Synthesis of L-daunosamine and L-ristosamine glycosides via photoinduced aziridination. Conversion to thioglycosides for use in glycosylation reactions

Article abstract of DOI:10.1021/jo061167z

Application of photoinduced acylnitrene aziridination to the syntheses of L-daunosamine and L-ristosamine glycosides is reported. Photoreaction of methyl 4-O-azidocarbonyl-2,3,6-trideoxy-L-hex-2-enopyranosides, followed by aziridine opening, leads to 3-am

Full text of DOI:10.1021/jo061167z

Synthesis of L-Daunosamine and L-Ristosamine Glycosides via
Photoinduced Aziridination. Conversion to Thioglycosides for Use in
Glycosylation Reactions
Matthew T. Mendlik, Peng Tao, Christopher M. Hadad, Robert S. Coleman,* and
Todd L. Lowary*,†
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue, Columbus, Ohio 43210
tlowary@ualberta.ca; coleman@chemistry.ohio-state.edu
ReceiVed June 7, 2006
Application of photoinduced acylnitrene aziridination to the syntheses of L-daunosamine and L-ristosamine
glycosides is reported. Photoreaction of methyl 4-O-azidocarbonyl-2,3,6-trideoxy-L-hex-2-enopyranosides,
followed by aziridine opening, leads to 3-amino-3-N-,4-O-carbonyl-2,3,6-trideoxy precursors to the
aminosugar methyl glycosides. Conversion of these precursors to their thioglycoside analogues followed
by N-acetylation of the carbamate moiety permits high yielding and, in some cases, stereoselective glyco-
sylations using the 1-benzenesulfinylpiperidine-triflic anhydride activation method developed by Crich
and co-workers. Glycosylations involving activation with N-iodosuccinimide and silver triflate were also
successful, but the stereoselectivities of these reactions in general were lower.
CHART 1
Introduction
2,6-Dideoxysugars are widespread in nature as components
of many natural products.1 Among the most prevalent are the
2,3,6-trideoxy-3-amino-hexopyranoses, e.g., L-daunosamine (1,
Chart 1) and L-ristosamine (2). L-Daunosamine and related
analogues are present in the carbohydrate moieties of the
anthracycline family of antitumor antibiotics.2 L-Ristosamine
is part of the carbohydrate appended to the ristomycins, members
of the vancomycin antibiotic family that cause platelet aggrega-
tion and that are used to diagnose variants of von Willebrand
disease.3
Considerable attention has been devoted to the syntheses of
these monosaccharides, utilizing both carbohydrate4,5 and non-
carbohydrate6 starting materials. Of those syntheses that begin
with carbohydrates, many involve stereoselective delivery of
nitrogen to C3 via an imidate ester.5 Another route to these
monosaccharides, recently reported by Renneberg and co-
workers, involves the addition of azide ion to a hex-2-
enopyranoside derivative prepared from L-rhamnose as the key
step.7 Both 1 and 2 were produced by this method, together
with acosamine (3) and 3-epi-daunosamine (4).
In considering stereocontrolled routes to 1 and 2, we thought
to combine elements from earlier syntheses with work8 by
Bergmeier and Stanchina (Figure 1), in which allylic alcohols
were efficiently converted to amino alcohols via a two-step
process involving an intramolecular acylnitrene aziridination
followed by nucleophilic opening of the aziridine ring. We
reasoned that installation of an acyl azide on the appropriate
† Current address: Alberta Ingenuity Centre for Carbohydrate Science and
Department of Chemistry, The University of Alberta, Gunning-Lemieux
Chemistry Centre, Edmonton, AB T6G 2G2, Canada.
(1) Johnson, D. A.; Liu, H.-W. Comp. Nat. Prod. Chem. 1999, 3, 311-
365.
(2) Arcamone, F.; Cassinelli, G. Curr. Med. Chem. 1998, 5, 391-419.
(3) (a) Sweeney, J. D.; Hoernig, L. A.; Fitzpatrick, J. E. Am. J. Hematol.
1989, 32, 190-193. (b) Zhou, L.; Schmaier, A. H. Am. J. Clin. Pathol.
2005, 123, 172-183.
10.1021/jo061167z CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/09/2006
J. Org. Chem. 2006, 71, 8059-8070
8059

Mendlik et al.
L-threo-hex-2-enopyranoside derivative 13 (Scheme 1), which
was prepared in six steps from commercially available
L-rhamnose.5a A modification of the method reported by
Bergmeier and Stanchina8 was used to access acyl azide 5:
reaction of 13 with N,N′-carbonyldiimidazole in pyridine and
benzene, followed by displacement of the resulting acyl imi-
dazole derivative with sodium azide in DMF afforded 5 in 98%
yield. The published workup for similar reactions involves
acidification with HCl in DMF; with our substrates, however,
better yields were obtained when the acidification was carried
out first by the addition of acetic acid in DMF, followed by
HCl. After several unsuccessful attempts to effect aziridination
using heat and pressure,8 we succeeded in converting 5 into 14
through photochemical generation of a presumed acylnitrene
intermediate upon exposure to UV light (254 nm).10 The yield
for this process was high (79%) when the concentration of
starting material was kept below 0.01 M; at higher concentra-
tions, the yield was reduced. For example, when a concentration
of 0.023 M was used, only a 64% yield of the product was
obtained, whereas at a concentration of 0.082 M, the reaction
did not proceed. Compound 14 has been reported11 once previ-
ously in the literature but was synthesized via a route different
than that reported here and data were not provided to support
its structure. In the 1H NMR spectrum of 14, the resonance for
the hydrogen on C-2 appeared at 2.80 ppm and was coupled to
hydrogens at C-1 (5.08 ppm, J ) 0.5 Hz) and C-3 (3.51 ppm,
J ) 4.7 Hz). Using an HMQC NMR experiment, the signals
for the C-2 and C-3 hydrogens could be correlated with carbon
resonances at 43.2 and 41.3 ppm, respectively. The chemical
shift of these carbons is indicative of their attachment to nitrogen
and supports the proposed structure. Further evidence for the
structure of 14 was obtained when, in a subsequent step, a
crystalline compound was obtained (see below).
FIGURE 1. Bergmeier-Stanchina route to amino alcohols from allylic
alcohols.8
hex-2-enopyranoside (e.g., 5, Figure 2), followed by cyclization
to the aziridine and reductive ring opening would yield the
carbamate-protected L-daunosamine derivative 6. Diastereofacial
selectivity would be determined by the absolute configuration
at C-4, thereby making the synthesis stereospecific. Subsequent
carbamate deprotection would afford the L-daunosamine methyl
glycoside 7. Alternatively, conversion of 6 into the correspond-
ing thioglycoside 8 would allow the efficient preparation of other
glycosides containing this aminosugar. A similar series of trans-
formations starting from hex-2-enopyranoside 9 would afford,
via 10, either the L-ristosamine methyl glycoside 11 or thioglyco-
side 12. We report the successful execution of these synthetic
routes to daunosamine and ristosamine and the use of the corre-
sponding thioglycosides in glycosylation reactions. The utility
of glycosyl donors containing fused cyclic carbonate or oxazo-
lidinone rings has been previously studied by a number of other
groups;9 however, these investigations have not employed
species that would lead directly to 2-deoxy sugar glycosides.
We were pleased to find that the aziridine ring in 14 could
then be opened regioselectively and in excellent yield (95%)
by hydrogenation over palladium on carbon to give the 3,4-
carbamate-protected methyl glycoside of daunosamine (6). The
regioselectivity of the opening could be readily established from
a 1H-1H COSY experiment, which showed correlations between
the protons on C1 (δ ) 4.84 ppm) and C2 (δ ) 1.75 and 2.08
ppm). In one large-scale reaction, we observed the formation
of trace amounts of the isomeric 2,4-carbamate derivative,
resulting from hydrogenation of the C3-N bond. Compound 6
was crystalline, and its structure was further confirmed by X-ray
crystallographic analysis.12 Perhaps not surprisingly, the carba-
mate ring induces significant conformational bias to the pyrano-
side ring, forcing it into a twist-boat (2SO) conformation, which
places both the methyl group at C-5 and the anomeric methoxy
group in pseudoequatorial orientations. Deprotection of the
Results and Discussion
Syntheses of Methyl Glycosides 7 and 11. The preparation
of L-daunosamine methyl glycoside 7 started from the known
(4) Selected methods: (a) Gurjar, M. K.; Pawar, S. M.; Mainkar, P. S.
J. Carbohydr. Chem. 1989, 8, 785-791. (b) Monneret, C.; Gagnet, R.;
Florent, J.-C. J. Carbohydr. Chem. 1987, 6, 221-229. (c) Grethe, G.; Mitt,
T.; Williams, T. H.; Uskokovic. M. R. J. Org. Chem. 1983, 48, 5309-
5315. (d) Boivin, J.; Pais, M.; Monneret, C. Carbohydr. Res. 1978, 64,
271-278. (e) Cheung, T.-M.; Horton, D.; Sorenson, R. J.; Weckerle, W.
Carbohydr. Res. 1978, 63, 77-89.
(5) (a) Szechner, B.; Achmatowicz, O; Badowska-Roslonek, K. Pol. J.
Chem. 1999, 73, 1133-1141. (b) Pauls, H. W.; Fraser-Reid, B. Carbohydr.
Res. 1986, 150, 111-119. (c) Cardillo, G.; Orena, M.; Sandri, S.; Tomasini,
C. J. Org. Chem. 1984, 49, 3951-3953.
(6) Selected methods: (a) Hayman, C. M.; Larsen, D. S.; Simpson, J.;
Bailey, K. B.; Gill, G. S. Org. Biomol. Chem. 2006, 4, 2794-2800. (b)
Ginesta, X.; Pasto´, M.; Perica`s, M. A.; Riera, A. Org. Lett. 2003, 5, 3001-
3004. (c) Davies, S. G.; Smyth, G. D.; Chippindale. A. M. J. Chem. Soc.,
Perkin Trans. 1 1999, 3089-3104. (d) Sibi, M. P.; Lu, J.; Edwards, J. J.
Org. Chem. 1997, 62, 5864-5872. (e) Banfi, L.; Cardani, S.; Potenza, D.;
Scolastico, C. Tetrahedron 1987, 43, 2317-2322. (f) Po, S.-Y.; Uang, B.-
J. Tetrahedron: Asymmetry 1994, 5, 1869-1872. (g) Jurczak, J.; Kocak.
J.; Golebiowski, A. Tetrahedron 1992, 48, 4231-4238. (h) Sammes, P. G.;
Thetford, D. J. Chem. Soc., Perkin Trans. 1 1988, 111-123. (i) Tietze,
L. F.; Voss, E. Tetrahedron Lett. 1986, 27, 6181-6184. (j) Warm, A.; Vogel,
P. J. Org. Chem. 1986, 51, 5348-5353. (k) Wovkulich, P. M.; Uskokovi.
M. R. Tetrahedron 1985, 41, 3455-3462. (l) Heathcock, C. H.; Montgom-
ery, S. H. Tetrahedron Lett. 1983, 24, 4637-4640. (m) Grethe, G.; Sereno,
J.; Williams, T. H.; Uskokovic. M. R. J. Org. Chem. 1983, 48, 5315-
5317.
(9) (a) Benakli, K.; Zha, C.; Kerns, R. J. J. Am. Chem. Soc. 2001, 123,
9461-9462. (b) Crich, D.; Vinod, A. U.; Picione, J. J. Org. Chem. 2003,
68, 8453-8458. (c) Kerns, R. J.; Zha, C.; Benakli, K.; Liang, Y.-Z.
Tetrahedron Lett. 2003, 44, 8069-8072. (d) Crich, D.; Jayalath. P. J. Org.
Chem. 2005, 70, 7252-7259. (e) Wei, P.; Kerns, R. J. J. Org. Chem. 2005,
70, 4195-4198. (f) Boysen, M.; Gemma, E.; Lahmann, M.; Oscarson, S.
Chem. Commun. 2005, 24, 3044-3046. (g) Tanaka, H.; Nishiura, Y.;
Takahashi, T. J. Am. Chem. Soc. 2006, 128, 7124-7125. (h) Manabe, S.;
Ishii, K.; Ito, Y. J. Am. Chem. Soc. 2006, 128, 10666-10667.
(10) Lwowski, W. Acyl azides and nitrenes. In Azides and Nitrenes:
ReactiVity and Utility; Scriven, E. F. V., Ed.; Academic Press: Orlando,
FL, 1984; pp 205-246.
(7) Renneberg, B.; Li, Y.-M.; Laatsch, H.; Fiebig, H.-H. Carbohydr. Res.
2000, 329, 861-872.
(8) (a) Bergmeier, S. C.; Stanchina, D. J. Org. Chem. 1999, 64, 2852-
2859. (b) Bergmeier, S. C.; Stanchina, D. J. Org. Chem. 1997, 62, 4449-
4456.
(11) Baer, H. H.; Mateo, F. H.; Siemsen, L. Carbohydr. Res. 1990, 195,
225-245.
(12) Mendlik, M. T.; Coleman, R. S.; Qi, G.; Lowary, T. L.; McDonald,
R. Acta Crystallogr., Sect. E 2006, 62, o2490-o2492.
8060 J. Org. Chem., Vol. 71, No. 21, 2006

Synthesis of L-Daunosamine and L-Ristosamine
FIGURE 2. Proposed routes to methyl glycoside and thioglycoside derivatives of L-daunosamine (7 and 8) or L-ristosamine (11 and 12).
a
SCHEME 1
envelope conformation in which C5 is below the plane of the
other five ring atoms (E5). Subsequent hydrogenolysis of 17
afforded 10 (92%), which was deprotected with barium hy-
droxide to provide 116g (95%). The same two reactions were
used to convert 18, via 19, to the corresponding â-glycoside,
20,6g in 72% overall yield.
Synthesis of Thioglycoside Donors. In the interest of using
this methodology as part of a larger project on the synthesis of
3-amino-2,3,6-trideoxysugar glycosides, it was necessary to
convert the carbamate-protected methyl glycosides shown in
Schemes 1 and 2 into potential glycosyl donors. For this purpose,
we synthesized the corresponding thioglycosides (Scheme 3)
of 6 and 10. For 6, this conversion could be readily achieved
upon treatment with p-thiocresol and boron trifluoride etherate,
which provided the thioglycoside 21 in excellent (99%) yield.
This reaction was highly R-selective, with less than 5% of
the â-anomer being isolated. Single-crystal X-ray analysis of
21 showed that, like its methyl glycoside counterpart 6, the
pyranoside ring adopts a 2SO twist-boat conformation, with the
R-thiocresyl moiety being oriented in a pseudoequatorial orien-
tation.18 Acetylation of the carbamate nitrogen under standard
conditions gave the expected product 22, also in high yield;
this step facilitated purification of the carbamate-protected sugars
and was later found to be necessary for certain glycosylation
protocols. An analogous series of reactions was used to convert
a mixture of 10 and 19 into thioglycosides 24 and 25 (82%
yield over two steps via 23) as a 1.8:1 R:â mixture of anomers.
A mixture of 10 and 19 was used in this sequence of reactions
as treatment of either of these (pure) compounds with p-
thiocresol and BF3‚Et2O led to the same ratio of thioglycosides
23 (data not shown). In addition, although the anomers of 23
were separated for the purposes of characterization, in large-
scale preparations they were carried through to the acetylation
step as a mixture. Thioglycosides 24 and 25 were used as a
mixture in the glycosylation reactions because their separation
by chromatography was difficult and the stereoselectivity of the
glycosylations was shown not to depend on the stereochemistry
at the anomeric center in the donor (see below). However, via
careful chromatography, it was possible to obtain these com-
pounds pure, and NOE studies were used to establish the stereo-
chemistry of the major and minor isomers in the mixture. The
major isomer (24) showed no NOE between the hydrogens on
a Reagents and conditions: (a) N,N′-Carbonyldiimidazole, pyridine,
benzene, rt, 2 h; (b) NaN3, HOAc, HCl, DMF, rt, 98%; (c) 254 nm light,
CH2Cl2, rt, 1 h, 79%; (d) Pd/C, H2, EtOH/EtOAc 5:1, rt, 3 h, 95%; (e)
Ba(OH)2‚8H2O (70 equiv), H2O, 125 °C, 1 h, then CO2(s), rt, 100%.
carbamate was achieved by reaction with barium hydroxide in
water,13 affording in quantitative yield the deprotected methyl
glycoside 7, which had NMR spectral data identical to that
reported previously.6g,14
The synthesis of 11 was achieved via an analogous series of
reactions that started with L-erythro-hex-2-enopyranoside deriv-
ative 15 (Scheme 2).15 Like its counterpart 13, alkene 15 was
prepared from L-rhamnose. A 2:1 R:â mixture was obtained,
which could not be easily separated, nor could the mixture of
acyl azides that were prepared in 67% yield upon treatment of
15 with N,N′-carbonyldiimidazole and then sodium azide.
However, upon irradiation (254 nm) of 16 in dichloromethane,
the resulting mixture of 17 and 18, produced together in 91%
yield, was separable by chromatography. Both 17 and 18 were
crystalline, and analysis by X-ray crystallography established
their structures.16,17 Despite the tricyclic system, the pyranoside
ring in 18 appears to be relatively unstrained and adopts an
(13) Horton, D.; Weckerle, W. Carbohydr. Res. 1975, 44, 227-240.
(14) Barthwal, R.; Mujeeb, A.; Srivastava, N.; Sharma, U. Chem. Biol.
Interact. 1996, 100, 125-139.
(15) Brimacombe, J. S.; Doner, L. W.; Rollins, A. J. J. Chem. Soc., Perkin
Trans. 1 1972, 2977-2979.
(16) Mendlik, M. T.; Coleman, R. S.; Qi, G.; Lowary, T. L.; McDonald,
R. Acta Crystallogr., Sect. E 2006, 62, o2573-o2575.
(17) Mendlik, M. T.; Coleman, R. S.; Qi, G.; Lowary, T. L.; Ferguson,
M. J. Acta Crystallogr., Sect. E 2006, 62, o2576-o2577.
(18) Mendlik, M. T.; Coleman, R. S.; Qi, G.; Lowary, T. L.; Ferguson,
M. J. Acta Crystallogr., Sect. E 2006, 62, o2788-o2790.
J. Org. Chem, Vol. 71, No. 21, 2006 8061

Mendlik et al.
a
SCHEME 2
a Reagents and conditions: (a) N,N′-Carbonyldiimidazole, pyridine, benzene, rt, 2 h; (b) NaN3, HOAc, HCl, DMF, rt, 67%; (c) 254 nm light, CH2Cl2, rt,
1 h, 92%; (d) Pd/C, H2, EtOH/EtOAc 5:1, rt, 3 h, 95%; (e) Ba(OH)2‚8H2O (70 equiv), H2O, 125 °C, 1 h, then CO2(s), rt, 100%; (f) Pd/C, H2, EtOH/EtOAc
5:1, rt, 3 h, 83%; (g) Ba(OH)2‚8H2O (70 equiv), H2O, 125 °C, 1 h, then CO2(s), rt, 87%.
a
a
SCHEME 3
SCHEME 4
a Reagents and conditions: (a) p-thiocresol, BF3‚OEt2, CH2Cl2, rt, 2 h,
99%; (b) Ac2O, DMAP, pyridine, rt, 2 h, 99%; (c) p-thiocresol, BF3‚OEt2,
CH2Cl2, rt, 2 h, 85%, 1.8:1 R:â; (d) Ac2O, DMAP, pyridine, rt, 2 h, 96%.
a Reagents and conditions: (a) Ba(OH)2‚8H2O, H2O, 125 °C, 1 h, then
CO2(s), rt, 85% (for 26); 86% (for 27); 87% (for 28); 87% (for 29).
FIGURE 3. NOEs in thioglycosides 24 and 25 that were used to
establish anomeric stereochemistry. Experiments were carried out by
irradiation of the anomeric hydrogen.
trivial to unambiguously assign the anomeric stereochemistry
in these glycosides as obtained from coupling of the thioglyco-
sides with different alcohols. Although we could rely on NOE
measurements (e.g., Figure 3), we sought a more direct method.
To this end, both 22 and 25 were converted to the corresponding
R/â mixture of cyclohexyl glycosides as described below. For
both ring systems, the anomers could be separated, and all four
compounds (26-29, Scheme 4) were fully characterized before
being individually deprotected to aminosugars 30-33. The
pyranoside rings of 30-33 adopt the canonical chair conformer;
C1 and C5, whereas in the minor isomer (25) a 4.2% NOE was
observed between these two hydrogens (Figure 3).
Determination of Glycoside Stereochemistry in Carbamate-
Protected Glycosides. It was clear from the crystal structures
of 6 and 21 that the presence of the carbamate protecting group
in these species substantially alters the conformation of the
pyranoside ring. We therefore expected that it would be non-
8062 J. Org. Chem., Vol. 71, No. 21, 2006

Synthesis of L-Daunosamine and L-Ristosamine
FIGURE 4. Multiplicity of anomeric hydrogen resonances in 26-29.
determination of the C1 stereochemistry using NMR spectros-
copy was consequently straightforward. Thus, the resonance for
the anomeric hydrogen of 30 and 32 appeared as an apparent
triplet with J ) 3.7 and 2.5 Hz, respectively, as expected given
the axial orientation of the aglycone. For 31 and 33, in which
the cyclohexyloxy group is equatorial, the multiplicity of
anomeric hydrogen resonance is a doublet of doublets with J )
2.2 and 9.6 (31) or 2.5 and 8.4 Hz (33), in line with predictions
made from the Karplus relationship.19 After unambiguously
determining the structures of 30-33, it was possible to assign
C1 stereochemistry in the precursors 26-29 from the multiplic-
ity of the anomeric hydrogen resonance. As depicted in Fig-
ure 4, for the isomers in which the carbamate and aglycone are
trans, the C1-H resonance appears as an apparent triplet with
J ) 4.9 Hz (26) or 3.0 Hz (29). For the other two isomers, 27
and 28 (cis carbamate and aglycone), the anomeric hydrogen
resonance appears as a doublet of doublets (J ) 2.7 and 5.5 Hz
for 27; 5.9 and 8.0 Hz for 28). Therefore, inspection of the
multiplicity of the anomeric hydrogen resonance in the 1H NMR
spectra of these carbamate-protected aminosugars enabled rapid
determination of the anomeric configuration. Further support
for this trend was achieved by N-acylation of the previously
prepared methyl glycosides 6, 10, and 19 (see Figure S1 in
Supporting Information). In addition, we investigated the use
of NOE measurements between the hydrogens on C1 and C5
for differentiating the glycoside anomers in 26-29. As illus-
trated in Figure S2 of Supporting Information, the NOE between
these hydrogens was substantially different in 26 and 27 (0.2
vs 1.7), but for 28 and 29, the difference was significantly less
(0.3 vs 0.7).
product ratios as those involving the mixture of 24 and 25.) In
all cases, the isomeric glycosides could be separated, and the
NMR parameters discussed above were used to prove anomeric
stereochemistry. Given these modest results, we chose to aban-
don the use of this activation method.
As an alternate promoter system for these glycosylations, we
examined the 1-benzenesulfinyl piperidine/triflic anhydride
(BSP/Tf2O) system recently developed by Crich and co-
workers.21 This method has been demonstrated to afford high
glycosylation yields and excellent stereoselectivity through the
formation of glycosyl triflate intermediates. We envisioned that
glycosylations with these thioglycosides might lead to a single
glycosyl triflate intermediate that, in turn, would react in a
stereospecific manner (via an “exploded” SN2-transition state22)
affording glycosides with high stereoselectivity.
To probe the feasibility of this hypothesis, we carried out
density functional theory calculations of the four possible triflate
intermediates (39-42, Chart 2) that would be produced from
the N-acylated thioglycosides 22 and 24/25. Each of the four
structures was initially optimized at the B3LYP/6-31G* level
of theory23 in the gas phase, and then single-point energies were
calculated at the B3LYP/6-311+G(3df,3pd) level of theory.
These triflate intermediates, if formed in the course of these
reactions, would be present in a relatively nonpolar reaction
medium (CH2Cl2), and therefore the energy differences between
a given pair of glycosyl triflates in the gas phase should be
representative of their relative energies in the reaction solvent.
Following zero-point vibrational energy (ZPE), thermal and
entropic corrections at 298 K, ∆G298, and ∆H298 values for each
isomer were determined as shown in Table 2. As can be seen
from the values for each pair of diastereomers, the isomer in
which the triflate moiety is trans to the oxazolidinone ring is
the most stable, although for the ristosamine precursors, the
energy difference between the two species is relatively small.
If the intermediate triflates are the species that react with
glycosyl acceptor alcohols, it would be anticipated that applica-
tion of the BSP/Tf2O approach to thioglycoside 22 would lead
Glycosylations with Thioglycosides. With a method in place
for differentiating anomeric stereochemistry, we explored the
potential of these thioglycosides as glycosylating agents by first
treating thioglycoside 21, 22 or 24/25 with various alcohols and
N-iodosuccinimide (NIS) and silver triflate20 in dichloromethane
(Table 1). Although the yields of these reactions were good to
excellent, the stereoselectivities were highly variable, ranging
from excellent with propargyl alcohol to poor with n-octanol.
(Glycosylation reactions with pure 24 or 25 afforded the same
(21) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015-9020.
(22) Crich, D.; Chandrasekera, N. S. Angew. Chem. Int. Ed. 2004, 43,
5386-5389.
(23) (a) Becke, A. D. Phys. ReV. A 1988, 38, 3098-3100. (b) Becke, A.
D. J. Chem. Phys. 1993, 98, 5648-5652. (c) Lee, C.; Yang, W.; Parr, R.
G. Phys. ReV. B 1988, 37, 785-789.
(19) Tvaroska. I.; Taravel, F. R. AdV. Carbohydr. Chem. Biochem. 1995,
51, 15-61.
(20) Konradsson, P.; Udodong, E. U.; Fraser-Reid, B. Tetrahedron Lett.
1990, 31, 4313-4316.
J. Org. Chem, Vol. 71, No. 21, 2006 8063

Mendlik et al.
TABLE 1. Glycosidation of 21, 22, and 24/25 Using NIS/AgOTf
Activationa
CHART 2
TABLE 2. Relative Gas-Phase Energies (kcal/mol) of Triflates
39-42a
compound
daunosamine glycoside
precursors
ristosamine glycoside
precursors
39
40
41
42
b
c
∆EBW
∆H298
∆G298
0
0
0
3.1
3.1
3.1
0.3
0.4
1.3
0
0
0
d
a Lowest energy species of a given triflate pair set to 0 kcal/mol.
b Relative bottom-of the well energies (kcal/mol) without ZPE, thermal, or
entropic corrections. c Relative enthalpies (kcal/mol) with (scaled) ZPE and
thermal corrections at 298 K. d Relative Gibbs free energies (kcal/mol) at
298 K.
1
were detected in H NMR spectrum of the crude product, and
none could be isolated. In all cases the mixture of glycosides
could be separated by chromatography.
When the same protocol was applied to glycosylations using
thioglycosides 24/25, only low yields of the desired glycosides
were obtained, and the reaction was accompanied by decom-
position of the donor. This problem was overcome by a slight
procedural modification in which the CH2Cl2 solution of the
acceptor was added immediately following the addition of the
Tf2O. Under these conditions, the same panel of acceptors was
glycosylated in good to excellent yields (Table 4).24 In compar-
ing the glycosylations with donors possessing the daunosamine
and ristosamine stereochemistry, 22 and 24/25, respectively,
there was an inverse relationship between yield and stereo-
selectivity. The daunosamine donor 22 generally gave lower
product yields but higher stereoselectivity, whereas 24/25, which
possess the ristosamine stereochemistry, gave lower selectivities
but higher yields. In a separate series of experiments (data not
shown), it was demonstrated that the stereochemistry at the
anomeric center of the donor had no effect on reaction stereo-
selectivity and yield, i.e., 24 and 25 gave identical results.
In rationalizing the stereoselectivities of the glycosylations
with the BSP/Tf2O activation method, it is interesting to note
that the major product formed from both donors is the
R-glycoside. This result suggests that the species that undergoes
reaction with the alcohols is not a glycosyl triflate intermediate
but rather an oxacarbenium ion. In such a regime (Figure 5)
where an oxacarbenium ion (e.g., 51) is in equilibrium with
a Thioglycoside 21 (0.33 mmol) and the alcohol (0.98 mmol) were
dissolved in CH2Cl2 (10 mL). Molecular sieves (4 Å, 250 mg) were added,
and the solution was cooled to 0 °C before NIS (0.36 mmol) and AgOTf
(0.07 mmol) were added. The reaction was allowed to warm to room
temperature over 1 h and then quenched by the addition of a saturated
aqueous solution of NaHCO3. b Isolated yield. c Ratio of anomers determined
1
by H NMR spectroscopy, by integration of resonances for the anomeric
hydrogens.
ultimately to â-glycosides of daunosamine, whereas donors 24/
25 would give R-ristosamine glycosides.
Our initial attempts to use the BSP/Tf2O activation method
with thioglycosides 21 and 23 led to extensive decomposition
of the donor. Fortunately, clean reactions were observed for
the N-acetylated derivatives 22 and 24/25. Using the reported
protocol,21 thioglycoside 22 was treated with BSP, tri-tert-
butylpyrimidine and molecular sieves in dichloromethane at
-60 °C, followed by addition of the Tf2O and a solution of the
glycosyl acceptor in dichloromethane. A range of alcohols was
cleanly glycosylated by 22 under these conditions (Table 3).
The yields of these reactions were generally lower than those
promoted by NIS/AgOTf, but the stereoselectivities were higher
in all cases, and with the R-glycoside being the favored product.
In the case of adamantol, only trace amounts of the â-glycoside
(24) Application of this modified procedure to the daunosamine series
(thioglycoside 22) did not lead to results significantly different from those
obtained previously.
8064 J. Org. Chem., Vol. 71, No. 21, 2006

Synthesis of L-Daunosamine and L-Ristosamine
TABLE 3. Glycosylations with 22 Using BSP/Tf2O Activationa
TABLE 4. Glycosylations with 24/25 Using BSP/Tf2O Activationa
a Thioglycoside 24/25 (0.33 mmol), 4 Å molecular sieves (250 mg), BSP
(0.33 mmol), and TTBP (0.33 mmol) were suspended in CH2Cl2 (5 mL)
and cooled to -60 °C before Tf2O (0.36 mmol) was added, followed
immediately by a solution of the acceptor (0.49 mmol) in CH2Cl2 (2 mL).
After 5 min, the mixture was warmed to room temperature and stirred until
complete by TLC. b Isolated yield. c Ratio of anomers determined by weight
after separation by chromatography, except for 48 and 49, which were
inseparable. In these cases, the ratios were obtained by 1H NMR spectros-
copy through integration of resonances for the anomeric hydrogens of the
aminosugar moiety.
a Thioglycoside 22 (0.33 mmol), 4 Å molecular sieves (250 mg), BSP
(0.33 mmol), and TTBP (0.66 mmol) were suspended in CH2Cl2 (5 mL)
and cooled to -60 °C before Tf2O (0.36 mmol) was added. After 2 min
of stirring, a solution of the acceptor (0.49 mmol) in CH2Cl2 (2 mL) was
added. After 5 min, the mixture was warmed to room temperature and stirred
until complete by TLC. b Isolated yield. c Ratio of anomers determined by
weight after separation by chromatography. d The â-anomer of 44 constituted
less than 5% of the reaction yield (from NMR spectrum of the crude reaction
mixture) and could not be isolated.
rationalized. In the case of 22, formation of the R-glycoside
would be favored as this product would result from attack of
the alcohol on the least hindered side of the molecule, anti to
the carbamate moiety. Furthermore, the R-glycoside would be
the product favored by the kinetic anomeric effect;25 in the X-ray
crystal structure of 6, the glycosidic bond is oriented anti-
periplanar to the position occupied by one of the lone pairs on
the pyran oxygen. The erosion of stereocontrol in the ristosamine
system is presumably due to steric effects of the carbamate ring.
In an analogous oxacarbenium ion formed from 24/25, formation
of the R-glycoside would be disfavored as it would result from
the corresponding glycosyl triflate intermediates (e.g., 39 and
40), it would be expected that the flattening of the pyranose
ring induced by the carbamate moiety would reduce the barrier
to formation of the charge-separated species from the covalent
triflate. This, in turn, would be expected to lead to a higher
concentration of the more reactive oxacarbenium ion in the
reaction mixture. If one assumes that the glycosidic bond is
formed in these reactions via the attack of an alcohol on a spe-
cies such as 51, the stereoselectivity of the reaction can be easily
(25) Juaristi, E.; Cuevas, G. The Kinetic Anomeric Effect. The Anomeric
Effect; CRC Press: Boca Raton, 1995; pp 183-194.
J. Org. Chem, Vol. 71, No. 21, 2006 8065

Mendlik et al.
FIGURE 5. Equilibrium between the oxacarbenium ion (51) and glycosyl triflate intermediates (39 and 40) produced from treatment of thioglycoside
22 with BSP and Tf2O. The flattening of the pyranose ring induced by the carbamate moiety would be expected to reduce the torsional barrier
leading to 51.
NaCl. The organic layer was dried (MgSO4) and concentrated. The
glycoside products were purified by column chromatography.
attack of the alcohol syn to the carbamate. That there is still a
preponderance of the R-glycoside suggests that there is also a
stereoelectronic bias leading to R-glycoside formation or some
participation of direct displacement of the triflate leaving group.
We note that increased R-selectivity in glycosyl donors pos-
sessing fused rings that in turn flatten the pyranose ring have
previously been reported by Crich and co-workers for 2,3-
carbonate protected systems with the D-manno and L-rhamno
stereochemistry.9b,26
In summary, we report here a new and stereospecific synthesis
of methyl glycoside derivatives of the 2,3,6-trideoxy-3-amino-
hexopyranoses with the L-xylo (daunosamine, 7) and L-lyxo
(ristosamine, 11 and 20) stereochemistry. The key steps in the
synthesis are a photochemically induced acylnitrene aziridination
reaction followed by a regioselecitve hydrogenolytic cleavage
of the aziridine. Appropriately protected thioglycoside deriva-
tives of these sugars have also been synthesized, and their utility
as glycosylating agents was studied using two promoter systems
(NIS/AgOTf and BSP/Tf2O). Of the two, the BSP/Tf2O method
provides glycosides with the best stereoselectivity, although
stereocontrol is not high in all cases. For the promoter systems
reported, it appears that these thioglycosides are of modest utility
in the stereocontrolled synthesis of ristosamine and duanosamine
glycosides.
Method C, BSP/Tf2O Glycosylation Reactions with Ristos-
amine Derivatives. Thioglycoside (0.327 mmol), BSP (0.327
mmol), and TTBP (0.653 mmol) were stirred in dichloromethane
(5 mL) with activated 4 Å molecular sieves for 30 min. The mixture
was cooled in a dry ice/acetone bath at -60 °C, and triflic anhydride
(0.359 mmol) was added, followed immediately by a solution of
the glycosyl acceptor (0.490 mmol) in dichloromethane (2 mL).
After 5 min the mixture was warmed to room temperature and was
diluted with dichloromethane (10 mL). The reaction mixture was
filtered and washed with saturated NaHCO3, 1 N HCl, and saturated
aqueous NaCl. The organic layer was dried (MgSO4) and concen-
trated. The glycosides were purified by column chromatography.
Methyl 4-O-Azidocarbonyl-2,3,6-trideoxy-R-L-threo-hex-2-
enopyranoside (5). Alcohol 135a (820 mg, 5.75 mmol), 1,1′-
carbonyldiimidazole (1.40 g, 8.64 mmol), and pyridine (1.40 mL,
17.3 mmol) were dissolved in benzene (20 mL) and stirred for 2 h
at room temperature. The reaction mixture was diluted with ethyl
acetate (20 mL) and washed with saturated aqueous NaCl (50 mL).
The organic layer was dried (MgSO4) and concentrated. The residue
was dissolved in DMF (20 mL), and sodium azide (1.87 g, 28.8
mmol) was suspended in the reaction mixture. This mixture was
acidified with glacial HOAc (10 mL) until conversion to the acyl
azide no longer proceeded, at which point concentrated HCl (5 mL)
was added to effect completion. The reaction mixture was poured
onto a saturated aqueous solution of NaHCO3, and the layers were
separated. The organic layer was washed with NaHCO3 solution,
dried (MgSO4), and concentrated. The crystalline solid obtained
(5, 1.21 g, 98%) was used without further purification: Rf 0.70
(1:1 hexane/ethyl acetate); [R]23D -265.0 (c 1.9, CHCl3); mp 70-
Experimental Section
General Procedures for Glycosylations. Method A, NIS/
AgOTf. Thioglycoside (0.327 mmol) and the glycosyl acceptor
(0.980 mmol) were stirred in dichloromethane (10 mL) with
activated 4 Å molecular sieves for 30 min. The reaction mixture
was cooled in an ice bath at 0 °C, and NIS (0.359 mmol) and AgOTf
(0.065 mmol) were added. The reaction mixture was stirred 1 h
and was diluted with dichloromethane (10 mL). The reaction
mixture was filtered, washed with saturated NaHCO3 and saturated
aqueous Na2S2O3. The organic layer was dried (MgSO4) and
concentrated. The glycoside products were purified by column
chromatography.
1
73 °C; IR 2988, 2194, 2154, 1724, 1266, 1241, 1108 cm-1; H
NMR (400 MHz, CDCl3) δ 6.12 (dd, 1 H, J ) 5.0, 10.0 Hz, C3-
H), 6.07 (dd, 1 H, J ) 2.7, 10.0 Hz, C2-H), 4.91 (d, 1 H, J ) 2.7
Hz, C1-H), 4.84 (dd, 1 H, J ) 2.4, 5.0 Hz, C4-H), 4.24 (dq, 1 H,
J ) 2.4, 6.6 Hz, C5-H), 3.43 (s, 3 H, OCH3), 1.28 (d, 3 H, J ) 6.6
Hz, C6-H); 13C NMR (100 MHz, CDCl3) δ 157.5 (CdO), 131.6,
124.5 (C-2, C-3), 95.4 (C-1), 69.4 (C-4), 64.3 (C-5), 55.7 (OCH3),
15.9 (C-6); HRMS (ESI) m/z calcd for C8H11N3O4 + Na 236.0647,
found 236.0647.
Method B, BSP/Tf2O Glycosylation Reactions with Daunos-
amine Derivatives. Thioglycoside (0.327 mmol), BSP (0.327
mmol) and TTBP (0.653 mmol) were stirred in dichloromethane
(5 mL) with activated 4 Å molecular sieves for 30 min. The reaction
mixture was cooled in a dry ice/acetone bath at -60 °C, and triflic
anhydride (0.359 mmol) was added. The reaction mixture was
stirred for 2 min, and a solution of the glycosyl acceptor (0.490
mmol) in dichloromethane (2 mL) was added. After 5 min, the
mixture was warmed to room temperature and was diluted with
dichloromethane (10 mL). The reaction mixture was filtered and
washed with saturated NaHCO3, 1 N HCl, and saturated aqueous
Methyl 3-Amino-3-N-,4-O-carbonyl-2,3,6-trideoxy-R-L-lyxo-
hexopyranoside (6). Aziridine 14 (460 mg, 2.48 mmol) and 10%
palladium on carbon (400 mg, 0.62 mmol Pd) were dissolved in
ethyl acetate (20 mL). The reaction vessel was charged with a
balloon of hydrogen gas, and the reaction mixture was stirred at
room temperature for 3 h, when it was filtered through Celite. The
filtrate was concentrated, and the residue was filtered through silica
(1 × 3 cm, 5:1 chloroform/methanol) to afford 6 as white crystalline
plates (440 mg, 95%): Rf 0.49 (6:1 chloroform/methanol); [R]23
D
-47.1 (c 0.4, CHCl3); mp 115-120 °C; IR 2936, 2253, 1757 cm-1
;
1H NMR (400 MHz, CDCl3) δ 6.87 (s, 1 H, NH), 4.84 (app t, 1 H,
J ) 6.0 Hz, C1-H), 4.46 (dd, 1 H, J ) 1.7, 8.8 Hz, C4-H), 4.19
(app dt, 1 H, J ) 4.3, 8.8 Hz, C3-H), 3.99 (dq, 1 H, J ) 1.7, 6.6
Hz, C5-H), 2.08 (app dt, 1 H, J ) 4.9, 15.0 Hz, C2-Hâ), 1.75 (ddd,
(26) Crich, D.; Vinod, A. U.; Picione, J.; Wink, D. J. ARKIVOC 2005,
339-344.
8066 J. Org. Chem., Vol. 71, No. 21, 2006

Synthesis of L-Daunosamine and L-Ristosamine
1 H, J ) 4.3, 6.0, 15.0 Hz, C2-HR), 1.31 (d, 3 H, J ) 6.6 Hz
C6-H); 13C NMR (100 MHz, CDCl3) δ 160.0 (CdO), 96.8 (C-1),
76.2 (C-4), 63.3 (C-5), 54.8 (OCH3), 47.8 (C-3), 30.0 (C-2), 15.6
(C-6); HRMS (ESI) m/z calcd for C8H13NO4 + Na 210.0742, found
210.0736.
Methyl 2,3-Diamino-3-N-,4-O-carbonyl-2,3-N-cyclo-2,3,6-
trideoxy-R/â-L-allopyranoside (17, 18). Acyl azide 16 (1.50 g,
7.02 mmol, 2:1 R/â) was dissolved in dichloromethane (702 mL,
0.01 M). In 150-mL portions, the reaction mixture was exposed to
254 nm light at room temperature in quartz vessels for 1 h. The
reaction mixture was concentrated, and the brown residue was
purified by column chromatography (6 × 12 cm silica, 0.9 L of
2:1 hexane/ethyl acetate followed by 1.5 L 1:2 hexane/ethyl acetate)
to afford 17 (788 mg, 61%) and 18 (394 mg, 30%) as white solids.
Data for 17: Rf 0.10 (1:1 hexane/ethyl acetate); mp 143-145 °C;
Methyl 3-Amino-3-N-,4-O-carbonyl-2,3,6-trideoxy-R-L-ribo-
hexopyranoside (10). Aziridine 17 (860 mg, 4.64 mmol) and 10%
palladium on carbon (1.24 g, 1.16 mmol Pd) were dissolved in a
5:1 solution of ethyl alcohol/ethyl acetate (42 mL). The reaction
vessel was charged with a balloon of hydrogen gas. The reaction
mixture was stirred at room temperature for 3 h and filtered through
Celite with a 10:1 solution of chloroform/methanol (50 mL). The
filtrate was concentrated, and the residue was purified by column
chromatography (5 × 10 cm silica, 20:1 chloroform/methanol) to
afford 10 as a crystalline, granular solid (800 mg, 92%): Rf 0.61
1
IR 1787, 1136, 1110, 1077 cm-1; H NMR (500 MHz, CDCl3) δ
5.29 (d, 1 H, J ) 2.6 Hz, C1-H), 4.60 (dd, 1 H, J ) 1.8, 6.0 Hz,
C4-H), 4.16 (dq, 1 H, J ) 1.8, 7.0 Hz, C5-H), 3.50 (s, 3 H, OCH3),
3.46 (dd, 1 H, J ) 4.9, 6.0 Hz, C3-H), 3.04 (dd, 1 H, J ) 2.6, 4.9
Hz, C2-H), 1.32 (d, 3 H, J ) 7.0 Hz, C6-H); 13C NMR (125.7
MHz, CDCl3) δ 163.7 (CdO), 93.5 (C-1), 72.9 (C-4), 70.9 (C-5),
56.5 (OCH3), 43.3 (C-2), 40.3 (C-3), 14.6 (C-6); HRMS (ESI) m/z
calcd for C8H11NO4 + Na 208.0580, found 208.0572. Data for 18:
(10:1 chloroform/methanol); [R]23 -202.0 (c 0.3, CHCl3); mp
D
136-138 °C; IR 3280, 2935, 1760, 1047 cm-1; 1H NMR (500 MHz,
CDCl3) δ 6.57 (s, 1 H, NH), 4.71-4.68 (m, 1 H, C1-H), 4.25 (app
t, 1 H, J ) 8.9 Hz, C4-H), 3.97 (dq, 1 H, J ) 6.2, 8.9 Hz, C5-H),
3.96-3.92 (m, 1 H, C3-H), 3.37 (s, 3 H, OCH3), 2.20 (app dt, 1 H,
J ) 5.6 14.4 Hz, C2-Hâ), 1.83 (ddd, 1 H, J ) 6.8, 9.5, 14.4 Hz,
C2-HR), 1.34 (d, 3 H, J ) 6.2 Hz, C6-H); 13C NMR (125.7 MHz,
CDCl3) δ 159.5 (CdO), 97.0 (C-1), 78.2 (C-4), 63.7 (C-5), 54.9
(OCH3), 47.9 (C-3), 31.9 (C-2), 18.7 (C-6); HRMS (ESI) m/z calcd
for C8H13NO4 + Na 210.0737, found 210.0738.
Rf 0.25 (1:1 hexane/ethyl acetate); [R]23 +139.7 (c 0.3, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 5.00 (s, 1 H, C1-H), 4.72 (dd, 1 H,
J ) 2.1, 6.3 Hz, C4-H), 3.94 (dq, 1 H, J ) 2.1, 7.2 Hz, C5-H),
3.52 (s, 3 H, OCH3), 3.51-3.48 (m, 1 H, C3-H), 2.91 (d, 1 H, J )
4.8 Hz, C2-H), 1.37 (d, 3 H, J ) 7.2 Hz, C6-H); 13C NMR (125.7
MHz, CDCl3) δ 163.1 (CdO), 92.6 (C-1), 73.0 (C-4), 66.8 (C-5),
55.9 (OCH3), 42.2 (C-2), 37.9 (C-3), 15.7 (C-6); HRMS (ESI) m/z
calcd for C8H11NO4 + Na 208.0580, found 208.0571.
Methyl 2,3-Diamino-3-N-,4-O-carbonyl-2,3-N-cyclo-2,3,6-
trideoxy-R-L-talopyranoside (14). Acyl azide 5 (1.46 g, 6.85
mmol) was dissolved in dichloromethane (685 mL, 0.01 M). In
150-mL portions, the reaction mixture was exposed to 254 nm light
at room temperature in quartz vessels for 1 h. The reaction mixture
was concentrated, and the brown residue was purified by column
chromatography (6 × 12 cm silica, 2:1 hexane/ethyl acetate) to
afford 14 as a slightly yellow oil (929 mg, 79%): Rf 0.25 (1:1
hexane/ethyl acetate); [R]23D -68.0 (c 0.3, CHCl3); IR 2938, 2254,
1784, 1340, 1259, 1118 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.08
(br. s, 1 H, C1-H), 4.57 (d, 1 H, J ) 6.3 Hz, C4-H), 3.95 (q, 1 H,
J ) 6.6 Hz, C5-H), 3.52-3.50 (m, 4 H, C3-H, OCH3), 2.80 (dd,
Methyl 3-Amino-3-N-,4-O-carbonyl-2,3,6-trideoxy-â-L-ribo-
hexopyranoside (19). Aziridine 18 (380 mg, 2.05 mmol) and 10%
palladium on carbon (546 mg, 0.513 mmol Pd) were dissolved in
a 5:1 solution of ethyl alcohol/ethyl acetate (20 mL). The reaction
vessel was charged with a balloon of hydrogen gas. The reaction
mixture was stirred at room temperature for 3 h and filtered through
Celite with a 6:1 solution of chloroform/methanol (35 mL). The
filtrate was concentrated, and the residue was purified by column
chromatography (5 × 10 cm silica, 20:1 chloroform/methanol) to
afford 19 as a clear, colorless oil (319 mg, 83%): Rf 0.08 (1:1
hexane/ethyl acetate); [R]23D +10.7 (c 0.2, CHCl3); IR 1761, 1522,
1420 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.49 (s, 1 H, NH), 4.71
(dd, 1 H, J ) 2.5, 7.1, C1-H), 4.30-4.25 (m, 1 H, C3-H), 4.20
(app t, 1 H, J ) 8.9 Hz, C4-H), 3.73 (dq, 1 H, J ) 6.2, 8.9 Hz,
C5-H), 3.45 (s, 3 H, OCH3), 2.07 (ddd, 1 H, J ) 2.5, 4.3, 14.4 Hz,
C2-Hâ), 1.94 (ddd, 1 H, J ) 5.5, 7.1, 14.4 Hz, C2-HR), 1.36 (d,
3 H, J ) 6.2 Hz, C6-H); 13C NMR (125.7 MHz, CDCl3) δ 159.7
(CdO), 98.5 (C-1), 76.8 (C-4), 69.3 (C-5), 55.9 (OCH3), 49.6 (C-
3), 32.1 (C-2), 18.7 (C-6); HRMS (ESI) m/z calcd for C8H13NO4
+ Na 210.0737, found 210.0738.
1 H, J ) 0.5, 4.7 Hz, C2-H), 1.21 (d, 3 H, J ) 6.6 Hz, C6-H); 13
C
NMR (100 MHz, CDCl3) δ 163.9 (CdO), 93.9 (C-1), 72.8 (C-4),
62.6 (C-5), 55.8 (OCH3), 43.2 (C-2), 41.3 (C-3), 16.3 (C-6); HRMS
(ESI) m/z calcd for C8H11NO4 + Na 208.0580, found 208.0578.
Methyl 4-O-Azidocarbonyl-2,3,6-trideoxy-R/â-L-erythro-hex-
2-enopyranoside (16). Alcohol 1515 (2:1 R:â mixture, 1.50 g, 10.41
mmol), 1,1′-carbonyldiimidazole (2.53 g, 15.61 mmol), and pyridine
(2.52 mL, 31.2 mmol) were dissolved in benzene (50 mL) and
stirred for 2 h at room temperature. The reaction mixture was diluted
with ethyl acetate (40 mL) and washed with saturated aqueous NaCl
(100 mL). The organic layer was dried (MgSO4) and concentrated.
The crude residue was then dissolved in DMF (40 mL), and sodium
azide (3.38 g, 52.0 mmol) was added. This mixture was then
acidified with a 1:2 solution of HCl/DMF to pH ∼4. When con-
version was complete, the reaction mixture was diluted with ethyl
acetate (40 mL) and washed with water (3 × 100 mL) and a
saturated aqueous solution of NaHCO3. The organic layer was dried
(MgSO4) and concentrated. The residue was purified by column
chromatography (6 × 12 cm silica, 6:1 hexane/ethyl acetate) to
afford 16 as a clear oil (1.65 g, 2:1 R/â, 67%): Rf 0.56 (1:1 hexane/
p-Tolyl 3-Amino-3-N-,4-O-carbonyl-1,2,3,6-tetradeoxy-1-thio-
R-L-lyxo-hexopyranoside (21). Methyl glycoside 6 (890 mg, 4.75
mmol) and 4-methylbenzenethiol (709 mg, 5.71 mmol) were
dissolved in dichloromethane (40 mL). Boron trifluoride diethyl
etherate (1.51 mL, 11.9 mmol) was added dropwise at room temper-
ature, and the solution was stirred for 2 h. The reaction mixture
was poured onto a saturated solution of NaHCO3 (60 mL), and the
layers were separated. The aqueous layer was back-extracted with
dichloromethane (3 × 10 mL), and the organic layers were com-
bined, dried (MgSO4), and concentrated. The resulting solid was
purified by column chromatography (6 × 15 cm silica, 1:1 toluene/
ethyl acetate) to afford 21 as white crystalline plates (1.31 g, 99%,
>10:1 R/â mixture): Rf 0.59 (6:1 chloroform/methanol); mp 155-
1
ethyl acetate); IR 2181, 2139, 1730, 1244, 1056 cm-1; H NMR
(400 MHz, CDCl3) δ 5.99-5.83 (m, 2 H, C2-H, C3-H, â/R), 5.05-
5.04 (m, 0.9 H, C1-H â), 5.01-4.99 (m, 1 H, C4-H â/R), 4.86 (br.
s, 0.1 H, C1-H R), 3.97 (dq, 0.1 H, J ) 2.9, 6.2 Hz, C5-H R), 3.90
(app p, 0.9 H, J ) 6.5 Hz, C5-H â), 3.48 (s, 2.7 H, OCH3 â), 3.43
(s, 0.3 H, OCH3 R), 1.35 (d, 2.7 H, J ) 6.5 Hz, C6-H â), 1.27 (d,
0.3 H, J ) 6.2 Hz, C6-H R); 13C NMR (100 MHz, CDCl3) δ (â):
157.1 (CdO), 131.3, 126.3 (C-2, C-3) 96.7, (C-1), 73.7 (C-4), 70.6
(C-5), 55.0 (OCH3), 18.3 (C-6); (R): 157.1 (CdO), 128.6, 128.1
(C-2, C-3) 95.2, (C-1), 75.0 (C-4), 64.2 (C-5), 55.7 (OCH3), 17.7
(C-6); HRMS (ESI) m/z calcd for C8H11N3O4 + Na 236.0647, found
236.0643.
1
159 °C; IR 2986, 2305, 1759, 1421, 1265 cm-1; H NMR (400
MHz, CDCl3) δ 7.38 (d, 2 H, J ) 8.1 Hz, ArH), 7.10 (d, 2 H, J )
7.9 Hz, ArH), 6.39 (s 1 H, NH), 5.48 (dd, 1 H, J ) 6.2, 9.1 Hz,
C1-H), 4.48 (dd, 1 H, J ) 1.7, 9.1 Hz, C4-H), 4.23 (app dt, 1 H,
J ) 4.0, 9.1 Hz, C3-H), 4.17 (dq, 1 H, J ) 1.7, 6.5 Hz, C5-H),
2.32 (s, 3 H, ArCH3), 2.22 (ddd, 1 H, J ) 4.0, 6.2, 15.2 Hz, C2-
Hâ), 1.87 (ddd, 1 H, J ) 4.0, 9.1, 15.2 Hz, C2-HR), 1.30 (d, 3 H,
J ) 6.5 Hz, C6-H); 13C NMR (100 MHz, CDCl3) δ 159.6 (CdO),
137.5 (aryl C), 132.6 (2 C, aryl), 130.0 (aryl C), 129.7 (2 C, aryl),
81.0 (C-1), 76.2 (C-4), 64.3 (C-5), 48.5 (C-3), 29.9 (C-2), 21.1
J. Org. Chem, Vol. 71, No. 21, 2006 8067

Mendlik et al.
(ArCH3), 15.8 (C-6); HRMS (ESI) m/z calcd for C14H17NO3S +
Na 302.0821, found 302.0810.
in an ice bath, and quenched with the slow addition of methanol
(10 mL). The mixture was diluted with dichloromethane (100 mL)
and poured into a saturated aqueous solution of NaHCO3 (100 mL).
The organic layer was washed with 2 N HCl (3 × 100 mL), dried
(MgSO4), and concentrated. The residue was purified by column
chromatography (4 × 15 cm silica, 4:1 hexane/ethyl acetate) to
afford white crystalline plates (1.53 g, 96%, 1.8:1 24:25). Data for
p-Tolyl 3-Acetamido-3-N-,4-O-carbonyl-1,2,3,6-tetradeoxy-1-
thio-R-L-lyxo-hexopyranoside (22). Thioglycoside 21 (1.27 g, 4.55
mmol), acetic anhydride (1.29 mL, 13.6 mmol), and DMAP (55
mg, 0.454 mmol) were dissolved in pyridine (25 mL). The reaction
mixture was stirred for 2 h at room temperature, cooled in an ice
bath, and quenched by the slow addition of methanol (10 mL). The
solution was diluted with dichloromethane (50 mL) and was washed
with a saturated aqueous solution of NaHCO3 (100 mL) followed
by 2 N HCl (200 mL). The organic layer was dried (MgSO4) and
concentrated. The residue was purified by column chromatography
(6 × 15 cm silica, 3:1 hexane/ethyl acetate) to afford 22 as white
crystalline plates (1.45 g, 99%): Rf 0.46 (1:1 hexane/ethyl acetate);
[R]23D -45.9 (c 1.0, CHCl3); mp 115-117 °C; IR 2934, 1785, 1706,
24: Rf 0.92 (6:1 chloroform/methanol); [R]23 -322.5 (c 0.2,
D
CHCl3); mp 156-159 °C; IR 1786, 1707, 1375, 1353, 1300, 1210
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.40-7.38 (m, 2 H, ArH),
7.12 (d, 2 H, J ) 8.0 Hz, ArH), 5.33 (dd, 1 H, J ) 6.2, 11.3 Hz,
C1-H), 4.49 (ddd 1 H, J ) 5.3, 8.6, 11.3 Hz, C3-H), 4.28 (app t,
1 H, J ) 8.6 Hz, C4-H), 4.11 (dq, 1 H, J ) 6.1, 8.6 Hz, C5-H),
2.85 (app dt, 1 H, J ) 5.3, 14.0 Hz, C2-Hâ), 2.51 (s, 3 H, C(O)-
CH3), 2.33 (s, 3 H, ArCH3), 1.76 (app dt, 1 H, J ) 11.3, 14.0 Hz,
C2-HR), 1.36 (d, 3 H, J ) 6.1 Hz, C6-H); 13C NMR (100 MHz,
CDCl3) δ 170.1 (C(O)CH3), 153.0 (CdO), 138.1 (aryl C), 133.1
(2 C, aryl), 129.7 (2 C, aryl), 129.6 (aryl C), 81.9 (C-1), 76.4 (C-
5), 66.0 (C-4), 51.4 (C-3), 29.5 (C-2), 23.6 (C(O)CH3), 21.1
(ArCH3), 18.8 (C-6); HRMS (ESI) m/z calcd for C16H19NO4S +
Na 344.0927, found 344.0928. Data for 25: Rf 0.90 (6:1 chloroform/
methanol); [R]23D -34.2 (c 0.23, CHCl3); mp 107-109 °C; IR 1786,
1711, 1370, 1294 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.42-7.39
(m, 2 H, ArH), 7.13 (d, 2 H, J ) 7.9 Hz, ArH), 5.06 (dd, 1 H, J )
4.1, 7.5 Hz, C1-H), 4.58 (app dt, 1 H, J ) 5.7, 8.5, Hz, C3-H),
4.27 (app t, 1 H, J ) 8.5 Hz, C4-H), 3.67 (dq, 1 H, J ) 6.2, 8.5
Hz, C5-H), 2.65 (ddd, 1 H, J ) 4.1, 5.7, 15.2 Hz, C2-Hâ), 2.51 (s,
3 H, C(O)CH3), 2.35 (ddd, 1 H, J ) 5.7, 7.5, 15.2 Hz, C2-HR),
2.34 (s, 3 H, ArCH3), 1.39 (d, 3 H, J ) 6.2 Hz, C6-H); 13C NMR
(100 MHz, CDCl3) δ 171.3 (C(O)CH3), 153.5 (CdO), 138.2 (aryl
C), 133.0 (2 C, aryl), 129.7 (2 C, aryl), 129.0 (aryl C), 80.9 (C-1),
74.1 (C-5), 71.7 (C-4), 52.0 (C-3), 29.9 (C-2), 24.3 (C(O)CH3),
21.1 (ArCH3), 19.0 (C-6); HRMS (ESI) m/z calcd for C16H19NO4S
+ Na 344.0927, found 344.0938.
1
1493, 1375 cm-1; H NMR (400 MHz, CDCl3) δ 7.39-7.37 (m,
2 H, ArH), 7.12 (d, 2 H, J ) 7.8 Hz, ArH), 5.33 (dd, 1 H, J ) 6.0,
8.5 Hz, C1-H), 4.68 (app dt 1 H, J ) 4.5, 8.5 Hz, C3-H), 4.44 (dd,
1 H, J ) 1.7, 8.5 Hz, C4-H), 4.31 (dq, 1 H, J ) 1.7, 6.6 Hz, C5-
H), 2.67 (ddd, 1 H, J ) 5.1, 6.0, 15.2 Hz, C2-Hâ), 2.51 (s, 3 H,
C(O)CH3), 2.33 (s, 3 H, ArCH3), 2.04 (ddd, 1 H, J ) 4.5, 8.5,
15.2 Hz, C2-HR), 1.34 (d, 3 H, J ) 6.6 Hz, C6-H); 13C NMR (100
MHz, CDCl3) δ 170.8 (C(O)CH3), 153.3 (CdO), 138.1 (aryl C),
132.7 (2 C, aryl), 129.82 (aryl C), 129.78 (2 C, aryl), 81.4 (C-1),
73.9 (C-4), 63.8 (C-5), 50.9 (C-3), 27.9 (C-2), 24.0 (C(O)CH3),
21.1 (ArCH3), 15.7 (C-6); HRMS (ESI) m/z calcd for C16H19NO4S
+ Na 344.0932, found 344.0932.
p-Tolyl 3-Amino-3-N-,4-O-carbonyl-1,2,3,6-tetra-deoxy-1-
thio-R/â-L-ribo-hexopyranoside (23). A mixture of methyl glyco-
sides 10 and 19 (1.10 g, 5.88 mmol) and 4-methylbenzenethiol (876
mg, 7.05 mmol) were dissolved in dichloromethane (55 mL). Boron
trifluoride diethyl etherate (1.86 mL, 14.7 mmol) was added drop-
wise at room temperature. The reaction mixture was stirred for 2 h
and poured onto a saturated aqueous solution of NaHCO3 (80 mL).
The aqueous layer was back-extracted with dichloromethane (3 ×
10 mL), and the organic layers were combined, dried (MgSO4),
and concentrated. The resulting solids were purified by column
chromatography (5 × 15 cm silica, 2:1 toluene/ethyl acetate) to
afford both anomers as white crystalline plates (1.40 g, 85%, 1.8:1
Cyclohexyl 3-Acetamido-3-N-,4-O-carbonyl-2,3,6-trideoxy-R/
â-L-lyxo-hexopyranoside (26, 27). These compounds were syn-
thesized from 22 and cyclohexanol via glycosylation method B,
yielding a 4:1 R:â mixture of anomers that was purified by column
chromatography (2 × 15 cm silica, 3:1 hexane/ethyl acetate) to
afford the R anomer as white crystals and the â anomer as white
crystals in 80% combined yield. Data for 26: Rf 0.63 (1:1 hexane/
R:â). Data for 23, R: Rf 0.30 (1:1 toluene/ethyl acetate); [R]23
D
-256.4 (c 0.3, CHCl3); mp 195-198 °C; IR 3682, 3619, 2400,
1763, 1521, 1476, 1423 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.39-
7.37 (m, 2 H, ArH), 7.12 (d, 2 H, J ) 7.9 Hz, ArH), 5.99 (s, 1 H,
NH), 5.31 (dd, 1 H, J ) 6.5, 9.4 Hz, C1-H), 4.32 (app t, 1 H, J )
8.9 Hz, C4-H), 4.20 (dq, 1 H, J ) 6.1, 8.9 Hz, C5-H), 4.02-3.98
(m, 1 H, C3-H) 2.39 (ddd, 1 H, J ) 5.5, 6.5, 14.3 Hz, C2-Hâ), 2.33
(s, 3 H, ArCH3), 1.99 (app dt, 1 H, J ) 9.4, 14.3 Hz, C2-HR), 1.35
(d, 3 H, J ) 6.1 Hz, C6-H); 13C NMR (100 MHz, CDCl3) δ 159.1
(CdO), 138.0 (aryl C), 132.7 (2 C, aryl), 130.3 (aryl C), 129.7 (2
C, aryl), 81.8 (C-1), 78.5 (C-5), 64.8 (C-4), 49.1 (C-3), 32.7 (C-2),
21.1 (ArCH3), 18.8 (C-6); HRMS (ESI) m/z calcd for C14H17NO3S
+ Na 302.0827, found 302.0817. Data for 23, â: Rf 0.40 (1:1
ethyl acetate); [R]23 +22.6 (c 1.0, CHCl3); mp 135-138 °C; IR
D
2936, 2858, 1783, 1705, 1376 cm-1; 1H NMR (500 MHz, CDCl3)
δ 4.99 (app t, 1 H, J ) 4.9 Hz, C1-H), 4.68 (ddd, 1 H, J ) 5.6,
6.5, 7.8 Hz, C3-H), 4.35 (dd, 1 H, J ) 2.0, 7.8 Hz, C4-H), 4.13
(dq, 1 H, J ) 2.0, 6.7 Hz, C5-H), 3.59-3.53 (m, 1 H, cyclohexyl
OCH), 2.51 (s, 3 H, C(O)CH3), 2.16 (ddd, 1 H, J ) 4.9, 6.5, 14.7
Hz, C2-Hâ), 2.04 (app dt, 1 H, J ) 5.6, 14.7 Hz, C2-HR), 1.86-
1.84 (m, 2 H, cyclohexyl CH2), 1.74-1.71 (m, 2 H, cyclohexyl
CH2), 1.54-1.51 (m, 1 H, cyclohexyl CH2), 1.39-1.18 (m, 5 H,
cyclohexyl CH2), 1.33 (d, 3 H, J ) 6.7 Hz, C6-H); 13C NMR (125.7
MHz, CDCl3) δ 170.4 (C(O)CH3), 153.4 (CdO), 93.6 (C-1), 75.2
(cyclohexyl OCH), 74.1 (C-4), 62.4 (C-5), 50.2 (C-3), 33.6, 31.6
(cyclohexyl CH2), 29.2 (C-2), 25.5, 24.1, 23.9 (cyclohexyl CH2),
23.8 (C(O)CH3), 15.8 (C-6); HRMS (ESI) m/z calcd for C15H23-
NO5 + Na 320.1474, found 320.1475. Data for 27: Rf 0.40 (1:1
hexane/ethyl acetate); [R]23D +147.1 (c 1.0, CHCl3); mp 132-135
toluene/ethyl acetate); [R]23 -22.0 (c 0.2, CHCl3); mp 140-142
D
1
°C; IR 3684, 3620, 2400, 1764, 1520, 1423 cm-1; H NMR (500
MHz, CDCl3) δ 7.39-7.36 (m, 2 H, ArH), 7.11 (d, 2 H, J ) 7.9
Hz, ArH), 6.17 (s, 1 H, NH), 4.96 (dd, 1 H, J ) 2.5, 11.4 Hz,
C1-H), 4.25-4.22 (m, 1 H, C3-H), 4.10 (dd, 1 H, J ) 7.1, 8.9 Hz,
C4-H), 3.64 (dq, 1 H, J ) 6.2, 9.0 Hz, C5-H), 2.33 (s, 3 H, ArCH3),
2.21 (app dt, 1 H, J ) 2.5, 14.9 Hz, C2-Hâ), 1.98 (ddd, 1 H, J )
4.7, 11.4, 14.9 Hz, C2-HR), 1.36 (d, 3 H, J ) 6.2 Hz, C6-H); 13C
NMR (100 MHz, CDCl3) δ 159.8 (CdO), 137.9 (aryl C), 132.2 (2
C, aryl), 129.6 (2 C, aryl), 129.3 (aryl C), 80.4 (C-1), 76.1 (C-5),
73.2 (C-4), 51.1 (C-3), 32.2 (C-2), 21.0 (ArCH3), 19.0 (C-6); HRMS
(ESI) m/z calcd for C14H17NO3S + Na 302.0827, found 302.0827.
p-Tolyl 3-Acetamido-3-N-,4-O-carbonyl-1,2,3,6-tetradeoxy-1-
thio-R/â-L-ribo-hexopyranoside (24, 25). Thioglycosides 23 (1.27
g, 4.55 mmol) were dissolved in pyridine (35 mL), followed by
addition of acetic anhydride (1.74 mL, 18.5 mmol) and DMAP (57
mg, 0.462 mmol). The reaction mixture was stirred for 2 h, cooled
1
°C; IR 2935, 2858, 1786, 1702, 1377 cm-1; H NMR (500 MHz,
CDCl3) δ 4.88 (dd, 1 H, J ) 2.7, 5.5 Hz, C1-H), 4.63 (app dt, 1 H,
J ) 6.1, 8.1 Hz, C3-H), 4.33 (dd, 1 H, J ) 1.6, 8.1 Hz, C4-H),
3.84 (dq, 1 H, J ) 1.6, 6.5 Hz, C5-H), 3.65-3.61 (m, 1 H, OCH),
2.49 (s, 3 H, C(O)CH3), 2.18 (ddd, 1 H, J ) 2.7, 6.1, 14.5 Hz,
C2-HR), 1.94 (app dt, 1 H, J ) 5.5, 14.5 Hz, C2-Hâ), 1.93-1.90
(m, 1 H, cyclohexyl H), 1.79 (br. s, 1 H, cyclohexyl H), 1.72-
1.68 (m, 2 H, cyclohexyl H), 1.50-1.47 (m, 1 H, cyclohexyl H),
1.40, (d, 3 H, J ) 6.5 Hz, C6-H), 1.38-1.18 (m, 5 H, cyclohexyl
H); 13C NMR (125.7 MHz, CDCl3) δ 170.2 (C(O)CH3), 153.3
(CdO), 95.2 (C-1), 75.5 (cyclohexyl OCH), 73.5 (C-4), 67.2 (C-5),
50.3 (C-3), 33.4, 31.4 (cyclohexyl CH2), 30.1 (C-2), 25.6, 24.0,
8068 J. Org. Chem., Vol. 71, No. 21, 2006

Synthesis of L-Daunosamine and L-Ristosamine
23.9 (cyclohexyl CH2), 23.7 (C(O)CH3), 17.1 (C-6); HRMS (ESI)
m/z calcd for C15H23NO5 + Na 320.1474, found 320.1477.
Cyclohexyl 3-Acetamido-3-N-,4-O-carbonyl-2,3,6-trideoxy-R/
â-L-ribo-hexopyranoside (28, 29). These compounds were syn-
thesized from 24/25 and cyclohexanol via glycosylation methods
A and C. Products from both methods were purified by column
chromatography (2 × 15 cm silica, 4:1 hexane/ethyl acetate).
Method A afforded the products in a 1.3:1 ratio of 28:29 in 97%
combined yield. Method C afforded the products in a 2:1 ratio of
28:29 in 81% combined yield. Compound 28 was isolated as white
crystals and 29 as a clear oil. Data for 28: Rf 0.53 (1:1 hexane/
3.53 (dq, 1 H, J ) 0.9, 6.5 Hz, C5-H), 3.36 (app d, 1 H, J ) 3.0
Hz, C4-H) 2.93 (ddd, 1 H, J ) 3.0, 4.5, 12.6 Hz, C3-H), 1.95-
1.88 (m, 2 H, cyclohexyl CH2), 1.74-1.70 (m, 3 H, cyclohexyl
CH2, C2-HR), 1.53 (ddd, 1 H, J ) 9.6, 12.6, 12.6 Hz, C2-Hâ), 1.56-
1.50 (m, 1 H, cyclohexyl CH2), 1.34-1.22 (m, 5 H, cyclohexyl
CH2), 1.24 (d, 3 H, J ) 6.5 Hz, C6-H); 13C NMR (125.7 MHz,
CD3OD) δ 99.6 (C-1), 77.4 (cyclohexyl OCH), 73.1 (C-5), 70.5
(C-4), 51.6 (C-3), 35.4 (C-2), 34.7, 33.0, 26.8, 25.2, 25.1 (cyclo-
hexyl CH2), 17.2 (C-6); HRMS (ESI) m/z calcd for C12H23NO3 +
H 230.1756, found 230.1759.
Cyclohexyl 3-Amino-2,3,6-trideoxy-R-L-ribo-hexopyranoside
(32). Cyclohexyl glycoside 28 was deprotected as described for
the synthesis of 30 to afford 32 in 87% yield: Rf 0.10 (6:1
ethyl acetate); [R]23 -230.7 (c 0.9, CHCl3); mp 87-90 °C; IR
D
1
2937, 2861, 2355, 1784, 1706, 1374, 1297, 1213 cm-1; H NMR
chloroform/methanol); [R]23 -131.6 (c 1.0, CH3OH); IR 3582,
(500 MHz, CDCl3) δ 5.00 (dd, 1 H, J ) 5.9, 8.0 Hz, C1-H), 4.41
(ddd, 1 H, J ) 5.3, 8.3, 11.7 Hz, C3-H), 4.21 (dd, 1 H, J ) 8.3,
8.6 Hz, C4-H), 4.43 (dq, 1 H, J ) 6.2, 8.6 Hz, C5-H), 3.62-3.58
(m, 1 H, OCH), 2.63 (app dt, 1 H, J ) 5.6, 14.1 Hz, C2-Hâ), 2.50
(s, 3 H, C(O)CH3), 1.85-1.81 (m, 2 H, cyclohexyl H), 1.73-1.66
(m, 2 H, cyclohexyl H), 1.70 (ddd, 1 H, J ) 8.0, 11.7, 14.1 Hz,
C2-HR), 1.53-1.51 (m, 1 H, cyclohexyl H), 1.43-1.19 (m, 5 H,
cyclohexyl H), 1.35 (d, 3 H, J ) 6.2 Hz, C6-H); 13C NMR (125.7
MHz, CDCl3) δ 170.2 (C(O)CH3), 153.3 (CdO), 94.1 (C-1), 76.4
(C-4), 75.2 (OCH), 64.1 (C-5), 50.4 (C-3), 33.7, 31.8 (cyclohexyl
C), 29.9 (C-2), 25.6, 24.0, 23.9 (cyclohexyl C), 23.6 (C(O)CH3),
18.9 (C-6); HRMS (ESI) m/z calcd for C15H23NO5 + Na 320.1474,
found 320.1467. Data for 29: Rf 0.73 (1:1 hexane/ethyl acetate);
D
1
2672, 2356, 1666, 1579 cm-1; H NMR (400 MHz, CD3OD) δ
5.01 (app t, 1 H, J ) 2.5 Hz, C1-H), 3.84 (dq, 1 H, J ) 6.2, 9.1
Hz, C5-H), 3.61-3.57 (m, 1 H, cyclohexyl OCH), 3.42-3.34 (m,
2 H, C3-H, C4-H) 2.03-2.01 (m, 2 H, C2-H), 1.94-1.87 (m, 2 H,
cyclohexyl CH2), 1.77-1.71 (m, 2 H, cyclohexyl CH2), 1.56-1.53
(m, 1 H, cyclohexyl CH2), 1.46-1.41 (m, 1 H, cyclohexyl CH2),
1.38-1.26 (m, 4 H, cyclohexyl CH2), 1.24 (d, 3 H, J ) 6.2 Hz,
C6-H); 13C NMR (125.7 MHz, CD3OD) δ 95.6 (C-1), 77.1
(cyclohexyl OCH), 70.9 (C-4), 64.9 (C-5), 50.5 (C-3), 34.5, 33.7
(cyclohexyl CH2), 32.5 (C-2), 26.7, 25.2, 25.0 (cyclohexyl CH2),
18.1 (C-6); HRMS (ESI) m/z calcd for C12H23NO3 + Na 252.1576,
found 252.1582.
[R]23 -31.4 (c 1.0, CHCl3); IR 2936, 2861, 2355, 1784, 1708,
Cyclohexyl 3-Amino-2,3,6-trideoxy-â-L-ribo-hexopyranoside
(33). Cyclohexyl glycoside 29 was deprotected as described for
the synthesis of 30 to afford to afford 33 in 87% yield: Rf 0.10
(6:1 chloroform/methanol); [R]23D +41.5 (c 1.2, CH3OH); IR 3546,
D
1368, 1295, 1223 cm-1; H NMR (500 MHz, CDCl3) δ 5.05 (dd,
1
1 H, J ) 2.6, 3.4 Hz, C1-H), 4.69 (ddd, 1 H, J ) 6.5, 8.6, 8.8 Hz,
C3-H), 4.41 (dd, 1 H, J ) 8.6, 9.4 Hz, C4-H), 3.71 (dq, 1 H, J )
6.1, 9.4 Hz, C5-H), 3.63-3.60 (m, 1 H, OCH), 2.63 (ddd, 1 H, J
) 3.4, 6.5, 14.1 Hz, C2-Hâ), 2.52 (s, 3 H, C(O)CH3), 1.98 (ddd,
1 H, J ) 2.6, 8.8, 14.1 Hz, C2-HR), 1.84-1.81 (m, 2 H, cyclohexyl
H), 1.72-1.66 (m, 2 H, cyclohexyl H), 1.53-1.50 (m, 1 H,
cyclohexyl H), 1.39-1.19 (m, 5 H, cyclohexyl H), 1.35 (d, 3 H, J
) 6.1 Hz, C6-H); 13C NMR (125.7 MHz, CDCl3) δ 171.0 (C(O)-
CH3), 153.6 (CdO), 94.3 (C-1), 75.0 (C-4), 74.9 (OCH), 67.7 (C-
5), 50.1 (C-3), 33.8, 31.7 (cyclohexyl C), 31.0 (C-2), 25.6, 24.1,
24.0 (cyclohexyl C), 23.8 (C(O)CH3), 19.0 (C-6); HRMS (ESI)
m/z calcd for C15H23NO5 + Na 320.1474, found 320.1463.
Cyclohexyl 3-Amino-2,3,6-trideoxy-R-L-lyxo-hexopyranoside
(30). Cyclohexyl glycoside 26 (20 mg, 0.067 mmol), barium
hydroxide octahydrate (1.49 g, 4.71 mmol), and water (3 mL) were
heated in an oil bath at 125 °C for 1 h, cooled slightly, diluted
with water (5 mL), and cooled to 25 °C. The reaction mixture was
filtered, and dry ice was added to the filtrate to precipitate BaCO3.
This mixture was filtered and concentrated, and the residue was
dissolved in methanol, filtered, and concentrated. The product was
purified by column chromatography (1 × 2 cm silica, 4:1 chloro-
form/methanol) to afford 30 as a colorless oil (13 mg, 85%): Rf
0.02 (6:1 chloroform/methanol); [R]D -125.9 (c 1.0, CH3OH); IR
1
3111, 2692, 2146, 1662, 1578 cm-1; H NMR (500 MHz, CD3-
OD) δ 4.98 (dd, 1 H, J ) 2.5, 8.4 Hz, C1-H), 3.71 (dq, 1 H, J )
6.4, 8.1 Hz, C5-H), 3.69-3.64 (m, 1 H, cyclohexyl OCH), 3.49
(app q, 1 H, J ) 4.5 Hz, C3-H) 3.40 (dd, 1 H, J ) 4.5, 8.1 Hz,
C4-H), 1.98 (ddd, 1 H, J ) 2.5, 4.5, 14.1 Hz, C2-HR), 1.89-1.87
(m, 2 H, cyclohexyl CH2), 1.80 (ddd, 1 H, J ) 4.5, 8.4, 14.1 Hz,
C2-Hâ), 1.74-1.71 (m, 2 H, cyclohexyl CH2), 1.55-1.52 (m, 1 H,
cyclohexyl CH2), 1.38-1.18 (m, 5 H, cyclohexyl CH2), 1.27 (d,
3 H, J ) 6.4 Hz, C6-H); 13C NMR (125.7 MHz, CD3OD) δ 95.8
(C-1), 77.1 (cyclohexyl OCH), 71.6, 71.4 (C-5, C-4), 50.1 (C-3),
35.9 (C-2), 34.6, 32.8, 26.8, 25.1, 25.0 (cyclohexyl CH2), 19.0 (C-
6); HRMS (ESI) m/z calcd for C12H23NO3 + Na 252.1576, found
252.1578.
Computational Methods
Initial structures of 39-42 were fully optimized at the B3LYP/
6-31G* level of theory in the gas phase.22 Each stationary point
was confirmed to be a minimum on the potential energy surface
by calculation of the vibrational frequencies (second derivatives
of the energy vs coordinate), and all vibrational modes of each
optimized structure possessed only real vibrational frequencies. A
scaling factor of 0.9806 was used for the zero-point vibrational
1
3594, 2356, 1665, 1578 cm-1; H NMR (400 MHz, CD3OD) δ
5.01 (app d, 1 H, J ) 3.7 Hz, C1-H), 3.95 (app q, 1 H, J ) 6.6 Hz,
C5-H), 3.59-3.52 (m, 1 H, cyclohexyl OCH), 3.50 (br. s, 1 H,
C4-H) 3.34-3.30 (m, 1 H, C3-H), 1.88-1.79 (m, 2 H, cyclohexyl
CH2), 1.83 (app dt, 1 H, J ) 3.7, 12.6 Hz, C2-Hâ), 1.74-1.65 (m,
3 H, cyclohexyl CH2, C2-HR), 1.54-1.51 (m, 1 H, cyclohexyl H),
1.41-1.21 (m, 5 H, cyclohexyl CH2), 1.18 (d, 3 H, J ) 6.6 Hz,
C6-H); 13C NMR (100 MHz, CD3OD) δ 95.9 (C-1), 75.8 (cyclo-
hexyl OCH), 70.3 (C-4), 67.7 (C-5), 48.2 (C-3), 34.5, 32.6
(cyclohexyl CH2), 32.4 (C-2), 26.8, 25.2, 25.0 (cyclohexyl CH2),
17.1 (C-6); HRMS (ESI) m/z calcd for C12H23NO3 + Na 252.1576,
found 252.1576.
(27) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502-16513.
(28) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Pettersson, G. A.;
Nakatsuji, H; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Lui, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
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Revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
Cyclohexyl 3-Amino-2,3,6-trideoxy-â-L-lyxo-hexopyranoside
(31). Cyclohexyl glycoside 27 was deprotected as described for
the synthesis of 30 to afford 31 in 86% yield: Rf 0.02 (6:1
chloroform/methanol); [R]D +31.0 (c 0.9, CH3OH); IR 3533, 3127,
1
1666, 1170 cm-1; H NMR (500 MHz, CD3OD) δ 4.60 (dd, 1 H,
J ) 2.2, 9.6 Hz, C1-H), 3.69-3.66 (m, 1 H, cyclohexyl OCH),
J. Org. Chem, Vol. 71, No. 21, 2006 8069

Mendlik et al.
energy (ZPE) correction.27 After optimization, a single-point energy
of each optimized structure was calculated at the B3LYP/6-311+G-
(3df,3pd) level of theory. All of the calculations for structures 39-
42 were performed with Gaussian03.28
Supporting Information Available: Additional data supporting
anomeric stereochemistry from glycosylation reactions; Cartesian
coordinates, vibrational frequencies and absolute energies of 39-
42; data for additional new compounds not included above; 1H and
13C NMR spectra of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The National Institutes of Health sup-
ported this work through grant AI44045. Computational re-
sources from the Ohio Supercomputer Center are gratefully
acknowledged.
JO061167Z
8070 J. Org. Chem., Vol. 71, No. 21, 2006