On the influence of the C2-O2 and C3-O3 bonds in 4,6-O-benzylidene-directed β-mannopyranosylation and α-glucopyranosylation

Article abstract of DOI:10.1021/jo061417b

The synthesis of 4,6-O-benzylidene-protected 2-deoxyarabino-, 3-deoxyarabino-, and 3-deoxyribothioglycosides is described and their glycosylation reactions, with activation by either 1-benzenesulfinyl piperidine/trifluoromethansulfonic anhydride or diphen

Full text of DOI:10.1021/jo061417b

On the Influence of the C2-O2 and C3-O3 Bonds in
4,6-O-Benzylidene-Directed â-Mannopyranosylation and
r-Glucopyranosylation
David Crich* and Olga Vinogradova
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
ReceiVed July 7, 2006
The synthesis of 4,6-O-benzylidene-protected 2-deoxyarabino-, 3-deoxyarabino-, and 3-deoxyribothio-
glycosides is described and their glycosylation reactions, with activation by either 1-benzenesulfinyl
piperidine/trifluoromethansulfonic anhydride or diphenyl sulfoxide/trifluoromethanesulfonic anhydride,
studied. In contrast to the corresponding 4,6-O-benzylidene-protected glucosyl and mannosyl donors,
which are R- and â-selective, respectively, poor diastereoselectivity is observed in all cases. The reasons
for this poor selectivity are discussed in terms of the interaction between the C2-O2 and C3-O3 bonds
in the glucosyl and mannosyl donors and of the influence of this interaction on the ease of formation of
the intermediate glycosyl oxacarbenium ions.
Introduction
3,4-O-carbonate-protected 6-deoxymanno (rhamno) donor 5 to
the corresponding gluco donor 6.11
One of the more intriguing aspects of the 4,6-O-benzylidene-
directed â-mannopyranosylation reactions developed in this
laboratory1-6 is the change in selectivity observed with the
corresponding glucopyranosyl and galactopyranosyl donors,
which are R-selective.4,6-9 This contrast in selectivity, originally
seen with donors 1 and 2,7 on activation with trifluoromethane-
sulfonic anhydride in the presence of a hindered non-nucleo-
philic base such as 2,4,6-tri-tert-butylpyrimidine (TTBP),10 and
subsequently observed with donors 3 and 4, on activation with
1-benzenesulfinyl piperidine (BSP) and triflic anhydride,4 is
reflected in the reduced â-selectivity seen on going from the
(1) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198-1199.
(2) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321-8348.
(3) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435-436.
(4) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015-9020.
(5) Crich, D.; Smith, M. J. Am. Chem. Soc. 2002, 124, 8867-8869.
(6) Crich, D.; de la Mora, M.; Vinod, A. U. J. Org. Chem. 2003, 68,
8142-8148.
This difference in selectivity between the 4,6-O-benzylidene-
protected manno- and glucopyranose series has been examined
computationally by Nukuda and Whitfield and their co-workers,
who viewed the problem in terms of the conformations of the
intermediate oxacarbenium ions and of the protonated glycosides
resulting from methanol attack on the oxacarbenium ions.12
(7) Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926-4930.
(8) Bousquet, E.; Khitri, M.; Lay, L.; Nicotra, F.; Panza, L.; Russo, G.
Carbohydr. Res. 1998, 311, 171-181.
(9) Kim, K. S.; Kang, S. S.; Seo, Y. S.; Kim, H. J.; Jeong, K.-S. Synlett
2003, 1311-1314.
(10) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323-
326.
(11) Crich, D.; Jayalath, P. J. Org. Chem. 2005, 70, 7252-7259.
10.1021/jo061417b CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/23/2006
J. Org. Chem. 2006, 71, 8473-8480
8473

Crich and Vinogradova
SCHEME 1. Glycosylation Mechanism
FIGURE 1. Destabilizing interaction in the contact ion pair, illustrated
for the 4,6-O-benzylidene-protected glucosyl triflates.
contact ion pair is in turn in equilibrium with a solvent separated
ion pair (SSIP) 9, which we presume to be the source of the
R-glycosides (Scheme 1). The function of the benzylidene acetal
is to shift the series of equilibria between 7 and the two ions as
far as possible toward the covalent triflate 7, thereby minimizing
the population of the SSIP 9 and, at least in the mannose series,
the formation of R-glycosides. The benzylidene acetal exerts
its influence through a combination of torsional factors that come
into play as the covalent triflate chair conformer flattens to the
oxacarbenium ion in 818,19 and by maintaining the C5-C6 bond
in the most electron-withdrawing tg conformer.20 On this basis,
the R-selective glucosylations arise through the SSIP 9 and the
problem is reduced to one of understanding the reasons for its
greater population in the glucose series. There remains the
alternative possibility that the R-glucosides are formed via the
intermediacy of a second contact ion pair, with the triflate
counterion shielding the â-face of the oxacarbenium ion, which
would necessarily be in equilibrium with a covalent â-glycosyl
triflate, much as envisaged by Lemieux in his halide ion
promoted R-glucosylations.21 While we cannot exclude this
mechanism conclusively, we consider it unlikely on the grounds
that our NMR experiments provided no evidence for the
existence of a â-glucosyl triflate.7
However, it was recognized that the analysis was based on
thermodynamic considerations and might not be relevant to
kinetically determined stereoselectivity. It is well-known that
the anomeric effect is higher in mannopyranosides than in
glucopyranosides, leading to a greater thermodynamic preference
for the R-anomers in the mannose series,13 and it is evident
that the glycosylation stereochemistries obtained with donors
1-4 at reaction temperatures from -78 to -60 °C are kinetic
in origin. Accordingly, while the geometries of the 4,6-O-
benzylidene-protected oxacarbenium ions computed by the
Nukuda and Whitfield groups are taken into account in the
discussion below, the rationale for glycosylation stereochemistry
presented by these authors is not further considered. Differences
in reactivity of mannopyranosyl and glucopyranosyl oxacarbe-
nium ions have also been discussed recently by Lucero and
Woerpel,14 in the context of a broader investigation into the
synthesis of C-glycosides and the influence of substituents on
the stereoselectivity of oxacarbenium ion trapping.15 In the
absence of a conformationally restricting group, such as the
benzylidene acetal, these authors considered the tetra-O-
benzylmannopyranosyl cation to exist predominantly in the 3H4
4
We considered that the shift toward the SSIP 9 implied by
the change from â- to R-selectivity observed on going from
the manno to the gluco series might be due to greater repulsion
between the O-2 substituent and the triflate counterion in the
CIP 8 in the gluco series, which would have the effect of
facilitating SSIP formation (Figure 1).
conformer but to react via the less populated H3 form, in a
typical Curtin-Hammett kinetic scheme to afford the R-C-
glycosides in high yield. The R-selective C-glycosylation of the
tetra-O-benzylglucopyranosyl cation was also considered to take
place through the 4H3 conformer.14 With the benzylidene acetal
in place, and the 3H4 conformer of the oxacarbenium ion
excluded from consideration, the problem is simplified and only
the 4H3 conformer need be considered along with the somewhat
Alternatively, we were intrigued by the notion that the O2-
C2-C3-O3 torsional interaction plays a significant role in the
observed differing selectivities between the manno and gluco
series. Effectively, as the mannosyl triflate 10 collapses to the
4
related B2,5 and E conformers preferred by the benzylidene-
protected manno- and glucopyranosyl cations according to the
calculations of Nukuda, Whitfield, and their co-workers.12
We currently view the mechanism of the 4,6-O-benzylidene-
directed glycosylations, which are preformed, operationally by
preactivation of the donor before addition of the acceptor, as
proceeding through the intermediacy of a covalent glycosyl
triflate 7, which has been demonstrated spectroscopically to have
the R-configuration in both the manno and the gluco series.7,16
This intermediate, which is formed rapidly and which is stable
for many hours at low temperature in CD2Cl2, acts as a reservoir
for a transient contact ion pair 8 (CIP) that is the true actual
glycosylating species in the â-mannosylation reaction.17 This
4
ion pair, in either the H3 chair 11 or the B2,5 conformer 12
preferred by Nukuda and Whitfield,12 the O2-C2-C3-O3
torsion angle decreases (Table 1), whereas when the gluco
4
4
triflate 13 is transformed into either the H3 chair 14 or the E
conformer 15 favored by the computations,12 the corresponding
torsion angle is increased (Table 2).
Examination of the change in the O2-C2-C1-O5 torsion
angle with formation of the oxacarbenium ion is also instructive.
In mannose (Table 1) there is an increase in this torsion angle
on going from the covalent triflate 10 to the 4H3 oxacarbenium
ion 11 and maximization of this torsion angle in the B2,5
conformer 12 of the oxacarbenium ion. On the other hand, in
glucose the O2-C2-C1-O5 torsion angle, which begins at
(12) Nukada, T.; Berces, A.; Whitfield, D. M. Carbohydr. Res. 2002,
337, 765-774.
(13) Lemieux, R. U. In Molecular Rearrangements, Part 2; De Mayo,
P., Ed.; Wiley: New York, 1964; pp 709-769.
(14) Lucero, C. G.; Woerpel, K. A. J. Org. Chem. 2006, 71, 2641-
2647.
(15) Smith, D. M.; Woerpel, K. A. Org. Biomol. Chem. 2006, 1195-
1201.
(16) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217-11223.
(17) Crich, D.; Chandrasekera, N. S. Angew. Chem., Int. Ed. 2004, 43,
5386-5389.
(18) Fraser-Reid, B.; Wu, Z. C.; Andrews, W.; Skowronski, E. J. Am.
Chem. Soc. 1991, 113, 1434-1435.
(19) Andrews, C. W.; Rodebaugh, R.; Fraser-Reid, B. J. Org. Chem.
1996, 61, 5280-5289.
(20) Jensen, H. H.; Nordstrom, M.; Bols, M. J. Am. Chem. Soc. 2004,
126, 9205-9213.
(21) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am.
Chem. Soc. 1975, 97, 4056-4062.
8474 J. Org. Chem., Vol. 71, No. 22, 2006

Benzylidene-Directed â-Mannopyranosylation and R-Glucopyranosylation
SCHEME 2. Synthesis of the 2-Deoxy Donor 19a
TABLE 1. Torsional Angle Values for Mannosyl Triflate (10) and
4
the H3 (11) and B2,5 (12) Conformers of the Mannosyl Cation22
O2-C2-C3-O3
torsion angle (deg)
O2-C2-C1-O5
torsion angle (deg)
10
11
60
45
-15
60
60
135
+75
180
a Reagents and conditions: (a) HCl, toluene, 0 °C; (b) PhSH, (i-Pr)2EtN,
toluene, rt, 47% over two steps; (c) NaOMe, MeOH; (d) PhCH(OMe)2,
p-TsOH, DMF, 50 °C, 60% over two steps; (e) NaH, BnBr, THF, reflux,
73%.
∆ (10 f 11)
12
∆ (10 f 12)
0
+120
SCHEME 3. Preparation of the 3-Deoxy Ribo Donor 25a
TABLE 2. Torsional Angle Values for Glucosyl Triflate (13) and
4
4
the H3 (14) and E (15) Conformers of the Glucosyl Cation
O2-C2-C3-O3
torsion angle (deg)
O2-C2-C1-O5
torsion angle (deg)
13
14
60
75
180
105
a Reagents and conditions: (a) IR-120 (H+), H2O, 80 °C; (b) Ac2O,
pyridine, DMAP, rt, 85% for two steps; (c) Bu3SnH, AIBN, toluene, reflux,
78%; (d) PhSH, BF3‚Et2O, DCM, 0 °C, 97%, R/â ) 1:4; (e) NaOMe,
MeOH; (f) PhCH(OMe)2, p-TsOH, DMF, 50 °C, 96% for two steps; (g)
NaH, BnBr, THF, reflux, 93%.
∆ (13 f 14)
+15
-75
15
90
120
∆ (13 f 15)
+30
-60
Obvious routes to the 3-deoxy donors beginning with the
Barton deoxygenation of 1,2;5,6-di-O-acetoneglucofuranose26
and proceeding through 3-deoxy-â-D-ribo-hexopyranose and
1,2,4,6-tetra-O-acetyl-3-deoxy-â-D-ribo-hexopyranose were not
satisfactory owing to formation of furanose isomers in significant
amounts.27 Eventually, a synthesis was devised in which 1,2;5,6-
di-O-acetoneglucofuranose was converted to the known 3-deoxy-
3-iodoallofuranose derivative 20,28,29 which on deprotection in
acidic media and subsequent acetylation gave mainly the desired
pyranose form. Radical deiodination then afforded 2127 in good
yield. Treatment with thiophenol and boron trifluoride afforded
a 4:1 separable mixture of the anomeric thioglycosides 22 and
23, of which only the major â-isomer was processed through
the subsequent routine steps of the synthesis to give the 3-deoxy
ribo donor 25 (Scheme 3).
the maximum of 180° in the covalent triflate 13, undergoes a
significant reduction regardless of whether the oxacarbenium
ion exists in the 4H3 or 4E conformations 14 and 15, respectively
(Table 2). By analogy with Bols’ rationale for the benzylidene
effect,20 it might be inferred that the higher O2-C2-C1-O5
torsion angle in the mannose oxacarbenium ions 12 and 13
maximizes the electron-withdrawing effect of the C2-O2 bond,
as compared to that in the glucosyl oxacarbenium ions 14 and
15. This in turn would contribute toward a destabilization of
the mannosyl oxacarbenium ions with respect to their glucosyl
counterparts, which translates into a longer lived glucosyl
oxacarbenium ion and a concomitant loss of selectivity.
The effect of the O2-O3 interaction on the rate of acid-
catalyzed hydrolyses of methyl glycopyranosides was one of
several factors considered by Edward,23 Feather and Harris,24
and others25 in some of the classical studies in the area, but has
subsequently been overlooked. With a view to probing these
effects we have investigated the glycosylation stereoselectivity
of a set of 4,6-O-benzylidene protected 2- and 3-deoxythiogly-
cosides and describe here the results of our investigations.
Adapting a classical scheme for the formation of â-man-
nopyranosides from the corresponding â-glucopyranosides,30-35
Dess-Martin oxidation36 of 24 gave the corresponding ketone,
which was stereoselectively reduced with L-Selectride to give
(26) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574-1585.
(27) Withers, S. G.; Percival, M. D.; Street, I. P. Carbohydr. Res. 1989,
187, 43-66.
Results
(28) Russell, R. N.; Weigel, T. M.; Han, O.; Liu, H.-w. Carbohydr. Res.
1990, 201, 95-114.
Preparation of Donors. The synthesis of the 2-deoxy donor
19 was straightforward and followed the protocol outlined in
Scheme 2 starting from triacetyl glucal.
(29) Classon, B.; Liu, Z.; Samuelsson, B. J. Org. Chem. 1988, 53, 6126-
6130.
(30) Theander, O. Acta Chem. Scand. 1958, 12, 1883-1885.
(31) Barresi, F.; Hindsgaul, O. In Modern Methods in Carbohydrate
Synthesis; Khan, S. H., O’Neill, R. A., Eds.; Harwood Academic Publish-
ers: Amsterdam, 1996; p 251-276.
(32) Pozsgay, V. In Carbohydrates in Chemistry and Biology; Ernst, B.,
Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim, 2000; Vol. 1, p 319-
343.
(33) Ito, Y.; Ohnishi, Y. In Glycoscience: Chemistry and Chemical
Biology; Fraser-Reid, B., Kuniaki, T., Thiem, J., Eds.; Springer-Verlag:
Berlin, 2001; Vol. 2, p 1589-1619.
(22) Torsion angles were determined with ring conformations fixed
according to the parameters provided by Be´rces and co-workers (http://
www.sao.nrc.ca/ibs/6ring.html). Be´rces, A.; Whitfield, D. M.; Nukuda, T.
Tetrahedron 2001, 57, 477-491.
(23) Edward, J. T. Chem. Ind. 1955, 1102-1104.
(24) Feather, M. S.; Harris, J. F. J. Org. Chem. 1965, 30, 153-157.
(25) Overend, W. G.; Rees, C. W.; Sequeira, J. S. J. Chem. Soc. 1962,
3429-3440.
J. Org. Chem, Vol. 71, No. 22, 2006 8475

Crich and Vinogradova
SCHEME 4. Preparation of the 3-Deoxy Arabino Donor 27a
a Reagents and conditions: (a) Dess-Martin periodinane, DCM, rt; (b)
L-Selectride, THF, -78 °C, 81% for two steps; (c) NaH, BnBr, THF, reflux,
94%.
the 3-deoxyarabino product 26. Benzylation then afforded the
desired donor 27 (Scheme 4).
Investigation of Key Intermediates. Exploratory experi-
1
ments conducted in CD2Cl2 by variable-temperature H NMR
spectroscopy revealed the 2-deoxy donor 19 to be fully activated
by the BSP/Tf2O combination within minutes at -60 °C.
However, only minor signals were observed in the region
anticipated16 (δ 6.0-6.3) for the anomeric signal of the putative
glycosyl triflate intermediate 28. On warming to -30 °C, one
major compound, the glycal 29,37 was formed, as determined
from key resonances at δ 6.38 (dd, J ) 6.0, 1.2 Hz) and δ 4.86
(dd, J ) 6.0, 2.0 Hz) indicative of the olefinic hydrogens, along
with other unidentified byproducts. The result suggested the
triflate 28 to be too unstable for the glycosylations in the 2-deoxy
series. This behavior appears to be typical of the 2-deoxy series
as a parallel experiment with donor 3038 also failed to afford
an observable glycosyl triflate but provided instead tribenzyl
glucal 31 on warming to -40 °C. Activation of thioglycoside
19 with 2 equiv of diphenyl sulfoxide39,40 and 1.1 equiv of triflic
anhydride was also rapid and provided a putative intermediate
glycosyl sulfonium ion 32 of the type observed by Gin in his
studies on the activation of anomeric hemiacetals with diphenyl
sulfoxide and triflic anhydride.41 On warming, decomposition
of this intermediate was complete by -50 °C. In the 3-deoxy
series, the chemistry reverted to the more typical pattern
observed previously in our laboratory4,7,11,16,42 with clean
activation of both 25 and 27 by the BSP/Tf2O couple at -60
°C in CD2Cl2 and the formation of the putative glycosyl triflates
33 and 34, respectively, neither of which underwent decomposi-
tion until the temperature was raised to -10 °C.
Satisfactory yields were obtained in this manner but selectivities
were poor, approaching a maximum of 4:1 â/R with a primary
alcohol (Table 3). As determined by NMR spectroscopy of the
crude reaction mixtures, comparable results were obtained when
diphenyl sulfoxide was replaced by BSP, but isolated yields
were reduced owing to difficulties in purification and are hence
not reported.
TABLE 3. Glycosylation of the 2-Deoxy Donor 19
Glycosylation Reactions. In view of the variable-temperature
NMR experiments, couplings to the 2-deoxy donor 19 were
conducted at -60 °C with preactivation by a combination of 2
equiv of diphenyl sulfoxide and 1.1 equiv of triflic anhydride
in the presence of TTBP, before addition of the acceptor alcohol.
1
a Determined by H NMR spectroscopy on the reaction mixture.
(34) Lichtenthaler, F. W.; Lergenmu¨ller, M.; Peters, S.; Varga, Z.
Tetrahedron: Asymmetry 2003, 14, 727-736.
Glycosylation reactions with the 3-deoxy donors 25 and 27
were conducted with preactivation by the BSP/Tf2O couple in
the presence of TTBP before addition of the acceptor and are
thought to proceed via the intermediacy of the glycosyl triflates
33 and 34, respectively, on the basis of the variable-temperature
experiments. The results of these experiments, all of which
proceeded with good yield but modest selectivity, are reported
in Tables 4 and 5.
While the assignment of stereochemistry in the 2-deoxy series
(Table 3) and in the 3-deoxy ribo series (Table 4) was
straightforward based on the 3JH1,H2 coupling constants, that in
the 3-deoxy arabino series relies on the magnitude of the 1JC1,H1
coupling constants.43,44
(35) Ekborg, G.; Lindberg, B.; Lonngren, J. Acta Chem. Scand. B 1972,
26, 3287-3292.
(36) Dess, P. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(37) Roush, W. R.; Sebesta, D. P.; Bennett, C. E. Tetrahedron 1997,
53, 8825-8836.
(38) Crich, D.; Ritchie, T. J. J. Chem. Soc., Perkin Trans. 1 1990, 945-
954.
(39) 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.
(40) Code´e, J. D. C.; Litjens, R. E. J. N.; Van den Bos, L. J.; Overkleeft,
H. S.; Van der Marel, G. Chem. Soc. ReV. 2005, 34, 769-782.
(41) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269-
4279.
(42) Crich, D.; Hutton, T. K.; Banerjee, A.; Jayalath, P.; Picione, J.
Tetrahedron: Asymmetry 2005, 16, 105-119.
8476 J. Org. Chem., Vol. 71, No. 22, 2006

Benzylidene-Directed â-Mannopyranosylation and R-Glucopyranosylation
TABLE 4. Glycosylation of the 3-Deoxy Donor 25
TABLE 5. Glycosylation of the 3-Deoxy Donor 27
a Determined by H NMR spectroscopy on the reaction mixture.
1
1
a Determined by H NMR spectroscopy on the reaction mixture.
Discussion
Various 3-deoxyglycopyranosyl donors have been described in
the literature, but with rare exceptions,54 all carried ester
protecting groups on O2 to direct the glycosylation stereo-
chemistry55-58 and are not relevant to the present discussion.
Interestingly, although the coupling was carried out under very
different conditions to the ones employed here, the benzyl-
protected 3-deoxyglucosyl chloride 50 gave an approximately
1:1 mixture of two anomers on coupling to methyl 2,3,6-tri-O-
benzyl-â-D-glucopyranoside by the Lemieux chloride ion-
catalyzed protocol.21,54 Classical work on the acid-catalyzed
hydrolysis of simple glycopyranosides revealed that removal
of the C3-O3 bond has only a relatively minor accelerating
effect,23-25,59 as might also be inferred from more recent work
on the disarming effect of ester protecting groups and their
location on the pyranoside ring.
In the 3-deoxy ribo series (Table 4) there is a significant
preference toward the formation of the â-glycosides, away from
the R-selectivity previously observed with the glucosyl donors
2 and 4. This does not accord with the hypothesis of Figure 1
in which repulsion between the 2-O-benzyl group and the triflate
counterion is responsible for a general loosening of the ion pair
in the glucose series. Possibly, the move away from R-selectivity
with donor 25 is a reflection of a minor change in conformation
of the oxacarbenium ion in the resulting CIP which facilitates
â-face attack. As noted below, conformation effects have been
shown to play a major role in the stereoselectivity of these
glycosylation reactions.
The lack of stereoselectivity observed with the 2-deoxy donor
19 (Table 3) is not surprising in view of the well-known
difficulties in the stereoselective formation of 2-deoxyglyco-
pyranosidic linkages, in general,45-47 and is somewhat antici-
pated on the basis of the variable-temperature experiments and
the manifest instability of the intermediates. These problems
obviously arise from the greater lability of the 2-deoxy systems,
which is the result of the absence of the electron-withdrawing
C2-O2 bond and the greater facility of oxacarbenium ion
formation that this affords.24,25,48-50 Accordingly, no further
account is taken here of the results presented in Table 3. We
do note, however, the reduced R-selectivity seen with the donor
19 as compared to the high R-selectivity seen by Kahne and
co-workers with a series of 2,6-dideoxy glycosyl sulfoxides in
the course of their syntheses of ciclamycin:51,52 evidently, the
4,6-O-benzylidene acetal is not without influence over the course
of these reactions. In a similar vein, we note the â-selective
glycosylations reported by Hashimoto on activation of the
2-deoxyglycosyl phosphite 49, and related phosphates, with
trimethylsilyl triflate at -94 °C, which were considered to take
place via intermediate glycosyl triflates, something that cannot
be excluded on the basis of the experiments presented here.53
In the 3-deoxyarabino series (Table 5) there is a strong shift
away from the high â-selectivity typically observed with donors
1 and 3. Obviously the absence of the electron-withdrawing C3-
The results obtained with the 3-deoxy donors 25 and 27
(Tables 4 and 5) are more germane to the question in hand.
(43) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293-
297.
(50) Namchuk, M. N.; McCarter, J. D.; Becalski, A.; Andrews, T.;
Withers, S. G. J. Am. Chem. Soc. 2000, 122, 1270-1277.
(51) Raghavan, S.; Kahne, D. J. Am. Chem. Soc. 1993, 115, 1580-1581.
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4589-4614.
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(46) Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 56, 8385-
8417.
(53) Hashimoto, S.; Sano, A.; Sakamoto, H.; Nakajima, M.; Yanagiya,
Y.; Ikegami, S. Synlett 1995, 1271-1273.
(47) Veyrie`res, A. In Carbohydrates in Chemistry and Biology; Ernst,
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Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734-753.
J. Org. Chem, Vol. 71, No. 22, 2006 8477

Crich and Vinogradova
noside (39R) and Methyl 4-O-(3′-O-Benzyl-4′,6′-O-benzylidene-
2′-deoxy-â-D-arabino-hexopyranosyl)-2,3-O-isopropylidene-R-L-
rhamnopyranoside (39â). Prepared by method A and purified by
means of radial chromatography, eluting consecutive plates with
hexanes to 1:9 diethyl ether/hexanes, and then with hexanes to 1:19
O3 bond cannot be totally neglected here, but it seems apparent
that the loss of the compression of the O2-C2-C3-O3 torsion
angle seen in the mannose series (Table 1) on going from the
covalent triflate to the oxacarbenium ion leads to a higher
population of CIP, and consequently of the SSIP, with an overall
reduction in â-stereoselectivity. In support of this argument, we
recall the mannosyl donor 51 and its rhamnosyl counterparts
52 and 53, which adopt a half-chair conformation in which the
O2-C2-C3-O3 torsion angle is 25-30°, as opposed to the
60° in 1 and 3, and which are highly R-selective in homogeneous
glycosylation reactions:60-62 subtle conformational effects play
a major role in these glycosylation reactions, even to the point
of overriding powerful electronic effects.
ethyl acetate/hexanes. Combined yield 94 mg (75%, 1:1.5 R/â).
1
39R: [R]24 +50.0 (c 0.53, CHCl3); H NMR (500 MHz, CDCl3)
D
δ 7.52-7.57 (m, 2H), 7.27-7.43 (m, 8H), 5.64 (s, 1H), 5.00 (d, J
) 3.5 Hz, 1H), 4.87 (d, J ) 11.9 Hz, 1H), 4.86 (s, 1H), 4.70 (d, J
) 11.9 Hz, 1H), 4.29 (dd, J ) 10.0, 5.0 Hz, 1H), 4.07-4.15 (m,
3H), 4.03 (ddd, J ) 11.2, 9.1, 5.1 Hz, 1H), 3.75 (t, J ) 10.1 Hz,
1H), 3.71 (t, J ) 9.4 Hz, 1H), 3.65 (dd, J ) 10.0, 6.3 Hz, 1H),
3.37 (s, 3H), 3.31-3.36 (m, 1H), 2.27 (dd, J ) 13.2, 5.1 Hz, 1H),
1.82 (ddd, J ) 13.3, 11.2, 3.9 Hz, 1H), 1.52 (s, 3H), 1.34 (s, 3H),
1.26 (d, J ) 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 138.7,
137.7, 128.8, 128.4, 128.2, 127.7, 127.6, 126.1, 109.1, 101.3, 98.6,
98.0, 84.0, 80.3, 76.9, 75.9, 73.0, 72.8, 69.1, 64.8, 63.0, 54.8, 36.6,
28.2, 26.4, 17.5; ESIHRMS calcd for C30H38NaO9 [M + Na]+
565.2414, found 565.2409. 39â: white solid; mp 108-111 °C;
[R]24D -40.3 (c 0.31, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.49-
7.54 (m, 2H), 7.27-7.42 (m, 8H), 5.61 (s, 1H), 5.04 (dd, J ) 9.9,
2.0 Hz, 1H), 4.86 (s, 1H), 4.81 (d, J ) 12.1 Hz, 1H), 4.72 (d, J )
12.3 Hz, 1H), 4.28 (dd, J ) 10.5, 5.0 Hz, 1H), 4.13-4.18 (m, 1H),
4.09 (d, J ) 5.5 Hz, 1H), 3.83 (t, J ) 10.3 Hz, 1H), 3.77 (ddd, J
) 11.2, 9.0, 5.1 Hz, 1H), 3.58-3.70 (m, 3H), 3.37 (s, 3H), 3.30-
3.36 (m, 1H), 2.36 (ddd, J ) 12.9, 5.1, 2.1 Hz, 1H), 1.65 (ddd, J
) 12.8, 11.2, 9.9 Hz, 1H), 1.51 (s, 3H), 1.35 (s, 3H), 1.28 (d, J )
5.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 138.5, 137.6, 128.9,
128.4, 128.2, 127.7, 127.6, 126.1, 109.3, 101.3, 98.7, 97.9, 83.2,
78.5, 77.8, 76.1, 74.6, 72.4, 69.0, 66.6, 64.1, 54.8, 37.8, 27.9, 26.4,
17.5; ESIHRMS calcd for C30H38NaO9 [M + Na]+ 565.2414, found
565.2411.
Finally, we return to the possibility of the formation of the
R-glucosides via the intermediacy of covalent â-glucosyl triflate
and an associated transient â-face contact ion pair. While this
mechanism cannot be ruled out as a contributing factor to the
overall R-selectivity seen in the glucose series,4,6-9 the poor
selectivity seen with the 3-deoxy donors 25 and 27, irrespective
of the configuration at C2, suggests that it is not a major
pathway.
Experimental Section
3-O-(3′-O-Benzyl-4′,6′-O-benzylidene-2′-deoxy-R-D-arabino-
hexopyranosyl)-1,2:5,6-di-O-isopropylidene-R-D-glucofura-
nose (40R) and 3-O-(3′-O-Benzyl-4′,6′-O-benzylidene-2′-deoxy-
â-D-arabino-hexopyranosyl)-1,2:5,6-di-O-isopropylidene-R-D-
glucofuranose (40â). Prepared by method A and purified by means
of radial chromatography, eluting consecutive plates with hexanes
to 1:9 ethyl acetate/hexanes and then with 7:13 or 1:4 diethyl ether:
General Coupling Protocol for S-Phenyl 3-O-Benzyl-4,6-O-
benzylidene-2-deoxy-â-D-arabino-thiohexopyranoside (19) Using
Ph2SO (Method A). To a stirred solution of 19 (100 mg, 0.23
mmol) in CH2Cl2 (6 mL) containing Ph2SO (93 mg, 0.46 mmol),
TTBP (114 mg, 0.46 mmol), and activated 3 Å powdered molecular
sieves was added Tf2O (42.6 µL, 0.25 mmol) at -60 °C under
argon atmosphere. After 5 min, a solution of acceptor (0.28 mmol)
in CH2Cl2 (2.4 mL) was added, and the reaction mixture was stirred
for an additional 2 min at -60 °C, then warmed to room
temperature, filtered, washed (saturated aqueous NaHCO3, brine),
and dried (Na2SO4). The solvent was removed under reduced
pressure. The crude was filtered through a pad of silica gel (with
ethyl acetate as an eluent) and chromatographed using SiO2.
General Coupling Protocol for S-Phenyl 2-O-Benzyl-4,6-O-
benzylidene-3-deoxy-â-D-ribo-thiohexopyranoside (25) and S-
Phenyl 2-O-Benzyl-4,6-O-benzylidene-3-deoxy-â-D-arabino-thio-
hexopyranoside (27) Using BSP (Method B). To a stirred solution
of 25 or 27 (50 mg, 0.12 mmol) in CH2Cl2 (3 mL) containing BSP
(24 mg, 0.12 mmol), TTBP (57 mg, 0.23 mmol), and activated 3
Å powdered molecular sieves was added Tf2O (21.3 µL, 0.13 mmol)
at -60 °C under argon atmosphere. After 5 min, a solution of
acceptor (0.14 mmol) in CH2Cl2 (1.2 mL) was added, and the
reaction mixture was stirred for an additional 2 min at -60 °C,
then warmed to room temperature, filtered, washed (saturated
aqueous NaHCO3, brine), and dried (Na2SO4). The solvent was
removed under reduced pressure. The crude was filtered through a
pad of silica gel (with ethyl acetate as an eluent) and chromato-
graphed using SiO2.
hexanes for 40R and 40â, respectively. 40R yield 39 mg (29%),
1
40â yield 62 mg (46%). 40R: [R]24 +38.4 (c 0.25, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 7.50-7.57 (m, 2H), 7.28-7.45 (m,
8H), 5.89 (d, J ) 3.7 Hz, 1H), 5.66 (s, 1H), 5.21 (d, J ) 3.7 Hz,
1H), 4.87 (d, J ) 11.7 Hz, 1H), 4.69 (d, J ) 12.5 Hz, 1H), 4.56
(d, J ) 3.7 Hz, 1H), 4.33 (dd, J ) 9.5, 4.4 Hz, 1H), 4.24 (d, J )
2.9 Hz, 1H), 4.09-4.18 (m, 2H), 3.96-4.09 (m, 3H), 3.78-3.90
(m, 2H), 3.73 (t, J ) 8.8 Hz, 1H), 2.29 (dd, J ) 13.2, 5.1 Hz, 1H),
1.78-1.86 (m, 1H), 1.50 (s, 3H), 1.41 (s, 3H), 1.33 (s, 3H), 1.32
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.6, 137.4, 129.0, 128.4,
128.3, 127.6, 126.0, 112.1, 109.3, 105.3, 101.3, 99.2, 84.1, 83.8,
81.4, 80.2, 73.1, 72.6, 72.4, 69.0, 67.9, 63.9, 36.1, 26.9, 26.3, 25.4;
ESIHRMS calcd for C32H40NaO10 [M + Na]+ 607.2519, found
607.2524. 40â: [R]24D -15.8 (c 0.36, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.47-7.54 (m, 2H), 7.27-7.44 (m, 8H), 5.92 (d, J )
3.7 Hz, 1H), 5.61 (s, 1H), 4.83 (d, J ) 12.1 Hz, 1H), 4.67-4.73
(m, 2H), 4.49 (d, J ) 3.9 Hz, 1H), 4.28-4.38 (m, 4H), 4.00-4.07
(m, 2H), 3.82 (t, J ) 10.3 Hz, 1H), 3.67-3.77 (m, 2H), 3.34 (td,
J ) 13.9, 5.0 Hz, 1H), 2.26 (ddd, J ) 13.2, 4.8, 2.2 Hz, 1H), 1.69
(ddd, J ) 13.2, 10.2 Hz, 1H), 1.50 (s, 3H), 1.44 (s, 3H), 1.38 (s,
3H), 1.32 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.4, 137.4,
129.0, 128.4, 128.3, 127.7, 126.0, 111.9, 108.5, 105.1, 101.3, 98.1,
82.84, 82.76, 80.3, 79.4, 74.2, 73.4, 72.6, 68.8, 66.8, 66.0, 37.5,
26.8, 26.6, 26.3, 25.5; ESIHRMS calcd for C32H40NaO10 [M + Na]+
607.2519, found 607.2524.
Methyl 4-O-(3′-O-Benzyl-4′,6′-O-benzylidene-2′-deoxy-R-D-
arabino-hexopyranosyl)-2,3-O-isopropylidene-R-L-rhamnopyra-
6-O-(3′-O-Benzyl-4′,6′-O-benzylidene-2′-deoxy-R-D-arabino-
hexopyranosyl)-1,2:3,4-di-O-isopropylidene-R-D-galactopyra-
nose (41R) and 6-O-(3′-O-Benzyl-4′,6′-O-benzylidene-2′-deoxy-
â-D-arabino-hexopyranosyl)-1,2:3,4-di-O-isopropylidene-R-D-
galactopyranose (41â). Prepared by method A and purified by
(60) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291-1297.
(61) Crich, D.; Vinod, A. U.; Picione, J.; Wink, D. J. ARKIVOC 2005,
(Vi), 339-344.
(62) Crich, D.; Vinod, A. U.; Picione, J. J. Org. Chem. 2003, 68, 8453-
8458.
8478 J. Org. Chem., Vol. 71, No. 22, 2006

Benzylidene-Directed â-Mannopyranosylation and R-Glucopyranosylation
means of radial chromatography, eluting consecutive plates with
hexanes to 3:17 ethyl acetate/hexanes and then with 1:3 to 3:7
(ddd, J ) 11.0, 4.3, 4.1 Hz, 1H), 2.04 (ddd, J1 ) J2 ) J3 )11.7
Hz, 1H), 1.52 (s, 3H), 1.37 (d, J ) 6.2 Hz, 3H), 1.35 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 137.8, 137.5, 129.1, 128.5, 128.4, 127.9,
127.7, 126.3, 109.1, 101.8, 97.9, 81.1, 76.1, 74.3, 71.1, 69.5, 64.9,
64.3, 54.7, 29.81, 29.75, 28.2, 26.5, 17.3; FABHRMS calcd for
diethyl ether/hexanes. Combined yield 82 mg (61%, 1:4 R/â).
1
41R: [R]24 +16.9 (c 0.14, CHCl3); H NMR (400 MHz, CDCl3)
D
δ 7.48-7.54 (m, 2H), 7.23-7.41 (m, 8H), 5.62 (s, 1H), 5.53 (d, J
) 5.3 Hz, 1H), 4.97 (d, J ) 3.5 Hz, 1H), 4.85 (d, J ) 12.0 Hz,
1H), 4.68 (d, J ) 12.0 Hz, 1H), 4.63 (dd, J ) 7.9, 2.3 Hz, 1H),
4.32 (dd, J ) 5.0, 2.3 Hz, 1H), 4.23-4.29 (m, 2H), 4.05 (ddd, J )
11.1, 9.1, 5.3 Hz, 1H), 3.97 (td, J ) 6.6, 1.8 Hz, 1H), 3.87 (td, J
) 9.9, 4.7 Hz, 1H), 3.64-3.79 (m, 4H), 2.32 (dd, J ) 13.2, 5.3
Hz, 1H), 1.80 (ddd, J ) 13.4, 11.1, 3.8 Hz, 1H), 1.55 (s, 3H), 1.45
(s, 3H), 1.35 (s, 3H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
138.8, 137.6, 128.9, 128.3, 128.2, 127.6, 127.5, 126.1, 109.4, 108.6,
101.3, 98.1, 96.4, 83.9, 73.0, 71.0, 70.6, 69.1, 65.9, 65.8, 63.1, 36.5,
26.2, 26.0, 25.0, 24.6; FABHRMS calcd for C32H40NaO10 [M +
C30H38NaO9 [M + Na]+ 565.2414, found 565.2390. 43â: [R]22
D
1
-43.9 (c 0.098, CHCl3); H NMR (500 MHz, CDCl3) δ 7.45-
7.49 (m, 2H), 7.27-7.39 (m, 8H), 5.49 (s, 1H), 5.03 (d, J ) 7.5
Hz, 1H), 4.87 (s, 1H), 4.82 (d, J ) 12.1 Hz, 1H), 4.65 (d, J ) 12.1
Hz, 1H), 4.23-4.29 (m, 2H), 4.11 (d, J ) 5.7 Hz, 1H), 3.63-3.76
(m, 3H), 3.51 (ddd, J ) 11.7, 8.9, 4.3 Hz, 1H), 3.31-3.43 (m,
5H), 2.40 (dt, J ) 12.0, 4.7 Hz, 1H), 1.79 (ddd, J1 ) J2 ) J3 )
11.7 Hz, 1H), 1.53 (s, 3H), 1.36 (s, 3H), 1.30 (d, J ) 5.9 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 138.6, 137.4, 129.1, 128.4, 127.7,
127.6, 126.2, 109.3, 103.1, 101.7, 98.1, 78.2, 77.9, 77.6, 76.3, 76.0,
75.5, 72.8, 70.0, 69.3, 64.2, 55.0, 34.9, 27.9, 26.4, 17.7; FABHRMS
calcd for C30H38NaO9 [M + Na]+ 565.2414, found 565.2398.
3-O-(2′-O-Benzyl-4′,6′-O-benzylidene-3′-deoxy-R-D-ribo-hex-
opyranosyl)-1,2:5,6-di-O-isopropylidene-R-D-glucofuranose (44R)
and 3-O-(2′-O-Benzyl-4′,6′-O-benzylidene-3′-deoxy-â-D-ribo-hex-
opyranosyl)-1,2:5,6-di-O-isopropylidene-R-D-glucofuranose (44â).
Prepared by method B. Purified by means of radial chromatography,
eluting with hexanes to 1:4 diethyl ether/hexanes, followed by
normal-phase HPLC, eluting with hexanes to 3:2 ethyl acetate/
Na]+ 607.2519, found 607.2515. 41â: [R]24 -51.4 (c 0.21,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.48-7.53 (m, 2H), 7.26-
7.42 (m, 8H), 5.59 (s, 1H), 5.55 (d, J ) 5.0 Hz, 1H), 4.79 (d, J )
12.3 Hz, 1H), 4.71 (d, J ) 12.1 Hz, 1H), 4.66 (dd, J ) 9.8, 2.1
Hz, 1H), 4.60 (dd, J ) 8.0, 2.5 Hz, 1H), 4.29-4.34 (m, 2H), 4.21
(dd, J ) 7.9, 1.8 Hz, 1H), 3.97-4.05 (m, 2H), 3.82 (t, J ) 10.3
Hz, 1H), 3.64-3.77 (m, 3H), 3.35 (td, J ) 9.6, 5.0 Hz, 1H), 2.44
(ddd, J ) 13.0, 5.0, 2.1 Hz, 1H), 1.69-1.78 (m, 1H), 1.54 (s, 3H),
1.45 (s, 3H), 1.34 (s, 3H),1.31 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 138.7, 137.7 129.1, 128.6, 128.4, 127.9, 127.8, 126.3, 109.6,
108.9, 101.5, 101.3, 96.5, 83.2, 74.6, 72.5, 71.7, 70.9, 70.6, 69.4,
69.1, 68.0, 66.8, 37.7, 26.3, 26.2, 25.2, 24.6; ESIHRMS calcd for
C32H40NaO10 [M + Na]+ 607.2519, found 607.2521.
haxanes. Combined yield 51 mg (76%, 4.7:1 R/â). 44R: [R]22
D
+38.7 (c 0.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.45-7.52
(m, 2H), 7.27-7.41 (m, 8H), 5.96 (d, J ) 3.5 Hz, 1H), 5.52 (s,
1H), 5.21 (d, J ) 3.2 Hz, 1H), 4.60-4.67 (m, 3H), 4.53 (dt, J )
8.6, 5.4 Hz, 1H), 4.27-4.34 (m, 2H), 4.10 (dd, J ) 8.5, 2.6 Hz,
1H), 4.06 (d, J ) 5.6 Hz, 2H), 3.75-3.83 (m, 1H), 3.70 (t, J )
10.2 Hz, 1H), 3.61 (ddd, J ) 11.7, 4.2, 3.9 Hz, 1H), 3.49-3.57
(m, 1H), 2.29 (ddd, J ) 11.3, 4.2, 4.1 Hz, 1H), 2.04 (ddd, J1 ) J2
) J3 ) 11.7 Hz, 1H), 1.51 (s, 3H), 1.43 (s, 3H), 1.33 (s, 3H), 1.28
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 137.9, 137.2, 129.2, 128.5,
128.4, 127.8, 127.4, 126.1, 112.0, 109.2, 105.2, 101.7, 97.5, 84.1,
81.4, 80.1, 73.9, 72.1, 70.9, 69.3, 67.3, 65.0, 29.8, 27.1, 26.9, 26.4,
1-Adamantyl 3-O-Benzyl-4,6-O-benzylidene-2′-deoxy-R-D-ara-
bino-hexopyranoside (42R) and 1-Adamantyl 3-O-Benzyl-4,6-
O-benzylidene-2′-deoxy-â-D-arabino-hexopyranoside (42â). Pre-
pared by method A and purified by means of radial chromatography,
eluting consecutive plates with hexanes to 1:39 ethyl acetate/hexanes
and then with 1:9 diethyl ether/hexanes. Combined yield 33 mg
(30%, 1:1.9 R/â). 42R: white solid; mp 160-162 °C; [R]24D +54.7
1
(c 0.086, CHCl3); H NMR (500 MHz, CDCl3) δ 7.50-7.55 (m,
2H), 7.22-7.42 (m, 8H), 5.63 (s, 1H), 5.35 (d, J ) 3.3 Hz, 1H),
4.87 (d, J ) 11.7 Hz, 1H), 4.69 (d, J ) 11.7 Hz, 1H), 4.22 (dd, J
) 10.3, 5.0 Hz, 1H), 4.01-4.15 (m, 2H), 3.73 (t, J ) 10.4 Hz,
1H), 3.67 (t, J ) 9.3 Hz, 1H), 2.08-2.18 (m, 4H),1.73-1.86 (m,
7H), 1.56-1.68 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 139.0,
137.8, 128.8, 128.3, 128.2, 127.6, 127.5, 126.0, 101.2, 91.2, 84.4,
74.2, 73.4, 73.0, 69.2, 62.7, 42.5, 38.1, 36.3, 30.6; ESIHRMS calcd
for C30H36NaO5 [M + Na]+ 499.2461, found 499.2472. 42â:
slightly yellow solid; mp 86-88 °C; [R]24D -11.5 (c 0.19, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.47-7.55 (m, 2H), 7.24-7.43 (m,
8H), 5.59 (s, 1H), 4.89 (dd, J ) 9.9, 2.3 Hz, 1H), 4.80 (d, J ) 12.0
Hz, 1H), 4.72 (d, J ) 12.0 Hz, 1H), 4.27 (dd, J ) 10.5, 5.0 Hz,
1H), 3.83 (t, J ) 10.4 Hz, 1H), 3.70-3.79 (m, 1H), 3.67 (t, J )
8.9 Hz, 1H), 3.35 (td, J ) 14.0, 5.0 Hz, 1H), 2.11-2.22 (m, 4H),
1.71-1.88 (m, 7H), 1.56-1.70 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 138.6, 137.6, 128.9, 128.4, 128.2, 127.63, 127.56, 126.1,
101.3, 93.1, 82.9, 75.0, 74.9, 72.3, 69.1, 66.5, 42.5, 39.1, 36.2, 30.6;
ESIHRMS calcd for C30H36NaO5 [M + Na]+ 499.2461, found
499.2452.
25.4; FABHRMS calcd for C32H40NaO10 [M + Na]+ 607.2519,
1
found 607.2524. 44â. [R]22 -50.0 (c 0.042, CHCl3); H NMR
D
(500 MHz, CDCl3) δ: 7.45-7.49 (m, 2H), 7.28-7.40 (m, 8H),
5.84 (d, J ) 3.7 Hz, 1H), 5.49 (s, 1H), 4.66 (d, J ) 11.7 Hz, 1H),
4.63 (d, J ) 12.1 Hz, 1 H), 4.54-4.58 (m, 2H), 4.33-4.39 (m,
3H), 4.29 (dd, J ) 10.5, 5.0 Hz, 1H), 4.04-4.09 (m, 2H), 3.72 (t,
J ) 10.3 Hz, 1H), 3.54 (ddd, J ) 16.2, 4.6, 4.5 Hz, 1H), 3.31-
3.43 (m, 2H), 2.47 (dt, J ) 12.0, 4.7 Hz, 1H), 1.75 (ddd, J1 ) J2
) J3 ) 11.9 Hz, 1H), 1.50 (s, 3H), 1.45 (s, 3H), 1.38 (s, 3H), 1.28
(s, 3H); 13C NMR (125 MHz, CDCl3) δ: 137.9, 137.2, 129.2, 128.5,
128.4, 127.9, 127.5, 126.1, 111.9, 108.6, 105.1, 103.1, 101.6, 82.6,
80.5, 80.2, 75.7, 75.3, 73.4, 72.6, 70.4, 69.0, 66.0, 34.6, 26.7, 26.6,
26.2, 25.6; FABHRMS calcd for C32H40NaO10 [M + Na]+
607.2519, found 607.2509.
1-Adamantyl 2-O-Benzyl-4,6-O-benzylidene-3-deoxy-R-D-ribo-
hexopyranoside (45R) and 1-Adamantyl 2-O-Benzyl-4,6-O-
benzylidene-3-deoxy-â-D-ribo-hexopyranoside (45â). Prepared by
method B. Purified by means of radial chromatography, eluting
consecutive plates with hexanes to 1:19 diethyl ether/hexanes, and
then with hexanes to 1:39 ethyl acetate/hexanes. Combined yield
Methyl 4-O-(2′-O-Benzyl-4′,6′-O-benzylidene-3′-deoxy-R-D-
ribo-hexopyranosyl)-2,3-O-isopropylidene-R-L-rhamnopyrano-
side (43R) and Methyl 4-O-(2′-O-Benzyl-4′,6′-O-benzylidene-3′-
deoxy-â-D-ribo-hexopyranosyl)-2,3-O-isopropylidene-R-L-
rhamnopyranoside (43â). Prepared by method B. Purified by
means of radial chromatography, eluting with hexanes to 3:17
diethyl ether/hexanes to give 43R (33 mg, 53%) and 43â (26 mg,
50.4 mg (92%, 1:1.8 R/â). 45R: white solid; mp 119-122 °C;
1
[R]22 +43.6 (c 0.078, CHCl3); H NMR (400 MHz, CDCl3) δ
D
7.45-7.53 (m, 2H), 7.27-7.43 (m, 8H), 5.50 (s, 1H), 5.28 (d, J )
3.5 Hz, 1H), 4.62 (d, J ) 12.3 Hz, 1H), 4.58 (d, J ) 12.3 Hz, 1H),
4.20 (dd, J ) 10.2, 4.7 Hz, 1H), 4.00 (td, J ) 9.9, 4.8 Hz, 1H),
3.63 (t, J ) 10.4 Hz, 1H), 3.53-3.59 (m, 1H), 3.49 (ddd, J )
11.4, 9.4, 4.4 Hz, 1H), 2.08-2.26 (m, 5H), 1.82-1.96 (m, 6H),
1.59-1.70 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 138.3, 137.5,
129.0, 128.5, 128.3, 127.7, 127.6, 126.2, 101.7, 89.7, 74.5, 74.0,
70.6, 69.6, 63.7, 42.6, 36.3, 30.7, 30.1; FABHRMS calcd for C30H36-
42%). 43R: white solid; mp 138-142 °C; [R]22 +31.1 (c 0.074,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.48-7.52 (m, 2 H) 7.28-
7.40 (m, 8H), 5.50 (s, 1H), 4.93 (d, J ) 3.3 Hz, 1H), 4.86 (s, 1H),
4.67 (d, J ) 12.1 Hz, 1H), 4.56 (d, J ) 12.3 Hz, 1H), 4.21-4.28
(m, 2H), 4.12 (d, J ) 5.5 Hz, 1H), 4.06 (td, J ) 9.8, 5.0 Hz, 1H),
3.75-3.82 (m, 1H), 3.57-3.67 (m, 2H), 3.49 (ddd, J ) 11.6, 9.5,
4.0 Hz, 1H), 3.39 (dd, J ) 10.1, 7.5 Hz, 1H), 3.36 (s, 3H), 2.31
NaO5 [M + Na]+ 499.2461, found 499.2447. 45â: [R]22 -19.2
D
1
(c 0.052, CHCl3); H NMR (500 MHz, CDCl3) δ 7.43-7.51 (m,
2H), 7.27-7.41 (m, 8H), 5.47 (s, 1H), 4.85 (d, J ) 12.1 Hz, 1H),
J. Org. Chem, Vol. 71, No. 22, 2006 8479

Crich and Vinogradova
4.78 (d, J ) 7.5 Hz, 1H), 4.68 (d, J ) 12.1 Hz, 1H), 4.26 (dd, J )
10.5, 5.0 Hz, 1H), 3.74 (t, J ) 10.3 Hz, 1H), 3.51 (ddd, J ) 11.7,
8.9, 4.3 Hz, 1H), 3.35-3.44 (m, 2H), 2.40 (dt, J ) 12.0, 4.6 Hz,
1H), 2.15-2.22 (m, 3H), 1.90-1.97 (m, 3H), 1.81-1.88 (m, 3H),
1.76 (ddd, J1 ) J2 ) J3 ) 11.7 Hz, 1H), 1.60-1.71 (m, 6H); 13C
NMR (125 MHz, CDCl3) δ 138.6, 137.4, 129.1, 128.3, 127.8, 127.6,
126.2, 101.6, 98.2, 76.2, 75.43, 75.37, 73.0, 70.0, 69.3, 42.8, 36.3,
35.3, 30.7; FABHRMS calcd for C30H36NaO5 [M + Na]+ 499.2461,
found 499.2447.
) 2.4 Hz, 1H), 4.28-4.31 (m, 1H), 4.00-4.15 (m, 5H), 3.81-
3.89 (m, 2H), 3.71-3.75 (m, 1H), 2.24 (dt, J ) 13.0, 3.3 Hz, 1H),
1.96 (td, J ) 12.5, 3.0 Hz, 1H), 1.51 (s, 3H), 1.42 (s, 3H), 1.33 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 137.7, 137.5, 129.1, 128.5,
128.4, 127.9, 127.6, 126.1, 112.1, 109.4, 105.3, 101.9, 98.1 (1JCH
) 172.0), 84.1, 81.5, 79.9, 74.5, 74.1, 72.5, 71.3, 69.3, 67.9, 66.0,
29.4, 26.9, 26.3, 25.5; EIHRMS calcd for C32H40O10 [M]+ 584.2622,
1
found 584.2659. 47â: [R]22 -30.3 (c 0.330, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 7.44-7.51 (m, 2H), 7.27-7.40 (m, 8H), 5.92
(d, J ) 3.8 Hz, 1H), 5.56 (s, 1H), 4.72 (d, J ) 12.6 Hz, 1H), 4.69
(s, 1H), 4.64 (d, J ) 12.6 Hz, 1H), 4.40-4.47 (m, 2H), 4.33-4.38
(m, 2H), 4.28 (dd, J ) 10.4, 4.8 Hz, 1H), 4.15-4.20 (m, 1H), 4.02-
4.11 (m, 2H), 3.87 (t, J ) 10.4 Hz, 1H), 3.71-3.75 (m, 1H), 3.46
(td, J ) 9.6, 5.0 Hz, 1H), 2.33 (dt, J ) 13.2, 4.2 Hz, 1H), 1.68-
1.78 (m, 1H), 1.51 (s, 3H), 1.45 (s, 3H), 1.36 (s, 3H), 1.32 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 138.0, 137.4, 129.1, 128.43, 128.36,
127.8, 126.1, 112.0, 108.6, 105.1, 101.8, 100.2 (1JCH ) 155.4), 82.7,
80.5, 80.2, 73.8, 73.6, 73.3, 72.6, 71.0, 69.0, 66.1, 32.8, 26.8, 26.6,
26.3, 25.5; EIHRMS calcd for C32H40O10 [M]+ 584.2622, found
584.2602.
Methyl 4-O-(2′-O-Benzyl-4′,6′-O-benzylidene-3′-deoxy-R-D-
arabino-hexopyranosyl)-2,3-O-isopropylidene-R-L-rhamnopyra-
noside (46R) and Methyl 4-O-(2′-O-Benzyl-4′,6′-O-benzylidene-
3′-deoxy-â-D-arabino-hexopyranosyl)-2,3-O-isopropylidene-R-L-
rhamnopyranoside (46â). Prepared by method B. Purified by
means of radial chromatography, eluting with hexanes to 3:17
diethyl ether/hexanes. Combined yield 53.0 mg (85%, 1.9:1 R/â).
Analytical samples of both isomers were obtained by reversed-
phase HPLC separation, eluting with 1:1 water/acetonitrile to
acetonitrile. 46R: white solid; mp 152-155 °C; [R]22 +54.6 (c
D
0.108, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48-7.54 (m, 2H),
7.27-7.41 (m, 8H), 5.59 (s, 1H), 4.84 (s, 1H), 4.79 (s, 1H), 4.67
(d, J ) 12.3 Hz, 1H), 4.56 (d, J ) 12.3 Hz, 1H), 4.23 (dd, J )
10.1, 4.8 Hz, 1H), 4.06-4.15 (m, 3H), 3.98-4.06 (m, 1H), 3.78
(t, J ) 9.9 Hz, 1H), 3.65-3.69 (m, 1H), 3.54-3.63 (m, 1H), 3.33-
3.41 (m, 4H), 2.23 (dt, J ) 13.1, 3.3 Hz, 1H), 1.92-2.01 (m, 1H),
1.52 (s, 3H), 1.34 (s, 3H), 1.13 (d, J ) 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 137.8, 137.7, 129.0, 128.5, 128.3, 127.9,
127.8, 126.2, 109.2, 102.0, 98.5, 98.0 (1JCH ) 166.5), 80.3, 76.9,
76.0, 74.6, 74.2, 71.3, 69.4, 65.1, 64.8, 54.8, 29.3, 28.2, 26.5, 17.3;
ESIHRMS calcd for C30H39O9 [M + H]+ 543.25886, found
1-Adamantyl 2-O-Benzyl-4,6-O-benzylidene-3-deoxy-R-D-ara-
bino-hexopyranoside (48R) and 1-Adamantyl 2-O-Benzyl-4,6-
O-benzylidene-3-deoxy-â-D-arabino-hexopyranoside (48â). Pre-
pared by method B. Purification by means of radial chromatography,
eluting with hexanes to 1:19 ethyl acetate/hexanes, gave crude
products. Further purification of crude 48R and 48â by means of
normal-phase HPLC, eluting with hexanes to 3:2 ethyl acetate/
hexanes, afforded pure 48R (35.4 mg, 65%) and 48â (9.6 mg, 18%).
48R: white solid; mp 110-114 °C; [R]22D +61.9 (c 0.690, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.49-7.53 (m, 2H), 7.28-7.41 (m,
8H), 5.59 (s, 1H), 5.15 (s, 1H), 4.67 (d, J ) 12.1 Hz, 1H), 4.59 (d,
J ) 12.1 Hz, 1H), 4.19 (dd, J ) 10.3, 4.8 Hz, 1H), 3.96-4.10 (m,
2H), 3.78 (t, J ) 10.2 Hz, 1H), 3.54-3.57 (m, 1H), 2.21 (dt, J )
12.8, 3.5 Hz, 1H), 2.11-2.17 (m, 3H), 2.06 (td, J ) 12.2, 2.9 Hz,
1H), 1.74-1.83 (m, 6H), 1.57-1.68 (m, 6H); 13C NMR (125 MHz,
CDCl3) δ 138.1, 137.8, 129.0, 128.5, 128.3, 127.8, 127.7, 126.2,
101.9, 91.0 (1JCH ) 166.5), 76.7, 74.6, 74.5, 71.2, 69.5, 64.9, 42.5,
36.3, 30.6, 29.2; FABHRMS calcd for C30H36NaO5 [M + Na]+
543.25986. 46â: white solid; mp 158-162 °C; [R]22 -67.1 (c
D
0.082, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.46-7.51 (m, 2H),
7.26-7.42 (m, 8H), 5.56 (s, 1H), 5.10 (d, J ) 0.9 Hz, 1H), 4.88
(s, 1H), 4.84 (d, J ) 12.5 Hz, 1H), 4.68 (d, J ) 12.5 Hz, 1H), 4.25
(dd, J ) 10.5, 5.0 Hz, 1H), 4.14-4.18 (m, 1H), 4.10 (d, J ) 5.5
Hz, 1H), 4.04 (ddd, J ) 11.8, 9.2, 4.5 Hz, 1H), 3.91 (t, J ) 10.4
Hz, 1H), 3.80-3.82 (m, 1H), 3.63-3.73 (m, 2H), 3.45 (td, J )
9.7, 4.9 Hz, 1H), 3.40 (s, 3H), 2.31 (dt, J ) 13.1, 3.9 Hz, 1H),
1.72-1.79 (m, 1H), 1.54 (s, 3H), 1.33-1.37 (m, 6H); 13C NMR
(125 MHz, CDCl3) δ 138.7, 137.6, 129.0, 128.32, 128.28, 127.7,
127.6, 126.1, 109.3, 101.9, 100.9 (1JCH ) 160.0), 97.9, 78.5, 77.7,
76.1, 74.6, 74.1, 73.3, 71.2, 69.1, 64.3, 54.9, 33.9, 27.9, 26.5, 17.7;
FABHRMS calcd for C30H38NaO9 [M + Na]+ 565.2414, found
565.2408.
499.2461, found 499.2492. 48â: [R]22 -33.2 (c 0.196, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 7.41-7.50 (m, 4H), 7.25-7.40 (m,
6H), 5.55 (s, 1H), 4.88 (d, J ) 13.1 Hz, 1H), 4.85 (d, J ) 0.9 Hz,
1H), 4.79 (d, J ) 12.9 Hz, 1H), 4.24 (dd, J ) 10.4, 4.8 Hz, 1H),
4.02 (ddd, J ) 11.8, 9.2, 4.4 Hz, 1H), 3.88 (t, J ) 10.4 Hz, 1H),
3.57-3.62 (m, 1H), 3.45 (td, J ) 9.6, 5.0 Hz, 1H), 2.30 (ddd, J )
13.0, 3.8, 3.7 Hz, 1H), 2.14-2.20 (m, 3H), 1.58-1.91 (m, 13H);
13C NMR (100 MHz, CDCl3) δ 138.8, 137.7, 129.0, 128.3, 128.2,
127.9, 127.4, 126.2, 101.9, 95.3 (1JCH ) 152.6), 75.4, 74.9, 74.0,
73.0, 70.9, 69.3, 42.4, 36.3, 34.1, 30.6; FABHRMS calcd for C30H36-
NaO5 [M + Na]+ 499.2461, found 499.2413.
3-O-(2′-O-Benzyl-4′,6′-O-benzylidene-3′-deoxy-R-D-arabino-
hexopyranosyl)-1,2:5,6-di-O-isopropylidene-R-D-glucofura-
nose (47R) and 3-O-(2′-O-Benzyl-4′,6′-O-benzylidene-3′-deoxy-
â-D-arabino-hexopyranosyl)-1,2:5,6-di-O-isopropylidene-R-D-
glucofuranose (47â). Prepared by method B. Purification by means
of radial chromatography, eluting with hexanes to 1:3 diethyl ether/
hexanes, gave crude products. Further purification of crude 47R
and 47â by means of normal-phase HPLC, eluting with hexanes
to 1:1 ethyl acetate/hexanes and hexanes to 3:2 ethyl acetate/hexanes
respectively, afforded pure products (53.5 mg, combined 80% yield,
Acknowledgment. We thank Dr. Tom Hutton for helpful
discussions and the NIH (GM 62160) for support of this work.
Supporting Information Available: Details of the preparation
of all donors and copies of NMR spectra for all compounds. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
1.3:1 R/â). 47R: white solid; mp 145-148 °C; [R]22 +37.6 (c
D
0.492, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.48-7.52 (m, 2H),
7.28-7.40 (m, 8H), 5.88 (d, J ) 3.5 Hz, 1H), 5.61 (s, 1H), 5.15
(s, 1H), 4.64 (d, J ) 12.3 Hz, 1H), 4.57-4.62 (m, 2H), 4.34 (d, J
JO061417B
8480 J. Org. Chem., Vol. 71, No. 22, 2006