An efficient and highly regioselective synthesis of 4-deoxy- and 2-acetamido-2,4-dideoxy-β-D-threo-hex-3-enopyranosides

Article abstract of DOI:10.1016/S0040-4039(02)00118-1

The preparation of the previously undescribed class of 4-deoxy- and 2,4-dideoxy-2-acetamido-β-D-threo-hex-3-enopyranosides was accomplished with a very high yield and a complete regioselectivity by means of a simultaneous activation-elimination process of

Full text of DOI:10.1016/S0040-4039(02)00118-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1685–1688
An efficient and highly regioselective synthesis of 4-deoxy- and
2-acetamido-2,4-dideoxy-b- -threo-hex-3-enopyranosides
D
Emanuele Attolino, Giorgio Catelani* and Felicia D’Andrea
Dipartimento di Chimica Bioorganica e Biofarmacia, Universita` degli Studi di Pisa, Via Bonanno, 33, I-56126 Pisa, Italy
Received 20 November 2001; revised 14 January 2002; accepted 16 January 2002
Abstract—The preparation of the previously undescribed class of 4-deoxy- and 2,4-dideoxy-2-acetamido-b-
ranosides was accomplished with a very high yield and a complete regioselectivity by means of a simultaneous activation–elimina-
tion process of the OH-4 group of b- -talopyranosides (5a,b) and 2-acetamido-2-deoxy-b- -talopyranosides (5c,d) with
-galactopyranosides (5e,f) is not regioselective, leading to
D-threo-hex-3-enopy-
D
D
NaH/N,N%-sulfuryldiimidazole. The same reaction of analogous b-
D
mixtures of 3- and 4-hexeno derivatives. This difference is evidently determined by the orientation of the C-2 substituent, which,
in the talo series, is anti diaxially disposed to the H-3 eliminating group. © 2002 Elsevier Science Ltd. All rights reserved.
Unsaturated monosaccharides are one of the most use-
ful classes of synthetic intermediates for the conversion
of common sugars into more sophisticated glycides,1 as
well as for the synthesis of other types of natural
compounds.2 Glycals, cyclic vinyl ethers involving the
ring oxygen atom, are by far the most popular unsatu-
rated glycide derivatives,3 but some other types of
olefinic pyranosides have received great attention, such
as for instance 2,3-dideoxy-hex-2-enopyranosides,4 eas-
ily obtained by Ferrier rearrangement of glycals.1 Much
less studied are pyranose vinyl ethers not involving the
anomeric centre, although their preparation is in princi-
ple very quick, requiring the activation of one hydroxyl
group (e.g. a sulfonate) followed by a simple base-pro-
moted elimination.1 The major drawback of this
approach is that a leaving group in a pyranose frame-
work, with the exception of those in position 1 or 6, is
flanked by two hydrogen atoms with approximately the
same reactivity, with the result that the formation of a
single enol ether is relayed only to favourable specific
cases.1
We present here a very efficient and regiospecific for-
mation of the title unsaturated pyranosides (4) through
a simultaneous activation–elimination process with
NaH/N,N%-sulfuryldiimidazole (Im2SO2) of 4-O-depro-
tected b-
D
-talopyranosides (3, X=OR) or 2-deoxy-2-
acetamido-b-
D
-talopyranosides (3, X=NHAc), in turn
obtained in very high yields by reduction5 or oxima-
tion/reduction6 of easily accessible 2-ulopyranosides 16,7
(Scheme 1).
Compounds 4 have, to our knowledge, not been previ-
ously reported, whereas their erythro analogues have
been obtained only in mixtures with other products
during nucleophilic substitution8a,b or elimination
reactions8c
derivatives.
of
4-O-sulfonyl-D-galactopyranoside
In the context of a general project on the chemical
transformation of common glycides into more rare
bioactive sugars, we started a study to determine useful
conditions for the epimerization at C-4 of 2-acetamido-
Scheme 1.
Keywords: 4-deoxy-
D-threo-hex-3-enopyranosides; N,N%-sulfuryldiimidazole; eliminations; sulfonates; talopyranosides.
* Corresponding author. E-mail: giocate@farm.unipi.it
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00118-1

1686
E. Attolino et al. / Tetrahedron Letters 43 (2002) 1685–1688
2-deoxy-b-
D
-talopyranosides, previously obtained6 with
reaction to other pyranosides15 of the
D-talo and D-
high yields by 2-amination with inversion of the
galacto series, having the same stereochemistry at C-3,
C-4 and C-5. The results (Table 1) show interesting
analogies and differences. The talosamine disaccharide
5d, prepared starting from triacetonlactose deriva-
tives,6b gives the 3-hexeno derivative 6d12,13 with a high
yield, like its monosaccharide analogue 5c; the only
difference observed is a marked reduction in the reac-
tion rate, requiring, for the complete transformation of
the starting material, a higher reaction temperature
(0°C instead −30°C), without, however, a significant
influence on the final yield. Also in the cases of the
neutral mono- and disaccharidic talopyranosides 5a
and 5b, treatment with NaH and Im2SO2 led directly to
the corresponding enol ethers 6a and 6b,12,13 without
the formation of isomeric enol ethers or other by-prod-
ucts, thus suggesting that the overall outcome of this
reaction is independent from the type of substituent at
C-2 and from the steric hindrance of the aglycon.
configuration of b-D-galactopyranosides, including lac-
tose. However, all attempts to obtain 4-O-sulfonates
(mesylate, tosylate, triflate) of methyl 2-acetamido-3,6-
di-O-benzyl-2-deoxy-b-
-talopyranoside (5c)9 gave
D
frustrating results, only starting material being recov-
ered even in forcing conditions, probably because of the
steric shielding exerted on OH-4 by the syn-diaxial
2-acetamido group. We thus tried to prepare 4-O-imi-
dazole-1-sulfonate (4-O-imidazylate)10 in accordance
with a procedure based on the preliminary activaction
of the hydroxyl group by salt formation with a large
excess of NaH.11 In the case of 5c, a smooth reaction
takes place leading with a high yield to a practically
pure product, not corresponding to the structure of the
expected 4-O-imidazylate, but identified as the 4-deoxy-
hex-3-enopyranoside 6c (Scheme 2).12 The formation of
6c is easily explainable, as determined by the transient
formation of the imidazole-1-sulfonate (8c) followed by
a b-elimination, favoured by the strongly alkaline
medium and by the anti disposition between the imi-
dazylate group and H-3. The elimination, probably
following an E2 mechanism, appears to be a very fast
process, the formation of the hypothesised intermediate
8c not being confirmed, at least by TLC analysis, at any
stage of the reaction. It is more difficult to explain the
observed complete regioselectivity of the reaction,
confirmed by the absence of product 7c arising from a
competitive b-elimination of H-5, despite its anti dispo-
sition with respect to the 4-leaving group (Scheme 2).
Prompted by this interesting result, we extended the
In the case of b- -galactopyranosides 5e,f, the reaction
D
is not regioselective and a mixture of 3-hexeno- (6e,f)
and 4-hexeno derivatives (7e,f) was obtained, with the
former prevailing over the latter. The two disaccharide
enol ethers 6f and 7f were separated over silica and
their structure was definitively assigned through NMR
analysis,13 while in the case of the monosaccharide, the
two products 6e and 7e proved to be unseparable, but
their structure and the composition of the mixture were
inferred by NMR.14 The observed difference in the
regioselectivity between the two stereochemical series is
Scheme 2.
Table 1. Product distribution in the reaction of some pyranosides of the
D-talo- and D
-galacto series with Im2SO2/NaHa
Compound
X
Y
Z
W
Temp (°C)
Reaction time (h)
Product distribution
(%)b
Yield (%)c
6
7
8
5a
5b
5c
5d
5e
5f
OMe
OGlce
OMe
OGlce
OMe
OGlce
H
H
H
H
H
H
H
OMe
OBn
OBn
NHAc
NHAc
H
H
H
H
H
OBn
OBn
OBn
−30
0
−30
0
−30
0
−30
3
24
3
24
4
100
100
100
100
65
–
–
–
–
35
40
10
–
–
–
–
–
–
90
95
90
93
79
75d
H
H
29
3
60
–
46 (6f), 30 (7f)
75 (8g)
5g
a All reactions were conducted in accordance with the procedure described in Ref. 11.
b Determined by NMR on the crude reaction products.
c Determined on analytically pure products (Ref. 12), fully characterised by NMR analysis (Ref. 13).
d Unseparable mixture of 6e+7e (Ref. 14).
e Glc=2,3:5,6-di-O-isopropylidene-aldehydo-
D-glucose dimethyl acetal.

E. Attolino et al. / Tetrahedron Letters 43 (2002) 1685–1688
J. Carbohydr. Chem. 2000, 19, 79–91.
1687
evidently due to their opposite configurations at C(2). It
can be supposed that an axially disposed heteroatom at
C(2), present in the talo series, co-operates on
stereoelectronic grounds in the breaking of the C(3)ꢀH
bond during the elimination step, making this process
easier than the competitive elimination involving the
C(5)ꢀH bond. The absence of this stereoelectronic fac-
tor in the galacto series reduces the energy difference
between the two competitive pathways, leading to mix-
tures of enol ethers, as generally observed during the
7. Barili, P. L.; Berti, G.; Catelani, G.; D’Andrea, F.;
Miarelli, L. Carbohydr. Res. 1995, 274, 197–208.
8. (a) Moreau, V.; Norrild, J. C.; Driguez, H. Carbohydr.
Res. 1997, 300, 271–277; (b) McAuliffe, J. C.; Stick, R. V.
Aust. J. Chem. 1997, 50, 203–208; (c) El Nemr, A.;
Tsuchiya, T. Carbohydr. Res. 2001, 330, 205–214.
9. Compound 5c was obtained from methyl 2-acetamido-
2 - deoxy - 3,4 - O - isopropylidene - b -
D
- talopyranoside,6a
through the following sequence: (a) 6-O-benzylation
(KOH, 18-crown-6, THF+0.5% H2O, 84% yield); (b)
3,4-de-O-isopropylidenation (80% aq. AcOH, 40°C, 2 h,
quant.); (d) 3-O-benzylation (1. Bu2SnO, toluene, reflux,
2. BnBr, Bu4NBr, toluene, 5 h, 80% yield).
reactions of 4-O-sulfonyl-
D-galactopyranosides with
various kinds of nucleophiles.8a,b
The reaction of methyl a-D-galactopyranoside deriva-
tive 5g with Im2SO2/NaH shows a further difference. A
fast reaction takes place at −30°C giving, however, only
10% of the enol ether 7g, the major product being,
unexpectedly, the 4-O-imidazylate 8g. When the reac-
tion was prolonged for a further 4 h at room tempera-
ture, TLC analysis showed the disappearance of 8g but
without any appreciable increase in 7g.
10. Vate`le, J.-M.; Hanessian, S. Tetrahedron 1996, 52, 10557–
10568.
11. Sodium hydride (5.0 mmol), suspended in dry DMF (5
mL), was treated at room temperature with a solution of
the appropriate sugar (1.0 mmol) in 20 mL of dry DMF.
The mixture was stirred at rt for 30 min, cooled, treated
with Im2SO2 (290 mg, 1.46 mmol) and further stirred (see
Table 1). Excess of NaH was destroyed with MeOH (5
mL) and, after routine work-up, the residue was purified
by flash chromatography on silica.
12. 6a: syrup, [h]D −1.6 (c 1.1, CHCl3); 6b: syrup, [h]D +3.9 (c
1.2, CHCl3); 6c: syrup, [h]D +2.1 (c 1.1, CHCl3); 6f:
syrup, [h]D −30.3 (c 0.9, CHCl3); 7f: syrup, [h]D +9.8 (c
1.2, CHCl3); 8g: syrup, [h]D +39.6 (c 1.4, CHCl3).
13. Selected NMR data (CDCl3, 1H, 200 MHz 13C, 50 MHz).
6a: lH 3.55 (dd, 1H, J5,6a=5.6 Hz, J6a,6b=9.7 Hz, H-6a),
3.72 (dd, 1H, J5,6b=6.2 Hz, H-6b), 4.51 (d, 1H, J1,2=2.0
Hz, H-1), 4.92 (d, 1H, J4,5=1.7 Hz, H-4), lC 98.6 (C-4),
101.6 (C-1), 152.1 (C-3); 6b: lH 3.46 (dd, 1H, J5%,6%a=5.3
Hz, J6%a,6%b=9.5 Hz, H-6%a), 3.68 (dd, 1H, J5%,6%b=6.5 Hz,
H-6%b), 4.90 (d, 1H, J1%,2%=1.9 Hz, H-1%), 4.99 (d, 1H,
J4%,5%=1.5 Hz, H-4%), lC 99.4 (C-4%), 101.6 (C-1%), 152.4
(C-3%); 6c: lH (CD3CN) 3.50 (dd, 1H, J5,6a=4.9 Hz,
A tentative explanation for the inhibition of the elimi-
nation step registered in the a-galacto series, is that the
attack of the hydride on the axially oriented H(3) or
H(5) is hindered, probably because of steric or field
factors, by the syn-1,3-diaxial a-aglycon. An analogous
difference in reactivity between the two anomeric series
of
D
-galactopyranosides has been previously reported17
also in the case of the base-promoted acetone elimina-
tion of 2,6-di-O-protected 3,4-O-isopropylidene
derivatives.
In conclusion, the reaction of an aldopyranoside having
a single deprotected and axially orientated hydroxyl
group with N,N%-sulfuryldiimidazole and NaH could
represent, in selected stereochemical series like the b-D-
talo one, a new, simple and very efficient way to obtain
with a high yield sugar enol ethers of potential utility in
glycide synthesis. Further studies on other favourable
stereochemical series, as well on the synthetic uses of
the enol ether products, are now planned in order to
define the scope and limitations of the reaction.
J6a,6b=9.9 Hz, H-6a), 3.57 (dd, 1H, J5,6b=6.1 Hz, H-6b),
4.58 (d, 1H, J1,2=1.9 Hz, H-1), 4.86 (d, 1H, J4,5=1.8 Hz,
H-4), lC (CD3CN) 97.3 (C-4), 100.1 (C-1), 152.6 (C-3);
6d: lH 4.77 (d, 1H, J1%,2%=1.6 Hz, H-1%), 4.99 (d, 1H,
J4%,5%=2.2 Hz, H-4%), lC 97.6 (C-4%), 99.3 (C-1%), 152.5
(C-3%); 6f: lH 3.39 (dd, 1H, J5%,6%a=5.3 Hz, J6%a,6%b=9.5 Hz,
H-6%a), 3.58 (dd, 1H, J5%,6%b=6.5 Hz, H-6%b), 4.92 (d, 1H,
J4%,5%=1.2 Hz, H-4%), 5.00 (d, 1H, J1%,2%=6.2 Hz, H-1%), lC
97.6 (C-4%), 102.2 (C-1%), 153.0 (C-3%); 7f: lH 3.91 (s, 2H,
H-6%a, and H-6%b), 5.07 (d, 1H, J3%,4%=3.1 Hz, H-4%), 5.31
(d, 1H, J1%,2%=6.9 Hz, H-1%), lC 98.7 (C-1%), 101.0 (C-4%),
References
1. Ferrier, R. J. In The Carbohydrates, Chemistry and Bio-
chemistry; Pigman, W.; Horton, D., Eds.; Academic
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149.6 (C-5%); 8g: lH 3.45 (tb, 1H, J5,6b=8.5 Hz, J6a,6b=
9.0 Hz, H-6b), 3.54 (dd, 1H, J5,6a=5.7 Hz, H-6a), 4.56 (d,
1H, J1,2=3.6 Hz, H-1), 6.98 and 7.88 (2s, 2H, H-4%, and
H-2%), lC 83.5 (C-4), 98.6 (C-1), 118.2, 130.2 and 137.1
(Im).
14. 6e: lH (CDCl3, 200 MHz) 3.44 (dd, 1H, J5,6a=6.0 Hz,
J6a,6b=9.4 Hz, H-6a), 3.61 (dd, 1H, J5,6b=6.7 Hz, H-6b);
4. Fraser-Reid, B. Acc. Chem. Res. 1996, 29, 57–66.
4.76 (d, 1H, J1,2=3.6 Hz, H-1); 4.92 (d, 1H, J4,5=2.3 Hz,
H-4); lC (CDCl3, 50 MHz) 96.9 (C-4); 102.1 (C-1); 151.4
(C-3); 7e lH (CDCl3, 200 MHz) 3.96 (s, 2H, H-6a, and
H-6b); 4.87 (d, 1H, J1,2=5.6 Hz, H-1); 5.07 (d, 1H,
J3,4=3.3 Hz, H-4); lC (CDCl3, 50 MHz) 99.0 (C-4); 101.3
(C-1); 149.2 (C-5).
5. The reduction of
in our hands, a complete stereoselectivity, leading with
$95% yields to b- -talopyranosides. A detailed discus-
D-lyxo ulosides 1 with NaBH4 showed,
D
sion of this point will be given in the full paper.
6. (a) Barili, P. L.; Berti, G.; Catelani, G.; D’Andrea, F.; Di
Bussolo, V. Carbohydr. Res. 1996, 290, 17–31; (b) Barili,
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15. The preparation of previously unreported derivatives
5,a,b,d was performed by classic manipulation of protect-

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E. Attolino et al. / Tetrahedron Letters 43 (2002) 1685–1688
16. Catelani, G.; D’Andrea, F.; Puccioni, L. Carbohydr. Res.
ing groups, as exemplified for 5c in Ref. 9, and will be
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18. Morishima, N.; Koto, S.; Oshima, M.; Sugimoto, A.;
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reported in detail in the full paper. 5f was prepared with
a good yield by stannylidene-mediated benzylation of
known (Ref. 16) 2%6%-di-O-benzyl-2,3:5,6-di-O-isopropyli-
denelactose dimethyl acetal. Derivatives 5e,g have previ-
ously been reported (Ref. 18).