Inter- and intramolecular alcohol additions to exo-glycals

Article abstract of DOI:10.1016/S0040-4039(02)01473-9

Various exo-glycals were explored for the glycosidic bond formation and synthesis of spiroacetals in a stereoselective manner. The former reaction was an intermolecular alcohol addition to give the S new stereogenic center, resulting from the nucleophilic

Full text of DOI:10.1016/S0040-4039(02)01473-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6515–6519
Inter- and intramolecular alcohol additions to exo-glycals
Chuan-Fa Chang,a,b Wen-Bin Yang,c,* Che-Chien Changb and Chun-Hung Lina,b,
*
aGraduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
bInstitute of Biological Chemistry, Academia Sinica No. 128, Academia Road Section 2, Nan-Kang, Taipei 11529, Taiwan
cGraduate Institute of Pharmacognosy Science, Taipei Medical University, Taipei, Taiwan
Received 12 June 2002; revised 17 July 2002; accepted 18 July 2002
Abstract—Various exo-glycals were explored for the glycosidic bond formation and synthesis of spiroacetals in a stereoselective
manner. The former reaction was an intermolecular alcohol addition to give the S new stereogenic center, resulting from the
nucleophilic attack from the bottom face of the sugar ring. The latter one was carried out by the hydroboration of a sugar diene,
followed by a subsequent acid workup. © 2002 Elsevier Science Ltd. All rights reserved.
endo-Glycals (1,2-unsaturated sugars) have been well
recognized as versatile building blocks in the prepara-
tion of numerous biomolecules. For example, the glycal
assembly method, developed by Danishefsky et al., has
offered a novel and efficient strategy to synthesize
Lewis and blood group determinants, gangliosides, and
tumor-associated antigens.1–7 endo-Glycals are also chi-
ral precursors for biologically interesting compounds
such as staurosporine8 and brevetoxin B,9 as well as
substrates for a variety of chemical transformations
including azidonitration10,11 and Michael addition to
2-nitrogalactal.12–14 Therefore, it is reasonable that exo-
glycals can be widely utilized with the same great
potential as endo-glycals.
dration.22,23 The method is applicable to the gluco-,
galacto-, and manno-type precursors, and stereoselec-
tive to give exclusively the (Z)-isomers of exo-glycals.23
Herein we demonstrate inter- and intramolecular addi-
tion reactions of exo-glycals leading to a new stereocen-
ter at the anomeric position. To build up the chemistry
with high stereoselectivity is indeed a synthetic chal-
lenge, the importance of which can be appreciated by
the example as follows. Schmidt’s group recently
reported a novel and potent galactosyltransferase
inhibitor based on the design of disubstrate analogue.24
The synthesis took more than six reaction steps from
fully protected galactonolactone to construct two teth-
ers extending from the anomeric center.24
1-exo-Methylene sugars, the simplest members in the
exo-glycal family, have been used as valuable glycosi-
dase inhibitors,15 and applied for the synthesis of C-gly-
cosides.16 However, the reactions of exo-glycals have
not been investigated in detail, which is attributed to no
universal procedures of preparation. The reported syn-
theses of substituted or specially functionalized exo-gly-
cals usually require more laborious efforts, including
Keck reaction of glycosyl dihalides,17 Wittig olefination
of sugar lactones,18 Ramburg-Ba¨cklund rearrangement
of S-glycosides,19,20 and [2,3]-Wittig sigmatropic rear-
rangement.21 We recently presented a general method
to synthesize exo-glycals by a nucleophilic addition of
fully protected sugar lactones and the subsequent dehy-
exo-Glycals were first explored for glycosidic bond
formation. Sugar diene 1 was subjected to the addition
of allyl alcohol in the presence of BF3–OEt2 to give a
single product 2 in 51% yield (entry a of Table 1). On
the basis of NOESY analysis, compound 2 was deter-
mined to have a C-substituent on the b-position and an
O-allyl group on the a-position.25 The reactivity was
greatly improved as the ethylene substituent was
replaced with carboxyethyl ester (entry b). Table 1 also
demonstrated the Michael addition reactions to conju-
gated esters 3–5 to generate products 6–14, respectively.
The reaction yields varied in different nucleophiles (e.g.
entries b–f). Apparently the steric hindrance played the
role here. When different types of exo-glycals were
investigated (e.g. entries b, g and i), the significant
difference in reactivity was observed. The exo-glycal of
manno-type was more reactive than those of gluco- and
galacto-types.
* Corresponding authors. Tel.: +886-2-2789-0110; fax: +886-2-2651-
4705; e-mail: chunhung@gate.sinica.edu.tw
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01473-9

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C.-F. Chang et al. / Tetrahedron Letters 43 (2002) 6515–6519
Table 1.
substrate
nucleophileb
OH
time
24 h
product
entry
a
yield
51%
6
BnO
OBn
O
1'
O
BnO
BnO
BnO
BnO
S
S
3
BnO
OBn
O
2
1
1"
BnO
OBn
O
O
BnO
BnO
CO2Et
BnO
BnO
12 h
b
92%
CO2Et
OH
BnO
OBn
O
R
3
6 (R = allyl)
OH
OH
c
d
e
24 h
16 h
7 (R = ethyl)
89%
93%
3
3
8 (R = 1-butyl)
9 (R = benzyl)
3
3
OH
24 h
24 h
78%
53%
f
10 (R = 2-propyl)
OH
BnO
OBn
O
BnO
BnO
BnO
4
OBn
1'
BnO
BnO
CO2Et
O
OH
g
h
6 h
98%
CO2Et
S
2
3
O
R
4
11 (R = allyl)
4
10 h
12 h
OH
OH
12 (R = ethyl)
91%
95%
OBn
O
BnO
BnO
BnO
OBn
O
CO2Et
BnO
i
j
CO2Et
S
BnO
BnO
O
R
5
5
13 (R = allyl)
HO
OH
14 (R = CH2CH2OH)
99%
16 h
a Reaction conditions: all the reactions were carried out at 25 oC in CH2Cl2 in the
.
presence of BF3 OEt2 (5 eq) and 4 A molecular seives.
b10 equivalents of nucleophiles were added.
functionalization of the terminal olefin and a subse-
quent acid-catalyzed cyclization.22a Further studies on
various types of sugar dienes 17–21 (Fig. 1) including
gluco-, galacto-, manno-, and fuco-type precursors
revealed several interesting features. Some of the glyco-
syl spiroacetals can be obtained in a stereoselective
manner. The hydroboration of dienes 17–19, quenched
by oxidation with H2O2 and camphor sulfonic acid
(CSA), gave spiroacetals 22–24 as a single isomer,
respectively. On the other hand, when dienes 20 and 21
were individually subjected to the same conditions, only
moderate selectivity was observed and pairs of separa-
ble isomers were obtained in ratios of 3:1 (25/26) and
8:1 (27/28), respectively. A mixture of 25 and 26 (3/1)
were deprotected using TBAF and benzylated to give
the known compounds 29 and 30 in the ratio of 3/1.28
Upon treatment with trifluoroacetic acid (TFA), only
the former product 29 was left as the thermodynami-
cally favored isomer. The result was in accordance with
the anomeric effect. Likewise, fully benzylated spiroac-
etals 31 and 32 (as a mixture of 8/1) can be derived
from the mixture of 27 and 28 (8/1). Compound 32
In addition, all the reactions led to the same stereo-
chemical outcome; i.e. the S-configuration was
obtained at the anomeric center of all the products. The
stereochemistry was consistent with a nucleophilic
attack from the bottom face of the sugar ring. All the
product structures were supported by DEPT26 and
NOESY spectra in addition to other spectroscopic
properties. For instance, the NOESY spectra of ester 11
indicated the cross peaks between H1% (l 3.22) and H2
(l 4.33); the ones between H1%% (l 4.10)27 and H5 (l
3.66). The data thus verify the O-allyl group located at
the a-position. It is of interest that the spatial correla-
tion always exists between H-1%% and H-5 among all the
glycoside products, consistent with that between H-1%
and H-2.
Furthermore, the addition reactions to exo-glycals were
carried out intramolecularly by a built-in alcohol. In
our previous work the hydroboration of exo-glycosyl
diene 15 resulted in the formation of isomeric spiroac-
etals 16 under an acidic workup condition, as shown in
Fig. 1.22a The result was realized due to the selective

C.-F. Chang et al. / Tetrahedron Letters 43 (2002) 6515–6519
6517
assigned for spiro sugars 23, 24, 29 and 31 were also
favored by the anomeric effect.
During the formation of these spiro sugars, a homoallyl
alcohol has been suggested to exist after the selective
hydration of the terminal olefin,22a which was followed
by the acid-catalyzed cyclization. According to Bald-
win’s rule for the five-membered ring closure, however,
5-endo-trigonal annulation (Fig. 2) is not favored. An
oxocarbenium ion was thus proposed to be the plausi-
ble intermediate to qualify for the stereochemical
requirement (5-exo-trigonal annulation) of Baldwin’s
ring forming processes.
Interestingly, when 2 equiv. of borane were used in the
hydroboration of diene 17, a C-glycosyl diol 33 was
produced (Fig. 3). Further derivatization with p-bro-
mobenzoyl chloride gave compound 34 as a crystalline
product, suitable for single crystal X-ray analysis as
shown in the ORTEP drawing in Fig. 3.30 Thus the new
stereogenic centers were corroborated to exhibit the
(1R, 1%R) chirality. The result can be rationalized that
the steric hindrance owing to the C2 silyl group forced
the syn addition of borane to occur in the top face of
the sugar ring. As a consequence, it is possible to
prepare C-glycosides by the hydroboration of exo-gly-
cals with high stereoselectivity.
In conclusion, exo-glycals were applied for the stereose-
lective alcohol additions to afford unusual glycosides
with both O- and C-glycosidic linkages, as well as
glycosyl spiroacetals. In addition to simple alcohols, we
are currently utilizing sugars as nucleophiles to generate
disaccharides or oligosaccharides, which will be
reported in due course. Also it is of interest to investi-
gate how various different factors affect the reactivity
of exo-glycals, such as Lewis acid and substituted
functionality.
Supplementary material available: 1H and 13C NMR
spectra of compounds 2, 6–14, 22–25, 28–34 and
NOESY spectra of compounds 2, 6, 11, 12, 24 to
indicate the correlation of H1% and H2 in space were all
included.
Figure 1. Reagents and conditions: (a) BH3–THF; (b) H2O2,
CSA; (c) (i) TBAF; (ii) NaH, BnBr; (d) TFA.
completely converted to the other more stable isomer
31 under the condition of TFA.
The new stereogenic center of the spiro sugars was
diagnosed by comparison with the reported NMR spec-
tral data (e.g. compounds 29 and 30)28 or NOESY
studies. For instance, the NOESY spectra of spiroacetal
24 indicated the cross peaks between H1% (l 1.95) and
H2 (l 4.03), which thus supported R-configuration at
C1 position.29 The stereochemical configurations
Figure 2.

6518
C.-F. Chang et al. / Tetrahedron Letters 43 (2002) 6515–6519
Figure 3. Reagents and conditions: (a) BH3–THF (2 equiv.); (b) H2O2, NaOH; (c) p-bromobenzoyl chloride, pyridine.
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The work is financially supported by National Science
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