Synthesis of phenyl 3,4-di-O-benzyl-2,6-dideoxy-3-C-methyl-1-thio-α,β-L-xylo-hexopyranoside. A glycosyl donor for axenose

Article abstract of DOI:10.1016/S0957-4166(99)00563-7

A new synthesis of the methyl-branched sugar axenose is described. Axenose is found in the antibiotics axenomycin, dutomycin, and polyketomycin. The synthesis is based on additions of organometallic reagents to pentodialdo-1,4-furanosides and allows the preparation of derivatives of methyl α-L-axenoside which are protected at the tertiary C-3 hydroxyl group. Conversion to thioglycoside derivatives for use in oligosaccharide synthesis was carried out directly from the methyl glycoside by treatment with phenylthiotrimethylsilane and trimethylsilyl trifluoromethanesulfonate. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00563-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 139–149
Synthesis of phenyl 3,4-di-O-benzyl-2,6-dideoxy-3-C-methyl-
1-thio-α,β-L-xylo-hexopyranoside. A glycosyl donor for axenose
Garry R. Smith, Frank J. Villani Jr., Luca Failli and Robert M. Giuliano ∗
Department of Chemistry, Villanova University, Villanova, PA 19085, USA
Received 5 November 1999; accepted 6 December 1999
Abstract
A new synthesis of the methyl-branched sugar axenose is described. Axenose is found in the antibiotics
axenomycin, dutomycin, and polyketomycin. The synthesis is based on additions of organometallic reagents to
pentodialdo-1,4-furanosides and allows the preparation of derivatives of methyl α-L-axenoside which are protected
at the tertiary C-3 hydroxyl group. Conversion to thioglycoside derivatives for use in oligosaccharide synthesis
was carried out directly from the methyl glycoside by treatment with phenylthiotrimethylsilane and trimethylsilyl
trifluoromethanesulfonate. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The methyl-branched sugar L-axenose occurs in disaccharides found in the antibiotics axenomycin,1
dutomycin,2 and polyketomycin.3 In axenomycin, axenose is glycosylated at the 4-position with the
trideoxy sugar amicetose, while in both dutomycin and polyketomycin, axenose is attached to amicetose
via an α-1,4 glycosidic linkage, giving the disaccharide shown in Fig. 1. The synthesis of disaccharides
of axenose is a challenging problem owing to the presence of the 2-deoxy glycosidic linkage and because
of the multiple steps required to obtain suitably protected monosaccharide derivatives. There have been
no syntheses of axenose-containing disaccharides described in the literature. We decided to investigate
this problem in the context of our studies of the synthesis of carbohydrate components of antibiotics. In
this paper, we describe a new synthesis of axenose and its thioglycoside derivatives for use in coupling
reactions.
The structure of axenose was reported by Arcamone and co-workers as 2,6-dideoxy-3-C-methyl-L-
xylo-pyranose in 1973.1 Three syntheses of axenose have been reported, the first, a racemic synthesis,
leading to D,L-axenose before the identification of the L-enantiomer as a natural product,4 and the second
by Garegg and Norberg, from L-fucose, based on the addition of methylmagnesium iodide to a keto
∗
Corresponding author.
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00563-7
tetasy 3197

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Fig. 1. Disaccharide found in dutomycin and polyketomycin (R=aglycone)
sugar in its pyranose form.5 The third synthesis was reported by our laboratory in 1995.6 Our approach
was developed in the context of the study of stereoselectivity of addition of organometallic reagents
to pentodialdo-1,4-furanoses and led to the synthesis of L-axenose and D-evermicose from a common
intermediate. Our finding that the configuration of the anomeric center in the starting furanoside had
a large effect on the stereochemical outcome of the chain extension reaction at C-5 prompted us to
investigate an alternative synthesis of axenose, in which the branching methyl group at C-3 is introduced
prior to the extension at C-5. This reordering of steps affords an intermediate with additional steric bulk
on the β-face (at C-3), so that chain extension reactions at C-5 would be expected to favor the product
of chelation control and give the L-xylo stereochemistry that is required for L-axenose. This route is
shorter and also allows for protection of the C-3 hydroxyl at an early stage in the synthesis, a step that
is necessary in order for glycosylation at the C-4 hydroxyl group to be carried out selectively. In this
paper, we describe the synthesis of derivatives of L-axenose based on this approach, key steps of which
are summarized in Scheme 1.
Scheme 1. Proposed synthesis of L-axenose
2. Results and discussion
Tritylation of a 1:1 mixture of anomers of methyl 2-deoxy-D-ribo-hexofuranoside7 by the method of
Leonard8 gave a 66% yield of trityl ethers 1α,β that were separable by flash chromatography on silica gel.
The acid sensitivity of 2-deoxy furanosides required careful handling in the purification and in subsequent
steps. Each anomer was carried through the sequence outlined in Scheme 2 independently, so that the
effects of anomeric configuration on the stereoselectivity of addition reactions could be determined. A
question that seemed important to address was whether the product of a chelation controlled addition
to C-5 would be favored with the additional oxygen on the β-face. If so, this would allow for a shorter,
more efficient synthesis of L-axenose. Oxidation of the C-3 hydroxyl group of 1α,β was carried out with

G. R. Smith et al. / Tetrahedron: Asymmetry 11 (2000) 139–149
141
methyl sulfoxide and oxalyl chloride or trifluoroacetic anhydride to provide the corresponding 3-uloses
2α,β. Both anomers of the ulose were susceptible to elimination of methanol, consistent with earlier
work of Villani6 on related compounds. Because of this, the branching C-3 methyl group could not be
introduced by treatment with methyllithium, which gave unsaturated products. However, the addition
of methylcerium9 occurred smoothly to give a 5:1 ratio of threo to erythro products in the case of the
α-anomer, and the threo product exclusively in the case of the β-anomer. Attempted benzylation of
the C-3 hydroxyl group in either anomer of the threo product proved difficult; however, treatment of
3β or 3α (threo) with powdered KOH in neat benzyl chloride, according to the procedure of Allerton
and Fletcher,10 gave benzyl ethers 4α and 4β in 70 and 87% yields, respectively. Protection of the
tertiary alcohol at this point in the synthesis enables the 4-hydroxyl group to be uniquely unmasked by
furanoside–pyranoside isomerization at a later stage. This protection would be necessary in disaccharide
syntheses in which axenose serves as the acceptor, as would be the case for axenomycin.
Scheme 2. Synthesis of L-axenose derivatives

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Several attempts for detritylation of 4 under acidic conditions or by hydrogenolysis gave unsatis-
factory results. Partial debenzylation occurred when hydrogenolysis was attempted, and ring isome-
rization/anomerization occurred under acidic conditions. After many experiments, it was found that
treatment of either 4α or 4β with Amberlyst-15 (H+) resin11 resulted in anomerization to mixtures
of approximately 7:1 and 4:1, respectively, of detritylated products 5α,β. In early attempts of this
deprotection with older resin, yields of less than 60% of products were obtained and the reaction time
varied from 8 to 10 h. However, with freshly generated resin, the deprotection proceeded in less than 3 h
in 85% yield on a multigram scale. We tried to substitute a TBDMS protecting group for the trityl ether
in this sequence, but found that the group was not stable to the strongly basic conditions required for the
benzylation.
The next step required oxidation of the C-5 hydroxyl group to the aldehyde to allow for chain extension
and completion of the synthesis. The use of trifluoroacetic anhydride in the place of oxalyl chloride
in the Swern procedure12 gave the respective dialdoses 6α,β which were used immediately owing to
their instability. Conditions for the chain extension reaction at C-5 of 6 were selected based on the
systematic study of Villani on the stereoselectivity of additions of organometallic reagents to pentodialdo-
1,4-furanosides.6 Consistent with predictions based on our studies, a greater proportion (1.4:1) of the
addition product 8β, resulting from chelation control, was obtained using methylmagnesium bromide in
ether. Due to solubility problems, it was necessary to include THF as a cosolvent in the addition to 6α. It
is interesting to note that the addition to 6β occurred with opposite stereoselectivity, giving a 1.3:1 ratio of
products 7β and 8α favoring the D-arabino isomer 7β. In our previous study, we discovered that additions
to pentodialdo-1,4-furanosides 14α and 14β, which lack the C-3 substituent on the β-face, also exhibited
a dependence on anomeric configuration, with the L-lyxo product (chelation-controlled) being favored for
14α, but not for 14β, which gives the product (D-ribo), consistent with a Felkin–Anh transition state.13 In
the chelation-control model for dialdoses, it is the ring oxygen and the aldehyde oxygen that are thought
to participate in chelation with the metal ion. Our previous study and the results described herein indicate
that the model is insufficient to account for the observed selectivity, which depends on additional factors
such as the anomeric substituent. Although selectivity for the L-xylo isomers 8α,β was not high, the
facile separation of 8β from the product mixture by flash chromatography afforded sufficient quantities
of axenose precursor for further studies.
The structure of 8β was confirmed by a comparison of NMR data of the reduction product methyl
2,6-dideoxy-3-C-methyl-β-L-xylo-hexofuranoside 9β with spectra obtained for material synthesized by
Villani.6b
Equilibration of 8β in methanolic hydrogen chloride gave α- and β-pyranosides 10 and 11, with the β-
pyranoside comprising about 35% of the total of 66% pyranoside, as measured by 1H NMR. The higher
amount of furanosides in this equilibration relative to those of unbranched monosaccharides is ascribed
to the unfavorable steric interactions of the axial C-3 substituent. Similar behavior was noted by Angyal
for methyl-branched sugars in their reducing form.14 Reequilibration of the product to give higher yields
of 11, while not attempted in this study, could be carried out as described in the synthesis of the methyl-
branched sugar L-nogalose developed in this laboratory.15 The β-anomer of 11 was the one most easily
separated from the furanosides present in the equilibration, so it was chosen to pursue the synthesis of
glycosyl donors for axenose (Scheme 3).
In dutomycin and polyketomycin, axenose is attached by an α-1,4-linkage to the C-4 hydroxyl group of
amicetose, so donors for the axenose residue are required for the synthesis of the dissacharide portion of

G. R. Smith et al. / Tetrahedron: Asymmetry 11 (2000) 139–149
143
Scheme 3. Synthesis of phenyl thioglycosides
these two antibiotics.† The versatility of thioglycosides as donors is well documented in oligosaccharide
synthesis.16 They can be activated by several methods and converted to glycosyl sulfoxides, glycosyl
halides, or to glycals. Protection of the C-4 hydroxyl group of 11 as its benzyl ether using benzyl
chloride and potassium hydroxide gave dibenzyl ether derivative 12 in 92% yield. Treatment of 12
with phenylthiotrimethylsilane and trimethylsilyl trifluoromethanesulfonate17 smoothly afforded the
phenylthioglycoside 13 as a 3:1 mixture of α:β anomers in 82% yield. In our recent synthesis of the
cororubicin trisaccharide,18 we observed no difference in the outcome of coupling reactions of separate
α- and β-anomers of phenylthioglycosides. Studies of the glycosylations of amicetose with 13 and its
derivatives are in progress.
3. Experimental
3.1. General methods
1H NMR spectra were recorded on a Varian XL 300 MHz spectrometer at 300 MHz with TMS as an
internal reference in CDCl3 unless otherwise noted. 13C NMR spectra were recorded on a Varian XL
300 MHz spectrometer at 75 MHz and referenced with CDCl3. Melting points were determined in an
open capillary tube with a Thomas Hoover apparatus and are uncorrected. TLC analyses were conducted
on silica gel Kieselgel 60 F254 (Merck) glass plates and visualized by UV254 nm or with ammonium
molybdate–ceric sulfate reagent. Flash chromatography19 was carried out with ‘Baker’ silica gel. Optical
rotations were recorded on a Perkin–Elmer 241 polarimeter as [α]D values at 23°C. Elemental analyses
were carried out at Merck Research Laboratories. High resolution mass spectra were measured at Merck
Research Laboratories using ES-FT/ICR/MS with propylene glycol as internal standard on a Bruker ES-
FT mass spectrometer.
†
The situation in axenomycin is opposite, as noted above, in which amicetose is attached to the C-4 hydroxyl group of
axenose.

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G. R. Smith et al. / Tetrahedron: Asymmetry 11 (2000) 139–149
3.2. Methyl 2-deoxy-5-O-trityl-α-D-glycero-pentofuranosid-3-ulose and methyl 2-deoxy-5-O-trityl-β-D-
glycero-pentofuranosid-3-ulose 2α,β
To a stirring solution of oxalyl chloride (2.73 g, 21.5 mmol, 1.9 mL) in dichloromethane (45 mL) at
−78°C was added a solution of methyl sulfoxide (3.36 g, 43 mmol, 3.05 mL) in dichloromethane (15
mL). After 15 min, a solution of methyl 2-deoxy-5-O-trityl-α-D-erythro-pentofuranoside 1α (7.0 g, 17.9
mmol) in dichloromethane (25 mL) was added and the reaction mixture was stirred for an additional
30 min. Triethylamine (9.1 g, 90 mmol, 12.5 mL) was added and the reaction mixture was allowed
to warm to 0°C for 1 h. Saturated aqueous sodium hydrogen carbonate (75 mL) was added and the
whole was extracted with ethyl acetate (2×75 mL). The organic layers were combined, washed with
saturated aqueous sodium chloride (50 mL), and the organic layer was dried with anhydrous magnesium
sulfate, filtered and concentrated at reduced pressure. The resulting syrup was purified by flash column
chromatography over silica gel (10 in×6 cm) with hexanes:ethyl acetate (4:1) to give (4.5 g, 65%) of 2α:
[α]D=+188 (c 1.09, CHCl3); Rf=0.53 in 4:1 hexanes:ethyl acetate; 1H NMR (300 MHz) δ 7.48–7.21 (m,
0
15H, Ar), 5.47 (d, J1,2=5.1 Hz, 1H, H-1), 4.04 (bt, J4,5, J4,5 =2.5, 3.5 Hz, 1H, H-4), 3.46 (s, 3H, OCH3),
0
0
0
3.44 (dd, J5,5 =10.2 Hz, 1H, H-5), 3.32 (dd, 1H, H-5 ), 2.81 (dd, J2,2 =18.1 Hz, 1H, H-2), 2.46 (d, 1H,
H-20); 13C NMR (75 MHz) δ 212.02 (C_O), 143.45 (ipso), 128.59, 127.91, 126.96 (Ar), 101.41 (C-1),
86.63 (Ph3C), 77.29 (C-4), 62.87 (C-5), 54.88 (OCH3), 44.02 (C-2).
Compound 2β was obtained as a syrup in 60% yield using the same method. From 6.1 g (15.6
mmol) of 1β, 3.6 g of 2β was obtained. In a scale-up preparation of 2β, oxidation by the following
procedure gave improved results. To a stirring solution of methyl sulfoxide (4.92 g, 63 mmol, 4.47 mL)
in dichloromethane (120 mL) at −78°C under nitrogen was added a solution of trifluoroacetic anhydride
(10.1 g, 48 mmol, 6.8 mL) in dichloromethane (20 mL). After 10 min, a solution of 1β (11.7 g, 30.0
mmol) in dichloromethane (120 mL) was added and the reaction mixture was stirred for an additional
15 min. Triethylamine (9.4 g, 93 mmol, 13.0 mL) was added and the reaction mixture was allowed to
warm to 0°C for 1 h. The reaction mixture was treated as described above to yield 2β as an amber oil
1
(9.1 g, 78% yield): [α]D=−28.5 (c 1.20, CHCl3); Rf=0.37 in 4:1 hexanes:ethyl acetate; H NMR (300
0
0
MHz) δ 7.58–7.19 (m, 15H, Ar), 5.34 (dd, J1,2, J1,2 =1.5, 5.7 Hz, 1H, H-1), 4.21 (ddd, J4,5, J4,5 , J2,4=2.9,
0
0
6.6, 0.9 Hz, 1H, H-4), 3.42 (dd, J5,5 =10.1 Hz, 1H, H-5), 3.33 (s, 3H, OCH3), 3.25 (dd, 1H, H-5 ), 2.75
(dd, J2.2 =18.2 Hz, 1H, H-2), 2.46 (dd, 1H, H-2 ); 13C NMR (75 MHz) δ 211.91 (C_O), 143.55 (ipso),
128.65, 127.66, 126.90 (Ar), 102.17 (C-1), 86.61 (Ph3C), 79.54 (C-4), 64.73 (C-5), 54.88 (OCH3), 43.48
(C-2).
0
0
3.3. Methyl 2-deoxy-3-C-methyl-5-O-triphenylmethyl-α-D-threo-pentofuranoside and methyl 2-deoxy-
3-C-methyl-5-O-triphenylmethyl-β-D-threo-pentofuranoside 3α,β
To a flask charged with dried cerium trichloride (4.88 g, 19.8 mmol, 130–140°C under vacuum for
24 h) under nitrogen was added dry tetrahydrofuran (60 mL) and the resulting suspension was stirred
for 18 h. The suspension was cooled to −78°C and a solution of methyllithium in diethyl ether (12.9
mL, 1.4 M, 18.1 mmol) was added. The resulting brownish suspension was stirred for an additional hour
after which a solution of 2α (3.2 g, 8.2 mmol) in tetrahydrofuran (18 mL) was added. The resulting
suspension was stirred at −78°C for 15 min and allowed to warm to 0°C. After 2 h, water (10 mL) was
added and the resulting slurry was stirred vigorously for 15 min. The organic layer was decanted off and
the semi-solid residue was washed with ethyl acetate (2×35 mL). The organic layers were combined and
washed with saturated aqueous sodium chloride (40 mL), and the organic layer was dried with anhydrous
magnesium sulfate, filtered and concentrated at reduced pressure. The resulting oil was purified by flash

G. R. Smith et al. / Tetrahedron: Asymmetry 11 (2000) 139–149
145
column chromatography over silica gel (6.5 in×6 cm) with hexanes:ethyl acetate (88:12 to 75:25) to
yield the threo product (2.6 g, 78%, Rf=0.52 in 4:1 toluene:ethyl acetate) and its C-3 epimer, the erythro
product (0.52 g, 16%, Rf=0.64 in 4:1 toluene:ethyl acetate). Data for the 3α threo isomer: [α]D=+56.5
1
0
(c 1.26; CHCl3); H NMR (300 MHz) δ 7.50–7.19 (m, 15H, Ar), 5.14 (dd, J1,2, J1,2 =3.3, 5.7 Hz, 1H,
H-1), 3.91 (app t, J4,5=4.8 Hz, 2H, H-5), 3.41 (d0, 1H, H-4), 3.39 (s, 3H, OCH3), 2.65 (s, 1H, OH), 2.31
(dd, J2,2 =14.0 Hz, 1H, H-2), 1.92 (dd, 1H, H-2 ), 1.38 (s, 3H, 3-CH3); 13C NMR (75 MHz) δ 143.45
0
(ipso), 128.45, 127.85, 127.06 (Ar), 103.94 (C-1), 82.27 (C-4), 78.54 (C-3), 62.19 (C-5), 55.19 (OCH3),
48.86 (C-2), 25.68 (3-CH3). HRMS: calcd for C26H28O4 (M+Na): 427.1872. Found: 427.1880.
The addition of methylcerium to 2β afforded threo product 3β as a single isomer. From 3.4 g (8.8
mmol) of 2β, 2.2 g (68%) of syrupy 3β was obtained: [α]D=−34.5 (c 1.36; CHCl3); Rf=0.63 in 4:1
1
0
toluene:ethyl acetate; H NMR (300 MHz) δ 7.56–7.19 (m, 15H, Ar), 5.05 (dd, J1,2, J1,2 =1.7, 3.3 Hz,
0
1H, H-1), 3.96 (dd, J4,5, J5,5 =6.4, 4.2 Hz, 2H, H-5), 3.37 (d, 1H, H-4), 3.35 (s, 3H, OCH3), 3.27 (s, 1H,
OH), 2.04 (dd, 2H, H-2), 1.26 (s, 3H, 3-CH3); 13C NMR (75 MHz) δ 143.94 (ipso), 128.70, 127.64,
126.79 (Ar), 104.42 (C-1), 87.20 (C-4), 77.41 (C-3), 64.31 (C-5), 54.75 (OCH3), 46.93 (C-2), 23.01
(3-CH3). Anal. calcd for C26H28O4: C, 77.20; H, 6.98. Found: C, 77.32; H, 7.15.
3.4. Methyl 3-O-benzyl-2-deoxy-3-C-methyl-5-O-triphenylmethyl-α-D-threo-pentofuranoside and
methyl 3-O-benzyl-2-deoxy-3-C-methyl-5-O-triphenylmethyl-β-D-threo-pentofuranoside 4α,β
To a solution of 3α (200 mg, 0.49 mmol) in benzyl chloride (neat, 1.5 mL) was added powdered
potassium hydroxide (1.0 g) and the resulting slurry was heated to 130–140°C for 2 h, after which
time no starting material was observed by TLC. The reaction mixture was allowed to cool to ambient
temperature and was then transferred to a separation funnel with water and ethyl acetate. The layers
were separated, the organic layer was washed with saturated aqueous sodium chloride and dried with
anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The resulting syrup was
purified by flash column chromatography over silica gel with hexanes:ethyl acetate (90:10 to 75:25) to
give 4α as a syrup (155 mg, 70% yield): [α]D=+14.6 (c 1.39; CHCl3); Rf=0.66 in 3:1 hexanes:ethyl
acetate; 1H NMR (300 MHz) δ 7.55–7.03 (m, 20H, Ar), 5.08 (dd, J1,2, J1,2 =3.5, 5.8 Hz, 1H, H-1), 4.37
0
(ABq, J=12.1 Hz, 2H, Bn), 4.09 (t, J4,5=3.7 Hz,02H, H-5), 3.45 (d, 1H, H-4), 3.41 (s, 3H, OCH3), 2.54
(dd, J2,2 =14.2 Hz, 1H, H-2), 1.79 (dd, 1H, H-2 ), 1.43 (s, 3H, 3-CH3); 13C NMR (75 MHz) δ 144.07
0
(ipso), 139.18 (ipso), 128.70, 127.58, 126.73 (Ar), 127.99, 126.80, 126.39 (Ar), 103.94 (C-1), 84.75
(C-4), 82.85 (C-3), 64.51 (Bn), 62.49 (C-5), 55.18 (OCH3), 43.76 (C-2), 21.51 (3-CH3). HRMS: calcd
for C33H34O4 (M+Na): 517.2349. Found: 517.2366. The β-anomer 4β was also prepared by the same
method. From 6.5 g (16.1 mmol) of 3β, 6.9 g (87%) of syrupy 4β was obtained, which was purified by
flash column chromatography over silica gel with hexanes:ethyl acetate (9:1 to 3:1): [α]D=–42.7 (c 1.41;
CHCl3); Rf=0.53 in 3:1 hexanes:ethyl acetate; 1H NMR (300 MHz) δ 7.55–7.06 (m, 20H, Ar), 5.06 (dd,
0
0
J1,2, J1,2 =2.5, 5.9 Hz, 1H, H-1), 4.37 (ABq, J=11.8 Hz, 2H, Bn), 4.03 (dd, J4,5, J5,5 =6.7, 4.8 Hz, 2H, H-
0
0
5), 3.46 (d, 1H, H-4), 3.39 (s, 3H, OCH3), 2.31 (dd, J2,2 =13.9 Hz, 1H, H-2), 1.99 (dd, 1H, H-2 ), 1.37 (s,
3H, 3-CH3); 13C NMR (75 MHz) δ 144.19 (ipso), 139.20 (ipso), 128.75, 127.88, 126.66 (Ar), 128.61,
127.52, 126.51 (Ar), 104.45 (C-1), 87.02 (C-4), 81.44 (C-3), 65.00 (Bn), 63.98 (C-5), 55.20 (OCH3),
42.29 (C-2), 22.49 (3-CH3). Anal. calcd for C33H34O4: C, 80.13; H, 6.93. Found: C, 79.71; H, 6.95.
3.5. Methyl 3-O-benzyl-2-deoxy-3-C-methyl-α-D-threo-pentofuranoside and methyl 3-O-benzyl-
2-deoxy-3-C-methyl-β-D-threo-pentofuranoside 5α,β
To a stirring solution of trityl ether 4α (0.88 g, 1.78 mmol) in methanol (20 mL) was added Amberlyst-
15 macroreticular resin (strongly acidic; 500 mg) and the reaction mixture was allowed to stir for 8 h at

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G. R. Smith et al. / Tetrahedron: Asymmetry 11 (2000) 139–149
room temperature, filtered through Celite, neutralized with triethylamine, and concentrated at reduced
pressure. Careful purification by flash column chromatography over silica gel with hexanes:ethyl acetate
(85:15 to 50:50) yielded a syrup (283 mg, 63%) containing a 7:1 mixture of α- and β-anomers with nearly
identical Rf values. Column fractions highly enriched in β-anomer were pooled for NMR analysis and
subsequent oxidation when the detritylation was carried out on a larger scale (see below). The α-anomer
eluted first. Compound 5α: Rf=0.5 in 1:1 hexanes:ethyl acetate; 1H NMR (300 MHz) δ 7.36–7.24 (m,
0
5H, Ar), 5.16 (dd, J1,2, J1,2 =2.5, 5.8 Hz, 1H, H-1), 4.46 (ABq, J=11.4 Hz, 2H, Bn), 3.99–3.83 (m, 2H, H-
0
0
4, H-5), 3.39 (s, 3H, OCH3), 2.77 (dd, J5,OH, J5 ,OH=3.9, 8.1, 1H, OH), 2.56 (dd, J2,2 =13.9 Hz, 1H, H-2),
1.89 (dd, 1H, H-20), 1.52 (s, 3H, 3-CH3); 13C NMR (75 MHz) δ 138.29 (ipso), 128.28, 127.43, 126.77
(Ar), 103.86 (C-1), 84.91 (C-4), 84.78 (C-3), 65.24 (Bn), 60.97 (C-5), 55. 13 (OCH3), 43.74 (C-2), 22.41
(3-CH3). HRMS: calcd for C14H20O4Na (M+Na): 275.1254. Found: 275.1258. Compound 5β: Rf=0.5
in 1:1 hexanes:ethyl acetate; 1H NMR (300 MHz) δ 7.36–7.24 (m, 5H, Ar), 5.04 (dd, J1,2, J1,2 =3.3, 5.9
0
Hz, 1H, H-1), 4.49 (ABq, J=11.0 Hz, 2H, Bn), 3.99-3.83 (m, 3H, H-4, H-5), 3.40 (s, 3H, OCH3), 2.71 (d,
J5,OH=6.2 Hz, 1H, OH), 2.37 (dd, J2,2 =13.8 Hz, 1H, H-2), 2.11 (dd, 1H, H-2 ), 1.49 (s, 3H, 3-CH3); 13C
NMR (75 MHz) δ 138.3 (Ar ipso), 128.36, 127.51, 127.03 (Ar), 104.7 (C-1), 86.4 (C-4), 84.80 (C-3),
66.08 (Bn), 62.3 (C-5), 55.13 (OCH3), 42.24 (C-2), 23.88 (3-CH3). HRMS: calcd for C14H21O4 (M+H):
253.1434. Found: 253.1429.
0
0
A larger scale detritylation of 4β (2.4 g, 4.85 mmol) under these conditions gave 700 mg (57%) of a
4:1 mixture of 5α and 5β.
3.6. Methyl 2-deoxy-3-C-methyl-α-D-threo-pentodialdo-1,4-furanoside 6α,β
To a stirring solution of methyl sulfoxide (0.91 g, 12 mmol, 0.83 mL) in dichloromethane (15 mL) at
−78°C under nitrogen was added a solution of trifluoroacetic anhydride (1.9 g, 8.9 mmol, 1.3 mL). After
10 min, a solution of alcohol 5α (1.4 g, 5.6 mol) in dichloromethane (15 mL) was added and the reaction
mixture was stirred for an additional 15 min. Triethylamine (1.7 g, 17 mmol, 2.4 mL) was added and
the reaction mixture was allowed to warm to room temperature for 1 h. Saturated aqueous ammonium
chloride (40 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The organic
layers were combined, washed with saturated aqueous sodium chloride (30 mL) and the organic layer
was dried with anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to give 1.2 g
of crude, unstable dialdose 6α which was used promptly: Rf=0.63 in 3:1 hexanes:ethyl acetate; 1H NMR
(300 MHz) δ 9.7 d, J=3.7 Hz, CHO); 13C NMR (75 MHz) δ 201.14 (CHO). Oxidation of 5β (0.68 g, 2.7
mmol) using the same method gave 0.6 g of dialdofuranoside 6β (Rf=0.66 in 3:1 hexanes:ethyl acetate).
3.7. Methyl 3-O-benzyl-2,6-dideoxy-3-C-methyl-α-D-arabino-hexofuranoside 7α and methyl
3-O-benzyl-2,6-dideoxy-3-C-methyl-β-L-xylo-hexofuranoside 8β
To a stirring solution of pentodialdo-1,4-furanoside 6α (1.2 g, 4.8 mmol) in diethyl ether (anhydrous,
20 mL) under nitrogen at room temperature was added a solution of methylmagnesium chloride in
tetrahydrofuran (3.2 mL of a 3.0 M solution). The resulting mixture was stirred for 1 h, after which
saturated aqueous ammonium chloride (10 mL) was added and the mixture was extracted with diethyl
ether (2×30 mL). The organic layers were combined, washed with saturated aqueous sodium chloride
(10 mL) dried with anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The
resulting oil was purified by flash column chromatography over silica gel with hexanes:ethyl acetate (4:1
to 7:3) to yield 345 mg (27%) of β-L-xylo isomer 8β and 260 mg (20%) of the α-D-arabino isomer 7α.
Compound 7α: Rf=0.79 in 1:1 hexanes:ethyl acetate; [α]D=+60.4 (c 0.81; CHCl3); 1H NMR (300 MHz)

G. R. Smith et al. / Tetrahedron: Asymmetry 11 (2000) 139–149
147
0
δ 7.38–7.23 (m, 5H, Ar), 5.05 (dd, J1,2, J1,2 =1.4, 5.6 Hz, 1H, H-1), 4.51 (ABq, J=11.5 Hz, 2H, Bn), 4.05
(ddq, J4,5, J5,OH, J5,6=8.0, 4.0, 6.4 Hz, 1H, H-5), 3.57 (d, 1H, H-4), 3.34 (s, 3H, OCH3), 3.21 (d, 1H, OH),
0
2.45 (dd, J2,2 =13.5 Hz, 1H, H-2), 1.98 (dd, 1H, H-2 ), 1.63 (s, 3H, 3-CH3), 1.30 (d, 3H, H-6); 13C NMR
(75 MHz) δ 138.28 (ipso), 128.43, 127.50, 126.88 (Ar), 103.49 (C-1), 88.83 (C-4), 84.47 (C-3), 67.43
(C-5), 65.52 (Bn), 54.64 (OCH3), 44.59 (C-2), 25.17 (3-CH3), 20.10 (C-6). HRMS calcd for C15H23O4
(M+H): 267.1591. Found: 267.1592.
0
Compound 8β: Rf=0.60 in 1:1 hexanes:ethyl acetate; [α]D=+58 (c 0.98; CHCl3); 1H NMR (300 MHz)
δ 7.36–7.24 (m, 5H, Ar), 5.19 (dd, J1,2, J1,2 =2.8, 5.7 Hz, 1H, H-1), 4.47 (ABq, J=11.4 Hz, 2H, Bn),
0
4.23–4.18 (m, 1H, H-5), 3.61 (brd, J4,5=2.2 Hz,01H, H-4), 3.39 (s, 3H, OCH3), 3.38 (d, 1H, OH), 2.60
0
(dd, J2,2 =14.0 Hz, 1H, H-2), 1.84 (dd, 1H, H-2 ), 1.50 (s, 3H, 3-CH3), 1.32 (d, J5,6=6.6 Hz, 3H, H-6);
13C NMR (75 MHz) δ 138.29 (Ar ipso), 128.48, 127.543, 126.89 (Ar), 103.38 (C-1), 87.43 (C-4), 85.15
(C-3), 65.11 (Bn), 60.97 (C-5), 55.06 (OCH3), 43.88 (C-2), 21.90 (3-CH3), 19.85 (C-6). HRMS calcd
for C15H23O4 (M+H): 267.1591. Found: 267.1593.
3.8. Methyl 3-O-benzyl-2,6-dideoxy-3-C-methyl-β-D-arabino-hexofuranoside 7β and methyl
3-O-benzyl-2,6-dideoxy-3-C-methyl-α-L-xylo-hexofuranoside 8α
To a stirring solution of pentodialdo-1,4-furanoside 6β (600 mg, 2.7 mmol) in diethyl ether (anhy-
drous, 10 mL) under nitrogen at room temperature was added a solution of methylmagnesium chloride
in tetrahydrofuran (1.8 mL of a 3.0 M solution). The resulting mixture was stirred for 1 h, after which
saturated aqueous ammonium chloride (10 mL) was added and the mixture was extracted with diethyl
ether (2×20 mL). The organic layers were combined, washed with saturated aqueous sodium chloride
(10 mL), dried with anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The
resulting oil was purified by flash column chromatography over silica gel with hexanes:ethyl acetate (4:1
to 7:3) to yield 148 mg (23%) of β-D-arabino isomer 7β and 107 mg (17%) of α-L-xylo isomer 8α.
Compound 7β: Rf=0.74 in 1:1 hexanes:ethyl acetate; [α]D=−61 (c 1.31; CHCl3); 1H NMR (300 MHz)
0
δ 7.38–7.23 (m, 5H, Ar), 4.96 (dd, J1,2, J1,2 =3.8, 5.8 Hz, 1H, H-1), 4.52 (ABq, J=10.9 Hz, 2H, Bn),
0
4.12 (dq, J4,5, J5,6=9.1, 6.3 Hz, 1H, H-5), 3.44 (d, 1H, H-4), 3.38 (s, 3H, OCH3), 2.31 (dd, J2,2 =13.5 Hz,
1H, H-2), 2.18 (dd, 1H, H-20), 1.54 (s, 3H, 3-CH3), 1.25 (d, 3H, H-6); 13C NMR (75 MHz) δ 137.89
(ipso), 128.45, 127.67, 127.22 (Ar), 104.69 (C-1), 89.76 (C-4), 84.34(C-3), 67.77 (C-5), 66.61(Bn), 55.37
(OCH3), 42.27 (C-2), 25.32 (3-CH3), 19.46 (C-6).
Compound 8α: Rf=0.57 in 1:1 hexanes:ethyl acetate; [α]D=−41 (c 1.22; CHCl3); 1H NMR (300 MHz)
0
δ 7.36–7.24 (m, 5H, Ar), 5.07 (dd, J1,2, J1,2 =2.2, 5.7 Hz, 1H, H-1), 4.49 (ABq, Jab=11.0 Hz, 2H, Bn),
0
4.12 (dq, J4,5, J5,6=2.8, 6.5 Hz, 1H, H-5), 3.59 (d, 1H, H-4), 3.44 (s, 3H, OCH3), 2.49 (dd, J2,2 =13.9 Hz,
1H, H-2), 2.00 (dd, 1H, H-20), 1.44 (s, 3H, 3-CH3), 1.27 (d, 3H, H-6); 13C NMR (75 MHz) δ 138.29
(Ar ipso), 128.24, 127.53, 127.07 (Ar), 104.11 (C-1), 90.533 (C-4), 82.93 (C-3), 65.65, 65.21 (Bn, C-5),
55.08 (OCH3), 41.77 (C-2), 23.10 (3-CH3), 20.17 (C-6).
3.9. Methyl 2,6-dideoxy-3-C-methyl-β-L-xylo-hexofuranoside 9β
A sample of 25 mg of 8β was treated with hydrogen and palladium hydroxide (20 mg) in ethanol
1
(5 mL) to give debenzylated product 9β, the H and 13C NMR spectrum of which matched reports by
Villani.6b

148
G. R. Smith et al. / Tetrahedron: Asymmetry 11 (2000) 139–149
3.10. Methyl 3-O-benzyl-2,6-dideoxy-3-C-methyl-α-L-xylo-hexopyranoside 10 and methyl 3-O-benzyl-
2,6-dideoxy-3-C-methyl-β-L-xylo-hexopyranoside 11
To a stirring solution of 8β (320 mg, 1.2 mmol) in methanol (anhydrous, 20 mL) was added hydrogen
chloride (1.32 mL of a 1.0 M solution in diethyl ether) and the resulting solution was heated at 50°C for
3 h. The reaction mixture was allowed to cool to room temperature after which silver carbonate (530 mg,
1.9 mmol) was added and the mixture was stirred for 0.5 h. The suspension was filtered through Celite
and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography
over silica gel with hexanes:ethyl acetate (4:1 to 7:3) to yield 130 mg (41%) of β-anomer 11 and 62 mg
(19%) of α-anomer 10.
Compound 11: [α]D=+13.1 (c 1.1; CHCl3); Rf=0.63 in 1:1 hexanes:ethyl acetate; 1H NMR (300 MHz)
0
δ 7.38–7.22 (m, 5H, Ar), 4.58 (dd, J1,2, J1,2 =2.4, 9.8 Hz, 1H, H-1), 4.51 (ABq, J=10.2 Hz, 2H, Bn), 4.19
(dq, J4,5, J5,6=0.9, 6.6 Hz, 1H, H-5), 3.49 (s, 3H, OCH3), 3.19 (dd, J4,OH=10.1 Hz, 1H, H-4), 2.08–1.95
0
(m, 2H, H-2, OH), 1.53 (dd, J2,2 =14.2 Hz, 1H, H-2 ), 1.40 (s, 3H, 3-CH3), 1.27 (d, 3H, H-6); 13C NMR
(75 MHz) δ 138.69 (ipso), 128.31, 127.36, 127.11 (Ar), 100.01 (C-1), 77.12 (C-3), 72.51 (C-4), 68.83
(C-5), 63.45 (Bn), 56.33 (OCH3), 35.30 (C-2), 21.38 (3-CH3), 16.54 (C-6). HRMS calcd for C15H23O4
(M+H): 267.1591. Found: 267.1592.
0
Compound 10: Rf=0.58 in 1:1 hexanes:ethyl acetate; 1H NMR (300 MHz) δ 7.38–7.22 (m, 5H, Ar),
4.71 (d, J1,2=4.8 Hz, 1H, H-1), 4.50 (ABq, J=10.2 Hz, 2H, Bn), 4.53 (q, J5,6=6.6 Hz, 1H, H-5), 3.36 (s,
0
3H, OCH3), 3.18 (d, J4,OH=9.3 Hz, 1H, H-4), 2.11 (dd, J2,2 =15.6 Hz, 1H, H-2), 1.92 (d, 1H, OH), 1.69
(dd, 1H, H-20), 1.34 (s, 3H, 3-CH3), 1.21 (d, 3H, H-6); 13C NMR (75 MHz) δ 139.33 (ipso), 128.46,
127.64, 127.11 (Ar), 97.95 (C-1), 74.23 (C-3), 73.56 (C-4), 63.76 (C-5), 62.32 (Bn), 54.82 (OCH3),
30.99 (C-2), 22.30 (3-CH3), 16.66 (C-6).
3.11. Methyl 3,4-di-O-benzyl-2,6-dideoxy-3-C-methyl-β-L-xylo-hexopyranoside 12
To a stirring solution of β-anomer 11 (430 mg, 1.61 mmol) in benzyl chloride (neat, 3.1 mL) was
added powdered potassium hydroxide (2.1 g) and the resulting slurry was heated to 120–130°C for 1.5
h, after which time no starting material was observed by TLC. The reaction mixture was allowed to cool
and was then transferred to a separation funnel with water and ethyl acetate. The layers were separated,
the organic layer was washed with saturated aqueous sodium chloride and was dried with anhydrous
magnesium sulfate, filtered and concentrated at reduced pressure. The resulting syrup was purified by
flash column chromatography over silica gel with hexanes:ethyl acetate (9:1) to give the product as a
1
syrup (530 mg, 92% yield): [α]D=−22.6 (c 1.29; CHCl3); Rf=0.66 in 3:1 hexanes:ethyl acetate; H
0
NMR (300 MHz) δ 7.47–7.22 (m, 10H, Ar), 4.70 (ABq, J=11.7 Hz, 2H, 4-OBn), 4.61 (dd J1,2, J1,2 =2.1,
9.9 Hz, 1H, H-1), 4.49 (ABq, J=11.1 Hz, 2H, 3-OBn), 4.15 (dq, J4,5, J5,6=1.2, 6.6 Hz, 1H, H-5), 3.50
0
0
(s, 3H, OCH3), 3.10 (d, 1H, H-4), 2.00 (dd, J2,2 =13.8 Hz, 1H, H-2), 1.73 (dd, 1H, H-2 ), 1.37 (s, 3H,
3-CH3), 1.29 (d, 3H, H-6); 13C NMR (75 MHz) δ 138.65, 137.94 (ipso), 128.28, 128.07, 127.85, 127.46,
127.31, 127.09 (Ar), 99.43 (C-1), 80.07 (4-OBn), 77.53 (C-3), 75.78 (C-4), 69.10 (C-5), 63.16 (Bn),
56.13 (OCH3), 35.86 (C-2), 21.43 (3-CH3), 16.89 (C-6). HRMS calcd for C22H29O4 (M+H): 357.2060.
Found: 357.2061.
3.12. Phenyl 3,4-di-O-benzyl-2,6-dideoxy-3-C-methyl-1-thio-α,β-L-xylo-hexopyranoside 13
To a stirring solution of dibenzyl ether 12 (750 mg, 2.1 mmol) in dichloromethane (dry, 8 mL)
under nitrogen at 0°C was added phenylthiotrimethylsilane (2.0 mL, 10.5 mmol), then trimethylsilyl

G. R. Smith et al. / Tetrahedron: Asymmetry 11 (2000) 139–149
149
trifluoromethanesulfonate (457 mL, 2.52 mmol). The reaction mixture was allowed to warm to ambient
temperature for 3 h. The reaction mixture was then poured into water and extracted with dichloromethane.
The organic layer was washed with saturated aqueous sodium chloride and was dried with anhydrous
sodium sulfate, filtered and concentrated at reduced pressure to give a syrup that was purified by flash
column chromatography over silica gel with hexanes:ethyl acetate (94:6). The product was obtained as a
syrup containing a 3:1 mixture of β- and α-anomers (748 mg, 82% yield): Rf=0.57 in 5:1 hexanes:ethyl
acetate; β-anomer: 1H NMR (300 MHz) δ 7.58–7.17 (m, 15H, Ar), 5.07 (dd, J1,2, J1,2 =5.4, 9.0 Hz, 1H,
0
H-1), 4.68 (ABq, J=11.7 Hz, 2H, 4-OBn), 4.45 (ABq, J=11.6 Hz, 2H, 3-OBn), 4.20 (dq, J4,5, J5,6=0.9,
6.5 Hz, 1H, H-5), 3.10 (brs, 1H, H-4), 2.29–2.02 (m, 2H, H-2), 1.33 (s, 3H, 3-CH3), 1.29 (d, 3H, H-6);
13C NMR (75 MHz) δ 138.52, 138.09 (ipso), 134.77 (SAr ipso), 130.68–126.56 (Ar), 80.02 (4-OBn),
79.90 (C-1), 76.82 (C-3), 75.64 (C-4), 71.95 (C-5), 63.26 (3-OBn), 35.69 (C-2), 21.39 (3-CH3), 17.37
(C-6). HRMS: calcd for C27H30O3SNa (M+Na): 457.1808. Found: 457.1816.
Acknowledgements
The authors thank Merck Research Laboratories, the R. W. Johnson Pharmaceutical Research Institute
and Villanova University for financial support of this work. We also thank Patrice Ciecko and C. W. Ross
III of Merck for elemental analyses and HRMS measurements, respectively.
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