Synthesis of α-2-deoxyglycosides by acid-mediated conjugate addition

Article abstract of DOI:10.1081/CAR-200059931

A new method for the synthesis of α-2-deoxyglycosides from hex-1-en-3-uloses is reported. Several acids were surveyed for their ability to mediate the conjugate addition of cyclohexanol to a glucal derived αβ-unsaturated ketone. Although several acids suc

Full text of DOI:10.1081/CAR-200059931

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Synthesis of α‐2‐Deoxyglycosides by
Acid‐Mediated Conjugate Addition
Brent Mann a , Daniel Pitts a & Jennifer Koviach a
a Department of Chemistry , Bates College , Lewiston, ME
Published online: 16 Aug 2006.
To cite this article: Brent Mann , Daniel Pitts & Jennifer Koviach (2005) Synthesis of
α‐2‐Deoxyglycosides by Acid‐Mediated Conjugate Addition, Journal of Carbohydrate Chemistry, 24:2,
161-168, DOI: 10.1081/CAR-200059931
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Journal of Carbohydrate Chemistry, 24:161–168, 2005
Copyright # Taylor & Francis, Inc.
ISSN: 0732-8303 print
DOI: 10.1081/CAR-200059931
Synthesis of a-2-
Deoxyglycosides
by Acid-Mediated
Conjugate Addition
Brent Mann, Daniel Pitts, and Jennifer Koviach
Department of Chemistry, Bates College, Lewiston, ME
A new method for the synthesis of a-2-deoxyglycosides from hex-1-en-3-uloses is
reported. Several acids were surveyed for their ability to mediate the conjugate
addition of cyclohexanol to a glucal derived a,b-unsaturated ketone. Although several
.
acids successfully afforded the a-2-deoxy-3-uloside as a single anomer, Ph3P HBr in
benzene afforded the highest yield of product. These conditions were then applied to
other alcohol nucleophiles, and it was found that nonsterically hindered alcohols
readily undergo conjugate addition. Finally, the stereoselectivity of reduction of the
resulting a-2-deoxy-3-uloside was determined for several hydride-reducing agents.
Keywords 2-Deoxyglycosides, Conjugate addition
INTRODUCTION
Many antibiotic and antitumor natural products contain one or more 2-deoxy-
glycosides.[1] Although the aglycon is typically responsible for the biological
activity, the carbohydrate moieties are necessary in many cases for the bioac-
tivity of the drug.[2] Since many 2-deoxy sugars are not readily isolated from
nature, it is important that we have access to the preparation of such
compounds. Many 2-deoxyglycosides also contain unusual stereochemistry or
functionality at C-3, including O-alkylation, branching, amines, and nitro
groups. Many of these functionalities could be installed from ketones such as
2 (Sch. 1).[3–6] We envisioned that ketone 2 could be readily prepared by
conjugate addition of nucleophilic alcohols to hex-1-en-3-uloses, such as 1
Received November 29, 2004; accepted January 1, 2005.
Address correspondence to Jennifer Koviach, Department of Chemistry, Bates College, 5
Andrews Road, Lewiston, ME. Tel.: 207-786-6292; Fax: 207-786-8336; E-mail: jkoviach@
bates.edu
161

B. Mann et al.
162
Scheme 1: Synthesis of 2-deoxyglycosides by conjugate addition followed by
functionalization.
(Sch. 1). There are several previous reports of conjugate addition of alcohols to
hex-1-en-3-uloses under basic conditions, but the reported yields are typically
low, unless the nucleophile is the solvent, such as methanol.[7] We report here
our studies on the acid-mediated conjugate addition of alcohols to the hex-1-en-
3-ulose 1, derived from D-glucal, as well as the stereoselectivity of reduction by
several hydride reagents to give compound 3.
RESULTS AND DISCUSSION
Compound 1 was prepared from 3,4,6-tri-O-acetyl-D-glucal either by direct
oxidation with in situ generated Koser’s reagent[8] or by a three-step procedure
involving (1) global deacetylation, (2) selective allylic oxidation with pyridi-
nium dichromate, and (3) acetylation.[9]
We first surveyed a series of acids in several solvents for the conjugate
addition of cyclohexanol to 1 (entries 1–5, Table 1). Very mild acids such as
pyridinium p-toluenesulfonic acid (PPTS) resulted in no conjugate addition.
However, stoichiometric amounts of acids, such as p-toluenesulfonic acid, cam-
.
phorsulfonic acid, and Ph3P HBr, afforded exclusively the a-cyclohexyl glyco-
side. The stereoselectivity most likely arises due to the reversibility of the
conjugate addition, resulting in the most stable glycoside. Nonpolar solvents
(CH2Cl2 and benzene) were found to be superior to polar solvents (CH3CN
and THF), which were either sluggish or resulted in decomposition of
.
starting material. The optimal conditions were found to be PPh3 HBr in
˚
benzene in the presence of 4 A molecular sieves, which afforded a 61% yield
of the cyclohexyl glycoside. Although the starting material is cleanly and com-
1
pletely converted into product as determined by monitoring by TLC and H
NMR, the product was found to be somewhat unstable and decomposed upon
isolation and purification, resulting in lower yields than expected.

Synthesis of a-2-Deoxyglycosides
Table 1: Acid-mediated addition of alcohols to hex-1-en-3-ulose 1.
163
Entry
Nucleophile
Acid
Solvent
Product
Yield
1
2
3
4
5
6
7
8
CyOH (1.5 eq.)
CyOH (1.5 eq.)
CyOH (1.5 eq.)
CyOH (2.5 eq.)
CyOH (1.5 eq.)
BnOH (1.5 eq.)
p-TsOH (1.0 eq.)
p-TsOH (1.0 eq.)
CH2Cl2
PhH
CH2Cl2
PhH
PhH
PhH
2a
2a
2a
2a
2a
2b
2c
2d
52%
38%
N.R.
61%
37%
51%
62%
40%
.
HBr PPh3 (1.0 eq.)
.
HBr PPh3 (1.5 eq.)
CSA (1.5 eq.)
.
HBr PPh3 (0.1 eq.)
.
4-penten-1-ol (1.5 eq.)
1,2:3,4-di-O-
HBr PPh3 (0.5 eq.)
PhH
PhH
.
HBr PPh3 (1.0 eq.)
isopropylidene-D-
galactose (1.5 eq.)
diacetone-D-glucose
(1.5 eq.)
.
9
HBr PPh3 (2.0 eq.)
PhH
PhH
N.A.
N.A.
N.R.
N.R.
.
HBr PPh3 (0.5 eq.)
10
CBZ-Ser-OMe (2.0 eq.)
We then investigated the use of other alcohols as nucleophiles using our
optimal conditions (entries 6–10, Table 1). Nonsterically hindered alcohols
such as benzyl alcohol and 4-penten-1-ol cleanly afforded exclusively the
.
a-anomers with catalytic Ph3P HBr. The yield was reduced when the more
sterically hindered 1,2:3,4-di-O-isopropylidene-D-galactose was utilized as
the nucleophile, and no product was observed with diacetone-D-glucose, even
under forcing conditions using excess acid and heat. In addition, as expected,
alcohols prone to acid-catalyzed elimination, such as N-CBZ-serine-OMe,
were not useful as nucleophiles.
With the hex-1-en-3-ulose 2a in hand, we investigated the stereoselectivity
of hydride reduction of the ketone to an alcohol, and these results are shown in
Table 2. Previous studies have shown that simple NaBH4 reduction of 2b
affords the allo isomer 3, while Luche reduction results in the gluco
isomer 4, which we verified.7b We found that NaBH4 and DIBAL-H afforded
the allo isomer as the major product, while L-Selectride was completely selec-
tive for the allo isomer. Reduction with LiAlH4 was not selective, affording both
3 and 4 almost equally. Because compound 2a is somewhat unstable to purifi-
cation by silica gel chromatography, we attempted a NaBH4 reduction of crude
2a. However, this sequence did not result in a higher overall yield, affording
3/4 in 56% yield from 1.

B. Mann et al.
164
Table 2: Hydride reduction of 2a.
Entry
Conditions
Yield
3:4
1
2
3
4
1. NaBH4; Amberlite IRN-78 2OH form, MeOH
DIBAL-H, CH2Cl2
L-Selectride
LiAlH4
85%
63%
50%
77%
6:1
7.7:1
25:1
1.6:1
CONCLUSIONS
We have developed a two-step method for the synthesis of 2-deoxyglycosides
from hex-1-en-3-uloses derived from glucal. The reaction is most useful when
nonsterically hindered alcohols that are not subject to elimination are
utilized as the nucleophile. Hydride reduction of the resulting ketone typically
affords a mixture of the allo and gluco isomers, though the allo glycoside can be
prepared almost exclusively by reduction with L-Selectride.
EXPERIMENTAL
General Methods
All reactions were performed under Ar in oven-dried glassware with anhy-
drous solvent. Melting points were obtained on a Mel-Temp apparatus and are
1
uncorrected. H NMR and 13C NMR spectra were recorded on a Bruker spec-
1
trometer at 400 MHz and 100 MHz for H and 13C, respectively. Elemental
analyses were performed by Prevalere Life Sciences. TLC was performed on
Merck 60 F254 plates with 1:1 hexanes/ethyl acetate as eluent, and visualized
first by UV light and second by anisaldehyde stain. Column chromatography
˚
was performed using silica gel 60 A 32–63 mm purchased from Sorbent
Technologies.
General procedure for the preparation of 2a–d: Cylcohexyl-4,6-di-O-acetyl-2-
deoxy-a-D-erythro-hexopyranosid-3-ulose (2a)
The enone 1 (139 mg, 0.609 mmol) was dissolved in benzene (6 mL) under
˚
.
Ar. Crushed 4 A molecular sieves, Ph3P HBr (250 mg, 0.728 mmol) and cyclo-
hexanol (0.16 mL, 1.5 mmol) were added, and the reaction was stirred at rt
overnight, at which time TLC analysis indicated disappearance of starting

Synthesis of a-2-Deoxyglycosides
165
material. The reaction was concentrated to approximately 1/2 volume and then
purified by pouring directly onto a silica gel column using hexane: ethyl acetate
(2:1) as eluent to afford 2a (121 mg, 0.369 mmol, 61%), which solidified on
standing. m.p. 60–628C. 1H NMR (CDCl3, 400 MHz) d 5.39 (d, J ¼ 4.5 Hz,
1H), 5.17 (d, J ¼ 10.2 Hz, 1H), 4.22–4.33 (m, 3H), 3.55 (m, 1H), 2.82
(dd, J ¼ 4.6, 14.2 Hz, 1H), 2.58 (d, J ¼ 14.1 Hz, 1H), 2.15 (s, 3H), 2.08 (s, 3H),
1.8 (m, 2H), 1.7 (m, 2H), 1.5 (m, 1H), 1.2–1.4 (m, 5H); 13C NMR (CDCl3,
100 MHz) d 198.1, 170.6, 169.4, 96.5, 75.8, 73.2, 69.5, 62.7, 46.6, 33.1, 31.2,
25.5, 24.0, 23.8, 20.7, 20.4. Anal. Calcd for C16H24O7: C, 58.52; H, 7.37.
Found: C, 58.21; H, 7.20.
Benzyl-4,6-di-O-acetyl-2-deoxy-a-D-erythro-hexopyranosid-3-ulose (2b)
.
Processed as described above, using 1 (45 mg, 0.20 mmol), Ph3P HBr
(6.8 mg, 0.020 mmol), and benzyl alcohol (0.062 mL, 0.60 mmol) to afford 2b
1
(34 mg, 0.10 mmol, 51%), which solidified on standing. m.p. 123–1268C. H
NMR (CDCl3, 400 MHz) d7.29–7.38 (m, 5H), 5.33 (d, J ¼ 4.3 Hz, 1H), 5.23
(d, J ¼ 10.3 Hz, 1H), 4.62 (AB, J ¼ 12.1, Dn ¼ 59.1 Hz, 2H), 4.33 (dd, J ¼ 4.1,
11.9 Hz, 1H), 4.2 (m, 2H), 2.85 (dd, J ¼ 4.6, 14.4 Hz, 1H), 2.71 (d, J ¼ 14.2 Hz,
1H), 2.17 (s, 3H), 2.12 (s, 3H). 13C NMR (CDCl3, 100 MHz) d 197.7, 170.6,
169.4, 136.4, 128.6, 128.1, 128.0, 97.6, 73.0, 69.7, 69.5, 62.5, 46.0, 20.8, 20.4.
Anal. Calcd for C17H20O7: C, 60.71; H, 5.99. Found: C, 60.71; H, 5.91.
(4-pentenyl)-4,6-di-O-acetyl-2-deoxy-a-D-erythro-hexopyranosid-3-ulose (2c)
Processed as described above, using 1 (135 mg, 0.591 mmol), 4-penten-1-ol
.
(0.092 mL, 0.89 mmol), and Ph3P HBr (102 mg, 0.297 mmol) to afford 2c as a
colorless oil (114 mg, 0.362 mmol, 62%). 1H NMR (CDCl3, 400 MHz) d 5.76
(dddd, J ¼ 6.6, 6.6, 10.3, 17.0 Hz, 1H), 5.23 (d, J ¼ 4.3 Hz, 1H), 5.19
(d, J ¼ 10.4 Hz, 1H), 5.00 (d, J ¼ 17.7 Hz, 1H), 4.96 (d, J ¼ 10.5 Hz, 1H),
4.33 (dd, J ¼ 4.4, 12.2 Hz, 1H), 4.35 (d, J ¼ 12.6 Hz, 1H), 4.20 (m, 1H), 3.65
(ddd, J ¼ 6.5, 6.5, 9.7 Hz, 1H), 3.41 (ddd, J ¼ 6.4, 6.5, 9.6 Hz, 1H), 2.83
(dd, J ¼ 4.5, 14.3 Hz, 1H), 2.65 (d, J ¼ 14.2 Hz, 1H), 2.17 (s, 3H), 2.08 (s, 3H),
2.0 (m, 2H), 1.65 (m, 2H). 13C NMR (CDCl3, 100 MHz) d 197.8, 170.6, 169.4,
137.8, 115.2, 98.5, 73.0, 69.4, 67.3, 62.5, 46.2, 30.1, 28.3, 20.8, 20.5. Anal.
Calcd for C15H22O7: C, 57.32; H, 7.05. Found: C, 56.96; H, 7.38.
(1,2:3,4-di-O-isopropylidene-D-galactosyl)-4,6-di-O-acetyl-2-deoxy-a-D-erythro-
hexopyranosid-3-ulose (2d)
Processed as described above, using 1 (43 mg, 0.19 mmol), 1,2:3,4-di-O-iso-
.
propylidene-D-galactose (73 mg, 0.28 mmol), and Ph3P HBr (64 mg, 0.19 mmol)
to afford 2d as a colorless oil (37 mg, 0.075 mmol, 40%). 1H NMR (CDCl3,
400 MHz) d5.48 (d, J ¼ 5.0 Hz, 1H), 5.30 (d, J ¼ 4.3 Hz, 1H), 5.22
(d, J ¼ 10.4 Hz), 4.60 (dd, J ¼ 2.4, 7.9 Hz, 1H), 4.38 (dd, J ¼ 4.1, 12.0 Hz, 1H),
4.19–4.4.35 (m, 4H), 3.90 (td, J ¼ 1.7, 6.4 Hz, 1H), 3.73 (ABX, Jax ¼ 6.2 Hz,

B. Mann et al.
166
Jbx ¼ 6.7 Hz, J AB ¼ 10.2 Hz, Dn ¼ 29.6 Hz, 2H), 2.84 (ddd, J ¼ 0.8. 4.6, 14.4 Hz,
1H), 2.69 (dd, J ¼ 0.8, 14.3 Hz, 1H), 2.17 (s, 3H), 2.11 (s, 3H), 1.51 (s, 3H), 1.43
(s, 3H), 1.32 (s, 6H). Anal. Calcd for C22H32O12: C, 54.09; H, 6.60. Found: C,
53.84; H, 6.87.
NaBH4 reduction of 2a
To the ketone 2a (110 mg, 0.335 mmol) in methanol (3 mL) was added
NaBH4 (6.3 mg, 0.34 mmol). The reaction was stirred for 3 hr, at which time
TLC analysis indicated disappearance of starting material. The reaction was
quenched with water and diluted with ethyl acetate. The layers were separ-
ated, and the organic layer was washed with brine. The combined aq. layers
were extracted with ethyl acetate. The combined organic layers were dried
over Na2SO4, filtered, and concentrated. The crude product was redissolved
in methanol (3 mL), and Amberlite IRN-78 2OH form was added. The
reaction was stirred for 2 hr, at which time TLC analysis indicated completion.
The reaction was filtered through Celite and concentrated, to afford an insepar-
able 6:1 mixture of 3 and 4 (71 mg, 0.29 mmol, 85%), which was not purified
1
further. 3: H NMR (CDCl3, 400 MHz) d 5.09 (d, J ¼ 3.3 Hz, 1H), 4.0 (br s,
1H), 3.72–3.89 (m, 4H), 3.61 (m, 1H), 3.48 (dd, J ¼ 3.2, 10.1 Hz, 1H), 2.9 (br
s, 1H), 2.5 (br s, 1H), 2.12 (ddd, J ¼ 0.85, 3.3, 14.6 Hz), 1.88 (dt, J ¼ 3.4,
14.6 Hz, 1H), 1.8 (m, 1H), 1.70 (m, 1H), 1.24–1.51 (m, 8H); 13C NMR (CDCl3,
100 MHz) d 94.8, 75.1, 68.7, 67.6, 67.5, 62.6, 35.2, 33.3, 31.0, 25.5, 24.0, 23.6.
Anal. Calcd for C12H22O5: C, 58.52; H, 9.00. Found: C, 58.62; H, 8.62.
DIBAL-H reduction of 2a
The ketone 2a (43 mg, 0.13 mmol) was dissolved in CH2Cl2 (1.2 mL) and
cooled to 08C. DIBAL-H (1.0 M in CH2Cl2, 0.52 mL, 0.52 mmol) was added,
and the reaction was stirred for 5 min before warming to rt. The reaction was
stirred for 2 hr, at which time TLC analysis indicated disappearance of
starting material. The reaction was cooled to 08C, and methanol followed by
sodium potassium tartrate were added, and the reaction was stirred for 1 hr.
The reaction was diluted with ethyl acetate, and the layers were separated.
The organic layer was washed with brine and the combined aq. layers were
extracted with ethyl acetate. The combined org. layers were dried over
Na2SO4, filtered, and concentrated. The crude product was purified by
column chromatography using 1:1 hexanes/ethyl acetate as eluent to afford
an inseparable 7.7:1 mixture of 3:4 (20 mg, 0.081 mmol, 63%).
L-Selectride reduction of 2a
The ketone 2a (37 mg, 0.11 mmol) was dissolved in THF and cooled to 08C.
L-Selectride (1 M in THF, 0.5 mL, 0.5 mmol) was added, and the reaction was
warmed to rt. The reaction was stirred for 6 hr, at which time TLC analysis
indicated completion. The reaction was cooled to 08C, and 3 M NaOH

Synthesis of a-2-Deoxyglycosides
167
(0.2 mL) followed by 30% H2O2 (0.1 mL) were added. The reaction was stirred
for 1 hr at 08C, and then warmed to rt. The solution was filtered through
Celite with ethyl acetate, and the organic layer was washed with brine. The
aq. layer was extracted with ethyl acetate, and the combined org. layers
were dried over Na2SO4,, filtered, and concentrated to afford an inseparable
25:1 mixture of 3:4 (13.4 mg, 0.054 mmol, 50%).
LiAlH4 reduction of 2a
The ketone 2a (50 mg, 11.4 mmol) was dissolved in THF and cooled to 08C.
LiAlH4 (23 mg, 0.61 mmol) was added, and the reaction was warmed to rt. The
reaction was stirred for 4 hr at which time TLC analysis indicated completion.
The reaction was cooled to 08C, quenched with water (0.23 mL), 1 M NaOH
(0.23 mL), and water (0.46 mL), and filtered through Celite with ethyl
acetate. The filtrate was washed with brine, dried over Na2SO4, filtered, and
concentrated. The crude product was purified by column chromatography
using 1:1 hexanes/ethyl acetate as eluent to afford an inseparable 1.6:1
mixture of 3 and 4 (28.5 mg, 0.116 mmol, 77%).
ACKNOWLEDGEMENT
We gratefully acknowledge financial support for this project from Research
Corporation in the form of a Cottrell College Science Award and a Bates
College intramural grant supported by the Howard Hughes Research
Institution. This work was greatly facilitated by a 400 MHz NMR spectrometer
that was purchased partly with funds from an NSF Major Research Instru-
mentation Program Grant, CHE-0115579.
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