Synthesis and biological evaluation of aza-C-disaccharides: (1→6), (1→4), and (1→1) linked sugar mimics

Article abstract of DOI:10.1021/ja9642929

The synthesis of (1→6), (1→4), and (1→1) linked aza-C- disaccharides, a novel class of glycomimetic compounds, is described. The polyhydroxylated piperidine ring was synthesized using vinyl bromide 11 as a common intermediate which was synthesized de novo

Full text of DOI:10.1021/ja9642929

4856
J. Am. Chem. Soc. 1997, 119, 4856-4865
Synthesis and Biological Evaluation of Aza-C-disaccharides:
(1f6), (1f4), and (1f1) Linked Sugar Mimics
Brian A. Johns,† Y. T. Pan,‡ Alan D. Elbein,‡ and Carl R. Johnson*,†
Contribution from the Department of Chemistry, Wayne State UniVersity,
Detroit, Michigan 48202-3489, and The Department of Biochemistry and
Molecular Biology, UniVersity of Arkansas for Medical Sciences,
Little Rock, Arkansas 72205-7199
ReceiVed December 31, 1996X
Abstract: The synthesis of (1f6), (1f4), and (1f1) linked aza-C-disaccharides, a novel class of glycomimetic
compounds, is described. The polyhydroxylated piperidine ring was synthesized using vinyl bromide 11 as a common
intermediate which was synthesized de noVo from bromobenzene utilizing the microbial oxidation metabolite bromodiol
10. A Suzuki coupling of 11 with an alkylboron reagent derived from olefinated carbohydrate precursors via
hydroboration was used to form the C-glycosidic bond. Ozonolysis and selective reduction of the resultant carbonyl
functions served to produce the azasugar ring. Fully deprotected aza-C-disaccharides were obtained upon acidic
deprotection. Biological screening of the title compounds against several common glycosidase enzymes as well as
in Vitro anti-HIV assays are reported.
Introduction
Polyhydroxylated piperidines (“azasugars”) have received a
great deal of attention from the scientific community recently.
These alkaloidal sugar mimics contain the same dense stereo-
chemical information as the common hexoses, and many exhibit
potent biological activity.1 The area of biological interest lies
in the inhibition of oligosaccharide-processing enzymes called
glycosidases and glycosyltransferases. These enzymes act upon
the glycosidic linkage of oligosaccharides and glycopeptides
by stabilizing an intermediate oxonium ion, thus facilitating the
lysis and modification of the anomeric center.2 Azasugars are
thought to be good inhibitors due to their ability to mimic the
transition state oxonium ion as a result of the heterocyclic
nitrogen being protonated at physiological pH.2d Glycosidases
are involved in many biological processes such as digestion and
glycopeptide synthesis, as well as the trimming of cell-surface
oligosaccharides and hence play a role in the cellular recognition
phenomena. Glycosidase inhibitors have potential in the
treatment of viral infections,3 cancer,4 and diabetes and other
metabolic disorders.5,2b
Most of the biologically interesting members of this class of
compounds are 1-deoxy analogues or diastereomers of deoxy-
nojirimycin (1), the stereochemical mimic of D-glucose (2). The
O/N acetal function of aza-O-glycosides is labile under hydro-
lytic conditions, thus limiting the development of this class of
glycomimetics.6 The presence of an anomeric group, particu-
larly one that resembles a second sugar unit, may provide for
greater potency and/or more selectivity in recognition by a
targeted enzyme. When carbon groups are used in place of the
exo-oxygen of traditional glycosidic links, so-called “C-glyco-
sides” are formed; these substances, which are inert to hydroly-
sis, appear to be conformationally similar to the oxygen-linked
natural substances.7 Several examples of homoazasugars such
as homomannojirimycin (3) have been isolated from natural
sources or prepared synthetically.8 These materials combine
the features of both azasugars and C-glycosides. A potent,
specific glycosidase inhibitor and an antidiabetic drug candidate
has been produced by carrying this concept further with the
synthesis of MDL 25,637 (4), in which a second sugar is linked
by a â-glycosidic bond.5c Such â-glycosides are generally more
stable toward hydrolysis by pertinent mammalian enzymes.
A first example of an aza-C-disaccharide D-azaMan-â-(1f6)-
D-Gal (5) was reported recently by our laboratories.9 Since this
(3) (a) Sunkara, P. S.; Bowlin, T. L.; Liu, P. S.; Sjoerdsma, A. Biochem.
Biophys. Res. Commun. 1987, 148, 206. (b) Gruters, R. A.; Neefjes, J. J.;
Tersmette, M.; de Goede, R. E.; Tulp, A.; Huisman, H. G.; Miedema, F.;
Ploegh, H. L. Nature 1987, 330, 74. (c) Walker, B. D.; Kowalski, M.;
Goh, W. C.; Kozarsky, K.; Krieger, M.; Rosen, C.; Rohrschneider, L.;
Haseltine, W. A.; Sodroski, J. Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 8120.
(d) Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.; Namgoong, S.
K.; Ramsden, N. G.; Jacob, G. S.; Rademacher, T. W. Proc. Natl. Acad.
Sci. U.S.A. 1988, 85, 9229.
(4) (a) Humphries, M. J.; Matsumoto, K.; White, S. L.; Olden, K. Cancer
Res. 1986, 46, 5215. (b) Spearman, M. A.; Jamieson, J. C.; Wright, J. A.
Exp. Cell Res. 1987, 168, 116.
(5) (a) Truscheit, E.; Frommer, W.; Junge, B.; Mu¨ller, L.; Schmidt, D.
D.; Wingender, W. Angew. Chem., Int. Ed. Engl. 1981, 20, 744. (b) Horii,
S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.; Matsui, K. J. Med.
Chem. 1986, 29, 1038. (c) Anzeveno, P. B.; Creemer, L. J.; Daniel, J. K.;
King, C.-H. R.; Liu, P. S. J. Org. Chem. 1989, 54, 2539.
† Wayne State University.
‡ University of Arkansas for Medical Sciences.
X Abstract published in AdVance ACS Abstracts, May 1, 1997.
(1) (a) Fleet, G. W. J.; Karpus, A.; Dwek, R. A.; Fellows, L. E.; Tyms,
A. S.; Petursson, S.; Namgoong, S. K.; Ramsden, N. G.; Smith, P. W.;
Son, J. C.; Wilson, F. X.; Witty, D. R.; Jacob, G. S.; Rademacher, T. W.
FEBS Lett. 1988, 237, 128. (b) Winchester, B.; Fleet, G. W. J. Glycobiology
1992, 2, 199. (c) Elbein, A. D. Ann. ReV. Biochem. 1987, 56, 497.
(2) (a) Jensen, J. L.; Tsuang, S. C.; Uslan, A. H. J. Org. Chem. 1986,
51, 816. (b) Liu, P. S. J. Org. Chem. 1987, 52, 4717. (c) Cogoli, A.;
Semenza, G. J. Biol. Chem. 1975, 250, 7802. (d) Sinnot, M. L. Chem.
ReV. 1990, 90, 1171.
(6) (a) Johnson, C. R.; Golebiowski, A.; Sundram, H.; Miller, M. W.;
Dwaihy, R. L. Tetrahedron Lett. 1995, 36, 653. (b) For a recent example
of an azasugar thioglycoside, see: Suzuki, K.; Hashimoto, H. Tetrahedron
Lett. 1994, 35, 4119.
(7) For detailed discussions and data on the topic of C- vs O-glycoside
similarities and differences, see: (a) Duda, C. A.; Stevens, E. S. J. Am.
Chem. Soc. 1993, 115, 8487. (b) Wei, A.; Kishi, Y. J. Org. Chem. 1994,
59, 88. (c) Espinosa, J.-F.; Can˜ada, J.; Asensio, J. L.; Mart´ın-Pastor, M.;
Dietrich, H.; Mart´ın-Lomas, M.; Schmidt, R. R.; Jime´nez-Barbero, J. J.
Am. Chem. Soc. 1996, 118, 10862.
S0002-7863(96)04292-8 CCC: $14.00 © 1997 American Chemical Society

Biological EValuation of Aza-C-disaccharides
Chart 1. Aza-C-disaccharides
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4857
Scheme 1
Scheme 2
an alkylboron transmetalation partner 12 generated from the
hydroboration of the appropriately olefinated sugar precursor
(Scheme 1).
initial report, the groups of Vogel and Martin have reported
syntheses of aza-C-disaccharides.10 We now report the synthesis
of D-azaMan-â-(1f6)-D-Man (6), D-azaMan-â-(1f6)-D-Glc (7),
D-azaMan-â-(1f4)-D-Talo (8), and D-azaMan-â-(1f1)-D-â-Glc
(9) (Chart 1).
Synthesis of Vinyl Bromide 11. Bromodiol 10 was pro-
tected as an acetonide and epoxidized according to the procedure
of Hudlicky using m-CPBA.13 The resultant vinyl epoxide was
opened regioselectively with LiCl14 to produce chlorohydrin 14
which was subsequently treated with sodium azide to yield azido
alcohol 15.15 After protection of the alcohol as its silyl ether
(tert-butyldimethylsilyl chloride (TBSCl), imidazole, DMF), the
azide function was reduced to an amine with triphenylphosphine
and protected as a carbamate (CbzCl, NaHCO3) to produce vinyl
bromide 11 (Scheme 2).
Results and Discussion
Recent developments in the microbial oxidation of haloben-
zenes to produce enantiopure halogen-substituted cyclohexa-
diene diols has led to the commercial availability of bromodiol
10 (eq 1).11
Synthesis of D-azaMan-â-(1f6)-D-Man (6). The 6-hy-
droxyl group of methyl R-D-mannopyranoside was protected
selectively as a silyl ether (t-BuPh2SiCl, imidazole, DMF)
followed by formation of the 2,3-acetonide ((CH3)2C(OCH3)2,
acetone, p-toluenesulfonic acid (p-TsOH)) to provide alcohol
17.16 The 4-hydroxyl group was then transformed into a
methoxymethyl ether (MOMCl, (i-Pr)2NEt), followed by re-
moval of the silyl group (n-Bu4NF, THF) to produce primary
alcohol 19. Oxidation of the resulting alcohol to aldehyde 20
(pyridinium chlorochromate (PCC), molecular sieves 4 Å)
followed by Wittig methylenation yielded the desired mono-
substituted olefin 21 (Scheme 3).
Our synthetic strategy centers on the palladium-catalyzed
Suzuki coupling12 of vinyl bromide 11 derived from 10 with
(8) (a) Kite, G. C.; Fellows, L. E.; Fleet, G. W. J.; Liu, P. S.; Schofield,
A. M.; Smith, N. G. Tetrahedron Lett. 1988, 32, 6483. (b) Aoyagi, S.;
Fujimaki, S.; Kibayashi, C. J. Chem. Soc., Chem. Commun. 1990, 1457.
(c) Bruce, I.; Fleet, G. W. J.; di Bello, I. C.; Winchester, B. Tetrahedron
1992, 48, 10191. (d) Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem.
Res. 1993, 26, 182. (e) Holt, K. E.; Leeper, F. J.; Handa, S. J. Chem. Soc.,
Perkin Trans. 1 1994, 231. (f) Henderson, I.; Laslo, K.; Wong, C.-H.
Tetrahedron Lett. 1994, 35, 359. (g) Martin, O. R.; Saavedra, O. M.
Tetrahedron Lett. 1995, 36, 799. (h) Martin, O. R.; Xie, F.; Liu, L.
Tetrahedron Lett. 1995, 36, 4027. (i) Wong, C.-H.; Provencher, L.; Porco,
J. A., Jr.; Jung, S.-H.; Wang, Y.-F.; Chen, L.; Wang, R.; Steensma, D. H.
J. Org. Chem. 1995, 60, 1492.
The desired alkylboron coupling partner was generated in situ
via the hydroboration of 21 with 9-borabicyclo[3.3.1]nonane
(12) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314. (b) Suzuki, A. Pure Appl.
Chem. 1991, 63, 419. (c) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457.
(13) Hudlicky, T.; Rulin, F.; Tsunoda, T.; Luna, H.; Anderson, C.; Price,
J. D. Isr. J. Chem. 1991, 31, 229.
(14) Bajwa, J. S.; Anderson, R. C. Tetrahedron Lett. 1991, 32, 3021.
(15) A similar protocol has been demonstrated by Hudlicky using the
corresponding vinyl chloride. Hudlicky, T.; Rouden, J.; Luna, H.; Allen,
S. J. Am. Chem. Soc. 1994, 116, 5099.
(16) Khan, S. H.; Jain, R. K.; Matta, K. L. Carbohydr. Res. 1990, 207,
57.
(9) (a) Johnson, C. R.; Miller, M. W.; Golebiowski, A.; Sundram, H.;
Ksebati, M. B. Tetrahedron Lett. 1994, 35, 8991.
(10) (a) Baudat, A.; Vogel, P. Tetrahedron Lett. 1996, 37, 483. (b)
Martin, O. R.; Liu, L.; Yang, F. Tetrahedron Lett. 1996, 37, 1991. (c)
Fre´rot, E.; Marquis, C.; Vogel, P. Tetrahedron Lett. 1996, 37, 2023. (d)
Saavedra, O. M.; Martin, O. R. J. Org. Chem. 1996, 61, 6987.
(11) The diol derived from bromobenzene is now prepared in crystalline
form on a multikilogram scale by Genecor International, Inc., Rochester,
NY.

4858 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Johns et al.
Scheme 3
Figure 1. (a) Preferred approach of hydrogenation catalyst. (b) Results
1
of H NMR NOE studies of protected aza-C-disaccharide 25.
Scheme 5
Scheme 4
(1f6)-D-Man (6) as its HCl salt. The â stereochemistry was
produced exclusively which is consistent with the delivery of
H2 from the R face of the cyclic iminium intermediate (Figure
1a). The stereochemistry was confirmed by a H1/H2 coupling
constant of 2.5 Hz and NOE enhancements between H1 and H5
in both directions (Figure 1b).
Synthesis of D-azaMan-â-(1f6)-D-Glc (7). Silylation of the
6-hydroxyl group of methyl R-D-glucopyranoside as described
above17 was followed by protection of the remaining hydroxyl
groups as their methoxymethyl ethers (MOMCl, (i-Pr)2NEt) to
provide fully protected glucose derivative 27. Removal of the
silyl group with tetrabutylammonium fluoride (TBAF) produced
primary alcohol 28 which was oxidized using modified Swern
conditions (trifluoroacetic anhydride (TFAA), DMSO, Et3N),18
followed by Wittig methylenation, to produce olefin 29 (Scheme
5).
The hydroboration of 29 (9-BBN-H, THF) followed by
coupling with 11 (PdCl2(dppf), 3 M aqueous K3PO4, DMF)
proceeded smoothly to provide trisubstituted olefin 30 (Scheme
6). Ozonolysis followed by reduction of the resultant aldehyde
(NaBH3CN, pH 4, THF) and finally intramolecular reductive
amination (Pd/C, H2, CH3OH) led to protected aza-C-disaccha-
ride 31 as a single diastereomer, the expected â isomer as
confirmed by NOE and H NMR coupling constants. Acid
hydrolysis of the remaining hydroxyl protecting groups provided
D-azaMan-â-(1f6)-D-Glc (7) as its HCl salt.
Synthesis of D-AzaMan-â-(1f4)-D-Talo (8). Alcohol 17
appeared to be well suited for functionalization at the 4-position.
Oxidation of the secondary alcohol (PCC, molecular sieves 4
Å) resulted in ketone 32. A routine Wittig olefination proved
to be disasterous, resulting in a poor yield at best of the desired
(9-BBN-H) in THF. The resulting borane and vinyl bromide
11 were coupled smoothly using standard conditions (PdCl2(dppf),
3 M aqueous K3PO4, DMF) to produce trisubstituted olefin 22
in excellent yield (Scheme 4). Olefin 22 was transformed into
protected disaccharide mimic 25 in three steps requiring only
one chromatographic purification. Ozonolysis followed by
DMS workup yielded keto aldehyde 23 (which is in equilibrium
with its closed form hemiaminal as was observed by 1H NMR).
The aldehyde was reduced chemoselectively (NaBH3CN, pH 4
AcOH/NaOAc buffer) producing keto alcohol 24 which was
converted to the protected azasugar 25 Via an intramolecular
reductive amination (Pd/C, H2, CH3OH). Acidic deprotection
(6 N HCl, CH3OH) produced aza-C-disaccharide D-azaMan-â-
1
(17) Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975.
(18) Yoshimura, J.; Sato, K.-i.; Hashimoto, H. Chem. Lett. 1977, 1327.

Biological EValuation of Aza-C-disaccharides
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4859
Scheme 6
Scheme 8
Scheme 7
Scheme 9
olefin along with epimerization and elimination products
resulting from the basic nature of the Wittig conditions. Our
efforts were then directed toward the milder metathesis meth-
ylenation, namely the Tebbe reaction. In our hands, the
traditional Tebbe titanium/aluminum complex gave only modest
yields (45-55%) of the desired olefin 33. The recent develop-
ment of dimethyltitanocene by Petasis came to our attention.19
This reagent generates in situ, upon warming in toluene, the
same titanium alkylidene as the Tebbe reagent. The lower cost
along with easier handling of this Tebbe surrogate should also
be noted. Methylenation of 32 proceeded nicely with dimeth-
yltitanocene to provide olefin 33 in 81% yield with no evidence
of epimerization or elimination products (Scheme 7).
When planning the synthesis of the (1f4) linked sugar, we
had concerns about the hydroboration step prior to the Suzuki
coupling due to literature precedence for the capricious nature
of the hydroboration of disubstituted olefins in the 4-position
of carbohydrates.20 More reactive sources of hydride (BH3‚
SMe2 or combinations of hydroboration reagents such as
thexylborane and BH3) along with extended reaction times were
reported as necessary for significant addition to occur. The use
of the more reactive and less sterically biased BH3 led to
mixtures of regio- and stereoisomers while only providing
moderate yields of products. Another concern was that while
the Suzuki coupling works well with 9-BBN-H-derived alkyl-
boron partners, very few other alkylboron reagents facilitate the
required transmetalation step to afford the desired coupled
product.12 Much to our delight, our first attempt at the
hydroboration of 33 (9-BBN-H, THF, reflux) followed by
coupling to 11 (PdCl2(dppf), 3 M aqueous K3PO4, DMF) led
to olefin 34 as a single diastereomer in good yield (Scheme 8).
The stereochemistry of the hydroboration of 33 was deter-
mined to be that corresponding to the talo configuration. This
result is consistent with an equatorial approach of the sterically
demanding borane. This was confirmed using a model system
1
due to the complexity of the H NMR spectra of 34 making
coupling assignments difficult along with the fact that H4 of
the talo ring resides in an equatorial position which is not set
up well for NOE experiments. Olefin 33 was coupled under
identical conditions as described above, but vinyl bromide 11
was replaced with 3-iodotoluene, vastly simplifying the 1H NMR
spectrum of the product 36 (Scheme 9). The toluene derivative
containing a methyl singlet was chosen for determining the
diastereomeric ratio resulting from the hydroboration. Only a
1
trace of the minor diastereomer was observed in the H NMR
spectra of the crude reaction mixture. A coupling constant of
3.0 Hz was observed between H3 and H4 of 36 in complete
agreement with the expected talo configuration. A trans diaxial
coupling constant between H3 and H4 of 9-10 Hz would be
expected for the manno diastereomer.
Ozonolysis of 34 followed by the previously described
sequence led to protected disaccharide 35 again as a single
diastereomer as confirmed by 1H NMR and NOE studies.
Acidic deprotection provided D-azaMan-â-(1f4)-D-Talo (8) as
its HCl salt.
(19) (a) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(b) Csuk, R.; Gla¨nzer, B. I. Tetrahedron 1991, 47, 1655.
(20) (a) Daly, S. M.; Armstrong, R. W. Tetrahedron Lett. 1989, 30, 5713.
(b) Preuss, R.; Jung, K.-H.; Schmidt, R. R. Liebigs Ann. Chem. 1992, 377.
Synthesis of D-azaMan-â-(1f1)-D-â-Glc (9). δ-D-Glucono-
lactone was protected exhaustively as its tetra(methoxymethyl

4860 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Johns et al.
Table 1. Comparison of Inhibitory Activities
Scheme 10
entry
compound
enzyme
IC50 (µM)
1
2
3
4
5
6
6
7
8
8
8
9
amyloglucosidase
amyloglucosidase
amyloglucosidase
R-glucosidase
R-galactosidase
amyloglucosidase
25
12
150
200
330a
26
a Value determined by extrapolation.
Scheme 11
H2 coupling of 3-4 Hz and was not observed. NOE experi-
ments were also conducted resulting in positive enhancements
between H1 and H3 as well as H1 and H5, all of which reside in
1,3 axial positions below the ring. This result is consistent with
the report that the perbenzylated derivative of 38 undergoes
hydroboration with 9-BBN-H followed by oxidation to give only
the â-homoglucose.21
Ozonolysis of 39 followed by reduction of the resultant
aldehyde (NaBH3CN, pH 4, THF) and finally intramolecular
reductive amination (Pd/C, H2, CH3OH) led to protected aza-
C-disaccharide 40 as a single diastereomer corresponding to the
expected â isomer which was confirmed by NOE and 1H NMR
coupling constants. Acid hydrolysis of the remaining alcohol
protecting groups provided D-azaMan-â-(1f1)-D-â-Glc (9) as
its HCl salt.
Biological Evaluation
Aza-C-disaccharides 6-9 were screened against seven com-
mon glycosidases (amyloglucosidase, R-glucosidase (yeast),
â-glucosidase, R-galactosidase, â-galactosidase, R-mannosidase,
and â-mannosidase) that accept p-nitrophenyl glycosides as
substrates.22 The compounds were tested up to a maximum
concentration of 100 µg/mL. All four compounds inhibited
amyloglucosidase with 7 exhibiting the best activity (IC50
)
12 µM) followed by 6 (IC50 ) 25 µM) and 9 (IC50 ) 26 µM),
and the weakest inhibitor was 8 (IC50 ) 150 µM).
Interestingly, derivative 8 exhibited the weakest amyloglu-
cosidase inhibition but was the only compound to inhibit any
of the other enzymes which were assayed (Table 1). It should
be noted that none of the compounds inhibited the mannosidase
enzymes even though the piperidine ring stereochemistry
corresponds to the parent mannojirimycin which is a potent
mannosidase inhibitor.1b This is not a completely unexpected
outcome since removal of the anomeric hydroxyl resulting in
deoxymannojirimycin (DMJ) vastly decreases the inhibition of
mannosidase, and any simple alkyl substitution at the C1 position
renders the DMJ derivatives completely inactive against man-
nosidase enzymes. The C1-substituted DMJ derivatives are
potent inhibitors of other glycosidases demonstrating that the
C1 position has a crucial role in the activity of azasugars.23 Our
results are consistent with this observation. It is also noteworthy
that the differences in biological activity of the title compounds
must be attributed to the variations in the linkage and stereo-
chemistry of the pyranose portion of the disaccharides due to
the identical nature of the piperidine ring segment.
Scheme 12
9 0
ether) 37 (MOMCl, (i-Pr)2NEt). The lactone function was
olefinated with dimethyltitanocene in good yield to provide enol
ether 38 (Scheme 10).
Hydroboration of 38 (9-BBN-H, THF, reflux), followed by
coupling of the product with vinyl bromide 11 (PdCl2(dppf), 3
M aqueous K3PO4, DMF) led smoothly to trisubstituted olefin
39 as a single diastereomer (Scheme 11).
Aza-C-disaccharides 6 and 9 were screened for in Vitro anti-
HIV activity. Unfortunately both compounds were confirmed
inactive with an IC50 > 2 × 10-4 M.
Conclusion
The stereochemical outcome of the hydroboration was
determined as previously described by coupling 38 to 3-iodo-
toluene under the same reaction conditions as were used to form
the parent system 39 (Scheme 12). The hydroboration resulted
in axial hydride delivery to form 41 having the â-glucose
stereochemistry. This was confirmed by a H1/H2 coupling
constant of 9.0 Hz corresponding to a trans diaxial relationship
as required by the â-oriented aryl group at C1 of 41. The
R-oriented aryl group at C1 would be expected to have an H1/
In summary, an efficient method for the construction of
(1f6), (1f4), and, (1f1) linked aza-C-disaccharides has been
(21) Rajanbabu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51, 5458.
(22) Tropea, J. E.; Molyneux, R. J.; Kaushal, G. P.; Pan, Y. T.; Mitchell,
M.; Elbein, A. D. Biochemistry 1989, 28, 2027.
(23) (a) Fleet, G. W. J.; Namgoong, S. K.; Barker, C.; Baines, S.; Jacob,
G. S.; Winchester, B. Tetrahedron Lett. 1989, 30, 4439. (b) Winchester,
B.; Barker, C.; Baines, S.; Jacob, G. S.; Namgoong, S. K.; Fleet, G. Biochem.
J. 1990, 265, 277.

Biological EValuation of Aza-C-disaccharides
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4861
14 as a viscous clear oil: Rf 0.44 (2:1, hexanes/EtOAc); IR (neat) 3450,
2976, 2912, 1640, 1077 cm-1; [R]20D -3.90° (c 1.20, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.43 (s, 3 H), 1.56 (s, 3 H), 2.74 (d, 1 H, J ) 2.7
Hz), 3.80 (td, 1 H, J ) 8.4, 2.7 Hz), 4.16 (dd, 1 H, J ) 8.4, 6.3 Hz),
4.32 (ddd, 1 H, J ) 8.4, 2.1, 1.5 Hz), 4.70 (dd, 1 H, J ) 6.3, 1.2 Hz),
6.26 (d, 1 H, J ) 2.1 Hz); 13C NMR (75 MHz, CDCl3) δ 25.87, 28.06,
58.99, 74.12, 77.01, 77.52, 111.27, 120.08, 132.63; HRMS (EI) calcd
for C9H12BrClO3 (M+) 281.9658 (M+ - CH3) 266.9424, found
266.9423.
developed. The hydroboration and Suzuki coupling of olefi-
nated sugar derivatives provides a mild method for further
functionalization and derivatization of one of the most widely
studied and diverse class of organic compounds found in nature.
Encouraging biological data has been reported for the title
compounds providing impetus for further studies in the area of
C1 substitution of this class of glycomimetics. The differing
biological data between the four compounds reported supports
our initial hypothesis that further stereochemical information
can help in the specificity of polyhydroxylated piperidine-
induced glycosidase inhibition. Further studies involving this
methodology for the synthesis of other classes of glycomimetics
is currently being pursued in our laboratories.
(1R,2R,5S,6S)-2-Azido-4-bromo-5,6-(O-Isopropylidenedioxy)cy-
clohex-3-en-1-ol (15). Chloro alcohol 14 (6.31 g, 22.2 mmol) was
taken up in 45 mL of DMF, and sodium azide (2.17 g, 33.4 mmol)
was added in one portion at rt. The resultant solution was heated to
55 °C for 40 h. The reaction mixture was cooled to rt, poured into
EtOAc, and washed with H2O and brine. The aqueous layers were
extracted with EtOAc (4×), and the combined organics were dried over
MgSO4. Filtration and concentration followed by flash chromatography
on silica gel (4:1, hexanes/EtOAc) gave 4.91 g (76%) of azido alcohol
15 as a white solid: mp 107-108 °C; Rf 0.61 (2:1, hexanes/EtOAc);
Experimental Section
General. 1H NMR and 13C NMR spectra were recorded on a Varian
Unity 500, a Varian Gemini 300, or a Nicolet QE 300 spectrometer.
Chemical shift values (δ) are reported in ppm. Infrared spectra were
recorded on a Nicolet 20DX FTIR spectrometer. High-resolution mass
spectra were recorded on a Kratos MS80RFA spectrometer. FAB mass
spectra were recorded on a Kratos MS50TC spectrometer. Optical
rotations were determined with a Perkin-Elmer 241 MC polarimeter.
Flash Chromatography was carried out uing Merck Kieselgel (230-
400 mesh). Thin-layer chromatography was performed on silica gel.
Melting points were taken on a Hoover UniMelt apparatus and are
uncorrected. Solvents were purified according to the literature
procedures.24 9-BBN-H was prepared and stored in its solid dimer
form by the known procedure.25 The 9-BBN-H dimer was typically
dissolved in THF as a 0.5 M solution for 3 h before use. The pH 4
buffer used for selective reductions along with NaBH3CN was prepared
as a stock solution by dissolving 1.5 g of sodium acetate along with
5.7 mL of glacial acetic acid in 6 mL of H2O. Ozonolysis was achieved
with an OREC ozonator (Model 03V5-0) and rated to produce ca. 5 g
of ozone per hour with a flow rate of 2.8 L/min using an oxygen source.
General Procedure A: Ozonolysis, Aldehyde Reduction, and
Subsequent Reductive Amination. A 50 mL flask equipped with a
side arm gas-bubbling inlet and a gas outlet was charged with the
trisubstituted olefin (1 equiv) in CH2Cl2/CH3OH (1:1) (0.2 M) and
cooled to -78 °C. An ozone/oxygen stream from a Model 03V5-0
OREC ozonator was bubbled through the reaction mixture at a rate of
2 L/min until no starting material remained as judged by TLC (5-15
min). Dimethyl sulfide (1.5 mL) was added at -78 °C, and the reaction
mixture was allowed to warm to room temperature (rt). The resultant
solution was stirred for 1.5-2 h and then concentrated in Vacuo. 1H
NMR of the crude product was obtained showing clean conversion to
the keto aldehyde unless otherwise stated. The crude material was taken
up in THF (0.07-0.1 M) and cooled to 0 °C. NaBH3CN (1.3 equiv)
was added in one portion followed by 1-2 drops of a AcOH/NaOAc
pH 4 buffer solution, and the resultant solution was allowed to warm
to rt and stirred for 2 h. The reaction mixture was poured into Et2O or
EtOAc and washed with NaHCO3 and brine. The aqueous layers were
extracted with Et2O (3×), and the combined organic layers were dried
over Na2SO4. Filtration and concentration in Vacuo provided the
corresponding crude keto alcohol. A high-pressure tube was charged
with the crude keto alcohol in CH3OH (0.03 M), 10% Pd/C (degussa
type 50 wt % based on substrate), and H2 (40 psi). The mixture was
stirred vigorously for 12 h. Filtration through Celite and concentration
in Vacuo, followed by flash chromatography on silica gel, gave the
desired protected azasugar.
IR (neat) 3378, 2977, 2871, 2121, 1632, 1073 cm-1; [R]20 -147.5°
D
(c 0.73, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.40 (s, 3 H), 1.44 (s,
3 H), 2.47 (br m, 1 H), 4.20 (m, 2 H), 4.40 (t, 1 H, J ) 5.4 Hz), 4.66
(dd, 1 H, J ) 5.4, 0.9 Hz), 6.15 (dd, 1 H, J ) 3.9, 0.9 Hz); 13C NMR
(75 MHz, CDCl3) δ 26.06, 27.64, 59.54, 69.17, 75.99, 76.12, 110.44,
125.38, 126.26; HRMS (EI) calcd for C9H12BrN3O3 (M+) 289.0062
(M+ - CH3) 273.9827, found 273.9832.
(3R,4R,5S,6S)-3-Azido-1-bromo-4-[(tert-butyldimethylsilyl)oxy]-
5,6-(O-isopropylidenedioxy)cyclohex-1-ene (16). A solution of azido
alcohol 15 (4.91 g, 16.9 mmol) in DMF (35 mL) was treated with
tert-butyldimethylsilyl chloride (3.84 g, 25.5 mmol) and imidazole (2.88
g, 42.3 mmol) at rt. The resultant solution was heated to 60 °C for 18
h. The reaction mixture was then cooled to rt, poured into pentane,
and washed with H2O and brine. The aqueous layers were extracted
with pentane (4×), and the combined organics were dried over MgSO4.
Filtration and concentration followed by flash chromatography on silica
gel (9:1, hexanes/EtOAc) gave 6.80 g (99%) of silyl ether 16 as a clear
oil: Rf 0.60 (8:1, hexanes/EtOAc); IR (neat) 2988, 2953, 2931, 2858,
2102, 1645, 1228, 1077 cm-1; [R]20D -42.5° (c 1.22, CHCl3); 1H NMR
(300 MHz, C6D6) δ -0.04 (s, 3 H), 0.02 (s, 3 H), 0.86 (s, 9 H), 1.11
(s, 3 H), 1.26 (s, 3 H), 3.48 (m, 1 H), 3.88 (dd, 1 H, J ) 6.3, 3.6 Hz),
4.15 (dd, 1 H, J ) 6.3, 5.7 Hz), 4.46 (d, 1 H, J ) 5.7 Hz), 5.73 (d, 1
H, J ) 4.2 Hz); 13C NMR (75 MHz, C6D6) δ -4.91, -4.81, 18.13,
25.84, 25.91, 27.66, 60.00, 71.74, 76.89, 77.04, 110.07, 125.57, 127.22;
HRMS (EI) calcd for C15H26BrN3O3Si (M+) 403.0927 (M+ - CH3)
388.0692, found 388.0700.
(3R,4R,5S,6S)-3-[(N-Benzyloxycarbonyl)amino]-1-bromo-4-[(tert-
butyldimethylsilyl)oxy]-5,6-(O-isopropylidenedioxy)cyclohex-1-
ene (11). Triphenylphosphine (5.50 g, 21 mmol) was added to azide
16 (6.80 g, 16.9 mmol) in THF (60 mL) at rt. The reaction mixture
began bubbling within 10 min. The resultant mixture was stirred at rt
for 2 h. H2O (3.0 mL) was then added, and the solution was heated to
reflux for 6 h. The mixture was cooled to rt and concentrated at reduced
pressure. EtOAc (60 mL) was then added to the reaction flask followed
by saturated aqueous NaHCO3 (30 mL). Benzyl chloroformate (3.62
mL, 25.3 mmol) was then added, and the biphasic mixture was stirred
vigorously at rt for 16 h. The layers were separated, and the organic
layer was washed with brine. The aqueous layer was extracted with
EtOAc (3×), and the combined organics were dried over MgSO4.
Filtration and concentration followed by flash chromatography on silica
gel (9:1, hexanes/Et2O) gave 8.60 g (99%) of vinyl bromide 11 as a
pale brown oil: Rf 0.58 (4:1, hexanes/EtOAc); IR (neat) 3449, 3347,
(1S,2S,5S,6S)-4-Bromo-2-chloro-5,6-(O-isopropylidenedioxy)cy-
clohex-3-en-1-ol (14). To a solution of epoxide 1313 (5.74 g, 23.4
mmol) in THF (100 mL) at rt were added LiCl (9.9 g, 232 mmol) and
nitromethane (3.8 mL). The resultant pale brown solution was stirred
for 4 d at rt. The reaction mixture was poured into Et2O and washed
with H2O and brine. The aqueous layers were extracted with Et2O
(3×), and the combined organic layers were dried over Na2SO4.
Filtration and concentration followed by flash chromatography on silica
gel (4:1 to 2:1, hexanes/EtOAc) gave 5.80 g (88%) of chloro alcohol
3033, 2986, 2952, 2931, 2857, 1727, 1500, 1216, 1076 cm-1; [R]20
D
-27.7° (c 1.90, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.07 (s, 3 H),
0.10 (s, 3 H), 0.87 (s, 9 H), 1.40 (s, 3 H), 1.41 (s, 3 H), 4.24 (t, 1 H,
J ) 4.5 Hz), 4.28 (t, 1 H, J ) 3.3 Hz), 4.50 (dd, 1 H, J ) 4.8, 1.8 Hz),
4.55 (br d, 1 H, J ) 8.7 Hz), 5.06 (d, 1 H, J ) 10.5 Hz), 5.13 (s, 2 H),
5.89 (t, 1 H, J ) 1.8 Hz), 7.33-7.38 (m, 5 H); 13C NMR (75 MHz,
CDCl3) δ -5.05, -4.76, 17.87, 25.60, 26.59, 27.62, 49.63, 66.91, 69.15,
75.71, 76.60, 110.59, 123.36, 128.15, 128.50, 129.39, 133.57, 136.29,
155.45; HRMS (EI) calcd for C23H34BrNO5Si (M+) 511.1390 (M+
C4H9) 454.0685, found 454.0694.
-
(24) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon: Oxford, 1989.
(25) Soderquist, J. A.; Negron, A. Org. Synth. 1991, 70, 169.
Methyl 6-O-(tert-Butyldiphenylsilyl)-2,3-O-isopropylidene-4-O-
(methoxymethyl)-r-D-mannopyranoside (18). To a cold (0 °C)

4862 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Johns et al.
solution of silyl ether 1716 (2.78 g, 5.9 mmol) in CH2Cl2 (60 mL) was
added diisopropylethylamine (3.07 mL, 17.6 mmol) dropwise, followed
by the addition of chloromethyl methyl ether (2.25 mL, 29.5 mmol).
Solid tetrabutylammonium iodide (0.65 g, 1.8 mmol) was then added
to the reaction mixture, and the solution was allowed to warm to rt.
The reaction mixture was stirred in the dark for 14 h. The reaction
mixture was poured into CH2Cl2 and washed with saturated aqueous
NH4Cl and brine. The aqueous layers were extracted with CH2Cl2 (3×),
and the combined organic layers were dried over MgSO4. Filtration
and concentration followed by flash chromatography on silica gel (8:
1, hexanes/EtOAc) gave 3.01 g (99%) of fully protected sugar 18 as a
clear oil: Rf 0.51 (8:1, hexanes/EtOAc); IR (neat) 3071, 3048, 2986,
2932, 2857, 1091, 1032 cm-1; [R]20D +15.5° (c 0.53, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.07 (s, 9 H), 1.36 (s, 3 H), 1.53 (s, 3 H), 3.22
(s, 3 H), 3.38 (s, 3 H), 3.63 (ddd, 1 H, J ) 10.2, 5.1, 2.4 Hz), 3.75 (dd,
1 H, J ) 10.2, 6.9 Hz), 3.84 (dd, 1 H, J ) 11.1, 5.1 Hz), 3.91 (dd, 1
H, J ) 11.1, 2.4 Hz), 4.12 (d, 1 H, J ) 5.4 Hz), 4.21 (t, 1 H, J ) 6.9
Hz), 4.65 (d, 1 H, J ) 6.3 Hz), 4.85 (d, 1 H, J ) 6.3 Hz), 4.94 (s, 1
H), 7.32-7.46 (m, 6 H), 7.71-7.76 (m, 4 H); 13C NMR (75 MHz,
CDCl3) δ 19.27, 26.39, 26.75, 27.80, 54.62, 55.79, 63.27, 69.61, 72.90,
75.85, 78.54, 96.26, 98.02, 109.24, 127.48, 127.58, 129.52, 133.36,
133.73, 135.61, 135.86; HRMS (EI) calcd for C28H40O7Si (M+)
516.2543 (M+ - CH3) 501.2308, found 501.2308.
and washed with 30 mL of H2O/saturated aqueous Rochelle’s salt (1:
1) and finally with brine. The aqueous layers were extracted with Et2O
(3×), and the combined organic layers were dried over MgSO4.
Filtration and concentration followed by flash chromatography on silica
gel (8:1 to 4:1, hexanes/EtOAc) gave 546 mg (90%) of olefin 21 as a
clear oil: Rf 0.55 (8:1, hexanes/EtOAc); IR (neat) 2987, 2937, 1093,
1032 cm-1; [R]20D +31.7° (c 1.02, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 1.34 (s, 3 H), 1.53 (s, 3 H), 3.36 (s, 3 H), 3.37 (s, 3 H), 3.53 (dd, 1
H, J ) 9.9, 7.2 Hz), 3.94 (dd, 1 H, J ) 9.9, 6.3 Hz), 4.11 (dd, 1 H, J
) 6.0, 0.6 Hz), 4.18 (dd, 1 H, J ) 7.2, 6.0 Hz), 4.63 (d, 1 H, J ) 6.9
Hz), 4.85 (d, 1 H, J ) 6.9 Hz), 4.92 (s, 1 H), 5.27 (dt, 1 H, J ) 10.5,
1.5 Hz), 5.42 (dt, 1 H, J ) 17.1, 1.5 Hz), 5.93 (ddd, 1 H, J ) 17.1,
10.5, 6.3 Hz); 13C NMR (75 MHz, CDCl3) δ 26.33, 27.80, 54.89, 55.79,
69.42, 75.82, 76.17, 78.23, 96.14, 98.10, 109.30, 118.07, 134.89; HRMS
(EI) calcd for C13H22O6 (M+) 274.1416 (M+ - CH3) 259.1182, found
259.1185.
Compound 22. A solution of 9-BBN-H (485 mg, 3.98 mmol) in
THF (8 mL) was added to olefin 21 (546 mg, 1.99 mmol) at rt. The
resultant solution was stirred at rt for 3 h and another one hour at reflux.
The reaction mixture was cooled to rt and 3 M aqueous K3PO4 (1.6
mL, 4.9 mmol) was added. After 15 min, a solution of vinyl bromide
11 (910 mg, 1.77 mmol) and PdCl2(dppf) (129 mg, 0.17 mmol) in DMF
(10 mL) was added Via cannula. The dark mixture was stirred at rt
for 18 h. The reaction mixture was poured into Et2O and washed with
H2O and brine. The aqueous layers were extracted with Et2O (3×),
and the combined organic layers were dried over MgSO4. Filtration
and concentration followed by flash chromatography on silica gel (8:1
to 4:1, hexanes/EtOAc) gave 1.12 g (89%) of olefin 22 as a clear oil:
Rf 0.34 (8:1, hexanes/EtOAc); IR (neat) 3451, 3352, 3031, 2985, 2951,
2898, 2856, 1728, 1500, 1219, 1091, 1028 cm-1; [R]20D -0.77° (c 0.78,
Methyl 2,3-O-Isopropylidene-4-O-(methoxymethyl)-r-D-man-
nopyranoside (19). A cold (0 °C) solution of silyl ether 18 (3.01 g,
5.84 mmol) in THF (50 mL) was treated with 7.59 mL of tetrabuty-
lammonium fluoride (1.0 M in THF, 7.59 mmol). The resultant solution
was then warmed to 25 °C, and stirring was continued for 16 h. The
reaction mixture was poured into EtOAc and washed with saturated
aqueous NH4Cl and brine. The aqueous layers were extracted with
EtOAc, and the combined organic layers were dried over MgSO4.
Filtration and concentration followed by flash chromatography on silica
gel (2:1 to 1:1, hexanes/EtOAc) gave 1.52 g (93%) of alcohol 19 as a
white solid: mp 41-45 °C; Rf 0.40 (1:1, hexanes/EtOAc); IR (neat)
1
CHCl3); H NMR (500 MHz, CDCl3) δ 0.05 (s, 3 H), 0.08 (s, 3 H),
0.84 (s, 9 H), 1.32 (s, 3 H), 1.33 (s, 3 H), 1.35 (s, 3 H), 1.52 (s, 3 H),
1.61 (m, 1 H), 1.99 (m, 1 H), 2.15 (m, 1 H), 2.46 (m, 1 H), 3.36 (s, 3
H), 3.37 (s, 3 H), 3.47 (m, 2 H), 4.07 (d, 1 H, J ) 6.0 Hz), 4.12 (t, 1
H, J ) 6.0 Hz), 4.18 (t, 1 H, J ) 4.5 Hz), 4.19 (dd, 1 H, J ) 7.5, 3.5
Hz), 4.43 (d, 1 H, J ) 4.5 Hz), 4.47 (br d, 1 H, J ) 8.5 Hz), 4.62 (d,
1 H, J ) 6.0 Hz), 4.86 (s, 1 H), 4.96 (br d, 1 H, J ) 9.5 Hz), 4.97 (d,
1 H, J ) 6.0 Hz), 5.09 (d, 1 H, J ) 12.5 Hz), 5.12 (d, 1 H, J ) 12.5
Hz), 5.24 (s, 1 H), 7.28-7.36 (m, 5 H); 13C NMR (125 MHz, CDCl3)
δ -5.08, -4.74, 17.88, 25.64, 26.35, 26.69, 27.76, 27.86, 28.77, 28.93,
48.06, 55.21, 56.00, 66.65, 67.61, 69.73, 73.10, 75.79, 75.80, 76.39,
78.36, 96.14, 98.03, 109.16, 109.55, 122.20, 128.03, 128.45, 136.56,
137.69, 155.67 (missing 1 quaternary C); HRMS (EI) calcd for C36H57-
NO11Si (M+) 707.3701 (M+ - C4H9) 650.2997, found 650.3006.
3486, 2986, 2906, 1090, 1031 cm-1; [R]20 +77.4° (c 1.44, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 1.34 (s, 3 H), 1.53 (s, 3 H), 2.34 (t, 1
H, J ) 6.9 Hz), 3.37 (s, 3 H), 3.41 (s, 3 H), 3.57 (dt, 1 H, J ) 10.2,
3.6 Hz), 3.72 (dd, 1 H, J ) 10.2, 7.2 Hz), 3.82 (m, 2 H), 4.11 (d, 1 H,
J ) 5.7 Hz), 4.21 (dd, 1 H, J ) 7.2, 5.7 Hz), 4.68 (d, 1 H, J ) 6.6
Hz), 4.92 (s, 1 H), 4.93 (d, 1 H, J ) 6.6 Hz); 13C NMR (75 MHz,
CDCl3) δ 26.30, 27.88, 54.96, 55.99, 62.00, 68.58, 73.59, 75.84, 78.25,
96.79, 98.32, 109.35; HRMS (EI) calcd for C12H22O7 (M+) 278.1365
(M+ - CH3) 263.1132, found 263.1134.
Methyl 2,3-O-Isopropylidene-4-O-(methoxymethyl)-6-oxo-r-D-
mannopyranoside (20). To a suspension of freshly activated powdered
4 Å molecular sieves (4.6 g) in CH2Cl2 (50 mL) was added pyridinium
chlorochromate (2.25 g, 10.4 mmol). Alcohol 19 (631 mg, 2.27 mmol)
in CH2Cl2 (5 mL) was added by a cannula at rt resulting in a brown
suspension. The reaction mixture was stirred for 35 min upon which
time TLC indicated the disappearance of starting material. The reaction
mixture was diluted with 125 mL of Et2O/hexanes (2:1) and filtered
through a pad of silica gel. The silica gel was eluted with Et2O (300
mL). Upon concentration of the eluent, 579 mg (92%) of aldehyde 20
was obtained as a pale brown oil: Rf (streak) 0.19-0.45 (1:1, hexanes/
Disaccharide 25. Olefin 22 (117 mg, 0.166 mmol) was subjected
to the conditions of general procedure A to provide, after flash
chromatography on silica gel (20:1, CH2Cl2/CH3OH), 29.2 mg (53%
from 22) of disaccharide 25 as a pale brown oil: Rf 0.52 (10:1, CH2-
Cl2/CH3OH); IR (neat) 3490, 3315, 2985, 2932, 1093, 1029 cm-1; [R]20
+21.74° (c 0.69, CHCl3); H NMR (500 MHz, CDCl3) δ 0.04 (s, 3
D
1
H), 0.12 (s, 3 H), 0.87 (s, 9 H), 1.32 (s, 3 H), 1.33 (s, 3 H), 1.48 (s, 3
H), 1.52 (s, 3 H), 1.60 (m, 2 H), 1.88 (m, 1 H), 2.02 (m, 1 H), 2.50
(ddd, 1 H, J ) 9.5, 8.0, 3.5 Hz), 2.85 (td, 1 H, J ) 7.0, 2.5 Hz), 3.35
(m, 1 H), 3.37 (s, 3 H), 3.39 (s, 3 H), 3.47 (m, 3 H), 3.87 (m, 2 H),
4.05 (dd, 1 H, J ) 5.5, 2.5 Hz), 4.08 (d, 1 H, J ) 6.0 Hz), 4.14 (t, 1
H, J ) 6.0 Hz), 4.65 (d, 1 H, J ) 6.5 Hz), 4.86 (s, 1 H), 4.95 (d, 1 H,
J ) 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ -5.13, -3.99, 18.05,
25.86, 26.33, 26.47, 27.81, 27.87, 28.19, 28.27, 55.06, 55.76, 55.99,
60.81, 63.40, 68.17, 74.25, 75.79, 75.82, 76.48, 78.42, 81.24, 96.28,
98.06, 108.73, 109.19; HRMS (EI) calcd for C28H53NO10Si (M+)
591.3439, found 591.3449.
EtOAc); IR (neat) 2985, 2936, 2908, 2828, 1742, 1092, 1033 cm-1
;
[R]20D +44.8° (c 0.78, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.33 (s,
3 H), 1.50 (s, 3 H), 3.33 (s, 3 H), 3.40 (s, 3 H), 3.89 (dd, 1 H, J ) 9.3,
6.3 Hz), 4.01 (dd, 1 H, J ) 9.3, 1.5 Hz), 4.11 (dd, 1 H, J ) 5.7, 1.2
Hz), 4.28 (t, 1 H, J ) 5.7 Hz), 4.63 (d, 1 H, J ) 6.6 Hz), 4.91 (d, 1
H, J ) 6.6 Hz), 4.96 (s, 1 H), 9.71 (d, 1 H, J ) 1.5 Hz); 13C NMR (75
MHz, CDCl3) δ 26.10, 27.64, 55.56, 56.03, 72.33, 73.04, 75.07, 77.25,
96.35, 98.52, 109.79, 197.76; HRMS (EI) calcd for C12H20O7 (M+)
276.1209 (M+ - CH3) 261.0974, found 261.0968.
Disaccharide 6. To a solution of protected disaccharide 25 (114.0
mg, 0.193 mmol) in CH3OH (4 mL) was added aqueous 6 N HCl (2
mL), and the mixture was stirred at rt for 18 h. The solvents were
then removed in Vacuo. The oily residue was taken up in a minimal
amount of CH3OH, and the product was precipitated with Et2O. The
white solid was allowed to settle, and the solution was decanted. The
solid was washed with Et2O followed by decantation (2×), and finally
the residual solvents were removed in Vacuo to provide 59.8 mg (83.4%)
of the HCl salt of disaccharide 6 as a white solid: mp > 220 °C (dec);
[R]20D +25.0° (c 0.14, CH3OH); 13C NMR (125 MHz, D2O with CD3-
OD as internal standard) δ 24.77, 27.17, 55.93, 59.13, 59.67, 61.37,
Methyl 2,3-O-Isopropylidene-4-O-(methoxymethyl)-6-methylene-
r-D-manno-pyranoside (21). Potassium bis(trimethylsilyl)amide (6.45
mL, 0.5 M toluene, 3.22 mmol) was added dropwise at rt to a
suspension of methyltriphenylphosphonium bromide (1.2 g, 3.36 mmol)
in THF (39 mL). The resultant bright yellow solution was stirred at rt
for 1.5 h. The ylide solution was then cooled to -78 °C, and a solution
of aldehyde 20 (613 mg, 2.22 mmol) in THF (5 mL) was added slowly
by cannula. After 15 min of stirring at -78 °C, the reaction mixture
was allowed to warm to rt and stirred for another 1.5 h. The reaction
mixture was quenched at 0 °C with CH3OH (9 mL), poured into Et2O,

Biological EValuation of Aza-C-disaccharides
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4863
66.62, 68.12, 70.79, 70.96, 71.52, 72.44, 74.25, 102.08; FAB MS for
to warm to rt, and stirring was continued for another 18 h. The reaction
was quenched at rt with CH3OH (5 mL), poured into Et2O, and washed
with 10 mL of H2O/saturated aqueous Rochelle’s salt (1:1) and finally
with brine. The aqueous layers were extracted with Et2O (3×), and
the combined organic layers were dried over MgSO4. Filtration and
concentration followed by flash chromatography on silica gel (4:1 to
2:1 to 1:1, hexanes/EtOAc) gave 877 mg (74% from 28) of olefin 29
as a clear oil: Rf 0.77 (1:1, hexanes/EtOAc); IR (neat) 2988, 2932,
2895, 1032 cm-1; [R]20D +80.0° (c 0.74, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 3.36 (m, 1 H), 3.37 (s, 3 H), 3.40 (s, 3 H), 3.41 (s, 3 H),
3.42 (s, 3 H), 3.53 (dd, 1 H, J ) 10.0, 3.5 Hz), 3.92 (t, 1 H, J ) 9.0
Hz), 4.01 (dd, 1 H, J ) 10.0, 7.0 Hz), 4.66 (d, 1 H, J ) 7.0 Hz), 4.71
(d, 1 H, J ) 6.5 Hz), 4.78 (d, 1 H, J ) 6.5 Hz), 4.79-4.84 (m, 4 H),
5.29 (ddd, 1 H, J ) 10.0, 1.5, 1.0 Hz), 5.41 (ddd, 1 H, J ) 17.0, 1.5,
1.0 Hz), 5.92 (ddd, 1 H, J ) 17.0, 10.0, 7.0 Hz); 13C NMR (125 MHz,
CDCl3) δ 55.16, 55.47, 56.20, 56.37, 71.49, 78.07, 78.98, 79.62, 97.69,
98.09, 98.35, 98.98, 118.97, 135.35; FAB MS C14H26O8 (M+) 322.1627,
found (M++H) 323 (3.8%).
Compound 30. A solution of 9-BBN-H (303 mg, 2.48 mmol) in
THF (5 mL) was added to olefin 29 (402 mg, 1.25 mmol) at rt. The
resultant solution was heated to reflux for 6 h. The reaction mixture
was cooled to rt, and 3 M aqueous K3PO4 (1.04 mL, 3.11 mmol) was
added. After 15 min, a solution of vinyl bromide 11 (556 mg, 1.09
mmol) and PdCl2(dppf) (45 mg, 0.06 mmol) in DMF (8 mL) was added
Via cannula. The dark mixture was stirred at rt for 18 h. The reaction
mixture was poured into Et2O and washed with H2O and brine. The
aqueous layers were extracted with Et2O (3×), and the combined
organic layers were dried over MgSO4. Filtration and concentration
followed by flash chromatography on silica gel (2:1 to 1:1, hexanes/
EtOAc) gave 768 mg (93%) of olefin 30 as a clear oil: Rf 0.60 (1:1,
hexanes/EtOAc); IR (neat) 3444, 3347, 2949, 2930, 2894, 1727, 1500,
1051, 1030 cm-1; [R]20D +19.50° (c 1.52, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 0.05 (s, 3 H), 0.08 (s, 3 H), 0.85 (s, 9 H), 1.32 (s, 3 H), 1.35
(s, 3 H), 1.59 (m, 1 H), 2.03 (m, 1 H), 2.15 (m, 1 H), 2.42 (m, 1 H),
3.25 (t, 1 H, J ) 9.5 Hz), 3.37 (s, 3 H), 3.38 (s, 6 H), 3.39 (s, 3 H),
3.47 (dd, 1 H, J ) 10.0, 3.5 Hz), 3.54 (td, 1 H, J ) 9.5, 2.0 Hz), 3.85
(t, 1 H, J ) 9.5 Hz), 4.19 (m, 2 H), 4.43 (d, 1 H, J ) 5.5 Hz), 4.47 (d,
1 H, J ) 8.5 Hz), 4.66 (d, 1 H, J ) 6.5 Hz), 4.70 (d, 1 H, J ) 7.0 Hz),
4.75 (d, 1 H, J ) 3.5 Hz), 4.76 (d, 1 H, J ) 6.0 Hz), 4.77 (d, 1 H, J
) 6.0 Hz), 4.81 (d, 1 H, J ) 6.0 Hz), 4.92 (d, 1 H, J ) 6.5 Hz), 4.95
(d, 1 H, J ) 9.5 Hz), 5.09 (d, 1 H, J ) 12.0 Hz), 5.12 (d, 1 H, J )
12.0 Hz), 5.25 (s, 1 H), 7.29-7.76 (m, 5 H); 13C NMR (125 MHz,
CDCl3) δ -5.03, -4.71, 17.92, 25.68, 26.72, 27.79, 28.62, 28.80, 48.10,
55.27, 55.44, 56.24, 56.47, 66.67, 69.14, 69.76, 73.20, 75.83, 78.63,
79.07, 80.08, 97.62, 98.36, 98.48, 98.77, 109.56, 122.14, 128.04, 128.47,
136.57, 137.74, 155.70; MS (EI) calcd for C37H61NO13Si (M+)
755.3912, found (M+ - C4H9) 698 (5.4%), (CI) (M+ - CH3) 740
(0.2%), (M+ - CH3O) 724 (5.0%), (M+ - C4H9) 698 (3.5%).
C14H27NO9 (M+) 353.1686, found (M+ + H) 354 (71.0%).
Methyl 6-O-(tert-Butyldiphenylsilyl)-2,3,4-tri-O-(methoxymethyl)-
r-D-glucopyranoside (27). To a cold solution (0 °C) of triol 2617 (3.96
g, 9.17 mmol) in CH2Cl2 (40 mL) was added diisopropylethylamine
(9.6 mL, 55 mmol) dropwise, followed by the addition of chloromethyl
methyl ether (6.9 mL, 91 mmol). Solid tetrabutylammonium iodide
(6.7 g, 18.3 mmol) was then added to the reaction mixture, and the
solution was allowed to warm to rt. The reaction mixture was stirred
in the dark for 20 h. The reaction mixture was cooled to 0 °C, and 20
mL of saturated aqueous NH4Cl was added. The layers were separated,
and the organic layer was washed with brine. The aqueous layer was
extracted CH2Cl2 (4×), and the combined organic layers were dried
over MgSO4. Filtration and concentration followed by flash chroma-
tography on silica gel (2:1, hexanes/EtOAc) gave 4.62 g (89%) of fully
protected sugar 27 as a clear oil: Rf 0.65 (1:1, hexanes/EtOAc); IR
(neat) 3071, 3048, 2951, 2931, 2893, 1152, 1111, 1032, 703 cm-1
;
[R]20D +43.4° (c 1.45, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.06 (s,
9 H), 3.16 (s, 3 H), 3.41 (s, 3 H), 3.42 (s, 3 H), 3.43 (s, 3 H), 3.52 (dd,
1 H, J ) 10.0, 3.5 Hz), 3.54 (t, 1 H, J ) 9.5 Hz), 3.69 (ddd, 1 H, J )
10.0, 5.5, 2.0 Hz), 3.82 (dd, 1 H, J ) 11.0, 5.5 Hz), 3.91 (m, 2 H),
4.68 (d, 1 H, J ) 6.5 Hz), 4.74 (d, 1 H, J ) 7.0 Hz), 4.80 (d, 1 H, J
) 6.5 Hz), 4.81 (d, 2 H, J ) 7.0 Hz), 4.84 (d, 1 H, J ) 6.5 Hz), 4.85
(d, 1 H, J ) 3.5 Hz), 7.35-7.44 (m, 6 H), 7.71-7.73 (m, 4 H); 13C
NMR (125 MHz, CDCl3) δ 19.28, 26.76, 54.84, 55.50, 56.23, 63.13,
71.17, 76.55, 78.64, 79.14, 97.70, 98.42, 98.67, 127.53, 127.61, 129.57,
133.44, 133.64, 135.65, 135.82.
Methyl 2,3,4-Tri-O-(methoxymethyl)-r-D-glucopyranoside (28).
A cold (0 °C) solution of silyl ether 27 (4.62 g, 8.2 mmol) in THF (41
mL) was treated with 10.6 mL of tetrabutylammonium fluoride (1.0
M in THF, 10.6 mmol). The resultant solution was then warmed to
25 °C, and stirring was continued for 18 h. The reaction mixture was
poured into EtOAc and washed with saturated aqueous NH4Cl and brine.
The aqueous layers were extracted with EtOAc, and the combined
organic layers were dried over MgSO4. Filtration and concentration
followed by flash chromatography on silica gel (1:2, hexanes/EtOAc)
gave 2.29 g (86%) of alcohol 28 as a clear oil: Rf 0.44 (1:4, hexanes/
EtOAc); IR (neat) 3489, 2932, 2896, 1152, 1108, 1037 cm-1; [R]20
D
+105.9° (c 1.18, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.60 (br s, 1
H) (OH), 3.38 (s, 3 H), 3.39 (s, 3 H), 3.40 (s, 3 H), 3.43 (s, 3 H), 3.51
(dd, 1 H, J ) 10.0, 3.5 Hz), 3.56 (t, 1 H, J ) 9.5 Hz), 3.62 (ddd, 1 H,
J ) 10.0, 3.5, 2.0 Hz), 3.77 (dd, 1 H, J ) 12.5, 2.0 Hz), 3.88 (dd, 1
H, J ) 12.5, 3.5 Hz), 3.92 (t, 1 H, J ) 9.5 Hz), 4.69 (d, 1 H, J ) 6.0
Hz), 4.70 (d, 1 H, J ) 6.5 Hz), 4.76 (d, 1 H, J ) 6.5 Hz), 4.77 (d, 1
H, J ) 6.5 Hz), 4.81 (d, 1 H, J ) 3.5 Hz), 4.82 (d, 1 H, J ) 6.0 Hz),
4.91 (d, 1 H, J ) 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ 55.15, 55.46,
56.10, 56.36, 61.59, 70.35, 76.57, 78.19, 79.04, 97.64, 98.19, 98.97,
99.11; HRMS (EI) calcd for C13H26O9 (M+) 326.1576 (M+ - CH3O)
295.1393, found 295.1397.
Disaccharide 31. Olefin 30 (52.3 mg, 0.069 mmol) was subjected
to the conditions of general procedure A to provide, after flash
chromatography on silica gel (20:1, CH2Cl2/CH3OH), 28.0 mg (63%)
of disaccharide 31 as a clear oil: Rf 0.50 (10:1, CH2Cl2:CH3OH); IR
Methyl 2,3,4-Tri-O-(methoxymethyl)-6-methylene-r-D-gluco-
pyranoside (29). To a cold (-78 °C) solution of DMSO (0.52 mL,
7.4 mmol) in CH2Cl2 (15 mL) was added trifluoroacetic anhydride (0.78
mL, 5.54 mmol) in CH2Cl2 (3 mL). The mixture was stirred for 10
min. Alcohol 28 (1.20 g, 3.7 mmol) in CH2Cl2 (4 mL) was added to
the cold reaction mixture slowly Via cannula, and the resultant solution
was stirred for 30 min. Triethylamine (1.44 mL, 10.3 mmol) was added
dropwise at -78 °C. The mixture was allowed to warm to rt after 10
min, and stirring was continued for another 20 min. The mixture was
then partitioned between CH2Cl2 and H2O. The organic layer was
washed with brine. The aqueous layer was extracted with CH2Cl2 (3×),
and the combined organic layers were dried over Na2SO4. After
filtration and removal of the solvent, the resultant oil was taken up in
Et2O and filtered through Celite to remove the remaining triethylamine
hydrochloride. Upon concentration, the corresponding aldehyde was
(neat) 3493, 3310, 2929, 1034 cm-1; [R]20 +46.1° (c 0.94, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 0.05 (s, 3 H), 0.13 (s, 3 H), 0.87 (s, 9
H), 1.34 (s, 3 H), 1.49 (s, 3 H), 1.54 (m, 1 H), 1.64 (m, 1 H), 1.86 (m,
1 H), 2.07 (m, 1 H), 2.19 (br m, 2 H), 2.54 (ddd, 1 H, J ) 10.0, 7.5,
3.5 Hz), 2.88 (td, 1 H, J ) 7.5, 2.5 Hz), 3.27 (t, 1 H, J ) 9.5 Hz), 3.38
(m, 1 H), 3.38 (s, 3H), 3.39 (s, 3 H), 3.40 (s, 3 H), 3.41 (m, 1 H), 3.41
(s, 3 H), 3.49 (dd, 1 H, J ) 9.5, 3.5 Hz), 3.58 (td, 1 H, J ) 9.5, 2.5
Hz), 3.87 (t, 1 H, J ) 9.5 Hz), 3.89 (m, 2 H), 4.07 (dd, 1 H, J ) 5.0,
2.5 Hz), 4.69 (d, 1 H, J ) 6.5 Hz), 4.70 (d, 1 H, J ) 6.5 Hz), 4.75 (d,
1 H, J ) 3.5 Hz), 4.76 (d, 1 H, J ) 7.0 Hz), 4.77 (d, 1 H, J ) 6.5 Hz),
4.82 (d, 1 H, J ) 6.5 Hz), 4.93 (d, 1 H, J ) 7.0 Hz); 13C NMR (125
MHz, CDCl3) δ -5.11, -3.99, 18.07, 25.86, 26.43, 27.59, 28.16, 28.23,
55.17, 55.45, 55.77, 56.24, 56.43, 60.87, 63.23, 69.71, 73.97, 75.89,
78.70, 79.09, 80.02, 81.09, 97.62, 98.38, 98.54, 98.75, 108.84; HRMS
(EI) calcd for C29H57NO12Si (M+) 639.3650 (M+ - CH3O) 608.3466,
found 608.3457.
1
obtained as determined by H NMR. This material was used without
further purification.
Potassium bis(trimethylsilyl)amide (16.25 mL, 0.5 M toluene, 8.12
mmol) was added dropwise at rt to a suspension of methyltri-
phenylphosphonium bromide (3.04 g, 8.5 mmol) in THF (40 mL). The
resultant bright yellow solution was stirred at rt for 1 h. The ylide
solution was then cooled to -78 °C, and a solution of the crude
aldehyde (3.69 mmol) in THF (15 mL) was added slowly by cannula.
After 30 min of stirring at -78 °C, the reaction mixture was allowed
Disaccharide 7. To a solution of protected disaccharide 31 (27.4
mg, 0.043 mmol) in CH3OH (1 mL) was added aqueous 6 N HCl (0.75
mL), and the mixture was stirred at rt for 18 h. The solvents were
then removed in vacuo. The oily residue was taken up in a minimal
amount of CH3OH, and the product was precipitated with Et2O. The

4864 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Johns et al.
white solid was washed with Et2O followed by decantation (2×), and
the residual solvents were removed in vacuo to provide 15.1 mg (90.5%)
of the HCl salt of disaccharide 7 as a white solid: mp 131-135 °C;
[R]20D +67.9° (c 0.61, CH3OH); 13C NMR (125 MHz, CD3OD) δ 25.46,
28.21, 55.95, 59.96, 60.44, 62.55, 67.58, 69.00, 72.02, 73.70, 74.95,
75.14, 75.46, 101.54; FAB MS for C14H27NO9 (M+) 353.1686, found
(M+ + H) 354 (28.9%).
1 H), 3.43 (s, 3 H), 3.82 (d, 1 H, J ) 8.0 Hz), 3.83 (dd, 1 H, J ) 6.5,
4.0 Hz), 4.02 (m, 2 H), 4.20 (m, 3 H), 4.43 (br d, 1 H, J ) 5.0 Hz),
4.46 (d, 1 H, J ) 4.0 Hz), 4.50 (br d, 1 H, J ) 9.0 Hz), 4.92 (t, 1 H,
J ) 10.0 Hz), 5.11 (d, 1 H, J ) 13.0 Hz), 5.14 (d, 1 H, J ) 13.0 Hz),
5.21 (s, 1 H), 7.30-7.39 (m, 11 H), 7.64-7.71 (m, 4 H); 13C NMR
(125 MHz, CDCl3) δ -4.99, -4.73, 17.90, 19.24, 25.09, 25.75, 26.63,
26.91, 27.01, 27.73, 31.41, 34.46, 48.02, 56.20, 62.42, 66.78, 69.71,
73.28, 73.44, 74.42, 75.21, 75.79, 98.22, 109.34, 109.64, 124.46, 127.59,
127.66, 128.07, 128.16, 128.47, 129.57, 129.63, 133.57, 133.64, 135.45,
135.64, 135.72, 136.47, 155.63; MS (EI) calcd for C50H71NO10Si2 (M+)
901.4617 (M+ - C4H9) 844 (4.5%), (CI) (M+ - CH3O) 870 (0.8%),
(M+ - C4H9) 844 (1.9%).
Methyl 6-O-(tert-Butyldiphenylsilyl)-2,3-O-isopropylidene-4-oxo-
r-D-lyxo-hexopyranoside (32). To a suspension of freshly activated
powdered 4 Å molecular sieves (8.5 g) in CH2Cl2 (80 mL) was added
pyridinium chlorochromate (4.10 g, 19.0 mmol). Alcohol 17 (2.0 g,
4.23 mmol) in CH2Cl2 (10 mL) was added by cannula at rt resulting in
a brown suspension. The mixture was stirred for 1.5 h upon which
time TLC indicated the disappearance of starting material. The reaction
mixture was diluted with 140 mL of Et2O/hexanes (2:1) and filtered
through a pad of silica gel. The silica was eluted with 500 mL of
Et2O. Upon concentration of the eluent, 1.85 g (93%) of ketone 32
was obtained as a clear oil: Rf 0.68 (4:1, hexanes/EtOAc); IR (neat)
Disaccharide 35. Olefin 34 (145.6 mg, 0.16 mmol) was subjected
to the conditions of general procedure A to provide, after flash
chromatography on silica gel (4:1 to 2:1, hexanes/EtOAc), 84.9 mg
(67%) of 35 as a clear oil: Rf 0.57 (2:1, hexanes/EtOAc); IR (neat)
3487, 3067, 3043, 2954, 2930, 1112 cm-1; [R]20 +18.3° (c 1.10,
D
1
CHCl3); H NMR (500 MHz, CDCl3) δ 0.05 (s, 3 H), 0.13 (s, 3 H),
2931, 2857, 1743, 1114, 1092 cm-1; [R]20 +56.4° (c 0.83, CHCl3);
0.88 (s, 9 H), 1.06 (s, 9 H), 1.26 (s, 3 H), 1.29 (s, 3 H), 1.31 (s, 3 H),
1.47 (s, 3 H), 1.66 (m, 2 H), 2.44 (ddd, 1 H, J ) 9.5, 8.0, 3.5 Hz), 2.61
(m, 1 H), 2.84 (m, 1 H), 3.31 (m, 2 H), 3.43 (s, 3 H), 3.84-3.92 (m,
5 H), 3.97-4.01 (m, 3 H), 4.31 (dd, 1 H, J ) 7.0, 3.5 Hz), 4.51 (d, 1
H, J ) 4.0 Hz), 7.35-7.42 (m, 6 H), 7.68-7.71 (m, 4 H); 13C NMR
(125 MHz, CDCl3) δ -5.14, -3.97, 18.05, 19.17, 24.95, 25.87, 26.52,
26.84, 27.02, 28.26, 29.38, 32.36, 52.59, 56.13, 60.71, 63.42, 72.83,
74.24, 74.70, 74.95, 76.65, 81.20, 98.48, 108.79, 109.24, 127.67, 129.65,
133.64, 135.65, 135.68; HRMS (EI) calcd for C42H67NO9Si2 (M+)
785.4354 (M+ - CH3) 770.4120, found 770.4106.
D
1H NMR (300 MHz, CDCl3) δ 1.05 (s, 9 H), 1.35 (s, 3 H), 1.39 (s, 3
H), 3.49 (s, 3 H), 3.99 (dd, 1 H, J ) 11.1, 6.9 Hz), 4.05 (dd, 1 H, J )
11.1, 3.9 Hz), 4.30 (dd, 1 H, J ) 6.9, 4.5 Hz), 4.39 (d, 1 H, J ) 6.9
Hz), 4.45 (dd, 1 H, J ) 6.6, 1.2 Hz), 4.94 (s, 1 H), 7.35-7.44 (m, 6
H), 7.67-7.73 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 19.22, 25.43,
26.69, 26.75, 55.71, 63.37, 75.18, 75.89, 78.73, 98.42, 111.51, 127.69,
129.70, 133.11, 133.29, 135.60, 135.70, 202.28; HRMS (EI) calcd for
C26H34O6Si (M+) 470.2125 (M+ - CH3) 455.1890, found 455.1876.
Methyl 6-O-(tert-Butyldiphenylsilyl)-2,3-O-isopropylidene-4-
deoxy-4-methylene-r-D-lyxo-hexopyranoside (33). A solution of
ketone 32 (1.85 g, 3.92 mmol) in toluene (20 mL) was treated with
dimethyltitanocene (0.401 M in toluene, 20.5 mL, 8.23 mmol) and
heated to 70 °C in the dark for 40 h. The resultant solution was cooled
to rt, and pentane was added producing a yellow precipitate. The
mixture was filtered through Celite, and the filtrate was concentrated
in Vacuo. Flash chromatography on silica gel (10:1, hexanes/EtOAc)
gave 1.48 g (81%) of olefin 33 as a yellow oil: Rf 0.55 (8:1, hexanes/
Disaccharide 8. To a solution of protected disaccharide 35 (52.8
mg, 0.067 mmol) in THF (2 mL) was added aqueous 1 N HCl (2 mL),
and the mixture was stirred at rt for 48 h. (Some hydrolysis of the
methyl glycoside was observed when reaction times were extended.
Too short of a reaction time resulted in incomplete hydrolysis of the
tert-butyldiphenylsilyl ether.) The solvents were then removed in
Vacuo. The oily residue was taken up in a minimal amount of CH3-
OH, and the product was precipitated with Et2O. The white solid was
allowed to settle, and the solution was decanted. The solid was washed
with Et2O followed by decantation (2×), and finally the residual
solvents were removed in Vacuo to provide 24 mg (91%) of the HCl
EtOAc); IR (neat) 3071, 3049, 2932, 2857, 1582, 1089 cm-1; [R]20
D
+45.7° (c 0.34, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.10 (s, 9 H),
1.34 (s, 3 H), 1.39 (s, 3 H), 3.42 (s, 3 H), 3.81 (dd, 1 H, J ) 10.2, 5.7
Hz), 4.02 (dd, 1 H, J ) 8.7, 7.2 Hz), 4.10 (d, 1 H, J ) 6.9 Hz), 4.36
(t, 1 H, J ) 6.3 Hz), 4.66 (s, 1 H), 4.69 (d, 1 H, J ) 7.2 Hz), 5.11 (s,
1 H), 5.32 (s, 1 H), 7.36-7.46 (m, 6 H), 7.71-7.76 (m, 4 H); 13C
NMR (75 MHz, CDCl3) δ 19.27, 25.19, 26.69, 26.86, 55.67, 67.74,
72.72, 75.11, 76.10, 99.52, 110.02, 116.67, 127.62, 129.59, 133.67,
133.71, 135.73, 138.75; HRMS (EI) calcd for C27H36O5Si (M+)
468.2332 (M+ - CH3) 453.2097, found 453.2087.
salt of disaccharide 8 as a white solid: mp > 220 °C (dec); [R]20
D
+10.1° (c 0.68, CH3OH); 13C NMR (125 MHz, CD3OD) δ 26.00, 37.50,
55.30, 59.63, 60.48, 62.41, 63.11, 67.84, 70.32, 70.60, 71.98, 72.80,
75.66, 103.97; FAB MS calcd for C14H27NO9 (M+) 353.1686, found
(M+ + H) 354 (51%).
Methyl 6-O-(tert-Butyldiphenylsilyl)-2,3-O-isopropylidene-4-
deoxy-4-[(3-methylphenyl)methyl]-r-D-talopyranoside (36). A solu-
tion of 9-BBN-H (101 mg, 0.83 mmol) in THF (1.7 mL) was added to
olefin 33 (155.4 mg, 0.33 mmol) at rt. The resultant solution was heated
to reflux for 6 h. The reaction mixture was cooled to rt, and 3 M
aqueous K3PO4 (0.31 mL, 0.93 mmol) was added. After 15 min, a
solution of 3-iodotoluene (0.038 mL, 0.30 mmol) and PdCl2(dppf) (12
mg, 0.016 mmol) in DMF (3 mL) was added Via cannula. The dark
mixture was stirred at rt for 18 h. The reaction mixture was poured
into Et2O and washed with H2O and brine. The aqueous layers were
extracted with Et2O (3×), and the combined organic layers were dried
over MgSO4. Filtration and concentration followed by flash chroma-
tography on silica gel (10:1, hexanes/EtOAc) gave 118.1 mg (71%) of
4-arylmethyl sugar 36 as a clear oil: Rf 0.85 (4:1, hexanes/EtOAc); IR
Compound 34. A solution of 9-BBN-H (552 mg, 4.52 mmol) in
THF (10 mL) was added to olefin 33 (847 mg, 1.81 mmol) at rt. The
resultant solution was heated to reflux for 6 h. The reaction mixture
was cooled to rt, and 3 M aqueous K3PO4 (1.7 mL, 5.1 mmol) was
added. After 15 min, a solution of vinyl bromide 11 (756 mg, 1.47
mmol) and PdCl2(dppf) (66 mg, 0.09 mmol) in DMF (18 mL) was
added Via cannula. The dark mixture was stirred at rt for 18 h. The
reaction mixture was poured into Et2O and washed with H2O and brine.
The aqueous layers were extracted with Et2O (3×), and the combined
organic layers were dried over MgSO4. Filtration and concentration
followed by flash chromatography on silica gel (8:1 to 4:1, hexanes/
EtOAc) gave 1.10 g of of olefin 34 contaminated with borane
byproducts. The impure product was dissolved in THF (40 mL) and
cooled to 0 °C. To this solution was added 10% aqueous NaOH (3
mL) followed by 30% aqueous H2O2 (3 mL), and the resultant solution
was stirred at 0 °C for 30 min and another 1 h at rt. The reaction
mixture was again cooled to 0 °C, and saturated aqueous NaHSO3 was
added dropwise (caution: can bubble Vigorously) until bubbling stopped.
The resultant solution was poured into Et2O, and the layers were
separated. The organic layer was washed with brine and dried over
MgSO4. Filtration and concentration followed by flash chromatography
on silica gel (4:1, hexanes/EtOAc) gave 1.00 g (76%) of olefin 34 as
a foam: Rf 0.56 (4:1, hexanes/EtOAc); IR (neat) 3553, 3447, 2930,
1728, 1500, 1212, 1081 cm-1; [R]20D +15.8° (c 1.20, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 0.04 (s, 3 H), 0.08 (s, 3 H), 0.85 (s, 9 H), 1.03
(s, 9 H), 1.15 (s, 3 H), 1.21 (s, 3 H), 1.28 (s, 3 H), 1.35 (s, 3 H), 2.04
(dd, 1 H, J ) 14.0, 8.0 Hz), 2.29 (dd, 1 H, J ) 14.0, 8.5 Hz), 2.58 (m,
(neat) 3072, 3046, 2931, 2857, 1104, 1088, 702 cm-1; [R]20 +43.2°
D
(c 1.14, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.06 (s, 9 H), 1.23 (s,
3 H), 1.33 (s, 3 H), 2.30 (s, 3 H), 2.45 (m, 1 H), 2.54 (dd, 1 H, J )
13.0, 5.5 Hz), 2.60 (dd, 1 H, J ) 13.0, 10.5 Hz), 3.47 (s, 3 H), 3.77
(dd, 1 H, J ) 6.5, 4.0 Hz), 3.87 (m, 1 H), 4.05 (dd, 1 H, J ) 6.5, 3.0
Hz), 4.10 (m, 2 H), 4.53 (d, 1 H, J ) 4.0 Hz), 6.93 (d, 1 H, J ) 7.5
Hz), 6.98 (s, 1 H), 7.01 (d, 1 H, J ) 7.5 Hz), 7.15 (t, 1 H, J ) 7.5 Hz),
7.36-7.43 (m, 6 H), 7.67-7.72 (m, 4 H); 13C NMR (125 MHz, CDCl3)
δ 19.22, 21.37, 25.05, 26.88, 27.25, 33.32, 38.41, 56.32, 62.79, 72.17,
74.88, 75.09, 98.44; 109.22, 126.02, 126.92, 127.68, 128.24, 129.62,
129.80, 133.63, 133.69, 135.63, 135.65, 137.92, 139.39; HRMS (EI)
calcd for C34H44O5Si (M+) 560.2958 (M+ - C4H9) 503.2254, found
503.2265.
2,6-Anhydro-3,4,5,7-tetra-O-(methoxymethyl)-1-deoxy-D-gluco-
hept-1-enitol (38). To a cold solution (0 °C) of δ-gluconolactone (1.00

Biological EValuation of Aza-C-disaccharides
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4865
g, 5.61 mmol) in CH2Cl2 (56 mL) was added diisopropylethylamine
(7.8 mL, 44.7 mmol) dropwise, followed by the addition of chloro-
methyl methyl ether (6.4 mL, 84.1 mmol). Solid tetrabutylammonium
iodide (10.4 g, 28.0 mmol) was then added to the reaction mixture,
and the solution was allowed to warm to rt. The reaction mixture was
stirred in the dark for 48 h. The reaction mixture was cooled to 0 °C,
and 10 mL of saturated aqueous NH4Cl was added. The layers were
separated, and the organic layer was washed with brine. The aqueous
layer was extracted with CH2Cl2 (3×), and the combined organic layers
were dried over MgSO4. Filtration and concentration followed by flash
chromatography on silica gel (1:1, hexanes/EtOAc) gave 1.88 g (95%)
of lactone 37 as a clear oil. A solution of lactone 37 (1.88 g, 5.32
mmol) in toluene (27 mL) was treated with dimethyltitanocene (0.331
M in toluene, 33.7 mL, 11.2 mmol) and heated to 70 °C in the dark
for 24 h. The resultant solution was cooled to rt, and hexane was added
producing a yellow precipitate. The mixture was filtered through Celite,
and the filtrate was concentrated in Vacuo. Flash chromatography on
silica gel (4:1 to 2:1, hexanes/EtOAc) gave 1.48 g (79%) of olefin 38
as a clear oil. A small amount of an unidentified inseparable impurity
was present but did not present any problems with further chemistry.
For 38: Rf 0.50 (1:1, hexanes/EtOAc); IR (neat) 2988, 2938, 2892,
1660, 1151, 1030 cm-1; [R]20D +97.6° (c 1.99, CHCl3); 1H NMR (500
MHz, CDCl3) δ 3.38 (s, 3 H), 3.40 (s, 3 H), 3.41 (s, 3 H), 3.42 (s, 3
H), 3.71 (dd, 1 H, J ) 11.5, 5.5 Hz), 3.74 (dd, 1 H, J ) 9.5, 5.5 Hz),
3.82 (t, 1 H, J ) 5.5 Hz), 3.85 (dd, 1 H, J ) 11.5, 2.0 Hz), 3.94 (ddd,
1 H, J ) 9.5, 5.5, 2.0 Hz), 4.15 (d, 1 H, J ) 5.5 Hz), 4.42 (s, 1 H),
4.66 (d, 1 H, J ) 6.5 Hz), 4.68-4.70 (m, 3 H), 4.71 (d, 1 H, J ) 6.5
Hz), 4.79-4.81 (m, 2 H), 4.82 (d, 1 H, J ) 6.5 Hz), 4.86 (d, 1 H, J )
6.5 Hz); 13C NMR (125 MHz, CDCl3) δ 55.32, 55.88, 56.06, 56.22,
66.75, 74.13, 75.74, 76.47, 79.84, 94.48, 94.62, 96.77, 96.99, 97.26,
154.50; HRMS (EI) calcd for C15H28O9 (M+) 352.1733 (M+ - C3H8O2)
276.1209, found 276.1203.
) 9.5 Hz), 3.30 (m, 1 H), 3.35 (m, 2 H), 3.36 (s, 3 H), 3.40 (s, 3 H),
3.41 (s, 3 H), 3.43 (s, 3 H), 3.45 (t, 1 H, J ) 9.5 Hz), 3.55 (td, 1 H,
J ) 9.5, 2.5 Hz), 3.59 (t, 1 H, J ) 9.0 Hz), 3.64 (dd, 1 H, J ) 11.5,
5.5 Hz), 3.83 (dd, 1 H, J ) 11.5, 2.0 Hz), 3.87 (m, 2 H), 4.02 (dd, 1
H, J ) 5.5, 2.5 Hz), 4.64 (d, 1 H, J ) 6.5 Hz), 4.66 (d, 1 H, J ) 6.5
Hz), 4.67 (d, 1 H, J ) 6.5 Hz), 4.72 (d, 1 H, J ) 6.5 Hz), 4.83 (m, 3
H), 4.89 (d, 1 H, J ) 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ -5.13,
-3.99, 18.06, 25.86, 26.48, 28.24, 33.97, 51.98, 55.36, 56.42, 56.44,
56.52, 60.82, 63.44, 66.76, 74.27, 75.97, 77.27, 77.50, 78.32; 80.30,
81.37, 84.51, 96.73, 98.47, 98.61, 98.74, 108.66; HRMS (EI) calcd
for C30H59NO13Si (M+) 669.3756 (M+ - CH3O) 638.3571, found
638.3558.
Disaccharide 9. To a solution of protected disaccharide 40 (197.3
mg, 0.294 mmol) in CH3OH (5 mL) was added aqueous 6 N HCl (3
mL), and the mixture was stirred at rt for 18 h. The solvents were
then removed in Vacuo. The oily residue was taken up in a minimal
amount of CH3OH, and the product was precipitated with Et2O. The
white solid was allowed to settle, and the solution was decanted. The
solid was washed with Et2O followed by decantation (2×), and finally
the residual solvents were removed in Vacuo to provide 102.5 mg
(92.5%) of the HCl salt of disaccharide 9 as a white solid: mp > 150
°C (dec); [R]20D -9.64° (c 0.17, CH3OH); 13C NMR (125 MHz, CD3-
OD) δ 32.49, 58.09, 59.93, 62.28, 62.90, 67.61, 71.54, 71.67, 74.65,
75.35, 78.58, 79.62, 81.99; FAB MS for C13H25NO9 (M+) 339.1529,
found (M+ + H) 340 (48.2%).
2,6-Anhydro-3,4,5,7-tetra-O-(methoxymethyl)-1-deoxy-1-(3-me-
thylphenyl)-â-D-gluco-heptanol (41). A solution of 9-BBN-H (53 mg,
0.43 mmol) in THF (1 mL) was added to olefin 38 (61.3 mg, 0.17
mmol) at rt. The resultant solution was heated to reflux for 6 h. The
reaction mixture was cooled to rt, and 3 M aqueous K3PO4 (0.17 mL,
0.52 mmol) was added. After 15 min, a solution of 3-iodotoluene
(0.023 mL, 0.18 mmol) and PdCl2(dppf) (11 mg, 0.015 mmol) in DMF
(2 mL) was added Via cannula. The dark mixture was stirred at rt for
18 h. The reaction mixture was poured into Et2O and washed with
H2O and brine. The aqueous layers were extracted with Et2O (3×),
and the combined organic layers were dried over MgSO4. Filtration
and concentration followed by flash chromatography on silica gel (2:1
to 1:1, hexanes/EtOAc) gave 34.5 mg (45%) of C-arylmethyl glycoside
41 as a clear oil: Rf 0.46 (1:1, hexanes/EtOAc); IR (neat) 2980, 2938,
Compound 39. A solution of 9-BBN-H (351 mg, 2.88 mmol) in
THF (6 mL) was added to olefin 38 (405 mg, 1.15 mmol) at rt. The
resultant solution was heated to reflux for 5 h. The reaction mixture
was cooled to rt, and 3 M aqueous K3PO4 (1 mL, 3 mmol) was added.
After 15 min, a solution of vinyl bromide 11 (412 mg, 0.81 mmol)
and PdCl2(dppf) (84 mg, 0.11 mmol) in DMF (10 mL) was added Via
cannula. The dark mixture was stirred at rt for 18 h. The reaction
mixture was poured into Et2O and washed with H2O and brine. The
aqueous layers were extracted three times with Et2O, and the combined
organic layers were dried over MgSO4. Filtration and concentration
followed by flash chromatography on silica gel (2:1 to 1:1, hexanes/
EtOAc) gave 458 mg (73%) of olefin 39 as a clear oil: Rf 0.51 (1:1,
hexanes/EtOAc); IR (neat) 3453, 3447, 3032, 2984, 2951, 2894, 1727,
2893, 2823, 1153, 1107, 1026, 920 cm-1; [R]20 -26.1° (c 1.33,
D
1
CHCl3); H NMR (500 MHz, C6D6) δ 2.17 (s, 3 H), 2.71 (dd, 1 H, J
) 14.0, 9.0 Hz), 3.10 (ddd, 1 H, J ) 10.0, 5.0, 2.0 Hz), 3.13 (s, 3 H),
3.17 (s, 3 H), 3.18 (s, 3 H), 3.22 (s, 3 H), 3.28 (dd, 1 H, J ) 14.0, 2.0
Hz), 3.31 (t, 1 H, J ) 9.0 Hz), 3.38 (td, 1 H, J ) 9.0, 2.0 Hz), 3.53 (t,
1 H, J ) 9.0 Hz), 3.62 (dd, 1 H, J ) 11.5, 5.0 Hz), 3.63 (t, 1 H, J )
9.0 Hz), 3.78 (dd, 1 H, J ) 11.5, 2.0 Hz), 4.53 (d, 1 H, J ) 6.5 Hz),
4.55 (d, 1 H, J ) 6.5 Hz), 4.57 (d, 1 H, J ) 6.0 Hz), 4.59 (d, 1 H, J
) 6.5 Hz), 4.74 (d, 1 H, J ) 6.5 Hz), 4.76 (d, 1 H, J ) 6.0 Hz), 4.80
(d, 1 H, J ) 6.0 Hz), 4.88 (d, 1 H, J ) 6.5 Hz), 6.91 (d, 1 H, J ) 7.5
Hz), 7.13 (m, 1 H), 7.20 (m, 2 H); 13C NMR (125 MHz, C6D6) δ 21.84,
38.83, 55.27, 56.49, 56.62, 67.18, 77.81, 79.25, 80.54, 81.35, 84.95,
97.31, 98.91, 99.15, 99.22, 127.47, 127.55, 131.25, 137.95, 139.99.
1501, 1152, 1103, 1078, 1025 cm-1; [R]20 -40.1° (c 1.45 CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 0.04 (s, 3 H), 0.08 (s, 3 H), 0.84 (s, 9
H), 1.31 (s, 3 H), 1.32 (s, 3 H), 2.26 (dd, 1 H, J ) 15.0, 10.0 Hz), 2.60
(d, 1 H, J ) 15.0 Hz), 3.23 (t, 1 H, J ) 9.0 Hz), 3.28 (m, 1 H), 3.31
(s, 3 H), 3.35 (m, 1 H), 3.40 (s, 3 H), 3.42 (s, 3 H), 3.43 (s, 3 H), 3.45
(t, 1 H, J ) 9.5 Hz), 3.57 (t, 1 H, J ) 9.5 Hz), 3.59 (dd, 1 H, J ) 11.0,
5.0 Hz), 3.76 (dd, 1 H, J ) 11.0, 2.0 Hz), 4.14 (t, 1 H, J ) 5.0 Hz),
4.19 (br m, 1 H), 4.48 (br d, 1 H, J ) 8.5 Hz), 4.61 (s, 2 H), 4.65 (d,
1 H, J ) 5.5 Hz), 4.69 (d, 1 H, J ) 6.5 Hz), 4.70 (d, 1 H, J ) 6.5 Hz),
4.81 (d, 1 H, J ) 6.0 Hz), 4.82 (d, 1 H, J ) 6.5 Hz), 4.84 (d, 1 H, J
) 6.5 Hz), 4.87 (d, 1 H, J ) 6.5 Hz), 5.02 (d, 1 H, J ) 9.5 Hz), 5.10
(s, 2 H), 5.34 (s, 1 H), 7.30-7.36 (m, 5 H); 13C NMR (125 MHz,
CDCl3) δ -5.08, -4.71, 17.90, 25.65, 26.67, 27.72, 35.13, 48.16, 55.08,
56.48, 66.49, 66.59, 69.81, 74.49, 75.80, 77.08, 78.12, 79.39, 80.77,
84.37, 96.57, 98.46, 98.69, 98.73, 109.33, 124.02, 127.98, 128.41,
136.06, 136.59, 155.64; HRMS (EI) calcd for C38H63NO14Si (M+)
785.4018, (M+ - C4H9) 728.3314, found 728.3333.
Acknowledgment. This paper is dedicated to Nelson J.
Leonard on the occasion of his 80th birthday. This work was
supported by a grant from the National Science Foundation
(CHE-9223011). We thank Dr. Adam Golebiowski and Dr.
Michael W. Miller for their valued input into this program. We
acknowledge the generous assistance of Genecor International
in providing the key intermediate (1S,2S)-3-bromo-3,5-cyclo-
hexadiene-1,2-diol and Dr. Gregg Whited of that company for
helpful discussions.
Disaccharide 40. Olefin 39 (317 mg, 0.404 mmol) was subjected
to the conditions of general procedure A to provide, after flash
chromatography on silica gel (20:1, CH2Cl2/CH3OH), 197.3 mg (73%)
of disaccharide 40 as a clear oil: Rf 0.26 (20:1, CH2Cl2/CH3OH); IR
(neat) 3489, 3315, 2930, 2893, 1105, 1026 cm-1; [R]20D -25.0° (c 1.34,
Supporting Information Available: 13C NMR spectra for
6-9, 1H and 13C NMR spectra for 11, 14-16, 18-22, 25, 27-
36, and 38-41 (52 pages). See any current masthead page for
ordering and Internet access instructions.
1
CHCl3); H NMR (500 MHz, CDCl3) δ 0.05 (s, 3 H), 0.12 (s, 3 H),
0.87 (s, 9 H), 1.31 (s, 3 H), 1.46 (s, 3 H), 1.73 (ddd, 1 H, J ) 14.5,
9.5, 2.5 Hz), 2.06 (ddd, 1 H, J ) 14.5, 10.0, 2.5 Hz), 2.49 (ddd, 1 H,
J ) 9.5, 8.0, 3.5 Hz), 3.16 (td, 1 H, J ) 10.0, 2.5 Hz), 3.27 (t, 1 H, J
JA9642929