Direct stereocontrolled synthesis of 3-amino-3-deoxy-β- mannopyranosides: Importance of the nitrogen protecting group on stereoselectivity

Article abstract of DOI:10.1021/jo070473p

(Chemical Equation Presented) The highly stereocontrolled synthesis of the 3-amino-3-deoxy-β-mannopyranosides is achieved by means of thioglycoside donors protected with a 4,6-O-benzylidene or alkylidene acetal and a benzylidene imine group. Among the var

Full text of DOI:10.1021/jo070473p

Direct Stereocontrolled Synthesis of
3-Amino-3-deoxy-â-Mannopyranosides: Importance of the Nitrogen
Protecting Group on Stereoselectivity
David Crich* and Huadong Xu
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
ReceiVed March 6, 2007
The highly stereocontrolled synthesis of the 3-amino-3-deoxy-â-mannopyranosides is achieved by means
of thioglycoside donors protected with a 4,6-O-benzylidene or alkylidene acetal and a benzylidene imine
group. Among the various nitrogen protecting groups investigated only the Schiff’s base was found to
give high â-selectivity. N-Phthalimido and N-acetamido protected donors were found to be highly
R-selective, whereas 3-azido-3-deoxy glycosyl donors gave intermediate selectivity. The reasons for the
protecting group dependency are discussed in terms of the change in the O2-C2-C3-N3 torsional
interaction on conversion of the covalent glycosyl triflates to the transient oxacarbenium ions.
Introduction
sulfinyl piperidine (BSP) and trifluoromethanesulfonic anhy-
dride,5 with that of diphenyl sulfoxide and trifluoromethane-
sulfonic anhydride,12 or by oxidation to the corresponding
glycosyl sulfoxide followed by activation with trifluoromethane-
sulfonic anhydride,3,4 and in other glycosylation systems
functioning by a similar mechanism.13
It is becoming increasingly apparent in the 4,6-O-benzylidene
directed â-mannopyranosylation developed in our laboratories1,2
that the substituent at the mannose 3-position plays a critical
role in determining the stereochemical outcome of the reaction.
Thus, while the 3-O-benzyl donor 1 and related benzylic-type
ethers are highly â-selective,3-5 3-O-carboxylate esters such as
2 give essentially pure R-glycosides.6,7 On the other hand,
intermediate selectivity, namely the formation of R/â mixtures,
is seen with a broad spectrum of compounds including the 3-O-
tert-butyldimethylsilyl ether 3,8 the 3-O-propargyl ether 4,9 the
3-deoxy system 5,10 and the 3-deoxy-3-fluoro system 6.11 This
variation of selectivity is seen irrespective of whether a
thioglycoside is activated with the combination of 1-benzene-
(1) Crich, D.; Lim, L. B. L. Org. React. 2004, 64, 115-251.
(2) Crich, D. In Glycochemistry: Principles, Synthesis, and Applications;
Wang, P. G., Bertozzi, C. R., Eds.; Dekker: New York, 2001; pp 53-75.
(3) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198-1199.
(4) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321-8348.
(5) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015-9020.
(6) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291-1297.
(7) Crich, D.; Yao, Q. J. Am. Chem. Soc. 2004, 126, 8232-8236.
(8) Crich, D.; Dudkin, V. Tetrahedron Lett. 2000, 41, 5643-5646.
(9) Crich, D.; Jayalath, P.; Hutton, T. K. J. Org. Chem. 2006, 71, 3064-
3070.
With exception of the ester 2 and its analogues, for which
we do not have a satisfactory explanation at present, these effects
are understood in terms of our general glycosylation mechanism
involving initial conversion of the donor to a demonstrable
R-mannosyl triflate intermediate14 that is in equilibrium with a
(12) Code´e, J. D. C.; van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft,
H. S.; van Boeckel, C. A. A.; van Boom, J. H.; van der Marel, G. A.
Tetrahedron 2004, 60, 1057-1064.
(13) Code´e, J. D. C.; Hossain, L. H.; Seeberger, P. H. Org. Lett. 2005,
7, 3251-3254.
(10) Crich, D.; Vinogradova, O. J. Org. Chem. 2006, 71, 8473-8480.
(11) Crich, D.; Li, L. J. Org. Chem. 2007, 72, 1681-1690.
10.1021/jo070473p CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/13/2007
J. Org. Chem. 2007, 72, 5183-5192
5183

Crich and Xu
SCHEME 1. Glycosylation Mechanism
SCHEME 2. Thioglycoside Synthesis
transient â-selective contact ion pair (CIP)15 and thereby with
an R-selective solvent separated ion pair (SSIP) (Scheme 1).16
â-Selectivity is obtained when the series of equilibria is shifted
as far as possible toward the covalent triflate, thereby minimizing
the concentration of the R-selective SSIP. The role of the 4,6-
O-benzylidene acetal, or its surrogates, is to fix the C5-C6 bond
of the donor in the most electron-withdrawing tg conformation
thereby destabilizing any glycosyl oxacarbenium ions and
favoring the covalent glycosyl triflate.17,18 As the covalent
SCHEME 3. Introduction of the
1-Cyano-2-(2-iodophenyl)ethylidene Acetal
4
triflate, with its C1 conformation, collapses to the CIP, with
4
the oxacarbenium ion in the likely H3 conformation,19,20 the
O2-C2-C3-R torsion angle is compressed from 60° to 45°.10
When R is benzyloxy this results in an increase in steric strain,
which further destabilizes the oxacarbenium ion and favors the
covalent triflate. When R is hydrogen, fluoride, or propargyloxy
the increase in steric strain is smaller and lower selectivity is
the result.11 The effect of the large tert-butyldimethylsiloxy
group, on the other hand, is explained by a steric buttressing
interaction with the O-2 protecting group, which results in
increased shielding of the â-face, resulting in reduced selectiv-
ity:8 the effect of the 3-O-tert-butyldimethylsilyl ether can be
thwarted when it is employed in conjunction with a sterically
minimal 2-O-propargyl ether.9
diazo transfer23 from trifluoromethanesulfonyl azide24 gave the
corresponding azide 9, which was converted to a mixture of
the peracetylated R- and â-thioglycosides 11 and 12 by standard
methods. X-ray crystallography confirmed the configuration of
12, and saponification of 11 gave the triol 13 (Scheme 2).
Our recent interest in the use of modified 4,6-O-acetal
protecting groups, particularly those suitable for subsequent
radical fission to give the 6-deoxy sugars, prompted the
employment of the 1-cyano-2-(2-iodophenyl)ethylidene acetal,25
with previous work having established the â-directing ability
of this group.25,26 Thus, reaction of triol 13 with triethyl 2-(2-
iodophenyl)orthoacetate25 gave an unstable orthoester 14, which
was converted in 62% yield to the stable cyanoacetal 15 by
treatment with trimethylsilyl cyanide and BF3 ethereate.25
Benzylation then gave the donor 16 in 93% yield. Interestingly,
a higher overall yield of 16 was obtained when the sequence of
cyanide introduction and benzylation was inverted (Scheme 3).
The complete stereochemical assignment of 15 was confirmed
crystallographically.
In this paper we report on the synthesis and glycosylation
reactions of a series of 4,6-O-alkylidene protected 3-amino-3-
deoxymannopyranosyl donors and provide further insight into
the range of acceptable substituents at the 3-position.
Results
Synthesis of Substrates. Methyl 3-amino-3-deoxy-R-D-
mannopyranoside 8 was most expediently prepared from methyl
R-D-glucopyranoside 7 by periodate cleavage followed by
double Henry reaction with nitromethane, as described by Baer
and Fischer,21 and as improved by Richardson.22 Metal-catalyzed
(14) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217-11223.
(15) Crich, D.; Chandrasekera, N. S. Angew. Chem., Int. Ed. 2004, 43,
5386-5389.
(16) As suggested by a reviewer of a recent manuscript, whom we thank,
an SNi mechanism cannot be completely excluded from consideration for
the formation of the R-mannosides.
The analogous benzylidene acetal 18 was also prepared in
the standard manner via the intermediacy of 17. Treatment of
16 with triphenylphosphine in the presence of water, followed
by acetylation provided an acetamide 19. Reaction of both 16
and 18 with triphenylphosphine under anhydrous conditions with
subsequent reaction of the intermediate iminophosphoranes with
(17) Jensen, H. H.; Nordstrom, M.; Bols, M. J. Am. Chem. Soc. 2004,
126, 9205-9213.
(18) Torsional effects also potentially contribute to the benzylidene acetal
effect. (a) Fraser-Reid, B.; Wu, Z. C.; Andrews, W.; Skowronski, E. J.
Am. Chem. Soc. 1991, 113, 1434-1435. (b) Andrews, C. W.; Rodebaugh,
R.; Fraser-Reid, B. J. Org. Chem. 1996, 61, 5280-5289.
(19) Nukada, T.; Berces, A.; Whitfield, D. M. Carbohydr. Res. 2002,
337, 765-774.
(23) Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996,
37, 6029-6032.
(20) Nukuda, T.; Be´rces, A.; Wang, L.; Zgierski, M. Z.; Whitfield, D.
M. Carbohydr. Res. 2005, 340, 841-852.
(21) Baer, H. H.; Fischer, H. O. L. J. Am. Chem. Soc. 1960, 82, 3709-
3713.
(24) Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-Lomas, M. HelV. Chim.
Acta 1991, 74, 2073-2077.
(25) Crich, D.; Bowers, A. A. J. Org. Chem. 2006, 71, 3452-3463.
(26) Crich, D.; Bowers, A. A. Org. Lett. 2006, 8, 4327-4330.
(22) Richardson, A. C. J. Chem. Soc. 1962, 373-374.
5184 J. Org. Chem., Vol. 72, No. 14, 2007

Synthesis of 3-Amino-3-deoxy-â-Mannopyranosides
p-trifluoromethylbenzaldehyde gave the imines 20 and 21,
respectively, both with yields in the range of 60-80%.27
that temperature provided the optimum results in terms of yield
and selectivity (entry 3). Using BSP in place of diphenyl
sulfoxide gave essentially analogous results (Table 1, entry 4),
and the attempted use of the nitrile effect29-33 was found to be
disappointing in line with previous observations in the man-
nose34 and rhamnose series (Table 1, entry 5).35 Initial stereo-
chemical assignments for 27R and 27â, and for all subsequent
coupling products, were based on the diagnostic chemical shift
1
(δ 3.0-3.3) of the â-mannose H5 resonance in the H NMR
spectra,4 and were subsequently verified by determination of
1
the JCH coupling constants for the anomeric carbon.36-38
Donors 16, 19-21, and 26 were then coupled to 1-adaman-
tanol with activation by the diphenyl sulfoxide/trifluoromethane-
sulfonic anhydride protocol with activation at -65 °C and
warming to -50 °C before addition of the acceptor (Table 2).
From the results presented in Table 2 it is evident that the
Schiff’s base is the ideal protecting group for N-3 in these
glycosylation reactions, being readily formed from the azide in
a single step, giving outstanding â-selectivity, and being
hydrolyzed directly to the amine in the course of the workup.
Equally, it is apparent that the nature of the acetal spanning O4
and O6 has little effect on the yield or stereochemical outcome
of the reaction, as had been anticipated from previous work.25
One interesting feature of this series of reactions was the
sulfenylation of the amide nitrogen of donor 19, ultimately
leading to glycoside 28R, whose structure rests on HRMS data,
and the absence of an NH resonance in the 1H NMR spectrum.
This N-acetylsulfenamide arises from the reaction of the amide
group with the byproducts of the thioglycoside activation
process.
Finally, a phthalimido protected donor 26 was prepared by
the route outlined in Scheme 4, the longer route being necessary
because introduction of the phthalimido group directly on the
amines derived from 16 and/or 18 failed, presumably for steric
reasons. In this scheme the use of methanolic HCl to effect
cleavage of the acetate groups in 23 was dictated by incompat-
ibility of the phthalimido group under the standard Zemplen
deacetylation conditions. Likewise, the use of the trimethylsilyl
ether as the protecting group for O-2 arose from difficulties in
attempted benzylation reactions.
SCHEME 4. Preparation of a Phthalimido Protected Donor
On the basis of these results, further reactions were carried
out in which the more typical glycosyl acceptors methyl 2,3-
O-isopropylidene-R-L-rhamnopyranoside 32 and methyl 2,3,4-
tri-O-benzyl-R-D-glucopyranoside 33 were coupled to donors
20 and 21 under the optimium conditions, resulting in the highly
â-selective formation of the products in each case (Table 3).
Overall, the picture that emerges for the 3-amino-3-deoxy-
mannopyranoside series closely follows that established by the
mannopyranosides themselves. Thus, the optimum protecting
group for N3 is a benzylidene imine group that mimics the steric
properties of a benzyl ether (steric A value ) 1.39).9 It is
appropriate to point out here that no attempt was made to prepare
or conduct glycosylation reactions with the reduced version of
the benzylidene imines, namely the N-benzylamines, as it was
considered that these would be protonated under the reaction
conditions. The smaller azide (steric A value ) 0.45-0.62),39,40
like fluoride (steric A value ) 0.25-0.42),39,41-45 is insuf-
ficiently bulky for the compression of the O2-C2-C3-X
Glycosylation Reactions. Our preferred candidate for the
3-position was the azide group and, thus, glycosylation studies
began with donor 16. A number of experiments were carried
out with 1-adamantanol as acceptor, with activation by the
diphenyl sulfoxide/trifluoromethanesulfonic anhydride couple12
in the presence of the hindered base 2,4,6-tri-tert-butylpyrimi-
dine (TTBP)28 in dichloromethane. Previous work had indicated
the 1-cyano-2-(2-iodophenyl)ethylidene acetal to be somewhat
disarming and to retard clean activation at -78 °C,25 thus a
series of experiments were conducted in which the donor/
diphenyl sulfoxide/trifluoromethanesulfonic anhydride/TTBP
was warmed to different temperatures before the acceptor was
added. The results presented in Table 1 indicate that warming
to -50 °C before addition of the acceptor and quenching at
(29) Majumdar, D.; Boons, G.-J. In Handbook of Reagents for Organic
Synthesis: Reagents for Glycoside, Nucleotide, and Peptide Synthesis; Crich,
D., Ed.; Wiley: Chichester, UK, 2005; pp 11-15.
(30) Lemieux, R. U.; Ratcliffe, R. M. Can. J. Chem. 1979, 57, 1244-1251.
(31) Pougny, J.-R.; Sinay¨, P. Tetrahedron Lett. 1976, 17, 4073-4076.
(32) Braccini, J.; Derouet, C.; Esnault, J.; de Penhoat, C. H.; Mallet,
J.-M.; Michon, V.; Sinay¨, P. Carbohydr. Res. 1993, 246, 23-41.
(33) Ratcliffe, A. J.; Fraser-Reid, B. J. Chem. Soc., Perkin Trans. 1 1990,
747-750.
(27) For previous application of benzylidene imines as amine protecting
groups in oligosaccharide synthesis see: Madsen, R.; Udodonge, U. E.;
Roberts, C.; Mootoo, D. R.; Konradsson, P.; Fraser-Reid, B. J. Am. Chem.
Soc. 1995, 117, 1554-1565. Also see: Khiar, N.; Fernandez, I.; Araujo,
C. S.; Rodriguez, J. A.; Suarez, B.; Alvarez, E. J. Org. Chem. 2003, 68,
1433-1442.
(34) Schmidt, R. R.; Behrendt, M.; Toepfer, A. Synlett 1990, 694-696.
(35) Crich, D.; Patel, M. Carbohydr. Res. 2006, 341, 1467-1475.
(36) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293-297.
(37) Tvaroska, I.; Taravel, F. R. AdV. Carbohydr. Chem. Biochem. 1995,
51, 15-61.
(38) Duus, J. O.; Gotfredsen, C. H.; Bock, K. Chem. ReV. 2000, 100,
4589-4614.
(28) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323-
326.
(39) Schneider, H.-J.; Hoppen, V. J. Org. Chem. 1978, 43, 3866-3873.
J. Org. Chem, Vol. 72, No. 14, 2007 5185

Crich and Xu
TABLE 1. Exploratory Coupling Reactions with Donor 16 and 1-Adamantanola
entry
activator
solvent
method
yield, %
R:â ratio
1
2
3
5
6
Ph2SO
Ph2SO
Ph2SO
BSP
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
A
B
C
D
E
97
94
98
99
65
1:1.7
1:1.5
1:3.3
1:3.2
1:1.2
Ph2SO
CH2Cl2/MeCN (95/5)
a Method A: Activation at -78 °C followed, after 30 min at -78 °C, by the addition of adamantanol then warming to 0 °C before quenching. Method
B: Activation at -78 °C followed, after 30 min at -78 °C, by the addition of adamantanol then quenching at -78 °C. Method C: Activation at -65 °C,
followed by warming to -50 °C over 30 before addition of 1-adamantanol, and final quenching at -50 °C after 1 h. Method D: Same as for method C
except that BSP was used as the activator in place of diphenyl sulfoxide. Method E: Activation at -65 °C, followed by warming to -30 °C over 30 min
before addition of 1-adamantanol, and final quenching at -30 °C after 1 h
TABLE 2. Investigation of Different N-3 Protecting Groupsa
aMethod C: Activation at -65 °C, followed by warming to -50 °C over 30 min before addition of 1-adamantanol, and final quenching at -50 °C after
1 h. Method F: As in method C except that the reaction mixture was allowed to warm to -10 °C before quenching.
torsion angle to impact significantly the covalent triflate-CIP
equilibrium (Scheme 1) resulting in a loss of â-selectivity. The
acetamide and phthalimido protected systems behave exactly
as the 3-O-carboxylate esters and lead to essentially complete
R-selectivity. We note that the bulk of the 2-O-trimethylsilyl
ether in donor 26 is unlikely to be a major factor in the
R-selectivity of this system as related 2-O-silyl-3-O-benzylm-
annopyranosyl donors have been shown previously to exhibit
good â-selectivity.4,8
Radical Fragmentation Reactions. In contrast to the clean
radical fragmentations observed previously with glycosides
38,25,26 attempted radical fragmentations of the various glyco-
sides prepared in this study with the 1-cyano-2-(2-iodophenyl)-
ethylidene acetals were disappointing. Typically relatively
complex reaction mixtures were observed and significant
amounts of initiator were required to drive the reactions to
completion irrespective of the nitrogen protecting group. By
way of example the 6-deoxy glycoside 39 could only be isolated
5186 J. Org. Chem., Vol. 72, No. 14, 2007

Synthesis of 3-Amino-3-deoxy-â-Mannopyranosides
TABLE 3. Further Couplings to Donors 20 and 21
in 20% yield even though TLC indicated it to be the major
product from the reaction of 29â with tributyltin hydride and
AIBN in toluene at reflux. In addition to the radical fragmenta-
tion sequence 29â has undergone an O to N shift of the (2-
cyano)phenylacetate group, which is the obligatory product of
the radical reaction. To prevent this migration 29â was converted
to the N-Boc derivative 40 in good yield by standard means,
but subsequent radical reactions continued to afford complex
mixtures with the isolation of the premature reduction product
41 in 10% yield, along with the desired deoxy sugar 42 in yields
ranging from 10% to 15%. Unfortunately, the reason for the
disappointing nature of the radical fragmentation reactions
remains unclear at this time.
affording high yields of coupled product and excellent â-se-
lectivity. The comparable steric bulk of this benzylidene imine
to the 3-O-benzyl ethers typically employed at the 3-position
in the mannopyranoside series provides considerable support
for our hypothesis of the importance of the O2-C2-C3-R3
torsional interaction in the stereocontrolled synthesis of â-man-
nopyranosides and related compounds. The benzylidene imine
methodology should facilitate the introduction of 3-amino-3-
deoxy-â-mannopyranosides into antibiotics, an area of current
interest,46,47 and other molecules. Unfortunately, at least at the
present stage of development, the unexpectedly poor results in
the radical fragmentation mean that the method is not suitable
for the introduction of the â-mycosamine (3-amino-3,6-dideoxy)
unit into macrolide antibiotics such as the amphotericins, the
nystatins, and the rimocidins.48-50
Experimental Section
Methyl 3-Amino-3-deoxy-R-D-mannopyranoside Hydrochlo-
ride (8). Sodium metaperiodate (55 g) was slowly added in 30 min
to a stirred solution of methyl R-D-glucopyranoside (25 g) in iced
water (30 mL) at <10 °C. The mixture was then stirred for 1 h,
and the released formic acid was carefully neutralized with sodium
(42) Bugay, D. E.; Bushweller, C. H.; Danehy, C. T.; Hoogasian, S.;
Blersch, J. A.; Leenstra, W. R. J. Phys. Chem. 1989, 93, 3908-3911.
(43) Subbotin, O. A.; Sergeyev, N. M. J. Am. Chem. Soc. 1975, 97,
1080-1084.
(44) Chu, P.-S.; True, N. S. J. Phys. Chem. 1985, 89, 5613-5616.
(45) Jensen, F. R.; Bushweller, C. H. AdV. Alicyclic Chem. 1971, 3, 139.
(46) Liang, C.-H.; Duffield, J.; Romero, A.; Chiu, Y.-H.; Rabuka, D.;
Yao, S.; Sucheck, S.; Marby, K.; Shue, Y.-K.; Ichikawa, Y.; Hwang, C.-K.
WO 2004080391, 2004.
Conclusion
Among the various protecting groups investigated for the
3-amino group in the 3-amino-3-deoxy mannopyranoside series
the p-trifluoromethylbenzylidene imine was by far the best,
(47) Judice, J. K.; Fatheree, P. R.; Lam, B. M. T.; Leadbetter, M.; Linsell,
M. S.; Mu, Y.; Trapp, S. G.; Yang, G.; Zhu, Y. WO 2000039156, 2000.
(48) Packard, G. K.; Rychnovsky, S. D. Org. Lett. 2001, 3, 3393-3396.
(49) Nicolaou, K. C.; Daines, R. A.; Ogawa, Y.; Chakraborty, T. K. J.
Am. Chem. Soc. 1988, 110, 4696-4705.
(40) Su¨lze, D.; Gatial, A.; Karlsson, A.; Klaeboe, P.; Nielsen, C. J. J.
Mol. Struct. 1988, 174, 207-214.
(41) Jensen, F. R.; Bushweller, C. H.; Beck, B. H. J. Am. Chem. Soc.
1969, 91, 344-351.
(50) Cereghetti, D. M.; Carreira, E. M. Synthesis 2006, 914-942.
J. Org. Chem, Vol. 72, No. 14, 2007 5187

Crich and Xu
bicarbonate (10 g). The mixture, from which much sodium iodate
had crystallized, was then poured into ethanol (150 mL) and the
precipitate was filtered off and washed with ethanol (100 mL). The
filtrate was condensed under vacuum at <10 °C and the residal
syrup, which contained solid, was taken up with ethanol. The solid
was filtered off and washed with ethanol and the filtrate was again
condensed under vacuum at <10 °C, and the same procedure was
repeated 4 to 6 times until a clear syrup (not contaminated with
visible solid) was obtained. Nitromethane (7.0 mL) was added to
the solution of the syrup in dry methanol (75 mL), followed by the
addition of a solution of sodium methoxide (30 mL, 25% w in
methanol) at -10 °C. The stirred mixture was brought to rt slowly
over 2 h, and was kept at rt for another 6 h. Amberlite-120H ion-
exchange resin was added to neutralize the reaction mixture, then
was removed by filtration, and the filtrate was condensed to give
an orange oil. This oil was shaken under hydrogen (50 psi) with
Raney Nickel (2.0 g) as the catalyst in ethanol (50 mL) for 24 h.
The catalyst was removed by filtration and the filtrate was
condensed to approximately 30 mL. To this brown solution was
added HCl in ether (70 mL, 2M) with vigorously stirring. Ether
was removed under vacuum and the residue was cooled in a
refrigerator overnight. The so formed crystals were collected by
filtration to give the product as a white powder (10-12 g, 30-
40%): [R]D +68.4 (c, 1.0, H2O); mp 208 °C dec [lit.21,22 [R]D +60
(c, 2.0, H2O); mp 210-240 °C dec]; 1H NMR (500 MHz, D2O) δ
4.66 (s, 1H), 3.96 (m, 1H), 3.78 (d, J ) 12.0 Hz, 1H), 3.63-3.72
(m, 2H), 3.55-3.60 (m, 1H), 3.38 (dd, J ) 10.0, 2.5 Hz, 1H), 3.30
(s, 3H); 13C NMR (125 MHz, D2O) δ 99.7, 72.2, 66.6, 63.3, 60.3,
54.7, 53.2.
added to quench the reaction. The organic layer was separated, and
the aqueous layer was extracted with dichloromethane (2 × 30 mL).
The combined dichloromethane layers were dried over Na2SO4 and
concentrated under vacuum. Silica gel chromatography (hexanes/
ethyl acetate: 5/2) was applied to the residue to give two
compounds: R-1-thio-D-mannopyranoside 11 (1.1 g, 60%) and â-1-
thio-D-mannopyranoside 12 (0.44 g, 26%). 11: oil, [R]D +109.2
(c, 1.0, ethyl acetate); 1H NMR (500 Mz, CDCl3) δ 7.47 (m, 2H),
7.32 (m, 3H), 5.50 (s, 1H), 5.42 (dd, J ) 3.0, 1.0 Hz, 1H), 5.33
(td, J ) 5.0, 2.5 Hz, 1H), 4.50 (m, 1H), 4.28 (dd, J ) 12.5, 6.0
Hz, 1H), 4.12 (dd, J ) 12.0, 2.5 Hz, 1 H), 3.81 (dd, J ) 10.5, 3.0
Hz, 1H), 2.17 (s, 3H), 2.16 (s, 3H), 2.05 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 170.6, 169.8, 169.6, 132.25, 132.17, 129.3, 128.3,
85.5 (1JCH ) 168.8 Hz), 72.2, 69.4, 67.1, 62.4, 59.5, 20.9, 20.8,
20.7; HRMS(ESI) m/z calcd for C18H21N3NaO7S [M + Na]+
446.0998; found 446.1005. 12: white solid; [R]D -62.4 (c, 1.0,
1
ethyl acetate); mp 121 °C; H NMR (500 Mz, CDCl3) δ 7.52 (m,
2H), 7.31 (m, 3H), 5.70 (dd, J ) 7.5, 0.5 Hz, 1H), 5.21 (t, J )
10.0 Hz, 1H), 4.85 (d, J ) 1.5 Hz, 1H), 4.26 (dd, J ) 12.0, 6.5
Hz, 1H), 4.17 (dd, J ) 12.0, 2.5 Hz, 1H), 3.68 (ddd, J ) 10.0, 6.5,
2.5 Hz, 1H), 3.63 (dd, J ) 10.0, 3.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 170.6, 170.0, 169.6, 133.0, 132.1, 129.1, 128.2, 86.0 (1JCH
) 152.5 Hz), 70.8, 66.9, 63.0, 62.8, 20.8, 20.7, 20.6. Anal. Calcd
for C18H21N3O7S: C, 51.06; H, 5.00. Found: C, 50.94; H, 4.93.
Phenyl 3-Azido-3-deoxy-R-1-thio-D-mannopyranoside (13). To
a stirred solution of 11 (1.06 g, 2.5 mmol) in methanol (20 mL)
was added one drop of NaOMe in methanol (25% w/w). The
reaction mixture was followed by TLC and, after 4 h, Amberlite
I-120H ion-exchange resin was added to neutralize the base and
then removed by filtration. Methanol was removed under vacuum
to give the triol as a syrup (0.72 g, 100%). [R]D +254.6 (c, 0.5,
Methyl 3-Azido-3-deoxy-R-D-mannopyranoside (9). To a
stirred mixture of salt 8 (3.4 g, 15 mmol), Na2CO3 (3.2 g, 30 mmol),
and CuSO4‚5H2O (50 mg) in dry methanol (100 mL) was added a
solution of trifluoromethanesulfonyl azide in dichloromethane,
prepared from sodium azide (8 g, 123 mmol) and triflic anhydride
(4.1 mL, 25 mmol) in dichloromethane (50 mL) according to
Vasella’s protocol,24 in 6 h by syringe pump. When the addition
was complete, the mixture was stirred overnight before the solvent
was removed under vacuum and the residue was purified by column
chromatography on silica gel (dichloromethane/MeOH: 10/1) to
1
MeOH); H NMR (500 MHz, MeOH-d4) δ 7.51-7.54 (m, 2H),
7.26-7.33 (m, 3H), 5.39 (d, J ) 1.0 Hz, 1H), 4.15 (dd, J ) 3.0,
1.5 Hz, 1H), 4.08 (ddd, J ) 10.0, 5.0, 2.5 Hz, 1H), 3.95 (t, J )
10.0 Hz, 1H), 3.76-3.83 (m, 2H), 3.47 (dd, J ) 10.0, 3.0 Hz, 1H);
13C NMR (125 MHz, MeOH-d4) δ 134.0, 131.7, 128.8, 127.3, 88.7
(1JCH ) 166.3 Hz), 74.4, 71.5, 65.4, 63.8, 61.0; HRMS(ESI) m/z
calcd for C12H15N3NaO4S [M + Na]+ 320.0676, found 320.0668.
Phenyl 3-Azido-2-O-benzyl-3-deoxy-4,6-O-[1-cyano-2-(2-io-
dophenyl)]ethylidene-R-1-thio-D-mannopyranoside (16). A mix-
ture of triol 13 (0.72 g, 2.42 mmol), triethyl 2-iodophenylorthoac-
etate (1.5 equiv about 50% purity), prepared from 2-iodophenyl
acetonitrile,25 and camphorsufonic acid (20 mg) in dry dichlo-
romethane (20 mL) was stirred at rt for 12 h. Triethylamine (drops)
was added to quench the reaction before removal of the solvent
under vacuum to afford an oily residue, which on silica gel
chromatography (hexanes/ethyl acetate: 10/3) gave a mixture of
orthoester isomers 14 (1.1 g, 80%) as an oil. The major component
had the following characteristics: 1H NMR (500 MHz, CDCl3) δ
7.83 (dd, J ) 8.0, 1.0 Hz, 1H), 7.52 (dd, J ) 8.0, 2.0 Hz, 1H),
7.40-7.43 (m, 2H), 7.27-7.33 (m, 4H), 6.91 (td, J ) 8.0, 2.0 Hz,
1H), 5.48 (s, 1H), 4.40 (t, J ) 10.0 Hz, 1H), 4.22 (td, J ) 3.0, 1.0
Hz, 1H), 4.10-4.15 (m, 1H), 4.02 (t, J ) 10.0 Hz, 1H), 3.80 (dd,
J ) 10.5, 3.0 Hz, 1H), 3.77 (dd, J ) 9.5, 5.0 Hz, 1H), 3.69 (q, J
) 7.0 Hz, 2H), 3.34 (d, J ) 15.0 Hz, 1H), 3.31 (d, J ) 15.0 Hz,
1H), 2.74 (d, J ) 3.0 Hz, 1H), 1.26 (t, J ) 7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 139.4, 138.2, 133.1, 131.6, 131.0, 129.3,
128.3, 127.9, 113.3, 102.7, 88.0 (1JCH ) 167.5 Hz), 71.9, 69.9,
64.8, 61.4, 61.0, 59.1, 45.5, 15.1.
1
give a colorless oil (3.2 g, 97%). [R]D +160 (c, 1.0, MeOH); H
NMR (500 MHz, MeOH-d4) δ 4.60 (d, J ) 1.5 Hz, 1H), 3.78-
3.86 (m, 3H), 3.72 (dd, J ) 11.5, 6 Hz, 1H), 3.53 (ddd, J ) 9.5,
6.0, 2.0 Hz, 1H), 3.43 (dd, J ) 10, 3.5 Hz, 1H), 3.38 (s, 3H); 13C
NMR (125 MHz, MeOH-d4) δ 100.6, 73.3, 69.9, 64.2, 63.4, 61.3,
53.8; HRMS(ESI) m/z calcd for C7H13N3NaO5 [M + Na]+
242.0748, found 242.0743.
Phenyl 2,4,6-Tri-O-acetyl-3-azido-3-deoxy-R-1-thio-D-man-
nopyranoside (11) and Phenyl 2,4,6-Tri-O-acetyl-3-azido-3-
deoxy-â-1-thio-D-mannopyranoside (12). A mixture of triol 9
(1.15 g, 5.25 mmol), Ac2O (6.0 mL), and concentrated H2SO4 (0.5
mL) was stirred at rt for 12 h. Then ice (15 g) was added followed
by cold water (30 mL). The resulting mixture was extracted with
ether (3 × 40 mL). The combined extracts were washed with
saturated NaHCO3 until the aqueous layer was neutral, then with
brine and dried over Na2SO4. The solvent was removed under
reduced pressure and the residue was purified by column chroma-
tography on silica gel (hexanes/ethyl acetate: 2/1) to give a mixture
of isomers 10 (1.54 g, 75%) as an oil. The major component of
this mixture was the R-isomer, which had the following charac-
teristics: 1H NMR (500 MHz, CDCl3) δ 6.07 (d, J ) 1.5 Hz, 1H),
5.34 (t, J ) 10.5 Hz, 1H), 5.20 (m, 1H), 4.26 (dd, J ) 12.5, 5.0
Hz, 1H), 3.99 (m, 1H), 3.85 (dd, J ) 10.5, 3.5 Hz, 1H), 2.19 (s,
3H), 2.16 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 170.7, 169.6, 169.5, 167.8, 89.9, 70.5, 69.5, 66.3, 62.1,
58.7, 20.83, 20.76, 20.72. To this mixture of isomers (1.54 g, 4.0
mmol) and thiophenol (0.6 mL, 6.0 mmol) in dry dichloromethane
(20 mL) was added dropwise BF3‚OEt2 (1.0 mL, 7.8 mmol) at 0
°C in 10 min. The reaction mixture was stirred overnight and
monitored by TLC, before cold saturated NaHCO3 (30 mL) was
Two sequences of transformations were applied to orthoester 14
to obtain donor 16:
Sequence A: To a stirred mixture of 14 (1.0 g, 1.76 mmol) and
TMSCN (1.2 mL, 8.8 mmol) in dry dichloromethane (15 mL) was
added BF3‚OEt2 (111 uL, 0.88 mmol) under Argon at 0 °C. After
2 h of stirring, the reaction was quenched by saturated aqueous
NaHCO3 (10 mL), washed with water (20 mL) and brine (20 mL),
dried over Na2SO4, and condensed under vacuum to give an oily
residue. Purification by silica gel chromatography (hexanes/ethyl
acetate: 10/3) afforded 15 as white crystals (0.60 g, 62%). [R]D
5188 J. Org. Chem., Vol. 72, No. 14, 2007

Synthesis of 3-Amino-3-deoxy-â-Mannopyranosides
184.2 (c, 0.5, CHCl3); mp 191-192 °C; 1H NMR (500 MHz,
CDCl3) δ 7.89 (d, J ) 8.0 Hz, 1H), 7.45 (m, 3H), 7.33 (m, 4H),
6.99 (td, J ) 8.0, 1.5 Hz, 1H), 5.51 (s, 1H), 4.37 (t, J ) 10.0 Hz,
1H), 4.28 (td, J ) 10.0, 5.0 Hz, 1H), 4.24 (s, 1H), 4.12 (dd, J )
11.0, 5.0 Hz, 1H), 4.02 (t, 10.5 Hz, 1H), 3.92 (dd, J ) 9.5, 3.0 Hz,
1H), 3.55 (s, 3H), 2.54 (d, J ) 3.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 140.0, 135.2, 132.6, 131.7, 131.6, 129.6, 129.4, 128.3,
128.1, 114.1, 102.8, 97.1, 87.8,75.2, 71.8, 65.7, 63.8, 60.7, 48.7.
Anal. Calcd for C21H19IN4O4S: C, 45.83; H, 3.48; N, 10.18; S,
5.83. Found: C, 45.84; H, 3.51; N, 10.04; S, 5.70. A mixture of
15 (0.41 g, 0.745 mmol), benzyl bromide (260 uL, 2.2 mmol), and
60% NaH (90 mg, 2.2 mmol) in dry THF (20 mL) was heated to
reflux under Argon for 2 h. The reaction mixture was cooled to rt
before it was passed through a short silica gel pad. Removal of the
solvent then afforded an oily residue that was purified by silica
gel chromatography (hexanes/ethyl acetate: 10/1) to give thiom-
annopyranoside 16 (0.45 g, 93%) as an oil. [R]D +100.6 (c, 1.0,
128.3, 128.22, 128.16, 128.0, 126.0, 101.7, 86.3, 79.0, 76.9, 73.3,
68.5, 65.3, 59.6. Anal. Calcd for C26H25N3O4S: C, 65.67; H, 5.30;
N, 8.84; S, 6.74. Found: C, 65.68; H, 5.27; N, 8.69; S, 6.54.
Phenyl 3-Acetamido-2-O-benzyl-3-deoxy-4,6-O-[1-cyano-2-(2-
iodophenyl)]ethylidene-R-1-thio-D-mannopyranoside (19). A mix-
ture of azide 16 (157 mg, 0.25 mmol), triphenylphosphine (77 mg,
0.29 mmol), and water (10 uL, 0.56 mmol) in THF (5 mL) was
stirred at rt overnight, after which Ac2O (53 uL, 0.56 mmol) was
added, followed by pyridine (50 uL, 0.62 mmol). The mixture was
allowed to stir for 12 h at rt before the solvent was removed to
afford an oily residue that was purified by silica gel chromatography
(hexanes/ethyl acetate: 10/3) to give donor 19 (120 mg, 75%) as
1
an oil. [R]D +71.4 (c, 1.0, ethyl acetate); H NMR (500 MHz,
CDCl3) δ 7.86 (dd, J ) 8.0, 1.0 Hz, 1H), 6.93-7.43 (m, 12H),
6.95 (td, J ) 8.0, 1.5 Hz, 1H), 5.60 (d, J ) 9.5 Hz, 1H), 5.53 (s,
1H), 4.71 (d, J ) 11.5 Hz, 1H), 4.56 (td, J ) 9.5, 3.5 Hz, 1H),
4.37 (d, J ) 12.0 Hz, 1H), 4.29 (td, J ) 9.5, 4.5 Hz, 1H), 4.10 (dd,
J ) 11.0, 5.0 Hz, 1H), 3.93-4.04 (m, 3H), 3.40 (d, J ) 14.5 Hz,
1H), 3.20 (d, J ) 14.0 Hz, 1H), 1.86 (s, 3H); 13C (125 MHZ, CDCl3)
δ 169.7, 139.8, 136.7, 135.4, 133.4, 132.4, 131.6, 129.5, 129.3,
1
ethyl acetate); H NMR (500 MHz, CDCl3) δ 7.89 (dd, J ) 8.0,
1.0 Hz, 1H), 7.47 (dd, J ) 7.5, 1.5 Hz, 1H), 7.30-7.35 (m, 6H),
6.90 (td, J ) 7.5, 1.5 Hz, 1H), 5.38 (d, J ) 1.0 Hz, 1H), 4.70 (d,
J ) 12.0 Hz, 1H), 4.60 (d. J ) 12.0 Hz, 1H), 4.47 (t, J ) 10.0 Hz,
1H), 4.19 (td, J ) 10.0, 4.5 Hz, 1H), 4.11 (dd, J ) 10.5, 5.0 Hz,
1H), 4.02 (t, J ) 10.0 Hz, 1H), 4.01 (dd, J ) 3.0, 1.0 Hz, 1H),
3.71 (dd, J ) 10.5, 3.0 Hz, 1H), 3.55 (s, 2H); 13C (125 MHZ,
CDCl3) δ 140.0, 136.8, 135.3, 133.0, 131.7, 131.6, 129.5, 129.3,
128.6, 128.3, 128.2, 128.0, 114.0, 102.8, 97.0, 86.5 (1JCH ) 167.5
Hz), 78.8, 74.2, 73.4, 65.6, 64.2, 59.4, 48.7; HRMS(ESI): m/z calcd
for C28H25IN4NaO4S [M + Na]+ 663.0534, found 663.0518.
Sequence B: A mixture of 14 (2.0 g, 3.6 mmol), benzyl bromide
(0.64 mL, 6.4 mmol) and 60% NaH (200 mg, 5.0 mmol) in dry
THF (30 mL) was heated to reflux for 3 h under Argon, then cooled
to rt. The reaction mixture was filtered through a thin silica gel
pad, and the filtrate was concentrated to afford a crude product,
which was used directly for the next reaction without further
purification. To a stirred mixture of this crude product and TMSCN
(1.2 mL, 9.0 mmol) in dry dichloromethane (20 mL) was added
BF3‚OEt2 (50 uL, 0.4 mmol) under Argon at 0 °C. The reaction
was kept at 0 °C for 2 h before being quenched by NaHCO3 (20
mL), washed with water and brine, and dried (Na2SO4). Evaporation
of the solvent under vacuum furnished an oily residue that was
purified by silica gel chromatography (hexanes/ethyl acetate:
10/1) to afford 16 (2.1 g, 90% for two steps).
128.9, 128.6, 128.4, 128.0, 127.9, 114.3, 102.8, 96.8, 85.6 (1JCH
)
166.5 Hz), 78.9, 74.3, 72.7, 65.6, 64.3, 48.4, 48.2, 23.4; HRMS-
(ESI) m/z calcd for C30H29IN2NaO5S [M + Na]+ 679.0734, found
679.0720.
Phenyl 2-O-Benzyl-4,6-O-(1-cyano-2-[2-iodophenyl])ethylidene-
3-(4-trifluoromethyl)benzylideneimino-3-deoxy-R-1-thio-D-man-
nopyranoside (20). A solution of azide 16 (128 mg, 0.2 mmol)
and triphenylphosphine (58 mg, 0.22 mmol) in dry dichloromethane
(6 mL) was stirred at rt overnight before 4-trifluoromethylbenzal-
dehyde (52 mg, 0.30 mmol) was added. The reaction mixture then
was stirred for 24 h before the solvent was evaporated. The residue
was purified by flash chromatography on neutral alumina (hexanes/
ethyl acetate/triethylamine: 100/10/1) to give 20 (60-80%) as an
oil. [R]D +87.3 (c, 1.0, ethyl acetate); 1H NMR (500 MHz, CDCl3)
δ 8.39 (s, 1H), 7.86 (d, J ) 8.0 Hz, 2H), 7.70-7.73 (m, 2H), 7.40-
74.1 (m, 2H), 7.23-7.34 (m, 9H), 7.01 (dd, J ) 2.5, 1.5 Hz, 1H),
6.80 (dd, J ) 2.5, 1.5 Hz, 1H), 5.53 (d, J ) 1.0 Hz, 1H), 4.80 (d,
J ) 12.0 Hz, 1H), 4.68 (d, J ) 11.5 Hz, 1H), 4.66 (t, 9.5 Hz, 1H),
4.29 (td, J ) 10.0, 5.0 Hz, 1H), 4.16 (dd, J ) 11.0, 5.0 Hz, 1H),
4.11 (t, J ) 10.5 Hz, 1H), 4.03 (dd, J ) 3.0, 1.0 Hz, 1H), 3.93 (dd,
J ) 10.0, 2.5 Hz, 1H), 3.47(d, J ) 14.5 Hz, 1H), 3.46 (d, J ) 14.5
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 162.5, 139.7, 138.9, 137.6,
135.6, 133.7, 131.4, 131.3, 129.9,129.3, 129.2, 128.8, 128.4, 128.0,
127.94, 127.88, 127.7, 125.5, 114.5, 102.7, 96.9, 87.4, 79.5, 73.9,
69.0, 66.0, 64.3, 48.7; HRMS(ESI) m/z calcd for C36H30F3IN2NaO4S
[M + Na]+ 793.0816, found 793.0800.
Phenyl 2-O-Benzyl-4,6-O-benzylidene-3-deoxy-3-(4-trifloro-
methyl)benzylideneimino-R-1-thio-D-mannopyranoside (21). The
protocol preparation of 20 was applied to azide 18 to give imine
21 (60-80%) as an oil. [R]D +72.0 (c, 0.5, ethyl acetate); 1H NMR
(500 MHz, CDCl3) δ 8.47 (s, 1H), 7.91 (d, J ) 3.0 Hz, 2H), 7.70
(d, J ) 3.0 Hz, 2H), 7.26-7.45 (m, 15 H), 5.62 (s, 1H), 5.60 (s,
1H), 4.84 (d, J ) 12.0 Hz, 1H), 4.77 (d, J ) 12.0 Hz, 1H), 4.41-
4.50 (m, 2H), 4.29 (dd, J ) 10.5, 4.5 Hz, 1H), 3.99-4.02 (m, 2H),
3.94 (t, J ) 10.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 162.6,
139.1, 137.7, 137.4, 134.0, 131.6, 129.2, 128.9, 128.7, 128.4, 128.2,
128.1, 127.9, 127.7, 126.0, 125.6, 101.5, 87.2, 80.0, 76.7, 73.7,
69.5, 68.7, 65.5; HRMS(ESI) m/z calcd for C34H31F3NO4S [M +
H]+ 606.19204, found 606.19200.
Phenyl 3-Azido-4,6-O-benzylidene-3-deoxy-R-1-thio-D-man-
nopyranoside (17). A mixture of 11 (550 mg, 1.85 mmol),
benzaldehyde dimethylacetal (300 mg, 1.97 mmol), and camphor-
sufonic acid (10 mg) in dry dichloromethane (10 mL) was stirred
at rt overnight. Triethylamine (drops) then was added before
the solvent was removed under vacuum. The residue was purified
by silica gel chromatography (hexanes/ethyl acetate/dichlo-
romethane: 10/3/2) to give 17 (605 mg, 85%) as a white solid.
[R]D +221 (c, 0.5, CHCl3); mp 134 °C; 1H NMR (500 MHz, CDCl3)
δ 7.45-7.52 (m, 4H), 7.30-7.41 (m, 6H), 5.67 (s, 1H), 5.53 (s,
1H), 4.41 (td, J ) 10.0, 5.0 Hz, 1H), 4.20-4.27 (m, 3H), 4.05 (dd,
J ) 10.5, 3.0 Hz, 1H), 3.88 (t, 10.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 136.9, 132.9, 131.9, 129.3, 129.1, 128.3, 128.0, 125.9,
101.7, 87.9, 77.9, 71.7, 68.6, 64.9, 60.9; HRMS(ESI) m/z calcd
for C19H19N3NaO4S [M + Na]+ 408.0989, found 408.0978.
Phenyl 3-Azido-2-O-benzyl-4,6-O-benzylidene-3-deoxy-R-1-
thio-D-mannopyranoside (18). A solution of 17 (542 mg, 1.41
mmol) and benzyl bromide (0.7 g, 4.09 mmol) together with 60%
NaH (112 mg, 2.8 mmol) in dry THF (30 mL) was heated to reflux
for 3 h. After cooling to rt, the solution was passed through a thin
silica gel pad then concentrated. The residue was purified by silica
gel chromatography (hexanes/ethyl acetate 10/1) to give 18 (670
mg, 100%) as a crystalline solid. [R]D +143 (c, 0.5, ethyl acetate);
Methyl 2,4,6-Tri-O-acetyl-3-deoxy-3-phthalimido-R-D-man-
nopyranoside (22). A mixture of 8 (1.15 g, 5 mmol), N-
ethoxyphthalimide (1.15 g, 5.25 mmol), and triethylamine (0.55 g,
5.4 mmol) in dry DMF (10 mL) was stirred at 100 °C for 12 h.
The solvent was removed under vacuum and the residue was mixed
with acetic anhydride (2.3 g, 22.8 mmol) and pyridine (3.5 g, 45.4
mmol) and stirred at rt for 12 h. Cold water (20 mL) was added to
the reaction mixture and the mixture was stirred for 3 h before it
was extracted with dichloromethane (3 × 30 mL). The combined
organic layers were washed by aqueous HCl (1.0 M) and saturated
1
mp 118 °C; H NMR (500 MHz, CDCl3) δ 7.51-7.53 (m, 2H),
7.30-7.40 (m, 13H), 5.67 (s, 1H), 5.48 (s, 1H), 4.71 (s, 2H), 4.23-
4.38 (m, 3H), 4.05 (d, J ) 2.5 Hz, 1H), 3.84-3.91 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 137.0, 133.2, 131.9, 129.3, 129.1, 128.6,
J. Org. Chem, Vol. 72, No. 14, 2007 5189

Crich and Xu
NaHCO3, dried over Na2SO4, and concentrated to give an oily
residue that was purified by silica gel chromatography (hexanes/
ethyl acetate: 1/1) to give 22 (2.2 g, 98%) as a colorless oil. [R]D
+23.2 (c, 1.0, ethyl acetate); 1H NMR (500 MHz, CDCl3) δ 7.79-
7.83 (m, 2H), 7.70-7.72 (m, 2H), 6.21 (t, J ) 10.5 Hz, 1H), 5.17
(dd, J ) 3.0, 1.5 Hz, 1H), 4.91 (dd, J ) 11.5, 3.0 Hz, 1H), 4.70 (d,
J ) 1.5 Hz, 1H), 4.27 (dd, J ) 12.0, 6.0 Hz, 1H), 4.19 (dd, J )
12.0, 3.0 Hz, 1H), 3.99 (ddd, J ) 12.0, 6.0, 3.0 Hz, 1H), 3.45 (s,
3H), 2.11 (s, 3H), 2.06 (s, 3H), 1.86 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 170.7, 169.2, 167.8, 134.3, 131.4, 123.5, 98.4, 71.0, 70.0,
64.1, 63.2, 55.2, 50.9, 21.0, 20.8, 20.6; HRMS(ESI) m/z calcd for
C21H23NNaO10 [M + Na]+ 472.1215, found 472.1217.
Phenyl 4,6-O-Benzylidene-3-deoxy-3-phthalimido-2-O-trim-
ethylsilyl-R-1-thio-D-mannopyranoside (26). TMSOTf (130 uL,
0.72 mmol) was added to a mixture of 25 (178 mg, 0.36 mmol)
and sym-collidine (142 uL, 1.08 mmol) in dichloromethane (4 mL)
at 0 °C. The resulting mixture was stirred for 30 min at rt before
it was washed with aqueous NaHCO3 and brine then dried over
Na2SO4 and condensed under vacuum. Purification of the residue
on silica gel (hexanes/ethyl acetate/triethylamine 100/30/0.5) gave
26 (168 mg, 83%) as an oil. [R]D +20.8 (c, 0.5, ethyl acetate); 1H
NMR (500 MHz, CDCl3) δ 7.83 (m, 2H), 7.72 (m, 2H), 7.54 (m,
2H), 7.28-7.43 (m, 8H), 5.70 (s, 1H), 5.43 (dd, J ) 11.5, 9.5 Hz,
1H), 5.33 (s, 1H), 4.72 (dd, J ) 11.5, 3.0 Hz, 1H), 4.42 (td, J )
9.5, 4.5 Hz, 1H), 4.36 (d, J ) 3.0 Hz, 1H), 4.26 (dd, J ) 10.5, 5.0
Hz, 1H), 3.97 (t, 10.0 Hz, 1H), -0.10 (s, 9H); 13C NMR (125 M
Hz, CDCl3) δ 168.8, 167.6, 137.4, 134.2, 133.9, 133.4, 132.4, 129.3,
129.0, 128.2, 127.9, 126.3, 123.2, 101.8, 89.4 (1JCH ) 166.0 Hz),
72.5, 72.3, 68.7, 66.8, 54.3, -0.4; HRMS(ESI) m/z calcd for C30H31-
NNaO6SSi [M + Na]+ 584.1534, found 584.1535.
General Procedure for Coupling of Donors 16, 19, and 26
with Adamantanol. A mixture of donor 16, 19, or 26 (0.10 mmol),
1-benzenesulfinyl piperidine or diphenyl sulfoxide (0.11 mmol),
and 2,4,6-tri-tert-butylpyrimidine (50 mg, 0.20 mmol) in dry
dichloromethane (4 mL) was stirred with 4 Å MS (30 mg) at rt for
30 min, then cooled to -78 or -65 °C. Trifluoromethanesulfonic
anhydride (20 uL, 0.12 mmol) was added in one portion under
Argon and the reaction mixture was kept at this temperature for
30 min. 1-Adamantanol (30 mg, 0.20 mmol) in dichloromethane
(1 mL) was added at either -78 or -50 °C, and after being stirred
for the requisite time the reaction mixture was quenched with
saturated NaHCO3 (2 mL) and extracted with dichloromethane (3
× 10 mL). The combined organic phases were washed with water
(10 mL) and brine (10 mL), dried over Na2SO4, and concentrated
under reduced pressure, and the resulting residue was purified by
silica gel chromatography.
Phenyl 2,4,6-Tri-O-acetyl-3-deoxy-3-phthalimido-R-1-thio-D-
mannopyranoside (23). To a solution of 22 (2.25 g, 5 mmol) in
acetic anhydride (10 mL) was added HClO4 (two drops) at 0 °C,
followed by stirring at rt for 24 h before cold water (50 mL) was
added. The resulting mixture was allowed to stir for 2 h before it
was extracted with dichloromethane (3 × 50 mL). The combined
organic layers were washed with water (50 mL), aqueous NaHCO3
(50 mL), and brine (50 mL), dried over Na2SO4, and concentrated
under vacuum to afford a crude product as an oil. BF3‚Et2O (2
mL, 18.6 mmol) and PhSH (0.8 mL, 7.8 mmol) were added to this
crude product in dry dichloromethane (30 mL) at 0 °C and the
reaction mixture was stirred overnight before NaHCO3 (30 mL)
was added. The dichloromethane phase was separated and washed
with brine (20 mL), dried over Na2SO4, and concentrated to a
residue that was purified by silica gel chromatography (hexanes/
ethyl acetate/dichloromethane: 10/10/3) to give 23 (2.0 g 75%) as
1
a white solid. [R]D +82.4 (c, 0.5, ethyl acetate); mp 195 °C; H
NMR (500 MHz, CDCl3) δ 7.85 (dd, J ) 5.5, 3.0 Hz, 2H), 7.74
(dd, J ) 5.5, 3.0 Hz, 2H), 7.30-7.35 (m, 2H), 7.30-7.35 (m, 3H),
6.32 (t, J ) 10.5 Hz, 1H), 5.52 (d, 1.0 Hz, 1H), 5.45 (dd, J ) 2.5,
1.0 Hz, 1H), 4.92 (dd, J ) 11.0, 2.5 Hz, 1H), 4.58 (m, 1H), 4.31
(dd, J ) 12.0, 6.5 Hz, 1H), 4.21 (dd, J ) 12.0, 2.5 Hz, 1H), 2.07
(s, 3H), 2.06 (s, 3H), 1.93 (s, 3H); 13C (125 MHZ, CDCl3) δ 170.62,
170.55, 169.2, 167.7, 134.4, 132.6, 132.2, 131.3, 129.2, 128.1,
123.7, 85.9 (1JCH ) 168.8 Hz), 72.5, 71.2, 64.2, 63.1, 51.9, 21.0,
20.8, 20.7; HRMS(ESI) m/z calcd for C26H25NNaO9S [M + Na]+
550.1543, found 550.1545.
1-Adamantanyl 3-Azido-2-O-benzyl-3-deoxy-4,6-O-[1-cyano-
2-(2-iodophenyl)]ethylidene-R-D-mannopyranoside (27R) and
1-Adamantanyl 3-Azido-2-O-benzyl-3-deoxy-4,6-O-[1-cyano-2-
(2-iodophenyl)ethylidene-â-D-mannopyranoside (27â). Coupling
of 16 with adamantanol, after column chromatography on silica
gel (hexanes/ethyl acetate: 10/1), gave two stereoisomers: 27R
Phenyl 3-Deoxy-3-phthalimido-R-1-thio-D-mannopyranoside
(24). Peracetyl thioglycoside 23 (1.24 g, 2.35 mmol) and HCl in
ether (3 mL, 2M) were mixed in dry methanol (30 mL) at rt and
stirred overnight. The solvent was removed by rotary evaporation
at rt and the residue was purified by silica gel chromatography
(dichloromethane/MeOH: 5/1) to give triol 24 (0.92 g, 98%) as a
solid. [R]D +82.8 (c, 1.0, CHCl3); mp 95 °C; 1H NMR (300 MHz,
MeOH-d4) δ 7.76-7.89 (m, 4H), 7.54-7.59 (m, 2H), 7.27-7.36
(m, 3H), 5.45 (d, J ) 0.9 Hz, 1H), 5.13 (dd, J ) 11.1, 9.9 Hz,
1H), 4.51 (dd, J ) 11.1, 3.0 Hz, 1H), 4.14-4.20 (m, 2H), 3.85 (m,
2H); 13C NMR (125 MHz, MeOH-d4) δ 168.9, 134.0, 133.9, 131.9,
131.8, 128.8, 127.3, 122.7, 88.8, 75.6, 72.2, 61.2, 60.8, 57.0;
HRMS(ESI) m/z calcd for C20H19NNaO6S [M + Na]+ 424.0826,
found 424.0815.
1
and 27â. 27R: oil, [R]D +39.8 (c, 1.0, ethyl acetate); H NMR
(500 MHz, CDCl3) δ 7.88 (dd, J ) 8.0, 1.0 Hz, 1H), 7.48 (dd, J )
8.0, 1.5 Hz, 1H), 7.25-7.55 (m, 6H), 6.80 (td, J ) 8.0, 1.5 Hz,
1H), 4.96 (d, J ) 1.5 Hz, 1H), 4.79 (d, 12.0 Hz, 1H), 4.59 (d, J )
12.0 Hz, 1H), 4.35 (t, J ) 10.0 Hz, 1H), 4.07 (dd, J ) 10, 5.0 Hz,
1H), 3.96 (t, 10.5 Hz, 1H), 3.87 (td, J ) 10.0, 5.0 Hz, 1H), 3.78
(dd, J ) 10.5, 3.0 Hz, 1H), 3.55 (dd, J ) 3.0, 2.0 Hz, 1H), 3.53 (s,
2H), 2.10 (s, 3H), 1.52-1.61 (m, 12H); 13C NMR (125 MHz,
CDCl3) δ 139.9, 137.4, 135.5, 131.7, 129.4, 128.6, 128.4, 128.2,
128.1, 114.2, 102.8, 97.0, 91.6 (1JCH ) 167.5 Hz), 78.6, 75.3, 74.6,
73.8, 66.1, 62.8, 59.1, 48.8, 42.1, 36.1, 30.5; HRMS(ESI) m/z calcd
for C32NaH35IN4O5 [M + Na]+ 705.1545, found 705.1527. 27â:
oil, [R]D -16.7 (c, 1.0, ethyl acetate); 1H NMR (500 MHz, CDCl3)
δ 7.86 (dd, J ) 8.0, 1.5 Hz, 1H), 7.42-7.45 (m, 3H), 7.28-7.35
(m, 4H), 6.97 (td, J ) 8.0, 1.5 Hz, 1H), 4.97 (d, J ) 12.0 Hz, 1H),
4.82 (d, J ) 12.0 Hz, 1H), 4.78 (s, 1H), 4.34 (t, J ) 10.0 Hz, 1H),
4.05-4.16 (m, 2H), 3.69 (d, 3.0 Hz, 1H), 3.51 (s, 2H), 3.39 (dd, J
) 10.5, 3.0 Hz, 1H), 3.28 (td, J ) 10.0, 5.0 Hz, 1H), 2.16 (s, 3H),
1.57-1.82 (m, 12 H); 13C NMR (125 MHz, CDCl3) δ 139.9, 137.6,
135.5, 131.7, 129.4, 128.8, 128.1, 127.8, 114.2, 102.9, 96.7, 94.9
(1JCH ) 151.3 Hz), 77.9, 75.8, 75.4, 73.6, 66.9, 65.9, 61.8, 48.6,
42.3, 36.1, 30.6; HRMS(ESI): m/z calcd for C32H35IN4NaO5
[M + Na]+ 705.1545, found 705.1528.
Phenyl 4,6-O-Benzylidene-3-deoxy-3-phthalimido-R-1-thio-D-
mannopyranoside (25). Triol 24 (305 mg, 0.76 mmol), benzal-
dehyde dimethylacetal (127 mg, 125 uL), and camphorsufonic acid
(5 mg) were stirred in dry dichloromethane (10 mL) overnight
before triethylamine (1 drop) was added. The solvent was removed
under reduced pressure and the residue was purified by silica gel
chromatography (hexanes/ethyl acetate: 1/1) to give compound 25
1
(298 mg, 80%) as an oil. [R]D +41.2 (c, 1.0, ethyl acetate); H
NMR (500 MHz, CDCl3) δ 7.85-7.87 (m, 2H), 7.72-7.75 (m,
2H), 7.51-7.53 (m, 2H), 7.26-7.37 (m, 8H), 5.59 (d, J ) 1.5 Hz,
1H), 5.58 (s, 1H), 4.92-5.01 (m, 2H), 4.52 (td, J ) 10.0, 5.0 Hz,
1H), 4.39-4.41 (m, 1H), 4.31 (d, J ) 4.5 Hz, 1H), 4.25 (dd, J )
10.5, 5.5 Hz, 1H), 3.93 (t, 10.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 137.1, 134.5, 133.2, 132.0, 129.2, 129.1, 128.2, 127.8,
126.3, 123.8, 102.1, 89.2, 73.7, 72.7, 68.6, 67.0, 53.4; HRMS(ESI)
m/z calcd for C27H23NNaO6S [M + Na]+ 512.1139, found 512.1126.
1-Adamantanyl 3-Acetamido-2-O-benzyl-3-deoxy-4,6-O-[1-
cyano-2-(2-iodophenyl)]ethylidene-R-D-mannopyranoside (28R).
Coupling of 19 with adamantanol gave 28R (56%), which was
separated by silica gel chromatography (hexanes/ethyl acetate: 10/
1
3): oil, [R]D +31.4 (c, 0.5, ethyl acetate); H NMR (500 MHz,
CDCl3, -40 °C) δ 7.77 (d, J ) 7.5 Hz, 1H), 6.93-7.42 (m, 13H),
5190 J. Org. Chem., Vol. 72, No. 14, 2007

Synthesis of 3-Amino-3-deoxy-â-Mannopyranosides
5.09 (s, 1H), 4.96 (d, J ) 11.0 Hz, 1H), 4.72 (t, J ) 10.5 Hz, 1H),
4.65 (d, J ) 12.5 Hz, 1H), 4.36 (d, J ) 12.0 Hz, 1H), 3.85-3.99
(m, 2H), 3.78 (t, J ) 10.5 Hz, 1H), 3.72 (s, 1H), 2.59 (d, J ) 14.0
Hz, 1H), 2.37 (d, J ) 14.5, 1H), 2.10 (m, 3H), 2.05 (s, 3H),
1.40-1.66 (m, 12H); 13C (125 MHZ, CDCl3) δ 177.7, 139.9, 139.7,
137.3, 135.7, 131.6, 129.1, 128.8, 128.72, 128.65, 128.2, 128.0,
125.5, 122.0, 113.9, 102.6, 96.6, 91.0 (1JCH ) 165.0 Hz), 75.1,
73.3, 73.0, 66.3, 62.8, 56.4, 47.6, 42.2, 36.2, 30.6, 22.4; HRMS-
(ESI) m/z calcd for C40H43IN2NaO6S [M + Na]+ 829.1779, found
829.1777.
1-Adamantanyl 4,6-O-Benzylidene-3-deoxy-3-phthalimido-2-
O-trimethylsilyl-R-D-mannopyranoside (31R). Coupling of 26
with adamantanol gave 31R (77%), which was separated by silica
gel chromatography (hexanes/ethyl acetate: 10/3). 31R: oil; [R]D
-30.0 (c, 0.5, ethyl acetate); 1H NMR (500 MHz, CDCl3) δ 7.80-
7.82 (m, 2H), 7.67-7.70 (m, 2H), 7.40-7.42 (m, 2H), 7.26-7.29
(m, 3H), 5.68 (s, 1H), 5.33 (dd, J ) 11.5, 9.5 Hz, 1H), 5.04 (d, J
) 1.0 Hz, 1H), 4.74 (dd, J ) 11.0, 3.0 Hz, 1H), 4.25 (dd, J )
10.0, 5.0 Hz, 1H), 4.16 (td, J ) 10.0, 5.0, 1H), 3.93 (m, 1H), 3.90
(t, J ) 10.5 Hz, 1H), 2.17 (br s, 3H), 1.81-1.89 (m, 6H), 1.61-
1.69 (m, 6H), -0.08 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 137.7,
134.0, 128.9, 128.1, 126.3, 123.0, 101.7, 94.1 (1JCH ) 166.3 Hz),
74.7, 73.0, 72.5, 69.1, 65.1, 53.8, 42.4, 36.3, 30.6, -0.4; HRMS-
(ESI) m/z calcd for C34H42NO7Si [M + H]+ 604.2725, found
604.2726.
General Procedure of the Coupling Reaction of Donors 20
and 21 with Acceptors 32 and 33 and Adamantanol. A mixture
of donor 20 or 21 (0.10 mmol), diphenyl sulfoxide (0.11 mmol),
and 2,4,6-tri-tert-butylpyrimidine (50 mg, 0.20 mmol) in dry
dichloromethane (4 mL) was stirred together with 4 Å MS (30 mg)
at rt for 30 min, then cooled to -78 °C. Trifluoromethanesulfonic
anhydride (20 uL, 0.12 mmol) then was added in one portion under
Argon. Then the reaction mixture was raised to -65 °C over 15
min before the acceptor (0.20 mmol for adamantanol, 0.15 mmol
for 32 and 33) in dichloromethane (1.5 mL) was added. The
resulting mixture was allowed to rise to -10 °C gradually before
it was quenched with NaHCO3. The resulting mixture was extracted
with dichloromethane and the extracts concentrated to give a
residue, which was mixed with silica gel (1.5 g) then loaded onto
a silica gel column. Elution of the products was achieved with a
solution of 5% ethyl acetate in hexanes (100 mL), then a solution
of 20% ethyl acetate in hexanes (100 mL), and then a mixture of
hexanes/ethyl acetate/MeOH (10/5/1).
1-Adamantanyl 3-Amino-2-O-benzyl-3-deoxy-4,6-O-[1-cyano-
2-(2-iodophenyl)]ethylidene-â-D-mannopyranoside (29â). Cou-
pling of 20 with 1-adamantanol gave 29â (83%) as an oil. [R]D
-129.2 (c, 0.25, ethyl acetate); 1H NMR (500 MHz, CDCl3) δ 7.85
(d, J ) 7.5 Hz, 1H), 7.26-7.41 (m, 7H), 6.96 (td, J ) 7.5, 1.5 Hz,
1H), 5.09 (d, J ) 11.5 Hz, 1H), 4.84 (s, 1H), 4.64 (d, J ) 12.0 Hz,
1H), 4.11 (dd, J ) 11.0, 5.0 Hz, 1H), 4.01 (t, J ) 10.5 Hz, 1H),
3.79 (t, 9.5 Hz, 1H), 3.69 (d, 3.0 Hz, 1H), 3.47 (s, 2H), 3.15 (td,
J ) 10.0, 5.0 Hz, 1H), 2.78 (dd, J ) 10.0, 3.0 Hz, 1H), 2.16 (s,
3H), 1.76-1.86 (m, 6H), 1.59-1.67 (m, 6H); 13C NMR δ (125
MHz, CDCl3) δ 139.9, 138.4, 135.8, 131.8, 129.3, 128.5, 128.4,
128.0, 127.8, 114.7, 102.8, 96.8, 95.9 (1JCH ) 151.3 Hz), 80.4,
76.0, 75.4, 67.2, 65.9, 54.4, 48.7, 42.4, 36.2, 30.6; HRMS(ESI)
m/z calcd for C32H38IN2O5 [M + H]+ 657.1820, found 657.1830.
68.9, 68.4, 54.7, 42.4, 36.2, 30.6; HRMS(ESI) m/z calcd for C30H37-
NNaO5 [M + Na]+ 514.2564, found 514.2561.
Methyl 4-O-{3-Amino-2-O-benzyl-3-deoxy-4,6-O-[1-cyano-2-
(2-iodophenyl)]ethylidene-â-D-mannopyranosyl}-(1f4)-2,3-O-
isopropylidene-R-L-rhamnopyranoside (34â). Coupling of 20 with
32 gave 34â (76%) as an oil. [R]D -52.8 (c, 1.0, ethyl acetate); 1H
NMR (500 MHz, CDCl3) δ 7.86 (d, J ) 7.5 Hz, 1H), 7.41 (d, J )
7.5 Hz, 1H), 7.26-7.34 (m, 6H), 6.97 (t, J ) 7.5 Hz, 1H), 5.04 (s,
1H), 4.96 (d, 11.0 Hz, 1H), 4.86 (s, 1H), 4.56 (d, J ) 12.0 Hz,
1H), 4.10-4.18 (m, 3H), 4.01 (t, J ) 11.0 Hz, 1H), 3.86 (d, J )
3.0 Hz, 1H), 3.77 (t, J ) 9.5 Hz, 1H), 3.63 (m, 2H), 3.47 (m, 2H),
3.37 (s, 3H), 3.15 (td, J ) 10.0, 5.0 Hz, 1H), 2.82 (dd, J ) 10.0,
3.5 Hz, 1H), 1.51 (s, 3H), 1.35 (s, 3H), 1.29 (d, J ) 5.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 139.9, 138.3, 135.7, 131.8, 129.4,
128.4, 128.14, 128.10, 127.8, 114.7, 109.4, 102.7, 101.4 (1JCH
)
157.5 Hz), 97.9, 96.9, 79.1, 78.32, 78.27, 77.7, 76.1, 75.8, 67.4,
65.9, 64.1, 54.9, 54.1, 48.7, 28.0, 26.4, 17.7; HRMS(ESI) m/z calcd
for C32H40IN2O9 [M + H]+ 723.1779, found 723.1773.
Methyl (3-Amino-2-O-benzyl-4,6-O-benzylidene-3-deoxy-â-D-
mannopyranosyl)-(1f4)-2,3-O-isopropylidene-R-L-rhamnopy-
ranoside (35â). Coupling of 21 with 32 gave 35â (82%) as an oil.
1
[R]D -86.8 (c, 1.0, ethyl acetate); H NMR (500 MHz, CDCl3) δ
7.45-7.50 (m, 2H), 7.30-7.40 (m, 8H), 5.52 (s, 1H), 5.13 (s, 1H),
5.02 (d, J ) 11.5 Hz, 1H), 4.88 (s, 1H), 4.60 (d, J ) 11.5 Hz, 1H),
4.26 (dd, J ) 10.5, 5.0 Hz, 1H), 4.21 (dd, J ) 7.0, 5.5 Hz, 1H),
4.11 (d, J ) 5.5 Hz, 1H), 3.90 (d, J ) 5.0 Hz, 1H), 5.87 (t, J )
10.0 Hz, 1H), 3.72 (dd, J ) 10.0, 2.5 Hz, 1H), 3.66 (m, 1H), 3.61
(t, J ) 10.0 Hz, 1H), 3.39 (s, 3H), 3.34 (m, 1H), 2.93 (dd, J )
10.0, 3.0 Hz, 1H), 1.54 (s, 3H), 1.36 (s, 3H), 1.33 (d, J ) 6.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 138.7, 137.5, 129.1, 128.4,
128.3, 128.1, 127.8, 126.2, 109.4, 102.0, 101.3 (1JCH ) 157.5 Hz),
97.9, 80.6, 79.6, 78.4, 77.9, 76.1, 75.8, 68.7,68.6, 64.2, 54.9, 54.4,
27.9, 26.5, 17.7; HRMS(ESI) m/z calcd for C30H40NO9 [M + H]+
558.2698, found 558.2694.
Methyl 2,3,6-Tri-O-benzyl-4-O-{3-amino-2-O-benzyl-3-deoxy-
4,6-O-[1-cyano-2-(2-iodophenyl)]ethylidene-â-D-mannopyrano-
syl}-R-D-glucopyranoside (36â). Coupling of 20 with 33 gave 36â
1
(82%) as an oil. [R]D +0.8 (c, 1.0, ethyl acetate); H NMR (500
MHz, CDCl3) δ 7.43 (dd, J ) 8.0, 1.5 Hz, 1H), 7.24-7.39 (m,
22H), 7.00 (td, J ) 8.0, 1.5 Hz, 1H), 4.95 (d, J ) 11.0 Hz, 1H),
4.94 (d, J ) 10.5 Hz, 1H), 4.86 (d, J ) 12.0 Hz, 1H), 4.75 (d, J )
12.0 Hz, 1H), 4.74 (d, J ) 10.0, 1H), 4.68 (d, J ) 12.0 Hz, 1H),
4.64 (d, J ) 3.5 Hz, 1H), 4.57 (d, J ) 11.5 Hz, 1H), 4.33 (d, J )
12.0 Hz, 1H), 4.28 (s, 1H), 3.92 (t, 9.0 Hz, 1H), 3.80-3.87 (m,
2H), 3.45-3.69 (m, 9H), 3.42 (s, 3H), 2.73 (td, J ) 10.0, 5.0 Hz,
1H), 2.36 (dd, J ) 10.0, 5.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 139.9, 139.1, 138.4, 138.1, 137.5, 135.9, 132.1, 129.5, 128.7,
128.6, 128.4, 128.3, 128.13, 128.09, 128.0, 127.9, 127.8, 127.5,
114.8, 102.9, 102.2 (1JCH ) 155.0 Hz), 98.5, 96.7, 80.2, 79.3, 79.0,
77.0, 76.0, 75.6, 73.7, 69.7, 68.1, 67.0, 65.7, 55.5, 53.9, 48.7;
HRMS(ESI) m/z calcd for C50H54IN2O10 [M + H]+ 969.2823, found
969.2827.
Methyl (3-Amino-2-O-benzyl-4,6-O-benzylidene-3-deoxy-â-D-
mannopyranosyl)-(1f4)-2,4,6-tri-O-benzyl-R-D-glucopyrano-
side (37â). Coupling of 21 with 33 gave 37â (92%) as a colorless
1
oil. [R]D -36.1 (c, 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ
7.25-7.47 (m, 25H), 5.43 (s, 1H), 5.07 (d, J ) 11.0 Hz, 1H), 5.00
(d, J ) 11.0 Hz, 1H), 4.82 (d, 12.0 Hz, 1H), 4.53-4.75 (m, 6H),
4.42 (d, J ) 12.0 Hz, 1H), 4.11 (dd, J ) 10.5, 5.0 Hz, 1H), 3.98
(t, J ) 9.0 Hz, 1H), 3.85 (t, 9.0 Hz, 1H), 3.64-3.71 (m, 4H), 3.55
(dd, J ) 10.0, 4.0 Hz, 1H), 3.49 (dd, J ) 18.0, 10.5 Hz, 2H), 3.41
(s, 3H), 3.07 (td, J ) 10.0, 5.0 Hz, 1H), 2.63 (dd, J ) 10.5, 3.0
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 139.4, 138.5, 138.4, 137.5,
129.2, 128.7, 128.41, 128.36, 128.2, 128.1, 127.82, 127.76, 127.3,
126.2, 102.5, 102.0 (1JCH ) 162.5 Hz), 98.5, 80.4, 80.2, 79.7, 78.9,
77.5, 76.0, 75.4, 73.7, 69.8, 68.7, 68.4, 68.3, 55.4, 54.2; HRMS-
(ESI) m/z calcd for C48H54NO10 [M + H]+ 804.3742, found
804.3727.
1-Adamantanyl 3-Amino-2-O-benzyl-4,6-O-benzylidene-3-
deoxy-â-mannopyranoside (30â). Coupling of 21 with 1-adaman-
tanol gave 30â (78%) as an oil. [R]D -50.0 (c, 1.0, ethyl acetate);
1H NMR (500 MHz, CDCl3) δ 7.27-7.51 (m, 10H), 5.50 (s, 1H),
5.16 (d, J ) 12.0 Hz, 1H), 4.91 (s, 1H), 4.65 (d, 11.5 Hz, 1H),
4.25 (dd, J ) 10.0, 5.0 Hz, 1H), 3.85 (t, J ) 10.0 Hz, 1H), 3.73 (d,
J ) 3.0 Hz, 1H), 3.61 (t, J ) 9.5 Hz, 1H), 3.35 (td, J ) 10.0, 5.0
Hz, 1H), 2.91 (dd, J ) 10.0, 3.0 Hz, 1H), 2.19 (s, 3H), 1.89 (d, J
) 11.5 Hz, 3H), 1.83 (d, J ) 11.0 Hz, 3H), 1.62-1.70 (m, 6H);
13C NMR (125 MHz, CDCl3) δ 138.8, 137.6, 129.1, 128.5, 128.3,
127.7, 126.2, 102.0, 95.8 (1JCH ) 151.3 Hz), 81.1, 80.3, 76.2, 75.2,
1-Adamantanyl 3-N-(tert-Butyloxycarbonylamino)-2-O-ben-
J. Org. Chem, Vol. 72, No. 14, 2007 5191

Crich and Xu
zyl-3-deoxy-4,6-O-[1-cyano-2-(2-iodophenyl)]ethylidene-â-D-
mannopyranoside (40). To a solution of amine 29â (75 mg, 0.11
mmol) and (Boc)2O (30 mg, 0.14 mmol) was added triethylamine
(30 uL, 0.23 mmol) in dry THF (5 mL). The reaction mixture was
stirred at rt for 4 h, then concentrated under vacuum to give a
residue, which was purified by chromatography on silica gel
(hexanes/ethyl acetate: 10/1) to give 40 (89 mg, 100%) as a white
solid. [R]D -42.6 (c, 0.5, ethyl acetate); mp 202-203 °C; 1H NMR
(500 MHz, CDCl3) δ 7.84 (dd, J ) 8.0, 1.0 Hz, 1H), 7.40, (dd, J
) 8.0, 1.5 Hz, 1H), 7.24-7.37 (m, 6H), 6.94 (td, J ) 8.0, 1.5 Hz,
1H), 5.01 (d, J ) 12.0 Hz, 1H), 4.87 (s, 1H), 4.79 (d, J ) 11.0 Hz,
1H), 4.66 (d, J ) 12.0 Hz, 1H), 4.11 (dd, J ) 11.0, 6.0 Hz, 1H),
4.00 (t, J ) 10.5 Hz, 1H), 3.83-3.92 (m, 2H), 3.67 (d, 2.5 Hz,
1H), 3.48 (d, J ) 14.5 Hz, 1H), 3.43 (d, J ) 14.5 Hz, 1H), 3.28
(m, 1H), 2.17 (s, 3H), 1.84 (d, J ) 10.5 Hz, 3H), 1.76 (d, J ) 11.5
Hz, 3H), 1.6 (d, J ) 12.5 Hz, 3H), 1.61 (d, J ) 12.0 Hz, 3H), 1.42
(s, 9H); 13C NMR (125 MHz, CDCl3) δ 155.3, 139.8, 138.0, 135.7,
128.9, 128.7, 128.2, 127.8, 117.8, 112.9, 94.3 (1JCH ) 151.3 Hz),
77.9, 75.2, 73.5, 73.4, 55.2, 42.5, 41.3, 36.3, 30.7, 17.9; HRMS-
(ESI) m/z calcd for C32H39N2O5 [M + H]+ 531.2854, found
531.2855.
1-Adamantanyl 2-O-Benzyl-3-N-(tert-butyloxycarbonylamino)-
3-deoxy-4,6-O-[2-(2-cyanophenyl)]ethylidene-â-D-mannopyrano-
side (41) and 1-Adamantanyl 2-O-Benzyl-3-N-(tert-butyloxy-
carbonylamino)-3-deoxy-â-D-rhamnopyranoside (42). Under a
variety of conditions of solvent, temperature, reductant, and initiator
for the radical reaction, 40 gave mixtures of two isomers after silica
gel chromatography (hexanes/ethyl acetate: 5/1) in low yield.
Saponification of these mixtures with catalytic MeONa in methanol
followed by silica gel chromatography (hexanes/ethyl acetate: 5/1
then 3/1) enabled the separation of 41 and 42. Reduction product
41: [R]D -20.4 (c, 0.5, ethyl acetate); 1H NMR (500 MHz, CDCl3)
δ 7.60 (d, J ) 8.0 Hz, 1H), 7.47 (t, J ) 7.0, Hz, 1H), 7.40 (d, J )
8.0 Hz, 1H), 7.27-7.35 (m, 6H), 5.01 (d, J ) 12.0 Hz, 1H), 4.86
(s, 1H), 4.76 (d, J ) 9.0 Hz, 1H), 4.71 (t, J ) 5.0 Hz, 1H), 4.61
(d, J ) 11.5 Hz, 1H), 4.06 (dd, J ) 11.0, 5.0 Hz, 1H), 3.83 (td, J
) 8.0, 3.5 Hz, 1H), 3.69 (d, J ) 2.0 Hz, 1H), 3.56 (t, J ) 10.5 Hz,
1H), 3.44 (t, J ) 10.5 Hz, 1H), 3.26 (td, J ) 9.5, 5.0 Hz, 1H), 3.16
(d, J ) 5.0 Hz, 1H), 2.16 (s, 3H), 1.83 (d, J ) 11.5 Hz, 3H), 1.76
(d, J ) 11.5 Hz, 3H), 1.63 (m, 6H), 1.41 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 155.5, 140.0, 132.9, 132.6, 132.4, 131.6, 128.7,
128.5, 127.9, 127.1, 118.1, 113.4, 101.0, 95.1, 79.4, 79.0, 76.3,
75.8, 75.4, 68.4, 68.3, 52.9, 42.4, 39.2, 36.2, 30.6, 28.4; HRMS-
(ESI) m/z calcd for C37H46N2NaO7 [M + Na]+ 653.3203, found
653.3177. Fragmentation product 42: [R]D -37.9 (c, 1.0, ethyl
131.8, 129.3, 128.9, 128.6, 128.0, 114.5, 102.9, 96.8, 95.3 (1JCH
)
156.3 Hz), 79.6, 78.5, 75.6, 73.9, 67.3, 65.9, 52.5, 48.7, 42.4, 36.2,
30.6, 28.4; HRMS(ESI) m/z calcd for C37H46IN2O7 [M + H]+
757.2344, found 757.2347.
General Procedure for Radical Fragmentation. A solution of
substrate (0.006 M) in dry toluene or xylenes was deoxygenated
by sparging with Argon at rt with stirring for 2 h then was heated
to reflux with stirring under Argon while a mixture of initiator
(azoisobutyronitrile or 1,1′-azobis(cyanocyclohexane) (0.2 equiv))
and hydrogen donor (tributyltin hydride or tris(trimethylsilylsilane)
(1.6 equiv)) in the same deoxygenated solvent (0.025 M) was added
by syringe pump in 2 h. The reaction mixture was cooled, the
solvent was removed under vacuum, and the residue was dissolved
in acetonitrile and washed with hexanes (5 times). The acetonitrile
phase was concentrated under vacuum and the residue subjected
to silica gel chromatography.
1-Adamantanyl 3-Amino-2-O-benzyl-3-deoxy-3-N-(2-cyanophe-
nyl)acetyl-â-D-rhamnopyranoside (39). With 29â as substrate the
radical reaction was executed in xylenes, with addition of the
reagents over 2 h. Silica gel chromatography (hexanes/ethyl acetate/
MeOH: 10/5/1) then preparative HPLC were applied to give
compound 39 in 20% yield: [R]D -59.8 (c, 0.5, ethyl acetate); 1H
NMR (500 MHz, CDCl3) δ 7.58 (d, J ) 8.0 Hz, 1H), 7.51 (td, J
) 7.5, 1.5 Hz, 1H), 7.30-7.42 (m, 7H), 6.01 (d, J ) 8.0 Hz, 1H),
5.08 (d, J ) 12.5 Hz, 1H), 4.82 (s, 1H), 4.58 (d, J ) 12.0 Hz, 1H),
3.87-3.92 (m, 1H), 3.56 (d, J ) 3.0 Hz, 1H), 3.49 (d, J ) 16.0
Hz, 1H), 3.41 (d, J ) 15.5 Hz, 1H), 3.27-3.34 (m, 2H), 2.79 (br
s, 1H), 2.18 (s, 3H), 1.89 (d, J ) 11.0 Hz, 3H), 1.81 (d, J ) 11.0
Hz, 3H), 1.61-1.68 (m, 6H), 1.33 (d, J ) 6.0 Hz, 3H); 13C NMR
(500 MHz, CDCl3) δ 170.4, 138.6, 138.2, 133.1, 132.8, 130.6,
1
acetate); H NMR (500 MHz, CDCl3) δ 7.30-7.37 (m, 5H), 5.70
(d, J ) 12.5 Hz, 1H), 4.96 (d, J ) 8.0 Hz, 1H), 4.79 (s, 1H), 4.63
(d, J ) 12.5 Hz, 1H), 3.50-3.54 (m, 2H), 3.32 (t, J ) 9.5 Hz,
1H), 3.22-3.27 (m, 1H), 2.95 (s, 1H), 2.17 (s, 3H), 1.88 (d, J )
11.5 Hz, 3H), 1.80 (d, J ) 11.5 Hz, 3H), 1.63 (m, 6H), 1.38 (s,
9H), 1.33 (d, J ) 5.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
157.5, 138.5, 128.6, 127.9, 94.6 (1JCH ) 151.3 Hz), 80.1, 77.9,
75.0, 73.6, 73.4, 55.9, 42.5, 36.3, 30.7, 28.3, 17.9; HRMS(ESI)
m/z calcd for C28H41NNaO6 [M + Na]+ 510.2832, found 510.2837.
Acknowledgment. We thank the NIH (GM57335) for
support of this work and Professor D. J. Wink for the X-ray
structures.
Supporting Information Available: Copies of spectra of all
compounds, and CIF files for compounds 12 and 15. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO070473P
5192 J. Org. Chem., Vol. 72, No. 14, 2007