Stereospecific synthesis of 1,2-cis glycosides by vinyl-mediated IAD

Article abstract of DOI:10.1021/ol048427o

(Chemical Equation Presented) Stereospecific 1,2-cis glycosylation of 2-O-vinyl thioglycosides, synthesized from the corresponding alcohols by Ir-catalyzed transvinylation with vinyl acetate, is achieved by iodine-mediated tethering of a range of primary

Full text of DOI:10.1021/ol048427o

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3797-3800
Stereospecific Synthesis of 1,2-cis
Glycosides by Vinyl-Mediated IAD
Kampanart Chayajarus, David J. Chambers, Majid J. Chughtai, and
Antony J. Fairbanks*
The Chemistry Research Laboratory, UniVersity of Oxford, Mansfield Road,
Oxford OX1 3TA, U.K.
antony.fairbanks@chem.ox.ac.uk
Received August 9, 2004
ABSTRACT
Stereospecific 1,2-cis glycosylation of 2-O-vinyl thioglycosides, synthesized from the corresponding alcohols by Ir-catalyzed transvinylation
with vinyl acetate, is achieved by iodine-mediated tethering of a range of primary and secondary carbohydrate acceptors, followed by
intramolecular aglycon delivery (IAD). The use of such an intramolecular glycosylation strategy furnishes the desired
disaccharides in an entirely stereoselective manner.
r-gluco and â-manno
The stereoselective synthesis of 1,2-cis glycosidic linkages,
wherein the interglycosidic oxygen is formally cis to the
2-hydroxyl group of the glycosyl donor, represents a major
challenge during oligosaccharide synthesis. While the use
of neighboring group participation of 2-O-acyl-protected
glycosyl donors reliably allows the synthesis of the corre-
sponding 1,2-trans glycosides,1 there is no correspondingly
easy and general technique which allows the synthesis of
1,2-cis stereoisomers with complete stereocontrol.2
The recent development of several intramolecular glyco-
sylation strategies3 has shown promise for achieving higher
levels of stereocontrol for glycoside and oligosaccharide
synthesis. In particular, the intramolecular glycosylation
strategy commonly referred to as intramolecular aglycon
delivery (IAD), wherein the glycosyl donor and the glycosyl
acceptor are linked prior to glycosylation by the 2-hydroxyl
of the donor and the alcohol of the acceptor to be glycosy-
lated, is perhaps the most predictable and reliable method
of achieving 1,2-cis stereocontrol. This approach was orig-
inally developed specifically for the synthesis of â-manno-
sides by Hindsgaul4 and Stork5 and then used subsequently
to greater effect by Ogawa.6
As part of our ongoing interest in the synthesis of
oligosaccharides containing 1,2-cis linkages,7 we reported
the development of an IAD approach based on the use of
2-O-allyl-protected glycosyl donors, which allows the stereo-
specific synthesis of a range of 1,2-cis glycosides and
disaccharides.8 Studies have detailed the use of both thiogly-
cosides9 and glycosyl fluorides10 as donors, and the strategy
(4) Barresi, F.; Hindsgaul, O. Can. J. Chem. 1994, 72, 1447-1465.
Barresi, F.; Hindsgaul, O. Synlett. 1992, 759-760. Barresi, F.; Hindsgaul,
O. J. Am. Chem. Soc. 1991, 113, 9377-9379.
(5) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087-1088. Stork,
G.; La Clair, J. J. J. Am. Chem. Soc. 1996, 118, 247-248.
(6) Lergenmuller, M.; Nukada, T.; Kuramochi, K.; Dan, A.; Ogawa, T.;
Ito, Y. Eur. J. Org. Chem. 1999, 1367-1376. Ito, Y.; Ogawa, T. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1765-1767.
(7) Ennis, S. C.; Fairbanks, A. J.; Tennant-Eyles, R. J.; Yeates, H. S.
Synlett 1999, 1387-1390. Ennis, S. C.; Fairbanks, A. J.; Slinn, C. A.;
Tennant-Eyles, R. J.; Yeates, H. S. Tetrahedron 2001, 57, 4221-4230.
(8) Fairbanks, A. J. Synlett 2003, 1945-1958.
(1) Wulff, G.; Ro¨hle, G. Angew. Chem., Int. Ed. Engl. 1974, 13, 157-
170.
(2) Demchenko, A. V. Curr. Org. Chem. 2003, 7, 35-79.
(3) Jung, K.-H.; Mu¨ller, M.; Schmidt, R. R. Chem. ReV. 2000, 100,
4423-4442.
(9) Aloui, M.; Chambers, D. J.; Cumpstey, I.; Fairbanks, A. J.; Redgrave,
A. J.; Seward, C. M. P. Chem. Eur. J. 2002, 8, 2608-2621. Seward, C. M.
P.; Cumpstey, I.; Aloui, M.; Ennis, S. C.; Redgrave, A. J.; Fairbanks A. J.
J. Chem. Soc., Chem. Commun. 2000, 1409-1410.
10.1021/ol048427o CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/18/2004

Scheme 1. Synthesis of 2-O-Vinyl Glycosyl Donors
has also been applied to less common 1,2-cis glycosides such
the gluco donor 7 was accessed from known ortho ester 514
by opening with p-thiocresol to yield the acetate 6 and then
deacetylation to yield the alcohol 7 (Scheme 1). Both
alcohols 3 and 7 were used as substrates in a search for an
efficient method for the synthesis of the corresponding 2-O-
vinyl glycosides. A variety of different literature methods
for the synthesis of vinyl ethers from alcohols were
investigated,15 but none proved particularly satisfactory. The
most efficient method investigated involved the use of vinyl
acetate in an iridium complex catalyzed transvinylation
process, as reported by Ishii.16 Optimization of this procedure
finally allowed the synthesis of the desired 2-O-vinyl
thioglycosides 4 and 8 in 78% and 60% yields, respectively
(Scheme 1).
as â-rhamnosides and R-glucofuranosides.11
One of the current limitations with the allyl IAD approach
is the moderate efficiency of the tethering of glycosyl donor
and acceptor when the acceptor is a hindered secondary
carbohydrate alcohol. On the basis of previous observations
of the greatly increased efficiency of mixed acetal tethering
of the allyl IAD system as compared to the original
Hindsgaul IAD approach, it was considered that a further
increase in efficiency of tethering could be achieved by the
use of 2-O-vinyl glycosyl donors (Figure 1). The caveat to
With both vinyl ethers in hand, tethering of a variety of
carbohydrate alcohols was undertaken using recently opti-
mized conditions17 for mixed acetal formation of iodine, and
silver triflate in the presence of di-tert-butylmethylpyridine
(DTBMP). In all cases, efficient tethering of the alcohol and
the vinyl ether was observed using 1 equiv of aglycon alcohol
(Table 1). Although the yield of mixed acetals was margin-
ally lower for the hindered secondary carbohydrate alcohols
(entries 4), these results were more efficient than for the
corresponding mixed acetals in the allyl IAD system.9,10
With a selection of mixed acetals in hand, attention turned
to the subsequent intramolecular glycosylation step. Mixed
acetal 10a, derived from diacetone galactose and the gluco
vinyl ether 8, was subjected to a range of activation
conditions in an attempt to induce efficient intramolecular
glycosylation (Table 2). Treatment with N-iodosuccinimide
and silver triflate, in the presence of di-tert-butylmethylpy-
ridine, produced only a poor yield of the desired R-gluco
disaccharide 12a, a result which contrasted with previous
investigations in the allyl IAD system. The use of either more
forcing reaction conditions, changes in activator to either
iodine/silver triflate, dimethyl (methylthio)sulfonium triflate
Figure 1. Comparison of Hindsgaul IAD, allyl IAD, and vinyl
IAD approaches.
this approach was the relative inefficiency of the synthesis
of the required vinyl ethers compared to the extremely
efficient access to enol ethers derived from 2-O-allyl glycosyl
donors by Wilkinson’s catalyst mediated isomerization.12
Thioglycosides 3 and 7 were synthesized as potential
donors for investigation of the vinyl IAD approach. Manno
donor 3 was accessed from the known ortho ester 113 by
reaction with p-thiocresol to yield the acetate 2. De-
acetylation then yielded the required alcohol 3. Similarly,
(DMTST),18
S-(4-methoxyphenyl)benzenethiosulfinate
(14) Lichtenthaler, F. W.; Schneider-Adams, T. J. Org. Chem. 1994, 59,
6728-6734.
(10) Cumpstey, I.; Fairbanks, A. J.; Redgrave, A. J. Monatsh. Chem.
2002, 133, 449-466. Cumpstey, I.; Fairbanks, A. J.; Redgrave, A. J. Org.
Lett. 2001, 3, 2371-2374.
(15) Dujardin, G.; Rossignol, S.; Brown, E. Tetrahedron Lett. 1995, 36,
1653-1656. Watanabe, W. H.; Conlon, L. E. J. Am. Chem. Soc. 1957, 79,
2828-2833.
(11) Cumpstey, I.; Fairbanks, A. J.; Redgrave, A. J. Tetrahedron 2004,
60, 9061-9074.
(16) Olimoto, Y.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2002, 124,
1590-1591.
(17) Cumpstey, I.; Chayajarus, K.; Fairbanks, A. J.; Redgrave, A. J.;
Seward, C. M. P. Tetrahedron: Asymmetry 2004, 15, in press.
(12) Boons, G.-J.; Isles, S. J. Org. Chem. 1996, 61, 4262-4271.
(13) Zhang, Y. M.; Mallet, J.-M.; Sinay¨, P. Carbohydr. Res. 1992, 236,
73-88.
3798
Org. Lett., Vol. 6, No. 21, 2004

derived system, as may have been predicted by consideration
of inductive effects on the stability of the oxonium produced
after glycosylation. Previous results had confirmed that
intramolecular glycosylation was more sluggish in the allyl
system than in the Hindsgaul acetate/Tebbe system, again
in line with inductive stabilization of the oxonium ion formed
after intramolecular glycosylation. However the use of iodine
and silver triflate, again in the presence of DTBMP as a base,
combined with changing the reaction solvent to acetonitrile
resulted in a significant improvement in the yield of
glycosylated product. In this instance the R-gluco disaccha-
ride 12a was isolated in 51% yield.
Table 1. Mixed Acetal Formation
Encouraged by this result, the remaining mixed acetals in
both the gluco and manno series were subjected to these
specific glycosylation conditions. Moreover, an acidic work-
up was employed for acetals derived from carbohydrate
acceptors that did not possess acid-labile protection of other
hydroxyl groups. In all cases, the 1,2-cis disaccharide product
(11a-d, 12a-d) was isolated as the sole glycosylated
product, in good to moderate yield (Table 3).
Table 3. Intramolecular Glycosylation of Mixed Acetals 9a-d
and 10a-d
(MPBT)/triflic anhydride,19 or 1-(benzenesulfinyl)piperidine
(BSP)/triflic anhydride20 or the use of 2,4,6-tri-tert-butylpy-
rimidine (TTBP)21 as an alternative base all resulted in only
slight alterations in yield (Table 2).
These results indicate that intramolecular glycosylation is
clearly more difficult in the vinyl system than in the allyl-
Table 2. Intramolecular Glycosylation of Mixed Acetals 10a
entry
glycosylation conditions
yield (%)
1
2
3
4
5
6
7
NIS, AgOTf, DTBMP, DCE, RT, 72 h
16
25
20
31
38
22
51
NIS, AgOTf, DTBMP, DCE, 80 °C, 48 h
I2, AgOTf, DTBMP, DCE, -78 °C to rt, 24 h
DMTST, DTBMP, CH2Cl2, -40 °C to rt, 2.5 h
MPBT, Tf2O, DTBMP, CH2Cl2, -60 °C, 6 h
BSP, Tf2O, TTBP, CH2Cl2, -60 °C to rt, 6 h
I2, AgOTf, DTBMP, MeCN, rt, 24 h
Org. Lett., Vol. 6, No. 21, 2004
3799

Once again, the efficiency of glycosylation can be seen
to be dependent on the nature of the glycosyl acceptor; more
hindered glycosyl acceptors, and in particular those in which
it is the 4-hydroxyl group to be glycosylated, react less
efficiently. However, even for the most hindered carbohy-
drate glycosyl acceptors the desired 1,2-cis disaccharide
products are formed in a totally stereoselective fashion.
In summary it has been demonstrated that the use of 2-O-
vinyl glycosyl donors allows the synthesis of a variety of
1,2-cis disaccharides in good yield and most importantly with
complete stereocontrol. This technique of vinyl IAD is
complementary to the approach based on 2-O-allyl-protected
donors (allyl IAD) in that it possesses the advantage of
increased tethering efficiency for particularly hindered
secondary carbohydrate acceptors. However, the synthesis
of the corresponding glycosyl donors and the efficiency of
the intramolecular glycosylation step of allyl IAD are more
efficient than those so far developed for the vinyl approach.
Further investigations into the use of both vinyl- and allyl-
derived IAD and their applications for the synthesis of a
variety of biologically important oligosaccharides are cur-
rently in progress, and the results will be reported in due
course.
Acknowledgment. We gratefully acknowledge financial
support from the Royal Thai Government (studentship to
K.C.) and the use of the EPSRC National Mass Spectrometry
Service at Swansea and the Chemical Database Service at
Daresbury.
Supporting Information Available: Synthetic procedures
are available, together with full characterization and spectral
data for compounds 1, 2, 4, 6-8, 9a-d, 10a-d, 11a-d,
and 12a-d. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Fu¨gedi, P.; Garegg, P. J. Carbohydr. Res. 1986, 149, C9-C12.
Andersson, F.; Fu¨gedi, P.; Garegg, P. J.; Nashed, M. Tetrahedron Lett. 1986,
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326.
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