De novo synthesis of a methylene-bridged Neu5Ac-α-(2,3)-Gal C-disaccharide

Article abstract of DOI:10.1021/jo015543l

A general strategy toward the synthesis of C-ketosides of N-acetylneuraminic acid (Neu5Ac) has been developed and successfully applied to the synthesis of methylene-bridged Neu5Ac-α-(2,3)-Gal C-disaccharide 2. The key strategic element of this novel approach is a stereoselective, 6-exo-trig selective, electrophilic cyclization of the appropriate open chain precursor 4 by means of phenylselenyl triflate. The open chain precursor was formed by the addition of lithiated iodide 18 accessible from D-galactose to open chain aldehyde 5a obtained from D-glucono-δ-lactone by chain elongation. Subsequent C₁-incorporation using Tebbe-reagent, formation of a cyclic carbonate, and deprotection of the two isopropylidene ketals afforded tetrol 4 which, upon treatment with phenylselenyl triflate, was stereoselectively cyclized in a 6-exo-trig selective manner. A selena-Pummerer rearrangement, oxidation, and esterification readily led to methyl ester 37 which, after deacetylation, could be regioselectively tetrabenzoylated with benzoyl cyanide. Triflate activation of the axial hydroxyl group in 40 and nucleophilic displacement by azide ion with inversion of configuration afforded azide 41, which was reduced with hydrogen and Pearlman's catalyst. Concomitant removal of the benzyl ethers and subsequent saponification of all ester moieties successfully completed the de novo synthesis of the desired methylene bridged Neu5Ac-α-(2,3)-Gal C-disaccharide 2.

Full text of DOI:10.1021/jo015543l

4250
J . Org. Chem. 2001, 66, 4250-4260
De Novo Syn th esis of a Meth ylen e-Br id ged Neu 5Ac-r-(2,3)-Ga l
C-Disa cch a r id e
Wolfgang Notz, Christian Hartel, Bernhard Waldscheck, and Richard R. Schmidt*
Fachbereich Chemie, Universita¨t Konstanz, Fach M 725, D-78457 Konstanz, Germany
Richard.Schmidt@uni-konstanz.de
Received J anuary 24, 2001
A general strategy toward the synthesis of C-ketosides of N-acetylneuraminic acid (Neu5Ac) has
been developed and successfully applied to the synthesis of methylene-bridged Neu5Ac-R-(2,3)-Gal
C-disaccharide 2. The key strategic element of this novel approach is a stereoselective, 6-exo-trig
selective, electrophilic cyclization of the appropriate open chain precursor 4 by means of
phenylselenyl triflate. The open chain precursor was formed by the addition of lithiated iodide 18
accessible from D-galactose to open chain aldehyde 5a obtained from D-glucono-δ-lactone by chain
elongation. Subsequent C1-incorporation using Tebbe-reagent, formation of a cyclic carbonate, and
deprotection of the two isopropylidene ketals afforded tetrol 4 which, upon treatment with
phenylselenyl triflate, was stereoselectively cyclized in a 6-exo-trig selective manner. A selena-
Pummerer rearrangement, oxidation, and esterification readily led to methyl ester 37 which, after
deacetylation, could be regioselectively tetrabenzoylated with benzoyl cyanide. Triflate activation
of the axial hydroxyl group in 40 and nucleophilic displacement by azide ion with inversion of
configuration afforded azide 41, which was reduced with hydrogen and Pearlman’s catalyst.
Concomitant removal of the benzyl ethers and subsequent saponification of all ester moieties
successfully completed the de novo synthesis of the desired methylene bridged Neu5Ac-R-(2,3)-Gal
C-disaccharide 2.
In tr od u ction
As terminating constituents of many glycoconjugates,1
e.g., gangliosides such as GM2 (1, Figure 1), sialic acids
are often found at the nonreducing end of the oligosac-
charide moiety, and due to this peripheral position they
are involved in a significant number of biological events.
In particular, they mediate numerous cellular recognition
events2 in cell migration and adhesion,3 immune re-
sponse,4 tumor metastasis,5 and the development of
neural cells.6 Furthermore, they influence aggregation
and agglutination, cell membrane permeability for amino
acids, ions, and proteins, mask antigenic oligosaccharides
and protect glycoproteins against proteolysis.7 Addition-
F igu r e 1. Ganglioside GM2sa Neu5Ac containing glyco-
sphingolipid.
ally, terminal sialic acids serve as attachment sites for
many infectious pathogens including viruses,8 bacteria,
and parasites,9 and upon recognition of this characteristic
ligand on the cellular surface by surface proteins of the
pathogen, the infection is initiated.10
(1) For reviews, see: (a) Horowitz, M. I.; Pigman, W. The Glycocon-
jugates; Academic Press: New York, 1977-1985; Vols. 1-4. (b)
Karlsson, K.-A. Curr. Opin. Struct. Biol. 1995, 5, 622-635. (c)
Wiegandt, H. Glycolipids; Wiegandt, H., Ed.; Elsevier: New York,
1985; Vol. 10, p 199. (d) Varki, A. Glycobiology 1993, 3, 97-130.
(2) (a) Magnani, J . L.; Nilsson, B.; Brockhaus, M.; Zopf, D.; Steplews-
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(b) Danishefsky, S. J .; Koseki, K.; Griffith, D. A.; Gervay, J .; Peterson,
J . M.; McDonald, F. E.; Oriyama, T. J . Am. Chem. Soc. 1992, 114,
8331-8333.
The most ubiquitous member of this class of structur-
ally unique, natural carbohydrates is N-acetylneuraminic
(7) (a) Sialic Acids; Schauer, R., Ed.; Springer-Verlag: New York,
1985. (b) Biological Roles of Sialic Acid; Rosenberg, V., Shengrund,
C., Eds.; Plenum: New York, 1976. (c) Sharon, N. Complex Carbohy-
drates; Addison-Wesley: London, 1975. (d) Varki, A. Glycobiology 1992,
2, 25-40.
(3) (a) Rossen, S. D.; Bertozzi, C. R. Curr. Opin. Cell Biol. 1994, 6,
663. (b) Springer, T. A. Annu. Rev. Physiol. 1995, 57, 827-872.
(4) (a) Kelm, S.; Pelz, A.; Schauer, R.; Filbin, M. T.; Tang, S.; Bellard,
M.-E. d.; Schnaar, R. L.; Mahoney, J . A.; Hartnell, A.; Bradfield, P.;
Crocker, P. R. Curr. Biol. 1994, 4, 965-972. (b) Hanasaki, K.; Varki,
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Chui, D.; Paulson, J . C.; Marth, J . D. Proc. Natl. Acad. Sci. U.S.A.
1998, 95, 4504-4509.
(8) (a) Watowich, S. J .; Skehel, J . J .; Wiley, D. C. Structure 1994, 2,
719-731. (b) Stehle, T.; Yan, Y.; Benjamin, T. L.; Harrison, S. C.
Nature 1994, 369, 160-163. (c) Roulston, A.; Beauparlant, P.; Rice,
N.; Hiscott, J . J . Virol. 1993, 67, 5235-5246. (d) Dallocchio, F.; Tomasi,
M.; Bellini, T. Biochem. Biophys. Res. Commun. 1995, 208, 36-41.
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Cockle, S. A.; Klein, M. H.; Read, R. J . Nature Struct. Biol. 1994, 1,
591-596. (b) Sim, B. K. L.; Chitnis, C. E.; Wasniowska, K.; Hadley, T.
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313-320. (b) Paulson, J . C. In The Receptors; Conn, P. M., Ed.;
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Whitesides, G. M. Angew. Chem. 1998, 110, 2908-2952; Angew. Chem.,
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10.1021/jo015543l CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/12/2001

Synthesis of a Neu5Ac-R-(2,3)-Gal C-Disaccharide
J . Org. Chem., Vol. 66, No. 12, 2001 4251
Resu lts a n d Discu ssion
In our endeavor toward the synthesis of C-glycosides
of N-acetylneuraminic acid in general and target mol-
ecule 2 in particular (Scheme 1) we envisioned an
electrophilic cyclization of an open chain precursor to be
the key step of the strategy thereby following approach
B (Figure 2). We assumed that open chain precursor 4
would be ideally suited to reduce the synthesis of target
molecule 2 to practice. As delineated in Scheme 1,
retrosynthetic processing of 2 by two functional group
interchanges readily gives rise to phenyl selenide 3 which
reveals the retron for a selenium-induced electrophilic
cyclization of open chain precursor 4. We reasoned that
of the four hydroxyl groups present in 4 only the one
leading to a six-membered cyclization product would
participate in the cyclization step in an exo-trig selective
manner,15 therefore rendering a selective protection
unnecessary. In addition, we decided to defer the intro-
duction of the nitrogen to a late stage of the synthesis,
i.e., after the cyclization step in order to avoid a competi-
tive participation of the nitrogen during the cyclization
step; we furthermore anticipated that embedding of the
erythro-diol unit of 4 into a cyclic carbonate framework
would decrease the conformational flexibility of the
acyclic scaffold and facilitate the electrophilic cycliza-
tion.16 Open chain precursor 4 was then dissected into
two building blocks of equal molecular complexity which
generates C8-electrophile 5a as the latent sialic acid
moiety and lithiated C7-nucleophile 6 which can be
obtained starting from D-galactose. Inspection of C8-
electrophile 5a reveals a â-hydroxy carbonyl unit together
with a stereochemical erythro-relationship between the
contiguous hydroxyl groups at C-3 and C-4. These
structural features could be established by an indirect
aldol reaction invoking the inherent stereochemical
information present in D-glucono-δ-lactone as commer-
cially available starting material.
F igu r e 2. Potential complementary disconnective approaches
A and B leading to the synthesis of Neu5Ac-R-(2,3)-Gal
C-disaccharides and the corresponding nucleophilic and elec-
trophilic building blocks.
acid (Neu5Ac)sa component essential to many glycocon-
jugates.1 Typically, Neu5Ac is attached via an R-O-
glycosidic linkage to the carbohydrate chain of these
glycoconjugates and an important structural motif fre-
quently found in glycoconjugates is the Neu5Ac-R-(2,3)-
Gal disaccharide (see also Figure 1).11
In vivo, terminal Neu5Ac is removed from the glyco-
conjugate by neuraminidase, a specific hydrolytic en-
zyme. Following cleavage, antigenic oligosaccharides are
unmasked thereby permitting the catabolism of the
entire glycoconjugate. The replacement of the inter-
glycosidic oxygen of such a Neu5Ac-R-(2,3)-Gal disaccha-
ride by a methylene group provides an interesting
approach to rationally control many of these important
processes in glycobiology since this structural transfor-
mation renders the natural disaccharide a nonhydrolyz-
able C-glycoside analogue which is inert to catabolism.
Despite numerous methodologies available for the
synthesis of C-glycosides of aldoses12 only a few syntheses
of C-glycosides of sialic acids have been reported.13 Only
recently, the elegant work of Linhardt and co-workers14
using samarium iodide provided an approach to the
synthesis of more complex C-glycosides of various sialic
acids including a hydroxymethylene-bridged Neu5Ac-R-
(2,3)-Gal C-disaccharide (Figure 2, A).
Herein, we disclose a different strategy (Figure 2, B)
leading to methylene bridged C-glycosides of N-acetyl-
neuraminic acid by applying a versatile approach that
is based on the electrophilic cyclization of an open chain
precursor using phenylselenyl triflate as cyclization
reagent, followed by the generation of the carboxylate
moiety and introduction of the nitrogen. For that purpose,
readily available and inexpensive precursors were se-
lected as starting materials.
Syn th esis of th e C8-Electr op h ile. The synthesis of
the C8-electrophile (Scheme 2) commences with a chain
elongation of known D-glucono-δ-lactone derived triac-
etonide 717 by single addition of freshly prepared allyl-
magnesium bromide18 at very low temperatures. After
acidic workup, R-hydroxy ketone 8 could be isolated in
89% yield together with unreacted starting material. In
this context, neither isomerization of 8 to the thermo-
dynamically more stable R,â-unsaturated enone system
nor double addition of the C-nucleophile to the ketone
carbonyl group of 8 was observed. Next, the resulting
R-hydroxy ketone 8 was stereoselectively reduced with
zinc borohydride19 in diethyl ether at -10 °C in 91% yield
to afford a 9.4:1-mixture of diastereomers 9a /b in favor
(11) Other important motifs yet less frequently occuring are the
Neu5Ac-R-(2,6)-Gal disaccharide as expressed, e.g., in N-glycans, and
the Neu5Ac-R-(2, 8)-Neu5Ac disaccharide as, e.g., in polysialic acid or
ganglioside GD2.
(12) For reviews, see: (a) Du, Y.; Linhardt, R. J .; Vlahov, I. R.
Tetrahedron 1998, 54, 9913-9961. (b) Postema, M. H. D., C-Glycoside
Synthesis; CRC Press: Boca Raton, 1995. (c) Levy, D. E. and Tang,
C., The Chemistry of C-Glycosides; Pergamon: Elsevier Science Ltd.:
Oxford, 1995. (d) Postema, M. H. D. Tetrahedron 1992, 48, 8545-8599.
(e) Schmidt, R. R. Proceedings of the 5th International Conference on
Chemistry and Biotechnology of Active Natural Products, Sept 18-23,
1989, Varna Bulgaria, Bulgarian Academy of Science: Sofia, 1989, Vol.
3, pp 560-575.
(13) (a) Luthman, K.; Orbe, M.; Waglund, T.; Claesson, A. J . Org.
Chem. 1987, 52, 3777-3784. (b) Paulsen, H.; Matschulat, P. Liebigs
Ann. Chem. 1991, 487-495. (c) Walliman, K.; Vasella, A. Helv. Chim.
Acta 1991, 74, 1520-1532. (d) Nagy, J .; Bednarski, M. Tetrahedron
Lett. 1991, 32, 3953-3956.
(14) (a) Vlahov, I. R.; Vlahova, P. I.; Linhardt, R. J . J . Am. Chem.
Soc. 1997, 119, 1480-1481. (b) Polat, T.; Du, Y.; Linhardt, R. J . Synlett
1998, 11, 1195-1196. (c) Du, Y.; Polat, T.; Linhardt, R. J . Tetrahedron
Lett. 1998, 39, 5007-5010. (d) Du, Y.; Linhardt, R. J . Carbohydr. Res.
1998, 308, 161-164. (e) Bazin, H. G.; Du, Y.; Linhardt, R. J . J . Org.
Chem. 1999, 64, 7254-7259. (f) Koketsu, M.; Kuberan, B.; Linhardt,
R. J . Org. Lett. 2000, 2, 3361-3363.
(15) (a) Baldwin, J . E. J . Chem. Soc. Chem. Commun. 1976, 734-
736. (b) Baldwin, J . E.; Cutting, J .; Dupont, W.; Kruse, L.; Silberman,
L.; Thomas, R. C. J . Chem. Soc. Chem. Commun. 1976, 736-738. (c)
Baldwin, J . E. J . Chem. Soc. Chem. Commun. 1976, 738-741.
(16) For an illustrative example, see: Nicolaou, K. C.; Daines, R.
A.; Ogawa, Y.; Chakraborty, T. K. J . Am. Chem. Soc. 1988, 110, 4696-
4705 and references therein.
(17) J arosz, S.; Zamoijski, A. J . Carbohydr. Chem. 1993, 12, 113-
118.
(18) For preparation of the Grignard reagent, see: Hwa, C. H.; Sims,
H. Organic Syntheses; Wiley: New York, 1973; Collect. Vol. V, pp 608-
610.
(19) (a) For preparation of the reagent, see: Gensler, W. J .; J ohnson,
F.; Sloan, A. D. B. J . Am. Chem. Soc. 1960, 82, 6074-6081. For
applications, see: (b) Nakata, T.; Tanaka, T.; Oishi, T. Tetrahedron
Lett. 1983, 24, 2653-2656. (c) Ranu, B. C. Synlett 1993, 885-892. (d)
Narasimhan, S.; Madhavan, S.; Ganeshwar Prasad, K. J . Org. Chem.
1995, 60, 5314-5315.

4252 J . Org. Chem., Vol. 66, No. 12, 2001
Sch em e 1. Retr osyn th etic An a lysis of Ta r get Molecu le 2
Notz et al.
Sch em e 2. Syn th esis of th e C8-Electr op h ilea
a
Reagents and conditions: (a) allylMgBr, Et2O, -95 °C, 89%; (b) Zn(BH4)2, Et2O, -10 °C, 91%; (c) t-BuMe2SiOTf (2.4 equiv), NEt3 (3.6
equiv), CH2Cl2, 0 °C f rt, 82%; (d) O3, CH2Cl2, -40 °C, then PPh3, Me2S, rt, 98%.
of isomer 9a with the desired C-4/C-5 erythro-configura-
tion. The stereocontrolled reduction can be rationalized
by transition state I20 (Scheme 2, as opposed to transition
state II) where, upon formation of an effective five-
membered chelate between the metal ion, the carbonyl,
and the adjacent hydroxyl group, the hydride delivery
preferentially occurs from the sterically less-hindered
side. Since the two diastereomeric diols 9a /b could not
be separated by column chromatography at this stage,
the mixture of isomers was further subjected to protection
of the two hydroxyl groups as tert-butyldimethylsilyl
(TBDMS) ethers. Initial attempts to achieve double
protection using TBDMS chloride as silylating agent
failed and resulted in selective monoprotection. However,
switching to TBDMS triflate and triethylamine as base
afforded the corresponding disilylated compounds 10a /b
in 82% yield; oxidative cleavage of the double bond in
10a /b with ozone followed by PPh3/Me2S workup provided
C8-electrophile 5a in almost quantitative yield thereby
completing the formally anti-selective aldol addition of
acetaldehyde to D-glucose.21,22 Most gratifyingly, the
minor C-3/C-4 threo-diastereomer 5b could now be re-
moved very easily by means of column chromatography,
thus affording pure C-3/C-4 erythro-diastereomer 5a in
multigram quantities and 65% overall yield from 7.
(20) (a) Cram, D. J .; Abd Elhafez, F. A. J . Am. Chem. Soc. 1952, 74,
5828-5835. (b) Cram, D. J .; Kopecky, K. R. J . Am. Chem. Soc. 1959,
81, 2748-2755. (c) Cram, D. J .; Wilson, D. R. J . Am. Chem. Soc. 1963,
85, 1245-1249. (d) Eliel, E. L. Asymmetric Synthesis; Morrison, J . D.,
Ed.; Academic Press: New York, 1982; Vol. 2, p 125. (e) Reetz, M. T.
Angew. Chem. 1984, 96, 542-555; Angew. Chem., Int. Ed. Engl. 1984,
23, 556-569. (f) Mulzer, J . Organic Synthesis Highlights; VCH
Publishers: Mulzer, J .; Altenbach, H. J .; Braun, M.; Krohn, K.; Reissig,
H. U.; Weinheim, New York: 1991, 3. (g) Still, W. C.; McDonald, J .
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Schneider, J . A. Tetrahedron Lett. 1980, 21, 1035-1038.

Synthesis of a Neu5Ac-R-(2,3)-Gal C-Disaccharide
J . Org. Chem., Vol. 66, No. 12, 2001 4253
Sch em e 3. Syn th esis of Iod id e 18sth e P r ecu r sor
Syn th esis of th e C7-Nu cleop h ile. As outlined in the
retrosynthetic analysis (Scheme 1), we planned the
coupling of C8-electrophile 5a with carbanionic C7-nucleo-
phile 6, which was conceived to be available from a
corresponding carbohydrate-based alkyl iodide via halo-
gen-metal exchange with organolithium compounds.
Both the addition of such anionic C7-nucleophiles to
electrophiles and routes to the corresponding C1-branched
monosaccharide precursors have been developed in our
laboratories and described earlier.23 Accordingly, iodide
18 (Scheme 3) was prepared as follows: Readily available
benzyl 3-O-allyl-â-D-galactoside 1124 was perbenzylated
under standard conditions to give 12 in 95% yield;
subsequent deallylation by treatment with Pd(PPh3)4,
acetic acid, and sodium p-toluenesulfinate following a
protocol described by Nagakura25 afforded alcohol 1324
in 89% yield which was oxidized with Dess-Martin
periodinane26 to ketone 14 (98%) and then methylenated
with Tebbe reagent27 in THF to install the C1-branching
required at the 3-position in 82% yield. Next, a regio-
selective borane addition to olefin 15 using 9-borabicyclo-
[3.3.1]nonane (9-BBN) and oxidative cleavage of the
carbon-boron bond with alkaline hydrogen peroxide
afforded an inseparable 3:2-mixture of gulo- and galacto-
isomers 16 (determined by NMR spectroscopy) in favor
of gulo-16 in 75% combined yield. Using Dess-Martin
periodinane, the mixture of isomers gulo/galacto-16 was
then oxidized almost quantitatively to the corresponding
aldehydes gulo/galacto-17 which were isomerized by
treatment with a 10% solution of triethylamine in di-
chloromethane at room temperature for 16 h to afford a
4:1 equilibrium in favor of galacto-17. After separation
of the two aldehydes by column chromatography, galacto-
17 was quantitatively reduced with excess of sodium
borohydride in methanol and the resulting alcohol ga-
lacto-16 was converted to iodide 18 (99%) by treatment
with iodine, PPh3, and imidazole28 thereby generating the
precursor for the C7-nucleophile in 50% overall yield (nine
steps) from known 11.
of th e C7-Nu cleop h ilea
The configuration at C-3 was deduced from the vicinal
coupling constants of the separable aldehydes gulo-17
(J 2,3 ) 6.6 Hz) and galacto-17 (J 2,3 ) 11.3 Hz). In addition,
a
Reagents and conditions: (a) BnBr, NaH, DMF, 0 °C f rt,
95%; (b) Pd(PPh3)4 (10 mol %), sodium p-toluenesulfinate (1.2
equiv), HOAc (2.4 equiv), CH2Cl2, rt, 89%; (c) Dess-Martin
periodinane, CH2Cl2, 98%; (d) Tebbe reagent (1.1 equiv, 1.5 M in
toluene), THF, 0 °C, 82%; (e) 9-BBN, THF, ∆; then NaOH, H2O2,
THF, rt, 75%; (f) Dess-Martin periodinane, CH2Cl2, 98%; (g)
CH2Cl2/NEt3 ) 9:1, 16 h, rt; (h) NaBH4, MeOH, rt, quant.; (i) I2
(2.5 equiv), PPh3 (3.0 equiv), imidazole (4.0 equiv), toluene, ∆, 99%.
(21) For examples using an allyl anion and oxidative cleavage of
the double bond as acetaldehyde equivalent, see: (a) BouzBouz, S.;
Cossy, J . Org. Lett. 2000, 2, 501-504. (b) Sharma, A.; Chattopadhyay,
S. J . Org. Chem. 1999, 64, 8059-8062. (c) Nicolaou, K. C.; Hepworth,
D.; Finlay, M. R. V.; King, N. P.; Werschkun, B.; Bigot, A. J . Chem.
Soc. Chem. Commun. 1999, 519-520. (d) Smith, A. B.; Ott, G. R. J .
Am. Chem. Soc. 1998, 120, 3935-3948. (e) Mohapatra, D. K.; Datta,
A. J . Org. Chem. 1998, 63, 642-64. (f) Tavares, F.; Lawson, J . P.;
Meyers, A. I. J . Am. Chem. Soc. 1996, 118, 3303-3304.
(22) Sn-mediated addtion of allyl bromides to an acyclic derivative
of D-glucose selectively afforded the corresponding syn-diol. See:
Hartel, C.; Diplomarbeit, Universta¨t Konstanz, 1996.
(23) (a) Schmidt, R. R.; Beyerbach, A. Liebigs Ann. Chem. 1992,
983-986. (b) R. Preuss, R.; J ung, K. H.; Schmidt, R. R. Liebigs Ann.
Chem. 1992, 377-382 and references therein. (c) Dietrich, H.; Schmidt,
R. R. Liebigs Ann. Chem. 1994, 975-981.
(24) David, S.; Thieffry, A.; Veyrie`res, A. J . Chem. Soc., Perkin
Trans. 1 1981, 1796-1801.
(25) Honda, M.; Morita, H.; Nagakura, I. J . Org. Chem. 1997, 62,
8932-8936.
F igu r e 3. Characteristic NMR data of compounds gulo/
galacto-16 and 17.
(26) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-
4156. (b) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277-
7287. (c) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(27) (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J . Am. Chem.
Soc. 1978, 100, 3611-3613. (b) Cannizzo, L. F.; Grubbs, R. H. J . Org.
Chem. 1985, 50, 2386-2387. (c) Pine, S. H.; Pettit, R. J .; Geib, G. D.;
Cruz, S. G.; Gallego, C. H.; Tijerina, T.; Pine, R. D. J . Org. Chem. 1985,
50, 1212-1216. (d) Lamberth, C. J . prakt. Chem. 1994, 336, 632-633.
(28) (a) Garegg, P. J .; Samuelsson, B. J . Chem. Soc., Perkin Trans.
1 1980, 2866-2869. (b) Garegg, P. J .; Samuelsson, B. Synthesis 1979,
813-814.
the corresponding nuclear Overhauser effect (NOE) cross-
peaks observed for these compounds are in accordance
with this assignment (Figure 3). It should be pointed out
that the values for the vicinal J 2,3 coupling constants of
the compounds with gulo-configuration suggest a twist
boat conformation of the pyranose ring rather than a

4254 J . Org. Chem., Vol. 66, No. 12, 2001
Sch em e 4. Cou p lin g, C1-In cor p or a tion , a n d Dep r otection a
Notz et al.
a
Reagents and conditions: (a) t-BuLi (1.5 equiv), THF, -100 °C, 2 min; (b) 5, THF, -100 °C, 5 min, then NH4Cl, 79%; (c) Dess-Martin
periodinane, CH2Cl2, 95%; (d) Tebbe reagent (20 equiv, 1.5 M in toluene), toluene/THF (4:1), -40 °C f rt, 62%; (e) TBAF, THF, 40 °C,
94%; (f) diphosgene, CH2Cl2/py, 0 °C f rt, 95%; (g) THF/H2O/TFA ) 5:2:2, ∆, 50 min, 69% of 4, 22% of 26. (h) Ac2O/py, quant.
chair conformation, whereas the pyranose ring of the
compounds possessing the desired galacto-configuration
preferentially adopts the expected chair conformation.
more stable threo-ketal could be cleaved in a very clean
reaction as well. This protocol led to a mixture of tetrol
4 (69%) together with monodeprotected diol 26 (22%)
which was subjected another time to these cleavage
conditions in a separate reaction. For full characteriza-
tion, both tetrol 4 and diol 26 were peracetylated in a
mixture of pyridine and acetic anhydride to the corre-
sponding acetates 25 and 27, respectively (Scheme 4).
Cou p lin g a n d Cycliza tion . With both C8-electrophile
5a and C7-nucleophile precursor 18 at hand, the stage
was set for the important coupling of these two building
blocks to form an open chain “disaccharide”. Therefore,
after careful preparation of the starting materials,29
iodide 18 was treated with t-BuLi (1.5 equiv) in THF at
-100 °C followed by addition of a THF solution of
aldehyde 5a (1.7 equiv) to organolithium intermediate 6
(Scheme 4) affording a 3:2-mixture of diastereomeric
alcohols 20a /b in 79% combined yield. Additionally, only
very small amounts (<4%) of reduced 3-C-methyl branched
galactose derivative 19 were isolated. The stereochem-
istry at the newly created stereogenic center in 20a /b was
not assigned since loss of this stereochemical information
occurred upon subsequent oxidation of that mixture with
Dess-Martin periodinane, which provided ketone 21 in
95% yield. Next, ketone 21 was treated with excess Tebbe
reagent in a 4:1 mixture of toluene/THF thereby incor-
porating the remaining carbon atom required for the
completion of the carbon scaffold of the C-disaccharide.
Thus, olefin 22 could be isolated in 62% yield together
with unreacted starting material 21(29%). After the
TBAF induced cleavage (94%) of the silyl ethers in 22,
the reaction of diol 23 with diphosgene resulted in a
smooth and almost quantitative formation of cyclic
carbonate 24. To establish reaction conditions for a clean
and complete cleavage of both of the isopropylidene ketals
in 24, we explored several acidic cleavage conditions and
found that a 5:2:2 mixture of THF, water, and TFA was
suited best. Treatment of a THF/H2O solution of 24 with
TFA at room-temperature resulted in almost instanta-
neous and quantitative cleavage of the primary ketal
moiety. Moreover, upon heating to reflux, the secondary,
Open chain precursor 4 was a pivotal intermediate in
our synthesis, and the stereochemical course of its
electrophilic cyclization was crucial for the endeavor
toward Neu5Ac-C-disaccharide 2. On the basis of the
potential and versatility of selenium based reagents30 as
well as our own results,31 we decided to exploit the
capability of cationic selenium species to induce an
electrophilic heterocyclization between an olefin and an
appropriately located hydroxyl functionality. Addition of
tetrol 4 to phenylselenyl triflate at -80 °C in propionitrile
resulted in quantitative formation of a 7:1 ratio of
products 3 and 28 (Scheme 5). Both 3 and 28 are very
sensitive to oxidation and, to avoid elevated temperatures
during workup as well as chromatographic purification,
the crude mixture was directly subjected to acetylation
which provided the more stable products 29 and 30,
respectively, in excellent overall yield.
NMR-studies of 29 and 30 revealed that the cyclization
occurred exclusively in a 6-exo-trig manner due to the
presence of a cross-peak between C-2′ and H-6′ in the
HMBC spectrum32 of advanced intermediate 39 (see
Scheme 6 for structure), and most importantly, the major
(30) (c) Nicolaou, K. C.; Petasis, N. A. Selenium in Natural Products
Synthesis; CIS: Philadelphia, 1984. (b) Sharpless, K. B.; Gordon, K.
M.; Lauer, R. F.; Patrick, D. W.; Singer, S. P.; Young, M. W. Chemica
Scripta 1975, 8A, 9-13. (c) Wirth, T. Angew. Chem. 2000, 112, 3890-
3900; Angew. Chem., Int. Ed. Engl. 2000, 39, 3740-3749.
(31) Schmidt, R. R.; Vlahov, I. V. Tetrahedron Asymmetry 1993, 4,
293-296.
(29) For details, see: Experiemental Section.
(32) See Supporting Information.

Synthesis of a Neu5Ac-R-(2,3)-Gal C-Disaccharide
J . Org. Chem., Vol. 66, No. 12, 2001 4255
Sch em e 5. Electr op h ilic Cycliza tion a
a
Reagents and conditions: (a) PhSeCl, AgOTf, EtCN, -80 °C, 98%; (b) Ac2O/py, quant.; (c) PhSeCl, AgOTf, MeCN, 0 °C, 83%.
Sch em e 6. Com p letion of Neu 5Ac-C-d isa cch a r id e 2a
a
Reagents and conditions: (a) mCPBA (1.0 equiv), THF, -80 °C, 15 min; (b) Ac2O/NaOAc, THF, -80 °C f rt f ∆, 90 min; (c) NaOMe,
THF/MeOH; (d) Ac2O/py, 90% overall yield; (e) NaClO2, KH2PO4, H2O, Me2CdCHMe/MeCN/t-BuOH (1:4:4), rt; (f) CH2N2, Et2O, rt, 89%
for two steps; (g) NaOMe, MeOH, quant.; (h) BzCN, THF/NEt3 ) 1:1, 0 °C f 5 °C, 64 h, 49% of 40, 24% of 39; (i) Tf2O, CH2Cl2/py; (j)
n-Bu4N-N3, toluene, rt, 94% for two steps; (k) Pd(OH)2/H2, MeOH/EtOAc, rt, 24 h; (l) Ac2O/py, NEt3 (f42); (m) THF/H2O, 0.1 M NaOH;
(n) RP-18 silica, Sephadex P-4, 0.3% NH4HCO3 buffer.
isomer formed was 333 which bears the phenylselenyl-
methyl moiety in the axial position at the newly formed
quaternary carbon center of the tetrahydropyran ring and
consequently possesses the desired R-linkage. The as-
signment of the stereochemistry of the quaternary carbon
center formed was based on the presence of NOE cross-
peaks between the protons of the corresponding axial
methylene group and H-4′ and H-6′, respectively (see 29
and 30, Scheme 5).
We assume that the high degree of stereoselectivity
during the course of the cyclization is mediated by the
cyclic carbonate unit present in 4 which provides (a)
decreased conformational flexibility of the acyclic scaffold
thereby facilitating the cyclization step and (b) a prefer-
ential conformation of the open chain precursor. Thus,
the participating hydroxyl group and the quaternary
olefinic carbon center are already in spatial proximity
prior to the cyclization. This was concluded from our
parallel findings in the cyclization of the structurally
analogous model system 3134 (Scheme 5) which gave
a similar stereochemical preference toward an axial
phenylselenylmethyl substituent when being cyclized
with phenylselenyl triflate in acetonitrile at room
temperature. In this case, determination of the coupling
constants and NOE data of starting material 31 in
CD3CN under the reaction conditions revealed that 31
adopts a preferential conformation which is similar to
the twist boat conformation of its acetylated cyclization
product 34 (Figure 4). In particular, the distinct confor-
mation around the C-2/C-3 bond in 31 favors a preferred
facial attack of the double bond by the electrophilic
selenium reagent as depicted in Figure 4, thus leading
to product 32 with the axial phenylselenylmethyl group.
Com p letion of th e Syn th esis. Following our strat-
egy, the next task was the installation of the carboxylate
functionality. This functional group transformation could
be achieved in a straightforward manner by subjecting
phenylselenide 29 to a selena-Pummerer rearrangement
to afford aldehyde 36 in four steps in 90% overall yield.
Oxidation of the aldehyde and subsequent esterification
(33) Isolated and characterized as acetylated 29.
(34) For preparation, see: Supporting Information.

4256 J . Org. Chem., Vol. 66, No. 12, 2001
Notz et al.
F igu r e 5. Proof of (a) the inversion of configuration at C-5′
during azide introduction and (b) of the erythro-selective Zn-
(BH4)2-reduction of 8 via R-chelation control.
F igu r e 4. Preferential conformation of open chain model
system 31 and comparison of the characteristic NMR data with
cyclized 32.
reductive cleavage of the benzyl ethers, and the crude
reaction product was directly peracetylated in a mixture
of acetic anhydride and pyridine. After removal of the
catalyst by filtration through silica, saponification of all
the ester moieties in 42 under mild conditions, and
purification by RP-18 silica and Sephadex P-4 column
using 0.3% aqueous ammonium bicarbonate buffer as
eluent, the de novo synthesis of the methylene bridged
Neu5Ac-R-(2,3)-Gal C-disaccharide 2 was complete.
of the carboxylic acid with diazomethane then provided
methyl ester 37 in 89% yield (Scheme 6).
To complete the assembly of the N-acetylneuraminic
acid moiety by the introduction of nitrogen, a different
protective group pattern of methyl ester 37 was required
to enable a selective nucleophilic displacement of the
hydroxyl group at C-5′. We anticipated that the use of
benzoyl cyanide could provide a regioselective tetra-
benzoylation35 of the five hydroxyl groups present in
deacetylated 38 thereby affording 40 which would be well
suited for the introduction of the nitrogen. In fact,
treatment of 38 with benzoyl cyanide in THF/NEt3 via
syringe pump addition over 64 h gave a 2:1 mixture of
regioisomers 39 and 40 in favor of the desired isomer 40
(Scheme 6) which could be isolated in 49% yield after
medium-pressure liquid chromatography. It should be
noted that the undesired regioisomer 39 can be easily
recycled by deprotection to afford 38 which in turn can
be subjected another time to the benzoylation protocol.
The regiochemistry of the benzoylation was proven by
the presence of cross-peaks between the proton of the
unprotected hydroxyl group and the proton at the adja-
cent carbon center in the DQF-COSY spectrum of 39
and 40. These results are also in accordance with the
chemical shifts observed for H-5′ (39: 5.84 ppm and 40:
4.30 ppm) and H-7′ (39: 4.24 ppm and 40: 5.97 ppm).
Next, the axial hydroxyl group of tetrabenzoate 40 was
converted into a leaving group by triflate activation and
smoothly displaced by treatment with tetra-n-butyl-
ammonium azide to afford azido compound 41 in 94%
yield.36 The inversion of the configuration at C-5′ in 40
could be unambiguously confirmed by the comparison of
the corresponding coupling constants and NOEs observed
for 40 and azide 41 (Figure 5). Moreover, the presence
Su m m a r y a n d Con clu sion
In summary, we have developed a novel approach
toward the synthesis of C-glycosides of N-acetylneuramin-
ic acid, and its potential was demonstrated by the
successful application to the synthesis of the important
Neu5Ac-R-(2,3)-Gal C-disaccharide 2. Important features
of this strategy are the following: (a) The approach is
general and allows for variability within the C-glycosidic
part as well as the sialic acid moiety (e.g., C-glycosides
of KDN); (b) The key step of this strategy consists of a
6-exo-trig selective electrophilic cyclization of open chain
precursor 4 by means of phenylselenyl triflate with a high
degree of stereoselectivity which can be attributed to a
preferential conformation adopted by the acyclic scaffold
and mediated by the cyclic carbonate unit present in 4;
(c) The strategy presented is not based on expensive
Neu5Ac precursors but uses inexpensive and readily
available precursors as starting materials; (d) Due to the
masked amino functionality, azide 41 constitutes a
valuable building block. This circumstance permits pos-
sible further transformations within the molecule with
an ideally protected nitrogen and furthermore provides
the option to attach, upon reduction, a large variety of
substituents other than N-acetyl to the nitrogen atom
(e.g., fluorescent or photosensitive groups).37
of an NOE between H-4′ and H-6′ together with J 4′,5′
)
The open chain precursor 4 was constructed by the
coupling of C8-electrophile 5a , obtained from D-glucono-
δ-lactone via chain elongation and erythro-selective ke-
tone reduction, with C7-nucleophile 6 having the desired
galacto-configuration and subsequent C1-incorporation.
In general, this C-disaccharide is suitable for incorpora-
tion into larger oligosaccharide structures which in turn
provides novel terminal C-sialylated glycoconjugates.
10.0 Hz for the value of the vicinal coupling constant
between H-4′ and H-5′ in 41 also proved the erythro-
selectivity of the Zn(BH4)2 reduction of 8 via the R-che-
lation-controlled transition state I (Scheme 2).
To accomplish the synthesis of the Neu5Ac-C-disac-
charide, the azide functionality in 41 was reduced with
hydrogen using Pearlman’s catalyst with concomitant
(35) Such regioselective benzoylations are not without precedent.
For an example with unprotected lactose derivatives, see: Lay, L.;
Windmu¨ller, R.; Reinhardt, S.; Schmidt, R. R. Carbohydr. Res. 1997,
303, 39-49.
(36) Successful transformation of 3-deoxy-2-glyculosonates into the
corresponding 5-azido-3,5-dideoxy derivatives has been already de-
scribed: (a) Danishefsky, S. J .; DeNinno, M. P.; Chen, S. J . Am. Chem.
Soc. 1988, 110, 3929-3940. (b) Haag-Zeino, B.; Schmidt, R. R. Liebigs
Ann. Chem. 1990, 1197-1203. (c) Yamamoto, T.; Teshima, T.; Inami,
K.; Shiba, T. Tetrahedron Lett. 1992, 33, 325-328.
(37) (a) Gross, H. J .; Rose, U.; Krause, J . M.; Paulson, J . C.; Schmid,
K.; Feeney, R. E.; Brossmer, R. Biochemistry 1989, 28, 7386-7392. (b)
Gross, H. J .; Brossmer, R. Eur. J . Biochem. 1988, 177, 583-589. (c)
Gross, H. J .; Sticher, U.; Brossmer, R. Anal. Biochem. 1990, 186, 127-
134. (d) Horst, G. T. J . v. d.; Mancini, G. M. S.; Brossmer, R.; Rose, U.;
Verheijen, F. W. J . Biol. Chem. 1990, 265, 10801-10804. (e) Mirelis,
P.; Brossmer, R. Bioorg. Med. Chem. Lett. 1995, 5, 2809-2814. (f)
Dufner, G.; Schwo¨rer, R.; Mu¨ller, B.; Schmidt, R. R. Eur. J . Org. Chem.
2000, 1467-1482.

Synthesis of a Neu5Ac-R-(2,3)-Gal C-Disaccharide
J . Org. Chem., Vol. 66, No. 12, 2001 4257
Ben zyl 2,4,6-Tr i-O-ben zyl-3-d eoxy-3-C-for m yl-â-D-ga -
la cto-h exop yr a n osid e (ga la cto-17). (a) From galacto-16: To
a solution of a mixture of gulo/galacto-16 (525 mg, 0.946 mmol)
in dry dichloromethane (15 mL), Dess-Martin periodinane26
(480 mg, 1.132 mmol, 1.2 equiv) was added, and the mixture
was stirred for 20 min at room temperature. Then a saturated
solution of sodium hydrogen carbonate (15 mL) containing
sodium thiosulfate (1.80 g) was added to the mixture with
vigorous stirring for 15 min. The mixture was washed with
dichloromethane, and the combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. Flash chroma-
tography (SiO2, petroleum ether/ethyl acetate ) 6:1) afforded
pure gulo-17 (331 mg, 0.599 mmol, 63%) and pure galacto-17
(184 mg, 0.333 mmol, 35%). (b) From isomerization of gulo-
17: Pure gulo-17 (1.00 g) was dissolved in dry CH2Cl2/NEt3
(50 mL, 9:1), and the mixture was stirred at room temperature
for 16 h. After removal of the solvents in vacuo at room
temperature, the residue was thoroughly dried in vacuo, and
the two isomers were separated by flash chromatography
(SiO2, petroleum ether/ethyl acetate ) 6:1) to give an ap-
proximate 4:1 ratio in favor of galacto-17. [R]D ) -0.8 (c ) 2;
CHCl3). TLC (SiO2): Rf ) 0.40 (petroleum ether/ethyl acetate
) 4:1). 1H NMR (600 MHz, CDCl3): δ ) 2.46 (ddd, 2 × J ≈ 2.4
Hz, J 2,3 ) 11.3 Hz, 1 H, 3-H); 3.64-3.69 (m, 3 H, 5-H, 6-Ha,
6-Hb); 4.13 (dd, J 1,2 ) 7.7 Hz, J 2,3 ) 11.3 Hz, 1 H, 2-H); 4.17
(d, J ) 3.1 Hz, 1 H, 4-H); 4.43-4.55 (m, 5 H, 1-H, PhCH2);
4.67 (d, J ) 11.9 Hz, 1 H, PhCH2); 4.71 (d, J ) 10.9 Hz, 1 H,
PhCH2); 4.96 (d, J ) 10.9 Hz, 1 H, PhCH2); 4.99 (d, J ) 11.9
Hz, 1 H, PhCH2); 7.18-7.38 (m, 20 H 4 × Ph); 9.50 (d, J ) 1.7
Hz, 1 H, CHO). Anal. Calcd for C35H36O6 (552.7): C: 76.06,
H: 6.57. Found: C: 75.76, H: 6.80.
Exp er im en ta l Section
Gen er a l Meth od s a n d In str u m en ta tion . See Supporting
Information.
3,4-Di-O-(ter t-bu tyld im eth ylsilyl)-2-d eoxy-5,6:7,8-d i-O-
isopr opyliden e-D-glycer o-D-gu lo-a ldeh ydo-octose (5a) an d
3,4-d i-O-(ter t-b u t yld im et h ylsilyl)-2-d eoxy-5,6:7,8-d i-O-
isop r op ylid en e-D-glycer o-D-id o-a ld eh yd o-oct ose (5b). A
solution of 10a /b (5.75 g, 10.83 mmol) in dry dichloromethane
(50 mL) was cooled to -40 °C and saturated with ozone until
the color of the mixture turned blue. Then argon was passed
through the mixture (15 min) followed by addition of dimethyl
sulfide (25 mL), and stirring was continued while warming
up to room temperature. Then PPh3 (2.84 g, 10.83 mmol, 1
equiv) was added, and the mixture was stirred until the
reaction was complete (monitored by TLC). Removal of the
solvent in vacuo and purification of the residue by flash
chromatography (SiO2, petroleum ether/ethyl acetate ) 15:1)
afforded both 5a (5.14 g. 9.65 mmol, 89%) and 5b (519 mg,
0.975 mmol, 9%) as a colorless syrup. 5a was formed from 10a .
Data for 5a : [R]D ) +8.8 (c ) 0.4; CHCl3). TLC (SiO2): Rf )
0.27 (SiO2, petroleum ether/ethyl acetate ) 15:1). 1H NMR (250
MHz, CDCl3): δ ) 0.09, 0.10, 0.11, 0.12 (4 s, 12 H, 2 × SiMe2);
0.89, 0.92 (2 s, 18 H, 2 × SitBu); 1.31, 1.33, 1.38, 1.39 (4 s, 2
× CMe2); 2.62 (ddd, J ) 2.9 Hz, J ) 6.7 Hz, J gem ) 16.8 Hz, 1
H, 2-Ha); 2.81 (ddd, J ) 1.7 Hz, J ) 4.0 Hz, J gem ) 16.8 Hz, 1
H, 2-Hb); 3.75-3.84 (m, 2 H, 6-H, 8-Ha); 3.91-4.03 (m, 3 H,
4-H, 5-H, 7-H); 4.18 (dd, J 7,8Hb ) 5.9 Hz, J gem ) 8.3 Hz, 1 H,
8-Hb); 4.41 (ddd, J ) 1.4 Hz, J ) 4.0 Hz, J ) 6.6 Hz, 1 H,
3-H); 9.82 (dd, J 1,2Ha ) 1.7 Hz, J 1,2Hb ) 2.9 Hz, 1 H, 1-H). Anal.
Calcd for C26H52O6Si2 (532.9): C: 58.60, H: 9.84. Found: C:
58.58 H: 9.67. Data for 5b: [R]D ) +42.9 (c ) 2; CHCl3);
TLC: Rf ) 0.39 (SiO2, petroleum ether/ethyl acetate ) 15:1).
1H NMR (600 MHz, CDCl3): δ ) 0.06, 0.09, 0.11 (3 s, 12 H, 2
× SiMe2); 0.87, 0.90 (2 s, 18 H, 2 × SitBu); 1.32, 1.36, 1.39 (3
s, 12 H, 2 × CMe2); 2.78-2.84 (m, 2 H, 2-Ha, 2-Hb); 3.76-3.86
(m, 3 H, 4-H, 6-H, 8-Ha); 3.99 (m, 1 H, 7-H); 4.16-4.29 (m, 3
H, 3-H, 5-H, 8-Hb); 9.82 (m, 1 H, 1-H). Anal. Calcd for C26H52O6-
Si2 (532.9): C: 58.60, H: 9.84. Found: C: 58.55, H: 9.56.
Ben zyl 2,4,6-Tr i-O-ben zyl-3-d eoxy-3-C-(iod om eth yl)-â-
D-ga la cto-h exop yr a n osid e (18). Galacto-16 (2.72 g, 4.90
mmol) was dissolved in dry toluene (150 mL) and PPh3 (3.86
g, 14.72 mmol, 3.0 equiv), imidazole (1.33 g, 19.54 mmol, 4.0
equiv), and iodine (3.11 g, 12.25 mmol, 2.5 equiv) were
successively added at room temperature, and the resulting
mixture was heated to reflux (15 min). After cooling to room
temperature and addition of saturated aqueous sodium hy-
drogen carbonate solution (75 mL), the mixture was vigorouly
stirred, and then iodine was added until the organic layer
remained iodine-colored. Excess iodine was removed by addi-
tion of sodium thiosulfate until the mixture was completely
decolorized. The layers were separated, the aqueous layer was
extracted with toluene (3×), and the combined organic layers
were dried (MgSO4). Filtration, concentration in vacuo, and
purification of the residue by flash chromatography (SiO2,
petroleum ether/ethyl acetate ) 12:1) afforded iodide 18 (3.22
g, 4.85 mmol, 99%) as a colorless syrup. [R]D ) +11.2 (c ) 2;
CHCl3). TLC (SiO2): Rf ) 0.38 (petroleum ether/ethyl acetate
Ben zyl 2,4,6-Tr i-O-ben zyl-3-deoxy-3-C-(h ydr oxym eth yl)-
â-D-ga la cto-h exop yr a n osid e (ga la cto-16). (a) From 15: A
solution of 15 (1.59 g, 2.963 mmol) in dry THF (75 mL) was
treated with a 9-BBN solution in THF (0.5 M, 37 mL) and
heated to reflux for 4 h. After cooling to 0 °C, a 10% aqueous
sodium hydroxide solution (30 mL) and a 30% hydrogen
peroxide solution (30 mL) were added simultaneously within
5 min and stirring was continued for 30 min. Then diethyl
ether was added followed by careful addition of a 20% aqueous
sodium hydrogen sulfite solution (2 mL). This mixture was
stirred for further 60 min and extracted with diethyl ether,
and the combined organic layers were dried (MgSO4), filtered,
and concentrated in vacuo. Flash chromatography (SiO2,
petroleum ether/ethyl acetate ) 2:1) of the residue afforded a
mixture of gulo-16 and galacto-16 (1.23 g, 2.217 mmol, 75%)
which cannot be separated. The ratio of gulo/galacto-16 was
determined by NMR-spectroscopy to be 3:2 in favor of the gulo-
isomer.
1
) 9:1); H NMR (600 MHz, CDCl3): δ ) 1.92 (dddd, 2 × J ≈
2.9 Hz, 2 × J ≈ 11.2 Hz, 1 H, 3-H); 3.13 (dd, J ) 9.7 Hz, J gem
) 11.4 Hz, 1 H, 3′-Ha); 3.37 (d, J 2,3 ) 11.2 Hz, J 1,2 ) 7.6 Hz, 1
H, 2-H); 3.61-3.69 (m, 4 H, 3′-Hb, 5-H, 6-Ha, 6-Hb); 4.02 (d, J
) 2.6 Hz, 1 H, 4-H); 4.44 (d, J 1,2 ) 7.6 Hz, 1 H 1-H); 4.50-
4.57 (m, 3 H, PhCH2); 4.65 (d, J ) 12.0 Hz, 1 H, PhCH2); 4.68
(d, J ) 11.4 Hz, 1 H, PhCH2); 4.75 (d, J ) 11.4 Hz, 1 H,
PhCH2); 4.93 (d, J ) 11.0 Hz, 1 H, PhCH2); 4.96 (d, J ) 12.0
Hz, 1 H, PhCH2); 7.24-7.36 (m, 20 H, 4 × Ph). Anal. Calcd
for C35H37IO5 (664.6): C: 63.26, H: 5.61. Found: C: 63.26,
H: 5.56.
(b) From reduction of galacto-17: Galacto-17 was dissolved
in methanol, and excess sodium borohydride was added. After
5 min, the mixture was concentrated in vacuo, the residue
dissolved in diethyl ether and washed with brine. The organic
phase was dried (MgSO4), filtered, concentrated in vacuo, and
purified by flash chromatography (SiO2, petroleum ether/ethyl
Ben zyl 2,4,6-Tr i-O-b en zyl-3-d eoxy-3-C-[4,5-d i-O-(ter t-
b u t yld im et h ylsilyl)-1,3-d id eoxy-6,7:8,9-d i-O-isop r op yli-
d en e-D-er yth r o-L-ta lo/L-ga la cto-n on it -1-yl]-â-D-ga la cto-
h exop yr a n osid e (20a /b). All starting materials were success-
ively coevaporated several times with dry toluene and then
dry dichloromethane and subsequently thoroughly dried in
vacuo (P e 0.5 mbar) for several days. All operations were
carried out under an inert atmosphere of nitrogen. At -100
acetate ) 2:1) to afford pure galacto-16 quantitatively. [R]D
)
-1.7 (c ) 2.7; CHCl3). TLC (SiO2): Rf ) 0.28 (petroleum ether/
ethyl acetate ) 2:1). 1H NMR (600 MHz, CDCl3): δ ) 1.80 (m,
1 H, 3-H); 2.03 (m, 1 H, OH); 3.59 (m, 1 H, 3′-Hb); 3.64-3.73
(m, 4 H, 2-H, 4-H, 6-Ha, 6-Hb); 3.79 (dd, J ) 10.9 Hz, J ) 4,7
Hz, 1 H, 3′-Hb); 3.89 (d, J ) 2.9 Hz, 1 H, 4-H); 4.51-4.58 (m,
5 H, 1-H, PhCH2); 4.63-4.66 (2d, J ) 11.5 Hz, J ) 12.0 Hz, 2
H, PhCH2); 4.93 (d, J ) 10.9 Hz, 1 H, PhCH2); 4.97 (d, J )
12.0 Hz, 1 H, PhCH2); 7.25-7.36 (m, 20 H, 4 × Ph). Anal. Calcd
for C35H38O6 (554.7): C: 75.78, H: 6.91. Found: C: 75.50, H:
7.10.
t
°C a 1.5 M solution of BuLi in pentane (8.2 mL, 12.3 mmol,
1.5 equiv) was quickly added to a solution of iodide 18 (5.48 g,
8.25 mmol) in dry THF (210 mL) via syringe. After stirring
for 2 min, a solution of aldehyde 5a (7.47 g, 14.02 mmol, 1.7
equiv) in dry THF (30 mL) was quickly added via syringe and
after stirring for further 5 min, the reaction was quenched by

4258 J . Org. Chem., Vol. 66, No. 12, 2001
Notz et al.
pouring the cold mixture into a saturated aqueous ammonium
chloride solution. The layers were separated, and the aqueous
layer was extracted several times with diethyl ether. The
combined organic layers were dried (MgSO4), filtered, concen-
trated in vacuo, and purified by flash chromatography (SiO2,
petroleum ether/ethyl acetate ) 7:1 f 3:1) to afford both 20a
(2.82 g, 2.67 mmol, 32%) and 20b (4.14 g, 3.86 mmol, 47%) as
a colorless syrup. Additionally, small amounts of 19 (437 mg,
0.81 mmol, 10%) could be isolated together with recovered
aldehyde 5a (3.84 g, 7.21 mmol). Data for 20a : [R]D ) -4.6 (c
) 1; CHCl3). TLC (SiO2): Rf ) 0.58 (petroleum ether/ethyl
acetate ) 4:1) 1H NMR (600 MHz, CDCl3): δ ) 0.06, 0.08, 0.11,
0.18 (4s, 12 H, 2 × SiMe2); 0.90, 0.92 (2s, 18 H, 2 × SitBu);
1.28, 1.30, 1.36, 1.38 (4s, 12 H, 2 × CMe2); 1.74 (m, 4 H, 3-H,
1′-Ha, 1′-Hb, 3′-Ha); 1.82 (ddd, J gem ) 15.2 Hz, J ) 4.7 Hz, J )
1.7 Hz, 1 H 3′-Hb); 3.39 (dd, J 2,3 ) 10.0 Hz, J 1,2 ) 7.3 Hz, 1 H,
2-H); 3.60-3.70 (m, 4 H, 5-H, 6-Ha, 6-Hb, OH); 3.75-3.80 (m,
2 H, 7′-H, 9′-Ha); 3.87 (m, 1 H, 5′-H); 3.93-3.99 (m, 4 H, 4-H,
2′-H, 6′-H, 8′-H); 4.01 (ddd, 2 × J ≈ 5.6 Hz, J < 1 Hz, 1 H,
4′-H); 4.15 (dd, J gem ) 8.5 Hz, J 8′,9′Ha ) 6.2 Hz, 1 H, 9′-Hb);
4.47 (m, 4 H, 1-H, PhCH2); 4.60 (d, J ) 11.4 Hz, 1 H, PhCH2);
4.64 (d, J ) 12.0 Hz, 1 H, PhCH2); 4.75 (d, J ) 11.4 Hz, 1 H,
PhCH2); 4.96 (d, J ) 10.9 Hz, 1 H, PhCH2); 4.97 (d, J ) 12.0
Hz, 1 H, PhCH2); 7.23-7.35 (m, 20 H, 4 × Ph). Anal. Calcd
for C61H90O12Si2 (1071.6): C: 68.37, H: 8.47. Found: C: 68.71,
H: 8.17. Data for 20b: [R]D ) +1.2 (c ) 2; CHCl3). TLC
(SiO2): Rf ) 0.24 (petroleum ether/ethyl acetate ) 4:1). 1H
NMR (600 MHz, CDCl3): δ ) 0.08, 0.10 (m, 12 H, 2 × SiMe2);
0.87, 0.90 (2s, 18 H, 2 × SitBu); 1.30, 1.32, 1.38, 1.39 (4s, 12
H, 2 × CMe2); 1.52-1.60 (m, 2 H, 1′-Ha, 3′-Ha); 1.64-1.73 (m,
2 H, 1′-Hb, 3′-Hb); 2.00 (dddd, 2 × J ≈ 10.5 Hz, 2 × J ≈ 3.0
Hz, 1 H, 3-H); 2.07 (bs, 1 H, OH); 3.40 (dd, J 2,3 ) 11.1 Hz, J 1,2
) 7.6 Hz, 1 H, 2-H); 3.66 (m, 1 H, 6-Ha); 3.75 (m, 2 H, 5-H,
6-Hb); 3.79 (m, 2 H, 4-H, 9′-Ha); 3.84-3.88 (m, 3 H, 2′-H, 5′-H,
7′-H); 3.92 (dd, J ) 3.1 Hz, J ) 6.9 Hz, 1 H, 6′-H); 4.00 (dd, J
) 8.1 Hz, J ) 5.8 Hz, 1 H, 8′-H); 4.10 (d, J ) 6.1 Hz, 1 H, 10
H); 4.14 (dd, J ) 6.1 Hz, J ) 8.5 Hz, 1 H, 9′-Hb); 4.49-4.52
(m, 3 H, 1-H, PhCH2); 4.55-4.58 (m, 3 H, PhCH2); 4.65 (d, J
) 12.1 Hz, 1 H, PhCH2); 4.95 (d, J ) 11.2 Hz, 1 H, PhCH2);
4.96 (d, J ) 12.1 Hz, 1 H, PhCH2); 7.23-7.35 (m, 20 H, 4 ×
Ph). Anal. Calcd for C61H90O12Si2 (1071.6): C: 68.37, H: 8.47.
Found: C: 68.16, H: 8.42.
Ben zyl 2,4,6-Tr i-O-ben zyl-3-d eoxy-3-C-[4,5-O-ca r bon -
ylid en e-1,2,3-tr id eoxy-2-m eth ylen e-D-glycer o-D-gu lo-n on -
2-u los-1-yl]-â-D-ga la cto-h exop yr a n osid e (4). (a) From 24:
Cyclic carbonate 24 (1.08 g, 1.25 mmol) was dissolved in THF/
H2O (28 mL, 5:2), and trifluoroacetic acid (8 mL) was added.
The mixture was placed in a hot oil bath (100 °C), stirred at
this temperature for 50 min, and then poured into ethyl acetate
containing ice with stirring. After 15 min, the layers were
separated and the aqueous layer was extracted with ethyl
acetate (3×). The combined organic layers were dried (MgSO4),
filtered, concentrated in vacuo, and coevaporated with toluene
until complete removal of trifluoroacetic acid. Flash chroma-
tography (SiO2, toluene/acetone ) 3:1) of the residue afforded
both 4 (675 mg, 0.860 mmol, 69%) and 26 (227 mg, 0.275 mmol,
22%) as a colorless syrup.
(b) From 26: A solution of monoprotected 26 (227 mg, 0.275
mmol) in THF/H2O was treated with TFA as described under
(a) to afford 4 (153 mg, 0.195 mmol, 71%). [R]D ) +4.8 (c ) 1;
CHCl3). TLC (SiO2): Rf ) 0.28 (toluene/acetone ) 1:1). 1H
NMR (600 MHz, CD3CN): δ ) 1.91 (dddd, 2 × J ≈ 10.5 Hz, 2
× J ≈ 3.2 Hz, 1 H, 3-H); 2.19 (dd, J 3,1′Ha ) 10.6 Hz, J gem
)
15.6 Hz, 1 H, 1′-Ha); 2.44 (dd, J gem ) 15.6 Hz, J 3,1′Hb < 1 Hz, 1
H, 1′-Hb); 2.50 (dd, J 3′Ha,4′ ) 5.0 Hz, J gem ) 16.1 Hz, 1 H, 3′-
Ha); 2.63 (dd, J 3′Hb,4′ ) 9.1 Hz, J gem ) 16.1 Hz, 1 H, 3′-Hb); 3.22
(dd J 2,3 ) 10.9 Hz, J 1,2 ) 7.6 Hz, 1 H, 2-H); 3.54-3.55 (m, 3 H,
7′-H, 8′-H, 9′-Ha); 3.60 (dd, J 5,6Ha ) 6.5 Hz, J gem ) 9.7 Hz, 1 H,
6-Ha); 3.63-3.67 (m, 3 H, 4-H, 6-Hb, 9′-Ha); 3.75 (dd, 2 × J )
6.5 Hz, 1 H, 5-H); 3.90 (d, J ) 3.2 Hz, 1 H, 6′-H); 4.49-4.56
(m, 6 H, PhCH2); 4.64 (d, J ) 11.9 Hz, 1 H, PhCH2); 4.82-
4.90 (m, 6 H, dCH2, 4′-H, 5′-H, PhCH2); 7.25-7.37 (m, 20 H,
4 × Ph). FAB-MS (positive mode, NBA): m/z ) 807 [M + Na]+;
Calcd: 784.3 for C45H52O12
.
Ben zyl 2,4,6-Tr i-O-ben zyl-3-d eoxy-3-C-[8,9-d i-O-a cetyl-
4,5-O-ca r bon ylid en e-1,2,3-tr id eoxy-6,7-O-isop r op ylid en e-
2-m eth ylen e-D-glycer o-D-gu lo-n on -2-u los-1-yl]-â-D-ga la cto-
h exop yr a n osid e (27). For characterization, 26 was peracetyl-
ated by treatment with a mixture of pyridine and acetic
anhydride to give 27 after coevaporation with toluene and
purification by flash chromatography (petroleum ether/ethyl
acetate ) 2:1). [R]D ) +18.7 (c ) 2; CHCl3); TLC (SiO2): Rf )
0.31 (petroleum ether/ethyl acetate ) 2:1). 1H NMR (600 MHz,
CDCl3): δ ) 1.36, 1.53 (2s, 6 H, CMe2); 1.8 (dddd, 2 × J ≈ 2.9
Hz, 2 × J ≈ 10.6 Hz, 1 H 3-H); 2.00, 2.05 (2s, 6 H, 2 × OAc);
2.18 (dd, J 3,1′Ha ) 10.2 Hz, J gem ) 15.0 Hz, 1 H, 1′-Ha); 2.34
(dd, J 3,1′Hb < 1 Hz, J gem ) 15.0 Hz, 1 H, 1′-Hb); 2.47 (dd, J gem
) 16.1 Hz, J 3′Ha,4′ ) 7.7 Hz, 1 H, 3′-Ha); 2.65 (dd, J gem ) 16.1
Hz, J 3′Hb,4′ ) 6.9 Hz, 1 H, 3′-Hb); 3.41 (dd, J 2,3 ) 11.0 Hz, J 1,2
) 7.5 Hz, 1 H, 2-H); 3.64-3.71 (m, 4 H, 4-H, 5-H, 6-Ha, 6-Hb);
3.94 (d, J ) 8.1 Hz, 1 H, 6′-H); 4.10 (dd, J 8′,9′Ha ) 5.5 Hz, J gem
) 12.4 Hz, 1 H, 9′-Ha); 4.21 (dd, 2 × J ≈ 7.7 Hz, 1 H, 7′-H);
4.36 (d, J ) 7.5 Hz, 1 H, 5′-H); 4.46-4.55 (m, 6 H, 1-H, 9′-Hb,
PhCH2); 4.64 (d, J ) 11.4 Hz, 1 H, PhCH2); 4.66 (d, J ) 12.0
Hz, 1 H, PhCH2); 4.75 (s, 2 H, dCH2); 4.97 (d, J ) 12.0 Hz, 1
H, PhCH2); 4.98 (d, J ) 11.4 Hz, 1 H, PhCH2); 5.02 (m, 1 H,
8′-H); 7.23-7.36 (m, 20 H, 4 × Ph). Anal. Calcd for C52H60O14
(909.0): C: 68.71, H: 6.65. Found: C: 68.46, H: 6.56.
Ben zyl 2,4,6-Tr i-O-b en zyl-3-d eoxy-3-C-[4,5-d i-O-(ter t-
bu tyld im eth ylsilyl)-1,2,3-tr id eoxy-6,7:8,9-d i-O-isop r op yl-
id en e-2-m eth ylen e-D-glycer o-D-gu lo-n on -2-u los-1-yl]-â-D-
ga la cto-h exop yr a n osid e (22). Ketone 21 (8.63 g, 8.069
mmol) was dissolved in dry toluene/THF (750 mL, 4:1) and
cooled to -40 °C. Then Tebbe reagent27 (160 mL, 1 M in
toluene) was added, and the mixture was stirred while
warming up to room temperature. After 48 h, the reaction was
cooled to 0 °C, diethyl ether was added followed by careful
addition of a 10% aqueous sodium hydroxide solution (30 mL).
The mixture was vigorously stirred (60 min) and filtered
through Celite. Concentration in vacuo and purification of the
residue by flash chromatography (SiO2, petroleum ether/ethyl
acetate ) 7:1) afforded 22 (5.34 g, 5.00 mmol, 62%) as colorless
syrup together with recovered, unreacted ketone 21 (2.50 g,
2.34 mmol, 29%). [R]D ) +1.2 (c ) 5; CHCl3). TLC (SiO2): Rf
) 0.39 (petroleum ether/ethyl acetate ) 7:1). 1H NMR (600
MHz, CDCl3): δ ) -0.08, -0.01, 0.07, 0.13 (m, 12 H, 2 ×
SiMe2); 0.84, 0.90 (2s, 18 H, 2 × SitBu); 1.24, 1.29, 1.33, 1.38
(4s, 12 H, 2 × CMe2); 1.95 (dddd, 2 × J ≈ 10.6 Hz, 2 × J ≈ 3.2
Hz, 1 H, 3-H); 2.11-2.16 (m, 2 H, 1′-Ha, 3′-Ha); 2.45 (dd, J gem
) 14.4 Hz, J 3′Hb,4′ ) 1.45 Hz, 1 H, 3′-Hb); 2.60 (dd, J gem ) 15.8
Ben zyl
2,4,6-Tr i-O-ben zyl-3-d eoxy-3-C-[(7,8,9-tr i-O-
a cet yl-2,6-a n h yd r o-4,5-O-ca r b on ylid en e-1,3-d id eoxy-1-
p h en ylselen yl-D-er yth r o-L-ta lo-n on it -2-yl)-m et h yl]-â-D-
ga la cto-h exop yr a n osid e (29) a n d Ben zyl 2,4,6-Tr i-O-
ben zyl-3-d eoxy-3-C-[(7,8,9-tr i-O-a cetyl-2,6-a n h yd r o-4,5-O-
ca r bon ylid en e-1,3-d id eoxy-1-p h en ylselen yl-D-er yth r o-L-
ga la ct o-n on it -2-yl)-m e t h yl]-â-D-ga la ct o-h e xop yr a n o-
sid e (30). Compound 4 was coevaporated several times with
dry toluene prior to use and dried in vacuo. All operations were
carried out under an inert atmosphere of nitrogen. To a
solution of phenylselenyl chloride (99 mg, 0.517 mmol, 1.5 eq)
in dry propionitrile (12 mL) was added silver trifluoromethane-
sulfonate (141 mg, 0.549 mmol, 1.6 equiv) at room tempera-
ture. A white solid precipitated, and the yellow mixture was
quickly cooled to -80 °C and stirred for 60 min. Then a
solution of 4 (270 mg, 0.344 mmol) in dry propionitrile (4 mL)
was added within 2 min via syringe, and the mixture was
stirred for another 60 min. The reaction was worked up by
pouring the cold reaction mixture on a cold (0 °C) mixture of
Hz, J 3,1′Hb ) 2.5 Hz, 1 H, 1′-Hb); 3.42 (dd, J 2,3 ) 10.2 H, J 1,2
)
7.6 Hz, 1 H, 2-H); 3.61 (m, 2 H, 6-Ha, 6-Hb); 3.67 (m, 1 H, 5-H);
3.74-3.77 (m, 2 H, 4-H, 9′-Ha); 3.84-3.89 (m, 3 H, 4′-H, 5′-H,
7′-H); 3.95 (dd, J ) 8.2 Hz, J ) 6.2 Hz, 1 H, 6′-H); 3.99 (m, 1
H, 8′-H); 4.14 (dd, J gem ) 8.2 Hz, J 8′,9′Hb ) 6.2 Hz, 1 H, 9′-Hb);
4.48-4.59 (m, 6 H, 1-H, PhCH2); 4.64 (d, J ) 12.0 Hz, 1 H,
PhCH2); 4.77 (s, 1 H, dCH2); 4.92 (s, 1 H, dCH2); 4.95-4.97
(m, 2 H, PhCH2); 7.24-7.34 (m, 20 H, 4 × Ph). Anal. Calcd for
C62H90O11Si2 (1067.6): C: 69.76, H: 8.50. Found: C: 69.97,
H: 8.28.

Synthesis of a Neu5Ac-R-(2,3)-Gal C-Disaccharide
J . Org. Chem., Vol. 66, No. 12, 2001 4259
dichloromethane and brine with vigorous stirring (5 min). The
layers were separated, the aqueous layer was extracted with
dichloromethane (3×), and the combined organic layers were
dried (MgSO4) and filtered. To this solution containing 3 and
28 were added pyridine and acetic anhydride, and the resulting
mixture was stirred at room temperature until acetylation was
complete (monitored by TLC). Removal of the solvents in vacuo
at 25 °C by coevaporation with toluene and rapid flash
chromatographic purification of the residue afforded 29 (317
mg. 0.297 mmol, 86%) as a colorless syrup and 30 (45 mg, 0.042
mmol, 12%) containing a very small amount of 25 as impurity.
Data for 29: [R]D ) +4.1 (c ) 2; CHCl3). TLC (SiO2): Rf )
0.37 (toluene/ethyl acetate ) 2:1). 1H NMR (600 MHz,
CDCl3): 1.63 (d, J gem ) 14.7 Hz, 1 H, 3′′-Ha); 1.85 (dd, J 3′Ha,4′
) 6.0 Hz, J gem ) 15.7 Hz, 1 H, 3′-Ha); 1.94 (ddd, J 2,3 ) 11.2
Hz, J 3,4 ) 2.7 Hz, J 3,3′′Hb ) 8.5 Hz, 1 H, 3-H); 2.00, 2.01, 2.02
(3s, 9 H, 3 × OAc); 2.18 (dd, J 3′Hb,4′ ) 6.2 Hz, J gem ) 15.7 Hz,
1 H, 3′-Hb); 2.27 (dd, J 3,3′′Hb ) 8.5 Hz, J gem ) 14.7 Hz, 1 H,
chromatography (SiO2, toluene/ethyl acetate ) 9:1) gave a
mixture of 39 and 40 (176 mg, 0.144 mmol, 95%). The two
isomers were separated by means of medium-pressure liquid
chromatography (SiO2, toluene/ethyl acetate ) 9:1, 4.5 bar,
flow: 6 mL/min) to afford pure 39 (41 mg, 34 µmol) and pure
40 (86 mg, 71 µmol). [R]D ) -2.4 (c ) 1; CHCl3). TLC (SiO2):
Rf ) 0.38 (toluene/ethyl acetate ) 9:1). 1H NMR (600 MHz,
CDCl3): δ ) 1.58 (m, 1 H, 3′′-Ha); 1.95-2.00 (m, 2 H, 3-H,
3′′-Hb); 2.08 (dd, J gem ) 12.9 Hz, J 3′Heq,4′ ) 5.0 Hz, 1 H, 3′-Heq);
2.12 (d, J ) 4.1 Hz, 1 H, OH); 2.28 (dd, 2 × J ≈ 12.7 Hz, 1 H,
3′-Hax); 3.20 (dd, J 2,3 ) 10.6 Hz, J 1,2 ) 7.3 Hz, 1 H, 2-H); 3.35
(s, 3 H, CO2Me); 3.64 (m, 1 H, 6-Ha); 3.72-3.76 (m, 3 H, 4-H,
5-H, 6-Hb); 4.03 (d, J ) 5.6 Hz, 1 H, 6′-H); 4.27-4.35 (m, 3 H,
1-H, 9′-Ha, PhCH2); 4.48 (d, J ) 11.9 Hz, 1 H, PhCH2); 4.54-
4.56 (m, 2 H, PhCH2); 4.86-4.90 (m, 3 H, 9′-Hb, PhCH2); 4.96
(ddd, J 4′,5′ ) 2.9 Hz, J 3′Heq,4′ ) 5.0 Hz, J 3′Hax,4′ ) 12.3 Hz, 1 H,
4′-H); 5.84 (m, 1 H, 8′-H); 5.97 (m, 1 H, 7′-H); 6.97-7.36 (m,
28 H, 4 × Ph, m-PhCO); 7.44-7.50 (m, 4 H, p-PhCO); 7.90-
8.00 (m, 8 H, o-PhCO). Anal. Calcd for C73H70O17 (1219.4): C:
71.91, H: 5.79. Found: C: 71.70, H: 5.82. FAB-MS (positive
mode, NBA): m/z ) 1241 [M + Na]+; 1257 [M + Na]+; Calcd:
3′′-Hb); 2.81 (d, J gem ) 12.1 Hz, 1 H, PhSeCH2); 3.09 (d, J gem
)
12.1 Hz, 1 H, PhSeCH2); 3.28 (dd, J 2,3 ) 11.2, J 1,2 ) 7.5 Hz, 1
H, 2-H); 3.69 (dd, J gem ) 9.5 Hz, J 5,6Ha ) 6.3 Hz, 1 H, 6-Ha);
3.76 (dd, J gem ) 9.5 Hz, J 5,6Hb ) 6.5 Hz, 1 H, 6-Hb); 3.80-3.82
(m, 2 H, 4-H, 5-H); 3.92 (dd, J 5′,6′ ) 2.5 Hz, J 6′,7′ ) 3.6 Hz, 1 H,
6′-H); 4.02 (dd, J 8′,9′Ha ) 5.7 Hz, J gem ) 12.6 Hz, 1 H, 9′-Ha);
4.39 (dd, J 8′,9′Hb ) 2.6 Hz, J gem ) 12.6 Hz, 1 H, 9′-Hb); 4.43 (d,
J ) 11.4 Hz, 1 H, PhCH2); 4.53-4.66 (m, 6 H, 1-H, 5′-H,
1218.5 for C73H70O17
.
Ben zyl 2,4,6-Tr i-O-b en zyl-3-d eoxy-3-C-[{m et h yl-(2,6-
a n h yd r o-5-a zid o-4,7,8,9-t et r a -O-b en zoyl-3,5-d id eoxy-D-
er yth r o-D-m a n n o-n on -2-yl)on a t e}-m et h yl]-â-D-ga la cto-
h exop yr a n osid e (41). A solution of 40 (18 mg, 15 µmol) in
dry dichloromethane (1 mL) was cooled to 0 °C, pyridine (50
µL) was added followed by trifluoromethanesulfonic anhydride
(20 µL), and the mixture was stirred for 12 h while warming
up to room temperature. Then the mixture was diluted with
dichloromethane (2 mL), saturated aqueous sodium hydrogen
carbonate solution (3 mL) was added, the layers were sepa-
rated, and the organic layer was extracted with dichloro-
methane (4×). The combined organic layers were concentrated
in vacuo at room temperature and purified by rapid flash
chromatography (SiO2, toluene/ethyl acetate ) 9:1) to afford
the corresponding triflate (Rf ) 0.45, toluene/ethyl acetate )
9:1) as a colorless syrup which was immediately subjected to
further conversion. The triflate was dissolved in dry toluene
(1 mL) and treated with tetra-n-butylammonium azide (52 mg).
After stirring for 15 min, the mixture was concentrated in
vacuo and purified by flash chromatography (SiO2, toluene/
ethyl acetate ) 25:1) to afford azide 41 (18 mg, 14 µmol, 94%)
as a colorless syrup. [R]D ) -5.3 (c ) 1; CHCl3). TLC (SiO2):
Rf ) 0.55 (toluene/ethyl acetate ) 9:1). 1H NMR (600 MHz,
CDCl3): δ ) 1.66 (J 3′Hax,4′ ) J gem ≈ 12.3 Hz, 1 H, 3′-Hax); 1.68
(d, J gem ) 14.4 Hz, 1 H, 3′′-Ha); 1.93 (ddd, J 2,3 ) 11.2 Hz, J 3,3′′Hb
) 7.3 Hz, J 3,4 ) 3.2 Hz, 1 H, 3-H); 2.13 (dd, J gem ) 14.4 Hz,
J 3,3′′Hb ) 7.3 Hz, 1 H, 3′′-Hb); 2.55 (dd, J gem ) 13.2 Hz, J 3′Heq,4′
PhCH2); 4.78 (d, J ) 11.6 Hz, 1 H, PhCH2); 4.83 (dd, J 4′,5′
)
5.3 Hz, J 3′Hb,4′ ) 6.3 Hz, 1H, 4′-H); 4.95 (d, J ) 10.7 Hz, 1 H,
PhCH2); 4.97 (d, J ) 11.3 Hz, 1 H, PhCH2); 5.28 (ddd, J 8′,9′Hb
) 2.5 Hz, J 8′,9′Ha ) 5.7 Hz, J 7′,8′ ) 6.2 Hz, 1 H, 8′-H); 5.52 (dd,
J 6′,7′ ) 3.7 Hz, J 7′,8′ ) 6.7 Hz, 1 H, 7′-H); 7.21-7.36 (m, 25 H,
5 × Ph). Anal. Calcd for C57H62O15Se (1066.1): C: 64.22, H:
5.86. Found: C: 64.05, H: 6.23. Data for 30: TLC (SiO2): Rf
) 0.55 (toluene/ethyl acetate ) 2:1). 1H NMR (600 MHz,
CDCl3): 1.25 (m, 1 H, 3-H); 1.62 (d, J gem ) 14.2 Hz, 1 H, 3′′-
Ha); 1.82 (dd, J 3′Ha,4′ ) 4.0 Hz, J gem ) 16.2 Hz, 1 H, 3′-Ha); 1.97,
2.00, 2.01 (3s, 9 H, 3 × OAc); 2.09 (dd, J 3′Hb,4′ ) 3.7 Hz, J gem
)
16.2 Hz, 1 H, 3′-Hb); 2.14 (dd, J gem ) 14.2 Hz, J 3,3′′Hb ) 4.0 Hz,
1 H, 3′′-Hb); 2.90 (d, J gem ) 12.8 Hz, 1 H, PhSeCH2); 3.16 (m,
1 H, 6′-H); 3.34 (d, J gem ) 12.8 Hz, 1 H, PhSeCH2); 3.45 (dd,
J 2,3 ) 11.0 Hz, J 1,2 ) 7.4 Hz, 1 H, 2-H); 3.60-3.66 (m, 3 H,
5-H, 6-Ha, 6-Hb); 3.70 (d, J ) 2.8 Hz, 1 H, 4-H); 3.97 (dd, J )
1.6 Hz, J ) 8.4 Hz, 1 H, 5′-H); 4.05 (dd, J gem ) 12.7 Hz, J 8′,9′Ha
) 6.0 Hz, 1 H, 9′-Ha); 4.37-4.43 (m, 4 H, 1-H, 4′-H, 9′-Hb,
PhCH2); 4.52 (m, 2 H, PhCH2); 4.61, 4.66 (2s, 2 H, PhCH2);
5.06 (ddd, 2 × J ≈ 6.3 Hz, J 7′,8′ ) 2.3 Hz, 1 H, 8′-H); 5.09 (d,
J ) 10.9 Hz, 1 H, PhCH2); 5.28 (dd, J ) 3.4 Hz, J ) 6.4 Hz, 1
H, 7′-H); 7.16-7.49 (m, 25 H, 5 × Ph). Anal. Calcd for
C
57H62O15Se (1066.1): C: 64.22, H: 5.86. Found: C: 64.05,
H: 6.23.
Ben zyl 2,4,6-Tr i-O-b en zyl-3-d eoxy-3-C-[{m et h yl-(2,6-
) 5.0 Hz, 1 H, 3′-Heq); 3.26 (s, 3 H, CO2Me); 3.30 (dd, J 2,3
)
11.2 Hz, J 1,2 ) 7.3 Hz, 1 H, 2-H); 3.34 (dd, 2 × J ≈ 10.3 Hz, 1
H, 5′-H); 3.76 (dd, J gem ) 7.0 Hz, J 5,6Ha ) 3.8 Hz, 1 H, 6-Ha);
3.84-3.88 (m, 3 H, 5-H, 6-Hb, 6′-H); 3.92 (d, J 3,4 ) 3.2 Hz, 1
H, 4-H); 4.28 (dd, J gem ) 12.6 Hz, J 8′,9′Ha ) 5.0 Hz, 1 H, 9′-Ha);
4.47-4.49 (m, 2 H, 1-H, PhCH2); 4.55-4.62 (m, 3 H, PhCH2);
4.79 (m, 2 H, PhCH2); 4.90 (d, J ) 11.3 Hz, 1 H, PhCH2); 4.95-
4.97 (m, 2 H, 9′-Hb, PhCH2); 5.01 (ddd, J 3′Hax,4′ ) 11.7 Hz, J 4′,5′
) 10.0 Hz, J 3′Heq,4′ ) 4.7 Hz, 1 H, 4′-H); 5.98 (ddd, J 7′,8′ ) 8.8
Hz, J 8′,9′Ha ) 5.0 Hz, J 8′,9′Hb ) 2.6 Hz, 1 H, 8′-H); 6.08 (dd, J <
1 Hz, J 7′,8′ ) 8.8 Hz, 1 H, 7′-H); 7.03-7.64 (m, 32 H, 4 × Ph,
m,p-PhCO); 7.95-8.15 (4m, 8 H, o-PhCO). FAB-MS (positive
mode, NBA): m/z ) 1266 [M + Na]+; 1282 [M + K]+; Calcd:
a n h ydr o-4,7,8,9-tetr a -O-ben zoyl-3-d eoxy-D-er yth r o-L-ta lo-
n on -2-yl)on ate}-m eth yl]-â-D-ga la cto-h exopyr an oside (40).
The reaction progress of the benzoylation of 38 was carefully
monitored by TLC. Deprotected methyl ester 38 (121 mg, 0.151
mmol) was dissolved in dry THF/NEt3 (8 mL, 1:1) and cooled
to 0 °C. Then, 0.5 mL of a freshly prepared solution of benzoyl
cyanide (80 mg, 0.610 mmol, 4.0 equiv) in THF (2 mL) was
added every 120 min while stirring at 0 °C. After complete
addition, the reaction mixture was stirred at 0 °C for further
18 h and then warmed to 5 °C. Further benzoyl cyanide was
added (21 mg), and stirring was continued for 24 h at 5 °C. At
this point of the reaction monitoring by TLC revealed the
formation of three products, two of which corresponded to 40
(Rf ) 0.38, toluene/ethyl acetate ) 9:1) and 39 (Rf ) 0.33,
toluene/ethyl acetate ) 9:1), together with a less mobile
product (Rf ) 0.53, toluene/ethyl acetate ) 3:1). Then, ad-
ditional benzoyl cyanide (25 mg) was added, the mixture was
stirred for 7 h, benzoyl cyanide (40 mg) was added once again,
and stirring was continued for another 12 h. Monitoring by
TLC now indicated both complete disappearance of the less
mobile spot and 39 and 40 to be the products exclusively
formed. For workup, methanol was added, the mixture was
allowed to warm to room temperature and stirred for 2 h.
Removal of the solvents in vacuo and purification by flash
1243.5 for C73H69N3O16
.
3-Deoxy-3-C-[{a m m on iu m -(5-a cet a m id o-2,6-a n h yd r o-
3,5-d id eoxy-D-er yth r o-L-m a n n o-n on -2-yl)on a te}-m eth yl]-
D-ga la cto-h exop yr a n ose (2). A mixture of azide 41 (10 mg,
32 µmol) and Pd(OH)2/C (18 mg) in MeOH/EtOAc ) 4:1 (6 mL)
was kept under an atmosphere of hydrogen for 24 h. Then,
the mixture was filtered through Celite and concentrated, and
the residue was taken up in a 1:1 mixture of pyridine and
acetic anhydride. After stirring for 24 h at room temperature,
the mixture was concentrated in vacuo and coevaporated
several times with toluene. Purification of the residue by flash
chromatography (toluene/acetone ) 6:1) afforded 42 (3.8 mg,
3.65 µmol, 45%). This was dissolved in THF/H2O (1:1, 10 mL)

4260 J . Org. Chem., Vol. 66, No. 12, 2001
Notz et al.
and aqueous NaOH solution (0.1 M, 2 mL) was added. After
stirring for 14 h at room temperature, the reacion mixture was
lyophilized and passed through a RP-18 silica gel column (H2O/
EtOH ) 9:1) and further purified by gel filtration on a
Sephadex P-4 column eluting with a 0.3% ammonium hydro-
gen carbonate buffer solution (flow rate: 0.7 mL/min, tR ) 28
min). After removal of the buffer solution, the residue was
lyophilized from water to give the ammonium salt 2 (0.9 mg)
as a white amorphous solid. 1H NMR (600 MHz, D2O): δ )
1.42-1.84 (m, 4 H, 3-H, 3′′-Ha, 3′′-Hb, 3′-Hax); 1.94 (s, 3H, NAc);
2.52 (dd, J ) 4.4 Hz, J ) 12.9 Hz, 1 H, 3′-Heq); 3.44-3.94 (m,
12 H, 2-H, 4-H, 5-H, 6-Ha, 6-Hb, 4′-H, 5′-H, 6′-H, 7′-H, 8′-H,
9′-Ha, 9′-Hb); 4.65 (bs, 1H, 1-H). MALDI-MS (positive mode,
DHB): m/z ) 487.2 [C18H30NO13 + NH4 + H]+; Calcd: 487.2
1H NMR (250 MHz, CDCl3): δ ) 1.81 (ddd, J gem ) 15.8 Hz,
J 2,3Ha ) 2.7 Hz, J 3Ha,4 ) 11.6 Hz, 1 H, 3-Ha); 2.05, 2.11, 2.15 (3
s, 9 H, 3 × OAc); 2.38 (ddd, J gem ) 15.8 Hz, J 2,3Hb ) 5.0 Hz,
J 3Hb,4 ) 3.0 Hz, 1 H, 3-Hb); 2.98 (dd, J 1Ha,1Hb ) 12.7 Hz, J 1Ha,2
) 7.5 Hz, 1 H, 1-Ha); 3.10 (dd, J gem ) 12.7 Hz, J 1Hb,2 ) 4.7 Hz,
1 H, 1-Hb); 3.95 (dd, J 5,6 ) 1.2 Hz, J 6,7 ) 3.3 Hz, 1 H, 6-H);
4.16 (dd, J gem ) 12.5 Hz, J 8,9Ha ) 5.7 Hz, 1 H, 9-Ha); 4.31 (m,
1 H, 2-H); 4.49 (dd, J gem ) 12.5 Hz, J 8,9Hb ) 2.4 Hz, 1 H, 9-Hb);
4.79 (dd, J 4,5 ) 9.0 Hz, J 5,6 ) 1.2 Hz, 1 H, 5-H); 5.03 (ddd,
J 3Hax,4 ) 11.6 Hz, J 3Heq,4 ) 3.0 Hz, J 4,5 ) 9.0 Hz, 1 H, 4-H);
5.31 (ddd, J 7,8 ) 6.5 Hz, J 8,9Ha ) 5.7 Hz, J 8,9Hb ) 2.4 Hz, 1 H,
8-H); 5.47 (dd, J 7,8 ) 6.5 Hz, J 6,7 ) 3.3 Hz, 1 H, 7-H); 7.24-
7.26 (m, 3 H, Ph); 7.46-7.48 (m, 2 H, Ph). Anal. Calcd for
C22H26O10Se (529.4): C: 49.91, H: 4.95. Found: C: 49.52, H:
5.15. Data for 35: [R]D ) +36.6 (c ) 1; CHCl3); TLC: Rf )
0.38 (SiO2, petroleum ether/ethyl acetate ) 1:2). 1H NMR (250
MHz, CDCl3): δ ) 1.67 (m, 1 H, 3-Ha); 2.04, 2.06, 2.15 (3 s, 9
H, 3 × OAc); 2.39 (ddd, J ) 3.1 Hz, J ) 6.6 Hz, J gem ) 14.1
Hz, 1 H, 3-Hb); 2.91 (dd, J gem ) 12.9 Hz, J 1Ha,2 ) 6.5 Hz, 1 H,
1-Ha); 3.20 (dd, J gem ) 12.9 Hz, J 1Hb,2 ) 6.7 Hz, 1 H, 1-Hb);
3.49 (m, 1 H, 2-H); 3.70 (dd, J 5,6 ) 1.8 Hz, J 6,7 ) 3.8 Hz, 1 H,
6-H); 4.15 (dd, J gem ) 12.5 Hz, J 8,9Ha ) 5.7 Hz, 1 H, 9-Ha); 4.45
(dd, J gem ) 12.5 Hz, J 8,9Hb ) 2.4 Hz, 1 H, 9-Hb); 4.57 (dd, J 4,5
) 6.5 Hz, J 5,6 ) 1.8 Hz, 1 H, 5-H); 4.84 (m, 1 H, 4-H); 5.32 (m,
1 H, 8-H); 5.52 (dd, J 6,7 ) 3.8 Hz, J 7,8 ) 6.5 Hz, 1 H, 7-H);
7.24-7.30 (m, 3 H, Ph); 7.45-7.55 (m, 2 H, Ph). Anal. Calcd
for C22H26O10Se (529.4): C: 49.91, H: 4.95. Found: C: 49.52,
H: 5.15.
for C18H34N2O13
.
7,8,9-Tr i-O-a cet yl-2,6-a n h yd r o-4,5-O-ca r b on ylid en e-
1,2,3-tr ideoxy-1-ph en ylselen o-D-er yth r o-D-ta lo-n on itol (34)
a n d 7,8,9-Tr i-O-a cetyl-2,6-a n h yd r o-4,5-O-ca r bon ylid en e-
1,2,3-tr id eoxy-1-p h en ylselen o-D-er yth r o-L-ga la cto-n on i-
tol (35). Compound 31 was coevaporated with dry toluene
several times prior to use and dried in vacuo. To a solution of
phenylselenyl chloride (106 mg, 0.553 mmol, 1.3 equiv) in dry
acetonitrile (5 mL) was added silver trifluoromethanesulfonate
(142 mg, 0.553 mmol, 1.3 equiv) at room temperature. A white
solid precipitated, and the yellow mixture was stirred for 5
min at room temperature. Then, a solution of 31 (106 mg, 0.427
mmol) in dry acetonitrile (10 mL) was added via syringe, and
the mixture was stirred for further 15 min. The reaction was
worked up by adding saturated sodium hydrogen carbonate
solution with vigorous stirring (5 min) and extracting the
mixture with ethyl acetate. The combined organic layers were
dried (MgSO4), filtered, concentrated in vacuo, and purified
by flash chromatography (SiO2, ethyl acetate) to afford an
inseparable mixture of 32 and 33 (144 mg, 0.357 mmol, 83%)
as a colorless syrup. The ratio of the two isomers was
determined by NMR spectroscopy to be approximately 2-3:1
in favor of 32. For further characterization, both isomers were
peracetylated in a mixture of pyridine and acetic anhydride.
Coevaporation with toluene and flash chromatography (SiO2,
petroleum ether/ethyl acetate ) 1:2) afforded 34 and 35 as a
colorless syrup. Data for 34: [R]D ) +42.3 (c ) 2; CHCl3).
TLC: Rf ) 0.33 (SiO2, petroleum ether/ethyl acetate ) 1:2).
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie. We thank Dr. Armin Geyer for
numerous insightful discussions and interpretation of
NMR spectra of these compounds.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of all
new compounds. Experimental procedures and analytical data
for all compounds not described herein. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O015543L