Stereoselective synthesis of tetrahydrofurans and linear methyl enol- ethers from glycals

Article abstract of DOI:10.1016/S0008-6215(97)10062-3

The O-benzyl derivatives of 1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol (D-glucal, 1), 1,5-anhydro-2,6-dideoxy-L-arabino-hex-1-enitol (L-rhamnal, 7), and 1,5-anhydro-2-deoxy-D-lyxo-hex-1-enitol (D-galactal, 9), underwent stereoselectively a ring contraction by treatment with thallium(III) nitrate (TTN) in MeOH, giving respectively the dimethylacetal derivatives of 3,4,6- tri-O-benzyl-2,5-anhydro-D-mannose, 3,4-di-O-benzyl-6-deoxy-2,5-anhydro-L- mannose (8) and 3,4,6-tri-O-benzyl-2,5-anhydro-D-talose (10). Conversely, the protected glycals 1, 7 and 9, underwent the ring opening reaction by action of the TTN-NaBH₄ reagent in MeOH, providing the enantiomerically pure methyl enol-ethers 3,4,6-tri-O-benzyl-2-deoxy-1-O-methyl-D-arabino-hex-1-enitol, 3,4-di-O-benzyl-2,6-dideoxy-1-O-methyl-L-arabino-hex-1-enitol and 3,4,6-tri- O-benzyl-2-deoxy-1-O-methyl-D-lyxo-hex-1-enitol. The perbenzylated glycosyl- glycals, such as 3,6-di-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-β-D- glucopyranosyl)-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol (cellobial) (16), 3,6-di-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-1,5- anhydro-2-deoxy-D-arabino-hex-1-enitol (lactal) (19) and 3,4-di-O-benzyl-6- O-(2, 3,4,6- tetra- O-benzyl- α-D-galactopyranosyl)- 1,5- anhydro-2-deoxy- D-arabino-hex-1-enitol (melibial) (22), showed the same reactivity as the corresponding glycals by reaction with TTN in MeOH, resulting selectively in the ring contracted compounds at the glycal moiety. The reaction with TTN- NaBH₄ in MeOH, carried out on 16, 19 and 22, led to the formation of the open chain derivatives at the glycal site.

Full text of DOI:10.1016/S0008-6215(97)10062-3

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Carbohydrate Research 306 1998 221–230
Stereoselective synthesis of tetrahydrofurans and
1
linear methyl enol-ethers from glycals
Enzo Bettelli, Piero D’Andrea, Stefano Mascanzoni,
)
2
Pietro Passacantilli , Giovanni Piancatelli
Dipartimento di Chimica and Centro CNR di Studio per la Chimica delle Sostanze Organiche
Naturali, 3 UniÕersity of Rome ‘La Sapienza’, P.le A. Moro 5, I-00185 Rome, Italy
Received 7 April 1997; accepted in revised form 15 October 1997
Abstract
The O-benzyl derivatives of 1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol D-glucal, 1 ,
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.
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.
1,5-anhydro-2,6-dideoxy-L-arabino-hex-1-enitol L-rhamnal, 7 , and 1,5-anhydro-2-deoxy-D-
lyxo-hex-1-enitol D-galactal, 9 , underwent stereoselectively a ring contraction by treatment
with thallium III nitrate TTN in MeOH, giving respectively the dimethylacetal derivatives
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.
.
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.
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of 3,4,6-tri-O-benzyl-2,5-anhydro-D-mannose, 3,4-di-O-benzyl-6-deoxy-2,5-anhydro-L-man-
Ž .
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.
nose 8 and 3,4,6-tri-O-benzyl-2,5-anhydro-D-talose 10 . Conversely, the protected glycals
1, 7 and 9, underwent the ring opening reaction by action of the TTN–NaBH4 reagent in
MeOH, providing the enantiomerically pure methyl enol-ethers 3,4,6-tri-O-benzyl-2-deoxy-1-
O-methyl-D-arabino-hex-1-enitol, 3,4-di-O-benzyl-2,6-dideoxy-1-O-methyl-L-arabino-hex-1-
enitol and 3,4,6-tri-O-benzyl-2-deoxy-1-O-methyl-D-lyxo-hex-1-enitol. The perbenzylated gly-
Ž
.
cosyl-glycals, such as 3,6-di-O-benzyl-4-O- 2,3,4,6-tetra-O-benzyl-b-D-glucopyranosyl -1,5-
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. Ž
.
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anhydro-2-deoxy-D-arabino-hex-1-enitol cellobial 16 , 3,6-di-O-benzyl-4-O- 2,3,4,6-tetra-
O-benzyl-b-D-galactopyranosyl -1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol lactal 19 and
3,4-di-O-benzyl-6-O- 2,3,4,6-tetra-O-benzyl-a-D-galactopyranosyl -1,5-anhydro-2-deoxy-D-
arabino-hex-1-enitol melibial 22 , showed the same reactivity as the corresponding glycals
by reaction with TTN in MeOH, resulting selectively in the ring contracted compounds at the
glycal moiety. The reaction with TTN–NaBH4 in MeOH, carried out on 16, 19 and 22, led to
the formation of the open chain derivatives at the glycal site. q 1998 Elsevier Science Ltd.
All rights reserved.
.
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. Ž
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Keywords: Synthesis, tetrahydrofurans; Synthesis, linear methyl enol-ethers; Glycals; Glycosyl-glycals;
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Thallium III nitrate; 2,5-Anhydro sugars
)
1
Corresponding author.
Dedicated to Prof. Carlo Javarone on the occasion of his 70th birthday.
Also corresponding author.
2
3
Associated to the National Institute ‘Chemistry of Biological Systems’.
0008-6215r98r$19.00 q 1998 Elsevier Science Ltd All rights reserved.

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E. Bettelli et al.rCarbohydrate Research 306 1998 221–230
1. Introduction
relationship between groups at C-3 and C-5 in the
protected glycals, such as 1, 7 and 9; this steric
hindrance could lead to a high stereoselectivity of the
electrophilic attack of TTN at C-2, which occurs
Electrophilic assistance to direct regio- and stere-
oselective transformations of carbohydrate deriva-
tives into enantiomerically pure tetrahydrofurans is of
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.
from the opposite side to the cis groups Scheme 4 .
When the C-3 and C-5 substituents do not have the
same relative orientation, the ring contraction did not
prove to be a fully stereocontrolled process. The
competing effect, which those groups could play
during the rearrangement, was witnessed by an exper-
iment that was carried out using the perbenzylated
w x
synthetic value 1 .
Ion-assisted transformations have been only occa-
sionally described in the carbohydrate field, utilizing
Ž .
w x
particularly mercury II sulfate in sulfuric acid 2
Ž
.
w
Ž
.
and thallium III nitrate, trihydrate TTN, Tl NO3 3 P
3 H2O 3 . Mercuric-ion-assisted acid hydrolysis of
1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol D-glu-
cal 1 resulted in the ring opening, providing the
x w x
Ž
Ž
. Ž
.
allal derivative 14 Scheme 2 . The treatment with
TTN under the usual procedure led to the formation
of two ring contracted products, epimers at C-1,
almost in the same ratio. Their chemical shift values
in 13C NMR are in complete agreement with the
structures proposed for 15a and 15b. The collected
experimental data clearly show that the attack of
TTN occurs from both sides at C-2 of 14 and that the
C-3 and the C-5 substituents of the protected glycal
14 exert a competing, but not dominating effect on
the stereochemical outcome of the molecular rear-
rangement.
. Ž .
w x
hydroxy-trans-enal 2 2 , losing one chiral centre.
However treatment of 1 with TTN in acetonitrile
w x
gave a ring contracted product 3 , the 2,5-anhydro-
Ž
.
D-mannose derivative 3 Scheme 1 . The lack of a
systematic study in this field prompted us to investi-
gate this reaction with other glycals and
disaccharide-derived glycals.
In this paper, we now report a general method that
can lead either to the ring contraction or to the ring
opening compounds with complete stereoselectivity.
Compounds 4 and 10 show a trans relationship
4
between C-1 and C-2, C-1 and C-4 substituents,
2. Results and discussion
Ž
.
Scheme 2 . Moreover, the dimethyl acetal derivative
4 was converted into the known perbenzylated 2,5-
w x
The perbenzylated glycals 1, 7 and 9 4 gave the
highly substituted, enantiomerically pure tetrahydro-
furan dimethylacetals 4, 8 and 10 Scheme 2 in high
Ž .
w
x
Ž .
anhydro-D-mannitol 6 3,7 by acid hydrolysis 3 ,
reduction with sodium carohydride 5 , and benzyla-
tion. The structure of the dimethyl acetal derivative
10 has been established following the previous se-
quence of reactions. Thus, 10 was converted into the
corresponding perbenzylated 2,5-anhydro-D-talitol
Ž .
Ž
.
Ž
.
yields 90% when treated with TTN in methanol at
35 8C for 8 h. According to the reaction mechanism
of TTN, the stereochemical outcome observed during
the ring contraction can be explained by a combina-
tion of stereoelectronic effects derived from the cis
Ž
.
Ž
w x
a
.
13 : its positive rotation
q39.48 in CHCl3
D
shows clearly that the C-2 and C-5 substituents must
possess a trans relationship, since a cis stereochem-
istry would have led to a meso structure. Conse-
quently, the rearranged compound 8 must possess the
same stereochemical outcome, with trans relation-
ships between C-1 and C-2, C-1 and C-4 substituents.
The acid hydrolysis of 4, carried out with hydro-
chloric acid in acetone at 50 8C for 2 h, allowed to
quantitatively hydrolyze the dimethyl acetal to the
corresponding 3,4,6-tri-O-benzyl-2,5-anhydro-D-man-
nose 3. The same reaction carried out on 10 afforded
Ž
.
the aldehyde 11 93% . All the compounds were pure
as shown by their 13C NMR data.
4 For other stereocontrolled synthesis of trans 2,5-dis-
w x
ubstituted tetrahydrofuran see Ref. 6 .
Scheme 1.

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E. Bettelli et al.rCarbohydrate Research 306 1998 221–230
223
Scheme 2.
The ring contraction was successfully applied to
reactivity of 1, 7 and 9 under the action of TTN and
w x
Ž
. w x
the perbenzylated glycosyl-glycals 16, 19 and 22 5 ,
sodium carohydride in methanol 1:4 molar ratio 3 .
In a typical experiment procedure, we reported that 1,
7 and 9 in methanol were first allowed to react with
TTN, then NaBH4 was immediately added before the
formation of the insoluble reduced TTN. All the
reactions were strongly exothermic and practically
instantaneous. Thus, the linear homochiral methoxy
ethers 25, 26 and 27 were isolated after chromatogra-
treatment with TTN in methanol at 35 8C for 8 h
leading stereospecifically to the formation of 17, 20
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.
and 23 in yields around 90% Scheme 3 . The struc-
tures were completely in agreement with the NMR
data.
By analogy with compounds 4, 8 and 10, it was
possible to remove easily the dimethylacetal groups
also in 17, 20 and 23 by treatment with hydrochloric
acid in acetone at 50 8C for 2 h, with formation of the
pure deprotected aldehydes 18, 21 and 24 in good
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.
phy on silica gel in a yield of 60% Scheme 5 .
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.
Yields are acceptable, since starting materials 35%
were recovered unchanged. It is interesting to note
that all chiral centres have been conserved unlike the
previous procedure for glycal derivatives ring open-
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.
yields 90% .
The structure and the stereochemistry of the new
compounds were established by chemical correlation
involving reduction of the aldehyde 21 with sodium
carohydride in methanol for 10 min, removal of the
sugar moiety by 0.1 M H2SO4 in 1:1 tetrahydrofu-
ran–water boiling solution for 1 h and then benzyla-
tion under the usual procedure which gave the pure
and previously described 6.
w x
ing by acids 2 , which gave hydroxy-trans-enals like
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.
2, losing one chiral centre Scheme 1 .
The reaction mechanism can be explained through
the initial formation of an intermediate from the
protected D-glucal 1, as previously described. The
Ž
.
Ž .
well-known reduction of Tl III to Tl I derivatives
represents the key-step that makes the oxidative
Ž
.
w
x
During the past few years, as a part of our continu-
ing interest in the reactivity of glycals, we studied the
molecular rearrangement possible Scheme 4 3,6 .
In the strong nucleophilic medium generated by

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224
E. Bettelli et al.rCarbohydrate Research 306 1998 221–230
Scheme 3.
adding a large excess of sodium carohydride, the
elimination from the initially formed intermediate of
drofuran mixture with TTN and sodium carohydride.
The reactions gave stereospecifically the ring opening
products 28, 29 and 30 in 65% yield, without losing
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.
some Tl III cationic species could be favoured
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.
Ž .
Scheme 6 . This elimination reaction gives rise to a
any chiral centre Scheme 5 . However, starting ma-
Ž
.
competing process that could lead both to the forma-
terials 30% were recovered unchanged.
tion of the ring opening product 25 and the starting
In order to show the flexibility and the utility of
our findings in organic chemistry, we studied the
TTN-promoted ring-transformations of cyclic enol-
Ž .
tri-O-benzyl-D-glucal 1 . Indeed, the cleavage of the
cyclic enol-ether should form the opening products,
y
Ž
.
w x
such as 25 route a , while the leaving of CH3O
ethers, such as the protected aucubin 31 9 , a
Ž
.
Ž
.
group should generate the starting material route b .
It is worth noting that the ring contraction products
were never observed under the above conditions,
completely in agreement with the proposed reaction
widespread iridoidic glycoside Scheme 7 . The O-
benzyl ether derivative 31, by reaction with TTN in
methanol, underwent the usual stereoselective ring
contraction, giving 32 in 94% yield, as shown by 13C
5
w
x
Ž
.
pathway.
NMR data: CDCl3, d 106.8 C-dimethylacetal .
Owing to these promising results, we focused our
attention on perbenzylated glycosyl-glycals, such as
w x
16, 19 and 22 8 . All these compounds showed the
same reactivity by treatment in 4:1 methanol–tetrahy-
5 A parallel experiment carried out by adding MeONa to
a hot solution of the glucal 1 and TTN in MeOH led to the
formation of the product 25, although in a low yield but
without any ring contracted derivative.
Scheme 4.

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E. Bettelli et al.rCarbohydrate Research 306 1998 221–230
225
Scheme 5.
1
However, the H NMR analysis did not allow to
Reactions were monitored on Silica Gel 60-F254
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.
establish the stereochemistry at C-4, since both pro-
tons at C-4 and C-5 appeared as a complex and broad
signal between d 4.4–4.1.
E. Merck detection was performed using UV light
.
Ž
all O-benzyl derivatives or H2SO4 all glycal or
.
glycosyl moiety . Chromatography was performed
using Silica Gel 60 230–400 mesh, and eluted with
Ž
.
On the other hand the reagent combination TTN–
sodium carohydride on 31 lead to the formation of
the solvent mentioned.
the ring opening compound 10 33, in 80% yield.
The structure of 33 was completely in agreement
with analytical and spectroscopic data, particularly
1H NMR spectra were recorded either at 200 or
300 MHz in CDCl3 soln, and 13C NMR were recorded
either at 50.3 or 75.4 MHz in CDCl3 soln.
As criteria of identity and degree of purity, TLC,
w
x
Ž
.
the observed J 12.3 Hz confirmed the E-configura-
tion of the methyl enol-ether, as always previously
described.
3. Experimental
General methods.—All moisture-sensitive reac-
tions were performed under nitrogen using flamed or
oven-dried glassware. Solvents were dried and dis-
tilled prior to use: tetrahydrofuran was distilled from
sodiumrbenzophenone. Anhydrous diethyl ether and
other common solvents were purchased and used as
received. All other reagents were used as received.
Scheme 6.
Scheme 7.

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226
E. Bettelli et al.rCarbohydrate Research 306 1998 221–230
1H NMR, 13C NMR, and elemental analysis were
used.
.
Ž
.
Ž
200 MHz : d 3.42 s, 3 H, OMe , 3.40 s, 3 H,
OMe , 1.28 d, 3 H, J 6.4 Hz, CH3 . 13C NMR
.
Ž
.
Ž
Ž
.
Starting materials.—Tri-O-benzyl-1,5-anhydro-2-
CDCl3, 50.3 MHz : d 138.7, 138.5, 129.1, 128.1
Ž
.
.
Ž
.
deoxy-D-arabino-hex-1-enitol tri-O-benzyl-D-glucal
aromatic , 104.3 C-1 , 89.6, 85.5, 82.7, 78.9, 72.2,
Ž .
Ž
.
Ž
.
1 , di-O-benzyl-1,5-anhydro-2,6-dideoxy-L-arabino-
hex-1-enitol di-O-benzyl-L-rhamnal 7 and tri-O-
benzyl-1,5-anhydro-2-deoxy-D-lyxo-hex-1-enitol tri-
72.1 C-2,3,4,5 and CH2–Ph , 55.8, 54.1 2 OMe ,
19.2. Anal. Calcd for C22 H28O5: C, 70.94; H, 7.58.
Found: C, 70.70; H, 7.60.
3,4,6-Tri-O-benzyl-2,5-anhydro-D-talose dimethylac-
etal 10 . From 3,4,6-tri-O-benzyl-D-galactal 9 150
mg, 0.36 mmol ; 163 mg 95% , colorless liquid;
q10.08 c 5.3, CHCl3 . H NMR CDCl3, 200
MHz : d 3.42 s, 3 H, OMe , 3.39 s, 3 H, OMe ;
Ž
. Ž .
Ž
. Ž .
O-benzyl-D-galactal
9
were prepared following
w x
2,3,4,6-tetra-O-benzyl-b-D-glucopyranosyl -D-glucal
Ž
.
Ž . Ž
standard procedures 4 . 3,6-Di-O-benzyl-4-O-
Ž
Ž
Ž
Ž
Ž
Ž
.
.
Ž
.
1
20
D
. Ž
.
w x
Ž . Ž
hexa-O-benzyl-cellobial 16 , 3,6-di-O-benzyl-4-O-
2,3,4,6-tetra-O-benzyl-b-D-galactopyranosyl -D-glucal
hexa-O-benzyl-lactal 19 and 3,4-di-O-benzyl-6-O-
2,3,4,6-tetra-O-benzyl-a-D-galactopyranosyl -D-glucal
a
.
.
Ž
.
.
Ž
.
13
. Ž
.
Ž
C NMR CDCl3, 50.3 MHz : d 138.9, 138.8, 138.7,
.
Ž
.
Ž
.
128.9–128.0 aromatic , 105.3 C-1 , 81.8, 79.6, 78.6,
78.3, 73.7, 73.4, 72.5, 69.3 C-2,3,4,5 and CH2–Ph ,
56.1, 55.5 2 OMe . Anal. Calcd for C29H34O6: C,
72.78; H, 7.16. Found: C, 72.60; H, 7.18.
1,3,4,6-Tetra-O-benzyl-2,5-anhydro-D-mannitol 6 .
The dimethylacetal 4 230 mg, 0.48 mmol was
stirred with 20:1 acetone–concentrated HCl 10 mL
for 2 h at 50 8C, after which no more starting material
. Ž
.
Ž
.
hexa-O-benzyl-melibial 22 were prepared follow-
Ž
.
ing standard procedures from the corresponding
w x
Ž
.
disaccharides 5 . Perbenzylated aucubin 31 was
w x
Ž .
prepared according to the literature 5 .
Ž
.
General procedure for reactions with TTN in
Ž
Ž
.
MeOH.—A mixture of per-benzylated glycal 0.30
.
Ž
.
Ž
.
mmol and TTN 0.90 mmol in MeOH 15 mL at
35 8C was stirred for 5 h, time after which no more
starting material could be detected on TLC and insol-
uble TLNO3 was precipitated. The mixture was di-
could be detected on TLC. The mixture was diluted
with diethyl ether 100 mL . The organic phase was
washed with saturated Na2CO3 10 mL , water until
Ž
.
Ž
.
Ž
Ž
.
.
Ž
.
Ž
.
luted with diethyl-ether 100 mL and the organic
neutrality , brine 10 mL , dried Na2SO4 and con-
Ž
.
phase washed with saturated Na2CO3 10 mL , water
until neutrality , brine 10 mL , followed by drying
Na2SO4 and concentration under reduced pressure.
centrated under reduced pressure. Then, the resulting
crude aldehyde 3 0.30 mmol dissolved in MeOH 8
Ž
.
Ž
.
Ž
.
Ž
Ž
.
.
Ž
.
mL was treated with NaBH4 40 mg under stirring
for 15 min, after which no more starting material
could be detected on TLC with the formation of
almost pure 5. The mixture was neutralized by bub-
bling carbon dioxide and then diluted with diethyl
Chromatography on a column of silica gel with
ether–hexane as the eluent afforded the required
product.
3,4,6-Tri-O-benzyl-2,5-anhydro-D-mannose dimeth-
Ž .
Ž .
Ž
.
ylacetal 4 . From 3,4,6-tri-O-benzyl-D-glucal
1
.
ether 100 mL . The organic phase was washed with
Ž
.
Ž
Ž
.
Ž
.
100 mg, 0.24 mmol and TTN 280 mg, 0.63 mmol
water and brine 10 mL , dried Na2SO4 and con-
centrated under reduced pressure. Sodium hydride
20 mg was added to the refluxing soln of the crude
5 in dry tetrahydrofuran 10 mL . After 30 min, BnBr
Ž
.
Ž
.
in MeOH 10 mL at 35 8C: 109 mg 95% , colorless
1
w x
Ž
.
.
Ž
Ž
.
liquid; a q118 in CHCl3 . H NMR CDCl3,
D
.
Ž
Ž
Ž
.
300 MHz : d 4.27 f, 1 H, H-5 , 3.61 d, 2 H J 5.7
.
Ž
.
.
Ž
Ž
.
Hz, CH2OBn , 3.45 s, 3 H, OMe , 3.42 s, 3 H,
OMe . C NMR CDCl3, 75.4 MHz d 138.7, 138.5,
138.4, 128.8–128.1 aromatic , 104.1 C-1 , 85.1,
85.0, 83.5, 82.5, 73.7, 72.0, 70.1 C-2,3,4,5,6 and
CH2–Ph , 55.8, 54.2 2 OMe . Anal. Calcd for
C29H34O6: C, 72.78; H, 7.16. Found: C,72.90; H,
7.15.
0.05 mL, 0.42 mmol was added. The mixture was
13
.
Ž
heated under reflux for 5 h, after which no starting
material could be detected on TLC. The mixture was
diluted with diethyl ether and treated with MeOH to
destroy the excess of NaH. The organic phase was
washed with water and brine until neutrality, dried
Ž
.
Ž
.
6
Ž
.
Ž
.
Ž
.
Na2SO4 , and evaporated under reduced pressure to
3,4-Di-O-benzyl-6-deoxy-2,5-anhydro-L-mannose
give a pale yellow oil. Chromatography on a column
Ž .
dimethylacetal 8 . From 2,3-di-O-benzyl-D-rhamnal
of silica gel with hexane and then with 3:7 ether–
Ž . Ž
. Ž .
100 mg, 0.32 mmol : 114 mg 95% , colorless
Ž
7
hexane as the eluant afforded 214 mg of 6 85%
1
w x
Ž
.
Ž
.
liquid; a y5.88 in CHCl3 . H NMR CDCl3,
overall yield for the three steps, starting from 4 ,
D
identical to perbenzylated authentic 2,5-anhydro-D-
1
mannitol superimposable H NMR and 13C NMR
Ž
.
w x
spectra 3 .
6 This signal can be referred to a couple of carbon atoms.
Ž
.
3,4,6-Tri-O-benzyl-2,5-anhydro-D-talose 11 . The

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E. Bettelli et al.rCarbohydrate Research 306 1998 221–230
227
Ž
.
conversion of 10 into aldehyde 11 was performed
according to the procedure described for the prepara-
tion of 3 from 4. Chromatography on a column of
56.6, 55.1 2 O–Me . Anal. Calcd for C29H34O6: C,
72.78; H, 7.16. Found: C, 72.58; H, 7.22. Compound
1
20
w x
Ž
.
Ž
15b: a q58.58 c 12.5, CHCl3 ; H NMR CDCl3,
200 MHz : d 4.3–4.1 non-resolved broad signal, 3
H at C-5, C-2 and at C-dimethylacetal , 3.43 OMe ,
D
.
Ž
silica gel with 1:4 ether–hexane as the eluant af-
20
Ž
.
w x
.
Ž
.
forded 11 185 mg, 93% as a colorless liquid; a
D
1
13
Ž
.
Ž
.
Ž
.
Ž
.
q7.68 c 5.3, CHCl3 . H NMR CDCl3, 300 MHz :
3.38 OMe ; C NMR CDCl3, 50.3 MHz : d 139.1,
Ž
.
Ž
d 9.60 d, J 1.5 Hz, 1 H, CHO , 3.78 d, J 6.6 Hz, 2
138.1, 137.9, 128.9, 128.7, 128.3, 128.2, 128.0
aromatic , 102.8 C-1 , 80.4, 80.1, 79.5, 74.2, 73.8,
13
.
Ž
.
Ž
Ž
.
Ž
.
H, H-6 . C NMR CDCl3, 75.4 MHz : d 201.2
Ž
.
.
Ž
.
Ž
C-1 , 138.0, 137.8, 137.2, 128.6–127.7 aromatic ,
73.2, 70.0 C-2,3,4,5,6 and CH2–Ph , 55.4, 53.4 2
Ž
.
84.7, 80.3, 79.8, 77.4, 73.6, 73.5, 72.7, 68.7 C-
2,3,4,5,6 and CH2–Ph . Anal. Calcd for C27H28O5:
O-Me . Anal. Calcd for C29H34O6: C, 72.78; H, 7.16.
Found: C, 72.89; H, 7.34.
.
C, 74.98; H, 6.53. Found: C, 74.85; H, 6.55.
General procedure for the reaction of glycosyl -
glycals with TTN in MeOH.—A solution of the gly-
(
.
3,4,6-Tri-O-benzyl-2,5-anhydro-D-talitol 12 . The
Ž
.
Ž
.
Ž
.
reduction of 11 125 mg, 0.29 mmol was performed
according to the procedure described for the prepara-
tion of 5 from 3. Chromatography on a column of
cosyl-glycal 0.40 mmol in MeOH 15 mL was
Ž
.
stirred with TTN 1,2 mmol at room temperature for
8 h, after which no more starting material could be
detected on TLC. The mixture was diluted with
silica gel with 1:4 ether–hexane as the eluant af-
20
Ž
.
w x
Ž
.
forded 12 124 mg, 98% as a colorless oil: a
diethyl ether 200 mL and transferred in a separatory
funnel. The organic phase was washed with saturated
D
1
Ž
Ž
.
Ž
.
q45.48 c 3.1, CHCl3 . H NMR CDCl3, 200 MHz :
d 3.71 d, J 6.6 Hz, 2 H, H-6 . C NMR CDCl3,
13
.
Ž
Ž
.
Na2CO3, water until neutrality and brine, then dried
.
Ž
.
50.3 MHz : d 138.8, 138.6, 138.3, 129.0–128.3
Na2SO4 and concentrated under reduced pressure.
Ž
.
aromatic , 80.5, 80.0, 79.4, 77.7, 73.9, 73.8, 73.2,
Chromatography on a column of silica gel with
ether–hexane as the eluent gave the required product.
Ž
.
Ž
.
69.4 C-2,3,4,5,6 and CH2–Ph , 62.3 C-1 . Anal.
Calcd for C27H30O5: C, 74.63; H, 6.96. Found: C,
74.73; H, 6.95.
(
3,6-Di-O-benzyl-4-O- 2,3,4,6-tetra-O-benzyl-b-D-glu-
)
copyranosyl -2,5-anhydro-D-mannose dimethylacetal
Ž
.
Ž
.
Ž
.
1,3,4,6-Tetra-O-benzyl-2,5-anhydro-D-talitol 13 .
17 . A solution of 16 315 mg, 0.37 mmol in
Ž
.
Ž
.
Ž
The benzylation of 12 100 mg, 0.23 mmol was
performed according to the procedure described for
the conversion of 5 into 6. Chromatography on col-
MeOH 15 mL was stirred with TTN 517 mg 1.16
mmol at room temperature for 8 h, after which no
more starting material could be detected on TLC. The
.
Ž
.
umn of silica gel with 1:4 ether–hexane as the eluant
mixture was diluted with diethyl ether 200 mL and
transferred in a separatory funnel. The organic phase,
washed with Na2CO3, water until neutrality and brine,
20
Ž
.
w x
afforded 13 116 mg, 96% as a colorless oil: a
D
13
Ž
d
.
.
Ž
q39.48 c 5.0, CHCl3 . C NMR CDCl3, 50.3
5
.
Ž
.
MHz :
Ž
138.9, 138.8,
138.4, 128.9–128.1
dried Na2SO4 and concentrated under reduced pres-
sure gave a colorless oil. Chromatography on a col-
umn of silica gel with 3:7 ether-hexane as the eluant
gave 17 308 mg, 90% as a colorless oil; a
q3.58 c 4.0, CHCl3 ; H NMR CDCl3, 200 MHz :
d 3.42 s, 3 H, OMe , 3.41 s, 3 H, OMe . C NMR
5
aromatic , 80.0, 79.8, 79.5, 77.6, 73.8, 73.7, 72.8,
Ž
.
70.4, 69.1 C-1,2,3,4,5,6 and CH2–Ph . Anal. Calcd
for C34H36O5: C, 77.84; H, 6.92. Found: C, 77.68;
H, 6.94.
20
Ž
.
w x
D
1
Ž
.
.
Ž
.
13
Ž
Ž
.
3,4,6-Tri-O-benzyl-2,5-anhydro-D-allose-dimethyl-
Ž
.
Ž
Ž
.
acetal 15a and 3,4,6-tri-O-benzyl-2,5-anhydro-D-al-
CDCl3, 50.3 MHz : d 139.2–138.7, 128.9–128.1
1
Ž
.
Ž
.
Ž
.
trose-dimethylacetal 15b . A stirred soln of 14 390
aromatic , 104.0, 103.9 2 C anomeric , 85.6 , 85.1,
83.8, 83.5, 82.6, 78.0, 76.1, 75.3, 75.21, 73.9, 73.7,
.
Ž
.
mg, 0.94 mmol in MeOH 25 mL was treated with
1.66 g of TTN for 4 h. Following the same procedure
for the working-up described for the ring contraction
Ž
.
71.9, 69.9, 69.1, 55.6, 54.1 2 O–Me . Anal. Calcd
for C56H62O11: C, 73.82; H, 6.86. Found: C, 73.60;
H 6.89.
Ž
.
of 1 into 4, the dimethylacetals 15a 144 mg and
Ž
.
(
15b 126 mg have been obtained as colorless oils.
3,6-Di-O-benzyl-4-O- 2,3,4,6-tetra-O-benzyl-b-D-
galactopyranosyl -2,5-anhydro-D-mannose dimeth-
ylacetal 20 . The above procedure was followed
with 19 280 mg, 0.33 mmol , affording 20 271 mg,
89% , as a colorless oil: a q3.38 c 1.8, CHCl3 .
H NMR CDCl3, 200 MHz : d 3.44 s, 3 H, OMe ,
3.42 s, 3 H, OMe . C NMR CDCl3, 50.3 MHz : d
139.3–138.3, 128.9–128.0 aromatic , 104.0, 103.9
1
20
w x
Ž
.
)
Compound 15a: a
q658 c 12.0, CHCl3 ; H
D
Ž
.
Ž
Ž
.
NMR CDCl3, 200 MHz ; d 4.3–4.15 non-resolved
Ž
.
Ž
broad signal, 3 H at C-5, C-2 and at C-dimethyl-
13
20
.
Ž
.
Ž
.
Ž
.
w x
Ž
.
.
acetal , 3.45 OMe , 3.41 OMe ; C NMR CDCl3,
D
.
1
.
Ž
Ž
50.3 MHz : d 138.2, 138.0, 137.9, 128.2, 127.6,
127.5 aromatic , 104.8 C-1 , 83.2, 80.0, 78.1, 76.2,
73.2, 71.9, 71.3, 70.1 C-2,3,4,5,6 and CH2–Ph ,
13
Ž
.
Ž
Ž
.
Ž
.
Ž
.
.
Ž
.

(
)
228
E. Bettelli et al.rCarbohydrate Research 306 1998 221–230
Ž
.
2 C anomeric , 85.4, 85.2, 83.8, 83.3, 82.5, 79.7,
87.9, 85.2, 83.9, 83.4, 79.3, 76.9, 75.4, 75.1, 73.8,
73.6, 73.4, 72.2, 71.8, 69.8, 69.3, 68.6. Anal. Calcd
for C54H56O10: C, 74.98; H, 6.53. Found: C, 74.98;
H, 6.56.
6
6
75.6, 75.0, 73.8, 73.6, 73.3, 71.9, 69.9, 68.8,
55.8, 54.0 2 O–Me . Anal. Calcd for C56H62O11: C,
73.82; H, 6.86. Found: C, 73.58; H 6.88.
Ž
.
(
3,4-Di-O-benzyl-6-O- 2,3,4,6-tetra-O-benzyl-a-D-
3,4,6-Tri-O-benzyl-2-deoxy-1-O-methyl-D-arabino-
)
Ž
.
Ž
.
galactopyranosyl -2,5-anhydro-D-mannose dimeth-
hex-1-enitol 25 . TTN 960 mg, 2.16 mmol dis-
Ž
.
Ž
.
Ž
.
ylacetal 23 . From 22 255 mg, 0.30 mmol ; 241 mg
87% , colorless oil: a
H NMR CDCl3, 200 MHz : d 3.37 s, 3 H, OMe ,
solved in MeOH 10 mL was added to a stirred
20
D
Ž
.
w x
Ž .
Ž
.
q42.28 c 2.3, CHCl3 .
solution of 300 mg, 0.72 mmol of glucal 1 in
1
Ž
.
Ž
.
Ž
.
MeOH 30 mL . Immediately after, a large excess of
NaBH4 was added. After 5 min, the suspension,
diluted with water was extracted then twice with
ether 200 mL . Combined extracts were dried with
Na2SO4, and evaporated to give a pale yellow oil.
Chromatography on a column of silica gel with 1:4
ether–hexane as the eluant gave the starting glucal 1
13
Ž
.
Ž
.
3.34 s, 3 H, OMe . C NMR CDCl3, 50.3 MHz : d
Ž
.
Ž
139.1–138.1, 128.5–127.5 aromatic , 103.7, 98.1 2
.
Ž
.
C anomeric , 85.3, 84.9, 83.0, 81.9, 78.8, 76.5, 75.0,
6
74.7, 73.4, 72.9 , 72.9, 71.7, 71.6, 69.3, 68.7, 68.1,
Ž
.
55.1, 53.5 2 O–Me . Anal. Calcd for C56H62O11: C,
73.82; H, 6.86. Found: C,73.65; H, 6.88.
(
Ž
.
Ž
.
3,6-Di-O-benzyl-4-O- 2,3,4,6-tetra-O-benzyl-b-D-glu-
105 mg, 35% and 25 195 mg, 58% as a colorless
1
20
)
Ž
.
w x
Ž
Ž
.
copyranosyl -2,5-anhydro-D-mannose 18 . The
dimethylacetal 17 175 mg, 0.19 mmol was treated
oil: a y21.88 C. H NMR CDCl3, 200 MHz : d
6.42 d, J1,2 12.8 Hz, 1 H, H-1 , 4.80 dd, J2,3 9.5
Hz, 1 H, H-2 , 3.92 dd, J3,4 3.8 Hz, 1 H, H-3 , 3.50
Ž
D
Ž
.
.
Ž
Ž
.
.
Ž
.
with 20:1 acetone–concd HCl 10 mL under stirring
at 50 8C for 2 h, after which no more starting material
could be detected on TLC. The reaction mixture was
diluted with diethyl ether 150 mL , washed with
Na2CO3, water until neutrality and brine, dried with
Na2SO4 and concentrated under reduced pressure.
Chromatography on column of silica gel with 1:1
s, 3 H, OMe , 2.96 bs, 1 H, H-5 . 13C NMR
CDCl3, 50.3 MHz : d 152.2 C-1 , 139.0, 138.7,
.
Ž
.
6
Ž
.
Ž
.
Ž
.
Ž
.
Ž
.
Ž
128.9–128.2 aromatic , 99.5 C-2 , 81.9, 77.8 C-3
.
.
Ž
Ž
.
Ž
and C-4 , 74.5 C-5 , 73.2, 71.5, 71.0, 69.8 C-6 and
CH2–Ph , 56.3 O–Me . Anal. Calcd for C28H32O5:
C, 74.98; H, 7.19. Found: C, 74.80; H, 7.22.
.
Ž
ether–hexane as the eluant gave 18 as an oil 148
3,4-Di-O-benzyl-2,6-dideoxy-1-O-methyl-L-arabino-
1
20
.
w x
Ž .
Ž
.
Ž
.
mg, 90% : a
Ž
q3.68 c 1.1, CHCl3 . H NMR
hex-1-enitol 26 . From 7 233 mg,0.75 mmol , af-
D
.
Ž
.
Ž
.
CDCl3, 300 MHz : d 9.62 d, J 1 Hz, 1 H, CHO .
fording 26 142 mg, 60% and the starting glycal 7
77 mg, 33% , colorless oil; a
CHCl3 H NMR CDCl3, 200 MHz : d 6.48 d, J1,2
12.8 Hz, 1 H, H-1 , 4.77 dd, J2,3 9.5 Hz, 1 H, H-2 ,
13C NMR CDCl3, 75.4 MHz : d 201.4 C-1 ,
20
Ž
.
Ž
Ž
.
Ž
.
w x
Ž
q288 c, 2.6,
D
X
1
Ž
.
.
Ž
.
Ž
138.5–137.4, 128.8–127.6 aromatic , 103.1 C-1 ,
88.2, 85.4, 84.5, 84.4, 83.6, 82.0, 77.5, 75.6, 75.0,
74.9, 73.5, 73.4, 71.9, 69.6, 68.7. Anal. Calcd for
C54H56O10: C, 74.98; H, 6.53. Found: C, 74.75; H,
6.56.
3,6-Di-O-benzyl-4-O- 2,3,4,6-tetra-O-benzyl-b-D-
galactopyranosyl -2,5-anhydro-D-mannose 21 .
From 20, 185 mg, 0.20 mmol ; 154 mg 89% ,
6
.
Ž
.
Ž
.
Ž
3.55 s, 3 H, OMe , 3.37 t, J3,4 5.3 Hz, J4,5 5.3 Hz, 1
H, H-4 , 1.13 d, J5,6 6.3 Hz, 3 H, H-6 . 13C NMR
.
Ž
.
Ž
.
Ž
.
CDCl3, 50.3 MHz : d 152.3 C-1 , 139.0, 138.5,
(
Ž
.
Ž
.
Ž
129.0–128.2 aromatic , 98.9 C-2 , 84.6, 78.7 C-3
)
(
.
.
Ž
.
Ž
.
and C-4 , 74.4 C-5 , 69.7, 67.8 2 CH2–Ph , 56.3
O–Me , 19.0 C-6 . Anal. Calcd for C21H26O4: C,
Ž
.
Ž
.
Ž
.
Ž
.
1
20
D
.
w x
Ž
.
colorless oil; a q3.78 c 8.0, CHCl3 . H NMR
73.66; H, 7.65. Found: C, 73.51; H, 7.67.
Ž
Ž
.
CDCl3, 200 MHz : d 9.61 d, J 1 Hz, 1 H, CHO .
3,4,6-Tri-O-benzyl-2-deoxy-1-O-methyl-D-lyxo-
13C NMR CDCl3, 50.3 MHz : d 202.2 C-1 ,
Ž
.
Ž
.
Ž
.
Ž
.
hex-1-enitol 27 . From 9 250 mg, 0.60 mmol ,
X
Ž
.
Ž
.
Ž
.
139.1–137.9, 128.9–128.1 aromatic , 103.4 C-1 ,
88.5, 85.8, 84.4, 83.5, 82.6, 79.5, 75.7, 74.9, 73.9,
73.7, 73.6, 73.3, 72.3, 70.0, 68.9. Anal. Calcd for
C54H56O10: C, 74.98; H, 6.53. Found: C, 74.78; H,
6.55.
3,4-Di-O-benzyl-6-O- 2,3,4,6-tetra-O-benzyl-a-D-
galactopyranosyl -2,5-anhydro-D-mannose 24 .
From 23 185 mg, 0.20 mmol ; 149 mg 86% ,
affording 27 159 mg, 59% and the starting glycal 9
20
Ž
.
w x
Ž
85 mg, 34% , colorless oil: a
y46.48 c, 2.0,
D
1
6
.
Ž
.
Ž
CHCl3 ; H NMR CDCl3, 200 MHz : d 6.45 d,
.
Ž
.
J1,2 12.6 Hz, 1 H, H-1 , 4.01–3.80 m, 1 H, H-3 ,
3.55 s, 3 H, OMe , 2.88 m, 1 H, H-5 . 13C NMR
Ž
.
.
Ž
.
7
(
Ž
Ž
.
CDCl3, 50.3 MHz : d 152.5 C-1 , 138.8, 128.9–
128.1 aromatic , 100.0 C-2 , 81.1, 78.2 C-3 and
C-4 , 74.4 C-5 , 73.7, 71.4, 70.3, 69.8 C-6 and
)
(
.
Ž
.
.
Ž
.
Ž
Ž
Ž
.
Ž
.
.
Ž
1
20
w x
Ž
.
colorless oil; a q42.08 c 2.0, CHCl3 . H NMR
D
Ž
.
Ž
.
CDCl3, 200 MHz : d 9.61 d, J 1 Hz, 1 H, CHO .
13C NMR CDCl3, 50.3 MHz : d 203.3 C-1 ,
Ž
.
Ž
.
X
7 This signal can be referred to three carbon atoms.
Ž
.
Ž
.
139.4–137.6, 129.1–127.9 aromatic , 98.5 C-1 ,

(
)
E. Bettelli et al.rCarbohydrate Research 306 1998 221–230
229
.
Ž
.
Ž
.
Ž
.
Ž
.
CH2–Ph , 56.4 OMe . Anal. Calcd for C28H32O5: C,
C-9 , 55.3, 54.2 2 OMe , 49.8 C-5 . Anal. Calcd
74.98; H, 7.19. Found: C, 74.82; H, 7.21.
for C59H64O11: C, 74.66; H, 6.80. Found: C, 74.52;
(
3,6-Di-O-benzyl-2-deoxy-4-O- 2,3,4,6-tetra-O-ben-
H, 6.82.
)
[
]
zyl-b-D-glucopyranosyl -1-O-methyl-D-arabino-hex-1-
1S,4S,5S -3-Benzyloxymethyl-4-hydroxymethyl-
X
Ž
.
Ž
.
[( )
(
)]
enitol 28 . From 16 330 mg, 0.39 mmol , affording
5 E -2 - methoxyethenyl -O-benzylcyclopent-2-en-1-
Ž
. Ž
Ž
.
28 and the starting glycal 16 99 mg, 30% 223 mg,
ol 33 . The ring opening of perbenzylated aucubin
1
20
.
w x
Ž
.
Ž
. Ž
.
65% , colorless oil: a q5.58 c, 4.8, CHCl3 ; H
31 220 mg, 0.25 mmol was performed according
D
Ž
.
Ž
NMR CDCl3, 200 MHz : d 6.55 d, J1,2 12.8 Hz, 1
to the procedure described for the opening of the
glycal 1 to 25. Chromatography on column of silica
13
.
Ž
.
Ž
H, H-1 , 3.53 s, 3 H, OMe . C NMR CDCl3, 50.3
.
Ž
Ž
.
.
Ž
MHz : d 152.3 C-1 , 139.2–138.8, 128.9–128.1
gel with 1:4 ether–hexane as the eluant gave 33 75
X
13
Ž
.
Ž
.
.
Ž
aromatic , 103.9 C-1 , 99.3 C-2 , 85.3, 82.5, 80.0,
mg, 80% as a colorless oil; C NMR CDCl3, 50.3
MHz : d 149.6 C-3 , 144.5 C-7 , 139.2, 138.4,
132.8, 129.0–128.0 C-8 and aromatic , 101.9 C-4 ,
88.9 C-6 , 73.2, 72.1, 68.6 C-10 and CH2–Ph , 62.2
6
6
.
Ž
.
Ž
.
78.2, 76.0, 75.3, 75.2, 73.8, 73.6, 71.3, 71.2,
Ž
.
Ž
.
Ž
.
69.9, 69.4, 56.2 OMe . Anal. Calcd for C55H60O10:
C, 74.98; H, 6.86. Found: C, 74.71; H, 6.89.
Ž
.
Ž
.
(
Ž
.
3,6-Di-O-benzyl-2-deoxy-4-O- 2,3,4,6-tetra-O-ben-
C-1 , 56.4, 52.7, 49.4. Anal. Calcd for C55H60O10:
)
zyl-b-galactopyranosyl -1-O-methyl-D-arabino-hex-
C, 74.98; H, 6.86. Found: C, 75.76; H, 7.42.
Ž
.
Ž
.
1-enitol 29 . From 19 315 mg, 0.37 mmol , afford-
Ž
.
Ž
ing 29 209 mg, 64% and the starting glycal 19 88
20
Acknowledgements
.
w x
Ž
.
mg, 28% , colorless oil:; a q3.38 c, 5.0, CHCl3 ;
D
1
Ž
.
Ž
H NMR CDCl3, 200 MHz : d 6.52 d, 1 H, J1,2
13
This work was supported from the Italian
.
Ž
Ž
.
Ž
12.8 Hz, H-1 , 3.53 s, 3 H, OMe . C NMR CDCl3,
50.3 MHz : d 152.0 C-1 , 139.4–138.5, 129.0–128.0
aromatic , 104.3 C-1 , 99.3 C-2 , 82.9, 80.6, 79.8,
78.0, 75.5, 75.0, 74.0, 73.9, 73.5, 73.5, 73.2, 71.2,
Ž
Ministero dell’Universita e della Ricerca Scientifica
`
.
.
X
. Ž
.
e Tecnologica, Rome MURST . Thanks are due to
the student Patrizia Chinzari for having carried out
some experiments described in this work.
Ž
.
Ž
.
Ž
.
5
6
Ž
.
69.8, 68.9, 56.1 OMe . Anal. Calcd for C55H60O10:
C, 74.98; H, 6.86. Found: C, 74.82; H, 6.88.
(
3,4-Di-O-benzyl-2-deoxy-6-O- tetra-O-benzyl-a-
References
)
galactopyranosyl -1-O-methyl-D-arabino-hex-1-enitol
Ž
.
Ž
.
30 . From 22 290 mg, 0.34 mmol , affording 30
w x
1 S. Hanessian, Total Synthesis of Natural Products.
Ž
.
Ž
187 mg, 62% and the starting glycal 22 90 mg,
The Chiron Approach, Oxford, 1983, pp. 40–183; H.
20
Kunz and K. Ruck, Angew. Chem., Int. Ed. Engl., 32
.
w x
Ž
.
¨
31% , colorless oil; a
q52.98 c, 2.3, CHCl3 ;
D
1
Ž
.
1993 336–358; S.J. Danishefsky and M.T. Bilodeau,
Ž
.
Ž
H NMR CDCl3, 200 MHz : d 6.45 d, 1 H, J1,2
Ž
.
Angew. Chem., Int. Ed. Engl., 35 1996 1381–1419;
T.L. Boivin, Tetrahedron, 43 1987 3309–3362; G.
Cardillo and M. Orena, Tetrahedron, 46 1990
13
.
Ž
Ž
.
Ž
12.8 Hz, H-1 , 3.51 s, 3 H, OMe . C NMR CDCl3,
50.3 MHz : d 152.0 C-1 , 139.2–138.5, 128.9–128.0
Ž
.
.
.
Ž
Ž
.
X
Ž
.
.
aromatic , 99.8, 99.1 C-2 and C-1 , 82.9, 79.3,
3321–3408.
6
6
w x
2 J. Wengel, J. Lau, and E.B. Pedersen, Chem. Scr., 29
77.8, 76.9, 75.2, 74.8, 73.9, 73.8, 73.1, 70.5,
Ž
.
1989 67–70; A.G. Tolstikov, N.V. Khakhalina, and
Ž
.
69.9, 69.8, 69.3, 56.2 OMe . Anal. Calcd for
C55H60O10: C, 74.98; H, 6.86. Found: C, 74.80; H,
6.88.
Ž
.
L. Spirikhin, Synthesis, 1988 221–222; S. Yik-Kai
Ž
.
Tam and B. Fraser-Reid, Carbohydr. Res., 25 1975
29–43.
[
]
(
)
1S,4S,5S,8S - 2 - Bis dimethoxymethyl - 4 - O -
w x
3 A. Kaye, S. Neidle, and C.B. Reese, Tetrahedron
(
)
Ž
.
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