Phosphonate versus phosphorane method in the synthesis of higher carbon sugars. Preparation of D-erythro-L-manno-D-glucododecitol

Article abstract of DOI:10.1039/a807190j

Higher sugar (C₁₂ and C₁₃) dialdose precursors 5, 10 and 15 were obtained by a coupling of C₇-phosphorane 1 or C₇-phosphonates 2 and 13 with C₅- or C₆-sugar aldehydes. These compounds were converted into higher dialdoses by (i) stereoselective reduction of a carbonyl group with zinc borohydride followed by (ii) osmylation of the resulting allylic alcohols. One of these derivatives - compound 8a - was converted into D-erythro-L-manno-D-gluco-dodecitol 23 on a 0.5 g scale.

Full text of DOI:10.1039/a807190j

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Phosphonate versus phosphorane method in the synthesis of higher
carbon sugars. Preparation of D-erythro-L-manno-D-gluco-
dodecitol
Sławomir Jarosz* and Mateusz Mach
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44, 01-224 Warszawa,
Poland. E-mail: sljar@ichf.edu.pl
Received (in Cambridge) 15th September 1998, Accepted 7th October 1998
Higher sugar (C12 and C13) dialdose precursors 5, 10 and 15 were obtained by a coupling of C7-phosphorane 1 or
C7-phosphonates 2 and 13 with C5- or C6-sugar aldehydes. These compounds were converted into higher dialdoses
by (i) stereoselective reduction of a carbonyl group with zinc borohydride followed by (ii) osmylation of the resulting
allylic alcohols. One of these derivatives – compound 8a – was converted into D-erythro-L-manno-D-gluco-dodecitol
23 on a 0.5 g scale.
coupling of terminal C-atoms of two sugar sub-units via the
Introduction
Cn bridge. This was accomplished by reaction of sugar-derived
The synthesis of higher carbon sugars having more than 10
stabilised phosphoranes,8 sugar-vinyl9 and propargyl10 anions
carbon atoms in the chain has gained considerable attention in
and sugar allyltin derivatives11 with aldehydes, which resulted
the past two decades, since they are components of some anti-
in formation of C12–C15 monosaccharides. The aldol condensa-
biotics1 and might be used as non-metabolised analogues of
tion between two sugar aldehydes also yielded a higher mono-
disaccharides. Preparation of such compounds can be accom-
saccharide.12 Recently a C21-monosaccharide13 was prepared by
plished now almost routinely,2 although for a long time it pre-
a high-pressure Wittig methodology.
sented a real challenge for organic chemists. The synthesis of
The main disadvantage of Wittig methodology is the low
higher alditols, however, is not easy, and little is known about
yield of conversion of uronic acids into stabilised phospho-
the properties of such compounds, although they might have
ranes.8 We have found that replacing the phosphorane with the
unique conformational and biological properties, and their
more nucleophilic phosphonate (which can be prepared in
specific complexation with chiral organic cations might be
expected. As was pointed out in 1993 by Köll ‘the conform-
much higher yield) may improve the overall yield of higher
carbon sugars.
ational behaviour of the 20 diastereoisomers of octitols in solution
as well as in crystalline state is almost unknown’;3 even less is
known about decitols.4 This results from the low accessibility of
Results and discussion
such compounds. The higher alditols are usually available by
Brimacombe’s C2-iteration methodology,5 although several
We faced serious problems in conversion of higher sugar
dialdoses (prepared by methods presented in Scheme 1) into
more efficient syntheses have been reported: -erythro--ido--
higher alditols. Here we present a useful methodology for the
high-yield, selective preparation of convenient higher sugar
precursors in which both sugar ‘sub-units’ are blocked with
gulo-dodecitol was obtained in low yield as a side product
during electrochemical reduction of -glucose,6 and the cis-
hydroxylation of sugar-derived diolefins leading to decitols and
dodecitols was described recently.7
easily removable protecting groups.
As a starting material phosphorane 18 – easily obtained from
In the past few years we have proposed a general method
for the preparation of higher sugar dialdoses (Scheme 1) by a
methyl 2,3,4-tri-O-benzyl-α--glucosiduronic acid 3 – was
employed. Treatment of phosphorane 1 with 2,3:4,5-di-O-
isopropylidene--arabinose14 4 resulted in clean formation of
O
Sug2
O
CO2H
Sug1
Sug2-CHO
ref. 8
PPh3
higher sugar enone 5. Although the yield of this process
amounted to 70%, the overall yield of enone 5 from acid 3 was
low because the conversion of uronic acid 3 into phosphorane
1 could be achieved in only 50%. Therefore, the alternative
starting material – phosphonate 2 – was used. Compound 2
was prepared according to the method of Yonemitsu and co-
workers15 from the methyl ester of uronic acid 3 in 91% yield.
Treatment of a toluene solution of reactants 2 and 4 with
K2CO3 and 18-crown-6 gave a 90% yield of the E-enone 5. This
compound was selectively reduced with zinc borohydride to
yield the allyl alcohol 6 (see Scheme 2).
The high selectivity of the reduction was explained by a cyclic
model presented in Scheme 3; complexation of zinc cation to
both ketone- and ring-oxygen atoms fixes the conformation and
makes the attack of hydride anion available only from the less
hindered side of the molecule, i.e. from ‘behind the ring’.8b The
-glycero-configuration of allylic alcohol 6 was confirmed by
chemical degradation to the known16 methyl -glycero-α--
gluco-heptopyranoside (6Ј; see Experimental section).
Sug1
Sug1
OH
OH
ref. 9c,10
Sug1
Sug2-CHO
Sug2
Sug2
Sug2
Sug1
HO
Sug1
SnBu3
ref. 9
Sug2-CHO
CHO
Sug1
Sug1
Sug1
OH
ref. 11
CHO
SnBu3
Sug1
Sug2
Sug1
CHO
Sug2
HO
+
Sug2
ref. 12
Sug1
Scheme 1
J. Chem. Soc., Perkin Trans. 1, 1998, 3943–3948
3943

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O
P
O
O
O
OH
O
OMe
OMe
PPh3
OMe
O
ref.8
O
OBzl
OBzl
ca. 50%
OBzl
91%
BzlO
OMe
OBzl
OMe
OBzl
BzlO
OBzl
BzlO
1
3
2
4
O
O
O
O
O
BzlO
O
O
8
BzlO
O
6
4
7
O
O
O
OR
O
1
Zn(BH4)2
BzlO
'Glu'
'Ara'
O
5
Glu
OMe
O
O
6 R = H
7 R = Bzl
OsO4
NMO
OH
OH
BzlO
Glu
BzlO
+
Ara
Glu
Ara
OH
8b
OH
8a
ratio 8b:8a = 4:96
Scheme 2
H –
O
R′
R′
OH
O
Ara
Glu'
O
O
Zn++
OH
8
OH
7
HO
Zn(BH4)2
O
7
8
HO
OH
OH
OBzl
OBzl
BzlO
OMe
OBzl
Glu'
Ara
OMe
OBzl
O
BzlO
5
6
selectivity > 97:3
O
1. O3 then Me2S 2. NaBH4
diacetone-D-mannitol (negative Cotton effect)
8a (positive Cotton effect)
λ
max(∆ε′): 270.4 (+0.04);
λ
max(∆ε′): 275.5 (–0.09);
311.1 (–0.595)
309.5 (+0.337)
RO
OR
Fig.
1
CD spectra of Mo2(OAc)4 complexes with diacetone--
mannitol and compound 8a.
O
OBzl
OMe
OBzl
BzlO
ylide 1 (80%) or aldehyde 9 and phosphonate 2 (85%). Reduc-
tion of enone 10 with Zn(BH4)2 afforded a single isomer 11, the
configuration of which was assigned also by chemical degrad-
ation to compound 6Ј (see Experimental section). Osmylation
of alkene 11 was highly stereoselective and led to a single
stereoisomeric triol 12 (Scheme 4). The configuration of
product 12 could be, therefore, safely assigned on the basis of
Kishi’s rule, but it was also verified by independent methods.
Thus, protection of the hydroxy function in the alcohol 11 as
benzyl ether 11Ј and subsequent osmylation afforded diol 12Ј,
the configuration of which was assigned on the basis of its CD
spectrum with [Mo2(OAc)4] (see Experimental section). Benzyl-
ation of diol 12Ј afforded compound 12Љ, which was identical
with the product of per-benzylation of triol 12.
6′ R = H
6′′ R = Ac
Scheme 3
Protection of the free hydroxy group in compound 6 as the
benzyl ether 7 and subsequent osmylation of the double bond
gave – with very high selectivity – diol 8a (ratio 8a:8b = 96:4).
Configuration of the main isomer 8a was assigned on the basis
of Kishi’s rule17 according to which the attack of osmylating
agent occurs from the side opposite to (any) alkoxy groups. In
compound 7 both alkoxy groups flanking the double bond
point in the same direction (Scheme 2) and the attack of OsO4
should lead with high selectivity to diol 8a. This assumption
was verified by the circular dichroism (CD) spectra of chiral
diol 8a with dimolybdenum tetraacetate [Mo2(OAc)4].18 In
Fig. 1 the CD spectra of diacetone--mannitol and diol 8a
with [Mo2(OAc)4] are presented. The Cotton effects in these two
complexes were opposite, which showed that the configuration
of the diol groupings should also be opposite. This result
supported our assumption based on Kishi’s model.
Reaction of phosphonate 1319 with 3-O-benzyl-1,2-O-
isopropylidene-α--xylofuranos-1,4-ulose 14 proceeded with
high yield to afford E-enone 15. Reduction of compound
15 with Zn(BH4)2 was – contrary to previous examples – non-
selective; alcohol 16 was produced as a 3:2 mixture of stereo-
isomers (Scheme 5, see Experimental section).
The explanation of the lack of selectivity is presented in
structure I. Although the complexation of zinc cation to
carbonyl- and α-oxygen atoms fixes the conformation, the
Similarly, a C13-enone 10 was prepared from 1,2:3,4-di-O-
isopropylidene-α--galacto-hexodialdo-1,5-pyranose
9
and
3944 J. Chem. Soc., Perkin Trans. 1, 1998, 3943–3948

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BzlO BzlO
OR
O
BzlO
O
O
O
O
BzlO
BzlO
+
1
H
O
O
BzlO
BzlO
O
O
O
O
O
O
O
O
OR
O
O
O
OMe
9
10
'Glu'
OMe
+
2
9
8a R = H
17 R = Bzl
Zn(BH4)2
OR
O
BzlO BzlO
OBzl
OR
O
O
Glu
BzlO
BzlO
OR
O
OR
OR
OBzl
O
O
OMe
11 R = H
18 R = H
19 R = Bzl
11′ R = Bzl
BzlO
OR OR'
O
O
H
O
BzlO
BzlO
O
O
OR'
O
BzlO BzlO
OBzl
OBzl
OMe
BzlO
BzlO
OBzl
OBzl OBzl
O
OBzl
12 R = R' = H
12′ R = Bzl, R' = H
12′′ R = R' = Bzl
OAc
Scheme 4
20
CHO
O
O
O
O
O
OMe
OMe
+
O
P
OBzl
OR OR OR OR OR
OR OR' OR OR OR
O
OBzl
R'O
O
O
OR
13
14
21 R = Bzl R' = H
22 R = R' = Bzl
23 R = R' = H
24 R = R' = Ac
O
O
O
Scheme 6
O
O
OBzl
Xyl
OBzl
15
O
O
O
O
O
Zn(BH4)2
O
O
O
RO
OH
O
O
Zn++
O
O
I
OBzl
O
OBzl
O
of this compound gave deca-O-benzyl ether 19 from which the
methoxy group was removed by acetolysis to provide dodecose
20 as a mixture of α,β-anomers. Reduction of this product with
lithium aluminium hydride afforded diol 21 which was con-
taminated with a more polar product assumed to be a partially
debenzylated dodecitol (this could happen during acetolysis).
This crude mixture was, therefore, benzylated to give fully pro-
tected derivative 22. Catalytic removal of the benzyl protecting
groups (H2/Pd) led to free -erythro--manno--gluco- (= -
threo--allo--manno-)dodecitol 23 [0.5 g, 25% overall yield
(7 steps from compound 8a)].
O
16
Scheme 5
differentiation between the re and si sides of the molecule is
not significant, because of the free rotation around the adjacent
C᎐C bond.
The methodology of transformation of higher carbon
dialdoses into higher alditols is illustrated by the conversion of
methyl 2,3,4,6-tetra-O-benzyl-9,10:11,12-di-O-isopropylidene-
-erythro--manno-α--gluco-dodeco-1,5-pyranoside 8a into
-erythro--manno--gluco- (= -threo--allo--manno-)dodeci-
tol 23 (see Scheme 6). Diol 8a was benzylated to hexakisbenzyl
ether 17 in which the isopropylidene groups were hydrolysed
with sulfuric acid in methanol to afford tetraol 18. Benzylation
Conclusions
We have demonstrated that the precursors of higher alditols –
higher sugar enones 5, 10, or 16 – can be obtained by a coupling
J. Chem. Soc., Perkin Trans. 1, 1998, 3943–3948
3945

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of sugar-derived phosphoranes, or sugar phosphonates, with
sugar aldehydes. The latter method is more practical, since
sugar phosphonates can be prepared in much higher yields than
can sugar phosphoranes. Transformation of higher sugar
enones into alditols can be conveniently performed on a quite
large scale, and no special techniques are required for the
isolation of the final products.
and concentrated. Crude product was purified by column
chromatography (hexane–ethyl acetate, 6:1 to 2:1).
General method for cis-hydroxylation (method E)
To a solution of an olefin (2 mmol) in a mixture of THF (15
cm3), tert-butyl alcohol (1 cm3) and water (0.5 cm3) was added
NMO (2.5 mmol) followed by osmium tetraoxide (0.8 cm3 of a
~2% solution in toluene). The mixture was stirred for 48–72 h
(TLC monitoring in hexane–ethyl acetate, 2:1), then was
diluted with methanol (20 cm3), and 40% aq. sodium hydrogen
sulfite was added. The mixture was stirred for 30 min, filtered
through Celite, concentrated, and partitioned between water
and diethyl ether. The organic phase was separated, dried and
concentrated, and the crude product(s) was (were) purified by
column chromatography (hexane–ethyl acetate, 4:1 to 3:2).
Experimental
NMR spectra were recorded with a Bruker AM 500 and a Var-
ian Gemini 200 spectrometer for solutions in CDCl3 (internal
Me4Si), unless otherwise stated; J-values are given in Hz. Most
1
of the resonances were assigned by 2D (1H–1H and H–13C)
correlations. Mass spectra [LSIMS (m-nitrobenzyl alcohol was
used as a matrix to which sodium acetate was added)] were
recorded with a AMD-604 (AMD Intectra GmbH, Germany)
mass spectrometer. The optical rotation (compound 23) was
measured on a JASCO P-1020 digital polarimeter, and the [α]D-
value is in units of 10Ϫ1 deg cm2 gϪ1. Column chromatography
was performed on silica gel (Merck, 70–230 mesh). Organic
solutions were dried over anhydrous magnesium sulfate. Methyl
2,3,4-tri-O-benzyl-7-deoxy-7-triphenylphosphoranylidene-α--
gluco-heptopyranoid-6-ulose 1 was prepared in 50% yield from
uronic acid 3 according to the methodology of ref. 8.
Methyl 2,3,4-tri-O-benzyl-7,8-dideoxy-9,10:11,12-di-O-iso-
propylidene-D-arabino-á-D-gluco-dodec-7(E)-eno-1,5-pyranosid-
6-ulose 5. This was prepared from phosphorane 1 and 2,3:4,5-
di-O-isopropylidene--arabinose14 4 in 75% yield (method A)
or from phosphonate 2 and aldose 4 in 90% yield (method B)
[HRMS: Calc. for C40H48O10Na (M ϩ Naϩ): m/z, 711.3145.
Found: m/z, 711.3190] (Found: C, 69.5; H, 7.0. Calc. for
C40H48O10: C, 69.75; H, 7.02%); δH 3.40 (3 H, s, OCH3), 3.56
(1 H, dd, J1,2 3.5, J2,3 9.0, H-2), 3.59 (1 H, t, J9,10 = J10,11 = 8.2,
H-10), 3.68 (1 H, dd, J3,4 9.4, J4,5 9.8, H-4), 3.90 (H-12), 4.04
(1 H, dd, H-4), 4.10 (2 H, m, H-11 and HЈ-12), 4.35 (1 H, d,
H-5), 4.48 (1 H, m, H-9), 6.66 (1 H, dd, J7,8 15.8, J7,9 1.6, H-7)
and 7.03 (1 H, dd, J8,9 4.4, H-8); δC 25.1, 26.6, 26.7, 26.9
(2 × CMe2), 56.8 (OCH3), 67.5 (C-12), 72.9 (C-5), 77.0 (C-11),
79.2 (C-9), 79.3 (C-2), 81.2 (C-10), 81.7 (C-3), 98.7 (C-1), 126.7
(C-7), 144.8 (C-8) and 195.2 (C-6).
General procedure for reaction of sugar phosphoranes with sugar
aldehydes (method A)
Phosphorane 1 (3 mmol) and an appropriate aldehyde (4 or 9,
3 mmol) were stirred in dry benzene (30 cm3) at rt until TLC
(hexane–ethyl acetate, 2:1) indicated disappearance of both
starting materials and formation of a new, less polar product
that was visible under UV light. The crude higher sugar enone
was purified by column chromatography (hexane–ethyl acetate,
5:1 to 3:1).
6-Deoxy-1,2:3,4-di-O-isopropylidene-6-C-[methyl (E)-2,3,4-
tri-O-benzyl-7-deoxy-á-D-gluco-heptopyranosid-6-ulos-7-
ylidene]-á-D-galacto-pyranose 10. This was prepared from
General procedure for reaction of sugar phosphonates with sugar
aldehydes (method B)
compound
1 and 1,2:3,4-di-O-isopropylidene-α--galacto-
hexodialdo-1,5-pyranose20 9 in 80% yield (method A) or from
reactants 2 and 9 in 85% yield (method B) [HRMS: Found: m/z,
739.3128. Calc. for C41H48NaO11 (M ϩ Naϩ): m/z, 739.3095]; δH
1.28, 1.32, 1.34 and 1.49 (12 H, 4 s, 2 × CMe2), 3.41 (3 H, s,
OCH3), 3.55 (1 H, dd, J1,2 3.5, J2,3 9.7, H-2), 3.68 (1 H, dd, J3,4
9.2, J4,5 9.7, H-4), 4.03 (dd, H-3), 4.26 (1 H, dd, J9,10 2.1, J10,11
7.8, H-10), 4.34 (1 H, dd, J12,13 5.0, J11,12 2.4, H-12), 4.37 (1 H, d,
H-5), 4.45 (1 H, m, H-9), 4.60 (1 H, H-11), 4.61 (1 H, d, H-1),
5.58 (1 H, d, H-13), 6.67 (1 H, dd, J7,8 15.7, J7,9 2.0, H-7) and
6.96 (1 H, dd, J8,9 4.1, 8); δC 24.3, 24.8, 25.8 and 26.1
(2 × CMe2), 55.8 (OCH3), 67.6 (C-9), 70.5 (C-12), 70.8 (C-11),
72.6 (C-10), 73.0 (C-5), 79.1 (C-4), 79.4 (C-2), 81.8 (C-3), 96.4
(C-13), 98.7 (C-1), 108.6 and 109.6 (2 × CMe2), 127.5 (C-7),
143.1 (C-8) and 195.0 (C-6).
An appropriate sugar phosphonate (2 or 13, 3 mmol), sugar
aldehyde (4, 9 or 14, 3 mmol) and 18-crown-6 (3 mmol) in
toluene (30 cm3) were stirred overnight at rt with potassium
carbonate (10 mmol). After this time TLC (hexane–ethyl acet-
ate, 2:1) indicated disappearance of both starting materials (16
h) and formation of a new, less polar product that was visible
under UV light. The mixture was partitioned between toluene
and brine, the organic phase was separated, washed with water,
dried and concentrated, and the product was isolated as in
method A.
General method for reduction of higher sugar enones with zinc
borohydride (method C)
To a cooled (0 ЊC) solution of an appropriate enone (2 mmol) in
dry diethyl ether (15 cm3) was added Zn(BH4)2 (~ 5 cm3 of a 0.5
M solution in diethyl ether) and the mixture was stirred for 30
min at 0 ЊC. Excess of borohydride was decomposed with water,
the organic phase was separated, washed successively with dil.
sulfuric acid and water, dried and concentrated, and the crude
product was purified by column chromatography (hexane–ethyl
acetate, 4:1 to 2:1).
3,8-Di-O-Benzyl-5,6-dideoxy-1,2:9,10:11,12-tri-O-iso-
propylidene-D-altro-D-gluco-dodec-5(E)-eno-1,4-furanos-7-ulose
15. This was prepared from phosphonate 13 and 3-O-benzyl-
1,2-O-isopropylidene-α--xylo-pentodialdo-1,4-furanose 14 in
75% yield (method B) [HRMS: Found: m/z, 647.2872. Calc. for
C35H44NaO10 (M ϩ Naϩ): m/z, 647.2832]; δH(200 MHz) inter
alia 1.28, 1.30 (2×), 1.33, 1.40 and 1.50 (3 × CMe2), 6.01 (1 H,
d, J1,2 3.7, H-1), 6.87 (1 H, dd, J5,6 15.8, J4,6 1.3, H-6) and 7.05
(1 H, dd, J5,4 4.7, H-5); δC(50 MHz) 25.7, 26.7, 27.1, 27.2, 27.4
and 27.8 (3 × CMe2), 68.3 (C-12), 77.4, 77.7, 80.4, 83.4, 83.7,
105.5 (C-1), 110.2, 110.9 and 112.4 (3 × CMe2), 127.2 (C-6),
141.3 (C-5) and 196.8 (C-7).
General procedure for benzylation reaction (method D)
A solution of an appropriate alcohol (~2 g) in DMF (30 cm3)
was stirred with sodium hydride (50% dispersion in mineral oil;
1.2 equiv. per hydroxy group) for 30 min; benzyl bromide (1.1
equiv. per one hydroxy group) was added and the mixture was
stirred at rt for 2–3 h (TLC monitoring in hexane–ethyl acetate,
2:1). Excess of hydride was carefully decomposed with water,
the mixture was partitioned between diethyl ether and water,
and the organic phase was separated, washed with water, dried
Dimethyl
(methyl
2,3,4-tri-O-benzyl-á-D-gluco-hepto-
pyranosid-6-ulos-7-yl)phosphonate 2. To a cooled (to Ϫ78 ЊC)
solution of dimethyl methylphosphonate (7.44 g, 6.4 cm3, 60
mmol) in dry THF (100 cm3) was added a solution of butyl-
lithium (2.5 M in hexane; 24 cm3, 60 mmol) and the mixture
3946
J. Chem. Soc., Perkin Trans. 1, 1998, 3943–3948

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was stirred for 15 min under argon. A solution of methyl
(methyl 2,3,4-tri-O-benzyl-α--glucopyranosid)uronate 3 (9.84
g, 20 mmol; prepared by esterification of methyl 2,3,4-tri-O-
benzyl-α--glucosiduronic acid 3 with diazomethane) was
added, the mixture was stirred for another 15 min, and was then
partitioned between ethyl acetate and brine. The organic phase
was separated, washed with water, dried and concentrated, and
the crude product was purified by column chromatography
(hexane–ethyl acetate, 1:1 to 1:3) to afford title phosphonate 2
as an oil (9.41 g, 91%) [HRMS: Found: m/z, 607.2074. Calc. for
C31H37NaO9P (M ϩ Naϩ): m/z, 607.2073]; δH(200 MHz) 3.47
(3 H, s, OCH3), 3.55 (1 H, dd, J2,3 9.7, H-2), 3.67 (dd, J4,5 9.9,
J3,4 9.0, H-4), 3.74 [d, JP, H 11.3, P(OCH3)], 3.77 [d, JP, H 11.4,
P(OCH3)], 4.07 (1 H, dd, H-3), 4.40 (d, H-5) and 4.64 (d, H-1);
δC 49.1 (d, JC–7,P 128.8, C-7), 52.9 [d, JC,P 6.8, P(OCH3)], 53.1 [d,
JC,P 7.1, P(OCH3)], 55.5 (OCH3), 73.8 (C-5), 78.8 (C-4), 79.3
(C-2), 81.8 (C-3), 98.6 (C-1) and 198.5 (d, JC–6,P 6.6, C-6).
70.3 (C-12), 72.0 (C-6), 73.3 (C-5), 73.8 (C-10), 79.0 (C-4), 80.2
(C-2), 82.4 (C-3), 96.4 (C-13), 97.9 (C-1) and 130 (C-7, -8).
Configuration of this product was determined by chemical
degradation to compound 6Ј (analogously as for 6). Thus, from
108 mg (0.15 mmol) of the allylic alcohol 11, 64 mg of diol 6Ј
(0.13 mmol, 86%) were obtained.
(7R/S)-3,8-Di-O-benzyl-5,6-dideoxy-1,2:9,10:11,12-tri-O-
isopropylidene-D-arabino-á-D-gluco-dodec-5(E)-eno-1,4-
furanose 16. This was obtained as an oil in 85% yield by reduc-
tion of enone 15 (method C) [HRMS: Found: m/z, 649.2970.
1
Calc. for C35H46NaO10 (M ϩ Naϩ): m/z, 649.2989]. In the H
NMR spectrum of a crude mixture all signals were duplicated,
confirming a mixture of stereoisomers (7R/S) had been
obtained. Acetylation of this mixture (Ac2O–Py–DMAP)
afforded a crude mixture of acetates in which all signals were
also duplicated. Integration of a CH3CO resonance (δH 2.04
and 1.83 for both isomers) indicated a ~3:2 proportion of
isomers.
Methyl 2,3,4-tri-O-benzyl-7,8-dideoxy-9,10:11,12-di-O-iso-
propylidene-D-gluco-á-D-gluco-dodec-7(E)-eno-1,5-pyranoside 6.
This was obtained as an oil in 95% yield by reduction of enone
5 (method C) [HRMS: Found: m/z, 713.3360. Calc. for
C40H50NaO10 (M ϩ Naϩ): m/z, 713.3301]; δH 3.38 (3 H, s,
OCH3), 3.41 (1 H, dd, J3,4 9.0, J4,5 9.9, H-4), 3.47 (1 H, dd, J1,2
3.6, J2,3 9.6, H-2), 3.77 (1 H, dd, J5,6 3.7, H-5), 4.02 (1 H, dd,
H-3), 4.31 (1 H, t, J8,9 = J9,10 = 6.6, H-9), 4.38 (1 H, J6,7 7.2,
H-6), 4.59 (1 H, d, H-1), 5.75 (1 H, ddd, J7,8 15.6, J 0.9, H-7)
and 5.94 (1 H, ddd, J 1.0, H-8); δC 25.2, 25.3, 26.6 and 26.9
(2 × CMe2), 56.8 (OCH3), 62.7 (C-12), 72.0 (C-6), 72.4 (C-5),
78.9 (C-4), 79.9 (C-9), 80.1 (C-2), 81.2 (C-10), 82.2 (C-3), 97.8
(C-1), 109.4 and 109.7 (2 × CMe2), 130.7 (C-8) and 131.0 (C-7).
Methyl 2,3,4,6-tetra-O-benzyl-7,8-dideoxy-9,10:11,12-di-O-
isopropylidene-D-gluco-á-D-gluco-dodec-7(E)-eno-1,5-pyrano-
side 7. This was obtained as an oil in 95% yield from the alcohol
6 according to method D [HRMS: Found: m/z, 803.3816.
Calc. for C47H56NaO10 (M ϩ Naϩ): m/z, 803.3772].
Methyl
2,3,4,6-tetra-O-benzyl-9,10:11,12-di-O-isopropyl-
idene-D-erythro-L-manno-á-D-gluco- and -D-erythro-L-ido-á-D-
gluco-dodeca-1,5-pyranoside 8a and 8b. Osmylation of ene 7
(3.9 g, 5 mmol) according to method E gave title compounds
8a (2.85 g, 3.5 mmol, 70%) and 8b (115 mg, 0.14 mmol, 2.8%).
Compound 8a.—[HRMS: Found: m/z, 837.3821. Calc. for
C47H58NaO12 (M ϩ Naϩ): m/z, 837.3826]; δH 1.26, 1.31, 1.33
and 1.39 (2 × CMe2), 3.39 (3 H, s, OCH3), 3.52 (1 H, dd, J1,2 3.5,
J2,3 9.6, H-2), 3.72 (1 H, dd, J3,4 9.2, H-4), 3.87 (1 H, H-7), 3.95
(2 H, m, H-5 and -12), 4.03 (1 H, dd, H-3), 4.10 (2 H, H-8 and
HЈ-12), 4.15 (1 H, H-6) and 4.64 (1 H, d, H-1); δC 25.1, 26.3,
26.8 and 26.9 (2 × CMe2), 55.0 (OCH3), 67.7 (C-12), 69.6, 70.6
(C-6), 70.8, 76.5, 78.8 (C-5), 80.1 (C-2), 80.2, 80.7 (C-4), 82.8
(C-3), 97.8 (C-1) and 109.4 and 110.1 (2 × CMe2). The CD
spectrum of compound 8a with [Mo2(OAc)4] showed a positive
Cotton effect (see Fig. 1), thus confirming that the configur-
ation of the diol grouping is opposite to that in diacetone--
mannitol and the same as that assigned on the basis of Kishi’s
rule.
Determination of the configuration of allylic alcohol 6. A solu-
tion of alcohol 6 (230 mg, 0.33 mmol) in methylene dichloride
(25 cm3) was ozonolyzed at Ϫ78 ЊC until the blue colour per-
sisted (ca. 15 min; also monitoring in hexane–ethyl acetate,
1:2). Dimethyl sulfide (0.5 cm3) was added to decompose the
ozonide, and then the mixture was stirred for 15 min at rt and
concentrated in vacuo. The residue was dissolved in methanol
(20 cm3) and reduced with sodium borohydride (30 mg) for
30 min to afford diol 6Ј and 2,3:4,5-di-O-isopropylidene--
arabinitol. Compound 6Ј (105 mg, 0.21 mmol, 64%) was isol-
ated by column chromatography (hexane–ethyl acetate, 2:1 to
1:2) and compared on TLC with methyl 2,3,4-tri-O-benzyl--
and --glycero-α--gluco-heptopyranoside (these diols have
slightly different polarities on TLC in toluene–methanol, 9:1,
2 developments).16 Compound 6Ј was different from the
-glycero--gluco-isomer and had the same polarity as the
-glycero--gluco-derivative. The 1H NMR spectrum of its
diacetate was identical with that reported for synthetic methyl
6,7-di-O-acetyl-2,3,4-tri-O-benzyl--glycero-α--gluco-hepto-
pyranoside 6Љ. The most diagnostic resonance was that of H-6:
for the -glycero-derivative 6Љ δ = 5.48 (ddd, J 2.0, 3.3 and 8.4)
and for its -glycero-diastereoisomer δ = 5.60 (ddd, J 1.4, 6.1
and 7.3).16 The signal of H-6 in the product obtained by deg-
radation of compound 6 resonated at δ 5.47 (ddd, J 2.0, 3.3
and 8.2).
Compound 8b.—[MS: 837 (M ϩ Naϩ)]; selected data δH 1.33
(2 × CMe2), 1.34, 1.35, 1.41, 3.52 (1 H, dd, J1,2 3.5, J2,3 9.7,
H-2), 3.83 (1 H, dd, J3,4 8.7, J4,5 9.7, H-4), 4.06 (1 H, d, H-3) and
4.60 (1 H, d, H-1); δC 25.1 (2 × CMe2), 26.4, 27.0, 27.1, 55.4
(OCH3), 67.6 (C-12), 79.9 (C-2), 81.0 (C-4) and 97.9 (C-1).
(7R)-1,2:3,4-Di-O-isopropylidene-7-C-(methyl
2,3,4-tri-O-
benzyl-á-D-gluco-hexopyranosid-6-yl)-L-threo-á-D-galacto-
heptopyranose 12. Osmylation of ene 11 (1.5 g, 2.02 mmol)
according to method E gave triol 12 (1.07 g, 1.42 mmol, 70.3%)
as a single stereoisomer [HRMS: Found: m/z, 775.3349. Calc.
for C41H52NaO13 (M ϩ Naϩ): m/z, 775.3306]; δH 1.30, 1.36, 1.41
and 1.48 (2 × CMe2), 3.39 (s, 3 H, OCH3), 3.51 (1 H, dd, J1,2 3.6,
J2,3 9.6, H-2), 3.73 (1 H, t, J3,4 = J4,5 = 9.4, H-4), 3.85 (1 H, dd,
J5,6 5.4, J4,5 9.7, H-5), 3.92 (1 H, dd, J6,7 9.1, J7,8 1.4, H-7), 4.02
(1 H, dd, H-3), 4.06 (1 H, dd, H-6), 4.28 (1 H, dd, J11,12 2.4, J12,13
4.9, H-12), 4.45 (1 H, dd, J10,11 8.1, H-10), 4.61 (1 H, d, H-1) and
4.61 (1 H, dd, H-11); δC 24.3, 25.1, 25.9 and 26.0 (2 × CMe2),
55.8 (OCH3), 66.5 (C-7), 69.0, 69.3 (C-6), 69.4 (C-5), 70.6
(C-11), 70.8 (C-10), 70.9 (C-12), 75.6, 79.8 (C-4), 80.1 (C-2),
82.2 (C-3), 96.3 (C-13), 98.0 (C-1) and 108.8 and 109.1
(2 × CMe2).
6-Deoxy-1,2:3,4-di-O-isopropylidene-6-C-[methyl 2,3,4-tri-
O-benzyl-7-deoxy-D-glycero-á-D-gluco-heptopyranosid-7(E)-
ylidene]-á-D-galactopyranose 11. This was obtained as an oil
in 90% yield by reduction of enone 10 (method C). [HRMS:
Found: m/z, 741.3239. Calc. for C41H50NaO11 (M ϩ Naϩ): m/z,
741.3251]; δH 1.25, 1.33, 1.34 and 1.50 (2 × CMe2), 3.38 (3 H, s,
OCH3), 3.39 (1 H, dd, J3,4 9.2, J4,5 10.2, H-4), 3.57 (1 H, dd, J1,2
3.6, J2,3 9.6, H-2), 3.80 (1 H, dd, J5,6 3.4, H-5), 4.02 (1 H, dd,
H-3), 4.12 (1 H, dd, J9,10 1.9, J10,11 7.9, H-10), 4.26 (1 H, m,
H-9), 4.28 (1 H, dd, J12,13 5.0, J11,12 2.4, H-12), 4.42 (1 H, m,
H-6), 4.61 (1 H, d, H-1), 5.52 (1 H, d, H-13) and 5.85 (2 H, m,
H-7, -8); δC 24.3 (2×), 24.8 and 25.9 (2 × CMe2), 68.4 (C-9),
Assignment of the configuration of triol 12. Alcohol 11 was
benzylated according to method D and the resulting ether 11Ј
J. Chem. Soc., Perkin Trans. 1, 1998, 3943–3948
3947

View Article Online
was osmylated (according to method E) to give a single stereo-
isomer 12Ј (in 90% yield). The CD spectrum of the complex of
diol 12Ј with [Mo2(OAc)4] showed a positive Cotton effect
[λmax(∆ε)]: 278 (Ϫ0.033) and 328.5 (0.205). Benzylation of this
diol (method D) afforded hexa-O-benzyl derivative 12Љ, m/z
1045 (M ϩ Naϩ). Selected data δH 1.06, 1.14, 1.24 and 1.40
(2 × CMe2), 3.14 (OCH3) and 5.41 (1 H, d, J1,2 5.0, H-1); δC 24.5
(double intensity), 25.5 and 26.0 (2 × CMe2), 54.9 (OCH3),
65.6, 69.7, 70.2, 70.8 and 70.9 (5 × CH), 72.0, 72.8, 73.1, 73.8,
74.9 and 75.3 (6 × CH2), 76.6, 76.8, 78.4 (double intensity),
79.8, 82.6, 96.6 and 97.9 (8 × CH) and 108.0 and 108.5
(2 × CMe2).
internal standard)] 62.4 and 63.3 (2 × CH2) and 68.1, 68.6,
69.2 (double intensity), 70.1, 70.9, 71.0, 71.7, 72.1 and 72.9
(10 × CH).
Acetylation of a part of this material (50 mg, 0.138 mmol)
with Ac2O–Py–DMAP overnight afforded per-acetate 24 (98.8
mg, 83%), δC(50 MHz; CDCl3) 61.5 and 61.8 (2 × CH2OAc),
66.6, 66.7, 67.2, 67.7, 68.1 (double intensity), 68.7, 68.8, 69.3
and 69.6 (10 × CHOAc), 169.20 (double intensity) and 169.36,
169.56, 169.65, 169.73 (triple intensity), 169.82, 169.90, 170.07
and 170.37 (12 × COCH3) [Found: C, 50.4; H, 6.4. C36H50O24
(866.77) requires C, 49.89; H, 5.81%]; m/z 867 (45%, M ϩ Hϩ),
807 (100, M ϩ Hϩ Ϫ AcOH); after addition of NaOAc,
m/z 889 (100%, M ϩ Naϩ) [Found: m/z, 889.26093. Calc. for
C36H50NaO24 (M ϩ Naϩ): m/z, 889.25897].
NMR spectra of this compound were identical with the
spectra of the product prepared by per-benzylation of triol 12.
D-erythro-L-manno-D-gluco-
(؍ L-threo-L-allo-D-manno)-
Acknowledgements
Dr Jadwiga Frelek (Institute of Organic Chemistry, PAS) is
thanked for recording the CD spectra.
dodecitol 23. Benzylation of diol 8a (7.7 g, 9.46 mmol) accord-
ing to method D gave methyl 2,3,4,6,7,8-hexa-O-benzyl-
9,10:11,12-di-O-isopropylidene--erythro--manno-α--gluco-
dodeco-1,5-pyranoside 17, which was hydrolysed (in reflux-
ing methanol containing 5% of 50% aq. sulfuric acid) to
give methyl 2,3,4,6,7,8-hexa-O-benzyl--erythro--manno-α--
gluco-dodeco-1,5-pyranoside 18 (6.8 g, 79% overall yield from
diol 8a), m/z 927 (M ϩ Naϩ).
References
1 hikizimycin: K. Uchida, T. Ishikawa, Y. Schimauchi, T. Ishikura and
A. Ozaki, J. Antibiot., 1971, 24, 259; anamarine: A. Alemany,
C. Marquez, C. Pascal, S. Valverde, M. Martinez-Ripall, J. Fayos
and A. Perales, Tetrahedron Lett., 1979, 3589; tunicamycin: A.
Takatsuki, K. Arima and G. Tamura, J. Antibiot., 1971, 24, 215;
streptovirudins: K. Eckhardt, W. Ihn, D. Tresselt and D. Krebs,
J. Antibiot., 1981, 34, 1631.
2 S. Hanessian, Total Synthesis of Natural Products: The Chiron
Approach, Pergamon Press, New York, 1983; C-trisaccharide:
T. Haneda, P. G. Goekjian, S. H. Kim and Y. Kishi, J. Org. Chem.,
1992, 57, 490; S. Jarosz, Pol. J. Chem., 1994, 68, 1333 and references
therein; W. Karpiesiuk and A. Banaszek, Biorg. Med. Chem. Lett.,
1994, 4, 879 and references therein; J. Langepe, J. Praudi and
J.-M. Beau, Angew. Chem., Int. Ed. Engl., 1997, 36, 72; O. Jarreton,
T. Skrydstrup and J.-M. Beau, Tetrahedron Lett., 1997, 38, 1767;
Z. Witczak, R. Chabra and J. Chojnacki, Tetrahedron Lett., 1997,
38, 2215.
3 P. Köll, M. Morf, B. Zimmer, J. Kopf, A. Berger, K. Dax and
A. E. Stutz, Carbohydr. Res., 1993, 242, 21.
4 P. Köll, J. Kopf, M. Morf, B. Zimmer and J. S. Brimacombe,
(a) Carbohydr. Res., 1992, 237, 289; (b) 1993, 238, 313.
5 J. S. Brimacombe, Studies in Natural Product Chemistry, ed. Atta-
ur-Rahman, Elsevier, Amsterdam, 1989, vol. 4C, p. 1157.
6 M. L. Wolfrom, W. W. Binkley, C. C. Spencer and B. W. Lew,
J. Am. Chem. Soc., 1951, 73, 3357.
7 N. Ikemoto and S. L. Schreiber, J. Am. Chem. Soc., 1992, 114, 2524.
8 (a) S. Jarosz, D. Mootoo and B. Fraser-Reid, Carbohydr. Res., 1986,
147, 59; (b) S. Jarosz, Carbohydr. Res., 1988, 183, 201.
Benzylation of this tetraol (method D) led to methyl
2,3,4,6,7,8,9,10,11,12-deca-O-benzyl--erythro--manno-α--
gluco-dodeco-1,5-pyranoside (19,
8 g, 84%), m/z 1297
(M ϩ Naϩ); δC(50 MHz; DEPT 135Њ) 54.9 (OCH3), 69.4 (C-12),
69.7 (CH), 71.6, 71.9, 72.0, 72.4, 73.2 (triple intensity), 73.9,
74.4 and 75.2 (10 × OCH2Ph), 77.1, 77.5, 78.0 (double inten-
sity), 78.5, 78.7, 79.3, 79.9 and 82.7 (9 × CH) and 97.7 (C-1).
This product (7.5 g, 5.88 mmol) was dissolved in ethyl acetate
(45 cm3) containing acetic anhydride (90 cm3) to which conc.
sulfuric acid (30 drops) was added and the mixture was stirred
at rt for 20 min. More ethyl acetate (300 cm3) was added, the
mixture was washed successively with water (2 × 200 cm3), aq.
sodium hydroxide (to pH ~8) and water, and dried. Evaporation
of the mixture afforded acetate 20 as a mixture of α/β anomers
[δH(200 MHz) 5.61 [d, J1,2 8.1, H-1(β)] and 6.27 [d, J1,2 3.6,
H-1(α)] (α:β = 7:1).
Compound 20 was dissolved in THF (50 cm3) and reduced
with an excess of LiAlH4 (1.3 g, 35.3 mmol) for 2 h at rt to yield
2,3,4,6,7,8,9,10,11,12-deca-O-benzyl--erythro--manno--
gluco-dodecitol 21 as an oil, which was contaminated (TLC
hexane–ethyl acetate 1:1) with a more polar product assumed
to be partially debenzylated derivative (one or more benzyl
groups were probably removed under the condition of acetoly-
sis). This crude mixture was benzylated according to method
D to afford fully protected derivative 22 (5.8 g, 69% overall
yield from glycoside 19), m/z 1466 (M ϩ 1 ϩ Naϩ) and 1465
(M ϩ Naϩ); δC(50 MHz; DEPT 135Њ) 70.0, 71.5, 71.7, 71.9,
72.0, 72.4, 72.9, 73.0, 73.1, 73.4, 74.0, 74.4 and 74.6 (double
intensity) (14 × CH2) and 77.2, 78.25, 78.31, 78.8, 79.0, 79.2,
79.4, 80.2, 80.4 and 80.7 (10 × CH).
This compound (4.0 g, 2.77 mmol) was dissolved in a mixture
of diethyl ether (30 cm3) and ethyl alcohol (120 cm3) and hydro-
genated with vigorous stirring over 10% Pd/C (~0.5 g) for 72 h.
After that time TLC indicated the disappearance of the starting
material and formation of a new product that was not mobile
even in ethyl acetate containing 5% methanol and 2% water.
The mixture was filtered through Celite and the filter was
washed with methanol (~0.5 cm3); concentration of the com-
bined filtrate and washings gave mostly an oily residue that
contained only traces of desired product. The Celite layer was
then subsequently washed with boiling water, which was con-
centrated to give crude dodecaol 23. Recrystallisation of the
residue from aq. acetone afforded the title product as fine
crystals (0.54 g, 54%), mp 213–223 ЊC; [α]D ϩ 3 (c 2.0, DMSO);
δC[50 MHz; D2O; DEPT 135Њ (dioxane: δC 66.5 was used as
9 S. Jarosz, (a) Carbohydr. Res., 1987, 167, 211; (b) Tetrahedron Lett.,
1988, 29, 1193; (c) J. Carbohydr. Chem., 1993, 12, 1149.
10 J. W. Krajewski, P. Gluzin´ski, S. Jarosz, A. Zamojski, J. Bleidelis,
A. Mishnyov and A. Kemme, Carbohydr. Res., 1985, 144, 183.
11 S. Jarosz and B. Fraser-Reid, J. Org. Chem., 1989, 54, 4011.
12 S. Jarosz and B. Fraser-Reid, Tetrahedron Lett., 1989, 30, 2359.
13 S. Jarosz, Tetrahedron Lett., 1994, 35, 7655; S. Jarosz, P. Sałan´ski
and M. Mach, Tetrahedron, 1998, 54, 2583.
14 E. J. Bourne, G. P. McSweeney, M. Stacey and L. F. Wiggins,
J. Chem. Soc., 1952, 1408; H. Regeglink, E. de Rouville and G. J. F.
Chittenden, Recl. Trav. Chim. Pays-Bas, 1987, 106, 461.
15 Y. Ojikawa, T. Tanaka and O. Yonemitsu, Tetrahedron Lett., 1986,
27, 3647; K. Horita, S. Nagato, Y. Ojikawa and O. Yonemitsu,
Tetrahedron Lett., 1987, 28, 3253; see also: K. C. Nicolaou, R. A.
Daines, T. K. Chakraborty and Y. Ogawa, J. Am. Chem. Soc., 1988,
110, 4685; T. Yamanoi, T. Akiyama, E. Ishida, H. Abe, M. Anemiya
and T. Inazu, Chem. Lett., 1989, 335.
16 S. Jarosz and E. Kozłowska, Pol. J. Chem., 1996, 70, 45.
17 J. K. Cha, W. J. Christ and Y. Kishi, Tetrahedron, 1984, 40, 2247.
18 J. Frelek, Z. Majer, A. Perkowska, G. Snatzke, I. Vlahov and
U. Wagner, Pure Appl. Chem., 1985, 57, 441.
19 S. Jarosz and Z. Ciunik, Pol. J. Chem., 1998, 72, 1182.
20 R. E. Arrick, D. C. Baker and D. Horton, Carbohydr. Res., 1972, 26,
315.
Paper 8/07190J
3948
J. Chem. Soc., Perkin Trans. 1, 1998, 3943–3948