accomplished
by the use of either ethyl chloroformate (6a, 60%)13 or
TBDMSCl (6b, 65%).‡ The hydroxy group at C-5 in 6a, or 6b,
was next treated with phenyl chlorothioformate14 to furnish
derivatives 7a (85%) and 7b (80%), respectively, which upon
The term ‘carba-sugar’ is currently used to describe mono-
saccharide analogs having a methylene group instead of the ring
oxygen atom.1 Carba-sugars derived from hexopyranoses,
‘carba-pyranoses’ (e.g. 1), were first prepared more than three
decades ago by McCasland and co-workers2 prior to their
isolation from natural sources as components of important
antibiotics.3 Many of these substances, owing to their close
structural resemblance to carbohydrates, are endowed with an
interesting range of biological activities4 which has triggered
the development of different synthetic approaches for their
preparation.1,5,6 However, to the best of our knowledge only
one synthetic approach involving radical ring closure7 leading
to 6-deoxy-5a-carba-pyranosides has been reported.8 A very
recent report by Maudru, Singh and Wightman9 on the synthesis
of carba-pyranoses by 6-exo-dig radical cyclization of carbohy-
drate derived alkynes prompts us to disclose our own results in
this area.
reaction with Bu3SnH and AIBN15 (toluene, 90 °C, 0.02
M)
afforded tricyclic derivatives 8§ and 9§ in 95% combined yield.
The synthetic scheme was next continued with compound 8b§
[two isomers: d 2.89 (ddt, J4,5 = J5,6ax = 10.8 Hz, J5,6eq = 4.5
Hz, J5,Holef = 2.8 Hz, H-5 one isomer), 2.48 (ddt, J4,5 = J5,6ax
= 11.1 Hz, J5,6eq = 5.1 Hz, J5,Holef = 2.3 Hz, H-5 other
isomer)]. Accordingly, after a change in the protecting group at
PhO
Ph
Ph
S
O
O
O
O
5
OH
1
O
O
O
i
iv
O
O
4
H
OR
H
OR
5
R = H
ii
6a R = CO2Et
b R = TBDMS
iii
7a R = CO2Et
b R = TBDMS
As a continuation of our interest in the synthesis of highly
functionalized carbocycles10 from carbohydrates,11 we turned
our attention to the preparation of 5a-carba-hexopyranosides by
radical ring closure of carbohydrate derived alkynes. Here we
report some preliminary results which have resulted on the
v
H4
H4
O
O
O
Ph
H5
5
O
O
O
OR
synthesis of 5a-carba-b-
D
-mannose pentaacetate 13. Our gen-
+
O
Ph
OR
eral approach, outlined in Scheme 1 for
D
-mannose, correlates
retrosynthetically the methylene group of the carba-pyranoside
(e.g. 1) with an exocyclic double bond in a highly functionalized
cyclohexane (e.g. 2). The latter could thus be obtained by a
6-exo-dig radical cyclization of a carbohydrate derived alkyne
(e.g. 3) easily derived from a pyranose 2,3:4,6-diacetonide
derivative (e.g. 4).
O
9a R = CO2Et
b R = TBDMS
8a R = CO2Et
b R = TBDMS
(1 : 3.5 ratio)
(1 : 1.5 ratio)
OH
O
O
Accordingly mannose diacetonide 4 (Scheme 2), prepared in
O
O
O
5
one single step from
-mannose by kinetic acetonation,12 was
D
O
O
H5a
OBn
ix
vi–viii
OBn
8b
O
O
treated with lithium phenylacetylide to yield, as a very major
H1
11
10
R'
6
O
O
4
O
2
x, xi
O
5a
1
5
5a
O
O
OR
OR
5
O
O
AcO
AcO
AcO
O
OAc
O
O
xii–xiv
OAc
OBn
1
2
O
12
13
R'
X
1
Scheme 2 Reagents and conditions: i, PhCNCLi, THF, 278 °C; ii, ClCO2Et,
O
O
O
O
5
O
O
Py, CH2Cl2, 0 °C; iii, TBDMSCl, Et3N, DMAP, CH2Cl2; iv, ClC(S)OPh,
O
O
D-mannose
O
Py, MeCN, 85 °C, 1 h; v, Bu3SnH, AIBN, toluene (0.02 M), 90 °C; vi,
O
1
TBAF, THF; vii, HNa, Bu4NI, BnBr; viii, O3, MeOH–CH2Cl2 (1:1), 278
°C, then Me2S; ix, BH3·SMe2, THF; x, HNa, CS2, MeI; xi, Bu3SnH, AIBN,
toluene, 90 °C; xii, H2, Pd/C, MeOH; xiii, AcOH–THF–H2O (4:2:1), 60 °C;
xiv, Ac2O, Py.
OR
OH
3
4
Scheme 1
Chem. Commun., 1999, 175–176
175

+2.9 (c 1.1, CHCl3); lit.,16b +2.53 (c 1.67, CHCl3); lit.,16c +2.9 (c 1.28,
CHCl3).
C-1 in 8b (OTBDMS?OBn), ozonolysis was carried out to
yield ketone 10, which upon reduction (BH3·SMe2) gave, in a
stereoselective manner, the highly functionalized cyclohexane
11 (J5a,1 = 3.8 Hz) (75%, three steps). The hydroxy function at
C-5a was deoxygenated under radical conditions, via its
-mannopyranoside derivative
12 (85%, two steps). Hydrolysis of the acetals followed by
1 T. Suami and S. Ogawa, Adv. Carbohydr. Chem. Biochem., 1990, 48,
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154, 257 and references cited therein.
xanthate,14,15 to afford 5a-carba-
D
hydrogenation and acetylation gave 5a-carba-b-
pentaacetate 1316¶ (87%, three steps).
D-mannose
In our opinion, several aspects of the synthetic scheme
deserve further comment: (i) the choice of a 2,3:4,6-diacetonide
derivative has reduced the protecting group manipulations in the
synthetic scheme to a minimum; (ii) the selection of a
phenylacetylide as the radical acceptor was made on the basis of
the beneficial effects of the phenyl group in alkyne cycliza-
tions;17,18 (iii) unlike other approaches to carba-sugars from
carbohydrates,8,9 in this synthetic scheme an hexose is corre-
lated with its corresponding carba-pyranoside; (iv) the present
method permits access to fully functionalized cyclohexanes
(e.g. 11) of potential interest in the synthesis of biologically
active compounds;4 (v) by changing the protecting group of the
hydroxy function a to the radical acceptor some stereocontrol
has been attained in the cyclization reaction in favor of the
isomer with trans 6,6-ring fusion19 (8, Scheme 2); (vi) similar
chemistry carried out on 9a or 9b would allow access to 5a-
5 S. Ogawa, in Studies in Natural Products Chemistry, ed. A-U Rahman,
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carba-a- -gulopyranose.
L
In conclusion we have disclosed a novel entry into function-
alized cyclohexane derivatives and carba-sugars from mono-
saccharides by 6-exo-dig cyclization of alk-6-ynyl radicals. Our
approach complements the one recently described by Maudru
et al.9 in the sense that it allows for functionalization at all
positions of the cyclohexane ring. The application of this
synthetic scheme to other pyranose derived diacetonides is
currently under study.
9 E. Maudru, G. Singh and R. H. Wightman, Chem. Commun., 1998,
1505.
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Reid and R Tsang, Strategies and Tactics in Organic Synthesis,
Academic Press, New York, 1989, vol. 2, p. 123.
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1997, 62, 6612; J. C. López, A. M. Gómez and S. Valverde, J. Chem.
Soc., Chem. Commun., 1992, 613.
This research was supported with funds from the Dirección
General de Enseñanza Superior (grants: PB96-0822 and PB97-
1244). A. M. G. thanks the Consejo Superior de Investigaciones
Científicas for financial support. G. O. D. thanks the Agencía
Española de Cooperacion Internacional for a MUTIS scholar-
ship.
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Notes and references
† Compound 5 was the major isomer observed in the crude reaction mixture
and could be easily separated by chromatography. The stereochemistry at C-
1 was probed at a later stage on the synthesis. The corresponding epimer at
C-1 was also observed ( > 4:1 ratio) together with some isomeric
2,3:5,6-diacetonides (13C NMR).
‡ Compounds resulting from the reaction of both hydroxy groups were
always present, in yields ranging from 10–15%, and could be easily
separated by chromatography.
§
Compounds 8a and 8b existed as two isomers (ca. 1:1 ratio),
corresponding to the orientation of the phenyl group in the exocyclic double
bond. Conversely, only one isomer at the phenyl group was observed for the
cis-fused products 9a and 9b.
¶ The spectral properties (1H NMR, C6D6, 400 MHz) were in accord with
those reported in the literature (ref. 16): [a]D +2.0 (c 0.6, CHCl3), lit.,16a
18 R. E. McDevitt and B. Fraser-Reid, J. Org. Chem., 1994, 59, 3250.
19 D. P. Curran, N. A. Porter and B. Giese, Stereochemistry of Radical
Reactions, VCH, Weinheim, 1996, p. 53.
Communication 8/08848I
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Chem. Commun., 1999, 175–176