Enhanced diastereoselectivity in β-mannopyranosylation through the use of sterically minimal propargyl ether protecting groups

Article abstract of DOI:10.1021/jo0526789

2-O-Propargyl ethers are shown to be advantageous in the 4,6-O-benzylidene acetal directed β-mannosylation reaction. The effect is most pronounced when the O3 protecting group is a bulky silyl ether or a glycosidic bond; however, even with a 3-O-benzyl et

Full text of DOI:10.1021/jo0526789

Enhanced Diastereoselectivity in â-Mannopyranosylation through
the Use of Sterically Minimal Propargyl Ether Protecting Groups
David Crich,* Prasanna Jayalath, and Thomas K. Hutton
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
ReceiVed December 31, 2005
2-O-Propargyl ethers are shown to be advantageous in the 4,6-O-benzylidene acetal directed â-manno-
sylation reaction. The effect is most pronounced when the O3 protecting group is a bulky silyl ether or
a glycosidic bond; however, even with a 3-O-benzyl ether, the use of a 2-O-propargyl ether results in a
significant increase in diastereoselectivity. The beneficial effect of the propargyl ether is thought to be
a combination of its minimal steric bulk, as determined by a measurement of the steric A-value and of
its moderately disarming nature, as reflected in the pKa of propargyl alcohol. Conversely, the application
of a 3-O-propargyl ether in the benzylidene acetal directed mannosylation has a detrimental effect on
stereoselectivity, for which no explanation is at present available. Deprotection is achieved by base-
catalyzed isomerization of the propargyl ether group to the corresponding allenyl ether, followed by
oxidative cleavage with N-methylmorpholine N-oxide and catalytic osmium tetroxide.
Introduction
of the transient contact ion pair10 that is in equilibrium with the
covalent glycosyl triflate intermediate.5c,11
Protecting groups play a central role in carbohydrate chem-
istry,1 with applications extending beyond the simple blocking
of hydroxyl groups to the modulation of reactivity of both
glycosyl donors and acceptors and, critically, the control of
anomeric stereochemistry. Indeed, the development of new
protecting groups capable of rendering enhanced control of
regioselectivity,2 reactivity,3 and stereoselectivity,4 can be said
to be one of the current frontiers of the discipline.
The influence of even remote protecting groups on the control
of anomeric stereochemistry is illustrated by the 4,6-O-ben-
zylidene protected â-mannosyl donors developed in this labora-
tory,5 in which the benzylidene acetal, or its surrogate,4d,6 is
now understood to function by restricting the C5-C6 bond to
the more disarming7 tg conformer,8,9 thereby limiting the lifetime
However powerful this method may be in the synthesis of
complex oligosaccharides containing the â-mannopyranoside
and related linkages,12,13 it is not without limitations. Thus, the
use of donors bearing bulky groups on O3, either silyl ethers
or glycosidic bonds, diminishes the selectivity of the manno-
sylation.14
Although the effect of the O3 protecting group on anomeric
stereoselectivity is not yet fully understood, we introduced the
use of 2-O-propargyl ether as a means of overcoming the loss
of selectivity as a result of the use of bulky groups at O3.15 In
(3) (a) Glaudemans, C. P. J.; Fletcher, H. G. J. Am. Chem. Soc. 1965,
87, 4636-4641. (b) Ishikawa, T.; Fletcher, H. G. J. Org. Chem. 1969, 34,
563-571. (c) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid,
B. J. Am. Chem. Soc. 1988, 110, 5583-5584. (d) Fraser-Reid, B.; Madsen,
R. In PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Dekker:
New York, 1997; pp 339-356. (e) Fraser-Reid, B.; Anilkumar, G.; Gilbert,
M. R.; Joshi, S.; Kraehmer, R. In Carbohydrates in Chemistry and Biology;
Ernst, B., Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim, 2000; Vol.
1, pp 135-154. (f) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S.
L. J. Chem. Soc., Perkin Trans. 1 1998, 51-65. (g) Zhang, Z.; Ollmann, I.
R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc.
1999, 121, 734-753.
(1) (a) Grindley, T. B. In Modern Methods in Carbohydrate Chemistry;
Khan, S. H., O’Neill, R. A., Eds.; Harwood Academic: Amsterdam, 1996;
pp 225-250. (b) Green, L. G.; Ley, S. V. In Carbohydrates in Chemistry
and Biology; Ernst, B., Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim,
2000; Vol. 1, pp 427-448. (c) Fraser-Reid, B.; Lo´pez, J. C.; Go´mez, A.
M.; Uriel, C. Eur. J. Org. Chem. 2004, 1387-1395.
(2) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.;
Priepke, H. W. M.; Reynolds, D. J. Chem. ReV. 2001, 101, 53-80.
10.1021/jo0526789 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/23/2006
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J. Org. Chem. 2006, 71, 3064-3070

DiastereoselectiVity in â-Mannopyranosylation
this article we examine in greater detail the potential of the
readily cleavable, minimally sterically unintrusive propargyl
ether protecting group and show how, in conjunction with the
correct choice of other protecting groups, it can lead to
considerable enhancements in the stereoselectivity of mannopy-
ranosylation reactions and even the very challenging rham-
nopyranosylations.
core pentasaccharide of the N-linked glycans,13a when coupling
of the 2-O-benzyl-3-O-TBDMS mannosyl donor 2 with pentenyl
glycoside acceptor 1 exhibited poor selectivity (77%, R/â )
1.8:1). In contrast, with the 2-O-TBDMS-3-O-benzyl donor 3,
the selectivity was significantly better (72%, R/â ) 1:3), albeit
still not at the high levels typically experienced with more
standard 2,3-di-O-benzyl protected donors.16
Results and Discussion
The problem of diminished selectivity caused by bulky groups
on O3 was initially encountered in the synthesis of the common
(4) (a) Crich, D.; Vinod, A. U. J. Org. Chem. 2005, 70, 1291-1296. (b)
Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2001, 121, 6819-6825. (c) Crich,
D.; Jayalath, P. J. Org. Chem. 2005, 70, 7252-7259. (d) Crich, D.; Yao,
Q. J. Am. Chem. Soc. 2004, 126, 8232-8236. (e) Crich, D.; Hutton, T. K.;
Banerjee, A.; Jayalath, P.; Picione, J. Tetrahedron: Asymmetry 2005, 16,
105-119. (f) Crich, D.; Vinod, A. U.; Picione, J. J. Org. Chem. 2003, 68,
8453-8458. (g) Crich, D.; Vinod, A. U.; Picione, J.; Wink, D. J. ARKIVOC
2005, Vi, 339-344. (h) Kim, J.-H.; Yang, H.; Boons, G.-J. Angew. Chem.,
Int. Ed. 2005, 44, 947-949. (i) Kim, J.-H.; Yang, H.; Park, J.; Boons, G.-
J. J. Am. Chem. Soc. 2005, 127, 12090-12097. (j) Smoot, J. T.;
Pornsuriyasak, P.; Demchenko, A. V. Angew. Chem., Int. Ed. 2005, 44,
7123-7126. (k) Bowers, S. G.; Coe, D. M.; Boons, G.-J. J. Org. Chem.
1998, 63, 4570-4571. (l) Jiao, H.; Hindsgaul, O. Angew. Chem., Int. Ed.
1999, 38, 346-348. (m) Debenham, J.; Rodebaugh, R.; Fraser-Reid, B.
Liebigs Ann./Recl. 1997, 791-802. (n) Yu, H.; Williams, D. L.; Ensley, H.
E. Tetrahedron Lett. 2005, 46, 3417-3421. (o) Che´ry, F.; Rollin, P.; De
Lucchi, O.; Cossu, S. Synthesis 2003, 286-292. (p) Imamura, A.; Ando,
H.; Korogi, S.; Tanabe, G.; Muraoka, O.; Ishidaa, H.; Kiso, M. Tetrahedron
Lett. 2003, 44, 6725-6728. (q) Haberman, J. M.; Gin, D. Y. Org. Lett.
2001, 3, 1665-1668. (r) Wei, P.; Kerns, R. J. J. Org. Chem. 2005, 70,
4195-4198. (s) Benakli, K.; Zha, C.; Kerns, R. J. J. Am. Chem. Soc. 2001,
123, 9461-9462.
A more critical manifestation of this problem presented itself
during the synthesis of the alternating â-(1 f 3)-â-(1 f 4)-
mannan common to Rhodotorula glutinis, Rhodotorula muci-
laginosa, and Leptospira biflexa.14b Donors 4 and 5, both
displaying very bulky glycosyl substituents on O3, showed
unusually poor â selectivity in coupling reactions, thereby
reducing the efficiency of the convergent synthesis of the target
polysaccharide.
(5) (a) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198-1199. (b) Crich,
D.; Sun, S. Tetrahedron 1998, 54, 8321-8348. (c) Crich, D.; Smith, M. J.
Am. Chem. Soc. 2001, 123, 9015-9020. (d) Crich, D. In Glycochemistry:
Principles, Synthesis, and Applications; Wang, P. G., Bertozzi, C. R., Eds.;
Dekker: New York, 2001; pp 53-75. (e) Crich, D. J. Carbohydr. Chem.
2002, 21, 663-686.
We hypothesized that the poor selectivity seen with donors
2, 4, and 5 was the result of steric buttressing between the O2
and O3 protecting groups, resulting in unusually high shielding
of the â face of the glycosyl donor.14a,15 Thus, as illustrated for
the triflate derived from 2, we reason that, of the three possible
staggered conformations around the O3-substituent bond, A is
disfavored by the steric interaction with the rigid benzylidene
ring leading to the preferential population of conformers B and
C in which the bulky silyl group is gauche to C2 and its
substituent (Figure 1).
(6) (a) Crich, D.; Smith, M. J. Am. Chem. Soc. 2002, 124, 8867-8869.
(b) Crich, D.; de la Mora, M.; Vinod, A. U. J. Org. Chem. 2003, 68, 8142-
8148.
(7) In the terminology of Fraser-Reid, a disarming protecting group is
one that deactivates a glycosyl donor, whereas an arming protecting group
is one that activates a glycosyl donor.1b,3c
(8) Jensen, H. H.; Nordstrom, M.; Bols, M. J. Am. Chem. Soc. 2004,
126, 9205-9213.
(9) For earlier studies on the disarming influence of acetal protecting
groups, see: (a) Andrews, C. W.; Rodebaugh, R.; Fraser-Reid, B. J. Org.
Chem. 1996, 61, 5280-5289. (b) Fraser-Reid, B.; Wu, Z. C.; Andrews,
W.; Skowronski, E. J. Am. Chem. Soc. 1991, 113, 1434-1435.
(10) Crich, D.; Chandrasekera, N. S. Angew. Chem., Int. Ed. 2004, 43,
5386-5389.
(11) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217-11223.
(12) For examples from this laboratory, see ref 4d and the following:
(a) Crich, D.; Li, H.; Yao, Q.; Wink, D. J.; Sommer, R. D.; Rheingold, A.
L. J. Am. Chem. Soc. 2001, 121, 5826-5828. (b) Crich, D.; Li, H. J. Org.
Chem. 2002, 67, 4640-4646. (c) Crich, D.; Dai, Z. Tetrahedron 1999, 55,
1569-1580. (d) Crich, D.; Barba, G. R. Tetrahedron Lett. 1998, 39, 9339-
9342. (e) Crich, D.; de la Mora, M. A.; Cruz, R. Tetrahedron 2002, 58,
35-44. (f) Crich, D.; Banerjee, A.; Yao, Q. J. Am. Chem. Soc. 2004, 126,
14930-14934. (g) Crich, D.; Banerjee, A. Org. Lett. 2005, 7, 1935-1938.
(h) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2002, 124, 2263-2266. (i)
Dudkin, V. Y.; Crich, D. Tetrahedron Lett. 2003, 44, 1787-1789.
(13) For examples from other laboratories, see: (a) Dudkin, V. K.; Miller,
J. S.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 736-738. (b) Miller,
J. S.; Dudkin, V. Y.; Lyon, G. J.; Muir, T. W.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2003, 42, 431-434. (c) Nicolaou, K. C.; Mitchell, H. J.;
Rodriguez, R. M.; Fylaktakidou, K. C.; Suzuki, H.; Conley, S. R. Chem.s
Eur. J. 2000, 6, 3149-3165. (d) Kim, K. S.; Kang, S. S.; Seo, Y. S.; Kim,
H. J.; Jeong, K.-S. Synlett 2003, 1311-1314. (e) Wu, X.; Schmidt, R. R.
J. Org. Chem. 2004, 69, 1853-1857. (f) Kwon, Y. T.; Lee, Y. J.; Lee, K.;
Kim, K. S. Org. Lett. 2004, 6, 3901-3904. (g) Tanaka, S.-i.; Takashina,
M.; Tokimoto, H.; Fujimoto, Y.; Tanaka, K.; Fukase, K. Synlett 2005, 2325-
2328.
FIGURE 1. Staggered conformations about the C3-O3 bond.
Viewed from the perspective of the O2-substituent bond, the
population of conformer D is likely extremely small due to high
steric congestion. The bulky group on O3 presumably destabi-
lizes conformation E, thus leaving F as the most populous state
(Figure 2). In conformer F the 2-O-benzyl ether is in close
(14) (a) Crich, D.; Dudkin, V. Tetrahedron Lett. 2000, 41, 5643-5646.
(b) Crich, D.; Li, W.; Li, H. J. Am. Chem. Soc. 2004, 126, 15081-15086.
(c) Code´e, J. D. C.; Hossain, L. H.; Seeberger, P. H. Org. Lett. 2005, 7,
3251-3254.
(15) Crich, D.; Jayalath, P. Org. Lett. 2005, 7, 2277-2280.
(16) Crich, D.; Lim, L. B. L. Org. React. 2004, 64, 115-251.
J. Org. Chem, Vol. 71, No. 8, 2006 3065

Crich et al.
TABLE 1. Influence of the O2 Protecting Group on Selectivity
FIGURE 2. Staggered conformations about the C2-O2 bond.
proximity to the â face of the R-mannosyl triflate. This enhanced
steric shielding retards attack on the â face, either on the
covalent triflate itself or on the transient contact ion pair arising
from the covalent triflate, thereby resulting in the observed loss
of â selectivity.
In systems such as 2 this problem can be circumvented by
the simple ruse of switching to a less bulky O3 protecting group,
however, in target-directed convergent oligosaccharide synthesis
there is no way to avoid the use of donors such as 4 and 5. We
reasoned that the unfavorable steric interaction in conformer E
could be reduced by minimizing the size of the O2 protecting
group, which should have the effect of increasing the population
of E at the expense of F. At the same time, the use of a
protecting group with a low steric demand on O2, should serve
to minimize the detrimental effect of any residual population
of conformer F. We were encouraged in this line of thinking
by the work of van Boom et al. on the successful â-glycosylation
of several acceptors by donor 6 with the relatively small 2-azido
group.17 However, the size 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 esters,4e and to focus instead on
the allyl and propargyl ethers.
These results strongly support the hypothesis of the beneficial
effect of reducing the bulk of the O2 protecting group on the
stereochemical outcome of the reaction, with the best anomeric
ratio obtained with the smallest O2 protecting group. To put
the inverse relationship between the steric bulk of the O2
protecting group and the anomeric selectivity on a more secure
footing, we measured steric A-values for the propargyloxy,
allyloxy, benzyloxy, and tert-butyldimethylsiloxy groups by the
classical 1H VT-NMR method (Table 2).18 The observed trend
in A-values fully supports the initial hypothesis, with the
propargyl ether being significantly smaller than the allyl ether,
which in turn is smaller than the benzyl ether. The A-value for
the tert-butyldimethylsiloxy group determined here, and included
for comparison purposes, is significantly greater than that
previously measured by Eliel for the same group using an
alternative 13C NMR method,19 but is consistent with the general
trend of coupling selectivities observed in this entire study.
SCHEME 1. Synthesis of Donors 10 and 13
We began with the synthesis of the 3-O-silyl compounds 10
and 13 (Scheme 1) by standard means from the known
thioglycoside 7.14b In these syntheses, the 3-O-silyl group was
introduced after the allyl or propargyl ethers to preempt
problems of silyl migration that were anticipated in the reverse
protocol.
Donors 10 and 13 were then coupled to the acceptor 14 by
our standard BSP/TTBP/Tf2O (BSP ) 1-benzenesulfinyl pip-
eridine, TTBP ) 2,4,6-tri-tert-butylpyrimidine, and Tf2O )
trifluoromethanesulfonic anhydride) protocol5c,16 leading to the
yields and selectivities outlined in Table 1. Included in Table 1
for comparison is the previous coupling14a of donor 2 to acceptor
1 by the directly analogous sulfoxide method.16
In addition to the smaller size of the propargyl ether, we also
considered the possibility that it might exhibit an electron-
withdrawing effect. Indeed, the sp-hybridization of the alkyne
carbon renders the propargyloxy group moderately electron-
withdrawing with respect to the other ethers studied, as seen
from the pKa’s of the corresponding alcohols (Table 2),20 and
(17) (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-
1522. (b) 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, 1057-1064.
(18) Jensen, F. R.; Bushweller, C. H.; Beck, B. H. J. Am. Chem. Soc.
1969, 91, 344-351.
(19) Eliel, E. L.; Satici, H. J. Org. Chem. 1994, 59, 688-689.
(20) Dictionary of Organic Compounds; Chapman and Hall: London,
1996.
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DiastereoselectiVity in â-Mannopyranosylation
TABLE 2. Steric A-Values and pKa’s
SCHEME 3. Synthesis of a Mannotriose Using
2-O-Propargyl Ethers
a Measurement temperature. b Equilbrium constant. c A ) RTlnK.
TABLE 3. Further Couplings to Donor 13
thiophiles. The coupling of the disaccharide donor 29 to acceptor
27 then gave the mannotriose in 80% yield with an R/â ratio of
1:5, presenting a very significant improvement over the ap-
proximately 1:1 R/â ratio observed with donor 4 and a related
acceptor.14b Additionally, the successful couplings employing
compounds 12 and 27 illustrate that propargyl ethers are also
suitable for the protection of acceptors.
it is likely that the beneficial effect of the 2-O-propargyl ethers
arises from a combination of the minimal steric bulk and its
moderately disarming property.
The coupling of donor 13 to two further substrates, again
with excellent results (Table 3), confirmed the ability of the
2-O-propargyl ether protecting group to overcome the deleteri-
ous effects of a 3-O-silyl ether.
Attention was next focused on donors bearing a glycosidic
bond at O3, analogous to the problematic 4 and 5. Furthermore,
bearing in mind the potential for the eventual use in mannan
synthesis, a glycosyl acceptor carrying a 2-O-propargyl ether
was also prepared (Scheme 2).
With a means to overcome the unfavorable effect of a bulky
O3 substituent in hand, we proceeded to undertake a broader
investigation into the general effects of propargyl ethers on
stereoselectivity in 4,6-O-benzylidene-directed â-mannosylation
reactions. Specifically, we reasoned that while the steric
buttressing effect discussed above and illustrated in Figures 1
and 2 will be maximized with a large group on O3, it will
necessarily be present with more common protecting groups
on O3, albeit to a lesser extent. Accordingly, the use of a 2-O-
propargyl ether, even in conjunction with a 3-O-benzyl ether,
should lead to enhanced selectivity over the more typical 2,3-
di-O-benzyl-protected donors. To probe this idea, a series of
four donors were prepared using standard techniques from diol
3114b via the known monobenzyl ethers 32 and 3414b (Scheme
4).
SCHEME 2. Synthesis of Acceptor 27
Subsequent coupling of this series of donors to a standard
acceptor 14 gave the results presented in Table 4. A comparison
of entries 1 and 2 in Table 4 clearly demonstrates that a 2-O-
propargyl ether leads to enhanced â selectivity even with the
3-O-benzyl-protected system, in accordance with the above
stated hypothesis. The 3-O-propargyl donor 35 (Table 4, entry
3) gave surprisingly poor but reproducible results for which we
have no satisfactory explanation at the present time. It is clear,
however, that the O3 group plays a major role in these 4,6-O-
benzylidene protected â-mannosylation reactions and that the
issue of steric bulk and buttressing discussed here is only one
facet of the problem.22 Taking into account the selectivities
obtained with donors 33 and 35, it is clear that the modest 10:1
â/R selectivity obtained with the 2,3-di-O-propargyl-protected
Acceptor 12 was successfully coupled to the known donor
285c with R/â selectivity of 1:16 in 88% yield (Scheme 3). Per
the protocol of van Boom et al.,14b,17,21 triethyl phosphite was
added after the addition of the acceptor 12 to limit the premature
activation of its thioglycoside functionality by any extraneous
(21) (a) 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-
1950. (b) Sliedregt, L. A. J. M.; van der Marel, G. A.; van Boom, J. H.
Tetrahedron Lett. 1994, 35, 4015-4018. (c) Alonso, I.; Khiar, N.; Martin-
Lomas, M. Tetrahedron Lett. 1996, 37, 1477-1480.
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Crich et al.
TABLE 5. Coupling of 33 to Further Acceptors
SCHEME 4. Synthesis of Donors 33, 35, and 36
TABLE 4. Coupling of Mono- and Di-O-proparyl Protected
Donors to 14
the investigation of suitable deprotection conditions. It has been
reported that propargyl ethers may be cleaved with benzyltri-
ethylammonium tetrathiomolybdate,24 with low-valent titanium
in hot THF,25 and by a nickel-catalyzed electrochemical
protocol.26 However, on the basis of experience in our laboratory
with allyl ethers in oligosaccharide synthesis,12c,d,27 we have
preferred a method involving base-catalyzed isomerization to
the corresponding allenyl ether, followed by an oxidative
cleavage with catalytic osmium tetroxide in the presence of
N-methyl morpholine N-oxide (NMNO), as reported by Mere-
yala and co-workers,28 albeit under somewhat milder conditions.
Thus, a representative series of propargyl ether-protected
saccharides was treated with potassium tert-butoxide in THF
at room temperature, followed by exposure to catalytic OsO4
in the presence of NMNO, also at room temperature, resulting
in a hydrolysis to the corresponding alcohols (Table 6).
Finally, we have briefly investigated the potential of the 2-O-
propargyl ether protecting group in the synthesis of â-L-
donor 36 (Table 4, entry 4) is a compromise between the
excellent selectivity obtained with a 2-O-propargyl group alone
and the obviously harmful effect of the 3-O-propargyl ether.
The very encouraging results obtained with donor 33,
featuring the combination of the 2-O-propargyl and 3-O-benzyl
ether protecting groups, were then extended to encompass a
broader range of typical acceptor alcohols (Table 5). In each
case, excellent yields and â/R selectivies surpassing 20:1 were
obtained.
While the use of allyl ethers as protecting groups is extremely
widespread,1a,23 that of propargyl ethers is novel and requires
(22) For example, we have previously discussed the highly R-selective
couplings obtained in the presence of a 3-O-carboxylate ester. The origin
of these effects is currently under active investigation in our laboratory.
See ref 4d and Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291-
1297.
(23) (a) Guibe´, F. Tetrahedron 1997, 53, 13509-13556. (b) Guibe´, F.
Tetrahedron 1998, 54, 2967-3042. (c) Kocienski, P. J. Protecting Groups,
3rd ed.; Thieme: Stuttgart, 2005. (d) Greene, T. W.; Wuts, P. G. M.
ProtectiVe Groups in Organic Synthesis, 3rd ed.; Wiley: New York, 1999.
(24) Swamy, V. M.; Ilankumaran, P.; Chandrasekaran, S. Synlett 1997,
513-514.
(25) Nayak, S. K.; Kadam, S. M.; Banerji, A. Synlett 1993, 581-582.
(26) Olivero, S.; Dunach, E. Tetrahedron Lett. 1997, 38, 6193-6196.
(27) Crich, D.; Hwang, J.-T.; Yuan, H. J. Org. Chem. 1996, 61, 6189-
6198.
(28) Mereyala, H. B.; Gurrala, S. R.; Mohan, S. K. Tetrahedron 1999,
55, 11331-11342.
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DiastereoselectiVity in â-Mannopyranosylation
TABLE 6. Cleavage of Propargyl Ethers
SCHEME 5. Preparation of Rhamnosyl Donor 64
SCHEME 6. Glycosylation in the Rhamnopyranose Series
tivity from changing the O2 protecting from the benzyl ether
to the propargyl ether is very small.
Overall, propargyl ethers are readily introduced and cleaved
protecting groups for alcohols that bring about significant
improvements in the diastereoselectivity of many mannosylation
reactions, which we attribute to the combination of their minimal
steric bulk and their modest disarming power. While we have
focused on the application of this protecting group to the solution
of current problems in our laboratory, we anticipate that it will
find a broader application in organic synthesis, especially in
situations in which the steric bulk of a protecting group is a
factor.
rhamnopyranosides, a cognate problem to that of the â-D-
mannopyranosides but one which does not allow the use of the
stereo-directing 4,6-O-benzylidene acetal function in the donor.
As part of our ongoing effort in this area,4e,29 we reported that
the 3,4-O-carbonate-protected rhamnosyl donor 60 gave moder-
ate to good â/R selectivity (1.5:1 to â only) on coupling to
various acceptors under the standard BSP/Tf2O/TTBP condi-
tions, depending on the reactivity of the acceptor.4f
Experimental Section
Phenyl 4,6-O-Benzylidene-2-O-(prop-2-ynyl)-3-O-p-methoxy-
benzyl-1-thio-r-D-mannopyranoside (11). To a stirred solution
of phenyl 4,6-O-benzylidene-3-O-p-methoxybenzyl-1-thio-R-D-
mannopyranoside (2.5 g, 5.5 mmol) in dry dimethylformamide (15
mL) at 0 °C was added 60% NaH in oil (0.33 g, 8.3 mmol). The
mixture was stirred for 15 min. Propargyl bromide (0.93 mL, 8.3
mmol) was added dropwise to the above reaction mixture, and
stirring was continued for 3 h. The reaction mixture was quenched
by the addition of methanol, diluted with CH2Cl2 (25 mL), and
washed with saturated NaHCO3. The organic layer was separated,
dried over anhydrous Na2SO4, and concentrated under vacuum. The
crude product was purified by flash column chromatography on
It was reasonable, therefore, to investigate the analogous 2,3-
O-carbonate 64, which was prepared as set out in Scheme 5
from the known4f bisacetal 61.
silica gel (hexane/ethyl acetate, 8:1) to give 11 (2.46 g, 85%):
1
Activation of 64, which proceeded smoothly under the
standard conditions, was followed by the addition of methyl
2,3,6-tri-O-benzyl-R-D-glucopyranoside 14, a member of the
glucose 4-OH derivatives that are known to be relatively difficult
to glycosylate,30 giving the disaccharide 65 in 65% yield in the
form of a 2:1 â/R mixture (Scheme 6). This represents only a
modest improvement of selectivity over the 1.5:1 â/R ratio
obtained on the coupling of 60 with 14,4f and this discouraged
us from further work with this donor. Presumably, there is very
little buttressing interaction between the tied back carbonate and
the protecting group on O2. As such, the effect on stereoselec-
[R]24.5 +155.8 (c 2.0, CHCl3). H NMR (500 MHz, CDCl3): δ
D
2.4 (t, J ) 2.4 Hz, 1H), 3.82 (s, 3H), 3.87 (t, J ) 11.0 Hz, 1H),
3.98 (dd, J ) 3.0, 10.0 Hz, 1H), 4.19-4.24 (m, 3H), 4.26-4.31
(m, 1H), 4.4 (dd, J ) 0.5, 2.0 Hz, 2H), 4.70 (d, J ) 12.0 Hz, 1H),
4.81 (d, J ) 12.0 Hz, 1H), 5.61 (d, J ) 1.5 Hz, 1H), 5.63 (s, 1H),
6.9 (d, J ) 8.6 Hz, 2H), 7.3-7.45 (m, 10H), 7.5-7.56 (m, 2H).
13C NMR (125 MHz, CDCl3): δ 55.3, 58.8, 65.4, 68.5, 72.9, 75.2,
75.7, 77.6, 79.0, 79.4, 87.4, 101.5, 113.8, 126.1, 127.6, 128.2, 128.8,
129.1, 129.2, 129.4, 130.2, 131.6, 133.7, 134.5, 137.5, 159.3. ESI-
HRMS calcd for C30H30O6S [M + Na]+, 541.1661; found,
541.1658.
Phenyl 4,6-O-Benzylidene-2-O-(prop-2-ynyl)-1-thio-r-D-man-
nopyranoside (12). To a stirred solution of 11 (0.47 g, 0.91 mmol)
in CH2Cl2 (8 mL) and water (0.4 mL) was added DDQ (0.3 g, 1.3
mmol) at room temperature. After 3 h, saturated NaHCO3 was
(29) Crich, D.; Picione, J. Org. Lett. 2003, 5, 781-784.
(30) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155-224.
J. Org. Chem, Vol. 71, No. 8, 2006 3069

Crich et al.
added, and the mixture was extracted with CH2Cl2. The extract
was washed several times with saturated NaHCO3 and dried over
Na2SO4. Evaporation of the solvent in vacuo gave an oil, which
was chromatographed on a flash silica gel column (hexane/ethyl
127.4, 127.6, 127.7, 127.8, 128.0, 128.1, 128.2, 128.3, 128.4, 128.8,
129.0, 129.2, 131.6, 133.6, 137.3, 137.6, 138.4, 138.7. ESI-HRMS
calcd for C49H48O10S [M + Na]+, 851.2866; found, 851.2875.
1
29r: [R]24 +76.4 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3):
D
acetate, 4:1) to give 12 (0.34 g, 93%) as a white solid: mp 128
δ 2.4 (t, J ) 2.4 Hz, 1H), 3.8 (t, J ) 10.5 Hz, 1H), 3.92-3.96 (m,
2H), 3.99-4.04 (m, 2H), 4.15 (t, J ) 9.5 Hz, 1H), 4.2 (dd, J )
2.5, 16.1 Hz, 1H), 4.25-4.38 (m, 7H), 4.5 (d, J ) 12.4 Hz, 1H),
4.62 (d, J ) 12.4 Hz, 1H), 4.63 (d, J ) 12.2 Hz, 1H), 4.7 (d, J )
12.2 Hz, 1H), 5.4 (d, J ) 1.2 Hz, 1H), 5.57 (s, 1H), 5.59 (s, 1H),
5.67 (s, 1H), 7.15-7.52 (m, 25H). 13C NMR (125 MHz, CDCl3):
δ 58.3, 64.7, 65.1, 68.5, 68.8, 72.1, 72.7, 72.8, 75.3, 75.7, 78.5,
79.0, 79.2, 86.9, 99.6, 101.4, 101.9, 125.9, 126.1, 127.5, 127.6,
127.7, 127.8, 128.2, 128.4, 128.8, 129.2, 129.3, 131.6, 133.5, 137.3,
137.7, 137.8, 138.5. ESI-HRMS calcd for C49H48O10S [M + Na]+,
851.2866; found, 851.2874.
1
°C; [R]27 +119 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ
D
2.49 (t, J ) 2.4 Hz, 1H), 2.5 (br s, 1H), 3.84 (t, J ) 10.2 Hz, 1H),
3.9 (t, J ) 9.6 Hz, 1H), 4.16 (dd, J ) 3.6, 10.0 Hz, 1H), 4.21-
4.24 (m, 2H), 4.27-4.32 (m, 1H), 4.34 (dd, J ) 2.4, 16.1 Hz, 1H),
4.42 (dd, J ) 2.4, 16.1 Hz, 1H), 5.59 (s, 1H), 5.68 (s, 1H), 7.32-
7.53 (m, 10H). 13C NMR (125 MHz, CDCl3): δ 58.6, 64.7, 68.4,
68.9, 75.7, 78.9, 79.3, 79.4, 86.4, 102.2, 126.3, 127.7, 128.3, 129.2,
131.7, 133.8, 137.2. ESI-HRMS calcd for C22H22O5S [M + Na]+,
421.1086; found, 421.1095.
Phenyl 4,6-O-Benzylidene-2-O-(prop-2-ynyl)-3-O-(2,3-di-O-
benzyl-4,6-O-benzylidene-â-D-mannopyranosyl)-1-thio-r-D-man-
nopyranoside 29â and the r-Anomer 29r. To a stirred solution
of donor 28 (480 mg, 0.88 mmol), BSP (223 mg 1.06 mmol), TTBP
(331 mg, 1.33 mmol), and 4-Å molecular sieves in CH2Cl2 (5 mL),
at -60 °C under an Ar atmosphere, was added Tf2O (195 µL 1.15
mmol). After 30 min, the temperature was brought down to -78
°C, and then acceptor 12 (424 mg 1.06 mmol) in CH2Cl2 (3 mL)
was slowly added. The reaction mixture was stirred for 2 h at -78
°C and quenched by the addition of triethyl phosphite (435 µL,
2.7 mmol). The mixture continued stirring for 1 h at -78 °C and
was then allowed to reach room temperature. The reaction mixture
was diluted with CH2Cl2 (10 mL), the molecular sieves were filtered
off, and the mixture was washed with saturated NaHCO3. The
organic layer was separated, dried, and concentrated. The crude
was purified by radial chromatography (hexane/ethyl acetate, 8:1)
General Procedure for the Deprotection of Propargyl Ethers.
To a stirred solution of propargyl ether (1 mmol) in dry THF (5
mL) was added KOt-Bu (1.1 mmol), and stirring was continued at
room temperature for 3-12 h until the TLC indicated completion.
The reaction mixture was diluted with CH2Cl2 (10 mL). The organic
phase was separated, washed with water, dried (Na2SO4), and
concentrated on a rotary evaporator to give the allenyl ethers in
quantitative yields. A homogeneous solution of allenyl ethers (1
mmol) in acetone/water (4:1, 5 mL) was treated with OsO4 (0.1
mmol) and N-methyl morpholine N-oxide (2 mmol), and the mixture
was stirred for 3 h at room temperature. After the completion of
the reaction, acetone was removed under vacuum, and the residue
was dissolved in CH2Cl2 (10 mL) and washed with saturated
NaHSO3. The organic phase was separated, dried (Na2SO4), and
concentrated on a rotary evaporator. The residues were purified by
flash or radial chromatography on silica gel to yield deprotected
di- and trisaccharides in 80-91%.
to give 29â and 29r in 83 and 5% yield, respectively. 29â: [R]24
D
1
+ 26.3 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ 2.23 (t, J
) 2.4 Hz, 1H), 3.29-3.34 (m, 1H), 3.6 (dd, J ) 3.2, 9.7 Hz, 1H),
3.86 (t, J ) 10.3 Hz, 1H), 3.93 (t, J ) 10.3 Hz, 1H), 4.0 (d, J )
3.0 Hz, 1H), 4.13 (t, J ) 9.7 Hz, 1H), 4.25-4.40 (m, 8H), 4.65 (d,
J ) 12.5 Hz, 1H), 4.76 (d, J ) 12.5 Hz, 1H), 4.84 (s, 1H), 4.86 (d,
J ) 11.9 Hz, 1H), 4.98 (d, J ) 11.8 Hz, 1H), 5.58 (s, 1H), 5.62 (s,
1H), 5.64 (s, 1H), 7.24-7.49 (m, 25H). 13C NMR (125 MHz,
CDCl3): δ 57.5, 65.3, 67.8, 68.5, 68.6, 72.3, 73.4, 74.8, 75.6, 75.7,
76.5, 77.5, 77.6, 78.6, 79.0, 86.0, 98.9, 101.3, 101.9, 126.0, 126.2,
Acknowledgment. We thank the NIH (GM57335) for
support of our work in this area.
Supporting Information Available: Full experimental details
and copies of NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO0526789
3070 J. Org. Chem., Vol. 71, No. 8, 2006