Carbohydrates to carbocycles: An expedient synthesis of pseudo-sugars

Article abstract of DOI:10.1039/a801989d

A short and versatile synthesis of pseudo-sugars from sugars utilizing the Claisen rearrangement as the key step is described.

Full text of DOI:10.1039/a801989d

View Article Online / Journal Homepage / Table of Contents for this issue
Carbohydrates to carbocycles: an expedient synthesis of pseudo-sugars
A. V. R. L. Sudha and M. Nagarajan*†
a School of Chemistry, University of Hyderabad, Hyderabad-500 046, India
A short and versatile synthesis of pseudo-sugars from sugars
utilizing the Claisen rearrangement as the key step is
described.
used without purification.15 In order to introduce the C6–C7
double bond in 2, methylenation of 5 was investigated under
various conditions. Treatment of 5 with methyltriphenyl-
phosphonium iodide and BunLi led to a complex mixture.
Wittig olefination of 5 with formylmethylene(triphenyl)-
phosphorane and decarbonylation of the resultant unsaturated
aldehyde with Wilkinson’s catalyst gave 2 in very low yield.
Finally, a combination of methyltriphenylphosphonium iodide
and sodamide gave 2 in 40% overall yield from 4.
Conversion of sugars into carbocycles is an area which has
attracted considerable attention in recent times.1 Some im-
portant methodologies for achieving this are (i) Ferrier’s
mercuric ion mediated conversion of 6-deoxyhex-5-enopyran-
osyl compounds to deoxyinosose derivatives,2 (ii) the radical
cyclization approach of RajanBabu3 and (iii) the zirconium
mediated ring contraction of carbohydrate derivates to carbo-
cycles by Taguchi.4
Heating 2 in a sealed tube in o-dichlorobenzene at 240 °C
afforded the rearranged chiral carbocycle 6 in 84% yield, based
on recovered starting material (4%). The product 6, being
unstable, was subjected to NaBH4 reduction without purifica-
tion to give 1.‡ The IR spectrum of 1 showed an olefin band at
1643 cm21 and the presence of a hydroxy absorption at 3445
cm21. Unlike 2,§ which showed the presence of five olefinic
Pseudo-sugars
are
2,3,4,5-tetrahydroxy-1-(hydroxy-
methyl)cyclohexanes, in which the ring oxygen atom of a sugar
has been replaced by a methylene group. Pseudo-d-glucose,
pseudo-d-galactose and pseudo-d-fructose have been suggested
as replacements for their sugar counterparts as non-nutritive
sweeteners.5 Amino pseudo-sugars, which form the aglycon
part of many aminoglycoside antibiotics, have chemo-
therapeutic potential as glycosidase inhibitors.6 Pseudo-sugars
and some related carbocyclic compounds are components of
some antibiotics (validamycins) and enzyme inhibitors (adi-
posins).7
The biological significance of pseudo-sugars has led to the
development of several approaches for their synthesis in
optically pure form from various chiral sources. A comprehen-
sive review on pseudo-sugars has been published.8 Pseudo-b-d-
altro-, pseudo-a-l-manno- and pseudo-b-d-gluco-pyranoses
have been synthesized by Hudlicky9 from homochiral microbial
metabolites. Vandewalle10 prepared eight pseudo-sugars be-
longing to the allo, gulo, manno and talo series which possess
2,3-cis-diol units from (1R,2S,3R,4S)-4-butyryloxy-2,3-(pro-
pane-2,2-diyldioxy)cyclohex-5-en-1-ol. The synthetic versatil-
ity of quinic acid was demonstrated by Shing in his synthesis of
pseudo-b-d-manno-,11 pseudo-b-d-fructo-,11 pseudo-a-d-
gluco-12 and pseudo-a-d-manno-pyranoses.12 Ferrier prepared
crystalline pseudo-a-d-glucopyranose13 from 2-deoxyinosose.
It occurred to us (as shown in the retrosynthesis in Scheme 1),
that controlled hydroxylation of cyclohexene 1 should lead to
the four pseudo-sugars, pseudo-a-d-glucopyranose, pseudo-
a-d-mannopyranose, pseudo-b-d-glucopyranose and pseudo-
b-d-mannopyranose. The conversion of 2 to 1 involves
transformation of a glycal derivative into a cyclohexene,
prototypes of which have been reported earlier by Bu¨chi.14
Compound 1 in turn can be readily derived from d-glucose via
2 and 3. We describe here the successful realization of this
strategy.
1
protons in its H NMR spectrum, the rearranged carbocycle 1
exhibited only two olefinic protons as a multiplet at d 5.74–5.78.
The presence of the double bond in 1 was further confirmed
from its 13C NMR spectrum, which displayed resonances at d
125.95 and 138.42 (Scheme 2).
Having synthesized the highly functionalized chiral synthon
1, attempts were made to prepare the four pseudo-sugars,
namely, pseudo-a-d-glucopyranose, pseudo-a-d-manno-
pyranose, pseudo-b-d-glucopyranose and pseudo-b-d-manno-
pyranose.
Catalytic OsO4 dihydroxylation16 of the double bond in 1
from the less hindered b-face gave the triol 7 in quantitative
yield, which on debenzylation with 20% Pd(OH)2/C/H2 yielded
pseudo-a-d-glucopyranose 8, [a]D +57.0 (c 0.65, H2O) [lit.,12
63.0 (c 0.6, H2O)].
+
The primary hydroxy group in 1 was protected as the benzyl
ether to yield 9.¶ A mixture of partially benzylated pseudo-a-d-
mannopyranose 10 and pseudo-b-d-glucopyranose 11 was
obtained in one step from 9 involving a sequence of epoxidation
and ring opening using MCPBA, water and 10% H2SO4.17
Purification and separation by preparative TLC of the partially
benzylated mixture gave 10 and 11 in 34 and 26% yields,
respectively. Deprotection under similar conditions as those for
OH
O
OHC
BnO
O
O
i
ii
65%
62%
BnO
BnO
OBn
OBn
OBn
The primary hydroxy group in 4 was oxidized using
pyridinium dichromate (PDC) to the aldehyde 5, which was
4
5
2
iii 84%
OH
CHO
iv
OH
90%
OR
O
O
OBn
OBn
D-Glucose
OBn
OBn
1
6
OR
BnO
HO
OR
OBn
OH
Scheme 2 Reagents and conditions: i, PDC, 4 Å molecular sieves, CH2Cl2,
room temp., 10 h; ii, Ph3MePI, NaNH2, Et2O, room temp., 30 min; iii,
o-dichlorobenzene, 240 °C (sealed tube), 1 h; iv, NaBH4, THF, room temp.,
10 min
1
2
3
Scheme 1
Chem. Commun., 1998
925

View Article Online
OH
HO
HO
OH
HO
HO
OH
Notes and References
i
ii
† E-mail: mnsc@uohyd.ernet.in
95%
100%
OBn
OBn
OH
‡ Selected data for 1: nmax(neat)/cm21 3445, 2924, 1454, 1093, 1028, 698;
dH(CDCl3) (200 MHz) 1.81–2.21 (m, 3 H), 2.52–2.66 (br s, 1 H), 3.57–3.71
(m, 3 H), 4.20–4.27 (m, 1 H), 4.67–5.03 (m, 4 H), 5.74–5.78 (m, 2 H),
7.30–7.48 (m, 10 H); dC(CDCl3; 50 MHz) 138.42, 128.57, 128.48, 128.21,
127.87, 127.72, 125.95, 82.00, 81.15, 74.30, 71.30, 65.53, 40.62, 28.05
(Found: C, 77.80; H, 7.46. Calc. for C21H24O3. C, 77.74; H, 7.46%).
§ Selected data for 2: nmax(neat)/cm21 3065, 2862, 1643, 1238, 1095, 696;
dH(CDCl3; 200 MHz) 3.58–3.65 (dd, 1 H), 4.21–4.26 (dd, 1 H), 4.30–4.40
(t, 1 H), 4.61–4.92 (m, 4 H), 5.29–5.48 (m, 3 H), 5.94–6.14 (m, 1 H),
6.40–6.45 (d, 1 H), 7.20–7.33 (m, 10 H); dC(CDCl3; 50 MHz) 144.63,
139.90, 139.82, 134.54, 128.47, 128.02, 127.81, 127.71, 118.23, 100.48,
78.50, 78.11, 75.63, 73.87, 70.74 (Found: C, 78.28; H, 6.85. Calc. for
C21H22O3; C, 78.23; H, 6.88%).
¶ Selected data for 9: nmax(neat)/cm21 3030, 1496, 1454, 1155, 1097, 696;
dH(CDCl3; 200 MHz) 2.02–2.30 (m, 3 H), 3.54–3.75 (m, 3 H), 4.12–4.24
(m, 1 H), 4.50–4.92 (m, 6 H), 5.66–5.85 (m, 2 H), 7.24–7.40 (m, 15 H);
dC(CDCl3; 50 MHz) 139.14, 138.76, 128.52, 128.34, 127.91, 127.78,
127.51, 126.17, 81.11, 79.62, 74.29, 73.17, 71.44, 70.64, 39.47, 28.80
(Found: C, 81.18; H, 7.31. Calc. for C28H30O3: C, 81.12; H, 7.29%).
OBn
1
OBn
7
OH
8
iii
85%
OBn
HO
OBn HO
+
OBn
iv
60%
OBn
HO
OBn
HO
OBn
OBn
9
OBn
10
ii
OBn
11
v
66%
HO
ii
100%
100%
OBn
HO
OH HO
OH
+
HO
OBn
HO
OH
HO
OH
OBn
14
OH
12
OH
13
Scheme 3 Reagents and conditions: i, OsO4, K3Fe(CN)6, K2CO3, ButOH,
H2O, 24 h; ii, 20% Pd(OH)2/C/H2, 55 psi, 2 h; iii, NaH, DMF, BnBr, room
temp., 10 h; iv, MCPBA, H2O, 10% H2SO4, 48 h; v, aq. AcOH, AgOAc, I2,
Na (cat.), MeOH, 15 h
1 R. J. Ferrier and S. Middleton, Chem. Rev., 1993, 93, 2779.
2 R. J. Ferrier, J. Chem. Soc., Perkin Trans. 1, 1979, 1455.
3 T. V. RajanBabu, Acc. Chem. Res., 1991, 24, 139.
4 T. Taguchi, H. Ito, Y. Motoki and Y. Hanzawa, J. Am. Chem. Soc., 1993,
115, 8835.
5 S. Ogawa, Y. Uematsu, S. Yoshida, N. Sesaki and T. Suami,
J. Carbohydr. Chem., 1987, 6, 471.
6 T. K. M. Shing and L. H. Wan, Angew. Chem., Int. Ed. Engl., 1995, 34,
1643.
7 S. Ogawa, Yuki. Gosei Kagaku Kyokai Shi, 1985, 43, 26.
8 T. Suami and S. Ogawa, Adv. Carbohydr. Chem. Biochem., 1990, 28,
41.
7 gave pseudo-a-mannopyranose 12, [a]D +1.5 (c 0.4, MeOH)
[lit.,12 [a]D +1.9 (c 1.0, MeOH)], and pseudo-b-d-glucopyr-
anose 13, [a]D +10.0 (c 0.3, H2O) [lit.,18 [a]D +10.9 (c 0.83,
H2O)], from 10 and 11, respectively, in quantitative yields
(Scheme 3).
cis-Hydroxylation19 of the alkene 9 under Woodward’s
conditions gave in 66% yield the tribenzyl diol 14 which on
debenzylation afforded only pseudo-a-d-glucopyranose instead
of the anticipated pseudo-b-d-mannopyranose, in quantitative
yield. This is surprising as Woodward’s hydroxylation is
expected to give overall syn-hydroxylation from the more
hindered face, in contrast to the osmium tetroxide hydroxyla-
tion.
9 D. A. Entwistle and M. Hudlicky, Tetrahedron Lett., 1995, 36, 2591.
10 L. Pingli and M. Vandewalle, Synlett, 1994, 228.
11 T. K. M. Shing and Y. Tang, Tetrahedron, 1991, 47, 4571.
12 T. K. M. Shing, Y. Cui and Y. Tang, J. Chem. Soc., Chem. Commun.,
1991, 756.
13 R. J. Ferrier and R. Blattner, J. Chem. Soc., Chem. Commun., 1987,
1008.
14 G. Bu¨chi and J. E. Powell Jr., J. Am. Chem. Soc., 1967, 89, 4559.
15 B. Fraser-Reid, R. A. Alonso, G. D. Vite and R. E. McDevitt, J. Org.
Chem., 1992, 57, 573.
16 K. Yamamoto, M. Minato and J. Tsuji, J. Org. Chem., 1990, 55, 766.
17 F. Fringuelli, R. Germani, F. Pizzo and G. Savelli, Synth Commun.,
1989, 19, 1939.
18 H. Paulsen and W. von Deyn, Justus Liebigs. Ann. Chem., 1987, 125.
19 R. B. Woodward and F. V. Brutcher Jr., J. Am. Chem. Soc., 1958, 80,
209.
The 1H NMR spectra of all the pseudo-sugars were in
consonance with the data reported in the literature. The
structures of all new compounds were unambiguously establi-
shed from their spectral and analytical data wherever approp-
riate.
A. V. R. L. thanks the CSIR (New Delhi) for providing
financial assistance in the form of a research fellowship. We
acknowledge the COSIST programme in chemistry for in-
strumental facilities.
Received in Cambridge, UK, 24th December 1997; Revised manuscript
received 5th March 1998; 8/01989D
926
Chem. Commun., 1998