Concerning the Origin of the High β-Selectivity of Glycosidation Reactions of 2-Deoxy-2-iodo-glucopyranosyl Trichloroacetimidates

Article abstract of DOI:10.1021/ol027066e

(Matrix Presented) Studies on the glycosidation reactions of conformationally constrained glycosyl imidates 8a and 8b were performed to evaluate the possible involvement of "conformationally inverted" oxonium ion intermediates in glycosidation reactions w

Full text of DOI:10.1021/ol027066e

ORGANIC
LETTERS
2
002
Vol. 4, No. 25
523-4526
Concerning the Origin of the High
â-Selectivity of Glycosidation Reactions
of 2-Deoxy-2-iodo-glucopyranosyl
Trichloroacetimidates
4
Pek Y. Chong and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received October 10, 2002
ABSTRACT
Studies on the glycosidation reactions of conformationally constrained glycosyl imidates 8a and 8b were performed to evaluate the possible
involvement of “conformationally inverted” oxonium ion intermediates in glycosidation reactions with 2-deoxy-2-iodo-glucopyranosyl donors.
The mechanistic implications of this study are discussed, and intermediates 23 and 24 are invoked to rationalize the observed â-selectivities.
We have previously reported several studies on the stereo-
with excellent â-stereoselectivities (in most cases, g19:1)
in CH Cl using either TMS-OTf or TBDMS-OTf as the
promoter (Scheme 1). During the course of the studies with
selective synthesis of 2-deoxy-â-glycosides, which are
2
2
1-4
important structural components of many natural products.
Readily accessible glycal precursors were elaborated to
glycosyl donors with equatorial C(2) heteroatom substituents
(
-SePh, -SPh, -Br, and -I), which are removed reduc-
5
Scheme 1
tively following glycosidation. While initial work with
-thiophenyl- and 2-selenophenyl-glucopyranosyl donors
2
1
indicated that selectivity was highly substrate dependent,
the 2-iodo substituent was later found to be an excellent and
considerably more general stereodirecting group. Thus,
glycosidations employing 2-deoxy-2-iodo-â-D-glucopyran-
osyl acetates (1) or 2-deoxy-2-iodo-R-D-glucopyranosyl
trichloroacetimidates (2) as the glycosyl donors proceeded
2
3
2
-deoxy-2-iodo-glucopyranosyl acetates, it was noted that
the reactivity was highly dependent on the conformational
preference of the donor ground state and, thus, the combina-
tion of protecting groups of the glycosyl donor. In general,
comparably substituted donors that exist in twist boat ground
state conformations underwent glycosidations at lower tem-
peratures than those in the normal chair conformation. This
led us to consider the possibility that conformationally
(
1) (a) Roush, W. R.; Sebesta, D.; Bennett, C. E. Tetrahedron 1997, 53,
8
5
825. (b) Roush, W. R.; Sebesta, D. P.; James, R. A. Tetrahedron 1997,
3, 8837 and references therein.
(
(
(
(
2) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541.
3) Roush, W. R.; Gung, B. W.; Bennett, C. E. Org. Lett. 1999, 1, 891.
4) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 2000, 122, 6124.
5) Approaches to the synthesis of 2-deoxy-â-glycosides have been
reviewed: (a) Castro-Palomino, J. C.; Schmidt, R. R. Synlett 1998, 501.
b) Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 56, 8385.
(
1
0.1021/ol027066e CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/13/2002

8
inverted intermediates represented by 6 might be kinetically
significant reaction intermediates (Scheme 2).1
direct â-face approach of the alcohol. We herein report the
stereochemical outcome of glycosidation reactions of imidate
8
and the mechanistic implications of these results.
Imidate 8 was prepared from tri-O-acetyl-D-glucal 9 as
summarized in Scheme 3. Deacetylation of 9 and reprotection
Scheme 3. Synthesis of Imidates 8a,b
Scheme 2. Mechanistic Pathways for Glycosidation Reactions
with 2-Deoxy-2-iodo-glucopyranosyl Trichloroacetimidates (2)
of the triol with the sterically bulky tert-butyldiphenylsilyl
9
5
Considering the likely pathways outlined in Scheme 2,
oxonium ion 5 can arise from the decomposition of inter-
mediate 4, upon activation of imidate 2 with TMS-OTf or
TBDMS-OTf. If 5 were an important reaction intermediate,
one would expect a significant amount of R-glycoside
products to be formed by stereoelectronically favored axial
addition. However, this outcome is not consistent with our
findings. To rationalize the observed highly favored â-face
approach of the acceptor, we speculated that the reaction
might operate by way of a conformationally inverted
4
groups afforded glycal 10, in which the H ground state
1
0
conformation (10′) is predominant. We were aware that
5
4
the iodoacetoxylation of glycals in the H conformation
proceeds with high stereoselectivity in favor of the gluco
1
1
isomer. Accordingly, treatment of glycal 10 with NIS in
HOAc provided iodoacetate 11 in a ca. 14:1 ratio of â-gluco:
R-manno isomers. The â-gluco anomer was isolated in 90%
yield and desilylated using HF‚Et N to provide the triol,
3
which was subsequently treated with benzaldehyde dimethyl
acetal in the presence of catalytic TsOH‚H O to afford the
2
1
oxonium ion 6. Axial approach of an acceptor to 6 should
4,6-O-benzylidene acetal 12 in 82% yield over two steps.
then be stereoelectronically favored, due to a resultant
anomeric effect as well as a Felkin-Anh-type stabilization
of the developing C-O bond (overlap with the σ* orbital of
the adjacent C-I bond in the transition state). A subsequent
report by Woerpel’s group on the involvement of pseudoaxial
conformers in the nucleophilic substitution of heteroatom-
substituted pyranyl oxonium ions lends support to the
Silylation of 12 using TBDMS-Cl followed by deacetylation
of the anomeric acetate using aqueous hydrazine in methanol
led to hemiacetal 13, which exists as a 1:1 ratio of R:â
anomers.
Synthesis of the trichloroacetimidates 8a,b was achieved
by treatment of hemiacetal 13 with CCl CN in CH Cl at 0
3
2
2
1
2
°C in the presence of catalytic DBU. Under these condi-
tions, R-imidate 8a was the major product, isolated in 54%
yield, while â-imidate 8b was formed in 10% yield. On the
other hand, when trichloroacetonitrile was used as the
reaction solvent, â-imidate 8b was isolated as the major
product in 50% yield, while R-imidate 8a was obtained in
6
possible involvement of intermediate 6. In addition, Bowen’s
group has reported molecular mechanics calculations that
suggest that six-membered ring oxonium ions prefer to adopt
conformations in which hydroxyl groups at C3 and C4
7
occupy pseudoaxial positions in the half-chair conformation.
1
3
To investigate the possible involvement of oxonium ion
13% yield.
6
as a stereodetermining intermediate in the glycosidation
Glycosidation reactions were performed by addition of
reactions of 2-iodoglycosyl donors of general structures 1
and 2, we targeted constrained glycosyl imidate 8, in which
the 4,6-O-benzylidene acetal renders conformationally in-
verted oxonium ion 6 inaccessible. We also considered that
the â-glucosides might arise from displacement of 4 by an
acceptor in an S 2-like manner or via substitution of a tightly
N
solvated ion pair, as well as a pathway that involves iodonium
ion 7, where participation of the C-2 iodo substituent would
catalytic TBDMS-OTf (0.2-0.4 equiv) to a precooled
(8) In the latter scenario, the transition state for substitution of 7 should
likely resemble the kinetically disfavored boatlike conformation (7′), as this
represents a formal diequatorial opening of the iodonium ion.
(9) Friesen, R. W.; Sturino, C. F.; Dalijeet, A. K.; Kolaczewska, A. J.
Org. Chem. 1991, 56, 1944.
5
(
10) The H4 conformation minimizes gauche interactions. This is evident
1
from H NMR analyses of 10, consistent with our previous work as well as
that of McDonald’s group. See refs 1, 2, and 11.
(11) McDonald, F. E.; Reddy, K. S.; D ´ı az, Y. J. Am. Chem. Soc. 2000,
1
22, 4303.
(
6) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2000, 122, 168.
7) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc. 1992,
14, 859. This has been attributed to an electrostatic stabilization.
(12) Use of NaH as a base led to lower isolated yields.
(13) In both cases, a small amount of R-manno imidate 14 was also
(
formed, presumably due to the base-catalyzed epimerization at C(2) via
the ring-opened aldehyde. See ref 5.
1
4524
Org. Lett., Vol. 4, No. 25, 2002

solution of imidate 8a or 8b and acceptor in CH
presence of 4 Å molecular sieves. Glycosidations of acceptors
5-17 with 4,6-O-benzylidene glucopyranosyl R-imidate 8a
2 2
Cl in the
Scheme 4
1
afforded disaccharides 18, 19 and 20 in 89, 76, and 86%
yields, respectively, and with high â-selectivities (Table 1,
Table 1. Glycosidations of Acceptors with Imidates 8a,b
we noted that in the absence of acceptor, both imidates 8a
and 8b are recovered stereochemically intact when treated
with TMS-OTf or TBDMS-OTf in CH Cl at -78 °C, with
2 2
only trace amounts of the other anomer. Clearly, under these
conditions, the anomeric C-O bond of the glycosyl imidate
remains either intact or as a tightly associated ion pair that
recombines upon workup without significant loss of stereo-
chemistry.
We performed the glycosidations of acceptors 15 and 17
with â-imidate 8b (entries 4 and 5) and observed the same
R:â product ratios as those found in the reactions with
R-imidate 8a (entries 1 and 3), indicating that both reactions
must proceed via a common intermediate that lacks the
yield
(%)
â:R
conditionsa
ratiob
entry acceptor donor
product
1
2
3
4
15
16
17
15
17
15
15
15
15
15
15
8a
8a
8a
8b
8b
8b
8b
8a
8b
8a
8b
-78 °C, 1 h
-78 °C, 2 h
-40 °C, 2 h
-78 °C, 1 h
-40 °C, 2 h
-78 °C, 1 h
-78 °C, 1 h
rt, 30 min
18
19
20
18
20
18
18
18
18
18
18
89
76
86
92
85
85
73
96
79
91
89
87:13
â only
â only
86:14
â only
86:14
86:14
93:7
5
6c
7d
8
c
d
stereochemical information of the starting imidate. Thus, we
16
N
ruled out an S 2-like pathway.
9e
0e
1e
-78 °C, 1 h
e
84:16
97:3
96:4
Crich has shown that glycosyl triflates are intermediates
in glycosidation reactions that proceed by activation of
anomeric sulfoxides and thioglycosides with Tf O and
2
e
1
1
rt, 30 min
rt, 30 mine
a
All reactions were performed in CH2Cl2 using 0.2-0.4 equiv of
PhSOTf, respectively, suggesting that they may also be
intermediates in other glycosidation reactions employing
TBDMS-OTf in the presence of 4 Å molecular sieves unless indicated
b
1
otherwise. â:R product ratios were determined by H NMR analysis of
c
15
the crude product. Donor was preequilibrated with promoter for 10 min
triflates as activating reagents. We found that despite the
d
prior to slow introduction of the acceptor. Donor was introduced by slow
addition to a preequilibrated solution of acceptor and TBDMS-OTf.
disarming effect of the benzylidene acetal, the order of
addition (entries 6 and 7) had no effect on R:â product ratios,
which suggests that a time-dependent intermediate is not
e
Reactions were performed in diethyl ether.
1
7
involved. Additionally, although glycosyl triflate 21 may
be an intermediate, we discounted it as being stereodeter-
mining on the basis of Crich’s reports that the glycosyl
triflates derived from 4,6-O-benzylidene-protected glucosides
gave rise to R-glycosides in the absence of protecting group
entries 1-3). In the latter two cases, no R-disaccharide was
detected. For the less reactive acceptors, longer reaction times
-78 °C, 2 h for 16) and/or elevated reaction temperatures
-40 °C, 2 h for 17) were required. The high â-selectivity
observed in these reactions is comparable to that previously
(
(
1
8
participation.
observed for analogous glycosidation reactions of glycosyl
imidates lacking the benzylidene acetal. As intermediate 6
is inaccessible for donor 8a, we looked for an alternative
mechanistic rationale for the observed â-selectivity.
Given the conformational constraint of the benzylidene
acetal, we rationalized the â-selectivity of the glycosidation
reactions of 8a and 8b by invoking twist boat conformation
23, in which the pseudoaxial orientation of the iodine
substituent sterically disfavors approach of the nucleophile
from the R-face (Scheme 4). Note that in this conformation,
axial approach to produce the â-product should be favored
for the same reasons as previously stated for the inverted
oxonium 6. Intermediate 23 approaches the geometry re-
quired for the participation of the iodine group, which gives
3
In light of the documented torsional disarming effect of a
,6-O-benzylidene acetal,14,15 we considered a scenario in
4
which slow collapse of activated imidate 4 to oxonium 5
might allow S 2-like displacement by an incoming alcohol
N
to be operative for imidate 8a but not necessarily for our
previously reported conformationally unconstrained 2-deoxy-
2-iodo-glucopyranosyl donors. In support of this possibility,
(16) At first, this seems to be inconsistent with the observation that the
imidates are stereochemically preserved in the presence of just activator.
To reconcile this, we speculate that the decomposition of 4 to oxonium 5
occurs rapidly in the presence of an acceptor (possibly due to the presence
of TfOH, generated from the promoter after activation of imidate in the
presence of acceptor).
(17) The existence of a time-dependent stereodetermining intermediate
would most likely change the R:â product ratio.
(18) Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926.
(
14) (a) Fraser-Reid, B.; Wu, Z.; Andrews, C. W.; Skowronski, E. J.
Am. Chem. Soc. 1991, 113, 1434. (b) Andrews, C. W.; Rodebaugh, R.;
Fraser-Reid, B. J. Org. Chem. 1996, 61, 5280.
(15) Crich has demonstrated that this torsional effect can strongly
influence anomeric selectivities of reactions of 4,6-O-benzylidene mannosyl
donors: (a) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321. (b) Crich, D.;
Sun, S. J. Am. Chem. Soc. 1997, 119, 11217.
Org. Lett., Vol. 4, No. 25, 2002
4525

rise to iodonium ion intermediate 24.19 Existing literature
examples of â-selective glycosidations using 4,6-O-benz-
ylidene donors typically utilize C(2) ester and carbamate
participating groups that benefit from facile five-membered
ring formation to exert high diastereocontrol on the glycosi-
ature effect indicating that conformation 23 and/or 24 is
thermodynamically preferred relative to 22. The slight
improvement in â-selectivity that is solvent derived (entry
8 vs 10) may be due to coordination of ether at the R-face
of 23.
2
0
dations. However, participation of the C(2)-iodo group to
give iodonium ion 24 is likely to be more torsionally strained.
It is worth noting that it is experimentally difficult to
distinguish between intermediates 23 and 24; however, they
are structurally similar, and the reaction pathway could
involve either or both of them as stereodetermining inter-
mediates.
Interestingly, in this and our previously reported studies
of glycosidation reactions with 2-deoxy-2-iodo-glucopyra-
nosyl donors, the less reactive or sterically more hindered
acceptors undergo glycosidations with higher â-selectivities
than do primary alcohols. In the present system, this can be
rationalized using intermediate 23 where the steric require-
ments of the acceptor should come into play, leading to
greater facial discrimination for the more sterically hindered
alcohols.
Although we believe that conformation 22 is not a major
stereodetermining intermediate, on the basis of the observed
â-selectivity, we wondered if the R:â ratio might be
influenced if 22 were stabilized by performing the glycosi-
dation reaction in diethyl ether. Schmidt has shown that
glycosidations performed in diethyl ether as a solvent, using
imidate donors containing C(2)-nonparticipating groups, lead
to selective R-glycosidation.2 Participation of the solvent
from the â-face (due to a reverse anomeric effect) has been
In summary, the use of 4,6-O-benzylidene glycosyl imi-
dates gave us some insight into the likely pathway of
glycosidation reactions using 2-deoxy-2-iodo-glucopyranosyl
donors. Using these conformationally constrained donors, we
found that the glycosidations were still highly â-selective.
1,22
N
An S 2-like displacement pathway was discounted because
the stereoselectivity of glycosidation was independent of the
starting donor configuration. Although this study cannot rule
out the possibility of conformationally inverted oxonium ions
2
3
proposed as an explanation for the observed R-selectivity.
We found no improvement in the R:â ratio (Table 1, entries
-11) under these conditions, even in reactions performed
9
6
in the unconstrained donors, it is clear that it is not
at room temperature. In fact, the â-selectivity was signifi-
cantly enhanced when the glycosidations were performed in
diethyl ether at room temperature (entries 10 and 11). The
equivalent reaction in methylene chloride (entry 8) led us to
conclude that this enhancement is predominantly a temper-
necessary to invoke them in order to explain the observed
â-selectivities. Twist boat conformation 23 and iodonium
ion 24 may be invoked to rationalize the â-selectivity of
imidates 8a,b and may also apply to the unconstrained
2
-deoxy-2-iodo-glucopyranosyl donors.
(
19) This would be mechanistically similar to the iodoglycosidation
reaction of glycals: Seeberger, P. H.; Bilodeau, M. T.; Danishefsky, S. J.
Aldrichimica Acta 1997, 30, 75.
Acknowledgment. We gratefully acknowledge the Na-
tional Institutes of Health (GM 38907) for financial support
and the Susan G. Komen Breast Cancer Foundation for a
postdoctoral fellowship to P.Y.C. We also thank D. J.
Mergott for providing 15-17.
(20) Selected references: (a) Chiesa, M. V.; Schmidt, R. R. Eur. J. Org.
Chem. 2000, 3541. (b) Duynstee, H. I.; de Koning, M. C.; Ovaa, H.; van
der Marel, G. A.; van Boom, J. H. Eur. J. Org. Chem. 1999, 2623. (c) Aly,
M. R. E.; Ibrahim, E. I.; El Ashry, E. H. Schmidt, R. R. Carbohydr. Res.
999, 316, 121. (d) Qui, D.; Koganty, R. R. Tetrahedron Lett. 1997, 38,
5.
1
4
(
(
21) Wegmann, B.; Schmidt, R. R. J. Carbohydr. Chem. 1987, 6, 357.
22) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994,
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
5
0, 21.
(
23) Glycosidations using 2-deoxy-2-azido-4,6-O-benzylidene gluco-
pyranosyl trichloroacetimidates in diethyl ether have been shown to proceed
with good R-selectivities: (a) Mart ´ı n-Lomas, M.; Khiar, N.; Garc ´ı a, S.;
Koessler, J.-L.; Nieto, P. M.; Rademacher, T. W. Chem. Eur. J. 2000, 6,
3
608. (b) Mart ´ı n-Lomas, M.; Flores-Mosquera, M.; Chiara, J. L. Eur. J.
Org. Chem. 2000, 1547.
OL027066E
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Org. Lett., Vol. 4, No. 25, 2002