Versatile functionalization of carbohydrate hydroxyl groups through their O-Cyanomethyl ethers

Article abstract of DOI:10.1021/jo960284z

O-Cyanomethyl ethers of carbohydrates are shown to be versatile intermediates for the preparation of sugar amines, carboxylic acids, amides, and amidine salts. This methodology for the functionalization of carbohydrates can thus provide a new array of analogs for the study of carbohydrate binding proteins. In addition, the resulting O-aminoethyl and O-carboxymethyl carbohydrates can be coupled to amino acids under standard conditions used in solid-phase peptide synthesis, providing a method for the construction of glycopeptides in which the carbohydrate moiety can be linked through any of its hydroxyl groups to the C- or the N-terminus of a given peptide.

Full text of DOI:10.1021/jo960284z

J . Org. Chem. 1996, 61, 4649-4654
4649
Ver sa tile F u n ction a liza tion of Ca r boh yd r a te Hyd r oxyl Gr ou p s
th r ou gh Th eir O-Cya n om eth yl Eth er s
Carles Malet and Ole Hindsgaul*
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2 Canada
Received February 12, 1996X
O-Cyanomethyl ethers of carbohydrates are shown to be versatile intermediates for the preparation
of sugar amines, carboxylic acids, amides, and amidine salts. This methodology for the function-
alization of carbohydrates can thus provide a new array of analogs for the study of carbohydrate
binding proteins. In addition, the resulting O-aminoethyl and O-carboxymethyl carbohydrates can
be coupled to amino acids under standard conditions used in solid-phase peptide synthesis, providing
a method for the construction of glycopeptides in which the carbohydrate moiety can be linked
through any of its hydroxyl groups to the C- or the N-terminus of a given peptide.
In tr od u ction
drate binding proteins still relies on the synthetic prepa-
ration of a large number of analogs of the natural cell
surface glycoconjugates.
The surface of animal cells is covered with glycopro-
teins and glycolipids that are directly involved in inter-
cellular recognition. They can be sites of attachment for
bacteria, toxins, viruses, essential ligands in fertilization,
antigenic determinants, and ligands in cell-cell adhe-
sion.1 The oligosaccharides controlling these events can
be large, but the actual size of the epitope that is
A general characteristic of the mode of binding of
oligosaccharides to proteins is summarized schematically
in Figure 1, part A. Many protein-combining sites are
cleft or groove-like and bind the oligosaccharide on one
“side”.5 Critical hydrogen-bonding interactions involve
several of the sugar OH groups which become involved
in intricate H-bonding networks that can include water
molecules. van der Waals contacts with non-hydroxy-
lated surfaces on the oligosaccharides also frequently
occur. The purpose of showing Figure 1, however, is to
illustrate that there must be protein structure adjacent
to the combining site that is not in contact with the
carbohydrate ligand, as well as ligand hydroxyl groups
that are not involved in binding. In principle, molecular
structure could be added to the ligand through these OH
groups, and if this structure formed favorable interac-
tions with the protein surface, then the affinity of the
ligand should be enhanced.
Since the features of the protein structure adjacent to
the combining site are generally not known, a large
number of oligosaccharide derivatizations will likely be
necessary to discover added structures that will enhance
affinity. Any systematic attempt to prepare such “en-
hanced” oligosaccharide ligands must therefore have, as
its base, a versatile and robust methodology for the
functionalization and modification of a given carbohy-
drate structure. In this paper we propose that O-
cyanomethyl derivatives of oligosaccharides can provide
such a base.
recognized is usually 2-4 sugar residues in size.
A
notable feature is that binding is often weak, with
dissociation constants rarely below the micromolar range
and much more commonly in the millimolar range. They
can nevertheless function as efficient adhesion sites since
the interactions can be polyvalent, leading to a net high-
affinity interaction.1
Inhibitors of carbohydrate-protein binding clearly
have potential as pharmaceutical agents since in prin-
ciple they could inhibit the binding events that lead to
disease. Because the association constants for monova-
lent carbohydrate-protein binding may be lower than
desired, however, this situation presents a major chal-
lenge to medicinal chemists: the affinity of a useful
inhibitor must be improved by orders of magnitude over
the natural and supposedly already near-optimum oli-
gosaccharide ligand.
Many groups have worked in the area of oligosaccha-
ride analog synthesis with the hopes of improving affini-
ties, and although an enormous amount of very difficult
and very elegant synthesis has been performed, usually
only marginal (ca. 10-fold) improvements were achieved.2
Exceptions include a 100-fold improvement in the affinity
of a trisaccharide binding to an antibody3 and the rational
design of a sialic acid based inhibitor for influenza
hemaglutinin4 (10000-fold improvement) based on a
crystal structure containing bound ligand. In the more
common situations where such structural information is
unavailable, the development of inhibitors of carbohy-
Resu lts a n d Discu ssion
The reason for selecting the O-cyanomethyl group for
the functionalization of sugar hydroxyl groups is based
on the rich chemistry of nitriles, key elements of which
are summarized in Figure 2. This single group should
be amenable to facile reduction to yield primary amines
and hydrolysis to yield carboxylic acids. Amide bond
X Abstract published in Advance ACS Abstracts, J une 15, 1996.
(1) Varki, A. Glycobiology 1993, 3, 97-130.
(2) Lemieux, R. U. Chem. Soc. Rev. 1989, 18, 347-374. Glaudemans,
C. P. J . Chem. Rev. 1991, 91, 25-33. Sierks, M. R.; Bock, K.; Refn, S.;
Svensson, B. Biochemistry 1992, 31, 8972-8977. Reck, F.; Meinjo-
hanns, E.; Springer, M.; Wilkens, R.; van Dorst, J .A. L. M.; Paulsen,
H.; Mo¨ller, G.; Brockhausen, I.; Schachter, H. Glycoconj. J . 1994, 11,
210-216. Kanie, O.; Crawley, S. C.; Palcic, M. M.; Hindsgaul, O.
Bioorg. Med. Chem. 1994, 2, 1231-1241.
(4) von Itzstein, M.; Wu, W.-Y; Kok, G. B.; Pegg, M. S.; Dyason, J .
C.; J in, B; Phan, T. V; Smythe, M.; White, H. F.; Oliver, S. W.; Colman,
P. M.; Varghese, J . N.; Ryan, D. M.; Woods, J . M.; Bethell, R. C.;
Hotham, V. J .; Cameron, J . M.; Penn, C. R. Nature 1993, 363, 418-
423.
(5) Quiocho, F. Pure Appl. Chem. 1989, 61, 1293-1306. Bundle, D.
R.; Young, N. M. Curr. Opin. Struct. Biol. 1992, 2, 666-673.
(3) Cygler, M.; Rose, D. R.; Bundle D. R. Science 1991, 253, 442-
446. Bundle, D. R.; Eichler, E. Bioorg. Med. Chem. 1994, 2, 1221-
1229.
S0022-3263(96)00284-8 CCC: $12.00 © 1996 American Chemical Society

4650 J . Org. Chem., Vol. 61, No. 14, 1996
Malet and Hindsgaul
In tr od u ction of th e O-Cya n om eth yl Gr ou p . 2,4,6-
Tri-O-acetyl-3-O-(cyanomethyl)galactopyranoside
2
(Scheme 1) was prepared in 51% yield by O-alkylation
of regioselectively stannylated galactopyranoside 16 with
bromoacetonitrile, followed by acetylation with Ac2O/py.
2,3,6-Tri-O-benzyl-4-O-(cyanomethyl)-â-D-glucopyrano-
side 10 (Scheme 2) was obtained by O-alkylation of the
sodium salt of octyl 2,3,6-tri-O-benzyl-â-D-glucopyrano-
side (9)7 in acetonitrile at -20 °C in 82% yield. Other
combinations of solvents (DMF, THF) or higher tempera-
tures produced a drastic decrease in the yield.
Con ver sion of Cya n om eth yl Eth er s to Am in es
a n d Ca r boxylic Acid s. The borane-methyl sulfide
complex is one of the most efficient reagents for the
reduction of nitriles8 and has been recently used in the
carbohydrate field for the reduction of 6-deoxy-6-cyano-
cyclodextrins.9 In our hands, BH3‚Me2S reduced acety-
lated nitrile 2 to amino ethyl sugar 3 in 72% yield, with
simultaneous cleavage of the O-acetyl protecting groups.
Hydrolysis of the cyano group with simultaneous saponi-
fication of the three acetates of 2 using refluxing 25%
NaOH in MeOH, followed by neutralization, yielded 3-O-
(carboxymethyl)galactopyranoside derivative 4 in 92%
yield. Similarly, benzylated glucopyranoside 10 yielded
4-O-aminoethyl derivative 11 upon reduction with BH3‚
Me2S (73%) and 4-O-(carboxymethyl)glucopyranoside 13
after basic hydrolysis (98%). Removal of the benzyl
groups of 11 and 13 by hydrogenolysis with 10% Pd-C
afforded fully deprotected amine 12 and carboxylic acid
14.
F igu r e 1. (A) Schematic representation of a disaccharide
bound to a protein indicating the OH groups that are directly
involved in complex formation. (B) Molecular structure has
been added to the ligand to enhance the affinity of the complex
by interaction with protein structure adjacent to the combining
site.
Con ver sion of Cya n om eth yl Eth er s to Am id es
a n d Am id in e Sa lts. As Schaefer and Peters reported
in the early 1960s10 aliphatic nitriles react with alcohols
under basic catalysis to yield the corresponding alkyl
imidates. The ratio of nitrile to alkyl imidate in the
equilibrium is strongly dependent on the presence of
electron-withdrawing substituents on the R carbon of the
nitrile. This reaction has attracted little attention in the
carbohydrate field with the exception of the use cyano-
methyl 1-thioglycosides for the amidination of proteins.11
1
In the present case, H-NMR monitoring of the reaction
of benzylated 4-O-(cyanomethyl)glucopyranoside 10 with
100 mM CD3ONa in CD3OD at 25 °C showed a charac-
teristic upfield shift in the resonance of the methylene
protons of the initial 4-O-cyanomethyl group from δ 4.41
and 4.45 (AB pattern, J gem ) 16 Hz) to δ 3.97 and 4.14
(AB pattern, J gem ) 15 Hz). The equilibrium mixture
after 24 h contained ca. 90% of the putative methyl
imidate, which was not isolated but directly converted
to the amide 15 (61%) or the amidine hydrochloride 17
(74%) by basic hydrolysis or by treatment with NH4Cl,
respectively. Finally, removal of the benzyl groups by
catalytic hydrogenation (10% Pd-C) afforded free sugar
amide 16 and sugar amidine 18. Similarly, treatment
of acetylated 3-O-cyanomethyl derivative 2 with anhy-
drous sodium methoxide in MeOH, followed by mild
hydrolysis, yielded the corresponding deprotected sugar
F igu r e 2. Versatile transformations of the O-cyanomethyl
group.
formation with commercial acids and amines, including
protected amino acids, could therefore yield large arrays
of analogs for testing. In addition, the cyano group can
be converted to amide derivatives and amidines. To
evaluate whether such functional group manipulations
are compatible with the general chemical manipulations
of carbohydrate synthesis, and the presence of polyhy-
droxylated species, two monosaccharides (the acetylated
galactopyranoside 2 and the benzylated glucopyranoside
10) carrying the most common O-protecting groups in
carbohydrate chemistry have been chosen at this stage
as initial models.
(6) De bruyne, C. K.; van der Groen, G. Carbohydr. Res. 1972, 25,
59-65.
(7) Lowary, T. L.; Hindsgaul O. Carbohydr. Res. 1993, 249, 163-
195.
(8) Brown, H. C.; Choi, Y. M.; Narasimhan S. Synthesis 1981, 605-
606.
(9) Defaye, J .; Gadelle, A. Carbohydr. Res. 1994, 265, 129-132.
(10) Schaefer, F. C.; Peters, G. A. J . Org. Chem. 1961, 26, 412-
418.
(11) Lee, Y. C.; Stowell, C. P.; Krantz, M. J . Biochemistry 1976, 15,
3956-3963. Stowell, C. P.; Lee, Y. C. Biochemistry 1980, 19, 4899-
4904.

Functionalization of Carbohydrate OH by O-Cyanomethyl Ethers
J . Org. Chem., Vol. 61, No. 14, 1996 4651
Sch em e 1a
a
Key: (i) (a) Bu2SnO, Bz, reflux, 16 h; (b) BrCH2CN, Bu4NI, reflux, 90 min; (c) Ac2O, py, rt, 51% (three steps); (ii) 100 mM NaOMe in
MeOH, rt, 6 h, then 5% NaHCO3(aq), 81%; (iii) 100 mM NaOMe in MeOH, rt, 6 h, then NH3(g), rt, 12 h, 50%; (iv) BH3‚Me2S, THF, reflux,
12 h, 72%; (v) 25% NaOH(aq) in MeOH, reflux, 12 h, 92%; (vi) (a) Fmoc-L-Trp-OPfp, DMF, rt, 3 h; (b) morpholine, rt, 2 h, 89% (two steps);
(vii) L-Leu-OMe‚HCl, py, DCC, 40 °C, 48 h, 62%.
Sch em e 2a
a
Key: (i) NaH, CH3CN, rt, then BrCH2CN, -20 °C to rt, 82%; (ii) 11, BH3‚Me2S, THF reflux, 12 h, 73%; 12, H2, 10% Pd-C, THF-
H2O-HCl, 76%; (iii) 13, 25% NaOH(aq) in MeOH, reflux, 12 h, 98%; 14, H2, 10% Pd-C, THF-H2O, 79%; (iv) 15, 100 mM NaOMe in
MeOH, 12 h, rt, then 5% NaHCO3, 50 °C, 5 days, 61%; 16, H2, 10% Pd-C, MeOH, 95%; (v) 17, 100 mM NaOMe in MeOH, 12 h, rt, then
anhydrous NH4Cl (5 equiv), 50 °C, 1 h, 74%; 18, H2, 10% Pd-C, MeOH, 89%.
amide 5 (81%), while treatment with NH3(g) of the
intermediate imidate gave the corresponding amidine
isolated in 50% yield as its hydrochloride salt 6.
Neutral sugar amides of type 5 and 16, carboxylic acids
of type 4 and 14, and basic sugar amines or amidines (3,
6, 12, 18) might be the first candidates to be tested in
the early stages of the development of inhibitors of a
given host protein, since they may potentially induce new
electrostatic and/or hydrogen-bonding carbohydrate-
protein interactions. Moreover, the availability of both
sugar amines and sugar acids from a common O-cya-
nomethyl intermediate represents a powerful approach
for the construction of glycopeptides in which the carbo-
hydrate moiety can be attached through any of its

4652 J . Org. Chem., Vol. 61, No. 14, 1996
Malet and Hindsgaul
4:1) yielded 7.4 g (51%) of 2 as a colorless oil: [R]D ) +9.3° (c
1.6, CHCl3); 1H NMR (360 MHz, CDCl3) δ 0.85 (t, J ) 7.0 Hz,
3H), 1.20-1.35 (m, 10H), 1.48-1.60 (m, 2H), 2.05, 2.10, 2.11
(3 s, 9H), 3.44 (dt, J ) 9.6, 6.9 Hz, 1H), 3.70 (dd, J ) 9.9, 3.6
Hz, 1H), 3.81 (dt, J ) 6.7, 1.2 Hz, 1H), 3.85 (dt, J ) 9.6, 6.2
Hz, 1H), 4.13 (dd, J ) 11.2, 6.9 Hz, 1H), 4.18 (dd, J ) 11.2,
6.5 Hz, 1H), 4.28, 4.31 (AB system, J ) 16.8 Hz, 2H), 4.41 (d,
J ) 8.0 Hz, 1H), 5.05 (dd, J ) 9.9, 8.0 Hz, 1H), 5.34 (dd, J )
3.6, 1.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.0, 20.6, 20.7,
22.6, 25.7, 29.2, 29.3, 31.7, 54.7, 61.4, 64.9, 69.5, 70.2, 70.4,
78.1, 101.1, 115.6, 169.5, 170.3, 170.6. Anal. Calcd for
C22H35O9N: C, 57.75; H, 7.71; N, 3.06. Found: C, 57.74; H,
8.01; N, 3.05.
hydroxyl groups to either the N- or C-terminus of a given
amino acid or peptide. Two examples are reported in
Scheme 1. The 3-O-(aminoethyl)galactopyranoside 3 was
coupled to the commercially available N-Fmoc-L-tryp-
tophan pentafluorophenyl ester to yield sugar amino acid
7 in 89% after removal of the Fmoc group. On the other
hand, sugar acid 4 was coupled to L-leucine methyl ester
hydrochloride using DCC in pyridine to yield glycocon-
jugate 8 in 62% yield. The O-cyanomethyl group is thus
shown to yield carbohydrate amine and acid derivatives
which are compatible with chemistry of solid-phase
peptide synthesis.
Octyl 3-O-(Am in oeth yl)-â-D-galactopyr an oside (3). Com-
pound 2 (1.83 g, 4.0 mmol) was dissolved in anhydrous THF
(25 mL), and the solution was heated to reflux under nitrogen.
A 2.0 M solution of BH3‚Me2S in THF (15 mL) was added
dropwise with stirring under reflux. After 12 h, the resulting
solution was cooled to room temperature, MeOH (15 mL) was
added, and stirring was continued for an additional 12 h. After
evaporation of the solvent, the crude product was purified by
column chromatography using a short SiO2-C18 column (30 g,
gradient H2O-MeOH 1:0 to 1:1) to give compound 3 as a white
amorphous solid (0.96 g, 72%). The free amino sugar was
converted to the corresponding hydrochloride for analytical
characterization (a sample of the free amine was dissolved in
In the examples reported here, the manipulation of the
cyanomethyl group is shown to be compatible with some
of the most common carbohydrate protecting groups. A
clear limitation of the method is that the cyanomethyl
group has been introduced on the carbohydrate moiety
only under basic conditions, either by regioselective
alkylation of dibutyltin acetals of polyhydroxylic com-
pounds or by alkylation of a hydroxyl group when the
rest of OH groups are protected as benzyl ethers. If acyl
groups are necessary for temporary protection or for
anchimeric assistance in glycosidation reactions, they
have to be introduced after O-cyanomethylation. Al-
though it is possible, in principle, to devise strategies for
the introduction of the cyanomethyl group in any OH
group of a given carbohydrate, milder O-cyanomethyla-
tion methods will have to be developped to increase the
versatility of protecting and deprotecting strategies.
The extension of this “O-cyanomethyl” methodology to
the synthesis of O-functionalized oligosaccharides and
their corresponding glycopeptides, and its application for
the preparation of inhibitors of carbohydrate-protein
binding, is currently in progress. In addition to this
stated objective, it is expected that this O-cyanomethyl
group may also find application in the preparation of
carbohydrates as scaffolds12 for pharmacophore presenta-
tion.
H2O, neutralized with 1 N HCl and freeze-dried): [R]D
)
1
+17.4° (c 1.5, H2O); mp 124-127 °C (from MeOH-Et2O); H
NMR (500 MHz, D2O) δ 0.87 (t, J ) 7.0 Hz, 3H), 1.24-1.38
(m, 10H), 1.60-1.68 (m, 2H), 3.22-3.33 (m, 2H), 3.51 (dd, J
) 9.8, 3.2 Hz, 1H), 3.59 (dd, J ) 9.8, 7.7 Hz, 1H), 3.61-3.67
(m, 2H), 3.75-3.81 (m, 3H), 3.90 (dt, J ) 9.9, 6.9 Hz, 1H), 3.99
(m, 1H), 4.20 (d, J ) 3.2 Hz, 1H), 4.39 (d, J ) 7.7 Hz, 1H); 13
C
NMR (75 MHz, D2O) δ 14.4, 23.1, 26.2, 29.6, 29.7, 29.8, 32.2,
40.3, 61.4, 65.7, 70.7, 71.4, 75.5, 81.8, 103.5; FAB-MS m/ z 336
((M - Cl-)+). Anal. Calcd for C16H34O6NCl‚1/2H2O: C, 50.45;
H, 9.26; N, 3.68; Cl, 9.31. Found: C, 50.41; H, 9.33; N, 3.62;
Cl, 9.70.
Octyl 3-O-(Ca r boxym eth yl)-â-D-ga la ctop yr a n osid e (4).
Compound 2 (1.74 g, 3.80 mmol) was dissolved in MeOH (50
mL). A solution of 25% NaOH in H2O (12 mL) was added,
and the mixture was stirred under reflux for 12 h. MeOH was
carefully evaporated from the reaction at reduced pressure,
and the residue was diluted with H2O (300 mL) and treated
with excess Amberlite IR-120 (H+). After filtration of the resin,
the aqueous solution was directly loaded on a small SiO2-C18
column (30 g), washed with H2O, and eluted with 40% CH3-
CN in H2O. Concentration under reduced pressure and freeze-
drying yielded 4 as a white solid (1.22 g, 92%): [R]D ) +4.9°
(c 1.5, H2O); mp 80-82 °C (from AcOEt-Et2O); 1H NMR (500
MHz, D2O) δ 0.87 (t, J ) 7.0 Hz, 3H), 1.22-1.40 (m, 10H),
1.60-1.68 (m, 2H), 3.51 (dd, J ) 9.8, 3.4 Hz, 1H), 3.60-3.67
(m, 3H), 3.76 (d, J ) 6.2 Hz, 2H), 3.90 (dt, J ) 9.9, 7.0 Hz,
1H), 4.16 (d, J ) 3.4 Hz, 1H), 4.32, 4.37 (AB system, J ) 16.9
Hz, 2H), 4.37 (d, J ) 7.9 Hz, 1H); 13C NMR (75 MHz, D2O) δ
14.6, 23.4, 26.6, 30.1, 30.2, 32.6, 61.1, 65.9, 67.5, 70.7, 71.1,
75.1, 83.0, 101.8, 175.5; FAB-MS m/ z 351 ((M + H)+); FT-IR
1730, 1690 cm-1 (CdO st). Anal. Calcd for C16H30O8‚H2O: C,
52.16; H, 8.75. Found: C, 52.13; H, 8.46.
Octyl 3-O-(Ca r ba m oylm eth yl)-â-D-ga la ctop yr a n osid e
(5). Compound 2 (144 mg, 0.315 mmol) was dissolved in 100
mM NaOMe in MeOH (2 mL), and the solution was stirred at
room temperature for 6 h. Aqueous 5% NaHCO3 (2 mL) was
then added, and stirring at room temperature was continued
overnight. After evaporation to dryness, the residue was
suspended in MeOH and the insoluble salts were removed by
filtration. Evaporation of the solvent and purification by
column chromatography (CH2Cl2-MeOH 7:1) yielded 5 (89 mg,
81%): [R]D ) +12.0° (c 1, MeOH); mp 148-150 °C (from
MeOH-AcOEt); 1H NMR (360 MHz, CD3OD) δ 0.89 (t, J )
7.0 Hz, 3H), 1.24-1.43 (m, 10H), 1.61 (m, 2H), 3.32 (dd, J )
9.7, 3.3 Hz, 1H), 3.47 (t, J ) 5.7 Hz, 1H), 3.54 (dt, J ) 9.5, 6.7
Hz, 1H), 3.64 (dd, J ) 7.7, 9.7 Hz, 1H), 3.70-3.79 (m, 2H),
3.89 (dt, J ) 9.5, 6.7 Hz, 1H), 4.01 (d, J ) 3.3 Hz, 1H), 4.09,
4.12 (AB system, J ) 16.1 Hz, 2H), 4.22 (d, J ) 7.7 Hz, 1H);
13C NMR (75 MHz, CD3OD) δ 14.4, 23.7, 27.1, 30.4, 30.5, 30.8,
Exp er im en ta l Section
Gen er a l. TLC was performed on silica gel 60-F254 with
detection by charring with a 10% solution of H2SO4 in ethanol.
Column chromatography was performed on silica gel 60 (230-
400 mesh), or with 10% C18-SiO2. Optical rotations were
measured at the sodium D line at 22 ( 2 °C. 1H NMR spectra
were recorded at 360 or 500 MHz as indicated. 13C-NMR
spectra were recorded at 75 MHz. FAB mass spectra were
recorded on samples suspended in a matrix of glycerol with
Xe as the bombarding gas.
Octyl 2,4,6-Tr i-O-a cetyl-3-O-(cya n om eth yl)-â-D-ga la c-
top yr a n osid e (2). Octyl â-D-galactopyranoside6 (10.0 g, 34.2
mmol) and dibutyltin oxide (9.3 g, 37.6 mol) in benzene (200
mL) were heated under reflux with azeotropic removal of water
for 16 h. To the resulting yellow solution were added Bu4NI
(12.6 g, 34.1 mol) and bromoacetonitrile (9.1 mL, 137 mol),
and stirring under reflux was continued for 90 min. The
solvent was evaporated, and the residue was redissolved in
CHCl3 and extracted with saturated aqueous Na2S2O3. After
the solution was dried (Na2SO4) and evaporated, the residual
brown oil was purified by flash chromatography (CHCl3-
MeOH 20:1 and then 5:1) to yield 5.5 g of a hygroscopic
material that was directly treated with 50 mL of anhydrous
pyridine and 50 mL of Ac2O. Evaporation of the solvent after
12 h and flash chromatography of the residue (toluene-AcOEt
(12) Hirschmann, R; Nicolau, 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

Functionalization of Carbohydrate OH by O-Cyanomethyl Ethers
J . Org. Chem., Vol. 61, No. 14, 1996 4653
33.0, 62.4, 66.9, 69.3, 70.9, 71.4, 76.2, 84.2, 104.8, 176.3; FAB-
MS m/ z 350 ((M + H)+); FT-IR (MeOH) 1670 cm-1 (CdO st).
Anal. Calcd for C16H31O7N: C, 55.00; H, 8.94; N 4.01.
Found: C, 54.74; H, 9.16; N, 3.92.
evaporation, diluted with CH2Cl2 (200 mL), and filtered. The
filtrate was concentrated and purified by flash chromatography
(hexane-AcOEt 8:1 and then 4:1) to yield 10 (1.80 g, 82%):
[R]D ) +21.5° (c 1, CHCl3); mp 52-53 °C (from MeOH); 1H
NMR (360 MHz, CDCl3) δ 0.85 (t, J ) 7.0 Hz, 3H), 1.20-1.40
(m, 10H), 1.63 (m, 2H), 3.36 (ddd, J ) 8.8, 4.3, 2.1 Hz, 1H),
3.40 (dd, J ) 7.8, 9.0 Hz, 1H), 3.47 (t, J ) 8.8 Hz, 1H), 3.50
(dt, J ) 9.5, 6.7 Hz, 1H), 3.57 (t, J ) 8.9 Hz, 1H), 3.69 (dd, J
) 10.9, 4.3 Hz, 1H), 3.74 (dd, J ) 10.9, 2.1 Hz, 1H), 3.92 (dt,
J ) 9.5, 6.7 Hz, 1H), 4.24, 4.28 (AB system, J ) 15.7 Hz, 2H),
4.34 (d, J ) 7.8 Hz, 1H), 4.55 (d, J ) 12.0 Hz, 1H), 4.62 (d, J
) 12.0 Hz, 1H), 4.66 (d, J ) 11.1 Hz, 1H), 4.67 (d, J ) 11.0
Hz, 1H), 4.92 (d, J ) 11.1 Hz, 1H), 4.94 (d, J ) 11.0 Hz, 1H),
7.25-7.35 (m, 15H); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.6,
26.1, 29.2, 29.4, 29.7, 31.8, 57.3, 68.6, 70.2, 73.5, 73.8, 74.6,
75.5, 78.6, 82.1, 84.0, 103.6, 116.1, 127.7, 127.8, 128.0, 128.1,
128.4, 128.5, 138.0, 138.1, 138.3. Anal. Calcd for C37H47O6N:
C, 73.85; H, 7.87; N 2.33. Found: C, 73.93; H, 7.93; N, 2.34.
Octyl 4-O-(Am in oeth yl)-2,3,6-tr i-O-ben zyl-â-D-glu cop y-
r a n osid e (11). Compound 10 (294 mg, 0.489 mmol) was
dissolved in anhydrous THF (5 mL), and the solution was
Octyl 3-O-(Am id in om eth yl)-â-D-ga la ctop yr a n osid e Hy-
d r och lor id e (6). Compound 2 (210 mg, 0.459 mmol) was
dissolved in 100 mM NaOMe in MeOH (2 mL), and the solution
was stirred at room temperature for 6 h. The solution was
then saturated with NH3(g) and stirred at room temperature
overnight. After evaporation of the solvent, the residue was
resuspended in H2O and neutralized with 1 N HCl, and the
resulting solution was applied to a column of SiO2-C18 and
eluted with H2O and then H2O-MeOH 95:5. After freeze-
drying, 6 was obtained as a white solid (89 mg, 50%): [R]D
)
+18.9° (c 1, H2O); mp 158-160 °C (from MeOH-Et2O); 1H
NMR (500 MHz, D2O) δ 0.86 (t, J ) 7.0 Hz, 3H), 1.24-1.40
(m, 10H), 1.63 (m, 2H), 3.61 (dd, J ) 9.8, 3.1 Hz, 1H), 3.64-
3.70 (m, 3H), 3.75 (dd, J ) 11.6, 4.7 Hz, 1H), 3.80 (dd, J )
11.6, 7.6 Hz, 1H), 3.93 (dt, J ) 9.8, 6.8 Hz, 1H), 4.18 (d, J )
3.2 Hz, 1H), 4.42 (d, J ) 7.6 Hz, 1H), 4.55, 4.65 (AB system,
J ) 16.3 Hz, 2H); 13C NMR (75 MHz, D2O) δ 14.5, 23.2, 26.4,
29.8, 29.9, 30.0, 32.4, 61.2, 65.2, 65.8, 70.6, 71.3, 75.2, 83.1,
103.6, 168.6; FAB-MS m/ z 349 ((M - Cl-)+); FT-IR 1710 cm-1
(CdN st). Anal. Calcd for C16H33O6N2Cl‚1/2H2O: C, 48.79; H,
8.70; N, 7.11; Cl, 9.00. Found: C, 48.94; H, 8.88; N, 6.99; Cl,
9.29.
heated to reflux under nitrogen. A 2.0 M solution of BH3
‚
Me2S in THF (0.5 mL) was added dropwise, and stirring under
reflux was continued for 12 h. The resulting solution was
cooled to room temperature, MeOH was added (0.5 mL), and
stirring was continued for an additional 12 h. After evapora-
tion of the solvent, the crude product was purified by column
chromatography (CHCl3-MeOH-concd aqueous NH3 300:10:
1) to yield 217 mg of a white solid (73%): [R]D ) +10.3° (c 1,
CHCl3); 1H NMR (360 MHz, CDCl3) δ 0.85 (t, J ) 7.0 Hz, 3H),
1.20-1.40 (m, 10H), 1.63 (m, 2H), 2.60-2.74 (m, 2H), 3.30-
3.77 (m, 9H), 3.92 (dt, J ) 9.5, 6.7 Hz, 1H), 4.35 (d, J ) 7.8
Hz, 1H), 4.55 (d, J ) 12.1 Hz, 1H), 4.63 (d, J ) 12.1 Hz, 1H),
4.67 (d, J ) 11.0 Hz, 1H), 4.71 (d, J ) 11.0 Hz, 1H), 4.89 (d,
J ) 11.0 Hz, 1H), 4.92 (d, J ) 11.0 Hz, 1H), 7.25-7.35 (m,
15H); 13C NMR (75 MHz, CDCl3) δ 13.9, 22.5, 26.0, 29.1, 29.2,
29.6, 31.6, 42.3, 68.8, 69.9, 73.3, 74.5, 74.8, 74.9, 75.3, 78.0,
82.1, 84.3, 103.5, 127.4, 127.6, 127.9, 128.1, 138.1, 138.4, 138.5.
Anal. Calcd for C37H51O6N: C, 73.36; H, 8.49; N 2.31.
Found: C, 73.19; H, 8.54; N, 2.24.
Oct yl 3-O-[N-(L-Tr p )a m in oet h yl]-â-D-ga la ct op yr a n o-
sid e (7). Compound 3 (29 mg, 0.086 mmol) and 4 Å molecular
sieves (300 mg) in dry DMF (5 mL) were stirred under vacuum
for 30 min to remove traces of volatile amines. N-Fmoc-L-
tryptophan pentafluorophenyl esther (205 mg, 0.346 mmol)
was added, and the mixture was stirred at room temperature
for 3 h. Filtration, evaporation of the solvent, and purification
by column chromatography (CHCl3-MeOH 10:1) yielded 64
mg of a white solid that was dissolved in morpholine (5mL)
and stirred at room temperature for 2 h. Evaporation of the
solvent followed by column chromatography (Iatrobeads SiO2,
CHCl3-MeOH-5% NH3(aq) 50:10:1) afforded
7 (40 mg,
89%): [R]D ) +14.2° (c 0.7, MeOH); 1H NMR (360 MHz, CD3-
OD) δ 0.89 (t, J ) 7.0 Hz, 3H), 1.25-1.42 (m, 10H), 1.55-1.65
(m, 2H), 2.82 (m, 2H), 2.98-3.90 (m, 13H), 4.08 (d, J ) 7.8
Hz, 1H), 7.00 (ddd, J ) 8.0, 8.0, 1.0, 1H), 7.09 (ddd, J ) 8.0,
8.0, 1.0, 1H), 7.10 (s, 1H), 7.33 (d, J ) 8.0 Hz, 1H), 7.58 (d, J
) 8.0 Hz, 1H); 13C NMR (75 MHz, CD3OD) δ 14.4, 23.7, 27.1,
30.4, 30.5, 30.8, 32.2, 33.0, 40.6, 57.3, 62.4, 66.9, 69.3, 70.8,
71.5, 76.2, 83.6, 104.8, 111.3, 112.3, 119.6, 119.8, 122.5, 124.8,
129.0, 138.0, 177.0.
Octyl 2,3,6-Tr i-O-ben zyl-4-O-(ca r boxym eth yl)-â-D-glu -
cop yr a n osid e (13). Compound 10 (305 mg, 0.507 mmol) was
dissolved in MeOH (6 mL), a 25% solution of NaOH(aq) (1.5
mL) was added, and the mixture was heated under reflux for
12 h. After evaporation of the solvent, the residue was diluted
with H2O (50 mL), acidified with 10% HCl, and extracted twice
with CH2Cl2 (50 mL). After the solvent was dried (Na2SO4)
and evaporated, the residue was purified by column chroma-
tography (CHCl3-MeOH 15:1) to yield 308 mg of 13 (98%):
[R]D ) +11.9° (c 1, CHCl3); 1H NMR (360 MHz, CDCl3) δ 0.85
(t, J ) 7.0 Hz, 3H), 1.20-1.40 (m, 10H), 1.63 (m, 2H), 3.36 (m,
1H), 3.41-3.53 (m, 3H), 3.60 (t, J ) 9.0 Hz, 1H), 3.68 (d, J )
3.3 Hz, 2H), 3.90 (dt, J ) 9.5, 6.7 Hz, 1H), 4.17, 4.25 (AB
system, J ) 17.1 Hz, 2H), 4.36 (d, J ) 7.6 Hz, 1H), 4.53 (d, J
) 12.1 Hz, 1H), 4.63 (d, J ) 12.1 Hz, 1H), 4.65 (d, J ) 10.9
Hz, 1H), 4.74 (d, J ) 11.1 Hz, 1H), 4.96 (d, J ) 10.9 Hz, 1H),
5.00 (d, J ) 11.1 Hz, 1H), 7.25-7.35 (m, 15H); 13C NMR (75
MHz, CDCl3) δ 13.9, 22.5, 26.0, 29.1, 29.2, 29.6, 31.6, 68.6,
69.2, 70.0, 73.4, 73.8, 74.4, 75.3, 78.8, 82.1, 83.1, 103.5, 127.6,
N-[[(1-O-Octyl-â-D-ga la ctop yr a n os-3-yl)m eth yl]ca r bo-
n yl]-L-Leu cin e Meth yl Ester (8). Compound 4 (72 mg, 0.21
mmol), L-leucine methyl ester hydrochloride (187 mg, 1.03
mmol), and N,N ′-dicyclohexylcarbodiimide (84 mg, 0.41 mmol)
were dissolved in pyridine (2 mL), and the solution was stirred
under Ar at 40 °C for 48 h. Evaporation of the solvent and
purification by column chromatography over SiO2 (CH2Cl2-
MeOH 20:1) followed by filtration over C18-SiO2 (MeOH-H2O
1:1 and then 1.2:1) afforded 8 (61 mg, 62%): [R]D ) +5.0° (c 1,
MeOH); 1H NMR (360 MHz, CD3OD) δ 0.89 (t, J ) 7.0 Hz,
3H), 0.92 (d, J ) 6.3 Hz, 3H), 0.95 (d, J ) 6.3 Hz, 3H), 1.24-
1.42 (m, 10H), 1.56-1.76 (m, 5H), 3.32 (1H, overlapped with
solvent signal), 3.46 (t, J ) 6.2 Hz, 1H), 3.53 (dt, J ) 9.5, 6.7
Hz, 1H), 3.65 (dd, J ) 7.9, 9.8 Hz, 1H), 3.70-3.79 (m, 2H),
3.71 (s, 3H), 3.88 (dt, J ) 9.5, 6.7 Hz, 1H), 4.03 (d, J ) 3.0 Hz,
1H), 4.12, 4.18 (AB system, J ) 16.4 Hz, 2H), 4.19 (d, J ) 7.8
Hz, 1H), 4.52 (dd, J ) 9.7, 5.0 Hz, 1H); 13C NMR (75 MHz,
CD3OD) δ 14.4, 21.8, 23.3, 23.7, 25.9, 27.0, 30.4, 30.5, 30.7,
33.0, 41.3, 51.8, 52.8, 62.4, 66.7, 69.1, 70.8, 71.1, 76.2, 84.3,
105.0, 173.2, 174.4.
Oct yl 2,3,6-Tr i-O-b en zyl-4-O-(cya n om et h yl)-â-D-glu -
cop yr a n osid e (10). Octyl 2,3,6-tri-O-benzyl-â-D-glucopyra-
noside7 (9, 2.04 g, 3.64 mmol) and NaH (0.54 g, 80% suspension
in mineral oil, 18 mmol) in anhydrous CH3CN (10 mL) were
stirred at room temperature under Ar for 1 h. The resulting
brownish suspension was cooled to -20 °C, and BrCH2CN (1.3
mL, 20 mmol) was added dropwise. The reaction was stirred
at -20 °C for 5 h and then allowed to reach room temperature
overnight. The resulting brown mixture was concentrated by
127.8, 127.9, 128.3, 137.5, 138.1, 173.3; FT-IR (CH2
Cl2) 1730,
1760 cm-1 (CdO st). Anal. Calcd for C37H48O8: C, 71.59; H,
7.79. Found: C, 71.69; H, 7.84.
Oct yl 2,3,6-Tr i-O-b en zyl-4-O-(ca r b a m oylm et h yl)-â-D-
glu cop yr a n osid e (15). Compound 10 (242 mg, 0.402 mmol)
was dissolved in 100 mM NaOMe in MeOH (3 mL), and the
solution was stirred at room temperature for 12 h. The
resulting solution was then heated to 50 °C, aqueous saturated
NaHCO3 was added dropwise until turbidity (ca. 0.4 mL), and
stirring at 50 °C was continued for 5 days. The crude was
diluted with CH2Cl2 (50 mL), washed with H2O, dried (Na2-
SO4), and evaporated. Column chromatography (CH2Cl2-
MeOH 100:1) afforded 15 as a white solid (153 mg, 61%): [R]D
) +10.4° (c 1, CHCl3); 1H NMR (360 MHz, CDCl3) δ 0.85 (t, J
) 7.0 Hz, 3H), 1.20-1.40 (m, 10H), 1.63 (m, 2H), 3.36 (m, 1H),
3.40-3.60 (m, 4H), 3.65 (dd, J ) 11.0, 3.6 Hz, 1H), 3.70 (dd, J
) 11.0, 2.8 Hz, 1H), 3.92 (dt, J ) 9.5, 6.7 Hz, 1H), 4.05, 4.19

4654 J . Org. Chem., Vol. 61, No. 14, 1996
Malet and Hindsgaul
(AB system, J ) 16.0 Hz, 2H), 4.37 (d, J ) 7.7 Hz, 1H), 4.54
(d, J ) 12.0 Hz, 1H), 4.60 (d, J ) 12.0 Hz, 1H), 4.63 (d, J )
10.9 Hz, 1H), 4.68 (d, J ) 11.0 Hz, 1H), 4.95 (d, J ) 11.0 Hz,
1H), 4.98 (d, J ) 10.9 Hz, 1H), 7.25-7.35 (m, 15H); 13C NMR
(75 MHz, CDCl3) δ 14.0, 22.6, 26.1, 29.1, 29.3, 29.7, 31.7, 68.8,
70.1, 71.1, 73.6, 74.4, 74.5, 74.4, 78.7, 82.2, 83.3, 103.6, 127.7,
127.8, 127.9, 128.0, 128.3, 128.4, 137.6, 138.2, 172.6; FT-IR
(CH2Cl2) 1700, 1660 cm-1 (amide bands I and II). Anal. Calcd
for C37H49O7N: C, 71.70; H, 7.97; N, 2.26. Found: C, 71.49;
H, 8.23; N, 2.21.
Octyl 4-O-(Am id in om eth yl)-2,3,6-tr i-O-ben zyl-â-D-glu -
cop yr a n osid e Hyd r och lor id e (17). Compound 10 (270 mg,
0.402 mmol) was dissolved in 100 mM NaOMe in MeOH (3
mL), and the solution was stirred at room temperature for 12
h. Anhydrous NH4Cl was then added (120 mg, 2.24 mmol),
and the solution was heated at 50 °C for 1 h. The mixture
was evaporated, and the residue was dissolved in MeOH-H2O
3:7 and loaded onto a SiO2-C18 column. After an extensive H2O
wash, compound 17 was eluted using MeOH-H2O 7:3 (219
mg, 74%): [R]D ) +13.5° (c 1, MeOH); 1H NMR (360 MHz,
CD3OD) δ 0.86 (t, J ) 7.0 Hz, 3H), 1.20-1.45 (m, 10H), 1.63
(m, 2H), 3.38 (dd, J ) 9.0, 7.8 Hz, 1H), 3.50-3.78 (m, 6H),
3.92 (dt, J ) 9.5, 6.7 Hz, 1H), 4.34, 4.49 (AB system, J ) 16.2
Hz, 2H), 4.46 (d, J ) 7.8 Hz, 1H), 4.53 (d, J ) 11.8 Hz, 1H),
4.64 (d, J ) 11.8 Hz, 2H), 4.68 (d, J ) 11.2 Hz, 1H), 4.95 (d,
J ) 11.4 Hz, 1H), 4.96 (d, J ) 11.2 Hz, 1H), 7.22-7.38 (m,
15H); 13C NMR (75 MHz, CDCl3) δ 13.9, 22.4, 25.9, 29.0, 29.1,
29.5, 31.6, 66.3, 68.2, 69.8, 73.2, 73.7, 74.2, 75.1, 78.7, 82.1,
103.4, 127.5, 127.6, 127.8, 127.9, 128.1, 128.2, 128.5, 136.8,
137.2, 137.9, 168.9. Anal. Calcd for C37H51O6N2Cl‚H2O: C,
66.01; H, 7.93; N, 4.16; Cl: 5.27. Found: C, 65.74; H, 8.08;
N, 4.06; Cl, 5.44.
to yield 17 mg of 14 (79%): [R]D ) -20.1° (c 0.7, H2O); 1H NMR
(360 MHz, D2O) δ 0.87 (t, J ) 7.0 Hz, 3H), 1.24-1.40 (m, 10H),
1.58-1.67 (m, 2H), 3.27 (dd, J ) 9.2, 7.9 Hz, 1H), 3.37 (t, J )
9.2 Hz, 1H), 3.51 (m, 1H), 3.66 (t, J ) 9.2 Hz, 1H), 3.67 (dt, J
) 9.9, 7.0 Hz, 1H), 3.77 (dd, J ) 12.4, 5.1 Hz, 1H), 3.87-3.95
(m, 2H), 4.29, 4.35 (AB system, J ) 16.6 Hz, 2H), 4.45 (d, J )
7.9 Hz, 1H); FAB-MS m/ z 373 ((M + Na)+); FT-IR 1725 cm-1
(CdO st).
Octyl 4-O-(Car bam oylm eth yl)-â-D-glu copyr an oside (16).
Compound 15 (39 mg, 0.063 mmol) in MeOH (3 mL) was
warmed until a clear solution was obtained and then stirred
under a stream of H2 in the presence of 10% Pd-C (30 mg) at
room temperature for 24 h. The reaction mixture was pro-
cessed as described for the preparation of 12 to yield 21 mg of
16 (95%): [R]D ) -28.5° (c 0.4, H2O); 1H NMR (360 MHz, CD3-
OD) δ 0.89 (t, J ) 7.0 Hz, 3H), 1.24-1.42 (m, 10H), 1.55-1.65
(m, 2H), 3.18 (dd, J ) 9.2, 7.8 Hz, 1H), 3.30 (m, 1H), 3.36 (t,
J ) 9.2 Hz, 1H), 3.51 (dt, J ) 9.9, 7.0 Hz, 1H), 3.53 (t, J ) 9.2
Hz, 1H), 3.73 (dd, J ) 12.2, 3.7 Hz, 1H), 3.82 (dd, J ) 12.2,
2.1 Hz, 1H), 3.86 (dt, J ) 9.9, 7.0 Hz, 1H), 4.20, 4.27 (AB
system, J ) 16.1 Hz, 2H), 4.24 (d, J ) 7.8 Hz, 1H); FAB-MS
m/ z 372 ((M + Na)+); FT-IR 1710, 1655 cm-1 (amide bands I
and II).
Octyl 4-O-(Am id in om eth yl)-â-D-glu cop yr a n osid e Hy-
d r och lor id e (18). Compound 17 (48 mg, 0.073 mmol) was
dissolved in MeOH (3 mL), and the solution was stirred under
a stream of H2 in the presence of 10% Pd-C (40 mg) for 6 h.
The reaction mixture was processed as described for the
preparation of 12 to yield 25 mg of 18 (89%): [R]D ) -25.9° (c
0.5, MeOH); 1H NMR (360 MHz, CD3OD) δ 0.89 (t, J ) 7.0
Hz, 3H), 1.24-1.42 (m, 10H), 1.55-1.65 (m, 2H), 3.18 (dd, J
) 9.1, 7.8 Hz, 1H), 3.35 (m, 1H), 3.46 (t, J ) 9.1 Hz, 1H), 3.52
(dt, J ) 9.9, 7.0 Hz, 1H), 3.58 (t, J ) 9.1 Hz, 1H), 3.74 (dd, J
) 12.3, 3.5 Hz, 1H), 3.83 (dd, J ) 12.3, 2.4 Hz, 1H), 3.86 (dt,
J ) 9.9, 7.0 Hz, 1H), 4.25 (d, J ) 7.8 Hz, 1H), 4.63, 4.68 (AB
system, J ) 16.7 Hz, 2H); FAB-MS m/ z 349 ((M - Cl-)+); FT-
IR 1700, 1690 cm-1 (CdN st).
Octyl 4-O-(Am in oeth yl)-â-D-glu cop yr a n osid e Hyd r o-
ch lor id e (12). Compound 11 (30 mg, 0.050 mmol) was
dissolved in a mixture of THF (0.5 mL), H2O (0.5 mL), and
5% HCl(aq) (0.05 mL), and the solution was stirred under a
stream of H2 in the presence of 10% Pd-C (30 mg) for 8 h.
The catalyst was removed by filtration and washed with MeOH
and H2O, and the resulting solution was passed through a C18
-
Ack n ow led gm en t. This work was supported by the
Natural Sciences and Engineering Research Council of
Canada.
SiO2 Sep-Pak which was washed with MeOH-H2O 1:1.
Evaporation of the solvent and freeze-drying yielded 14 mg of
1
12 (76%): [R]D ) -27.8° (c 0.6, MeOH); H NMR (360 MHz,
D2O) δ 0.87 (t, J ) 7.0 Hz, 3H), 1.24-1.40 (m, 10H), 1.58-
1.67 (m, 2H), 3.16-3.31 (m, 3H), 3.36 (t, J ) 9.2 Hz, 1H), 3.51
(m, 1H), 3.63 (t, J ) 9.2 Hz, 1H), 3.67 (dt, J ) 9.9, 7.0 Hz,
1H), 3.77 (dd, J ) 12.3, 5.1 Hz, 1H), 3.87-4.04 (m, 4H), 4.44
(d, J ) 8.0 Hz, 1H); FAB-MS m/ z 336 ((M - Cl-)+).
Octyl 4-O-(Ca r boxym eth yl)-â-D-glu cop yr a n osid e (14).
Compound 13 (38 mg, 0.062 mmol) was dissolved in 1:1 THF-
H2O (1 mL), and the solution was stirred under a stream of
H2 in the presence of 10% Pd-C (30 mg) for 6 h. The reaction
mixture was processed as described for the preparation of 12
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
assignments for all compounds and 1H NMR spectra for
compounds 3, 4, 5, 6, 7, 8, 12, 14, 16, and 18 (39 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O960284Z