Development of an efficient, regio- and stereoselective route to libraries based on the β-D-glucose scaffold

Article abstract of DOI:10.1021/jo001099v

The design and execution of an efficient synthetic route for the sequential functionalization of the five hydroxyl substituents of β-D-glucose has been achieved. This strategy, based on the stereoselective glycosidation of thioglycosides, provides a new approach for the parallel construction of a wide variety β-D-glucose analogues and as such holds promise for solid-support library syntheses.

Full text of DOI:10.1021/jo001099v

J . Org. Chem. 2000, 65, 8307-8316
8307
Develop m en t of a n Efficien t, Regio- a n d Ster eoselective Rou te to
Libr a r ies Ba sed on th e â-D-Glu cose Sca ffold
Ralph Hirschmann,* Laurent Ducry, and Amos B. Smith, III*
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
smithab@sas.upenn.edu.
Received J uly 20, 2000
The design and execution of an efficient synthetic route for the sequential functionalization of the
five hydroxyl substituents of â-D-glucose has been achieved. This strategy, based on the stereose-
lective glycosidation of thioglycosides, provides a new approach for the parallel construction of a
wide variety of â-D-glucose analogues and as such holds promise for solid-support library syntheses.
In the early 1990s we reported that â-D-glucose deriva-
tives that lack the amide backbone of peptides but retain
peptidal side chains can serve as competent nonpeptidal
peptidomimetics1 of the hormone somatostatin (SRIF).2
This and more recent observations demonstrate that
monosaccharides possess many characteristics which
afford them particularly attractive scaffolds. They are
readily available, chiral, conformationally rigid, highly
functionalized, displaying the five hydroxyl groups in a
well defined, three-dimensional arrangement as vectors
for the introduction of diverse side-chains. In addition
they possess pseudo symmetry,2a a potential advantage
in the evaluation of new compounds in diverse screens.2c
They have also been shown to be stable in gastric acid
(pH 1.2 at 37 °C) and to glycosidases,2d thus offering a
potential advantage to the limitations of peptidal thera-
peutic agents, such as low metabolic stability. The recent
discovery that some congeners of â-D-glucose are also
potent â-adrenergic and NK-1 antagonists2b suggested
that â-D-glucose, and more generally monosaccharides,
are privileged platforms for the design of therapeutically
important agents. Taken together these observations
raised our interest in the development of an efficient
route for the selective functionalization of all five hy-
droxyl groups of the â-D-glucose scaffold. In this full
account we describe a new approach for the preparation
of carbohydrate-based libraries for broad screening.
Solid-support synthesis is presently the most widely
used method to generate a library for lead discovery.3 Our
goal, therefore, was to develop a viable synthetic sequence
in solution that could later be extended to solid-support.
Much of the recent progress in carbohydrate solid-phase
chemistry involves oligosaccharides or glycopeptides4 and
relies on two broad strategies.5 In the first, the saccharide
is anchored to the support via the C(6) hydroxyl group
and functions as a donor in the coupling event. Alterna-
tively, the saccharide can be linked to the resin via the
C(1) hydroxyl group and serves as a glycosyl acceptor.
For our purposes both protocols suffer from a common
limitation: removal from the resin at the end of the on-
resin synthetic sequence would reveal a free hydroxyl
group, either at C(1) or at C(6), that would require
additional solution-phase functionalization. A related
strategy consists of attaching the monosaccharide scaffold
to the solid support through a prelinked diversity ele-
ment; this approach, however, restricts the choice for this
side-chain (e.g., amino acids).6 We instead envisaged use
of a thioglycoside anchor that would serve as glycosyl
donor, thus permitting glycosidation to remove the
monosaccharide from the resin with simultaneous intro-
duction of a diversity element at C(1).7
The use of thiol linkers has been used previously for
oligosaccharide synthesis,8,9 as well as for the sequential
functionalization of D-galactose wherein an orthogonally
protected10 thioglycoside 1 was attached to a polystyrene
resin via formation of an amide linkage (Scheme 1).11 The
requirement of monosaccharides with orthogonal protect-
ing groups, however, would increase the synthetic com-
plexity and the cost of such a library. We therefore
devised a different strategy in which a thiol-functional-
(1) (a) Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30, 1278-
1301. (b) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993,
32, 1244-1267. (c) Gante, J . Angew. Chem., Int. Ed. Engl. 1994, 33,
1699-1720.
(4) (a) Osborn, H. M. I.; Khan, T. H. Tetrahedron 1999, 55, 1807-
1850. (b) Sofia, M. J . Mol. Diversity 1998, 3, 75-94.
(5) Seeberger, P. H.; Danishefsky, S. J . Acc. Chem. Res. 1998, 31,
685-695.
(6) Sofia, M. J .; Hunter, R.; Chan, T. Y.; Vaughan, A.; Dulina, R.;
Wang, H.; Gange, D. J . Org. Chem. 1998, 63, 2802-2803.
(7) For a review on glycosidation, see: Toshima, K.; Tatsuta, K.
Chem. Rev. 1993, 93, 1503-1531.
(8) (a) Rademann, J .; Schmidt, R. R. Tetrahedron Lett. 1996, 37,
3989-3990. (b) Rademann, J .; Schmidt, R. R. J . Org. Chem. 1997, 62,
3650-3653.
(9) Yan, L.; Taylor, C. M.; Goodnow, R., J r.; Kahne, D. J . Am. Chem.
Soc. 1994, 116, 6953-6954.
(10) For orthogonal protection-deprotection strategies, see: (a)
Wunberg, T.; Kallus, C.; Opatz, T.; Henke, S.; Schmidt, W.; Kunz, H.
Angew. Chem., Int. Ed. 1998, 37, 2503-2505. (b) Wong, C.-H.; Ye, X.-
S.; Zhang, Z. J . Am. Chem. Soc. 1998, 120, 7137-7138.
(11) Kallus, C.; Opatz, T.; Wunberg, T.; Schmidt, W.; Henke, S.;
Kunz, H. Tetrahedron Lett. 1999, 40, 7783-7786.
(2) (a) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E.
M.; Salvino, J .; Arison, B.; Cichy, M. A.; Spoors, P. G.; Shakespeare,
W. C.; Sprengeler, P. A.; Hamley, P.; Smith, A. B., III; Reisine, T.;
Raynor, K.; Maechler, L.; Donaldson, C.; Vale, W.; Freidinger, R. M.;
Cascieri, M. R.; Strader, C. D. J . Am. Chem. Soc. 1993, 115, 12550-
12568. (b) Hirschmann, R.; Hynes, J ., J r.; Cichy-Knight, M. A.; van
Rijn, R. D.; Sprengeler, P. A.; Spoors, P. G.; Shakespeare, W. C.;
Pietranico-Cole, S.; Barbosa, J .; Liu, J .; Yao, W.; Rohrer, S.; Smith, A.
B., III. J . Med. Chem. 1998, 41, 1382-1391. (c) Liu, J .; Underwood,
D. J .; Cascieri, M. A.; Rohrer, S. P.; Cantin, L.-D.; Chicchi, G.; Smith,
A. B, III.; Hirschmann, R. Manuscript in preparation. (d) Prasad, V.
Manuscript in preparation.
(3) (a) Thompson, L. A.; Ellman, J . A. Chem. Rev. 1996, 96, 555-
600. (b) Obrecht, D.; Villalgordo, J . M. Solid-Supported Combinatorial
and Parallel Synthesis of Small-Molecular-Weight Compound Librar-
ies; Tetrahedron Organic Chemistry Series Vol. 17; Pergamon: Oxford,
1998.
10.1021/jo001099v CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/08/2000

8308 J . Org. Chem., Vol. 65, No. 24, 2000
Hirschmann and Ducry
Sch em e 1
Sch em e 3
ized resin would be employed as the nucleophile to react
with an 1,2-R-anhydro sugar [e.g., (+)-3]. This tactic has
the advantage of starting from the known epoxide (+)-3,
readily available from tri-O-acetyl-D-glucal.12 What re-
mained was to design a short, efficient route to function-
alize selectively the four hydroxyl substituents of the
resin-bound thioglycoside 4, noting that at this stage
three of the hydroxyls were not differentiated. Toward
this end, we explored the solution functionalization of
(-)-5 as a model for 4. These studies permitted both the
optimization of the individual steps and validation of our
overall strategy for the diversity-oriented derivatization
of the â-D-glucose scaffold.
Va lid a tion of th e Solu tion -P h a se Syn th etic Str a t-
egy. Ethanethiol was used as the nucleophile for the
opening of epoxide (+)-3, to mimic the thiol-functionalized
resin (Scheme 2). Initial attempts employed zinc chloride
as a Lewis acid promoter; the reaction, however, only
proceeded in low yield (27%) and with no diastereoselec-
tivity.12 In contrast, use of trifluoroacetic anhydride in
furnished (-)-7 in 95% yield (Scheme 3). The silyl
protecting groups in thioglycoside (-)-7 were then re-
moved with tetrabutylammonium fluoride (TBAF) under
acidic conditions14 so as to avoid benzoyl group migration
from one hydroxyl to another. Both the C(4) and C(6)
hydroxyls of (-)-8 were then protected as the p-meth-
oxybenzylidene (PMB) acetal. Unfortunately, alkylation
of the remaining C(3) hydroxyl in (-)-9 proved difficult;
basic conditions (NaH) led to migration of the benzoyl
group, while acidic reagents such as trichloroacetimi-
dates15 failed to react, presumably due to steric conges-
tion. The C(3) hydroxyl group was therefore functional-
ized via a Cu(I)-mediated reaction with isopropyl isocy-
anate to afford carbamate (-)-10 in good yield.16 The
p-methoxybenzylidene acetal in (-)-10 was then reduced
with borane-trimethylamine/aluminum(III) chloride in
THF,17 to install selectively a PMB ether at C(6) and to
liberate a free hydroxyl group at C(4), while maintaining
the benzoyl group intact. It is particularly noteworthy
that reduction of benzylidene acetals under these condi-
tions furnished substrates with a benzyl ether at C(4)
Sch em e 2
dichloromethane13 furnished the desired â-anomer (-)-5
in 85% yield together with 4% of the R-anomer (+)-6 (19:1
selectivity). Toluene also proved effective as solvent,
providing similar yields with good selectivity; the faster
reaction time also facilitated reaction scale-up. We next
introduced an ester group at C(2) to ensure formation of
a â-D-glycosidic linkage (e.g., neighboring-group partici-
pation) in the final glycosidation reaction. Treatment of
(-)-5 with benzoyl chloride in pyridine/dichloromethane
(14) Smith, A. B., III; Ott, G. R. J . Am. Chem. Soc. 1996, 118,
13095-13096 and references therein.
(15) (a) Iversen, T.; Bundle, D. R. J . Chem. Soc., Chem. Commun.
1981, 1240-1241. (b) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J . Chem.
Soc., Perkin Trans. 1 1985, 2247-2250.
(16) Duggan, M. E.; Imagire, J . S. Synthesis 1989, 131-132.
(17) (a) Ek, M.; Garegg, P. J .; Hultberg, H.; Oscarson, S. J .
Carbohydr. Chem. 1983, 2, 305-311. (b) As reported in Smith, A. B.,
III; Hale, K. J .; Vaccaro, H. A.; Rivero, R. A. J . Am. Chem. Soc. 1991,
113, 2112-2122; in this case, however, the solvent was CH2Cl2.
(12) Halcomb, R. L.; Danishefsky, S. J . J . Am. Chem. Soc. 1989,
111, 6661-6666.
(13) Seeberger, P. H.; Eckhardt, M.; Gutteridge, C. E.; Danishefsky,
S. J . J . Am. Chem. Soc. 1997, 119, 10064-10072.

â-D-Glucose Scaffold-Based Libraries
J . Org. Chem., Vol. 65, No. 24, 2000 8309
and a hydroxyl group at C(6),17 a result expected due to
the large steric demand of the Lewis acid (kinetic
product),18 whereas p-methoxybenzylidene acetals under
the same conditions lead to the opposite regioselectivity.19
Presumably, the p-methoxy group decreases the reactiv-
ity of the acetal sufficiently via resonance to permit
equilibration of the Lewis acid. Coordination of AlCl3 to
the more acidic C(4)-oxygen would then result in the
formation of the thermodynamic product.
Sch em e 4
Continuing with the functionalization of (+)-11, alky-
lation afforded benzyl ether (+)-12 in 95% yield. Oxida-
tive-removal of the PMB group with 1,2-dichloro-4,5-
dicyanobenzoquinone (DDQ) then gave alcohol (+)-13.
Next, a second carbamate side-chain was introduced,
yielding (+)-14, thereby illustrating that functionaliza-
tion at C(6) is possible. In most cases, however, the C(6)-
hydroxyl group was retained unfunctionalized partly to
keep the molecular weight of the final products below
600 Da, while increasing water-solubility. Maintaining
a free hydroxyl at C(6) could also be beneficial for
binding.20 Finally, glycosidation can be reliably ac-
complished with methanol, using promoters such as
N-iodosuccinimide (NIS) and trifluorosulfonic acid,21 to
furnish the desired â-anomers (+)-15 and (+)-16 in 91%
and 80% yield, respectively. Retention of configuration
at the anomeric position through double inversion (an-
chimeric assistance) accounts for the observed greater
than 9:1 â-stereoselectivity (1H NMR). The fully substi-
tuted â-D-glucose derivative (+)-16 is thus available in
10 steps and in 17.7% overall yield, corresponding to an
average yield of 84% for each step.
Syn th esis of a Sm a ll Libr a r y of â-D-Glu cosid es.
To explore the scope of this reaction sequence as well as
building block compatibility, we devised a small library
of â-D-glucosides with potentially interesting biological
properties. We were in particular interested in introduc-
ing side-chains that are not found among the coded amino
acids. After replacement of the peptidic backbone by the
â-D-glucose scaffold, this approach takes us one step
further away from peptides in order to establish monosac-
charides not only as peptidomimetics, but as an inde-
pendent class of potentially important therapeutic agents.
Glucoside (+)-18, incorporating a morpholine functional-
ity, was selected as our first target. Attempted direct
glycosidation of (+)-13 with 4-(2-hydroxyethyl)morpho-
line afforded only unchanged starting material. Presum-
ably the basic tertiary amine inhibits the acid-promoted
glycosidation. To circumvent this difficulty, we employed
a two-step sequence consisting of glycosidation with
2-bromoethanol as the nucleophile to furnish bromide
(+)-17 (Scheme 4); the reaction proceeded with greater
than 9:1 â-selectivity. Substitution of the terminal bro-
mide with morpholine then led to (+)-18 as a beautifully
crystalline solid. Single-crystal X-ray analysis confirmed
the structure and stereochemistry. Glycosides (+)-19 and
(+)-20 were similarly prepared from (+)-17, using pip-
eridine and N-methylpiperazine as nucleophiles. Hydro-
lytic removal of the benzoyl groups then furnished the
more hydrophilic glycosides (+)-21, (+)-22, and (+)-23,
with molecular weights of 468, 466, and 481 Da, respec-
tively.
Derivatives lacking the C(4)-benzyl groups were also
targeted to increase the diversity of our library while
again reducing molecular weights. Toward this end,
reductive removal of the benzyl group in (+)-18 furnished
(+)-25 in 89% yield (Scheme 5). Interestingly, we discov-
ered that glycosidation of (+)-11 under the same condi-
tions as previously presented simultaneously removed
Sch em e 5
the PMB group at C(6) to give diol (+)-24 in 48% yield
(4:1 â-selectivity), thus offering an alternative route
toward C(6)-unfunctionalized derivatives. Substitution of
the bromide with morpholine, piperidine, and N-meth-
ylpiperazine generated (+)-25, (+)-26 and (+)-27 respec-
tively, in yields ranging from 70 to 99%. This result also
enabled us to convert thioglycoside (+)-12 directly to (+)-
(18) Garegg, P. J .; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982,
108, 97-101.
(19) Sanders, W. J .; Manning, D. D.; Koeller, K. M.; Kiessling, L. L.
Tetrahedron 1997, 53, 16391-16422.
(20) Dinh, T. Q.; Smith, C. D.; Du, X.; Armstrong, R. W. J . Med.
Chem. 1998, 41, 981-987.
(21) (a) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J . H.
Tetrahedron Lett. 1990, 31, 1331-1334. (b) Konradsson, P.; Udodong,
U. E.; Fraser-Reid, B. Tetrahedron Lett. 1990, 31, 4313-4316.

8310 J . Org. Chem., Vol. 65, No. 24, 2000
Hirschmann and Ducry
Sch em e 6
17 in 70% yield, with greater than 9:1 â-selectivity.
Interestingly removal of the PMB group in (+)-12 was
faster than the glycosidation reaction, as evidenced by
the isolation of thioglycoside (+)-13 as the only product,
upon premature quenching of the reaction. This observa-
tion supports NIS-mediated PMB oxidation of (+)-12, as
opposed to deprotection via the in situ generated thiol.22
N-Bromosuccinimide (NBS) has been reported to remove
the p-methoxybenzyl moiety from ethers,23 but to the best
of our knowledge this is the first use of NIS. It is also
notable that the benzyl moiety at C(4) remains intact
under these conditions, illustrating that this protocol is
selective for p-methoxybenzyl over benzyl ethers.
An ch im er ic Assista n ce a t C(2) via th e Ca r ba m a te
Gr ou p . A key element of our strategy for â-glucosides is
the use of a participating group at C(2) to ensure
formation of the desired 1,2-trans-â-glycoside in the final
glycosidation. As discussed above, esters are well-known
to furnish â-selective glucosidation. A participating group
at C(2) that, unlike esters,24 cannot be removed by
proteases would be highly desirable. Although amides
would fulfill this criteria, conversion of the C(2)-hydroxyl
to the corresponding primary amine would significantly
lengthen the synthetic sequence.25 Carbamates appeared
to be a better choice since they combine stability toward
hydrolytic enzymes with ease of introduction. Moreover
the effectiveness of C(2)-carbamates for stereoselective
Koenigs-Knorr glycosidation of altrosyl fluorides has
been reported.26 Encouraged by this observation, a benzyl
carbamate was installed at the C(2)-hydroxyl of (-)-5 via
reaction with benzyl isocyanate in pyridine/dichlo-
romethane on the way to (+)-37. On small scale (ca. 100
mg) the reaction proved near quantitative; however, on
larger scale complete conversion could not be achieved
leading to significant recovered starting material (34%).
Continuing with the synthesis of (+)-37 (Scheme 6),
removal of the three TBS groups in carbamate (-)-28
proved much faster and more efficient with hydrogen
fluoride (HF) than with TBAF, as used previously
(Scheme 3). Formation of the PMB acetal then permitted
selective functionalization of the C(3)-hydroxyl again as
a carbamate; reduction of the PMB acetal led to (+)-32
in 56% isolated yield, along with 30% of the diol (+)-33.
O-Benzylation of alcohol (+)-32 next generated ether (-)-
34 in 86% yield. We were pleased to discover that both
(+)-33 and (-)-34 could be glycosidated selectively (>95:
5), albeit both in moderate yield (39% and 44%, respec-
tively). Presumably the increased stability of the cyclic
imminium intermediate compared to the cyclic oxonium
species accounts for the better stereoselectivity but lower
conversion. Substitution of (-)-35 with morpholine then
furnished diol (+)-37 in 85% yield.
been developed. This work sets the stage for the prepara-
tion of monosaccharide libraries in which â-D-glucose will
serve as platform with the groups attached to the
hydroxyls as diversity elements. The efficacy of the
solution protocols has been demonstrated via the prepa-
ration of a small library of monosaccharides. We antici-
pate that the reaction sequence will prove easily ame-
nable to solid-phase synthesis thereby facilitating the
construction of diverse monosaccharide libraries. Studies
toward this end are currently underway in our labora-
tory.
Su m m a r y. A new reaction pathway for the regio- and
stereoselective functionalization of â-D-glucosides has
(22) For thiol-mediated PMB deprotection, see for example: (a)
Bouzide, A.; Sauve´, G. Tetrahedron Lett. 1999, 40, 2883-2886. (b) Yu,
W.; Xiaobang, G.; Yang, Z.; J in, Z. Tetrahedron Lett. 2000, 41, 4015-
4017.
(23) Classon, B.; Garegg, P. J .; Samuelsson, B. Acta Chem. Scand.
B 1984, 38, 419-422.
(24) Wermuth, C. G., Testa, B. In The Practice of Medicinal
Chemistry; Wermuth, C. G., Ed.; Academic Press: London, 1996; pp
615-641.
Exp er im en ta l Section 27
Th ioeth yl 3,4,6-Tr i-O-(ter t-bu tyld im eth ylsilyl)-â -D-glu -
cop yr a n r ose (-)-5. To a solution of epoxide (+)-3 (1.0 g, 1.98
mmol) and ethanethiol (1.47 mL, 19.84 mmol) in toluene (25
mL) at -78 °C under argon atmosphere was added trifluoro-
acetic anhydride (28 µL, 0.20 mmol). The reaction mixture was
slowly allowed to warm to rt and stirred for 48 h. The excess
ethanethiol was evaporated in vacuo and the resulting solution
(25) A new method to install a C(2)-N-acetylamino functionality
directly from glucal derivatives has recently been published: Di
Bussolo, V.; Liu, J .; Huffman, L. G., J r.; Gin, D. Y. Angew. Chem., Int.
Ed. 2000, 39, 204-207.
(26) Miethchen, R.; Rentsch, R. Liebigs Ann. Chem. 1996, 539-543.

â-D-Glucose Scaffold-Based Libraries
J . Org. Chem., Vol. 65, No. 24, 2000 8311
purified by flash chromatography (hexane/EtOAc 99:1) on
silica gel to give (-)-5 as a colorless oil (828 mg, 74%) and
R-anomer (+)-6 as a colorless oil (80 mg, 7%):
mL) and glacial acetic acid (1.5 mL) was added a 1 M
tetrabutylammonium fluoride solution in THF (20.41 mL,
20.41 mmol), and the solution was stirred at rt for 5 days. The
reaction was quenched with ice/water (10 mL), and the THF
was evaporated in vacuo. The solution was diluted with EtOAc
(100 mL) and washed with a saturated aqueous NaCl solution
(100 mL), 1 M aq HCl (100 mL), a saturated aqueous NaHCO3
solution (100 mL), and water (100 mL). The organic phase was
dried (Na2SO4), evaporated in vacuo, and purified by flash
chromatography (hexane/EtOAc 15:85) on silica gel to give
(-)-8 as a colorless solid (704 mg, 63%): mp 145-146 °C;
[R]2D5 ) -11.7 (c 1.0, MeOH); IR (CHCl3) 3040 (s), 2420 (m),
1530 (w), 1440 (w) cm-1; 1H NMR (500 MHz, CD3OD) δ 8.05-
8.02 (m, 2 H), 7.60-7.58 (m, 1 H), 7.49-7.46 (m, 2 H), 5.00-
4.96 (m, 1 H), 4.66 (d, J ) 10.0 Hz, 1 H), 3.91-3.87 (m, 1 H),
3.71-3.68 (m, 2 H), 3.46-3.37 (m, 2 H), 3.31-3.29 (m, 1 H),
2.77-2.67 (m, 2 H), 1.20 (t, J ) 7.4 Hz, 3 H); 13C NMR (125
MHz, CD3OD) δ 167.42, 134.40, 131.72, 130.90, 129.62, 84.85,
82.46, 77.65, 74.76, 71.86, 63.04, 25.03, 15.38; ES-MS m/z 351
[100, (M + Na)+]. Anal. Calcd for C15H20O6S: C, 54.86; H, 6.14.
Found: C, 55.06; H, 6.12.
(-)-5: [R]2D5 ) -49.0 (c 1.0, CHCl3); IR (CHCl3) 2980 (w),
2960 (w), 2880 (w), 1270 (w), 850 (m) cm-1; 1H NMR (500 MHz,
CDCl3) δ 4.62 (d, J ) 7.0 Hz, 1 H), 4.05 (dd, J ) 10.4, 6.2 Hz,
1 H), 3.76-3.71 (m, 3 H), 3.56-3.53 (m, 1 H), 3.45-3.41 (m, 1
H), 2.83 (d, J ) 5.3 Hz, 1 H), 2.73-2.64 (m, 2 H), 1.31-1.27
(m, 3 H), 0.91 (s, 9 H), 0.89 (s, 9 H), 0.88 (s, 9 H), 0.13 (s, 3 H),
0.12 (s, 3 H), 0.11 (s, 3 H), 0.10 (s, 3 H), 0.04 (s, 6 H); 13C NMR
(125 MHz, CDCl3) δ 84.83, 81.64, 75.97, 73.63, 70.78, 63.41,
26.29, 26.00, 25.93, 25.36, 18.49, 18.33, 18.02, 15.31, -3.49,
-3.78, -3.95, -4.36, -5.19, -5.26; high-resolution mass
spectrum (ES) m/z 589.3216 [(M + Na)+; calcd for C26H58O5-
SSi3Na: 589.3211].
(+)-6: [R]2D5 ) +28.6 (c 1.0, CHCl3); IR (CHCl3) 3040 (m),
2980 (w), 2940 (w), 2420 (w), 1430 (w), 1260 (s) cm-1; 1H NMR
(500 MHz, CDCl3) δ 5.01 (s, 1 H), 3.95-3.84 (m, 4 H), 3.73 (d,
J ) 3.3 Hz, 1 H), 3.62 (d, J ) 11.2 Hz, 1 H), 3.53-3.51 (m, 1
H), 2.72 (q, J ) 7.3 Hz, 2 H), 1.29 (t, J ) 7.3 Hz, 3 H), 0.89 (s,
9 H), 0.88 (s, 9 H), 0.87 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 9 H),
0.03 (s, 6 H); 13C NMR (125 MHz, CDCl3) δ 80.75, 78.01, 72.39,
71.47, 68.87, 60.86, 25.86, 25.79, 25.76, 25.21, 18.19, 17.97,
17.93, 15.15, -4.73, -4.85 (2×), -4.98, -5.35, -5.37; high-
resolution mass spectrum (ES) m/z 589.3195 [(M + Na)+; calcd
for C26H58O5SSi3Na: 589.3211].
Th ioeth yl 2-O-Ben zoyl-4,6-O-(4-m eth oxyben zylid en e)-
â-D-glu cop yr a n ose (-)-9. A solution of thioglycoside (-)-8
(1.25 g, 3.81 mmol), p-methoxybenzaldehyde dimethylacetal
(3.25 mL, 19.05 mmol), and p-toluenesulfonic acid monohy-
drate (72 mg, 0.38 mmol) in CHCl3 (200 mL) was stirred at rt
for 3 h. The reaction mixture was evaporated in vacuo and
purified by flash chromatography (hexane/EtOAc 75:25) on
silica gel to give (-)-9 as a colorless solid (1.56 g, 92%): mp
99-102 °C; [R]2D5 ) -35.0 (c 1.0, CHCl3); IR (CHCl3) 3020 (s),
Th ioet h yl 2-O-Ben zoyl-3,4,6-t r i-O-(ter t-b u t yld im et h -
ylsilyl)-â-D-glu cop yr a n ose (-)-7. A solution of thioglycoside
(-)-5 (2.04 g, 3.60 mmol) and benzoyl chloride (4.18 mL, 36.04
mmol) in pyridine (25 mL) and CH2Cl2 (50 mL) was heated at
50-60 °C for 36 h. The reaction mixture was allowed to cool,
quenched with 1 M aq HCl (100 mL), and extracted with CH2-
Cl2 (3 × 100 mL). The combined organic extracts were dried
(Na2SO4), evaporated in vacuo, and purified by flash chroma-
tography (hexane/EtOAc 99:1) on silica gel to give (-)-7 as a
colorless oil (2.29 g, 95%): [R]2D5 ) -0.7 (c 1.0, CHCl3); IR
(CHCl3) 2980 (m), 2960 (m), 2880 (m), 1735 (m), 1270 (m), 1120
2420 (m), 1750 (w), 1530 (m), 1440 (m) cm-1 1H NMR (500
;
MHz, CDCl3) δ 8.06 (d, J ) 7.4 Hz, 2 H), 7.58-7.55 (m, 1 H),
7.46-7.42 (m, 2 H), 7.40 (d, J ) 8.7 Hz, 2 H), 6.88 (d, J ) 8.7
Hz, 2 H), 5.51 (s, 1 H), 5.23-5.20 (m, 1 H), 4.66 (d, J ) 10.0
Hz, 1 H), 4.36 (dd, J ) 10.5, 4.9 Hz, 1 H), 4.05-4.02 (m, 1 H),
3.78 (s, 3 H), 3.78-3.75 (m, 1 H), 3.64-3.61 (m, 1 H), 3.59-
5.53 (m, 1 H), 2.73-2.67 (m, 3 H), 1.23 (t, J ) 7.4 Hz, 3 H);
13C NMR (125 MHz, CDCl3) δ 165.77, 160.33, 133.32, 129.97,
129.61, 129.37, 128.41, 127.60, 113.74, 101.88, 84.04, 80.80,
73.59, 73.07, 70.56, 68.53, 55.31, 24.10, 14.84; ES-MS m/z 469
[100, (M + Na)+]. Anal. Calcd for C23H26O7S: C, 61.87; H, 5.87.
Found: C, 61.84; H, 6.05.
Th ioeth yl 2-O-Ben zoyl-3-O-isop r op ylca r ba m oyl-4,6-O-
(4-m eth oxyben zylid en e)-â-D-glu cop yr a n ose (-)-10. To a
mixture of thioglycoside (-)-9 (1.56 g, 3.50 mmol) and copper-
(I) chloride (346 mg, 3.50 mmol) in DMF (50 mL) was added
isopropyl isocyanate (360 µL, 3.67 mmol), and the reaction
mixture was stirred at rt for 5 h. The reaction mixture was
evaporated in vacuo and purified by flash chromatography
(hexane/EtOAc 8:2) on silica gel to give (-)-10 as a colorless
solid (1.70 g, 92%): mp 190-192 °C; [R]2D5 ) -19.8 (c 1.0,
CHCl3); IR (CHCl3) 1750 (s), 1280 (m), 1260 (m), 1110 (s), 1080
(m) cm-1; 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J ) 7.2 Hz, 2
H), 7.56-7.53 (m, 1 H), 7.44-7.40 (m, 2 H), 7.38 (d, J ) 8.7
Hz, 2 H), 6.85 (d, J ) 8.7 Hz, 2 H), 5.47 (s, 1 H), 5.40-5.35
(m, 1 H), 5.26-5.21 (m, 1 H), 4.72 (d, J ) 10.0 Hz, 1 H), 4.46-
4.40 (m, 1 H), 4.36 (dd, J ) 10.5, 4.8 Hz, 1 H), 3.82-3.70 (m,
1 H), 3.78 (s, 3 H), 3.68-3.50 (m, 3 H), 2.74-2.68 (m, 2 H),
1.22 (t, J ) 7.5 Hz, 3 H), 0.98 (d, J ) 6.5 Hz, 3 H), 0.73-0.72
(m, 3 H); 13C NMR (125 MHz, CDCl3) δ 165.51, 160.15, 133.29,
130.01, 129.43, 128.38, 127.57, 113.57, 101.50, 84.39, 78.64,
73.28, 71.61, 71.05, 68.52, 55.27, 43.08, 24.45, 22.56, 22.38,
14.83; high-resolution mass spectrum (ES) m/z 554.1841 [(M
+ Na)+; calcd for C27H33NO8SNa: 554.1826].
1
(s), 850 (s) cm-1; H NMR (500 MHz, CDCl3) δ 8.04-8.02 (m,
2 H), 7.55-7.52 (m, 1 H), 7.42-7.39 (m, 2 H), 5.11-5.08 (m, 1
H), 4.90 (d, J ) 9.0 Hz, 1 H), 3.91-3.84 (m, 3 H), 3.78-3.74
(m, 2 H), 2.76-2.60 (m, 2 H), 1.25-1.22 (m, 3 H), 0.89 (s, 9
H), 0.88 (s, 9 H), 0.86 (s, 9 H), 0.09 (s, 6 H), 0.07 (s, 3 H), 0.05
(s, 6 H), 0.04 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 165.43,
132.96, 130.22, 129.93, 128.22, 83.26, 80.62, 75.78, 74.87,
70.49, 63.74, 25.93, 25.91, 25.90, 24.17, 18.34, 18.02, 17.96,
14.94, -3.94, -4.21, -4.39, -4.43, -5.26 (2×); high-resolution
mass spectrum (ES) m/z 693.3499 [(M + Na)+; calcd for
C
33H62O6SSi3Na: 693.3473].
Th ioeth yl 2-O-Ben zoyl-â-D-glu cop yr a n ose (-)-8. To a
solution of thioglycoside (-)-7 (2.29 g, 3.42 mmol) in THF (48.5
(27) Ma ter ia ls a n d Meth od s: All reactions were carried out in
oven- or flame-dried glassware under an argon atmosphere, unless
otherwise noted. All solvents were reagent grade. Diethyl ether and
tetrahydrofuran (THF) were freshly distilled from sodium/benzophe-
none under argon. Triethylamine (TEA) was distilled from calcium
hydride and stored over potassium hydroxide. Anhydrous pyridine,
N,N-dimethylformamide (DMF), toluene, and dimethyl sulfoxide (DMSO)
were purchased from Aldrich and used without purification. Except
as otherwise indicated, all reactions were magnetically stirred and
monitored by thin-layer chromatography with Whatman 0.25-mm
precoated silica gel plates. Flash column chromatography was per-
formed using silica gel 60 (particle size 0.023-0.040 mm) supplied by
E. Merck. Yields refer to chromatographically and spectroscopically
pure compounds, unless otherwise stated. All melting points were
obtained on a Thomas-Hoover apparatus and are corrected. Infrared
spectra were recorded on a Perkin-Elmer Model 283B spectrometer
with polystyrene as external standard. Proton and carbon-13 NMR
spectra were recorded on a Bruker AM-500 spectrometer. Chemical
shifts are reported relative to internal chloroform (δ 7.24) or methanol
(δ 4.78) for 1H and chloroform (δ 77.0) or methanol (δ 49.0) for 13C.
Optical rotations were measured with a Perkin-Elmer Model 241
polarimeter. High-resolution mass spectra were obtained at the
University of Pennsylvania Mass Spectrometry Service Center with
Th ioeth yl 2-O-Ben zoyl-3-O-isop r op ylca r ba m oyl-6-O-
(4-m eth oxyben zyl)-â-D-glu cop yr a n ose (+)-11. A solution of
thioglycoside acetal (-)-10 (322 mg, 0.61 mmol) and borane-
trimethylamine complex (266 mg, 3.64 mmol) in THF (200 mL)
was stirred at rt for 30 min. Aluminum chloride (485 mg, 3.64
mmol) was added, and the mixture was stirred at rt for 2 h.
The reaction was quenched with a saturated aqueous NaCl
solution (50 mL) and extracted with CH2Cl2 (3 × 50 mL). The
combined organic extracts were dried (Na2SO4), evaporated in
vacuo, and purified by flash chromatography (hexane/EtOAc
either
a VG Micromass 70/70H or VG ZAB-E spectrometer. Mi-
croanalyses were performed at the University of Pennsylvania. Single-
crystal X-ray structure determinations were performed at the Univer-
sity of Pennsylvania with an Enraf Nonius CAD-4 automated
diffractometer.

8312 J . Org. Chem., Vol. 65, No. 24, 2000
Hirschmann and Ducry
mg, 88%): mp 152-154 °C; [R]2D5 ) +21.4 (c 1.0, CHCl3); IR
6:4 to 5:5) on silica gel to give (+)-11 as a colorless solid (245
mg, 76%): mp 105-106 °C; [R]2D5 ) +27.6 (c 1.0, CHCl3); IR
(CHCl3) 1750 (s), 1530 (m), 1390 (s), 1360 (m), 1200 (s), 1090
(CHCl3) 3018 (m), 1729 (m), 1602 (w), 1509 (w), 1267 (w), 1224
1
(s) cm-1; H NMR (500 MHz, CDCl3) δ 8.02 (d, J ) 8.3 Hz, 2
1
(s) cm-1; H NMR (500 MHz, CDCl3) δ 8.01 (d, J ) 7.4 Hz, 2
H), 7.54-7.52 (m, 1 H), 7.42-7.39 (m, 2 H), 7.32-7.24 (m, 10
H), 5.35-5.29 (m, 1 H), 5.14-5.08 (m, 1 H), 5.04-5.00 (m, 1
H), 4.65-4.52 (m, 3 H), 4.44-4.30 (m, 5 H), 3.68-3.54 (m, 3
H), 2.68-2.65 (m, 2 H), 1.20 (t, J ) 7.4 Hz, 3 H), 1.00 (d, J )
6.0 Hz, 3 H), 0.72 (d, J ) 5.8 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 165.59, 156.02, 154.21, 138.33, 137.39, 133.20, 129.94,
129.46, 128.66, 128.35, 128.32, 128.23, 127.90, 127.50, 83.51,
77.50, 76.48, 75.52, 74.36, 71.35, 63.53, 45.13, 43.09, 24.45,
22.68, 22.33, 14.83; high-resolution mass spectrum (ES) m/z
659.2427 [(M + Na)+; calcd for C34H40N2O8SNa: 659.2403].
H), 7.55-7.52 (m, 1 H), 7.43-7.40 (m, 2 H), 7.25 (d, J ) 8.9
Hz, 2 H), 6.86 (d, J ) 8.9 Hz, 2 H), 5.19-5.15 (m, 1 H), 4.99 (t,
J ) 9.3 Hz, 1 H), 4.59 (d, J ) 10.0 Hz, 1 H), 4.52 (s, 2 H),
3.80-3.72 (m, 3 H), 3.78 (s, 3 H), 3.64-3.57 (m, 3 H), 2.71-
2.67 (m, 2 H), 1.22 (t, J ) 7.5 Hz, 3 H), 1.04 (d, J ) 6.2 Hz, 3
H), 0.81 (d, J ) 6.3 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
165.47, 159.25, 155.76, 133.22, 129.98, 129.85, 129.48, 129.29,
128.34, 113.79, 83.40, 79.16, 77.95, 73.27, 70.59, 69.73, 55.22,
43.25, 24.22, 22.47, 22.40, 14.87; ES-MS m/z 556 [100, (M +
Na)+]. Anal. Calcd for C27H35NO8S: C, 60.77; H, 6.61; N, 2.62.
Found: C, 60.93; H, 6.41; N, 2.03.
Meth yl 2-O-Ben zoyl-4-O-ben zyl-3-O-isop r op ylca r ba m -
oyl-â-D-glu cop yr a n ose (+)-15. To a solution of thioglycoside
(+)-13 (14 mg, 0.03 mmol) in CH2Cl2 (4.75 mL) and methanol
(0.25 mL) at 0 °C was added a solution of N-iodosuccinimide
(13 mg, 0.06 mmol) and trifluoromethane sulfonic acid (1 drop)
in CH2Cl2/Et2O 1:1 (2 mL), and the solution was stirred at 0
°C for 15 min. The reaction was quenched with a 10% aq
Na2S2O3 solution (20 mL) and extracted with CH2Cl2 (3 × 20
mL). The combined organic extracts were dried (Na2SO4),
evaporated in vacuo, and purified by flash chromatography
(hexane/EtOAc 7:3) on silica gel to give (+)-15 as a colorless
solid (12 mg, 91%): mp 184-185 °C; [R]2D5 ) +30.4 (c 1.0,
CHCl3); IR (CHCl3) 3040 (s), 2420 (m), 1740 (s), 1520 (m), 1280
Th ioeth yl 2-O-Ben zoyl-4-O-ben zyl-3-O-isop r op ylca r -
ba m oyl-6-O-(4-m eth oxyben zyl)-â-D-glu cop yr a n ose (+)-12.
To a 0 °C solution of thioglycoside (+)-11 (100 mg, 0.19 mmol)
and benzyl bromide (224 µL, 1.88 mmol) in anhydrous THF
(5 mL) was added 60% sodium hydride (11 mg, 0.28 mmol),
and the solution was stirred at rt for 3 h. The reaction was
quenched with 1 M aq HCl (20 mL) and extracted with CH2-
Cl2 (3 × 20 mL). The combined organic extracts were dried
(Na2SO4), evaporated in vacuo, and purified by flash chroma-
tography (hexane/EtOAc 9:1 to 7:3) on silica gel to give (+)-12
as a colorless solid (111 mg, 95%): mp 123-125 °C; [R]D25
)
1
+22.4 (c 1.0, CHCl3); IR (CHCl3) 3040 (s), 2420 (m), 1750 (m),
(m), 1110 (m), 1090 (m) cm-1; H NMR (500 MHz, CDCl3) δ
1
1530 (m), 1520 (m), 1440 (m), 1280 (m) cm-1; H NMR (500
8.03 (d, J ) 7.3 Hz, 2 H), 7.55-7.52 (m, 1 H), 7.42-7.39 (m, 2
H), 7.32-7.25 (m, 5 H), 5.33-5.29 (m, 1 H), 5.11-5.07 (m, 1
H), 4.68 (d, J ) 11.2 Hz, 1 H), 4.60 (d, J ) 11.2 Hz, 1 H), 4.55
(d, J ) 7.9 Hz, 1 H), 4.42 (d, J ) 6.9 Hz, 1 H), 3.92 (d, J )
11.9 Hz, 1 H), 3.79-3.70 (m, 2 H), 3.60-3.50 (m, 2 H), 3.47 (s,
3 H), 1.93 (br s, 1 H), 1.00 (d, J ) 6.2 Hz, 3 H), 0.73 (d, J ) 6.0
Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 165.65, 154.32, 137.68,
133.14, 129.95, 129.64, 128.41, 128.31, 128.15, 127.93, 101.87,
75.44, 75.30, 75.17, 74.50, 72.54, 61.69, 57.14, 43.10, 22.72,
22.38; high-resolution mass spectrum (ES) m/z 496.1967 [(M
+ Na)+; calcd for C25H31NO8Na: 496.1947].
MHz, CDCl3) δ 8.02 (d, J ) 7.8 Hz, 2 H), 7.54-7.51 (m, 1 H),
7.42-7.39 (m, 2 H), 7.28-7.23 (m, 5 H), 7.19-7.18 (m, 2 H),
6.86 (d, J ) 8.5 Hz, 2 H), 5.31-5.27 (m, 1 H), 5.17-5.13 (m, 1
H), 4.61-4.56 (m, 3 H), 4.50-4.46 (m, 2 H), 4.35 (d, J ) 7.4
Hz, 1 H), 3.79 (s, 3 H), 3.75-3.69 (m, 3 H), 3.60-3.56 (m, 2
H), 2.74-2.66 (m, 2 H), 1.23 (t, J ) 7.4 Hz, 3 H), 0.99 (d, J )
6.3 Hz, 3 H), 0.72 (d, J ) 6.0 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 165.63, 159.27, 154.35, 137.88, 133.14, 130.23, 129.98,
129.61, 129.46, 128.31, 128.27, 128.03, 127.71, 113.80, 83.43,
79.41, 76.55, 75.72, 74.31, 73.14, 71.42, 68.39, 55.26, 43.06,
24.24, 22.72, 22.39, 14.92; ES-MS m/z 646 [100, (M + Na)+].
Anal. Calcd for C34H41NO8S: C, 65.47; H, 6.63; N, 2.25.
Found: C, 65.55; H, 6.41; N, 1.91.
Meth yl 2-O-Ben zoyl-4-O-ben zyl-6-O-ben zylca r ba m oyl-
3-O-isop r op ylca r ba m oyl-â-D-glu cop yr a n ose (+)-16. To a
solution of thioglycoside (+)-14 (28 mg, 0.04 mmol) in CH2Cl2
(4.75 mL) and methanol (0.25 mL) at 0 °C was added a solution
of N-iodosuccinimide (20 mg, 0.09 mmol) and trifluoromethane
sulfonic acid (1 drop) in CH2Cl2/Et2O 1:1 (2 mL), and the
solution was stirred at 0 °C for 15 min. The reaction was
quenched with a 10% aq Na2S2O3 solution (20 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were dried (Na2SO4), evaporated in vacuo, and puri-
fied by flash chromatography (hexane/EtOAc 7:3) on silica gel
to give (+)-16 as a colorless solid (21 mg, 80%): mp 183-184
°C; [R]2D5 ) +32.9 (c 1.0, CHCl3); IR (CHCl3) 3018 (m), 1730
(s), 1509 (m), 1270 (m), 1220 (s), 1093 (m) cm-1; 1H NMR (500
MHz, CDCl3) δ 8.03-8.01 (m, 2 H), 7.54-7.51 (m, 1 H), 7.42-
7.39 (m, 2 H), 7.33-7.20 (m, 10 H), 5.33-5.28 (m, 1 H), 5.12-
5.07 (m, 1 H), 5.04-4.99 (m, 1 H), 4.63 (d, J ) 10.5 Hz, 1 H),
4.54 (d, J ) 10.5 Hz, 1 H), 4.50 (d, J ) 7.8 Hz, 1 H), 4.43-4.34
(m, 5 H), 3.65-3.55 (m, 3 H), 3.44 (s, 3 H), 1.00 (d, J ) 6.3 Hz,
3 H), 0.73 (d, J ) 6.2 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
165.63, 156.06, 154.24, 138.32, 137.42, 133.13, 130.05, 129.95,
129.65, 128.70, 128.39, 128.31, 127.94, 127.56, 101.72, 75.51,
75.31, 74.38, 73.44, 72.47, 63.28, 56.99, 45.20, 43.12, 22.72,
22.37; ES-MS m/z 629 [100, (M + Na)+]. Anal. Calcd for
Th ioeth yl 2-O-Ben zoyl-4-O-ben zyl-3-O-isop r op ylca r -
ba m oyl-â-D-glu cop yr a n ose (+)-13. To a solution of thiogly-
coside (+)-12 (120 mg, 0.19 mmol) in CH2Cl2 (10 mL) and water
(0.5 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(48 mg, 0.21 mmol), and the solution was stirred at rt for 5 h.
The reaction was quenched with a saturated aqueous NaHCO3
solution (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The
combined organic extracts were dried (Na2SO4), evaporated in
vacuo, and purified by flash chromatography (hexane/EtOAc
8:2 to 6:4) on silica gel to give (+)-13 as a colorless solid (90
mg, 93%): mp 178-180 °C; [R]2D5 ) +32.1 (c 1.0, CHCl3); IR
(CHCl3) 3040 (s), 2420 (m), 1750 (s), 1520 (m), 1280 (m), 1110
(m), 1090 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J )
7.7 Hz, 2 H), 7.55-7.52 (m, 1 H), 7.42-7.39 (m, 2 H), 7.32-
7.24 (m, 5 H), 5.35-5.31 (m, 1 H), 5.14-5.10 (m, 1 H), 4.69-
4.65 (m, 2 H), 4.60 (d, J ) 11.2 Hz, 1 H), 4.46 (d, J ) 7.2 Hz,
1 H), 3.93-3.90 (m,1 H), 3.76-3.69 (m, 2 H), 3.59-3.52 (m, 2
H), 2.72-2.67 (m, 2 H), 1.21 (t, J ) 7.4 Hz, 3 H), 0.99 (d, J )
6.3 Hz, 3 H), 0.71 (d, J ) 6.1 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 165.61, 154.29, 137.67, 133.21, 129.96, 129.47, 128.37,
128.33, 128.10, 127.89, 83.61, 79.56, 76.42, 75.38, 74.46, 71.38,
61.84, 43.07, 24.45, 22.69, 22.34, 14.87; ES-MS m/z 526 [60,
(M + Na)+], 504 [70, (M + H)+], 277 (100). Anal. Calcd for
C
33H38N2O9: C, 65.33; H, 6.31; N, 4.62. Found: C, 65.58; H,
6.48; N, 4.40.
C
26H33NO7S: C, 62.01; H, 6.60; N, 2.78. Found: C, 61.94; H,
2-Br om oeth yl 2-O-Ben zoyl-4-O-ben zyl-3-O-isop r op yl-
ca r ba m oyl-â-D-glu cop yr a n ose (+)-17. Meth od A. To a
solution of thioglycoside (+)-13 (50 mg, 0.10 mmol) in CH2Cl2
(4.75 mL) and 2-bromoethanol (0.25 mL) at 0 °C was added a
solution of N-iodosuccinimide (45 mg, 0.20 mmol) and trifluo-
romethane sulfonic acid (1 drop) in CH2Cl2/Et2O 1:1 (2 mL),
and the solution was stirred at 0 °C for 30 min. The reaction
was quenched with a 10% aq Na2S2O3 solution (50 mL) and
extracted with CH2Cl2 (3 × 50 mL). The combined organic
extracts were dried (Na2SO4), evaporated in vacuo, and puri-
6.68; N, 2.65.
Th ioeth yl 2-O-Ben zoyl-4-O-ben zyl-6-O-ben zylca r ba m -
oyl-3-O-isop r op ylca r ba m oyl-â-D-glu cop yr a n ose (+)-14. To
a solution of thioglycoside (+)-13 (45 mg, 0.09 mmol) and
copper(I) chloride (9 mg, 0.09 mmol) in DMF (5 mL) was added
benzyl isocyanate (22 µL, 0.18 mmol), and the solution was
stirred at rt for 24 h. The DMF was evaporated in vacuo and
the residue purified by flash chromatography (hexane/EtOAc
9:1 to 7:3) on silica gel to give (+)-14 as a colorless solid (50

â-D-Glucose Scaffold-Based Libraries
J . Org. Chem., Vol. 65, No. 24, 2000 8313
fied by flash chromatography (hexane/EtOAc 8:2 to 6:4) on
silica gel to give (+)-17 as a colorless solid (37 mg, 66%).
1.36 (m, 4 H), 1.28-1.25 (m, 2 H), 1.00 (d, J ) 6.3 Hz, 3 H),
0.75 (d, J ) 6.1 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 165.53,
154.35, 137.72, 133.14, 129.88, 129.62, 128.39, 128.32, 128.13,
127.89, 100.84, 75.60, 75.45, 75.08, 74.40, 72.58, 67.70, 61.72,
58.12, 54.75, 43.09, 25.54, 23.88, 22.72, 22.41; high-resolution
mass spectrum (ES) m/z 571.2993 [(M + H)+; calcd for
C31H43N2O8: 571.3019].
Meth od B. To a solution of thioglycoside (+)-12 (100 mg,
0.16 mmol) in CH2Cl2 (9 mL) and 2-bromoethanol (1 mL) at 0
°C was added a solution of N-iodosuccinimide (90 mg, 0.40
mmol) and trifluoromethane sulfonic acid (3 drops) in CH2-
Cl2/Et2O 1:1 (2 mL), and the solution was stirred at 0 °C for 2
h. The reaction was quenched with a 10% aq Na2S2O3 solution
(30 mL) and extracted with CH2Cl2 (3 × 30 mL). The combined
organic extracts were dried (Na2SO4), evaporated in vacuo, and
purified by flash chromatography (hexane/EtOAc 8:2 to 6:4)
on silica gel to give (+)-17 as a colorless solid (64 mg, 70%).
2-(4-Meth ylp ip er a zin -1-yl)eth yl 2-O-Ben zoyl-4-O-ben -
zyl-3-O-isop r op ylca r ba m oyl-â-D-glu cop yr a n ose (+)-20. A
solution of glycoside (+)-17 (20 mg, 0.04 mmol), potassium
carbonate (48 mg, 0.35 mmol), and N-methylpiperazine (39 µL,
0.35 mmol) in THF (5 mL) was heated at reflux for 8 h. The
reaction was allowed to cool, quenched with a saturated
aqueous NaHCO3 solution (25 mL), and extracted with CH2-
Cl2 (3 × 25 mL). The combined organic extracts were dried
(Na2SO4), evaporated in vacuo, and purified by flash chroma-
tography (CH2Cl2/MeOH/Et3N 90:9:1 to 80:19:1) on silica gel
to give (+)-20 as a colorless solid (18 mg, 87%): mp 115-117
°C; [R]2D5 ) +20.0 (c 1.0, CHCl3); IR (CHCl3) 2960 (w), 1750
(s), 1520 (m), 1470 (w), 1290 (s), 1120 (m), 1100 (s), 1040 (m)
(+)-20: mp 158-160 °C; [R]2D5 ) +25.8 (c 1.0, CHCl3); IR
(CHCl3) 3040 (s), 2420 (m), 1750 (s), 1520 (m), 1440 (w), 1430
(w), 1270 (s), 1110 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.98
(d, J ) 8.0 Hz, 2 H), 7.49-7.46 (m, 1 H), 7.37-7.34 (m, 2 H),
7.27-7.19 (m, 5 H), 5.28-5.25 (m, 1 H), 5.08-5.05 (m, 1 H),
4.66 (d, J ) 8.0 Hz, 1 H), 4.64 (d, J ) 11.6 Hz, 1 H), 4.55 (d,
J ) 11.6 Hz, 1 H), 4.46 (d, J ) 7.4 Hz, 1 H), 4.06-4.01 (m, 1
H), 3.87-3.84 (m, 1 H), 3.79-3.66 (m, 3 H), 3.56-3.52 (m, 1
H), 3.49-3.46 (m, 1 H), 3.30 (app. t, J ) 6.3 Hz, 2 H), 1.96 (br
1
cm-1; H NMR (500 MHz, CDCl3) δ 8.01 (d, J ) 7.5 Hz, 2 H),
s, 1 H), 0.95 (d, J ) 6.3 Hz, 3 H), 0.70 (d, J ) 6.1 Hz, 3 H); 13
C
7.54-7.51 (m, 1 H), 7.42-7.39 (m, 2 H), 7.31-7.25 (m, 5 H),
5.31-5.28 (m, 1 H), 5.10-5.07 (m, 1 H), 4.68-4.66 (m, 2 H),
4.60 (d, J ) 11.2 Hz, 1 H), 4.45 (d, J ) 7.1 Hz, 1 H), 3.98-3.94
(m, 1 H), 3.89 (dd, J ) 12.1, 2.3 Hz, 1 H), 3.77 (dd, J ) 12.1,
4.0 Hz, 1 H), 3.73-3.70 (m, 1 H), 3.67-3.63 (m, 1 H), 3.60-
3.57 (m, 1 H), 3.52-3.50 (m, 1 H), 2.56 (t, J ) 5.3 Hz, 2 H),
2.49 (br s, 4 H), 2.29 (br s, 4 H), 2.20 (s, 3 H), 1.00 (d, J ) 6.1
Hz, 3 H), 0.74 (d, J ) 5.9 Hz, 3 H); 13C NMR (125 MHz, CDCl3)
δ 165.46, 154.34, 137.71, 133.16, 129.88, 129.61, 128.38 (2×),
128.12, 127.89, 100.85, 75.57, 75.41, 75.05, 74.45, 72.53, 67.58,
61.55, 57.16, 54.58, 52.67, 45.53, 43.09, 22.71, 22.40; high-
resolution mass spectrum (ES) m/z 586.3128 [(M + H)+; calcd
for C31H44N3O8: 586.3142].
NMR (125 MHz, CDCl3) δ 165.87, 154.56, 137.88, 133.40,
130.15, 129.84, 128.65, 128.56, 128.39, 128.18, 101.32, 75.75,
75.53, 75.30, 74.76, 72.60, 69.94, 61.84, 43.35, 29.79, 22.95,
22.63; ES-MS m/z 590/588 [100, (M + Na)+]. Anal. Calcd for
C
26H32BrNO8: C, 55.21; H, 5.71; N, 2.48. Found: C, 55.56; H,
5.81; N, 2.40.
2-(Mor p h olin -4-yl)eth yl 2-O-Ben zoyl-4-O-ben zyl-3-O-
isop r op ylca r ba m oyl-â-D-glu cop yr a n ose (+)-18. A solution
of glycoside (+)-17 (28 mg, 0.05 mmol), potassium carbonate
(68 mg, 0.49 mmol), and morpholine (43 µL, 0.49 mmol) in THF
(5 mL) was heated at reflux for 7 h. The reaction was allowed
to cool, quenched with a saturated aqueous NaHCO3 solution
(25 mL), and extracted with CH2Cl2 (3 × 25 mL). The combined
organic extracts were dried (Na2SO4), evaporated in vacuo, and
purified by flash chromatography (CH2Cl2/MeOH/Et3N 90:9:
1) on silica gel to give (+)-18 as a colorless solid (24 mg, 85%):
mp 138-140 °C; [R]D25 ) +15.6 (c 1.0, CHCl3); IR (CHCl3)
2960 (w), 1750 (s), 1520 (m), 1470 (m), 1280 (s), 1120 (s), 1110
(s), 1100 (s), 1090 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 8.01
(d, J ) 7.4 Hz, 2 H), 7.55-7.52 (m, 1 H), 7.42-7.39 (m, 2 H),
7.32-7.25 (m, 5 H), 5.32-5.29 (m, 1 H), 5.11-5.07 (m, 1 H),
4.68 (d, J ) 11.2 Hz, 1 H), 4.67 (d, J ) 7.9 Hz, 1 H), 4.60 (d,
J ) 11.2 Hz, 1 H), 4.46 (d, J ) 7.4 Hz, 1 H), 3.99-3.95 (m, 1
H), 3.89 (dd, J ) 12.1, 2.5 Hz, 1 H), 3.76 (dd, J ) 12.1, 4.1 Hz,
1 H), 3.73-3.69 (m, 1 H), 3.67-3.62 (m, 1 H), 3.62-3.56 (m, 1
H), 3.53-3.50 (m, 1 H), 3.47-3.38 (m, 4 H), 2.51-2.49 (m, 2
H), 2.36-2.31 (m, 4 H), 2.20 (br s, 1 H), 1.00 (d, J ) 6.3 Hz, 3
H), 0.74 (d, J ) 6.1 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
165.46, 154.33, 137.67, 133.27, 129.82, 129.52, 128.40 (2×),
128.14, 127.93, 100.87, 75.52, 75.42, 75.05, 74.47, 72.46, 67.97,
66.64, 61.70, 57.82, 53.93, 43.11, 22.72, 22.41; ES-MS m/z 573
[100, (M + H)+]. Anal. Calcd for C30H40N2O9: C, 62.91; H, 7.04;
N, 4.89. Found: C, 62.62; H, 7.12; N, 4.61.
2-(Mor p h olin -1-yl)eth yl 4-O-Ben zyl-3-O-isop r op ylca r -
ba m oyl-â-D-glu cop yr a n ose (-)-21. A solution of glycoside
(+)-18 (10 mg, 0.02 mmol) in methanol (2 mL) and 1 M aq
NaOH (2 mL) was stirred at rt for 12 h. The reaction mixture
was diluted with a saturated aqueous NaCl solution (20 mL)
and extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were dried (Na2SO4), evaporated in vacuo, and puri-
fied by flash chromatography (CH2Cl2/MeOH/Et3N 90:9:1 to
80:19:1) on silica gel to give (-)-21 as a colorless solid (8 mg,
98%): mp 51-53 °C; [R]2D5 ) -20.3 (c 0.75, CHCl3); IR
(CHCl3) 3040 (s), 2420 (m), 1740 (m), 1520 (m), 1090 (s), 1070
(s) cm-1 1H NMR (500 MHz, CDCl3) δ 7.33-7.25 (m, 5 H),
;
4.94-4.90 (m, 1 H), 4.66 (d, J ) 11.1 Hz, 1 H), 4.59 (d, J )
11.1 Hz, 1 H), 4.52 (d, J ) 7.0 Hz, 1 H), 4.37 (d, J ) 7.7 Hz, 1
H), 4.05-4.00 (m, 1 H), 3.86 (dd, J ) 12.1, 2.6 Hz, 1 H), 3.85-
3.77 (m, 1 H), 3.76-3.69 (m, 6 H), 3.59-3.55 (m, 1 H), 3.44-
3.40 (m, 2 H), 2.68-2.63 (m, 1 H), 2.56-2.48 (m, 5 H), 1.14 (d,
J ) 6.5 Hz, 3 H), 1.12 (d, J ) 6.4 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 155.58, 137.88, 128.41, 128.11, 127.90, 103.63,
78.08, 75.50, 75.45, 74.58, 73.06, 66.58, 66.44, 61.78, 57.86,
53.52, 43.33, 23.05, 22.79; high-resolution mass spectrum (ES)
m/z 491.2387 [(M + Na)+; calcd for C23H36N2O8Na: 491.2369].
2-(P ip er id in -1-yl)et h yl 2-O-Ben zoyl-4-O-b en zyl-3-O-
isop r op ylca r ba m oyl-â-D-glu cop yr a n ose (+)-19. A solution
of glycoside (+)-17 (17 mg, 0.03 mmol), potassium carbonate
(41 mg, 0.30 mmol), and piperidine (30 µL, 0.30 mmol) in THF
(5 mL) was heated at reflux for 8 h. The reaction was allowed
to cool, quenched with a saturated aqueous NaHCO3 solution
(25 mL), and extracted with CH2Cl2 (3 × 25 mL). The combined
organic extracts were dried (Na2SO4), evaporated in vacuo, and
purified by flash chromatography (CH2Cl2/MeOH/Et3N 90:9:
1) on silica gel to give (+)-19 as a colorless solid (15 mg, 88%):
mp 105-106 °C; [R]D25 ) +13.9 (c 1.0, CHCl3); IR (CHCl3)
2960 (m), 1750 (s), 1520 (w), 1480 (w), 1290 (s), 1100 (s), 1080
2-(P ip er id in -1-yl)eth yl 4-O-Ben zyl-3-O-isop r op ylca r -
ba m oyl-â-D-glu cop yr a n ose (-)-22. A solution of glycoside
(+)-19 (10 mg, 0.02 mmol) in methanol (2 mL) and 1 M aq
NaOH (2 mL) was stirred at rt for 12 h. The reaction mixture
was diluted with a saturated aqueous NaCl solution (10 mL)
and extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were dried (Na2SO4), evaporated in vacuo, and puri-
fied by preparative thin-layer chromatography (CH2Cl2/MeOH
80:20) on silica gel to give (-)-22 as a colorless solid (7 mg,
86%): mp 58-60 °C; [R]D25 ) -15.6 (c 0.8, CHCl3); IR (CHCl3)
2960 (m), 1730 (s), 1510 (m), 1460 (m), 1240 (m), 1100 (s), 1060
(s) cm-1
;
1H NMR (500 MHz, CDCl3) δ 8.02-8.01 (m, 2 H),
(s) cm-1 1H NMR (500 MHz, CDCl3) δ 7.33-7.25 (m, 5 H),
;
7.54-7.51 (m, 1 H), 7.42-7.38 (m, 2 H), 7.32-7.25 (m, 5 H),
5.31-5.28 (m, 1 H), 5.10-5.07 (m, 1 H), 4.70-4.66 (m, 2 H),
4.60 (d, J ) 11.2 Hz, 1 H), 4.43 (d, J ) 7.5 Hz, 1 H), 3.97-3.93
(m, 1 H), 3.88 (dd, J ) 11.1, 2.5 Hz, 1 H), 3.76 (dd, J ) 11.1,
4.2 Hz, 1 H), 3.73-3.66 (m, 2 H), 3.63-3.57 (m, 1 H), 3.54-
3.51 (m, 1 H), 2.51 (t, J ) 5.5 Hz, 2 H), 2.31 (br s, 5 H), 1.42-
4.94-4.90 (m, 1 H), 4.67 (d, J ) 11.1 Hz, 1 H), 4.58 (d, J )
11.1 Hz, 1 H), 4.58-4.55 (m, 1 H), 4.37 (d, J ) 7.7 Hz, 1 H),
4.09-4.04 (m, 1 H), 3.86 (dd, J ) 12.1, 2.6 Hz, 1 H), 3.85-
3.74 (m, 2 H), 3.72 (dd, J ) 12.1, 4.2 Hz, 1 H), 3.58-3.54 (m,
1 H), 3.44-3.41 (m, 2 H), 2.66-2.61 (m, 2 H), 2.56 (br s, 4 H),
1.66-1.62 (m, 4 H), 1.44 (br s, 2 H), 1.14 (d, J ) 6.4 Hz, 3 H),

8314 J . Org. Chem., Vol. 65, No. 24, 2000
Hirschmann and Ducry
1.11 (d, J ) 6.4 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 155.59,
137.94, 128.39, 128.12, 127.85, 103.76, 78.15, 75.63, 75.50,
74.52, 72.81, 65.89, 61.80, 57.97, 54.36, 43.27, 24.84, 23.74,
23.06, 22.80; high-resolution mass spectrum (ES) m/z 467.2764
[(M + H)+; calcd for C24H39N2O7: 467.2757].
H), 3.85 (dd, J ) 11.9, 4.9 Hz, 1 H), 3.77-3.74 (m, 1 H), 3.69-
3.61 (m, 2 H), 3.57-3.44 (m, 5 H), 2.55 (br s, 2 H), 2.38 (br s,
4 H), 1.07 (d, J ) 6.4 Hz, 3 H), 0.88 (d, J ) 6.4 Hz, 3 H); 13C
NMR (125 MHz, CDCl3) δ 165.33, 156.15, 133.43, 129.76,
129.44, 128.50, 100.84, 76.12, 71.72, 69.96, 67.68, 66.50, 62.25,
57.79, 53.88, 43.40, 22.54, 22.48; high-resolution mass spec-
trum (ES) m/z 483.2323 [(M + H)+; calcd for C23H35N2O9:
483.2342].
2-(4-Met h ylp ip er a zin -1-yl)et h yl 4-O-Ben zyl-3-O-iso-
p r op ylca r ba m oyl-â-D-glu cop yr a n ose (-)-23. A solution of
glycoside (+)-20 (21 mg, 0.04 mmol) in methanol (2 mL) and
1 M aq NaOH (2 mL) was stirred at rt for 12 h. The reaction
mixture was diluted with a saturated aqueous NaCl solution
(20 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were dried (Na2SO4), evaporated in vacuo, and
purified by preparative thin-layer chromatography (CH2Cl2/
MeOH 80:20) on silica gel to give (-)-23 as a colorless solid
(10 mg, 58%): mp 57-59 °C; [R]2D5 ) -29.8 (c 1.0, CHCl3); IR
(CHCl3) 2960 (m), 2830 (m), 1740 (s), 1520 (m), 1470 (m), 1240
(m), 1180 (m), 1160 (m), 1090 (s), 1070 (s) cm-1; 1H NMR (500
MHz, CDCl3) δ 7.34-7.25 (m, 5 H), 4.95-4.92 (m, 1 H), 4.66
(d, J ) 11.1 Hz, 1 H), 4.58 (d, J ) 11.1 Hz, 1 H), 4.55 (d, J )
6.1 Hz, 1 H), 4.37 (d, J ) 7.7 Hz, 1 H), 4.04-3.99 (m, 1 H),
3.86 (dd, J ) 12.1, 2.5 Hz, 1 H), 3.85-3.77 (m, 1 H), 3.75-
3.70 (m, 1 H), 3.73 (dd, J ) 12.1, 3.7 Hz, 1 H), 3.60-3.56 (m,
1 H), 3.43-3.40 (m, 2 H), 2.69-2.63 (m, 1 H), 2.57-2.52 (m, 5
H), 2.45 (br s, 4 H), 2.27 (s, 3 H), 1.14 (d, J ) 6.5 Hz, 3 H),
1.11 (d, J ) 6.4 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 155.55,
137.92, 128.38, 128.09, 127.85, 103.58, 78.04, 75.53, 75.46,
74.53, 72.95, 66.45, 61.68, 57.34, 54.61, 52.80, 45.85, 43.28,
23.05, 22.81; high-resolution mass spectrum (ES) m/z 482.2844
[(M + H)+; calcd for C24H40N3O7: 482.2866].
2-(P ip er id in -1-yl)eth yl 2-O-Ben zoyl-3-O-isop r op ylca r -
ba m oyl-â-D-glu cop yr a n ose (+)-26. A solution of glycoside
(+)-24 (11 mg, 0.02 mmol), potassium carbonate (32 mg, 0.23
mmol), and piperidine (23 µL, 0.23 mmol) in THF (3 mL) was
heated at reflux for 8 h. The reaction was allowed to cool,
quenched with a saturated aqueous NaHCO3 solution (20 mL),
and extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were dried (Na2SO4), evaporated in vacuo, and puri-
fied by flash chromatography (CH2Cl2/MeOH/Et3N 90:9:1) on
silica gel to give (+)-26 as a colorless solid (11 mg, 99%): mp
120 °C (dec); [R]2D5 ) +23.4 (c 1.0, CHCl3); IR (CHCl3) 2940
(m), 1740 (s), 1290 (s), 1100 (s) cm-1 1H NMR (500 MHz,
;
CDCl3) δ 8.01 (d, J ) 7.2 Hz, 2 H), 7.57-7.53 (m, 1 H), 7.44-
7.41 (m, 2 H), 5.17-5.13 (m, 1 H), 4.97-4.93 (m, 1 H), 4.79 (d,
J ) 7.8 Hz, 1 H), 4.68 (d, J ) 7.9 Hz, 1 H), 4.05-4.01 (m, 1
H), 3.95 (dd, J ) 11.9, 3.1 Hz, 1 H), 3.85 (dd, J ) 11.9, 5.0 Hz,
1 H), 3.78-3.70 (m, 2 H), 3.67-3.61 (m, 1 H), 3.50-3.47 (m, 1
H), 2.58 (t, J ) 5.5 Hz, 2 H), 2.40 (br s, 4 H), 1.47-1.38 (m, 4
H), 1.31-1.27 (m, 2 H), 1.06 (d, J ) 6.4 Hz, 3 H), 0.87 (d, J )
6.4 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 165.45, 156.03,
133.34, 129.81, 129.50, 128.44, 100.69, 76.41, 71.94, 69.71,
66.52, 62.06, 57.66, 54.48, 45.73, 43.32, 24.66, 23.29, 22.56,
22.50; high-resolution mass spectrum (ES) m/z 481.2532 [(M
+ H)+; calcd for C24H37N2O8: 481.2550].
2-Br om oeth yl 2-O-Ben zoyl-3-O-isop r op ylca r ba m oyl-â-
D-glu cop yr a n ose (+)-24. To a solution of thioglycoside (+)-
11 (200 mg, 0.38 mmol) in CH2Cl2 (9.0 mL) and 2-bromoeth-
anol (1.0 mL) at 0 °C was added a solution of N-iodosuccinimide
(169 mg, 0.75 mmol) and trifluoromethane sulfonic acid (2
drops) in CH2Cl2/Et2O 1:1 (5 mL), and the solution was stirred
at 0 °C for 1 h. The reaction was quenched with a 10% aq
Na2S2O3 solution (30 mL) and extracted with CH2Cl2 (3 × 30
mL). The combined organic extracts were dried (Na2SO4),
evaporated in vacuo, and purified by flash chromatography
(hexane/EtOAc 5:5 to 3:7) on silica gel to give (+)-24 as a
colorless solid (85 mg, 48%): mp 157-159 °C; [R]2D5 ) +36.8 (c
1.0, CHCl3); IR (CHCl3) 2940 (m), 1740 (s), 1280 (s), 1130 (s),
2-(4-Meth ylp ip er a zin -1-yl)eth yl 2-O-Ben zoyl-3-O-iso-
p r op ylca r ba m oyl-â-D-glu cop yr a n ose (+)-27. A solution of
glycoside (+)-24 (11 mg, 0.02 mmol), potassium carbonate (32
mg, 0.23 mmol), and N-methylpiperazine (26 µL, 0.23 mmol)
in THF (3 mL) was heated at reflux for 8 h. The reaction was
allowed to cool, quenched with a saturated aqueous NaHCO3
solution (20 mL), and extracted with CH2Cl2 (3 × 20 mL). The
combined organic extracts were dried (Na2SO4), evaporated in
vacuo, and purified by flash chromatography (CH2Cl2/MeOH/
Et3N 90:9:1 to 80:19:1) on silica gel to give (+)-27 as a colorless
solid (8 mg, 70%): mp 160 °C (dec); [R]2D5 ) +14.0 (c 0.8,
CHCl3); IR (CHCl3) 2960 (m), 1740 (s), 1280 (s), 1270 (m), 1100
1
1100 (s) cm-1; H NMR (500 MHz, CDCl3) δ 8.02 (d, J ) 7.5
Hz, 2 H), 7.57-7.54 (m, 1 H), 7.44-7.41 (m, 2 H), 5.19-5.16
(m, 1 H), 4.97-4.93 (m, 1 H), 4.81 (d, J ) 7.6 Hz, 1 H), 4.71
(d, J ) 8.0 Hz, 1 H), 4.14-4.09 (m, 1 H), 3.98-3.74 (m, 5 H),
3.67-3.60 (m, 1 H), 3.52-3.48 (m, 1 H), 3.39-3.32 (m, 2 H),
2.28 (br s, 1 H), 1.06 (d, J ) 6.3 Hz, 3 H), 0.87 (d, J ) 6.3 Hz,
3 H); 13C NMR (125 MHz, CDCl3) δ 165.49, 156.20, 133.31,
129.85, 129.51, 128.39, 101.09, 76.07, 71.53, 69.99, 69.63,
62.29, 43.42, 29.60, 22.51, 22.45; high-resolution mass spec-
trum (ES) m/z 498.0738 [(M + Na)+; calcd for C19H26BrNO8-
Na: 498.0740].
1
(s) cm-1; H NMR (500 MHz, CDCl3) δ 8.01 (d, J ) 7.4 Hz, 2
H), 7.57-7.54 (m, 1 H), 7.44-7.41 (m, 2 H), 5.17-5.14 (m, 1
H), 4.96-4.92 (m, 1 H), 4.77 (d, J ) 7.8 Hz, 1 H), 4.67 (d, J )
7.9 Hz, 1 H), 4.00-3.96 (m, 1 H), 3.94 (dd, J ) 11.9, 3.1 Hz, 1
H), 3.85 (dd, J ) 11.9, 4.8 Hz, 1 H), 3.78-3.75 (m, 1 H), 3.66-
3.62 (m, 2 H), 3.49-3.46 (m, 1 H), 2.54 (t, J ) 5.5 Hz, 2 H),
2.43 (br s, 4 H), 2.22 (br s, 4 H), 2.15 (s, 3 H), 1.06 (d, J ) 6.4
Hz, 3 H), 0.87 (d, J ) 6.4 Hz, 3 H); 13C NMR (125 MHz, CDCl3)
δ 165.34, 156.19, 133.29, 129.82, 129.58, 128.45, 100.94, 77.37,
76.09, 71.82, 69.96, 67.68, 62.28, 57.28, 54.75, 53.04, 45.78,
43.39, 22.57, 22.50; high-resolution mass spectrum (ES) m/z
496.2664 [(M + H)+; calcd for C24H38N3O8: 496.2659].
2-(Mor p h olin -4-yl)eth yl 2-O-Ben zoyl-3-O-isop r op ylca r -
ba m oyl-â-D-glu cop yr a n ose (+)-25. Rou te A. A solution of
benzylglycoside (+)-18 (8 mg, 0.01 mmol) and 10% Pd/C (2 mg)
in cyclohexene (0.1 mL) and ethanol (2 mL) was heated at
reflux for 12 h. The reaction mixture was filtered over Celite
to give (+)-25 as a colorless solid (6 mg, 89%).
Th ioet h yl 2-O-Ben zylca r b a m oyl-3,4,6-t r i-O-(ter t-b u -
tyld im eth ylsilyl)-â-D-glu cop yr a n ose (-)-28. To a solution
of thioglycoside (-)-5 (2.00 g, 3.53 mmol) and benzyl isocyanate
(4.35 mL, 35.27 mmol) in pyridine (10 mL) and CH2Cl2 (40
mL) was added 60% sodium hydride (141 mg, 3.53 mmol), and
the mixture was heated at reflux for 5 days. The reaction
mixture was allowed to cool, quenched with 1 M aq HCl (50
mL), and extracted with CH2Cl2 (3 × 50 mL). The combined
organic extracts were dried (Na2SO4), evaporated in vacuo, and
purified by flash chromatography (hexane/EtOAc 95:5) on
silica gel to give (-)-28 as a colorless solid (1.52 g, 62%): mp
89-90 °C; [R]2D5 ) -12.0 (c 1.0, CHCl3); IR (CHCl3) 3040 (s),
2940 (m), 2420 (m), 1740 (m), 1540 (m), 1480 (m), 1440 (m),
Rou te B. A solution of glycoside (+)-24 (30 mg, 0.06 mmol),
potassium carbonate (87 mg, 0.63 mmol), and morpholine (55
µL, 0.63 mmol) in THF (5 mL) was heated at reflux for 8 h.
The reaction was allowed to cool, quenched with a saturated
aqueous NaHCO3 solution (20 mL), and extracted with CH2-
Cl2 (3 × 20 mL). The combined organic extracts were dried
(Na2SO4), evaporated in vacuo, and purified by flash chroma-
tography (CH2Cl2/MeOH/Et3N 90:9:1) on silica gel to give (+)-
25 as a colorless solid (22 mg, 72%).
(+)-25: mp 140-142 °C; [R]2D5 ) +21.2 (c 1.0, CHCl3); IR
1
(CHCl3) 2900 (m), 1740 (s), 1280 (s), 1270 (s), 1100 (s), 1080
1120 (m), 940 (m) cm-1; H NMR (500 MHz, CDCl3) δ 7.34-
1
(s) cm-1; H NMR (500 MHz, CDCl3) δ 8.00 (d, J ) 7.4 Hz, 2
7.23 (m, 5 H), 4.87-4.85 (m, 2 H), 4.74 (dd, J ) 8.8, 3.2 Hz, 1
H), 4.63 (d, J ) 9.1 Hz, 1 H), 4.40 (dd, J ) 14.8, 5.9 Hz, 1 H),
4.35 (dd, J ) 14.8, 5.9 Hz, 1 H), 3.84-3.78 (m, 2 H), 3.73-
3.69 (m, 1 H), 3.62-3.59 (m, 1 H), 2.73-2.63 (m, 2 H), 1.24 (t,
H), 7.58-7.55 (m, 1 H), 7.45-7.42 (m, 2 H), 5.18-5.14 (m, 1
H), 4.96-4.92 (m, 1 H), 4.73 (d, J ) 7.4 Hz, 1 H), 4.66 (d, J )
7.9 Hz, 1 H), 4.05-4.01 (m, 1 H), 3.95 (dd, J ) 11.9, 3.2 Hz, 1

â-D-Glucose Scaffold-Based Libraries
J . Org. Chem., Vol. 65, No. 24, 2000 8315
J ) 7.4, 3 H), 0.87 (s, 18 H), 0.87 (s, 9 H), 0.11 (s, 3 H), 0.08
(s, 3 H), 0.07 (s, 3 H), 0.06 (s, 3 H), 0.04 (s, 6 H); 13C NMR
(125 MHz, CDCl3) δ 155.37, 138.44, 128.58, 127.52, 127.43,
82.97, 81.27, 76.06, 74.69, 70.67, 63.53, 45.16, 25.96, 25.92,
25.90, 24.02, 18.31, 18.05, 17.97, 14.86, -3.68, -3.91, -4.19,
-4.32, -5.27 (2×); ES-MS m/z 722 [100, (M + Na)+]. Anal.
Calcd for C34H65NO6SSi3: C, 58.32; H, 9.36; N, 2.00. Found:
C, 58.62; H, 9.56; N, 2.11.
Th ioeth yl 2-O-Ben zylca r ba m oyl-3-O-isopr op ylca r ba m -
oyl-6-O-(4-m eth oxyben zyl)-â-D-glu cop yr a n ose (+)-32. A
solution of thioglycoside acetal (-)-31 (90 mg, 0.16 mmol) and
borane-trimethylamine complex (70 mg, 0.96 mmol) in an-
hydrous THF (20 mL) was stirred at rt for 30 min. Aluminum
chloride (128 mg, 0.96 mmol) was then added and the mixture
stirred at rt for 12 h. The reaction was quenched with a
saturated aqueous NaCl solution (20 mL), the THF evaporated
in vacuo, and the residual solution extracted with CH2Cl2 (3
× 20 mL). The combined organic extracts were dried (Na2SO4),
evaporated in vacuo, and purified by flash chromatography
(hexane/EtOAc 6:4 to 5:5) on silica gel to give (+)-32 as a
colorless solid (51 mg, 56%) and (+)-33 as a colorless solid (21
mg, 30%):
Th ioeth yl 2-O-Ben zylcar bam oyl-â-D-glu copyr an ose (-)-
29. To a solution of thioglycoside (-)-28 (1.92 g, 2.74 mmol)
in acetonitrile (100 mL) at 0 °C was added 49% aq hydrofluoric
acid (0.86 mL, 27.43 mmol), and the solution was stirred at rt
for 1 h. The reaction mixture was evaporated in vacuo and
purified by flash chromatography (EtOAc/MeOH 100:0 to 90:
10) on silica gel to give (-)-29 as a colorless solid (930 mg,
95%): mp 195-197 °C; [R]2D5 ) -23.2 (c 1.0, MeOH); IR
(CHCl3) 3040 (s), 2420 (m), 1540 (m), 1530 (m), 1440 (m), 940
(+)-32: mp 146-148 °C; [R]2D5 ) +15.4 (c 1.0, CHCl3); IR
(CHCl3) 3020 (w), 3000 (w); 2940 (w), 2900 (w), 2420 (w), 1750
(s), 1620 (w), 1530 (s), 1470 (w), 1430 (w), 1090 (m), 1060 (m),
1
940 (m) cm-1; H NMR (500 MHz, CDCl3) δ 7.28-7.21 (m, 7
1
(m) cm-1; H NMR (500 MHz, CD3OD) δ 7.38-7.24 (m, 5 H),
H), 6.84 (d, J ) 8.6 Hz, 2 H), 5.21-5.18 (m, 1 H), 4.86-4.76
(m, 2 H), 4.48 (s, 2 H), 4.42 (d, J ) 9.5 Hz, 1 H), 4.36-4.32 (m,
1 H), 3.77 (s, 3 H), 3.77-3.66 (m, 4 H), 3.64-3.59 (m, 1 H),
3.53-3.48 (m, 1 H), 2.73-2.67 (m, 2 H), 1.24 (t, J ) 7.4, 3 H),
1.11 (d, J ) 6.0 Hz, 3 H), 1.08 (d, J ) 6.2 Hz, 3 H); 13C NMR
(125 MHz, CDCl3) δ 159.22, 156.16, 155.31, 138.24, 130.03,
129.26, 128.55, 127.41, 127.28, 113.77, 83.50, 79.19, 78.27,
73.22, 70.83, 70.63, 69.69, 55.22, 45.03, 43.36, 24.03, 22.74,
22.58, 14.85; ES-MS m/z 585 [100, (M + Na)+]. Anal. Calcd
for C28H38N2O8S: C, 59.77; H, 6.81; N, 4.98. Found: C, 59.72;
H, 7.03; N, 4.97.
(+)-33: mp 160-162 °C; [R]2D5 ) +28.9 (c 1.0, CHCl3); IR
(CHCl3) 3013 (w), 2974 (w), 2932 (w), 2875 (w), 1731 (s), 1515
(s), 1456 (w), 1226 (s), 1078 (m), 1050 (m) cm-1; 1H NMR (500
MHz, CDCl3) δ 7.32-7.24 (m, 5 H), 5.12-5.08 (m, 1 H), 4.91-
4.88 (m, 1 H), 4.86-4.81 (m, 1 H), 4.75-4.70 (m, 1 H), 4.44 (d,
J ) 10.0 Hz, 1 H), 4.42-4.33 (m, 2 H), 3.92 (dd, J ) 12.0, 3.3
Hz, 1 H), 3.80-3.74 (m, 2 H), 3.67-3.64 (m, 1 H), 3.44-3.41
(m, 1 H), 2.72-2.69 (m, 2 H), 1.25 (t, J ) 7.4, 3 H), 1.13 (d, J
) 6.4 Hz, 3 H), 1.10 (d, J ) 6.3 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 156.58, 155.30, 138.18, 128.65, 127.57, 127.36, 83.67,
80.08, 78.89, 70.61, 70.36, 62.63, 45.16, 43.52, 24.10, 22.76,
22.61, 14.83; ES-MS m/z 465 [100, (M + Na)+]. Anal. Calcd
for C20H30N2O7S: C, 54.28; H, 6.83; N, 6.33. Found: C, 54.26;
H, 7.04; N, 6.18.
4.65-4.61 (m, 1 H), 4.51 (d, J ) 10.0 Hz, 1 H), 4.41 (d, J )
15.4 Hz, 1 H), 4.32 (d, J ) 15.4 Hz, 1 H), 3.91 (dd, J ) 12.0,
1.9 Hz, 1 H), 3.70 (dd, J ) 12.0, 5.8 Hz, 1 H), 3.58-3.54 (m, 1
H), 3.43-3.39 (m, 1 H), 3.36-3.31 (m, 2 H), 2.81-2.71 (m, 2
H), 1.28 (t, J ) 7.4, 3 H); 13C NMR (125 MHz, CD3OD) δ
158.47, 140.54, 129.36, 128.23, 128.03, 85.10, 82.23, 77.64,
74.80, 71.70, 62.92, 45.50, 24.86, 15.17; ES-MS m/z 380 [100,
(M + Na)+]. Anal. Calcd for C16H23NO6S: C, 53.77; H, 6.49;
N, 3.92. Found: C, 54.08; H, 6.25; N, 3.85.
Th ioeth yl 2-O-Ben zylca r ba m oyl-4,6-O-(4-m eth oxyben -
zylid en e)-â-D-glu cop yr a n ose (-)-30. To a solution of thiogly-
coside (-)-29 (280 mg, 0.78 mmol) and p-toluenesulfonic acid
monohydrate (15 mg, 0.08 mmol) in chloroform (75 mL) was
added p-methoxybenzaldehyde dimethylacetal (0.67 mL, 3.92
mmol), and the solution was stirred at rt for 5 h. The reaction
mixture was evaporated in vacuo without heating and purified
by flash chromatography (hexane/EtOAc 5:5) on silylated silica
gel to give (-)-30 as a colorless solid (185 mg, 50%): mp 183-
185 °C; [R]2D5 ) -43.8 (c 1.0, CHCl3); IR (CHCl3) 3050 (s), 2430
(m), 1740 (w), 1530 (m), 1440 (m), 1110 (m), 1060 (m), 980 (m)
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.39 (d, J ) 7.9 Hz, 2 H),
7.34-7.25 (m, 5 H), 6.87 (d, J ) 7.9 Hz, 2 H), 5.50 (s, 1 H),
5.11-5.09 (m, 1 H), 4.83-4.80 (m, 1 H), 4.49 (d, J ) 10.0 Hz,
1 H), 4.48-4.43 (m, 1 H), 4.38-4.31 (m, 1 H), 3.90-3.88 (m, 1
H), 3.78 (s, 3 H), 3.76-3.72 (m, 1 H), 3.60-3.56 (m, 1 H), 3.48-
3.44 (m, 1 H), 2.95 (br s, 1 H), 2.75-2.71 (m, 2 H), 1.26 (t, J )
7.5, 3 H); 13C NMR (125 MHz, CDCl3) δ 160.28, 155.95, 138.05,
129.42, 128.67, 127.61, 127.57, 127.45, 113.69, 101.81, 84.04,
80.81, 73.99, 73.68, 70.47, 68.51, 55.30, 45.27, 24.00, 14.81;
ES-MS m/z 973 [65, (2M + Na)+], 539 [100, (M + Na +
MeCN)+], 498 [50, (M + Na)+]. Anal. Calcd for C24H29NO7S:
C, 60.62; H, 6.15; N, 2.95. Found: C, 60.95; H, 6.32; N, 2.87.
Th ioet h yl 4-O-Ben zyl-2-O-b en zylca r b a m oyl-3-O-iso-
p r op ylca r ba m oyl-6-O-(4-m eth oxyben zyl)-â-D-glu cop yr a -
n ose (-)-34. To a 0 °C solution of thioglycoside (+)-32 (25 mg,
0.04 mmol) and benzyl bromide (52 µL, 0.44 mmol) in
anhydrous THF (5 mL) was added 60% sodium hydride (2 mg,
0.05 mmol), and the solution was stirred at rt for 1 h. The
reaction was quenched with 1 M aq HCl (20 mL) and extracted
with CH2Cl2 (3 × 20 mL). The combined organic extracts were
dried (Na2SO4), evaporated in vacuo, and purified by flash
chromatography (hexane/EtOAc 8:2) on silica gel to give (-)-
Th ioeth yl 2-O-Ben zylcar bam oyl-3-O-Isopr opylcar bam -
oyl-4,6-O-(4-m eth oxyben zylid en e)-â-D-glu cop yr a n ose (-)-
31. To a solution of thioglycoside (-)-30 (500 mg, 1.05 mmol)
and copper(I) chloride (104 mg, 1.05 mmol) in DMF (25 mL)
was added isopropyl isocyanate (124 µL, 1.26 mmol), and the
solution was stirred at rt for 12 h. The DMF was evaporated
in vacuo, and the mixture was purified by flash chromatog-
raphy (hexane/EtOAc 6:4) on silica gel to give (-)-31 as a
colorless solid (470 mg, 80%): mp 205-207 °C; [R]2D5 ) -42.1
(c 1.0, CHCl3); IR (CHCl3) 3050 (s), 2420 (m), 1750 (s), 1530
34 as a colorless solid (25 mg, 86%): mp 148-151 °C; [R]D25
)
-1.8 (c 1.0, CHCl3); IR (CHCl3) 3019 (s), 1732 (s), 1513 (s),
1
1224 (s), 1082 (m) cm-1; H NMR (500 MHz, CDCl3) δ 7.28-
7.16 (m, 12 H), 6.86-6.83 (m, 2 H), 5.15-5.05 (m, 2 H), 4.86-
4.79 (m, 1 H), 4.60-4.29 (m, 9 H), 3.78 (s, 3 H), 3.71-3.63 (m,
3 H), 3.52-3.49 (m, 1 H), 2.74-2.68 (m, 2 H), 1.25 (t, J ) 7.2
Hz, 3 H), 1.09-1.06 (m, 6 H); 13C NMR (125 MHz, CDCl3) δ
159.23, 155.37, 154.68, 138.21, 137.82, 130.22, 129.42, 128.55,
128.26, 128.06, 127.71, 127.39, 127.30, 113.77, 83.55, 79.26,
75.83, 74.36, 73.10, 71.55, 68.37, 55.24, 45.06, 43.18, 23.98,
22.86, 22.80, 14.88; high-resolution mass spectrum (ES) m/z
675.2732 [(M + Na)+; calcd for C35H44N2O8SNa: 675.2716].
2-Br om oeth yl 2-O-Ben zylca r ba m oyl-3-O-isop r op ylca r -
ba m oyl-â-D-glu cop yr a n ose (-)-35. To a solution of thiogly-
coside (+)-33 (50 mg, 0.11 mmol) in CH2Cl2 (4.75 mL) and
2-bromoethanol (0.25 mL) at 0 °C was added a solution of
N-iodosuccinimide (52 mg, 0.23 mmol) and trifluoromethane
sulfonic acid (1 drop) in CH2Cl2/Et2O 1:1 (2 mL), and the
solution was stirred at 0 °C for 30 min. The reaction was
quenched with a 10% aq Na2S2O3 solution (20 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic
1
(s), 1120 (m), 1100 (m), 1090 (m), 1050 (m), 940 (m) cm-1; H
NMR (500 MHz, CDCl3) δ 7.36 (d, J ) 8.5 Hz, 2 H), 7.31-7.24
(m, 5 H), 6.84 (d, J ) 8.5 Hz, 2 H), 5.44 (s, 1 H), 5.20-5.14 (m,
1 H), 5.14-5.09 (m, 1 H), 4.95-4.88 (m, 1 H), 4.60-4.55 (m, 1
H), 4.54 (d, J ) 10.0 Hz, 1 H), 4.42 (dd, J ) 14.8, 5.9, 1 H),
4.34-4.31 (m, 2 H), 3.77 (s, 3 H), 3.77-3.72 (m, 2 H), 3.64-
3.59 (m, 1 H), 3.55-3.50 (m, 1 H), 2.73 (q, J ) 7.3 Hz, 2 H),
1.25 (t, J ) 7.3, 3 H), 1.09-1.07 (m, 6 H); 13C NMR (125 MHz,
CDCl3) δ 160.05, 155.23, 154.63, 138.14, 129.43, 128.54, 127.46,
127.40, 127.28, 113.49, 101.28, 84.49, 78.66, 73.42, 71.77,
70.76, 68.44, 55.23, 45.06, 43.17, 24.17, 22.75, 22.66, 14.77;
ES-MS m/z 583 [100, (M
28H36N2O8S: C, 59.98; H, 6.47; N, 5.00. Found: C, 59.97; H,
6.50; N, 4.89.
+
Na)+]. Anal. Calcd for
C

8316 J . Org. Chem., Vol. 65, No. 24, 2000
Hirschmann and Ducry
extracts were dried (Na2SO4), evaporated in vacuo, and puri-
fied by flash chromatography (hexane/EtOAc 4:6 to 2:8) on
silica gel to give (-)-35 as a colorless solid (22 mg, 39%): mp
188-189 °C; [R]2D5 ) -4.4 (c 1.0, MeOH); IR (CHCl3) 3014 (m),
1732 (m), 1699 (m), 1517 (m), 1212 (s), 1086 (m) cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.32-7.24 (m, 5 H), 5.11-5.06 (m, 1 H),
4.92 (d, J ) 6.6 Hz, 1 H), 4.84-4.79 (m, 1 H), 4.73-4.69 (m, 1
H), 4.52 (d, J ) 7.9 Hz, 1 H), 4.40-4.32 (m, 2 H), 4.14-4.09
(m, 1 H), 3.92 (dd, J ) 11.9, 3.3 Hz, 1 H), 3.84-3.64 (m, 3 H),
3.81 (dd, J ) 11.9, 4.8 Hz, 1 H), 3.44-3.37 (m, 3 H), 1.14 (d,
J ) 6.5 Hz, 3 H), 1.11 (d, J ) 6.7 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 156.62, 155.39, 138.16, 128.68, 127.62, 127.48,
101.19, 77.69, 75.94, 71.84, 70.28, 69.48, 62.39, 45.22, 43.53,
29.90, 22.75, 22.61; high-resolution mass spectrum (ES) m/z
527.1026 [(M + Na)+; calcd for C20H29BrN2O8Na: 527.1005].
2-Br om oet h yl 4-O-Ben zyl-2-O-b en zylca r ba m oyl-3-O-
isop r op ylca r ba m oyl-â-D-glu cop yr a n ose (+)-36. To a solu-
tion of thioglycoside (-)-34 (10 mg, 0.02 mmol) in CH2Cl2 (2.30
mL) and 2-bromoethanol (0.20 mL) at 0 °C was added a
solution of N-iodosuccinimide (9 mg, 0.04 mmol) and trifluo-
romethane sulfonic acid (1 drop) in CH2Cl2/Et2O 1:1 (2 mL),
and the solution was stirred at 0 °C for 4 h and at rt for 2 h.
The reaction was quenched with a 10% aq Na2S2O3 solution
(20 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were dried (Na2SO4), evaporated in vacuo, and
purified by flash chromatography (hexane/EtOAc 6:4) on silica
gel to give (+)-36 as a colorless amorphous solid (4 mg, 44%):
[R]2D5 ) +2.7 (c 0.5, CHCl3); IR (CHCl3) 3019 (s), 1732 (m),
1514 (m), 1220 (s), 1208 (s), 1082 (m) cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.32-7.21 (m, 10 H), 5.15-5.08 (m, 2 H), 4.77 (d, J
) 9.2 Hz, 1 H), 4.66 (d, J ) 10.8 Hz, 1 H), 4.61-4.54 (m, 2 H),
4.52 (d, J ) 7.9 Hz, 1 H), 4.41-4.29 (m, 2 H), 4.12-4.07 (m, 1
H), 3.89-3.70 (m, 4 H), 3.67-3.62 (m, 1 H), 3.45-3.39 (m, 3
H), 1.11 (d, J ) 6.5 Hz, 3 H), 1.09 (d, J ) 6.7 Hz, 3 H); 13C
NMR (125 MHz, CDCl3) δ 155.42, 154.68, 137.59, 128.64,
128.51, 128.44, 128.21, 127.99, 127.53, 127.44, 101.26, 75.33,
74.59, 69.64, 61.64, 45.16, 43.29, 29.74, 29.70, 22.90, 22.88;
high-resolution mass spectrum (ES) m/z 617.1480 [(M + Na)+;
calcd for C27H35BrN2O8Na: 617.1475].
glycoside (-)-35 (14 mg, 0.03 mmol), potassium carbonate (39
mg, 0.28 mmol), and morpholine (24 µL, 0.28 mmol) in THF
(5 mL) was heated at reflux for 7 h. The reaction was allowed
to cool, quenched with a saturated aqueous NaHCO3 solution
(20 mL), and extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were dried (Na2SO4), evaporated in vacuo, and
purified by flash chromatography (CH2Cl2/MeOH/Et3N 90:9:
1) on silica gel to give (+)-37 as a colorless solid (12 mg, 85%):
mp 181-183 °C; [R]D25 ) +15.6 (c 1.0, CHCl3); IR (CHCl3)
3018 (s), 1732 (m), 1702 (m), 1517 (m), 1224 (s), 1207 (s) cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.32-7.24 (m, 5 H), 5.17-5.13
(m, 1 H), 4.96 (d, J ) 7.1 Hz, 1 H), 4.82-4.78 (m, 1 H), 4.75-
4.70 (m, 1 H), 4.49 (d, J ) 7.7 Hz, 1 H), 4.37-4.30 (m, 2 H),
4.05-4.00 (m, 1 H), 3.91 (dd, J ) 11.9, 2.5 Hz, 1 H), 3.80 (dd,
J ) 11.9, 4.8 Hz, 1 H), 3.74-3.65 (m, 7 H), 3.41-3.38 (m, 1
H), 2.64 (br s, 2 H), 2.55 (br s, 4 H), 1.13 (d, J ) 6.3 Hz, 3 H),
1.09 (d, J ) 6.2 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 156.39,
155.53, 138.21, 128.68, 127.60, 127.36, 100.93, 76.06, 72.34,
69.68, 66.76, 66.46, 62.05, 57.89, 53.88, 45.10, 43.38, 22.75,
22.58; high-resolution mass spectrum (ES) m/z 512.2586 [(M
+ H)+; calcd for C24H37N3O9: 512.2608].
Ack n ow led gm en t. Financial support was provided
by the National Institutes of Health (National Institute
of General Medical Sciences) through grant GM-41821.
L.D. gratefully acknowledges a postdoctoral fellowship
from the Swiss National Science Foundation. In addi-
tion, we thank Drs. George T. Furst and Patrick J .
Carroll and Mr. J ohn Dykins of the University of
Pennsylvania Spectroscopic Service Center for assis-
tance in securing and interpreting high-field NMR
spectra, X-ray crystal structures, and mass spectra,
respectively.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
for glycosides (+)-15, (+)-16, (+)-25, and (+)-37. This material
is available free of charge via the Internet at http://pubs.acs.org.
2-(Mor p h olin -4-yl)eth yl 2-O-Ben zylca r ba m oyl-3-O-iso-
p r op ylca r ba m oyl-â-D-glu cop yr a n ose (+)-37. A solution of
J O001099V