Does neighboring group participation by non-vicinal esters play a role in glycosylation reactions? Effective probes for the detection of bridging intermediates

Article abstract of DOI:10.1021/jo801630m

(Chemical Equation Presented) Neighboring group participation in glycopyranosylation reactions is probed for esters at the 3-O-axial and -equatorial, 4-O-axial and -equatorial, and 6-O-sites of a range of donors through the use tert-butoxycarbonyl esters. The anticipated intermediate cyclic dioxanyl cation is interrupted for the axial 3-O-derivative, leading to the formation of a 1,3-O-cyclic carbonate ester, with loss of a tert-butyl cation, providing convincing evidence of participation by esters at that position. However, no evidence was found for such a fragmentation of carbonate esters at the 3-O-equatorial, 4-O-axial and -equatorial, and 6-O positions, indicating that neighboring group participation from those sites does not occur under typical glycosylation conditions. Further probes employing a 4-O-(2-carboxy)benzoate ester and a 4-O-(4-methoxybenzoate) ester, the latter in conjunction with an ¹⁸O quench designed to detect bridging intermediates, also failed to provide evidence for participation by 4-O-esters in galactopyranosylation.

Full text of DOI:10.1021/jo801630m

Does Neighboring Group Participation by Non-Vicinal Esters Play a
Role in Glycosylation Reactions? Effective Probes for the Detection
of Bridging Intermediates
David Crich,* Tianshun Hu, and Feng Cai
Chemistry Department, Wayne State UniVersity, 5101 Cass AVenue, Detroit, Michigan 48202, and
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
dcrich@chem.wayne.edu
ReceiVed July 23, 2008
Neighboring group participation in glycopyranosylation reactions is probed for esters at the 3-O-axial
and -equatorial, 4-O-axial and -equatorial, and 6-O-sites of a range of donors through the use
tert-butoxycarbonyl esters. The anticipated intermediate cyclic dioxanyl cation is interrupted for the axial
3-O-derivative, leading to the formation of a 1,3-O-cyclic carbonate ester, with loss of a tert-butyl cation,
providing convincing evidence of participation by esters at that position. However, no evidence was
found for such a fragmentation of carbonate esters at the 3-O-equatorial, 4-O-axial and -equatorial, and
6-O positions, indicating that neighboring group participation from those sites does not occur under typical
glycosylation conditions. Further probes employing a 4-O-(2-carboxy)benzoate ester and a 4-O-(4-
methoxybenzoate) ester, the latter in conjunction with an 18O quench designed to detect bridging
intermediates, also failed to provide evidence for participation by 4-O-esters in galactopyranosylation.
Introduction
selective nature of these reactions. Participation by other groups,
such as the 2-O-(2-pyridyl)methyl ethers and several 2-O-(2-
thio)ethyl ethers, has been demonstrated spectroscopically
recently, 7 and the similar involvement of other groups such as
the 2-O-phosphate esters,8,9 the 2-deoxy-2-dibenzylamino sys-
tems,10 and other bulky benzyl type ethers11 has been suggested
on the basis of stereochemical evidence.
In this paper, we address the possibility of neighboring group
participation by carboxylate esters located on more remote
positions, specifically on O3, O4, and O6 of glycopyranosyl
donors. In 2000, we observed the thioglycoside 1, with its 3-O-
Neighboring group participation, or anchimeric assistance,1
by 2-O-carboxylate esters is of fundamental importance to
carbohydrate chemistry and is responsible for the facile, reliable,
highly stereoselective synthesis of the 1,2-trans class of glyco-
sidic bonds (ꢀ-glucosides and R-mannosides and related gly-
cosidic bonds).2 The intervention of 2-O-carboxylate esters in
this manner is supported by the isolation of crystalline diox-
alenium ions in some cases,3 by the spectroscopic observation
of the same species as intermediates in other cases,4 by
computational work,5 by rate acceleration in the case of weakly
activated donors,3,6 and is implied by the highly 1,2-trans-
(5) Nukada, T.; Berces, A.; Zgierski, M. Z.; Whitfield, D. M. J. Am. Chem.
Soc. 1998, 120, 13291–13295.
(1) Capon, B.; McManus, S. P. Neighboring Group Participation; Plenum:
New York, 1976.
(6) (a) Crich, D.; Li, M. Org. Lett. 2007, 9, 4115–4118. (b) Konradsson, P.
In Glycoscience: Chemistry and Chemical Biology; Fraser-Reid, B., Tatsuta, K.,
Thiem, J., Eds.; Springer: Berlin, 2001; Vol. 1, pp 535-549.
(7) (a) Smoot, J. T.; Pornsuriyasak, P.; Demchenko, A. V. Angew. Chem.,
Int. Ed. 2005, 44, 7123–7126. (b) Kim, J.-H.; Yang, H.; Boons, G.-J. Angew.
Chem., Int. Ed. 2005, 44, 947–949. (c) Kim, J.-H.; Yang, H.; Park, J.; Boons,
G.-J. J. Am. Chem. Soc. 2005, 127, 12090–12097.
(8) Yamada, T.; Takemura, K.; Yoshida, J.-i.; Yamago, S. Angew. Chem.,
Int. Ed. 2006, 45, 7575–7578.
(9) For a different opinion on participation by 2-O-phosphate esters, see:
Crich, D.; Hutton, T. K.; Banerjee, A.; Jayalath, P.; Picione, J. Tetrahedron:
Asymmetry 2005, 16, 105–119.
(2) (a) Capon, B. Chem. ReV. 1969, 69, 407–498. (b) Bochkov, A. F.; Zaikov,
G. E. Chemistry of the O-Glycosidic Bond; Pergamon: Oxford, 1979. (c) Ernst,
B.; Hart, G. W.; Sinay¨, P., Eds. Carbohydrates in Chemistry and Biology; Wiley-
VCH: Weinheim, 2000. (d) Fraser-Reid, B.; Kuniaki, T.; Thiem, J., Eds.
Glycoscience: Chemistry and Chemical Biology; Springer-Verlag: Berlin, 2001.
(e) Demchenko, A. V., Ed. Handbook of Chemical Glycosylation: AdVances in
StereoselectiVity and Therapeutic ReleVance; Wiley-VCH: Weinheim, 2008. (f)
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. (g) Sinnott, M. L. Carbohydrate Chemistry and Biochemistry; RSC
Publishing: Cambridge, 2007.
(10) Jiao, H.; Hindsgaul, O. Angew. Chem., Int. Ed. 1999, 38, 346–348.
(11) Kulkarni, S. S.; Liu, Y.-H.; Hung, S.-C. J. Org. Chem. 2005, 70, 2808–
2811.
(3) Paulsen, H.; Herold, C.-P. Chem. Ber. 1970, 103, 2450–2462.
(4) Crich, D.; Dai, Z.; Gastaldi, S. J. Org. Chem. 1999, 64, 5224–5229.
8942 J. Org. Chem. 2008, 73, 8942–8953
10.1021/jo801630m CCC: $40.75 2008 American Chemical Society
Published on Web 10/22/2008

Group Participation in Glycosylation Reactions?
benzoate ester, to be highly R-selective,12 in contrast with the
excellent ꢀ-selectivity seen with the corresponding 3-O-benzyl
ether 2.13 The phenomenon was subsequently extended to other
esters at the 3-position of mannose and was successfully
exploited in the synthesis of a complex oligosaccharide.14 Our
results are related to an earlier observation by van Boeckel and
co-workers in which it was found that a 3-O-acetyl-protected
mannopyranosyl bromide was less ꢀ-selective than the corre-
sponding 3-O-benzyl derivative under insoluble silver salt
conditions,15,16 but they differ in that the changes are consider-
ably greater in our work. At the time we speculated that the
R-selectivity observed with 1 might be derived from neighboring
group participation by the ester and invoked intermediates
related to 3 that readily accommodate the trans-fused ben-
zylidene acetal.12 Subsequent work from our laboratory, how-
ever, has highlighted the high sensitivity of these 4,6-O-
benzylidene-protected ꢀ-mannosylations to a range of substituents
at the 3-position, causing us to doubt our original interpreta-
tion.17
method for the activation of glycosyl bromides, it is not
necessary to invoke neighboring group participation by esters
at the 3- and/or 4-positions of glucose and mannose in order to
explain the selectivities observed.15 In discussing the increased
ꢀ-selectivities observed in rhamnopyranosylation reactions with
donor 5, as compared to 6, under homogeneous activation
conditions, we agreed with van Boeckel and inclined toward
the effect of the ester being one of an electron-withdrawing
group influencing the tightness of the ion pairs on activation of
the donor.9 In line with this hypothesis, Takahashi and co-
workers observed excellent ꢀ-selectivity in a series of glyco-
sylations conducted with a set of donors carrying electron-
withdrawingbutnonparticipating4-O-sulfonateesters.22 Demchenko
and co-workers, on the other hand, recently came down strongly
on the side of neighboring group participation from O4 with
donors 6 and 7, even though the best ꢀ-selectivity recorded was
only 7:1.21
With respect to the effect of esters and related functions on
O6 in glycosylation reactions, early work by the Schuerch group
with glucosyl sulfonates as donors indicated that 6-O-(N-
phenylcarbamates) afforded high selectivity for R-glucosides,23
but the effect did not extend to the galactopyranosides.24
However, rather than postulating neighboring group participation
in the glucose series, the authors inclined toward the functional-
ity at O6 influencing stereoselectivity by modulation of the
tightness of the ion pair obtained on ionization of the glycosyl
donor.23 In another study by the Schuerch laboratory, investiga-
tion of a series of glucosyl donors carrying substituted 6-O-
benzoates revealed that greater ꢀ-selectivity was observed with
the more electron-rich esters, which was discussed in terms of
the stabilization of the glycosyl oxocarbenium ion by the ester
group, without the formation of a cyclic intermediate such as
would be required by classical neighboring group participation.25,26
In spite of this background, neighboring group participation by
esters at O6, through seven-membered cyclic transition states
and leading to the formation of R-glycosides, continues to be
invoked frequently in the literature.27
Neighboring group participation by esters at the 3-position,
both axial and equatorial, has previously been discussed by other
groups,15,18 most recently in the equatorial series by Nifantiev
and co-workers for the donors 4,19 but the evidence rarely
extends beyond stereochemical arguments. A similar situation
pertains with respect to esters in the 4-O-position with numerous
claims of neighboring group participation leading to improved
synthesis of either R-galacto and fucosides,20 or ꢀ-gluco and
mannosides.21 van Boeckel argued strongly that, at least for the
systems studied in his laboratory using the insoluble silver salt
The rational development of stereocontrolled oligosaccharide
synthesis requires the resolution of these fundamental issues,
and it is with this in mind that we advance here a series of
probes capable of unambiguously establishing the presence of
neighboring group participation in glycosylation reactions.
(12) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291–1297.
(13) (a) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321–8348. (b) Crich, D.;
Lim, L. B. L. Org. React. 2004, 64, 115–251.
Results and Discussion
(14) (a) Crich, D.; Vinod, A. U.; Picione, J. J. Org. Chem. 2003, 68, 8453–
8458. (b) Crich, D.; Yao, Q. J. Am. Chem. Soc. 2004, 126, 8232–8236.
(15) van Boeckel, C. A. A.; Beetz, T.; van Aelst, S. F. Tetrahedron 1984,
4097–4107.
(16) Also see Paulsen, H.; Lebuhn, R. Liebigs 1983, 1047–1072.
(17) (a) Crich, D.; Li, L. J. Org. Chem. 2007, 72, 1681–1690. (b) Crich, D.;
Vinogradova, O. J. Org. Chem. 2006, 71, 8473–8480. (c) Crich, D.; Jayalath,
P.; Hutton, T. K. J. Org. Chem. 2006, 71, 3064–3070. (d) Crich, D.; Wu, B.
Org. Lett. 2006, 8, 4879–4882.
Concept. We conceived that participation by a carboxylate
ester might be reliably established if the ester could be modified
in such a way as to trap the intermediate dioxocarbenium ion
by fragmentation. We considered that a tert-butoxycarbonyl
(Boc) group would be a suitable system for use in this manner
(18) (a) Tsai, T. Y. R.; Jin, H.; Wiesner, K. HelV. Chim. Acta 1984, 62,
1403–1405. (b) Smid, P.; de Ruiter, G. A.; van der Marel, G.; van Boom, J. H.
J. Carbohydr. Chem. 1991, 10, 833–849. (c) Jin, H.; Tsai, R.; Wiesner, K. Can.
J. Chem. 1983, 61, 2442. (d) Chiba, S.; Kitamura, M.; Narasaka, K. J. Am. Chem.
Soc. 2006, 128, 6931–6937.
(19) Ustyuzhanina, N.; Komarova, B.; Zlotina, N.; Krylov, V.; Gerbst, A.;
Tsvetkov, Y.; Nifantiev, N. Synlett 2006, 921–923.
(20) (a) Dejter-Juszynski, M.; Flowers, H. M. Carbohydr. Res. 1972, 23,
41–45. (b) Corey, E. J.; Carpino, P. J. Am. Chem. Soc. 1989, 111, 5472–5473.
(c) Demchenko, A. V.; Rousson, E.; Boons, G.-J. Tetrahedron Lett. 1999, 40,
6523–6536. (d) Mukaiyama, T.; Suenaga, M.; Chiba, H.; Jona, H. Chem. Lett.
2002, 56–57. (e) Cheng, Y.-P.; Chen, H.-T.; Lin, C.-C. Tetrahedron Lett. 2002,
43, 7721–7723.
(22) Tanaka, H.; Yoshizawa, A.; Takahashi, T. Angew. Chem., Int. Ed. 2007,
46, 2505–2507.
(23) Eby, R.; Schuerch, C. Carbohydr. Res. 1974, 34, 79–90.
(24) (a) Lucas, T. J.; Schuerch, C. Carbohydr. Res. 1975, 39, 39–45. (b)
Marousek, V.; Lucas, T. J.; Wheat, P. E.; Schuerch, C. Carbohydr. Res. 1978,
60, 85–96.
(25) Fre´chet, J. M.; Schuerch, C. J. Am. Chem. Soc. 1972, 94, 604–609.
(26) Note that classical neighboring group participation from an O6 ester
leading to ꢀ-glycosides is stereoelectronically improbable, as the intermediate
would correspond to an inside,outside bicyclo[5.3.1]undecane-type system: (a)
Alder, R. W.; East, S. P. Chem. ReV. 1996, 96, 2097–2111. (b) Kim, S.; Winkler,
J. Chem. Soc. ReV. 1997, 26, 387–400.
(27) (a) Mukaiyama, T.; Suenaga, M.; Chiba, H.; Jona, H. Chem. Lett. 2002,
56–57. (b) Cheng, Y.-P.; Chen, H.-T.; Lin, C.-C. Tetrahedron Lett. 2002, 43,
7721–7723.
(21) De Meo, C.; Kamat, M. N.; Demchenko, A. V. Eur. J. Org. Chem.
2005, 70, 6–711.
J. Org. Chem. Vol. 73, No. 22, 2008 8943

Crich et al.
with loss of a tert-butyl-cation from the cyclic intermediate
leading to the formation of a cyclic carbonate ester.
Axial 3-O-Esters. The possibility of participation by axial
esters at O3 in the pyranose series was investigated with the
allose donor 15, which was obtained in a straightforward manner
via Dess-Martin oxidation of the 2,4,6-tri-O-benzyl-ꢀ-D-
thioglucoside 13, reduction with L-Selectride, and condensation
with Boc2O (Scheme 3).
The capture of vicinal electrophilic centers by carbonate
esters, especially tert-butoxycarbonates, leading to the formation
of five-membered cyclic carbonates with the loss of an alkyl
cation or equivalent is classical in organic synthesis,28 and the
comparable use of carbamates has found application in carbo-
hydrate chemistry.29 Although unusual, such chemistry has also
been extended to the formation of a seven-membered cyclic
carbonate through cyclization of a carbamate derived from a
4-pentenol with N-bromosuccinimide in a favorably conforma-
tionally constrained system.30 More generally, the possibility
of neighboring group participation in simple acyclic systems
through six- and seven-membered cyclic dioxocarbenium ions
has found some support in elegant labeling experiments
conducted by Wilen and co-workers.31 We note that the
Hammett parameter, σp, for the CO2Me group is +0.45, which
is closely related to the +0.50 of the acetyl group,32 from which
we deduce that carbonate esters should be somewhat akin to
acetate esters in their ability to take part in neighboring group
participation. Likewise, the field effect parameter F, of the
CO2Me and COMe groups are very similar (0.34 and 0.33,
respectively), indicating that both groups stabilize positive
charge by field effects to a similar extent.32
SCHEME 3. Preparation of a 3-O-Boc-Allopyranoside
Donor
The activation of 15 was investigated under three sets of
conditions. Treatment with BSP and trifluoromethanesulfonic
anhydride at -60 °C in dichloromethane in the absence of an
external nucleophile led to the isolation of the cyclic carbonate
16 in 70% yield (Table 1, entry 1). However, inclusion of the
mild, non-nucleophilic base tri-tert-butylpyrimidine (TTBP)34
in the reaction mixture and addition of cyclohexanol following
activation resulted in the formation of the cyclohexyl glycoside
17 in 61% yield as an 11:1 ꢀ:R mixture, together with 7% of
the expected cyclic carbonate 16 (Table 1, entry 2). Finally,
activation by N-iodosuccinimide and trifluoromethanesulfonic
anhydride in the absence of nucleophile gave the hydrolysis
product 18 as the only isolable product (Table 1, entry 3) from
a complex mixture in which the tert-butyl group was mostly
Proof of Concept. Activation of the 2-O-Boc protected
thioglucoside 9, readily available through reaction of ethyl
3,4,6-tri-O-benzyl-ꢀ-D-thioglucopyranoside and Boc2O, with
N-iodosuccinimide and silver triflate in dichloromethane at
-10 °C afforded the cyclic carbonate 10 in 75% isolated
yield (Scheme 1).
SCHEME 1. Cyclic Carbonate Formation from a 2-O-Boc
Group: Glucose
1
retained as judged from the H NMR spectrum of the crude
reaction mixture.
TABLE 1. The Axial 3-O-Boc Group
The 2-O-mannosyl carbonate 11, available from phenyl 3,4,6-
tri-O-benzyl-R-D-thiomannopyranoside and Boc2O, gave the
cyclic carbonate 12 in 74% yield on treatment with 1-benze-
nesulfinyl piperidine (BSP)33 and trifluoromethanesulfonic
anhydride in dichloromethane at -60 °C (Scheme 2).
SCHEME 2. Cyclic Carbonate Formation from a 2-O-Boc
Group: Mannose
product,
anomeric
entry
conditions
yield (%)
ratio (R:ꢀ)
1
2
BSP, Tf2O, CH2Cl2, -60 °C
TTBP, BSP, Tf2O,
16, 70
17, 61; 16, 7
-
1:11.2
cyclohexanol, CH2Cl2, -60 °C
NIS, Tf2O, CH2Cl2, -60 °C
3
18, 55
-
These two experiments serve as proof of concept of cyclic
carbonate formation from Boc esters in systems for which
classical neighboring group participation by carboxylates is well-
established.
The isolation of cyclic carbonate 16 on activation with BSP
and Tf2O (Table 1, entry 1) clearly demonstrates the possibility
of participation by axial esters at the 3-O-position. The formation
of the cyclohexyl glycosides 17 on inclusion of the nucleophile,
however, strongly suggests that such neighboring group par-
ticipation is not necessary for the selective formation of
ꢀ-glycosides in this system and suggests that developing 1,3-
diaxial interactions in transition state for formation of the
R-glycoside are sufficient to explain the preferential formation
(28) Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.; Jernstedt,
K. K. J. Org. Chem. 1982, 47, 4013–4018.
(29) Guenther, W.; Kunz, H. Carbohydr. Res. 1992, 228, 217–241.
(30) Kocovsky, P.; Stieborova, I. J. Chem. Soc., Perkin Trans. 1 1987, 1969–
1974.
(31) Wilen, S. H.; Delguzzo, L.; Saferstein, R. Tetrahedron 1987, 43, 5089–
5094.
(32) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165–195.
(33) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015–9020.
(34) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323–326.
8944 J. Org. Chem. Vol. 73, No. 22, 2008

Group Participation in Glycosylation Reactions?
TABLE 2. The Equatorial 3-O-Boc Group
SCHEME 4. Possible Mechanisms for the Formation of 18
product,
anomeric
entry
conditions
yield (%)
ratio (R:ꢀ)
1
2
22, Tf2O, CH2Cl2, -60 °C
22, TTBP, Tf2O, C6H12O,
CH2Cl2, -60 °C
21, TTBP, BSP, Tf2O, C6H12O, 23, 69
CH2Cl2, -60 °C
complex mixture
23, 75
-
R only
3
R only
Following workup, acetylation of the crude reaction mixture
enabled isolation of the glycosyl acetates 25 as an anomeric
mixture (Table 3, entry 1). When cyclohexanol was added as
acceptor, the cyclohexyl glycosides 26 were obtained in high
yield, with the anomeric ratio being dependent on the solvent,
but favoring the ꢀ-anomer in both ether and dichloromethane
(Table 3, entries 2 and 3). These results effectively rule out
neighboring group participation from an axial ester at O-4.
of ꢀ-glycosides in this type of system. The isolation of the
hydrolysis product 18 on activation with NIS/Tf2O presumably
is due to trapping of a cyclic intermediate 19, before loss of
the tert-butyl group, by iodide or by succinimide (vide infra)
to give an unstable orthocarbonate-type species (20), which
undergoes hydrolysis on workup (Scheme 4). We prefer this
mechanism over the trapping of the glycosyl oxocarbenium ion
by iodide or succinimide, followed by hydrolysis on workup,
as both glycosyl iodides35 and succinimides36 have been
demonstrated on numerous occasions to be isolable substances
that are readily handled under standard conditions.
TABLE 3. Axial 4-O-Boc Group
Equatorial 3-O-Esters. A 3-O-Boc ester 21 was readily
prepared from phenyl 2-O-benzyl-4,6-O-benzylidene-R-D-thi-
omannoside, and a portion was converted to the sulfoxide 22,
which was formed as a single diastereomer, presumed to have
the (R)S configuration on the basis of previous work.37 When
sulfoxide 22 was activated with Tf2O at low temperature in
dichloromethane followed by aqueous workup, a complex
mixture was obtained that nevertheless retained the 3-O-Boc
1
product,
yield (%)
anomeric
ratio (R:ꢀ)
ester as determined from the H NMR spectrum of the crude
entry
1
conditions
2O, Et2O,
-60 °C; (ii) Ac2O, py
TTBP, BSP, Tf2O, cyclohexanol,
CH2Cl2, -60 °C
reaction mixture (Table 2, entry 1). On activation of the
sulfoxide in the presence of TTBP followed by addition of
cyclohexanol, the R-glycoside 23 was formed as a single
R-anomer in 75% isolated yield (Table 2, entry 2). Activation
of the thioglycoside 21 with BSP and Tf2O followed by trapping
with cyclohexanol gave the same glycoside with the same
exquisite R-selectivity (Table 2, entry 3). In none of the
experiments conducted with donors 21 and 22 were we able to
find any evidence supporting the formation of a cyclic carbonate
spanning positions 1 and 3 of the pyranose ring, and it is
apparent that the R-selectivity observed by ourselves with donors
carrying equatorial carboxylate esters on the 3-position of
glycosyl donors does not arise from classical neighboring group
participation.
(i) BSP, Tf
25, 92
26, 88
26, 62
1:7.1
1:3.9
1:1.3
2
3
TTBP, BSP, Tf2O, cyclohexanol,
Et2O, -60 °C
Equatorial 4-O-Esters. Two 4-O-Boc donors, 27 and 30,
were prepared in the usual manner from the corresponding
alcohols and subjected to a series of activation and coupling
reactions as set out in Table 4.
With the mannosyl donor 27, activations were conducted by
the NIS and BSP/Tf2O methods with 2-propanol as acceptor
(Table 4, entries 1-3) with no indication of the formation of a
cyclic carbonate. In each case, the isopropyl glycoside 28 was
isolated as an anomeric mixture slightly favoring the ꢀ-anomer,
consistent with the general results of Demchenko with donors
7 and 8. When the acceptor was omitted from the NIS-type
activation, the ring-inverted R-glycosyl succinimide 29 was
isolated in good yield (Table 4, entry 4), consistent with trapping
of the glycosyl oxocarbenium ion being more rapid than any
participation by the Boc group. With the 3-azido-2,3,6-trideoxy
system 30, anticipated to undergo more facile ring inversion
than 27 and so to have a greater predisposition toward
neighboring group participation from the 4-position,38 no cyclic
carbonate was found (Table 4, entries 5 and 6). When the
Axial 4-O-Esters. A 4-O-Boc galactosyl donor 24 was readily
obtained from ethyl 2,3,6-tri-O-benzyl-ꢀ-D-thiogalactopyrano-
side and activated with BSP and Tf2O in ether at -60 °C.
(35) (a) Caputo, R.; Kunz, H.; Mastroianni, D.; Palumbo, G.; Pedatella, S.;
Solla, F. Eur. J. Org. Chem. 1999, 314, 7–3150. (b) Bickley, J.; Cottrell, J. A.;
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Law, J. L.; Scheinman, F.; Stachulski, A. V. Chem. Commun. 2003, 1266–1267.
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(b) Bai, Y.; Lowary, T. L. J. Org. Chem. 2006, 71, 9672–9680. (c) Grayson,
E. J.; Ward, S. J.; Hall, A. J.; Rendle, P. M.; Gamblin, D. P.; Batsanov, A. S.;
Davis, B. G. J. Org. Chem. 2005, 70, 9740–9754.
(37) (a) Crich, D.; Mataka, J.; Sun, S.; Lam, K.-C.; Rheingold, A. R.; Wink,
D. J. Chem. Commun. 1998, 2763–2764. (b) Crich, D.; Mataka, J.; Zakharov,
L. N.; Rheingold, A. L.; Wink, D. J. J. Am. Chem. Soc. 2002, 124, 6028–6036.
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J. Org. Chem. Vol. 73, No. 22, 2008 8945

Crich et al.
TABLE 4. Equatorial 4-O-Boc Group
TABLE 5. 6-O-Boc Group
product,
anomeric
entry
1
conditions
yield (%)
ratio (R:ꢀ)
1.2 equiv of NIS,
0.3 equiv of TfOH,
3 equiv of iPrOH
CH2Cl2, 0 °C
1.2 equiv of NIS,
0.3 of equiv TfOH,
3 of equiv iPrOH,
Et2O, 0 °C
34, 80
34, 74
35, 16
1:1
1.5:1
-
2
3
products
yield (%)
anomeric
ratio (R:ꢀ)
1.2 equiv of NIS,
0.3 equiv of TfOH,
CH2Cl2, 0 °C
entry
1
donor
conditions
27
1.2 equiv of NIS,
0.3 equiv of AgOTf,
3 equiv of iPrOH,
CH2Cl2, -10 °C
1.2 equiv of BSP,
1.5 equiv of TTBP,
3 equiv of iPrOH,
CH2Cl2, -40 °C
1.2 equiv of BSP,
1.5 equiv of TTBP,
3 equiv of iPrOH,
Et2O, -60 °C
1.2 equiv of NIS,
0.3 equiv of AgOTf,
CH2Cl2, -10 °C
(i) BSP, Tf2O, CH2Cl2,
-60 °C; (ii) Ac2O, py
TTBP, BSP, Tf2O,
cyclohexanol,
28, 72
28, 76
28, 65
29, 59
0.9:1
0.8:1
0.7:1
R-only
Axial Esters at O4 Revisited. One of the more supportive
papers in the literature for neighboring group participation by
remote groups is that of Boons and co-workers on a series of
4-O-acyl-galactosyl donors.20c This paper appears to provide
evidence for a shift in mechanism between alkanoate and
arylcarboxylate esters, as the data, some of which is reproduced
in Table 6, clearly shows a jump in anomeric ratio between the
acetate and the substituted benzoates. The situation, however,
is complicated by the high R-selectivity obtained with the
pivalate ester, particularly when it is realized that the Hammett
σp value for a pivaloyl group is smaller than that of an acetyl
group (σp pivaloyl ) +0.32; σp acetyl ) +0.50) and that the
field effect parameter for pivaloyl is also smaller than that of
an acetyl group (F pivaloyl ) 0.26; F acetyl 0.33).32 Apparently,
steric effects are also at play here, as is the possibility of the
intermediate glycosyl oxocarbenium ions assuming different
conformations depending on the size of the group at O4.
2
3
4
27
27
27
5
6
30
30
31, 73
32, 46
1:1.7
1:3.7
CH2Cl2, -60 °C
activation was conducted without acceptor, only the hydrolysis
product was isolated, whereas quenching with cyclohexanol
allowed isolation of the glycoside as an anomeric mixture
favoring the ꢀ-isomer. Overall, the results obtained argue
strongly against neighboring group participation by equatorial
esters at O-4 as playing a significant role in glycosylation
reactions.
TABLE 6. Literature Data on 4-O-Acyl Galactosyl Donors
6-O-Esters. With the 6-O-Boc glucosyl donor 33 and
2-propanol as acceptor, the glycoside 34 was obtained in high
yield as an anomeric mixture, irrespective of whether the
reaction was conducted in dichloromethane or ether (Table 5,
entries 1 and 2). In the absence of acceptor, a crude reaction
mixture containing predominantly one product, with an anomeric
doublet at δ 6.21 (J ) 3.0 Hz), was obtained. Chromatographic
purification was accompanied by substantial decomposition;
nevertheless, the same product was isolated in 16% yield and
characterized on the basis of its NMR and mass spectrometric
data as the macrocyclic bis-carbonate 35. The symmetric R,R-
nature of this macrolide strongly mitigates against its formation
by dimerization of any monomeric cyclic carbonate, as this
would necessarily require inversion of configuration at the
anomeric center. Neighboring group participation by esters at
O-6 is deemed unlikely on the basis of these results.
entry
R
anomeric ratio (R:ꢀ)
1
2
3
4
5
6
acetyl
7.2:1
14:1
17:1
18:1
14:1
16:1
4-nitrobenzoyl
benzoyl
4-methylbenzoyl
4-methoxybenzoyl
pivaloyl
8946 J. Org. Chem. Vol. 73, No. 22, 2008

Group Participation in Glycosylation Reactions?
SCHEME 6. Application of an Axial 4-O-Hemiphthalate
Probe
For this reason, we believed it was important to develop an
independent probe specifically for neighboring group participa-
tion by benzoate-type esters. We took inspiration from a seminal
paper of Lemieux and Hindsgaul39 in which it was demonstrated
that 3,4,6-tri-O-acetyl-2-O-(carboxybenzoyl)-R-D-glucopyrano-
syl bromide underwent cyclization to an ortho-spiro ester (3,4,6-
tri-O-acetyl-1,2-O-phthalidylidene-R-D-glucopyranose) on treat-
ment with tetrabutylammonium bromide and 2,6-lutidine in 60%
yield and, importantly, that one of these ortho-spiro esters could
be isolated and fully characterized. Applying this concept, we
prepared the hemiphthalate 36, by reaction of the corresponding
alcohol with sodium hydride and phthalic anhydride, and treated
it with NIS and TMSOTf in dichloromethane at room temper-
ature, leading to the isolation of ortho ester 37 in 79% yield as
an inseparable mixture of two diastereomers (Scheme 5). In
addition to the 1H NMR spectrum with a characteristic anomeric
hydrogen resonance at δ 6.10, compound 37 featured a strong
IR carbonyl absorption at υ 1783 cm-1
.
ment.4 Thus, we anticipated that low temperature activation of
41 in the absence of acceptors would lead to the glycosyl cation
42, in equilibrium with the corresponding glycosyl triflate (not
shown), and that this cation would be in equilibrium with the
bridged cation 44 in the event that neighboring group participa-
tion occurs. Quenching of the glycosyl cation with 18O-labeled
water would lead to incorporation of the label solely at the
anomeric center 43, whereas quenching of the bridged cation
44 would ultimately lead to location of the label at the carbonyl
carbon, as in 46.
This experiment was conducted with the 4-methoxyben-
zoate 41, with 95% 18O-enriched water, leading to isolation
of the hydrolysis product 43/46 in 82% yield, principally as
the R-anomer. Unfortunately, this sample was not amenable
to mass spectrometric analysis, and therefore, it was con-
verted to the acetate 47, isolated in 90% yield as a 4.1:1 R:ꢀ
anomeric mixture. Mass spectrometry of 47 revealed the
incorporation of one atom of 18O to the extent of ap-
proximately 50%. Inspection by 13C NMR spectroscopy
revealed the presence of an isotopically shifted anomeric
carbon and of a similarly shifted acetyl carbonyl group for
both anomers. However, no isotopically shifted signals were
apparent for either C-4 or the benzoyl carbonyl group,
strongly suggesting incorporation of the label only at the
anomeric site. Further confirmation of the location of the label
was sought by treatment of the anomeric acetates 47 with
thiophenol and BF3 · OEt2 in acetonitrile, resulting in the
isolation of thioglycoside 41 in 97% yield as a 2.2:1 R:ꢀ-
mixture. Interrogation of this mixture of anomeric thiogly-
cosides by mass spectrometry revealed the absence of the
18O label, leading to the conclusion that, in the quenching
reaction, quenching only took place at the anomeric center.
SCHEME 5. Proof of Concept for the Hemiphthalate Probe
With proof of concept established, we proceeded to prepare
the galactosyl hemiphthalate 38 from phenyl 2,3,6-tri-O-benzyl-
ꢀ-D-thiogalactopyranoside by treatment with sodium hydride and
phthalic anhydride in DMF. On activation with N-iodosuccin-
imide and TMSOTf at -30 °C in dichloromethane, no evidence
could be found for the formation of a bridged phthalide such
as 39, either by NMR or IR spectroscopy of the crude reaction
mixture. Otherwise identical reactions run in CD2Cl2 with direct
NMR examination also failed to provide evidence for the
formation of 39. However, it was possible to isolate from these
reaction mixtures a compound to which we assign the B3,O
diolide structure 40 (Scheme 6).40,41 This compound might
presumably arise by direct trapping of the glycosyl oxocarbe-
nium ion by the acid group in 38, but it is also conceivably the
product of the rapid rearrangement of the putative intermediate
39. This experiment was therefore deemed inconclusive and a
further probe was sought.
To probe further the possibility of neighboring group
participation by axial O4 esters, we conceived that the existence
of bridging intermediates might be investigated by quenching
with 18O-enriched water and determination of the site of
incorporation of the label (Scheme 7). The success of this
experiment is predicated upon the kinetic mode of attack on
the bridging cation taking place at the cationic carbon. This
has been clearly demonstrated to be the case in our earlier work
when, working in the presence of a non-nucleophilic base, we
were able to monitor by 13C NMR spectroscopy the formation
of glycosyl orthoesters from preformed 2-phenyl-1,3-dioxale-
nium ions, rather than the glycosides observed on rearrange-
Conclusion
Our results unambiguously establish that neighboring group
participation by axial esters at O3 is possible in the course of
glycopyranosylation reactions, in general agreement with the
work of Weisner and others.18 On the other hand, no evidence
was found in support of neighboring group participation by an
equatorial O3 ester, by axial or equatorial O4 esters, or by esters
at O6. In the case of axial O4 esters, for which the strongest
case had been made in the literature, an isotopic labeling probe
also failed to find evidence in support of a bridging intermediate.
We conclude that participation by esters at these positions is
(39) Lemieux, R. U.; Hindsgaul, O. Carbohydr. Res. 1980, 82, 195–206.
(40) The structure of this compound is based on the examination of 1H NMR
data, which display 3J1,2, 3J2,3, and 3J3,4 coupling constants of 4.0, 10.0, and 2.4
Hz, consistent with a B3,O conformation for the pyranose ring. The mass spectrum
does not display a molecular ion, but has [M-phthalic anhydride]+ (10%).
(41) A Chemical Abstracts search revealed 22 ten-membered diolides derived
from phthalic anhydride, thereby indicating the accessibility of this structural
class.
J. Org. Chem. Vol. 73, No. 22, 2008 8947

Crich et al.
SCHEME 7. An Isotopic Labeling Probe
purification (eluent EtOAc/hexanes ) 1/5) afforded the Boc
protected donors.
unlikely and that alternative explanations must be found for any
stereochemical effects arising from the presence of esters at these
positions.42
General Procedure for Thioglycoside Activation by the
BSP Method. The donor (0.1 mmol), BSP (0.12 mmol), TTBP
(0.15 mmol), and activated 4 Å powdered molecular sieves (100
mg) were dissolved in dry CH2Cl2 (0.1 M) and stirred at -60
°C under N2 atmosphere for 10 min, and then freshly distilled
Tf2O (0.15 mmol) was added. The reaction mixture was stirred
at -60 °C for 1 h before quenching with saturated aqueous
NaHCO3. After extraction with CH2Cl2 (3 × 5 mL), the
combined organic phase was washed with brine, dried, and
concentrated. The crude reaction mixture was purified by
chromatography on silica gel.
General Procedure for Thioglycoside Activation by the
NIS Method. The donor (0.1 mmol), NIS (0.15 mmol), and
activated 4 Å powdered molecular sieves (100 mg) were dissolved
in dry CH2Cl2 (0.1 M) at room temperature and then stirred at -40
°C for 10 min before TMSOTf (0.01 mmol) was added dropwise
at -40 °C. The reaction mixture was stirred at -40 °C for 1 h
before quenching with Na2S2O3 (20%) and extraction with CH2Cl2
(3 × 5 mL). The combined organic phase were washed with brine,
dried, and concentrated. The crude reaction mixture was purified
by chromatography on silica gel.
General Procedure for Glycosylation Reactions by the
BSP/TTBP Method. The donor (0.1 mmol), BSP (0.12 mmol),
TTBP (0.15 mmol), and activated 4 Å powdered molecular sieves
(100 mg) were dissolved in dry CH2Cl2 (0.1 M) and stirred at -60
°C under N2 atmosphere for 10 min, before redistilled Tf2O (0.15
mmol) was added dropwise. After 10 min, the acceptor (0.15 mmol)
was added and stirring maintained at -60 °C for 2 h. The reaction
mixture was then allowed to warm to room temperature before it
was quenched with saturated aqueous NaHCO3 and extracted with
CH2Cl2 (3 × 5 mL), and the combined organic phase was washed
with brine, dried, and concentrated. The crude reaction mixture was
purified by chromatography on silica gel.
The elimination of neighboring group participation from
consideration, particularly for the O3 equatorial, O4 axial, and
O6 esters, ultimately requires the formulation of alternative
hypotheses for the interesting stereochemical effects sometimes
observed in the presence of these groups.43,44 Remote protecting
groups and/or substituents have long been known to influence
the outcome of a variety of different reaction types,45 as
exemplified in glycopyranosylation by the influence of 4,6-O-
alkylidene and silylene acetals, and have been variously
attributed to conformational, inductive, stereoelectronic, and
other effects.13a,46 It is unlikely that one single effect will be
found to be responsible for the effects of all remote esters in
glycosylation reactions, but this remains to be determined by
further investigation.
Experimental Section
General Procedure for Preparation of Boc-Protected
Alcohols. To a solution of substrate (2.0 mmol) in CH2Cl2 (30 mL)
were added Boc2O (1.75 g, 8.0 mmol), Et3N (362 µL, 2.6 mmol),
and DMAP (24.4 mg, 0.2 mmol) followed by stirring at room
temperature overnight. The mixture was washed with saturated
NaHCO3 and brine, dried, and concentrated. Chromatographic
(42) Our conclusions largely parallel those of Woerpel in his recent
investigation of the transannular participation of 4-thioethers in the reactions of
cyclic tetrahydropyranyl oxocarbenium ions: Beaver, M. G.; Billings, S. B.;
Woerpel, K. A. J. Am. Chem. Soc. 2008, 130, 2082–2086.
(43) We consider the effect of the O4 equatorial esters to be satisfactorily
explained by their effect on the equilibrium between the covalent glycosyl donors
and the various ion pairs implicated in glycosylation, as discussed by van
Boeckel.15
(44) An anonymous reviewer has offered the insightful suggestion that the
effect of esters at O4 may be explained by their influence on the conformation
about the C5-C6 bond, thereby affecting the proximity of the O6 group to the
ring oxygen.
(45) (a) Barton, D. H. R.; McCapra, F.; May, P. J.; Thudium, F. J. Chem.
Soc. 1960, 1297–1311. (b) Magnus, N.; Magnus, P. Tetrahedron Lett. 1997, 38,
3491–3494. (c) Cieplak, A. S. Chem. ReV. 1999, 99, 1265–1336.
(46) (a) Fraser-Reid, B.; Wu, Z. C.; Andrews, W.; Skowronski, E. J. Am.
Chem. Soc. 1991, 113, 1434–1435. (b) Imamura, A.; Ando, H.; Korogi, S.;
Tanabe, G.; Muraoka, O.; Ishida, H.; Kiso, M. Tetrahedron Lett. 2003, 44, 6725–
6728. (c) Jensen, H. H.; Nordstrom, M.; Bols, M. J. Am. Chem. Soc. 2004, 126,
9205–9213. (d) McDonnell, C.; Lo´pez, O; Murphy, P. V.; Ferna´ndez Bolan˜os,
J. G.; Hazell, R. G.; Bols, M. J. Am. Chem. Soc. 2004, 126, 12374–12385. (e)
Pedersen, C. M.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc. 2007, 129,
9222–9235. (f) Jensen, H. H.; Pedersen, C. M.; Bols, M. Chem. Eur, J. 2007,
13, 7576–7581. (g) Okada, Y.; Mukae, T.; Okajimia, K.; Taira, M.; Fujita, M.;
Yamada, H. Org. Lett. 2007, 8, 1573–1576. (h) Okada, Y.; Nagata, O.; Taira,
M.; Yamada, H. Org. Lett. 2007, 9, 2755–2758. (i) Jensen, H. H.; Bols, M. Acc.
Chem. Res. 2006, 39, 259–265.
General Procedure for Glycosylation Reactions by the
NIS/AgOTf Method. A solution of donor (0.05 M), acceptor (1.5
equiv), and 3 Å molecular sieves in dry CH2Cl2 was stirred at room
temperature for 0.5 h under argon before it was cooled to 0 °C.
NIS (1 equiv) was then added followed by AgOTf or TMSOTf
(0.3 equiv), and the resulting mixture was stirred for 30 min before
it was filtered. The filtrate was washed by 20% Na2S2O3 solution
and brine. The aqueous layer was extracted with CH2Cl2 and the
combined organic layer was dried and concentrated under vacuum.
The residue was purified by flash column chromatography on silica
gel (hexanes/EtOAc ) 5-10/1) to afford the glycosylation products.
Ethyl 3,4,6-Tri-O-benzyl-2-O-tert-butyloxycarbonyl-1-thio-ꢀ-
D-glucopyranoside (9). Compound 9 was formed from 3,4,6-tri-
O-benzyl-ꢀ-D-thioglucopyranoside and Boc2O by the general
1
procedure in 78% yield as a colorless oil: [R]D -0.8° (c, 1.2); H
8948 J. Org. Chem. Vol. 73, No. 22, 2008

Group Participation in Glycosylation Reactions?
NMR δ 1.27 (t, J ) 7.5 Hz, 3H), 1.49 (s, 9H), 2.72-2.76 (m, 2H),
3.48-3.51 (m, 1H), 3.67 (t, J ) 9.0 Hz, 1H), 3.69-3.73 (m, 2H),
3.75 (dd, J ) 2.0, 11.0 Hz, 1H), 4.40 (d, J ) 10.0 Hz, 1H), 4.55
(d, J ) 12.5 Hz, 1H), 4.56 (d, J ) 11.0 Hz, 1H), 4.60 (d, J ) 12.0
Hz, 1H), 4.78-4.82 (m, 4H), 7.16-7.29 (m, 15H); 13C NMR δ
14.9, 23.9, 27.8 (3C), 68.9, 73.5, 75.0, 75.2, 75.4, 77.7, 79.5, 82.8,
83.5, 84.4, 127.6-128.5 (15C), 137.9, 138.2 (2C), 152.4; ESI
HRMS calcd for C34H42O7SNa [M + Na]+ 617.2544, found
617.2542.
137.4, 137.6, 138.4; IR 1066, 1283, 1454 cm-1; ESI HRMS calcd
for C33H34O5SNa [M + Na]+ 565.2020, found 565.2009.
Phenyl 3-O-tert-Butoxycarbonyl-2,4,6-tri-O-benzyl-1-thio-ꢀ-
D-allopyranoside (15). Compound 15 was formed from 14 and
Boc2O by the general procedure in 91% yield as a colorless oil:
1
[R]D ) 12.3° (c, 0.13); H NMR δ 1.42 (s, 9H), 3.38 (dd, J )
10.0, 3.0 Hz, 1H), 3.61 (dd, J ) 10.0, 3.0 Hz, 1H), 3.71 (dd, J )
11.0, 4.0 Hz, 1H), 3.78 (dd, J ) 10.5, 2.0 Hz, 1H), 3.93-3.96 (m,
1H), 4.40 (d, J ) 10.5 Hz, 1H), 4.49-4.52 (m, 2H), 4.58-4.61
(m, 1H), 4.67-4.71 (m, 2H), 5.06 (d, J ) 6.5 Hz, 1H), 5.75 (t, J
) 3.0 Hz, 1H), 7.21-7.39 (m, 18H), 7.56-7.58 (m, 2H); 13C NMR
δ 27.7, 68.9, 69.0, 71.3, 71.8, 72.8, 73.4, 75.0, 75.4, 82.2, 83.6,
127.4, 127.5, 127.6, 127.9, 128.1, 128.2, 128.3, 128.7, 132.3, 133.3,
3,4,6-Tri-O-benzyl-1,2-O-carbonyl-r-D-glucopyranose (10).
Compound (10) was formed from compound (9) and NIS by the
general procedure in 75% yield as a white solid: mp 60.1-61.2
°C; [R]D +4.8° (c, 0.5) [lit.47 mp 60-61 °C; [R]2D3 +4.9° (c, 4.8,
CHCl3)]; 1H NMR δ 3.65-3.72 (m, 2H), 3.80-3.86 (m, 2H), 3.94
(t, J ) 4.0 Hz, 1H), 4.43 (d, J ) 11.5 Hz, 1H), 4.49 (d, J ) 12.0
Hz, 1H), 4.57 (d, J ) 12.0 Hz, 1H), 4.59-4.71 (m, 4H), 6.07 (d,
J ) 6.5 Hz, 1H), 7.17-7.30 (m, 15H); 13C NMR δ 68.4, 71.8,
72.7, 73.2, 73.3, 73.5, 75.9, 77.3, 97.4, 127.9-128.7 (15C), 136.9,
137.3, 137.5, 138.5, 153.5; IR 1091, 1280, 1369, 1454, 1740 cm-1
;
ESI HRMS calcd for C38H42O7SNa [M + Na]+ 665.2544, found
665.2539.
2,4,6-Tri-O-benzyl-1,3-O-carbonyl-r-D-allose (16). Compound
16 was formed from 15 and BSP by the general procedure in 70%
yield as a colorless oil: [R]D ) 80.0° (c, 0.01); 1H NMR δ 3.53 (t,
J ) 2.0 Hz, 1H), 3.69-3.78 (m, 4H), 3.82-3.85 (m, 1H), 4.45
(dd, J ) 12.0, 6.0 Hz, 1H), 4.56-4.67 (m, 4H), 4.86 (d, J ) 2.0
Hz, 1H), 5.57 (t, J ) 2.5 Hz, 1H), 7.22-7.34 (m, 15H); 13C NMR
δ 67.1, 67.0, 69.5, 71.0, 71.6, 71.9, 73.6, 74.7, 96.2, 127.4, 127.8,
128.00, 128.02, 128.3, 128.51, 128.56, 128.63, 128.8, 129.3, 129.5,
136.1, 136.8, 137.5, 146.6; IR 1124, 1180, 1454, 1766 cm-1; ESI
HRMS calcd for C28H28O7Na [M + Na]+ 499.1728, found
499.1711.
137.4, 137.6, 152.5; IR 1812 cm-1
.
Phenyl 2-O-tert-Butoxycarbonyl-3,4,6-tri-O-benzyl-1-thio-r-
D-mannopyranoside (11). Compound 11 was formed from 3,4,6-
tri-O-benzyl-R-D-thiomannopyranoside and Boc2O by the general
procedure in 75% yield as a colorless oil: [R]D ) 98.0° (c, 0.3); 1H
NMR δ 1.47 (s, 9H), 3.74 (dd, J ) 10.5, 2.0 Hz, 1H), 3.84 (dd, J
) 10.5, 5.0 Hz, 1H), 3.92-3.97 (m, 2H), 4.34-4.37 (m, 1H), 4.47
(d, J ) 12.0 Hz, 1H), 4.52 (d, J ) 10.5 Hz, 1H), 4.61 (d, J ) 11.0
Hz, 1H), 4.65 (d, J ) 11.5 Hz, 1H), 4.76 (d, J ) 11.0 Hz, 1H),
4.90 (d, J ) 11.0 Hz, 1H), 5.37 (t, J ) 2.5 Hz, 1H), 5.61 (d, J )
1.5 Hz, 1H), 7.19-7.38 (m, 18H), 7.49-7.51 (m, 2H); 13C NMR
δ 27.8, 69.0, 71.9, 72.5, 73.0, 73.4, 74.7, 75.3, 78.6, 82.7, 86.1,
127.5, 127.6, 127.7, 127.8, 127.9, 128.0, 128.1, 128.3, 128.37,
128.40, 129.0, 131.9, 133.8, 137.8, 138.3, 138.4, 153.1; IR 1097,
1277, 1740 cm-1; ESI HRMS calcd for C38H42O7SNa [M + Na]+
665.2544, found 665.2548.
Cyclohexyl 3-O-tert-Butoxycarbonyl-2,4,6-tri-O-benzyl-r-D-
allopyranoside (17r) and Cyclohexyl 3-O-tert-Butoxycarbonyl-
2,4,6-tri-O-benzyl-ꢀ-D-allopyranoside (17ꢀ). These glycosides
were prepared by the general procedure with a combined yield of
61% (R:ꢀ ) 1:11.2). Chromatographic separation on silica gel
eluting with EtOAc/hexanes (1/6) enabled pure samples of the two
anomers to be obtained. 17r: colorless oil; yield 5%; [R]D ) 22.9°
(c, 0.2); 1H NMR δ 1.22-1.25 (m, 4H), 1.38-1.51 (m, 2H), 1.41
(s, 9H), 1.76-1.79 (m, 2H), 1.83-1.86 (m, 2H), 3.47-3.48 (m,
1H), 3.58-3.65 (m, 3H), 3.76-3.78 (m, 1H), 4.16 (d, J ) 10.0
Hz, 1H), 4.34 (d, J ) 12.0 Hz, 1H), 4.45 (d, J ) 12.0 Hz, 1H),
4.55-4.61 (m, 2H), 4.68-4.73 (m, 2H), 4.97 (d, J ) 4.0 Hz, 1H),
5.67 (s, 1H), 7.20-7.34 (m, 15H); 13C NMR δ 23.8, 24.1, 25.8,
27.8, 31.3, 33.3, 65.7, 68.6 (2C), 70.5, 71.4, 72.6, 72.7, 73.6, 75.6,
81.7, 94.8, 127.66, 127.73, 127.9, 128.1, 128.2, 128.3, 128.4, 137.7,
138.0, 138.1, 154.2; IR 1100, 1284, 1367, 1454, 1735 cm-1; ESI
HRMS calcd for C38H48O8Na [M + Na]+ 655.3242, found
3,4,6-Tri-O-benzyl-1,2-O-carbonyl-r-D-mannopyranose (12).
Compound 12 was formed from 11 and BSP by the general
procedure in 74% yield as a colorless oil: [R]D ) -1.5° (c, 0.7);
1H NMR δ 3.56-3.57 (m, 2H), 3.82-3.85 (m, 2H), 3.91 (t, J )
7.5 Hz, 1H), 4.50-4.53 (m, 3H), 4.73-4.79 (m, 4H), 5.79 (d, J )
5.0 Hz, 1H), 7,19-7.21 (m, 2H), 7.26-7.38 (m, 13H); 13C NMR
δ 69.4, 73.0 (2C), 73.6, 74.7, 75.3, 75.9, 76.8, 96.4, 127.8, 127.9,
128.0, 128.1, 128.2, 128.46, 128.50, 128.7, 137.2, 137.6, 137.7,
153.0; IR 1027, 1111, 1453, 1823 cm-1; ESI HRMS calcd for
C28H28O7Na [M + Na]+ 499.1728, found 499.1724.
1
655.3237. 17ꢀ: colorless oil; yield 56%; [R]D ) 5.1° (c, 0.2); H
Phenyl 2,4,6-Tri-O-benzyl-1-thio-ꢀ-D-allopyranoside (14). To
a stirred solution of 1348 (0.3 g, 0.55 mmol) in CH2Cl2 (5 mL)
was added Dess-Martin periodinane (0.28 g, 0.66 mmol) followed
by stirring at room temperature for 2 h. The reaction mixture was
then diluted with CH2Cl2 (10 mL) and washed with saturated
NaHCO3 and brine. The organic layer was separated and concen-
trated and the residue was dissolved in THF (10 mL) before
L-Selectride (1.1 mL, 1.1 mmol) was added at -78 °C. The reaction
mixture was stirred at -78 °C for 20 min and then quenched with
water, diluted with CH2Cl2 (10 mL), and washed with saturated
NaHCO3 and brine. The organic layer was dried and concentrated
and purified by column chromatography (eluent EtOAc/hexanes )
1/4) to give 14 (0.14 g, 47%) as a colorless oil: [R]D ) 5.0° (c,
NMR δ 1.21-1.33 (m, 4H), 1.44 (s, 9H), 1.48-1.55 (m, 2H),
1.74-1.76 (m, 2H), 1.92-1.94 (m, 1H), 2.00-2.02 (m, 1H), 3.31
(dd, J ) 8.0, 3.0 Hz, 1H), 3.52 (dd, J ) 10.0, 3.0 Hz, 1H),
3.61-3.64 (m, 1H), 3.67-3.77 (m, 2H), 3.91 (dd, J ) 10.0, 3.0
Hz, 1H), 4.35 (d, J ) 11.0 Hz, 1H), 4.52-4.62 (m, 2H), 4.66-4.73
(m, 2H), 4.79 (d, J ) 12.0 Hz, 1H), 4.86 (d, J ) 7.5 Hz, 1H), 5.63
(t, J ) 2.5 Hz, 1H), 7.22-7.38 (m, 15H); 13C NMR δ 24.2, 24.5,
25.6, 27.8, 31.6, 33.4, 67.7, 68.8, 71.2, 72.2, 73.3, 73.7, 75.8, 75.9,
76.4, 82.1, 95.6, 127.4, 127.5, 127.7, 127.8, 127.9, 128.1, 128.3,
128.4, 138.0, 138.5, 138.8, 153.4; IR 1097, 1280, 1741 cm-1; ESI
HRMS calcd for C38H48O8Na [M + Na]+ 655.3242, found
655.3237.
3-O-tert-Butoxycarbonyl-2,4,6-tri-O-benzyl-D-allose (18). The
donor 15 (17.8 mg, 0.028 mmol), NIS (7.5 mg, 0.033 mmol), and
activated 4 Å powdered molecular sieves (80 mg) were dissolved
in dried CH2Cl2 (0.1 M) at room temperature and then stirred at
-60 °C for 10 min. Tf2O (6.9 µL, 0.042 mmol) was then added
dropwise at -40 °C. The reaction mixture was stirred at -40 °C
for 1 h before it was quenched with Na2S2O3 (20%). The reaction
mixture was extracted with CH2Cl2 (3 × 5 mL), and the combined
organic phase was washed with brine, dried, and concentrated.
Chromatographic purification (eluent EtOAc/hexanes ) 1/4 then
1/2) then gave 18 (8.4 mg, 55%) as a colorless oil: [R]D ) 21.8°
1
0.2); H NMR δ 2.47 (s, 1H), 3.33 (dd, J ) 12.2, 3.6 Hz, 1H),
3.53 (dd, J ) 12.2, 3.4 Hz, 1H), 3.68-3.72 (m, 1H), 3.79 (dd, J )
13.5, 2.1 Hz, 1H), 3.94-3.98 (m, 1H), 4.33 (t, J ) 3.5 Hz, 1H),
4.48-4.54 (m, 2H), 4.58-4.72 (m, 4H), 5.08 (d, J ) 12.2 Hz,
1H), 7.22-7.37 (m, 18H), 7.56-7.58 (m, 2H); 13C NMR δ 66.3,
69.2, 71.4, 72.3, 73.4, 74.0, 74.5, 76.4, 83.4, 127.3, 127.5, 127.7,
128.0, 128.1, 128.2, 128.3, 128.48, 128.53, 128.8, 132.0, 133.8,
´
(47) Chiara, J. L.; Garc´ıa, A. Synlett 2005, 2607–2610.
(48) Suzuki, K.; Ohtsuka, I.; Kanemitsu, T.; Ako, T.; Kanie, O. J. Carbohydr.
Chem. 2005, 24, 219–236.
1
(c, 0.1); H NMR major isomer δ 1.45 (s, 9H), 3.10 (d, J ) 5.5
J. Org. Chem. Vol. 73, No. 22, 2008 8949

Crich et al.
Hz, 1H), 3.28 (dd, J ) 8.0, 3.5 Hz, 1H), 3.59 (dd, J ) 10.0, 3.0
Hz, 1H), 3.65 (dd, J ) 10.5, 4.5 Hz, 1H), 3.71-3.73 (m, 1H),
3.96-3.99 (m, 1H), 4.36 (d, J ) 10.5 Hz, 1H), 4.50 (d, J ) 12.0
Hz, 1H), 4.60 (d, J ) 12.0 Hz, 1H), 4.67 (d, J ) 13.5 Hz, 1H),
4.76 (d, J ) 12.0 Hz, 1H), 5.07 (dd, J ) 7.5, 5.5 Hz, 1H), 5.71 (t,
J ) 3.0 Hz, 1H), 7.20-7.24 (m, 2H), 7.25-7.38 (m, 13H); minor
isomer δ 1.43 (s, 9H), 3.53 (t, J ) 2.0 Hz, 1H), 3.55-3.56 (m,
1H), 3.68-3.70 (m, 1H), 3.75-3.76 (m, 2H), 3.78-3.80 (m, 1H),
3.81-3.85 (m, 1H), 4.44-4.48 (m, 2H), 4.85-4.87 (m, 1H), 5.23
(dd, J ) 9.5, 3.0 Hz, 1H), 5.58 (t, J ) 2.0 Hz, 1H), 7.20-7.24 (m,
2H), 7.25-7.38 (m, 13H); 13C NMR major isomer δ 27.7, 65.7,
68.9, 69.3, 71.5, 71.8, 72.8, 72.9, 73.6, 82.2, 94.4, 127.69, 127.72,
127.80, 127.85, 127.88, 127.95, 128.02, 128.04, 128.2, 128.3,
128.40, 128.43, 128.53, 128.55, 128.6, 128.8, 137.4, 137.7, 138.0,
153.5; minor isomer δ 27.6, 67.0, 67.1, 68.2, 69.5, 70.5, 71.0, 71.6,
82.9, 92.0, 95.5, 136.2, 136.8, 137.2, 137.5, 138.1, 146.6, 152.7;
IR 1096, 1280, 1369, 1454, 1740 cm-1; ESI HRMS calcd for
C32H38O8Na [M + Na]+ 573.2459, found 573.2448.
Phenyl 3-O-tert-Butoxycarbonyl-2-O-benzyl-4,6O-benzyli-
dene-1-thio-r-D-mannopyranoside (21). This compound was
formed by the general procedure in 98% yield as a white foam:
[R]D ) 102.3° (c, 0.13); 1H NMR δ 1.48 (s, 9H), 3.88 (t, J ) 10.0
Hz, 1H), 4.23 (dd, J ) 10.0, 5.0 Hz, 1H), 4.28-4.33 (m, 2H),
4.38-4.42 (m, 1H), 4.67 (s, 2H), 5.10 (dd, J ) 10.0, 3.5 Hz, 1H),
5.52 (s, 1H), 5.59 (s, 1H), 7.28-7.37 (m, 11H), 7.41-7.43 (m,
2H), 7.50-7.51 (m, 2H); 13C NMR δ 27.8, 65.3, 68.5, 73.3, 76.3,
77.6, 82.9, 86.8, 101.8, 126.3, 127.7, 128.0, 128.2, 128.5, 129.0,
129.2, 131.7, 133.7, 137.3, 137.4, 152.7; IR 1099, 1253, 1282, 1742
cm-1; ESI HRMS calcd for C31H34O7SNa [M + Na]+ 573.1918,
found 573.1914.
Phenyl 3-O-tert-Butoxycarbonyl-2-O-benzyl-4,6-O-benzyli-
dene-1-thio-r-D-mannopyranoside S-Oxide (22). To a solution
of 21 (137.9 mg, 0.25 mmol) in CH2Cl2 (5 mL) was added m-CPBA
(77%, 56.1 mg) at -78 °C, after which the reaction mixture was
warmed with stirring to -30 °C over 40 min before it was quenched
with saturated NaHCO3, washed with brine, and dried. After
concentration, the crude reaction mixture was purified by column
chromatography (eluent EtOAc/hexanes ) 1/4) to give the sulfoxide
(22) (127.8 mg, 90%) as a white foam: [R]D ) -61.5° (c, 0.2); 1H
NMR δ 1.48 (s, 9H), 3.73 (t, J ) 9.5 Hz, 1H), 4.15-4.23 (m, 2H),
4.30 (t, J ) 9.5 Hz, 1H), 4.50 (d, J ) 10.5 Hz, 2H), 4.55 (d, J )
11.5 Hz, 1H), 4.64 (d, J ) 3.0 Hz, 1H), 5.43 (dd, J ) 10.0, 3.5
Hz, 1H), 5.57 (s, 1H), 7.24-7.31 (m, 5H), 7.35-7.49 (m, 3H),
7.47-7.49 (m, 2H), 7.55-7.56 (m, 3H), 7.63-7.64 (m, 2H); 13C
NMR δ 27.7, 68.1, 68.9, 72.7, 73.0, 73.8, 75.5, 82.9, 97.6, 101.8,
124.6, 126.2, 128.1, 128.2, 128.4, 129.1, 129.5, 131.8, 136.9, 137.0,
141.4, 152.4; IR 1115, 1280, 1743 cm-1; ESI HRMS calcd for
C31H34O8SNa [M + Na]+ 589.1867, found 589.1866.
(d, J ) 8.3 Hz, 1H), 4.79-4.84 (m, 3H), 5.43 (dd, J ) 3.1, 0.7
Hz, 1H), 7.26-7.38 (m, 15H); 13C NMR δ 15.1, 24.9, 27.7, 68.5,
69.7, 71.9, 73.9, 75.8, 75.9, 76.8, 81.2, 82.0, 85.3, 127.6, 127.7,
127.8, 127.9, 128.0, 128.2, 128.3, 128.4, 137.8, 138.0, 138.3, 153.5;
IR 1104, 1280, 1741 cm-1; ESI HRMS calcd for C34H42O7SNa
[M + Na]+ 617.2544, found 617.2532.
4-O-tert-Butoxycarbonyl-2,3,6-O-tribenzyl-r-D-galactopy-
ranosyl Acetate (25r) and 4-O-tert-Butoxycarbonyl-2,3,6-O-
benzyl-ꢀ-D-galactopyranosyl Acetate (25ꢀ). To a solution of
compound 24 (32.4 mg, 0.054 mmol), BSP (13.7 mg, 0.065 mmol),
and 4Å powdered molecular sieves (100 mg) in Et2O (1.0 mL)
was added Tf2O (11.0 µL, 0.065 mmol) at -60 °C under N2. The
reaction mixture was stirred at -60 °C for 30 min and then
quenched with saturated NaHCO3 and extracted with CH2Cl2 (3 ×
5 mL), and the combined organic phase washed with brine, dried,
and concentrated. The residue was dissolved in Ac2O (1.0 mL),
pyridine (1.0 mL) was added, and the mixture was stirred at room
temperature overnight. After removal of the solvent, the residue
was dissolved in CH2Cl2 (5 mL) and washed with saturated
NaHCO3, and the organic phase was washed with brine and dried.
After concentration the crude reaction mixture was purified by
column chromatography (eluent EtOAc/hexanes ) 1/4) to give 25
(29.7 mg, 92%, R:ꢀ ) 1:7.1) as a colorless oil. 25r: yield 10%;
[R]D ) 14.7° (c, 0.2); 1H NMR δ 1.47 (s, 9H), 2.10 (s, 3H),
3.51-3.59 (m, 2H), 3.90-3.97 (m, 2H), 4.16 (t, J ) 7.5 Hz, 1H),
4.50 (s, 2H), 4.59 (d, J ) 11.0 Hz, 1H), 4.66-4.73 (m, 2H), 4.81
(d, J ) 10.5 Hz, 1H), 5.49 (s, 1H), 6.35 (d, J ) 3.0 Hz,
1H),7.20-7.38 (m, 15H); 13C NMR δ 21.0, 27.7, 68.2, 70.2, 70.3,
72.1, 73.6, 73.9, 74.7, 76.0, 82.3, 90.6, 127.5, 127.6, 127.8, 127.9,
128.1, 128.3, 128.4, 137.7, 138.1, 138.2, 153.2, 169.3; IR 1108,
1279, 1369, 1454, 1744 cm-1; ESI HRMS calcd for C34H40O9Na
[M + Na]+ 615.2565, found 615.2559. 25ꢀ: yield 71%; [R]D
)
1
11.2° (c, 0.2); H NMR δ 1.48 (s, 9H), 2.04 (s, 3H), 3.56 (t, J )
8.5 Hz, 1H), 3.65 (t, J ) 10.0 Hz, 2H), 3.79 (t, J ) 8.5 Hz, 1H),
3.85 (t, J ) 5.0 Hz, 1H), 4.51 (s, 2H), 4.55 (d, J ) 11.5 Hz, 1H),
4.69 (d, J ) 11.0 Hz, 1H), 4.82-4.86 (m, 2H), 5.44 (s, 1H), 5.59
(d, J ) 8.0 Hz, 1H), 7.26-7.35 (m, 15H); 13C NMR δ 21.0, 27.8,
67.7, 69.1, 72.1, 72.8, 73.9, 75.5, 77.6, 79.8, 82.3, 94.0, 127.69,
127.72, 127.8, 127.9, 128.0, 128.1, 128.3, 128.4, 128.5, 137.6,
137.8, 138.4, 153.3, 169.3; IR 1105, 1280, 1368, 1454, 1743 cm-1
;
ESI HRMS calcd for C34H40O9Na [M + Na]+ 615.2565, found
615.2560.
Cyclohexyl 4-O-tert-Butoxycarbonyl-2,3,6-tri-O-benzyl-r-D-
galactopyranoside (26r) and Cyclohexyl 4-O-tert-Butoxycarbo-
nyl-2,3,6-tri-O-benzyl-ꢀ-D-galactopyranoside (26ꢀ). These gly-
cosides were obtained by the general procedure with a combined
yield of 88% (R:ꢀ ) 1:3.9). When the reaction was conducted in
diethyl ether as solvent, the yield was 62% and the R:ꢀ ratio 1:1.3.
Cyclohexyl 3-O-tert-Butoxycarbonyl-2-O-benzyl-4,6-O-benzyli-
dene-r-D-mannopyranoside (23). Compound 23 was formed from
21 and BSP or from sulfoxide 22 and Tf2O in 69% (from 21) or
1
26r: colorless oil; yield 18%; [R]D ) 88.6° (c, 0.2); H NMR δ
1.15-1.26 (m, 3H), 1.31-1.38 (m, 1H), 1.44-1.53 (m, 11H),
1.71-1.78 (m, 2H), 1.86-1.91 (m, 2H), 3.54-3.59 (m, 3H), 3.82
(dd, J ) 10.0, 3.5 Hz, 1H), 3.98 (dd, J ) 9.5, 3.0 Hz, 1H), 4.21 (t,
J ) 6.0 Hz, 1H), 4.49-4.54 (m, 2H), 4.59-4.65 (m, 2H),
4.78-4.82 (m, 2H), 4.99 (d, J ) 3.5 Hz, 1H), 5.42 (s, 1H),
7.20-7.38 (m, 15H); 13C NMR δ 24.2, 24.5, 25.6, 27.8, 31.6, 33.4,
67.7, 68.8, 71.2, 72.2, 73.3, 73.7, 75.8, 75.9, 76.4, 82.1, 95.7, 127.4,
127.5, 127.7, 127.8, 127.9, 128.1, 128.3, 128.4, 128.0, 138.6, 138.8,
153.4; IR 1102, 1279, 1453, 1741 cm-1; ESI HRMS calcd for
C38H48O8Na [M + Na]+ 655.3242, found 655.3245. 26ꢀ: colorless
1
75% (from 22) yield as a colorless oil: [R]D ) 35.3° (c, 1.0); H
NMR δ 1.20-1.27 (m, 5H), 1.36-1.41 (m, 1H), 1.48 (s, 9H),
1.66-1.72 (m, 3H), 1.81-1.83 (m, 1H), 3.52-3.53 (m, 1H), 3.84
(t, J ) 10.0 Hz, 1H), 3.94-3.98 (m, 2H), 4.19 (t, J ) 10.0 Hz,
1H), 4.23-4.25 (m, 1H), 4.60 (d, J ) 12.0 Hz, 1H), 4.76 (d, J )
12.0 Hz, 1H), 4.89 (s, 1H), 5.14 (dd, J ) 10.5, 3.5 Hz, 1H), 5.57
(s, 1H), 7.28-7.42 (m, 7H), 7.46-7.50 (m, 2H), 7.56-7.59 (m,
1H); 13C NMR δ 23.8, 24.0, 25.6, 27.8, 31.1, 33.2, 64.0, 68.8, 73.5,
73.9, 75.3, 82.5, 97.1, 101.6, 126.2, 127.6, 127.9, 128.1, 128.5,
128.8, 128.9, 129.4, 131.4, 133.6, 136.6, 137.4, 137.8, 152.9; IR υ
1070, 1274, 1451, 1720 cm-1; ESI HRMS calcd for C31H40O8Na
[M + Na]+ 563.2616, found 563.2611.
1
oil; yield 70%; [R]D ) 17.4° (c, 0.4); H NMR δ 1.22-1.30 (m,
4H), 1.40-1.53 (m, 11H), 1.74-1.76 (m, 2H), 1.90-1.97 (m, 2H),
3.55 (dd, J ) 9.5, 3.5 Hz, 1H), 3.60-3.69 (m, 5H), 4.48 (d, J )
8.0 Hz, 1H), 4.54 (d, J ) 2.5 Hz, 2H), 4.57 (d, J ) 11.0 Hz, 1H),
4.72 (d, J ) 11.0 Hz, 1H), 4.79 (d, J ) 11.5 Hz, 1H), 4.92 (d, J )
Ethyl 4-O-tert-Butoxycarbonyl-2,3,6-tri-O-benzyl-1-thio-ꢀ-
D-galactopyranoside (24). Compound 24 was formed from 2,3,6-
tri-O-benzyl-ꢀ-D-thiogalactopyranoside and Boc2O by the general
procedure in 90% yield as a colorless oil: [R]D ) 16.8° (c, 1.7); 1H
NMR δ 1.31 (t, J ) 7.4 Hz, 3H), 1.49 (s, 9H), 2.70-2.80 (m, 2H),
5.57-3.72 (m, 5H), 4.46 (d, J ) 9.3 Hz, 1H), 4.53 (s, 2H), 4.55
10.5 Hz, 1H), 5.34 (d, J ) 3.5 Hz, 1H), 7.26-7.39 (m, 15H); 13
C
NMR δ 24.0, 24.1, 25.7, 27.8, 31.9, 33.7, 68.7, 69.8, 72.2, 73.9,
75.3, 76.8, 77.7, 79.0, 79.6, 81.9, 102.0, 127.5, 127.8, 127.9, 128.0,
128.1, 128.2, 128.3, 128.5, 138.0, 138.2, 138.9, 153.6; IR 1080,
8950 J. Org. Chem. Vol. 73, No. 22, 2008

Group Participation in Glycosylation Reactions?
1280, 1454, 1741 cm-1; ESI HRMS calcd for C38H48O8Na [M +
Na]+ 655.3242, found 655.3231.
1132, 1255, 1749, 2103 cm-1. Acetylation of this pyranose
according to the procedure used for 25 gave the title compound 31
in 73% combined yield (R:ꢀ ) 1:1.7) as a colorless oil: [R]D
)
Phenyl 2,3,6-Tri-O-benzyl-4-O-tert-butyloxycarbonyl-1-thio-
r-D-mannopyranoside (27). Compound 27 was formed from 2,3,6-
tri-O-benzyl-R-D-thiomannopyranoside and Boc2O by the general
procedure in 76% yield as a colorless oil: [R]D +49.0° (c, 1.45);
1H NMR δ 1.47 (s, 9H), 3.68 (dd, J ) 3.0, 11.0 Hz, 1H), 3.73 (dd,
J ) 6.0, 11.0 Hz, 1H), 3.85 (dd, J ) 3.0, 9.5 Hz, 1H), 4.00 (d, J
) 2.0, 2.5 Hz, 1H), 4.43-4.47 (m, 1H), 4.53 (d, J ) 10.0 Hz,
1H), 4.54 (s, 2H), 4.57 (d, J ) 10.0 Hz, 1H), 4.64 (d, J ) 12.0 Hz,
1H), 4.70 (d, J ) 12.0 Hz, 1H), 5.24 (t, J ) 10.0 Hz, 1H), 5.57 (d,
J ) 1.5 Hz, 1H), 7.19-7.39 (m, 13H), 7.49 (d, J ) 7.5 Hz, 2H);
13C NMR δ 27.8 (3C), 69.6, 71.2, 71.8, 71.9, 72.1, 73.4, 75.8, 77.5,
82.5, 85.8, 127.4-128.5 (18C), 129.0, 131.9, 134.0, 137.8, 138.0,
138.3, 152.7; ESI HRMS calcd for C38H42O7 SNa [M + Na]+
665.2544, found 665.2540.
Isopropyl 2,3,6-Tri-O-benzyl-4-O-tert-butyloxycarbonyl-r-
D-mannopyranoside (28r) and Isopropyl 2,3,6-Tri-O-benzyl-4-
O-tert-butyloxycarbonyl-ꢀ-D-mannopyranoside (28ꢀ). 28r: [R]D
+21.6° (c, 0.3); 1H NMR δ 1.06 (d, J ) 6.0 Hz, 3H), 1.16 (d, J )
6.0 Hz, 3H), 1.42 (s, 9H), 3.60-3.68 (m, 2H), 3.73 (t, J ) 2.5 Hz,
1H), 3.88-3.98 (m, 3H), 4.54 (dd, J ) 4.5, 12.0 Hz, 2H), 4.60
(dd, J ) 1.5, 12.0 Hz, 2H), 4.67 (d, J ) 12.0 Hz, 1H), 4.78 (d, J
) 12.5 Hz, 1H), 4.93 (d, J ) 1.5 Hz, 1H), 5.16 (t, J ) 10.0 Hz,
1H), 7.20-7.40 (m, 15H); 13C NMR δ 21.2, 23.2, 27.7, 69.0, 69.8,
70.2, 72.0, 72.2, 72.8, 73.4, 74.6, 77.7, 82.2, 95.9, 127.3-128.3
(15C), 138.4 (3C), 152.7; IR 1746 cm-1; ESI HRMS calcd for
C35H44O8Na [M + Na]+ 615.2929, found 615.2930. 28ꢀ: [R]D
-54.3° (c, 0.3); 1H NMR δ 1.16 (d, J ) 6.0 Hz, 3H), 1.30 (d, J )
6.0 Hz, 3H), 1.46 (s, 9H), 3.46 (dd, J ) 3.0, 9.5 Hz, 1H), 3.56-3.59
(m, 1H), 3.67-3.74 (m, 2H), 3.84 (d, J ) 3.0 Hz, 1H), 4.01 (m,
1H), 4.35 (d, J ) 12.0 Hz, 1H), 4.44 (d, J ) 12.0 Hz, 1H), 4.47
(br. s, 1H), 4.54 (d, J ) 12.0, 1H), 4.61 (d, J ) 12.0 Hz, 1H), 4.88
(d, J ) 12.5 Hz, 1H), 4.96 (d, J ) 12.5 Hz, 1H), 5.04 (t, J ) 10.0
Hz, 1H), 7.20-7.49 (m, 15H); 13C NMR δ 21.8, 23.6, 27.7 (3C),
70.4, 71.3, 71.5, 72.2, 73.6, 73.7, 74.3, 76.4, 78.1, 79.8, 82.4, 99.4,
126.7-128.9 (15C), 138.1, 138.3, 138.6, 152.7; ESI HRMS calcd
for C35H44O8Na [M + Na]+ 615.2929, found 615.2925.
1
-21.9° (c, 0.2); H NMR (400 MHz) major isomer (ꢀ) δ 1.27 (d,
J ) 6.0 Hz, 3H), 1.51 (s, 9H), 1.73-1.82 (m, 1H), 2.12 (s, 3H),
2.23-2.28 (m, 1H), 3.57-3.67 (m, 2H), 4.43 (t, J ) 9.6 Hz, 1H),
5.72 (dd, J ) 9.6, 1.6 Hz, 1H); minor isomer (R) δ 1.22 (d, J )
6.0 Hz, 3H), 1.57 (s, 9H), 1.85-1.89 (m, 1H), 2.09 (s, 3H),
2.15-2.20 (m, 1H), 3.86-3.93 (m, 2H), 4.46 (t, J ) 10.0 Hz, 1H),
6.15 (d, J ) 2.4 Hz, 1H); 13C NMR (100 MHz) δ major isomer
(ꢀ) 17.5, 21.2, 27.9, 35.2, 59.6, 71.9, 77.4, 83.5, 91.5, 152.8, 169.2;
minor isomer (R) δ 17.6, 31.1, 34.3, 57.4, 68.5, 78.1, 83.7, 90.6,
152.1, 169.1; IR 1259, 1752, 2101 cm-1; ESI HRMS calcd for
C13H21N3O6Na [M + Na]+ 338.1328, found 338.1322.
Cyclohexyl 4-O-tert-Butoxycarbonyl-3-azido-2,3,6-trideoxy-L-
lyxopyranoside (32). Compound 32 was formed from 30 by the
general procedure in 46% yield (R:ꢀ ) 1:3.7) as a colorless oil:
[R]D ) -3.3° (c, 0.15); 1H NMR major isomer δ 1.26 (d, J ) 6.5
Hz, 3H), 1.22-1.32 (m, 4H), 1.34-1.41 (m, 2H), 1.51 (s, 9H),
1.69-1.77 (m, 3H), 1.85-1.94 (m, 2H), 2.17-2.21 (m, 1H),
3.41-3.46 (m, 1H), 3.52-3.57 (m, 1H), 3.61-3.66 (m, 1H),
4.36-4.42 (m, 1H), 4.62 (dd, J ) 9.5, 2.0 Hz, 1H); minor isomer
δ 1.19 (d, J ) 6.5 Hz, 3H), 1.55 (s, 9H), 2.09-2.13 (m, 1H),
3.88-3.97 (m, 2H), 3.52-3.57 (m, 1H), 5.00 (d, J ) 3.0 Hz, 1H);
13C NMR δ 17.5, 24.0, 24.2, 25.6, 27.7, 31.8, 33.5, 36.8, 59.9,
70.6, 76.4, 77.3, 78.0, 78.1, 83.2, 96.1, 97.2, 152.6; IR 1130, 1749,
2103 cm-1; ESI HRMS calcd for C17H29N3O5Na [M + Na]+
378.2000, found 378.2005.
Phenyl 2,3,4-Tri-O-benzyl-6-O-tert-butyloxycarbonyl-1-thio-
ꢀ-D-glucopyranoside (33). Compound 33 was formed from 2,3,4-
tri-O-benzyl-ꢀ-D-thioglucopyranoside and Boc2O by the general
1
procedure in 80% yield as a colorless oil: [R]D +2.7° (c, 0.8); H
NMR δ 1.53 (s, 9H), 3.55 (t, J ) 9.0 Hz, 1H), 3.60-3.64 (m, 2H),
3.74-3.79 (m, 1H), 4.33 (dd, J ) 5.0 Hz, 1H), 4.39 (dd, J ) 1.5,
10.0 Hz, 1H), 4.63 (d, J ) 10.5 Hz, 1H), 4.70 (d, J ) 10.0 Hz,
1H), 4.77 (d, J ) 10.0 Hz, 1H), 4.89 (d, J ) 10.0 Hz, 1H), 4.90
(d, J ) 10.0 Hz, 1H), 4.94-4.99 (m, 2H), 7.26-7.50 (m, 18H),
7.61 (d, J ) 7.5, 1H); 13C NMR δ 27.9, 65.7, 75.3, 75.6, 75.9,
77.0, 77.7, 80.9, 82.3, 86.7, 87.7, 127.6-129.0 (18C), 132.0 (2C),
133.8, 137.7, 138.0, 138.3, 153.5; ESI HRMS calcd for
C38H42O7SNa [M + Na]+ 665.2544, found 665.2539.
N-(2′,3′,6′-Tri-O-benzyl-4′-O-tert-butyloxycarbonyl-r-D-
mannopyranosyl)succinimide (29). [R]2D3 +62.0° (c, 0.5); 1H NMR
δ 1.49 (s, 9H), 2.48-2.56 (m, 2H), 3.67 (dd, J ) 5.0, 11.0 Hz,
1H), 3.78 (dd, J ) 6.5, 11.0 Hz, 1H), 3.96 (t, J ) 2.5 Hz, 1H),
4.36 (d, J ) 12.0 Hz, 1H), 4.43 (t, J ) 5.0 Hz, 1H), 4.48 (d, J )
12.0 Hz, 1H), 4.54 (s, 2H), 4.71 (d, J ) 12.0 Hz, 1H), 4.75 (d, J
) 12.0 Hz, 1H), 4.78 (dd, J ) 3.0, 8.0 Hz, 1H), 4.94 (dd, J ) 3.0,
5.0 Hz, 1H), 5.77 (d, J ) 9.0 Hz, 1H), 7.18-7.40 (m, 17H); 13C
NMR δ 27.8, 28.0, 68.2, 71.6, 71.8, 72.1, 72.3, 73.4, 74.4, 75.3,
83.0, 127.6-128.4 (15C), 137.8, 138.1 (2C), 152.6, 176.7 (2C);
IR 1711, 1720, 1739 cm-1; ESI HRMS calcd for C36H41O9NNa
[M + Na]+ 654.2674, found 654.2669.
Isopropyl 2,3,4-Tri-O-benzyl-6-O-tert-butyloxycarbonyl-r-D-
glucopyranoside (34r) and Isopropyl 2,3,4-Tri-O-benzyl-6-O-
tert-butyloxycarbonyl-ꢀ-D-glucopyranoside (34ꢀ). Compounds
34r and 34ꢀ were formed from 33 by the general NIS procedure
in 80% yield (R:ꢀ ) 1:1, dichloromethane) or 74% yield (R:ꢀ )
1.5:1, diethyl ether) as a colorless oily mixture: ESI HRMS calcd
1
for C35H44O8Na [M + Na]+ 615.2929, found 615.2922. 34r: H
NMR δ 1.18 (d, J ) 6.0 Hz, 3H), 1.22 (d, J ) 6.0 Hz, 3H), 1.46
(s, 9H), 3.54-3.57 (m, 1H), 3.87 (m, J ) 6.0 Hz, 1H), 3.91 (m,
1H), 4.01 (t, J ) 9.0 Hz, 1H), 4.19 (dd, J ) 2.0, 12.0 Hz, 1H),
4.28 (m, 1H), 4.33 (dd, J ) 4.5, 11.5 Hz, 1H), 4.55 (d, J ) 12.0
Hz, 1H), 4.69 (d, J ) 10.5 Hz, 1H), 4.76 (d, J ) 12.0 Hz, 1H),
4.82 (d, J ) 10.5 Hz, 1H), 4.84 (d, J ) 3.0 Hz, 1H), 4.88 (d, J )
p-Tolyl 4-O-tert-Butoxycarbonyl-3-azido-2,3,6-trideoxy-1-
thio-r-L-lyxopyranoside (30). Compound 30 was formed by the
general procedure in 98% yield as a colorless oil: [R]D ) -287.1°
1
(c, 0.24); H NMR δ 1.21 (d, J ) 6.0 Hz, 3H), 1.53 (s, 9H), 2.12
(td, J ) 13.5, 5.5 Hz, 1H), 2.33 (s, 3H), 2.36 (dd, J ) 13.5, 5.5
Hz, 1H), 3.89-3.95 (m, 1H), 4.34-4.37 (m, 1H), 4.43 (t, J ) 9.5
Hz, 1H), 5.49 (d, J ) 5.5 Hz, 1H), 7.11 (d, J ) 8.0 Hz, 2H), 7.32
(d, J ) 8.0 Hz, 2H); 13C NMR δ 17.2, 21.1, 27.7, 36.0, 58.3, 66.7,
78.7, 83.2, 83.4, 129.9, 130.3, 132.1, 137.8, 152.7; IR 1097, 1274,
1750, 2104 cm-1; ESI HRMS calcd for C18H25N3O4SNa [M + Na]+
402.1458, found 402.1456.
11.0 Hz, 1H), 5.02 (d, J ) 11.0 Hz, 1H), 7.21-7.29 (m, 15H); 13
C
NMR δ 21.4, 23.4, 28.0 (3 C), 65.7, 68.9, 69.5, 73.4, 75.5, 78.0,
80.1, 82.2, 82.3, 95.0, 127.8-128.7 (15 C), 138.2, 138.4, 139.1,
153.7. 34ꢀ:1H NMR δ 1.23 (d, J ) 6.0 Hz, 3H), 1.28 (d, J ) 6.0
Hz, 3H), 1.47 (s, 9H), 3.42 (t, J ) 8.0 Hz, 1H), 3.46-3.54 (m,
3H), 3.64 (t, J ) 9.0 Hz, 1H), 4.00 (m, 1H), 4.27 (m, 1H), 4.46 (d,
J ) 8.0 Hz), 4.56 (d, J ) 10.5 Hz, 1H), 4.64 (d, J ) 12.0 Hz, 1H),
4.78 (d, J ) 10.5 Hz, 1H), 4.85 (d, J ) 10.5 Hz, 1H), 4.93 (d, J )
4-O-tert-Butoxycarbonyl-3-azido-2,3,6-trideoxy-1-L-lyxopy-
ranosyl Acetate (31). Application of the BSP protocol to compound
30 gave 4-O-tert-butoxycarbonyl-3-azido-2,3,6-trideoxy-1-R-L-lyx-
opyranose in 30% yield as a colorless oil with 1H NMR δ 1.21 (d,
J ) 6.0 Hz, 3H), 1.52 (s, 9H), 1.79 (td, J ) 13.0, 3.5 Hz, 1H),
2.05 (dd, J ) 13.0, 5.0 Hz, 1H), 3.75-3.78 (m, 1H), 3.86-3.91
(m, 1H), 4.42 (t, J ) 10.0 Hz, 1H), 5.12 (d, J ) 3.0 Hz, 1H); 13C
NMR δ 17.4, 27.7, 34.8, 57.2, 66.5, 76.4, 91.4, 96.1, 152.6; IR
12.5 Hz, 1H), 4.96 (d, J ) 12.0 Hz, 1H), 7.21-7.29 (m, 15H); 13
C
NMR δ 22.4, 23.9, 28.0 (3 C), 66.0, 72.6, 73.1, 75.1, 75.3, 75.9,
78.1, 82.4, 85.0, 102.3, 127.8-128.7 (15 C), 138.0, 138.7, 138.8,
153.6.
Di-(2,3,4-tri-O-benzyl-D-glucopyranoside)-(1,6),(6,1)-dicar-
bonate (35). [R]D +88.7° (c, 0.3); 1H NMR (C6D6) δ 3.12 (t, J )
9.0 Hz, 2H), 3.53 (ddd, J ) 1.2, 4.0, 9.0 Hz, 2H), 4.14 (t, J ) 9.0
J. Org. Chem. Vol. 73, No. 22, 2008 8951

Crich et al.
Hz, 2H), 4.22 (t, J ) 9.0 Hz, 2H), 4.33 (t, J ) 9.0 Hz, 2H), 4.48
(dd, J ) 12.0, 20.0 Hz, 4H), 4.61 (d, J ) 11.5 Hz, 2H), 4.68 (d, J
) 11.0 Hz, 2H), 4.81 (d, J ) 11.5 Hz, 2H), 4.93 (d, J ) 11.5 Hz,
2H), 6.21 (d, J ) 3.0 Hz, 2H), 7.14-7.37 (m, 30H); 13C NMR δ
67.0, 72.5, 72.6, 75.4, 77.3, 78.7, 81.7, 93.6, 127.6-128.4 (30C),
138.0, 138.1, 139.1, 153.0; IR 1768 cm-1; ESI HRMS calcd for
C56H56O14Na [M + Na]+ 975.3568, found 975.3582.
4.93 (d, J ) 13.2 Hz, 1H), 5.85 (d, J ) 2.4 Hz, 1H), 6.58 (d, J )
4.0 Hz, 1H), 6.97-6.99 (m, 3H), 7.03-7.04 (m, 2H), 7.09 (d, J )
8.0 Hz, 1H), 7.20-7.31 (m, 6H), 7.39-7.43 (m, 5H), 7.51-7.54
(m, 1H), 8.30 (d, J ) 8.0 Hz, 1H); 13C NMR (100 Hz) δ 67.0,
68.6, 69.9, 70.9, 73.8, 74.9, 75.2, 75.7, 77.4, 93.1, 125.7, 127.6,
127.7, 127.8, 127.9, 128.1, 128.3, 128.47, 128.51, 128.8, 129.6,
132.0, 133.0, 135.9, 137.4, 138.3, 138.6, 164.0, 167.1; IR 1067,
1105, 1261, 1724 cm-1; ESI HRMS calcd for C27H28O5SNa [M -
C8H4O3 (phthalic anhydride) + Na]+ 455.1834, found 455.1855.
Phenyl 2,3,6-Tri-O-benzyl-4-O-(4-methoxybenzoyl)-1-thio-ꢀ-
D-galactopyranoside (41). To a solution of 4-methoxybenzoic acid
(102.1 mg, 0.76 mmol) in dry CH3CN (5 mL) was added 1,1′-
carbonyldiimidazole (129.2 mg, 0.80 mmol) under N2. The reaction
mixture was stirred at 60-70 °C for 2 h and then cooled to room
temperature before phenyl 2,3,6-tri-O-benzyl-ꢀ-D-thiogalactopyra-
noside (196.6 mg, 0.36 mmol) in CH3CN (4 mL) was added
dropwise followed by DBU (121.0 µL, 0.76 mmol). The reaction
mixture was stirred at 60 °C overnight, cooled, poured into saturated
aqueous NaHCO3, and extracted with CH2Cl2 (3 × 20 mL). The
combined organic phase was washed with brine, dried, and
concentrated. The residue was purified by column chromatography
(eluent EtOAc/hexanes ) 1/4) to give the 41 in 93% yield as a
colorless oil: [R]D ) 22.5° (c, 2.2); 1H NMR δ 3.60 (dd, J ) 10.0,
6.5 Hz, 1H), 3.69-3.78 (m, 3H), 3.89 (d, J ) 7.5 Hz, 1H), 3.91 (s,
3H), 4.46-4.55 (m, 3H), 4.72 (d, J ) 9.5 Hz, 1H), 4.76 (s, 2H),
4.87 (d, J ) 11.5 Hz, 1H), 5.88 (d, J ) 3.0 Hz, 1H), 6.93-6.96
(m, 2H), 7.24-7.41 (m, 18H), 7.65-7.67 (m, 2H), 7.96-7.99 (m,
2H); 13C NMR δ 55.7, 67.3, 68.8, 72.0, 74.0, 75.9, 76.6, 76.9, 81.7,
87.4, 113.9, 122.4, 127.8, 127.9, 128.0, 128.1, 128.4, 128.5, 128.56,
128.58, 128.6, 129.1, 132.3, 133.1, 133.3, 137.90, 137.92, 138.5,
163.8, 165.6; IR 1102, 1257, 1454, 1605, 1716 cm-1; ESI HRMS
calcd for C41H40O7SNa [M + Na]+ 699.2392, found 699.2397.
2,3,6-Tri-O-benzyl-4-O-(4-methoxybenzoyl)-D-[1-16/18O]-galac-
topyranosyl Acetate (47). To a solution of donor 41 (35.7 mg,
0.053 mmol), BSP (13.2 mg, 0.063 mmol), and activated 4 Å
molecular sieves (100 mg) in dichloromethane (1 mL) was added
Tf2O (13.3 µL, 0.079 mmol) at -60 °C. The mixture was stirred
at -60 °C for 2 h before H218O (95% 18O, 50 µL) was added. The
reaction mixture was filtered, dried, and concentrated. The residue
was purified by column chromatography (eluent EtOAc/hexanes
) 1/2) to give 2,3,6-tri-O-benzyl-4-O-(4-methoxybenzoyl)-R-D-[1-
16/18O]-galactopyranose (43) (38.1 mg, 82%) as a colorless oil: from
Ethyl 3,4,6-Tri-O-benzyl-2-O-(2-carboxybenzoyl)-1-thio-ꢀ-
D-glucopyranoside (36). To a solution of ethyl 3,4,6-tri-O-benzyl-
ꢀ-D-thioglucopyranoside (460 mg, 0.92 mmol) in dry DMF (10.0
mL) was added NaH (60%, 73.6 mg, 1.84 mmol) at room
temperature. The reaction mixture was stirred for 10 min, and then
phthalic anhydride (272.5 mg, 1.84 mmol) was added and the
mixture was stirred at room temperature overnight. After removal
of the solvent, the residue was taken up in 5% HCl (20 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic phase
was washed with brine and dried. After concentration, the residue
was purified by column chromatography (eluent EtOAc/hexanes
) 1/1) to give the compound 36 in 37% yield as a colorless oil:
[R]D ) 15.9° (c, 4.3); 1H NMR (400 MHz) δ 1.27 (t, J ) 7.6 Hz,
3H), 2.70-2.80 (m, 2H), 3.59 (dd, J ) 9.6, 2.4 Hz, 1H), 3.70-3.80
(m, 3H), 3.88 (t, J ) 8.8 Hz, 1H), 4.55-4.64 (m, 4H), 4.76-4.82
(m, 3H), 5.29-5.36 (m, 1H), 7.15-7.35 (m, 15H), 7.51-7.57 (m,
2H), 7.76-7.84 (m, 2H), 9.22 (br. s, 1H); 13C NMR (100 MHz) δ
15.1, 24.0, 69.1, 73.5, 73.7, 75.3, 75.3, 78.1, 79.7, 83.4, 84.2,
127.82, 127.84, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 128.61,
128.64, 129.5, 130.2, 130.7, 131.4, 132.0, 132.7, 138.2, 138.3,
138.4, 165.7, 172.6; IR 1070, 1266, 1454, 1704, 1729 cm-1; ESI
HRMS calcd for C37H38O8SNa [M + Na]+ 665.2185, found
665.2186.
3,4,6-Tri-O-benzyl-1,2-O-phthalidylidene-r-D-glucopyra-
nose (37) (endo and exo mixture). Compound 37 was formed from
36 and NIS by the general procedure in 79% yield as a colorless
1
oil: [R]D ) 48.2° (c, 0.6); H NMR (400 MHz) major isomer δ
3.70-3.81 (m, 3H), 4.02 (t, J ) 3.6 Hz, 1H), 4.10-4.14 (m, 1H),
4.40 (d, J ) 11.6 Hz, 1H), 4.51-4.63 (m, 4H), 4.71-4.76 (m,
2H), 6.09-6.11 (m, 1H), 7.18-7.20 (m, 2H), 7.26-7.34 (m, 13H),
7.61-7.67 (m, 3H), 7.86-7.88 (m, 1H); minor isomer δ 3.85 (dd,
J ) 10.8, 3.2 Hz, 1H), 4.19-4.23 (m, 1H), 4.43-4.46 (m, 1H),
4.81-4.87 (m, 2H), 7.21-7.23 (m, 2H), 7.57 (d, J ) 7.2 Hz, 1H),
7.75 (t, J ) 7.2 Hz, 1H); 13C NMR (100 MHz) major isomer δ
69.4, 71.4, 72.2, 73.2, 73.8, 74.8, 75.8, 80.4, 82.8, 98.9, 123.6,
125.5, 127.94, 127.99, 128.03, 128.1, 128.2, 128.3, 128.4, 128.5,
128.6, 128.8, 132.4, 135.0, 137.3, 137.8, 138.2, 140.9, 165.7; minor
isomer δ 68.4, 72.1, 73.5, 74.9, 75.0, 101.7, 123.1, 125.4, 127.89,
132.2, 135.1, 138.0, 138.4, 142.6; IR 891, 1061, 1108, 1283, 1453,
1783 cm-1; ESI HRMS calcd for C35H32O8Na [M + Na]+ 603.1995,
found 603.1994.
1
the 13C NMR, 16O/18O is around 4:1; [R]D ) 98.3° (c, 1.0); H
NMR δ 3.49 (d, J ) 6.5 Hz, 2H), 3.89 (s, 3H), 3.95 (dd, J ) 10.0,
3.5 Hz, 1H), 4.13 (dd, J ) 10.0, 3.5 Hz, 1H), 4.36 (d, J ) 12.5
Hz, 1H), 4.44 (d, J ) 11.5 Hz, 1H), 4.56 (d, J ) 11.5 Hz, 1H),
4.60 (t, J ) 6.0 Hz, 1H), 4.68-4.71 (m, 2H), 4.86 (d, J ) 11.5
Hz, 1H), 5.35 (d, J ) 3.5 Hz, 1H), 5.83 (d, J ) 2.5 Hz, 1H), 6.90
(d, J ) 8.5 Hz, 2H), 7.19-7.27 (m, 13H), 7.32 (d, J ) 6.5 Hz,
2H), 7.96 (d, J ) 9.0 Hz, 2H); 13C NMR δ 55.7, 68.7, 68.9, 69.2,
71.8, 73.5, 73.8, 75.0, 76.6, 94.1(94.050, 94.072), 113.8, 122.7,
127.6, 127.69, 127.73, 127.9, 128.06, 128.08, 128.4, 128.45, 128.50,
132.2, 138.1, 138.5, 138.7, 163.7, 165.7; IR 1100, 1257, 1454, 1605,
1717 cm-1. This pyranose was dissolved in Ac2O, pyridine was
added, and the mixture was stirred at 80 °C overnight. After removal
of the solvents, the residue was dissolved in CH2Cl2, washed with
saturated NaHCO3 and brine, and dried. After concentration, the
crude reaction mixture was purified by column chromatography
(eluent EtOAc/hexanes ) 1/4) to give compound 47 (90%, R:ꢀ )
4.1:1) as a colorless oil: from the 13C NMR, the 16O/18O ratio is
∼1:1; mass spectrometry also displayed a 1:1 16O/18O ratio for the
Phenyl 2,3,6-Tri-O-benzyl-4-O-(2-carboxybenzoyl)-1-thio-ꢀ-
D-galactopyranoside (38). Compound 38 was formed from phenyl
2,3,6-tri-O-benzyl-ꢀ-D-thiogalactopyranoside and phthalic anhydride
by the same procedure as compound 36 in 48% yield as a colorless
1
oil: [R]D ) 16.2° (c, 1.1); H NMR (400 MHz) δ 3.67-3.77 (m,
4H), 3.84 (t, J ) 6.0 Hz, 1H), 4.49-4.56 (m, 3H), 4.71-4.79 (m,
3H), 4.82 (d, J ) 11.2 Hz, 1H), 5.85 (d, J ) 1.6 Hz, 1H), 7.15-7.38
(m, 18H), 7.49-7.58 (m, 4H), 7.68 (d, J ) 8.0 Hz, 1H), 7.77 (d,
J ) 8.0 Hz, 1H); 13C NMR (100 MHz) δ 68.7, 69.0, 72.3, 73.9,
76.0, 76.6, 77.0, 81.5, 88.0, 127.6, 127.98, 128.02, 128.1, 128.3,
128.5, 128.61, 128.63, 128.7, 129.1, 129.67, 129.74, 130.4, 131.3,
131.5, 131.8, 132.0, 132.1, 133.9, 137.8, 138.1, 138.4, 166.9, 171.1;
IR 1067, 1102, 1280, 1728 cm-1; ESI HRMS calcd for
C41H38O8SNa [M + Na]+ 713.2185, found 713.2191.
1
sodiated molecular ion; [R]D ) 40.9° (c, 0.5); H NMR major
3,4,6-Tri-O-benzyl-1,4-O-phthaloyl-r-D-galactopyranose
(40). Compound 40 was formed from 38 and NIS by the general
procedure in 41% yield as a colorless oil: [R]D ) 80.0° (c, 0.3);1H
NMR (400 MHz) δ 3.19-3.27 (m, 2H), 3.71 (dd, J ) 10.0, 2.4
Hz, 1H), 3.79-3.81 (m, 1H), 4.13 (d, J ) 12.0 Hz, 1H), 4.32 (dd,
J ) 10.0 4.4 Hz, 1H), 4.35 (d, J ) 12.0 Hz, 1H), 4.68 (d, J ) 12.4
Hz, 1H), 4.81 (d, J ) 10.4 Hz, 1H), 4.87 (d, J ) 10.4 Hz, 1H),
isomer δ 3.48-3.56 (m, 3H), 3.88 (s, 3H), 3.98-4.03 (m, 2H),
4.25 (t, J ) 6.5 Hz, 1H), 4.39-4.41 (m, 1H), 4.46-4.50 (m, 1H),
4.54-4.59 (m, 1H), 4.66-4.70 (m, 3H), 4.87 (d, J ) 11.5 Hz,
2H), 5.91 (s, 1H), 6.41 (d, J ) 3.0 Hz, 1H), 6.92 (d, J ) 9.0 Hz,
2H), 7.21-7.33 (m, 15H), 7.97 (d, J ) 9.0 Hz, 2H); minor isomer
δ 3.60-3.62 (m, 1H), 3.89 (s, 3H), 3.95 (t, J ) 6.0 Hz, 1 Hz),
4.81 (d, J ) 12.0 Hz, 1H), 5.67 (d, J ) 7.5 Hz, 1H), 5.86 (d, J )
8952 J. Org. Chem. Vol. 73, No. 22, 2008

Group Participation in Glycosylation Reactions?
2.5 Hz, 1H), 6.94 (d, J ) 9.0 Hz, 2H), 7.21-7.36 (m, 15H), 8.05
(d, J ) 9.0 Hz, 2H); 13C NMR major isomer δ 21.4, 55.7, 67.8,
68.5, 70.8, 72.0, 74.0, 74.6, 76.4, 80.1, 91.0 (high resolution: 90.991,
91.020), 113.9, 127.9, 128.0, 128.07, 128.14, 128.18, 128.23, 128.3,
128.4, 128.52, 128.55, 128.59, 132.2, 137.8, 138.2, 138.3, 163.79,
165.6, 169.7 (169.739, 169.752); minor isomer δ 21.2, 66.8, 67.9,
72.1, 73.5, 73.86, 73.90, 75.6, 77.8, 94.3 (94.243, 94.267), 122.4,
127.7, 132.3, 137.7, 137.9, 138.5, 163.83, 156.5, 169.4; IR υ 1100,
1257, 1605, 1717, 1750 cm-1; ESI HRMS calcd for C37H38O9Na
[M + Na]+ 649.2414, found 649.2404; ESI HRMS calcd for
C37H38O818ONa [M + Na]+ 651.2456, found 651.2465.
Phenyl 2,3,6-Tri-O-benzyl-4-O-(4-methoxybenzoyl)-1-thio-
r,ꢀ-D-galactopyranoside (41r and 41ꢀ). To a solution of phenyl
2,3,6-tri-O-benzyl-4-O-(4-methoxybenzoyl)-D-[1-16/18O]-galactopy-
ranosyl acetate (47) (13.9 mg, 0.022 mmol) in CH3CN (1 mL) were
added thiophenol (34 µL, 0.033 mmol) and BF3 ·Et2O (9.3 µL, 0.07
mmol) under N2 at room temperature. The reaction mixture was
stirred at room temperature overnight then was poured into saturated
aqueous NaHCO3 and extracted with CH2Cl2 (3 × 5 mL). The
combined organic phase was washed with brine and dried.
Concentration and purification of the residue by column chroma-
tography (eluent EtOAc/hexanes ) 1/4) gave 41 (R:ꢀ ) 2.2:1) in
97% yield as a colorless oil: [R]D ) 58.4° (c, 0.5); 1H NMR major
isomer δ 3.48-3.53 (m, 2H), 3.67-3.76 (m, 1H), 3.80 (s, 3H),
3.87 (dd, J ) 10.0, 3.0 Hz, 1H), 4.15 (dd, J ) 10.0, 5.05 Hz, 1H),
4.38-4.43 (m, 1H), 4.56 (d, J ) 11.5 Hz, 1H), 4.66-4.80 (m,
3H), 4.78 (d, J ) 12.0 Hz, 1H), 5.65 (d, J ) 5.5 Hz, 1H), 5.79 (d,
J ) 3.0 Hz, 1H), 6.83-6.86 (m, 2H), 7.13-7.27 (m, 16H),
7.29-7.31 (m, 2H), 7.46-7.48 (m, 2H), 7.90-7.91 (m, 2H); minor
isomer δ 3.67-3.76 (m, 1H), 3.83 (s, 3H), 4.38-4.43 (m, 2H),
4.44- 4.46 (m, 1H), 4.62 (d, J ) 9.0 Hz, 1H), 4.77 (d, J ) 11.0
Hz, 1H), 5.79 (d, J ) 3.0 Hz, 1H), 6.83-6.86 (m, 2H), 7.13-7.27
(m, 16H), 7.29-7.31 (m, 2H), 7.56-7.58 (m, 2H), 7.87-7.89 (m,
2H); 13C NMR major isomer δ 55.70, 68.5, 69.0, 69.3, 72.2, 73.1,
73.7, 75.5, 76.8, 88.1, 113.9, 122.5, 127.5, 127.7, 127.8, 127.9,
127.95, 127.97, 128.06, 128.12, 128.2, 128.3, 128.4, 128.46, 128.52,
128.56, 128.61, 129.10, 132.2, 132.5, 133.0, 138.2, 138.3, 163.7,
165.6; minor isomer δ 55.73, 67.2, 68.8, 71.9, 73.9, 75.9, 76.6,
77.0, 81.7, 87.4, 122.4, 129.1, 132.3, 133.2, 134.2, 137.8, 138.0,
138.5, 163.7, 165.6; IR 1101, 1256, 1605, 1716 cm-1; ESI HRMS
calcd for C41H40O7SNa [M + Na]+ 699.2392, found 699.2372.
Inspection by 13C NMR spectroscopy revealed no isotopically
shifted signal for the anomeric carbon. No evidence was found by
mass spectrometry for the presence of 18O.
Acknowledgment. We thank the NIH (GM62160) for support
of this work, Prof. Todd Lowary (University of Alberta) for
donation of the immediate precursor to compound 30, and an
anonymous reviewer for an insightful suggestion regarding the
effect of esters at O4.
Supporting Information Available: General experimental
methods and copies of spectra of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO801630M
J. Org. Chem. Vol. 73, No. 22, 2008 8953