2-O-Propargyl ethers: Readily cleavable, minimally intrusive protecting groups for β-mannosyl donors

Article abstract of DOI:10.1021/ol050680g

(Chemical Equation Presented) The use of 2-O-propargyl ethers as protecting groups in 4,6-O-benzylidene-protected mannopyranosyl donors bearing either bulky silyl groups or glycosidic linkages on O3 overcomes the poor stereoselectivity achieved with the c

Full text of DOI:10.1021/ol050680g

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2277-2280
2-O-Propargyl Ethers: Readily
Cleavable, Minimally Intrusive Protecting
Groups for
â-Mannosyl Donors
David Crich* and Prasanna Jayalath
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
Received March 30, 2005
ABSTRACT
The use of 2-O-propargyl ethers as protecting groups in 4,6-O-benzylidene-protected mannopyranosyl donors bearing either bulky silyl groups
or glycosidic linkages on O3 overcomes the poor stereoselectivity achieved with the corresponding 2-O-benzyl ethers, due to a reduction of
steric buttressing. Deprotection is conducted by treatment with potassium tert-butoxide followed by catalytic osmium tetroxide and
N-methylmorpholine N-oxide.
Some time ago, we introduced 4,6-O-benzylidene-protected
R-mannosyl triflates carrying non-participating, ether-type
groups on O2 and O3 as highly stereoselective â-mannosyl
donors,1 thereby removing many of the barriers to the
efficient solution of this classical problem in carbohydrate
chemistry.2 This protecting group array, whose effectiveness
is now understood in terms of the locking of the mannose
C5-C6 bond in the tg-conformation,3 and which has
subsequently been shown to be applicable to other rapid
activation systems,4 has permitted the synthesis of many
â-mannopyranosidic linkages with a very broad range of
acceptors.5 Most recently, we have shown the same protect-
ing group set also enables the direct synthesis of â-D- and
-L-glycero-D-mannoheptopyranosides and,6 with the help of
a novel radical fragmentation,7 â-D-rhamnopyranosides.8
There remain, however, occasional linkage types that have
not succumbed to this methodology and which continue to
challenge our ingenuity. A case in point, and the focus of
this paper, is the class of â-mannosides necessitating the use
of a bulky protecting group, or a glycosidic bond, on O3 of
the donor. We first became aware of this problem when
attempting glycosylation of acceptor 1 with a view to the
eventual synthesis of the common core pentasaccharide of
the N-linked glycans.9 With the donor 2 poor selectivity
(77%, â/R ) 1:1.8) was observed, in contrast to the coupling
of 1 to 3 when results were much more favorable (72%, â/R
) 3:1). Indeed, the poor selectivity observed with donor 2
caused us to modify our general strategy for the core
pentasaccharide to one employing a 3-O-p-methoxybenzyl-
(1) (a) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321. (b) Crich, D.;
Sun, S. J. Am. Chem. Soc. 1997, 119, 11217.
(2) (a) Barresi, F.; Hindsgaul, O. In Modern Methods in Carbohydrate
Synthesis; Khan, S. H., O’Neill, R. A., Eds.; Harwood Academic Publish-
ers: Amsterdam, 1996; p 251. (b) Demchenko, A. V. Synlett 2003, 1225.
(c) Pozsgay, V. In Carbohydrates in Chemistry and Biology; Ernst, B., Hart,
G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim, 2000; Vol. 1, p 319. (d)
Gridley, J. J.; Osborn, H. M. I. J. Chem. Soc., Perkin Trans. 1 2000, 1471.
(3) Jensen, H. H.; Nordstrom, M.; Bols, M. J. Am. Chem. Soc. 2004,
126, 9205.
(4) (a) Weingart, R.; Schmidt, R. R. Tetrahedron Lett. 2000, 41, 8753.
(b) Kim, K. S.; Kim, J. H.; Lee, Y. J.; Lee, Y. J.; Park, J. J. Am. Chem.
Soc. 2001, 123, 8477. (c) Tsuda, T.; Sato, S.; Nakamura, S.; Hashimoto, S.
Hetereocycles 2003, 59, 509.
(5) (a) Crich, D.; Lim, L. B. L. Org. React. 2004, 64, 115. (b) Dudkin,
V. K.; Miller, J. S.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 736.
(c) Wu, X.; Schmidt, R. R. J. Org. Chem. 2004, 69, 1853. (d) Crich, D.;
Banerjee, A.; Yao, Q. J. Am. Chem. Soc. 2004, 126, 14930. (e) Crich, D.;
Li, W.; Li, H. J. Am. Chem. Soc. 2004, 126, 15081. (f) Shao, N.; Guo, Z.
Pol. J. Chem. 2005, 79, 297.
(6) Crich, D.; Banerjee, A. Org. Lett. 2005, 7, 1935.
(7) Crich, D.; Yao, Q. Org. Lett. 2003, 5, 2189.
(8) (a) Crich, D.; Yao, Q. J. Am. Chem. Soc. 2004, 126, 8232. (b) Kwon,
Y. T.; Lee, Y. J.; Lee, K.; Kim, K. S. Org. Lett. 2004, 6, 3901.
(9) Crich, D., Dudkin, V. Tetrahedron Lett. 2000, 41, 5643.
10.1021/ol050680g CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/26/2005

protected mannosyl donor in which the PMB group had to
be exchanged for the desired silyl ether post-glycosylation.10
Figure 2. Staggered conformations about the O2 bond.
R-mannosyl triflate, or the transient contact ion pair derived
from it,11 resulting in the observed loss of â-selectivity.
For donor 2 the problem may be circumvented by avoiding
the use of the bulky O3 silyl protecting group but in target-
directed convergent oligosaccharide synthesis there is no way
around the use of donors such as 4 and 5. This led us to
reason that the steric congestion between the substituents
on O2 and O3, which disfavors conformation E, and the
detrimental effects of conformation F on stereoselectivity
might both be reduced by the use of a much less sterically
demanding protecting group for O2. We were encouraged
in this line of thinking by the successful â-glycosylation of
several acceptors by donor 6 reported by the van Boom
laboratory,12 but obviously the minimal steric bulk of the
azido group cannot be viewed independently of its strongly
disarming properties, thereby complicating the interpretation
of this precedent. For similar reasons, we decided not to
pursue the very small but also moderately disarming cyanate
esters13 and focused instead on the arming allyl and propargyl
ethers.
More recently, and even more problematic, we have found
that disaccharide donors 4 and 5 gave very poor selectivities
in coupling reactions, thereby significantly reducing the
efficiency of our convergent synthesis of an alternating
â-(1f3)-â-(1f4)-mannan common to Rhodotorula glutinis,
Rhodotorula mucilaginosa, and Leptospira biflexa.5e
The common feature of donors 2, 4, and 5 is the presence
of a bulky substituent on O3 which, in the absence of unusual
ring conformations, reinforces our initial belief9 that the
problem is one of steric buttressing. Thus, as illustrated for
the triflate derived from 2 (Figure 1), we reason that of the
Thus, we began with the preparation of donors 10 and 13
by standard means from the known5e thiomannoside 7
(Scheme 1). A series of coupling reactions were then carried
Scheme 1. Preparation of 2-O-Allyl and 2-O-Propargyl
Figure 1. Staggered conformations about the O3 bond.
Donors
three possible staggered conformations around the O3-
substituent bond, the first (A) is disfavored by the steric
interaction with the rigid benzylidene ring. In the two
remaining conformers, B and C, the steric interaction with
the O2 benzyl group is minimized by rotating the benzyl
ether over the anomeric center. In other words, viewed in
terms of the conformation about the O2-substituent bond
(Figure 2), the bulky group on O3 presumably destabilizes
conformation E and leads to an increase in the population
of F, if not of the highly congested D. This in turn leads to
increased steric hindrance toward â-face attack on the
(10) Dudkin, V. Y.; Crich, D. Tetrahedron Lett. 2003, 44, 1787.
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Org. Lett., Vol. 7, No. 11, 2005

Table 1. Coupling Reactions with Donors 10 and 13 and Deprotection of the Products
a Only the â-isomer was deprotected.
out with activation by the 1-benzenesulfinyl piperidine
(BSP)/triflic anhydride couple14 in the presence of 2,4,6-tri-
tert-butylpyrimidine (TTBP)15 at -60 °C in CH2Cl2 before
addition of the acceptor alcohol. On the basis of these
couplings (Table 1),16 it is clear that the use of the 2-O-
propargyl ether 13 successfully overcomes the effect of the
bulky silyl ether at O3, thereby vindicating our buttressing
hypothesis. The allyl protected donor 10, on the other hand,
was only moderately successful in this respect and was not
pursued further. Removal of the propargyl ether was achieved
in a one pot protocol by isomerization to the corresponding
allene with potassium tert-butoxide in THF, followed by
cleavage with catalytic osmium tetroxide and N-methyl-
morpholine N-oxide (Table 1).17 Direct exposure of the
propargyl ethers to the OsO4/NMNO conditions, without
prior isomerization, also successfully brought about cleavage
although in lower yields (70-80%).18
We next turned to the investigation of the potential use of
the 2-O-propargyl ether in overcoming the effect of bulky
glycosidic linkages at O3 of mannosyl donors. Thus, activa-
tion of 11 with BSP/Tf2O/TTBP followed by addition of
methanol gave the â-mannoside 24 in 79% yield, as a single
anomer, from which removal of the PMB group afforded
acceptor 25 in 95% yield (Scheme 2).
Scheme 2. Preparation of Acceptor 25
(11) Crich, D.; Chandrasekera, N. S. Angew. Chem., Int. Ed. 2004, 43,
5386.
(12) Code´e, J. D. C.; van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft,
H. S.; van Boeckel, C. A. A.; van Boom, J. H.; van der Marel, G. A.
Tetrahedron 2004, 60, 1057.
(13) Crich, D.; Hutton, T. K.; Banerjee, A.; Jayalath, P.; Picione, J.
Tetrahedron: Asymmetry 2005, 16, 105.
Activation of the known donor 2614 with BSP/Tf2O/TTBP
followed by the addition of 12 gave the disaccharide donor
27 in 88% yield with anomeric selectivity of 16:1 in favor
of the â-anomer. In this type of coupling, in which the
acceptor alcohol is also a thioglycoside, the reaction mixture
is treated with triethyl phosphite after the addition of the
(14) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015.
(15) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323.
(16) The anomeric configuration at the newly formed glycosidic bonds
of all couplings described here was assigned on the basis of the diagnostic
chemical shift of the mannose H5 as discussed previously1 and was
confirmed by the measurement of 1JC,H coupling constants for the anomeric
carbon: Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293.
(17) Cleavage with tetrabutylammonium tetrathiomolybdate, as recom-
mended for the removal of propargyl oxycarbonyl groups, was not
successful: Ramesh, R.; Ramakrishna, G. B.; Chandrasekarahan, S. J. Org.
Chem. 2005, 70, 837.
(18) Presumably, this chemistry results from â-elimination at the level
of the intermediate 1,2-dihydroxyalkene.
Org. Lett., Vol. 7, No. 11, 2005
2279

Scheme 3. Stereoselective Synthesis of a â-(1f3)-Mannan
acceptor and before it is allowed to warm to room temper-
The 5:1 â/R ratio obtained in the coupling of 27 to 25
represents a very significant improvement over the ratios
obtained previously5e in couplings to the related disaccharide
donors 4 and 5 and, together with the facile removal of the
propargyl ether group, suggests that a means to the conver-
gent, stereoselective assembly of â-mannans linked via O3
is at hand.
ature. This protocol, introduced by van Boom,12a,19,20 is
designed to quench any thiophilic species in the reaction
mixture before they are able to activate the thioglycoside in
the product, reduce yields and complicate isolation.21,22
Coupling of disaccharide donor 27 to acceptor 25 was
achieved by the standard BSP/Tf2O/TTBP preactivation
protocol, yielding the trisaccharide 28 in 80% yield as a 5:1
separable â/R mixture. Finally, the two propargyl ether
protecting groups were cleaved from 28 in 82% yield by
the isomerization/catalytic osmoylation protocol (Scheme 3).
We conclude that 2-O-propargyl ether protected mannosyl
donors provide a means of overcoming the poor stereo-
selectivity previously observed with donors bearing bulky
groups, silyl ethers or glycosidic bonds, on O-3. We
hypothesize that the increased selectivity arises because of
a minimization of a buttressing effect between the O2 and
O3 protecting groups, which generally results in a more open
â-face in the glycosyl donor.
(19) (a) Code´e, J. D. C.; Litjens, R. E. J. N.; den Heeten, R.; Overkleeft,
H. S.; van Boom, J. H.; van der Marel, G. A. Org. Lett. 2003, 5, 1519. (b)
Code´e, J. D. C.; van den Bos, J.; Litjens, R. E. J. N.; Overkleeft, H. S.; van
Boom, J. H.; van der Marel, G. A. Org. Lett. 2003, 5, 1947.
(20) The use of phosphites to clean up extraneous thiophiles in sulfoxide
glycosylations has also been described by van Boom and others: (a)
Sliedregt, L. A. J. M.; van der Marel, G. A.; van Boom, J. H. Tetrahedron
Lett. 1994, 35, 4015. (b) Alonso, I.; Khiar, N.; Martin-Lomas, M.
Tetrahedron Lett. 1996, 37, 1477.
(21) For a recent synthesis of a small oligosaccharide library using the
thioglycoside/BSP method and involving the use of thioglycoside alcohols
as acceptors, see: Yamago, S.; Yamada, H.; Maruyama, T.; Yoshida, J.-i.
Angew. Chem., Int. Ed. 2004, 43, 2145.
Acknowledgment. We thank the NIGMHS for financial
support (GM 57335).
Supporting Information Available: Full experimental
details and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) Other traps for thiophilic agents previously employed in the sulfoxide
method include alkenes and alkynes: (a) Yan, L.; Kahne, D. J. Am. Chem.
Soc. 1996, 118, 9239. (b) Raghavan, S.; Kahne, D. J. Am. Chem. Soc. 1993,
115, 1580.
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