Synthesis of the central portion of cycloviracin

Full text of DOI:10.1021/jo961623r

J . Org. Chem. 1996, 61, 9541-9545
9541
Sch em e 1
Syn th esis of th e Cen tr a l P or tion of
Cyclovir a cin
Steve Velarde, J ames Urbina,† and Michael R. Pen˜a*
Department of Chemistry and Biochemistry, Arizona State
University, Box 871604, Tempe, Arizona 85287-1604
Received August 20, 1996
In tr od u ction
Sch em e 2
Cycloviracin B1 (1) was recently isolated from a soil
microorganism and discovered to have activity against
Herpes simplex virus.1 The interesting structure of the
cycloviracins reveals the presence of a “core” portion
composed of two glucose molecules as part of the mac-
rolactone.2 Attached to the glycosidic core are two alkyl
side chains with several 2-methylglucopyranosides. The
stereogenic centers of the alkyl group at the site of
attachment to the macrolactone portion and those along
the alkyl side chains are currently unknown. To help
elucidate the various stereogenic centers and because of
the unique structure and antiviral activity, we set out to
synthesize the core region of cycloviracin. In this paper,
we wish to communicate our results in preparing a
suitably protected glycoside intermediate 16 that served
as a precursor for the stepwise construction of the
cycloviracin core. This effort should aid in the determi-
nation of the two unknown stereogenic centers of the core.
ate, such as 2 (Scheme 1). We reasoned that an enzy-
matic approach would “dimerize” glucopyranoside 2 to 3
using porcine pancreatic lipase (PPL) or chromobacte-
rium viscosum lipase (CVL).4 Early results with a simple
model system (methyl â-glucopyranoside) were discour-
aging as acylations with simple trichloroethyl esters did
not yield the desired 6-acylated monosaccharide. These
results prompted us to employ a different approach.
Retrosynthetic analysis identified the needed compo-
nents and reduced the problem to glucopyranoside 7
(Scheme 2), which may be available from 4 and 5 via 6.
The goal became preparation of glycoside 7 that is both
suitably functionalized and protected to allow for a
stepwise construction of the core region. The presence
of the pivolates on the glucopyranosyl bromide 4 sug-
gested the need for conversion of the carboxylic ester to
a protected p-methoxybenzyl ether that is stable to the
base-catalyzed removal of the pivolates yet can be oxi-
datively removed. We arbitrarily choose the S-configu-
ration for the â-hydroxy ester as 9 can be obtained from
the Bakers’ yeast reduction of ethyl acetoacetate.5 The
â-hydroxy ester can also be obtained by ruthenium-
BINAP reduction of â-keto esters.6 Reductions of various
â-keto esters using Bakers’ yeast typically give 70-90%
ee and in our hands, â-hydroxy ester 9 of 85% ee was
obtained. The enantiomeric purity was determined by
Resu lts An d Discu ssion
An examination of the cycloviracin core reveals a
macrolactone consisting of two nearly identical glycosidic
esters with the core reminiscent of crown ethers.3 As the
cycloviracin core is composed of two glucose molecules
acylated at the 6-position, we initially investigated
enzymatic methods for esterifying a glucopyranoside at
the 6-position with an appropriate activated ester. An
enzymatic approach would have allowed for a facile entry
of the core region in one step from a suitable intermedi-
† Undergraduate research participant.
(1) Tsunakawa, M.; Komiyama, N.; Tenmyo, O.; Tomita, K.; Kawano,
K.; Kotake, C.; Konishi, M.; Oki, T. J . Antibiot. 1992, 45, 1467-1471.
(2) Tsunakawa, M.; Kotake, C.; Yamasaki, T.; Moriyama, T.; Kom-
ishi, M.; Oki, T. J . Antibiot. 1992, 45, 1472-1480.
(4) Therisod, M.; Klibanov, A. M. J . Am. Chem. Soc. 1986, 108,
5638-5640. Therisod, M.; Klibanov, A. M. J . Am. Chem. Soc. 1987,
109, 3977-3981. Riva, S.; Chopineau, J .; Kieboom, A. P. G.; Klibanov,
A. M. J . Am. Chem. Soc. 1988, 110, 584-589.
(3) For an example of crown ethers: Lein, G. M.; Cram, D. J . J .
Am. Chem. Soc. 1985, 107, 448-455. McDaniel, C. W.; Bradshaw, J .
S.; Izath, R. M. Heterocycles 1990, 30, 665-706. Aza-crown ethers:
Krakowiak, K. E.; Bradshaw, J . S.; Zamecka-Krakowiak, D. J . Chem.
Rev. 1989, 89, 929-972. Aza-crown ethers incorporating a carbohy-
drate: Bako, P.; Fenichel, L.; Toke, L.; Davison, B. E. J . Chem. Soc.,
Perkin Trans. 1 1989, 2514-2516.
(5) Seebach, D.; Sutter, M. A.; Weber, R. H.; Zu¨ger, M. F. Org. Synth.
1984, 63, 1-9. Nakamura, K.; Kawai, Y.; Oka, S.; Ohno, A. Bull. Chem.
Soc. J pn. 1989, 62, 875-879. Crump, D. R. Aust. J . Chem. 1982, 35,
1945-1948.
(6) Keck, G. E.; Murry, J . A. J . Org. Chem. 1991, 56, 6606-6611.
Noyori, R.; Ohkuma, T.; Kitamura, M.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S. J . Am. Chem. Soc. 1987, 109, 5856-5858.
S0022-3263(96)01623-4 CCC: $12.00 © 1996 American Chemical Society

9542 J . Org. Chem., Vol. 61, No. 26, 1996
Notes
Sch em e 3
Sch em e 4
conversion to the O-methylmandelate7 and Mosher’s
ester8 followed by examination of 1H- and 19F-NMR
spectral data, respectively. Saponification of ethyl ester
9 and benzylation afforded 10.9
groups with 4-azidobutyryl chloride13 yielded 16, which
gave spectral data (1H, 13C-NMR, COSY, and NOE) that
were consistent with the correct placement of protecting
groups. Intermediate 16 was then ready for divergence
to the two coupling partners 17 and 19 for the stepwise
construction of the core region (Scheme 4). Desilylation
of 16 afforded 17, whereas oxidative removal of the PMB
group from 16 followed by RuCl3-mediated oxidation
yielded acid 19.
The two components were coupled (DCC/DMAP) to
yield 20, and after oxidative removal of the p-methoxy-
benzyl ether, oxidation of the alcohol to the acid, and
desilylation ((a) DDQ; (b) NaIO4/RuCl3/CCl4-CH3CN-
water; (c) HF-pyridine), precursor 23 was obtained
(Scheme 5). Disaccharide 23 was submitted to the
Yamaguchi macrocyclization14 to give protected 24 in 73%
yield. We were quite pleased with the cyclization because
few side products were obtained as judged by TLC
analysis. The last step, reductive removal of the azi-
dobutryrate groups to give 25, was initially troublesome.
The product was finally obtained by employing distilled
ethanol in both the reduction and thermolysis to 25 and
the pyrrolidinone byproduct. Purification by column
chromatography (30% MeOH-CHCl3) yielded a white
solid whose spectral data (1H, 13C, HMBC, HMQC, MS)
indicated >95% purity. A minor side product isolated
and identified was the ethyl ester of the monosaccharide.
Synthetic lactone 25 was nearly consistent with cyclo-
viracin. The 13C, HMBC, HMQC, and HRMS were
exceedingly useful in confirming 25; however, two of the
When R-glucopyranosyl bromide 4 was employed as the
glycosylation reagent10 glycoside 11 was obtained in good
yield and anomeric control (Scheme 3). Spectral analysis
of 11 revealed that the anomeric integrity was main-
tained. A closer examination showed the presence of a
small amount (∼5%) of the diastereomer resulting from
the inefficient Bakers’ yeast reduction of the â-keto ester;
however, we anticipated removal of the unwanted dias-
tereomer at latter stages. Reductive removal of the
benzyl ester afforded the crystalline acid 12 and following
diborane reduction in the presence of the pivolates
yielded alcohol 13. Protection of 13 (PMBO-trichloro-
acetimidate/triflic acid catalyst)11 followed by pivolate
removal cleanly afforded glycoside 14. Spectral exami-
nation of 14 (1H- and 13C-NMR) showed removal of the
unwanted diastereomer by flash chromatography. Sily-
lation of 14 occurred regioselectively12 to place the tert-
butyldimethylsilyl protecting group at the 6-position,
affording 15. Esterification of the remaining hydroxyl
(7) Trost, B. M.; Belletire, J . L.; Godleski, S.; McDougal, P. G.;
Balkovec, J . M.; Baldwin, J . J .; Christy, M. E.; Ponticello, G. S.; Varga,
S. L.; Springer, J . P. J . Org. Chem. 1986, 51, 2370-2374. Bonner, W.
A. J . Am. Chem. Soc. 1951, 73, 3126-3132.
(8) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512-
519. Ko¨nig, W. A.; Nippe, K.-S.; Mischnick, P. Tetrahedron Lett. 1990,
31, 6867-6868.
(9) Sakaki, J .-i.; Kobayashi, S.; Sato, M.; Kaneko, C. Chem Pharm.
Bull. 1989, 37, 2952-2960.
(10) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212-
235. Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155-173. Mori,
K.; Qian, Z.-H. Leibigs Ann. Chem. 1994, 291-295. Kunz, H.; Harreus,
A. Liebigs Ann. Chem. 1982, 41-48. Collins, P.; Ferrier, R. Mono-
saccharidessTheir Chemistry and Their Roles in Natural Products;
Wiley: New York, 1995; pp 60-184.
(11) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron
Lett. 1988, 29, 4139-4142.
(12) Hanessian, S.; Lavalee, P. Can. J . Chem. 1975, 53, 2975-2977.
Franke, F.; Guthrie, R. D. Aust. J . Chem. 1977, 639-647.
(13) Kucumoto, S.; K. Sakai, K.; Shiba, T. Bull. Chem. Soc. J pn.
1986, 59, 1296-1298. Goel, O. P.; Seamans, R. E. Synthesis 1973, 538-
539.
(14) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamuguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.

Notes
J . Org. Chem., Vol. 61, No. 26, 1996 9543
stirred in the dark, under N2, for 2 d. The mixture was filtered
through Celite and the solvent removed under reduced pressure.
The residue was purified by column chromatography (25%
EtOAc/hexane) to give 1.3 g (83% yield) of 11 as a colorless
viscous oil that slowly crystallized upon standing: mp 76-77
°C; Rf ) 0.54 (25% EtOAc/hexane); [R]24D +12.6° (c 12.5, CHCl3);
1H(CDCl3) δ 1.0, 1.1, 1.13, 1.18 (4s, 36H), 1.2 (d, 3H, J ) 6.0
Hz), 2.3 (dd, 1H, J ) 5.5, 16.5 Hz), 2.5 (dd, 1H, J ) 7.7, 16.5
Hz), 3.5-3.6 (m, 1H), 3.9 (dd, 1H, J ) 6.0, 12.1 Hz), 4.1-4.2
(m, 1H, methine), 4.1-4.2 (m, 1H), 4.6 (d, 1H, J ) 8.2 Hz),
4.8-5.0 (m, 3H), 5.1-5.2 (m, 2H), 7.3-7.4 (m, 5H); 13C (CDCl3)
δ 177.9, 177.0, 176.4, 176.3, 170.6, 135.5, 128.6, 128.4, 128.4,
100.1, 72.2, 72.1, 71.9, 71.2, 68.2, 66.3, 62.0, 41.9, 38.7, 38.6,
38.6, 27.0 (overlapping signals), 21.8. Anal. Calcd for C37H56O12
(692.84): C, 64.14; H, 8.15. Found: C, 63.89; H, 8.21.
Sch em e 5
(3S)-3-[(2,3,4,6-Tetr a-O-pivaloyl-â-D-glu copyr an osyl)oxy]-
bu ta n oic Acid (12). A solution containing 4.46 g (6.43 mmol)
of 11, 200 mL of methanol, and 400 mg of Pd-C (5% Pd) was
hydrogenated for 5 h using a Parr hydrogenation apparatus.
Filtration of the mixture through a pad of Celite and evaporation
of solvent in vacuo left a viscous oil that was further purified
by column chromatography (50% EtOAc/hexane followed by 50%
EtOAc/methanol) to give 3.67 g (95% yield) of 12 as a white
solid: Rf ) 0.1 (25% EtOAc/hexane); mp 171.5-173 °C; [R]24
D
+7.8° (c 17.7, CHCl3); 1H(CDCl3) δ 1.1, 1.11, 1.13, 1.2 (4s, 36H),
1.3 (d, 3H, J ) 6.3 Hz), 2.4 (dd, 1H, J ) 5.5, 16.7 Hz), 2.6 (dd,
1H, J ) 7.1, 16.5 Hz), 3.7-3.8 (m, 1H), 3.9 (dd, 1H, J ) 6.3,
12.1 Hz), 4.15 (m, 1H), 4.2 (dd, 1H, J ) 1.9, 12.1 Hz), 4.7 (d, 1H,
J ) 8.0 Hz), 4.94-5.1 (m, 2H), 5.3 (t, 1H, J ≈ 9.4 Hz); 13C (CDCl3)
δ 178.1, 177.2, 176.6, 176.5, 176.1, 100.6, 72.4, 72.2, 71.4, 68.3,
62.1, 41.5, 38.9, 38.8, 38.7, 38.7, 27.1 (overlapping signals), 21.9.
Anal. Calcd for C30H50O12 (602.72): C, 59.78; 8.36. Found: C,
59.67; H, 8.37.
carbon atoms, C-3′ and C-1 (anomeric), were slightly
different (<4 ppm). All of the other carbons were within
1 ppm with authentic cycloviracin. We are currently
examining 25 and another simple analog of cycloviracin
in order to determine the configuration of the two
stereogenic centers at the â-hydroxy glycosidic portion.
Our findings will be reported in the future.
(3S)-3-[(2,3,4,6-Tetr a-O-pivaloyl-â-D-glu copyr an osyl)oxy]-
1-bu ta n ol (13). A solution of 2.52 g (4.19 mmol) of 12, 30 mL
of THF, and 8.4 mL (1 M, 8.4 mmol) of BH3-THF was allowed
to stir at 0 °C for 30 min, followed by warming to rt for an
additional 30 min. The reaction was slowly quenched by
dropwise addition of 16 mL of water. The mixture was poured
into a separatory funnel containing Et2O/water. The aqueous
layer was extracted with ether (2 × 20 mL), and the combined
organic layers were washed with saturated aqueous NaHCO3
(2 × 30 mL) and then dried over MgSO4. Filtration and
evaporation of solvent in vacuo left a solid that was further
purified by column chromatography (50% EtOAc/hexane) to give
2.92 g (93% yield) of 13 as a white solid: Rf ) 0.68 (50% EtOAc/
Exp er im en ta l Section
Gen er a l Meth od s. All solvents were distilled from calcium
hydride prior to use except for tetrahydrofuran (THF), which
was distilled from molten potassium, and ethyl ether, which was
distilled from sodium-benzophenone. Methanol and ethanol
were distilled from Mg turnings. All reagents were used as
obtained from commercial suppliers unless otherwise noted. Thin
layer chromatography was performed with glass-backed pre-
coated plates (Si-254F). Column chromatography utilized silica
gel 230-400 mesh, 60 Å. The following deuterated solvents and
their following internal reference points were used: deuterio-
chloroform (CDCl3) with tetramethylsilane (TMS) referenced to
TMS (0.000 ppm 1H) or chloroform (77.00 ppm 13C), methanol-
d4 referenced to methanol (3.48 ppm 1H and 39.00 ppm 13C),
and pyridine-d5 referenced to pyridine (7.22 ppm 1H and 123.5
ppm 13C). Melting points are uncorrected. Elemental analyses
were performed by Atlantic Microlab (Norcross, GA). Mass
spectroscopy (FAB) was performed at the Nebraska Center for
Mass Spectroscopy and Washington University Resource for
Biomedical and Bioorganic Mass Spectrometry.
2,3,4,6-Tetr a -O-p iva loyl-r-D-glu cop yr a n osyl Br om id e (4).
This compound was prepared in two steps from D-glucose and
pivoyl chloride, according to a literature procedure.10 Glucose
was first converted to 1,2,3,4,6-penta-O-pivaloyl-â-D-glucopyra-
nose [mp 145-149 °C; Rf ) 0.43 (12% EtOAc/hexane); 1H (CDCl3)
δ 1.1 (s, 18H), 1.13 (s, 9H), 1.15 (s, 9H), 1.18 (s, 9H), 3.8-3.9
(m, 1H), 4.1-4.2 (m, 2H), 5.1-5.2 (m, 2H), 5.3-5.4 (t, 1H, J )
9.4 Hz), 5.7 (d, 1H, J ) 8.3 Hz)], which was then treated with
HBr in acetic acid to give 4 as a white solid: mp ) 145 °C; Rf )
0.53 (12% EtOAc/hexane); 1H (CDCl3) δ 1.1 (s, 9H), 1.14 (s, 9H),
1.15 (s, 9H), 1.2 (s, 9H), 4.1 (m, 2H), 4.2-4.3 (dt, 1H, J ) 3.2
Hz, 10.5 Hz), 4.7-4.8 (dd, 1H, J ) 4.1 Hz, 9.9 Hz), 5.2 (t, 1H, J
) 9.9 Hz), 5.6 (t, 1H, J ) 9.7 Hz), 6.6 (d, 1H, J ) 4.0 Hz); 13C
(CDCl3) δ 177.9, 177.3, 176.8, 176.4, 86.9, 72.6, 70.9, 69.6, 66.6,
60.9, 38.9, 38.8, 38.680, 27.2, 27.1.
hexane); mp 125-127 °C; [R]24 +10.1° (c 25.6, CHCl3); 1H
D
(CDCl3) δ 1.1, 1.12, 1.13, 1.2 (4s, 36H), 1.23 (d, 3H, J ) 6.4 Hz),
1.6-1.8 (m, 2H), 3.6 (pent, 1H), 3.66-3.7 (m, 2H), 3.9 (m, 1H),
3.95 (dd, 1H, J ) 6.4, 12.1 Hz), 4.6 (d, 1H, J ) 7.7 Hz), 4.9-5.1
(m, 2H), 5.3 (t, 1H, J ) 9.5 Hz); 13C (CDCl3) δ 181.1, 177.1, 176.6,
176.5, 100.5, 75.2, 72.4, 72.1, 71.6, 68.3, 62.2, 59.3, 39.4, 38.8,
38.7, 38.7, 27.1, 27.1, 27.1, 27.0, 21.5. Anal. Calcd for C30H52O11
1/2H2O: C, 60.28; H, 8.94. Found: C, 60.28; H, 8.94.
‚
1-[(p -Met h oxyb en zyl)oxy]-(3S)-3-(â-D-glu cop yr a n osyl-
oxy)bu ta n e (14). A solution of 4.16 g (7.07 mmol) of 13, 3.0 g
(10.6 mmol, 1.50 equiv) of 4-methoxybenzyl 2,2,2-trichloroace-
timidate, 50 mL of Et2O, and one drop (from a microliter syringe)
of trifluoromethanesulfonic acid (TfOH) was stirred under N2
at rt until TLC analysis showed complete consumption of
starting material (about 2 h). The reaction mixture was poured
into a separatory funnel containing aqueous saturated NaHCO3
and ether. The aqueous phase was washed with ether (2 × 50
mL), and the combined organic layers were dried over MgSO4.
Filtration and evaporation of solvent in vacuo left a viscous oil
that was further purified by column chromatography (25%
EtOAc/hexane) to give a solid that by 1H-NMR showed the
product and excess 4-methoxybenzyl alcohol (obtained by the
hydrolysis of the trichloroacetimidate during workup). HPLC
analysis showed a 4:1 ratio of product over 4-methoxybenzyl
alcohol. The product was not fully characterized but carried on
1
to the next step: Rf ) 0.46 (25% EtOAc/hexane); H (CDCl3) δ
1.1, 1.15, 1.17, 1.21 (4s, 36H), 1.2 (d, 3H), 1.6-1.8 (m, 2H), 3.4-
3.5 (m, 2H), 3.6 (m, 1H), 3.8 (s, 3H), 4.0 (dd, 1H, J ) 6.6, 12.1
Hz), 4.2 (dd, 1H, J ) 1.9, 12.1 Hz), 4.9-5.5.1 (m, 2H), 5.2 (t,
1H, J ≈ 9.5 Hz), 6.9 (d, 2H, J ) 8.7), 7.25 (d, 2H, J ) 8.7 Hz) for
selected peaks. A solution made up of the crude glucoside, 30
mL of a 3% NaOH solution, and 80 mL of ethanol was stirred
(3S)-Ben zyl 3-[(2,3,4,6-Tetr a -O-p iva loyl-â-D-glu cop yr a -
n osyl)oxy]bu ta n oa te (11). A solution of 200 mg (1.00 mmol)
of 10, 1.19 g (2.1 mmol, 2.00 equiv) of 4, 568 mg (2.1 mmol) of
Ag2CO3, 2.50 g of 4 Å molecular sieves, and 50 mL of ether was

9544 J . Org. Chem., Vol. 61, No. 26, 1996
Notes
until TLC analysis showed complete comsumption of starting
material (about 36 h). The reaction mixture was quenched by
the addition of 4 g of Amberlite until pH 7. The solution was
filtered and the Amberlite washed with MeOH. Evaporation of
solvent in vacuo gave a viscous oil that was further purified by
column chromatography (10% MeOH/CHCl3) to give 2.39 g
(90.8% from 13) of 14 as a viscous oil that slowly crystallized
5.2 (t, 1H, J ) 9.3 Hz), 6.9 (d, 2H, J ) 8.6 Hz), 7.25 (d, 2H, J )
8.4 Hz); 13C (CDCl3) δ 171.9, 171.8, 171.0, 159.3, 130.3, 129.3,
113.9, 100.4, 74.5, 73.8, 73.1, 72.6, 71.9, 68.9, 65.8, 61.4, 55.2,
50.3, 50.3, 37.0, 30.9, 30.8, 30.7, 24.0, 22.0. Anal. Calcd for
C
30H43N9O11 (705.72): C, 51.06; H, 6.14; N, 17.86. Found: C,
50.99; H, 6.16; N, 17.80.
(3S)-3-[[2,3,4-Tr is-O-(4-a zid ob u t a n oyl)-6-O-(ter t-b u t yl-
d im eth ylsilyl)-â-D-glu cop yr a n osyl]oxy]-1-bu ta n ol (18). To
a solution of 2.40 g (2.93 mmol) of 16 in 35 mL of CH2Cl2/water
(18:1) at 5 °C was added in one portion (730 mg, 3.22 mmol, 1.1
equiv) of DDQ. The reaction was allowed to proceed for 4 h and
then quenched by addition of saturated NaHCO3. The product
was extracted with several portions of EtOAc. The organic
layers were combined, washed once with water, and dried over
MgSO4. Filtration and evaporation of solvent in vacuo left a
viscous oil and was further purified by column chromatography
(50% EtOAc/hexane) to give 1.75 g (83%) of 18: Rf ) 0.38 (50%
upon standing: mp 75-76 °C; Rf ) 0.13 (10% MeOH/CHCl3);
1
[R]24 -10.6° (c 12.6, CHCl3); H (CDCl3) δ 1.2 (d, 3H, J ) 4.2
D
Hz), 1.6-1.70 (m, 1H), 1.8-1.85 (m, 1H), 3.2 (d, 1H, J ) 6.9
Hz), 3.4-3.52 (m, ∼2H), 3.53-3.63 (m, ∼3H), 3.7-3.8 (t, 1H, J
) 6.1 Hz), 3.74 (s, 3H), 3.76 (br s, ∼1H), 3.87 (sext, 1H), 4.3 (d,
1H, J ) 5.40 Hz), 4.34-4.4 (AB quartet, 2H, J ≈ 8.8 Hz), 6.84
(d, 2H, J ) 6.3 Hz), 7.2 (d, 2H, J ) 6.3 Hz); 13C (CDCl3) δ 159.1,
130.2, 129.4, 113.8, 102.8, 76.4, 75.5, 74.9, 73.5, 72.4, 69.4, 66.3,
61.5, 55.2, 36.4, 21.8. Anal. Calcd for C18H28O8: C, 58.05; H,
7.58 (372.41). Found: C, 58.11; H, 7.58.
1-[(p -Met h oxyb en zyl)oxy]-(3S)-3-[[6-O-(ter t-b u t yld im e-
th ylsilyl)-â-D-glu cop yr a n osyl]oxy]bu ta n e (15). A solution
of 1.69 g (4.53 mmol) of 14, 650 mg (9.52 mmol, 2.10 equiv) of
imidazole, and 30 mL of CH2Cl2 was stirred at 0 °C. To this
solution was added in a single portion 752 mg (5.00 mmol, 1.1
equiv) of tert-butyldimethylsilyl chloride dissolved in 5 mL of
CH2Cl2. After the mixture was stirred for 1 d at 0 °C, TLC
analysis showed complete conversion of starting material. The
solvent was removed under reduced pressure, and the residue
was directly applied to a column (10% MeOH/CHCl3) to give 2.0
g (92% yield) of 15 as a viscous oil: Rf ) 0.40 (10% MeOH/
CHCl3); [R]24D -11.6° (c 7.1, CHCl3); 1H (CDCl3) δ 0.05, 0.06 (2s,
6H), 0.9 (s, 9H), 1.22 (d, 3H, J ) 6.6 Hz), 1.70-1.80 (m, 2H),
3.26-3.33 (m, 2H), 3.39-3.53 (m, 3H), 3.56-3.62 (m, 1H), 3.77
(s, 3H), 3.75-3.80 (m, 1H), 3.84-3.93 (m, 2H), 4.04 (br s, 3H),
4.26 (d, 1H, J ) 7.8 Hz), 4.40 (s, 2H), 6.86 (d, 2H, J ) 8.4 Hz),
7.23 (d, 2H, J ) 8.4 Hz); 13C (CDCl3) δ 159.1, 130.1, 129.4, 113.7,
102.7, 76.4, 75.1, 74.9, 73.6, 72.4, 71.6, 66.2, 64.0, 55.1, 36.4,
25.8, 21.8, 18.1, -5.5. Anal. Calcd for C24H42O8Si (486.68): C,
59.23; H, 8.70. Found: C, 59.04; H, 8.74.
EtOAc/hexane); [R]24 +7.57° (c 2.7, THF); 1H (CDCl3) δ 0.04,
D
0.06 (2s, 6H), 0.9 (s, 9H), 1.3 (d, 3H, J ) 6.6 Hz), 1.6-1.75 (m,
4H), 1.8-1.92 (m, 6H), 2.3-2.4 (m, 6H), 3.3-3.37 (m, 6H), 3.5-
3.6 (m, 1H), 3.6-3.75 (m, 4H), 3.9-4.0 (m, 1H), 4.6 (d, 1H, J )
8.1 Hz), 4.9-4.98 (dd, 1H, J ) 7.8, 9.3 Hz), 5.0-5.1 (t, 1H, J ≈
9.6 Hz), 5.17-5.2 (t, 1H, J ) 9.3 Hz); 13C (CDCl3) δ 172.1, 171.3,
171.2, 100.7, 76.1, 74.5, 73.5, 72.0, 68.9, 62.2, 59.3, 50.3, 39.1,
30.9, 30.8, 30.6, 25.8, 25.7, 25.6, 24.0, 23.9, 23.8, 21.8, 18.2,
-5.47, -5.50. Anal. Calcd for C28H49N9O10Si (699.84): C, 48.05;
H, 7.06; N, 18.01. Found: C, 47.78; H, 7.02; N, 17.86.
(3S)-3-[[2,3,4-Tr is-O-(4-a zid ob u t a n oyl)-6-O-(ter t-b u t yl-
dim eth ylsilyl)-â-D-glu copyr an osyl]oxy]-1-bu tan oic Acid (19).
A two-phase solution of 18 (177 mg, 0.253 mmol), 120 mg (0.760
mmol) of KMnO4, 40 mL of water, 30 mL of benzene, and 245
mg (0.760 mmol) of tetrabutylammonium bromide (Bu4NBr) was
stirred until TLC analysis showed complete consumption of 18
(about 3 d). The reaction was quenched by addition of saturated
NaHSO3 and Amberlite. Filtration left a solution that was
extracted with several portions of EtOAc. The organic layers
were combined and washed with brine and dried over MgSO4.
Filtration and evaporation of solvent in vacuo left a viscous oil
that was further purified by column chromatography (50%
EtOAc/hexane) to give 108 mg (60%) of 19 as a visous oil: Rf )
0.32 (50% EtOAc/hexane); [R]24D +2.17° (c 2.0, THF); 1H (CDCl3)
δ 0.04, 0.06 (2s, 6H), 0.9 (s, 9H), 1.25 (br s, 1H), 1.3 (d, 3H, J )
6.6 Hz), 1.8-1.9 (m, 6H), 2.3-2.5 (m, 7H), 2.53-2.61 (dd, 1H, J
) 8.7, 16.2 Hz), 3.3-3.37 (m, 6H), 3.5-3.6 (m, 1H), 3.64-3.73
(m, 2H), 4.2-4.23 (m, 1H), 4.6 (d, 1H, J ) 7.8 Hz), 4.9-4.95
(dd, 1H, J ) 8.4, 9.5 Hz), 5.1 (t, 1H, J ≈ 9.6 Hz), 5.2 (t, 1H, J ≈
9.6 Hz); 13C (CDCl3) δ 175.0, 172.1, 171.2, 171.1, 101.1, 74.4,
74.1, 73.5, 71.7, 68.9, 62.2, 50.4, 41.6, 30.9, 30.8, 30.4, 25.7, 24.0,
1-[(4-Met h oxyb en zyl)oxy]-(3S)-3-[[2,3,4-t r is-O-(4-a zid o-
bu t a n oyl)-6-O-(ter t-b u t yld im et h ylsilyl)-â-D-glu cop yr a n o-
syl]oxy]bu ta n e (16). A solution of 2.38 g (4.90 mmol) of
glycoside 15, 30 mL of CH2Cl2, 2.4 mL (29.4 mmol, 6 equiv) of
pyridine, and 4.34 g (29.4 mmol, 6 equiv) of 4-azidobutyryl
chloride was stirred at 0 °C for 6 h under N2. The reaction
mixture was poured into a separatory funnel containing water
and CH2Cl2. The product was extracted with three (10 mL)
portions of CH2Cl2. The organic layers were combined, washed
with saturated NaHCO3 and brine, and dried over MgSO4.
Filtration and evaporation of solvent in vacuo left a viscous oil
that was further purified by column chromatography (25%
EtOAc/hexane) to give 3.5 g (86% yield) of 16 as a viscous oil:
23.9, 23.7, 21.9, 18.2, -5.4, -5.5. Anal. Calcd for C28H47N9O11
-
Si (713.82): C, 47.11; H, 6.64; N, 17.66. Found: C, 46.83; H,
6.56; N 17.82. Alternatively, compound 19 was obtained using
the NaIO4/RuCl3 method. From 1.18 g (1.68 mmol) of 18, 20
mL of acetonitrile, 35 mL of CCl4, 25 mL of water, 1.48 g (6.91
mmol, 4.1 equiv) of NaIO4, and 22 mg (5 mol %) of RuCl3‚3H2O
was obtained 1.02 g (85%) of 19, which was identical to the acid
using the two-phase permanganate method.
Rf ) 0.35 (25% EtOAc/hexane); [R]24 +15.4° (c 6.4, THF); 1H
D
(CDCl3) δ 0.04, 0.057 (2s, 6H), 0.9 (s, 9H), 1.23 (d, 3H, J ) 5.1
Hz), 1.67-1.74 (m, 2H), 1.8-1.89 (m, 6H), 2.3-2.39 (m, 6H),
3.3-3.35 (m, 6H), 3.4-3.5 (m, 3H), 3.66-3.68 (m, 2H), 3.8 (s,
3H), 3.86-3.9 (m, 1H), 4.37 (d, 1H, J ) 11.6 Hz), 4.44 (d, 1H, J
) 8.4 Hz), 4.5 (d, 1H, J ) 11.6 Hz), 4.9 (dd, 1H, J ≈ 9.4 Hz),
5.05 (t, 1H, J ≈ 9.8 Hz), 5.1 (t, 1H, J ) 9.6 Hz), 6.9 (d, 2H, J )
6.6 Hz), 7.25 (d, 2H, J ) 6.3 Hz); 13C (CDCl3) δ 172.1, 171.1,
171.0, 159.2, 130.4, 129.3, 113.9, 100.6, 74.4, 74.4, 73.6, 72.5,
72.0, 69.0, 65.9, 62.3, 55.3, 50.4, 50.4, 50.3, 37.1, 30.9, 30.9, 30.8,
(3S,3′S)-1-[(4-Meth oxyben zyl)oxy]-3-[[2,3,4-tr is-O-(4-a zi-
dobu tan oyl)-6-[3′-(2′,3′,4′-tr is-O-(4-azidobu tan oyl)-6′-O-(ter t-
bu tyld im eth ylsilyl)-â-D-glu cop yr a n osyl]oxy]-1′-bu ta n oyl-
â-D-glu cop yr a n osyl]oxy]bu ta n e (20). To a solution of 1.32 g
(1.85 mmol) of 19, 1.30 mg (1.85 mmol) of 17, 113 mg (0.923
mmol, 0.5 equiv) of DMAP, and 30 mL of CH2Cl2 at 0 °C was
slowly added (over 7 h) 380 mg (1.85 mmol) of DCC dissolved in
20 mL of CH2Cl2 and the resulting mixture stirred overnight at
rt. The reaction mixture was diluted with EtOAc and filtered
to remove DCU. Evaporation of solvent in vacuo left a waxy
solid that was further purified by column chromatography (50%
EtOAc/hexane) to give 1.94 g (75%) of 20 as a white solid: mp
24.0, 23.9, 21.9, 18.2, -5.4, -5.5. Anal. Calcd for C36H57N9O11
-
Si (819.98): C, 52.73; H, 7.01; N, 15.37. Found: C, 52.64; H,
7.03; N, 15.26.
(3S)-1-[(4-Met h oxyben zyl)oxy]-3-[[2,3,4-t r is-O-(4-a zid o-
bu ta n oyl)-â-D-glu cop yr a n osyl]oxy]bu ta n e (17). A solution
of 2.95 g (3.61 mmol) of 16, 30 mL of dry THF, and excess HF-
pyridine (added via pipet) was stirred overnight at rt. The
reaction was extracted three times from saturated aqueous
NaHCO3 and EtOAc. The organic layers were combined and
dried over MgSO4. Filtration and evaporation of solvent in vacuo
left a pale yellow oil and was further purified by column
chromatography (50% EtOAc/hexane) to afford 2.11 g (83%) of
1
55-56.5 °C; Rf ) 0.59 (50% EtOAc/hexane); H (CDCl3) δ 0.04,
0.06 (2s, 6H), 0.9 (s, 9H), 1.23 (d, 3H, J ) 6 Hz), 1.28 (d, 3H, J
) 6 Hz), 1.65-1.70 (m, 2H), 1.8-1.85 (m, 12H), 2.3-2.4 (m, 13H),
2.5 (dd, 1H, J ) 8, 16 Hz), 3.3-3.4 (m, 12H), 3.4-3.5 (m, 3H),
3.6-3.7 (m, 3H), 3.8 (s, 3H), 3.86-3.9 (m, 1H), 4.1-4.2 (m, 3H),
4.4 (d, 1H, J ) 11.2 Hz), 4.4-4.5 (m, 2H), 4.6 (d, 1H, J ) 8 Hz),
4.9-5.0 (m, 2H), 5.0-5.1 (m, 2H), 5.14-5.2 (m, 2H), 6.9 (d, 2H,
J ) 8.8 Hz), 7.24 (d, 2H, J ) 8.8 Hz); 13C (CDCl3) δ 171.9, 171.8,
171.2, 171.1, 171.0, 170.9, 170.2, 159.2, 130.3, 129.2, 113.8, 100.8,
100.5, 74.9, 74.2, 73.5, 73.4, 73.0, 72.5, 71.6, 71.5, 71.4, 68.8,
17: Rf ) 0.27 (50% EtOAc/hexane); [R]24 +11.7° (c 2.55, THF);
D
1H (CDCl3) δ 1.23 (d, 3H, J ) 6 Hz), 1.6-1.9 (m, 9H), 2.0 (br s,
1H), 2.3-2.43 (m, ∼6H), 3.3-3.35 (m, 6H), 3.4-3.6 (m, 3H), 3.72
(dd, 1H, J ) 2.4, 12.3 Hz), 3.82 (s, 3H), 3.87-3.9 (m, 1H), 4.35
(d, 1H, J ) 11.5 Hz), 4.47 (d, 1H, J ) 11.5 Hz), 4.5 (d, 1H, J )
8.1), 4.9-5.0 (dd, 1H, J ) 7.8, 9.6 Hz), 5.05 (t, 1H, J ) 9.6 Hz),

Notes
J . Org. Chem., Vol. 61, No. 26, 1996 9545
68.5, 65.7, 62.0, 61.8, 55.2, 50.3, 50.27, 50.24, 50.2 (two overlap-
ping carbons), 41.6, 37.0, 30.8, 30.74, 30.70, 30.66, 30.62 (one
overlapping carbon), 25.7, 23.92, 23.88, 23.84, 23.82 (two over-
lapping carbons), 21.9, 21.7, 18.2, -5.4, -5.5. Anal. Calcd for
P r otected Ma cr ola cton e 24. In a 100 mL round-bottomed
flask was placed 100 mg (0.085 mmol) of 23 and 4 mL of THF.
The solution was stirred under N2, and then 0.013 mL (0.093
mmol, 1.1 equiv) of TEA was added via syringe. The solution
was stirred for 5 min, and then 0.013 mL (0.085 mmol) of 2,4,6-
trichlorobenzoyl chloride was added via syringe. The reaction
mixture was stirred at rt for 2.5 h and then filtered using a
Schlenk filtration apparatus. The solvent was removed in vacuo,
and the mixed anhydride was diluted with 160 mL of toluene.
The solution of the mixed anhydride was transferred via cannula
to a 250 mL addition funnel atop a 1 L 2 N round-bottomed flask
containing 250 mL of toluene and 62.1 mg (0.51 mmol, 6 equiv)
of DMAP. The solution was slowly added (over 30 h) to the
DMAP solution, which was heated to reflux. The reaction
mixture was cooled, diluted with ether, and washed successively
with 20 mL of 0.1 N HCl and 100 mL water. The organic layer
was dried over MgSO4. Filtration and evaporation of solvent
in vacuo gave a viscous oil. Purification of the residue by column
chromatography (50% EtOAc/hexane) gave 72 mg (73%) of 24
as a white solid: mp 150-151 °C; Rf ) 0.48 (50% EtOAc/hexane);
1H (CDCl3) δ 1.24 (d, 6H, J ) 6 Hz), 1.8-1.9 (m, 12H), 2.3-2.4
(m, 14H), 2.7 (dd, 2H, J ) 3.7, 14.2 Hz), 3.3-3.4 (m, 12H), 3.8-
3.9 (dt, 2H, J ) 2.1, 9.3 Hz), 4.0-4.2 (m, 6H), 4.64 (d, 2H, J )
7.5 Hz), 4.8-4.95 (m, 4H), 5.3 (t, 2H, J ) 9.3 Hz); 13C(CDCl3) δ
171.9, 171.3, 170.9, 169.0, 98.2, 72.8, 71.6, 71.5, 71.3, 69.3, 63.6,
50.28, 50.26, 50.2, 41.4, 30.8, 30.7 (one overlapping carbon), 24.0,
23.8 (one overlapping carbon), 21.0; FAB HRMS C44H62N18O20
calcd 1163.4471, found 1163.4465 (10 ppm deviation).
C
58H88N18O21Si (1401.53): C, 49.70; H, 6.33; N, 17.99. Found:
C, 49.99; H, 6.24; N, 17.93.
(3S,3′S)-3-[[2,3,4-Tr is-O-(4-a zid obu ta n oyl)-6-[3′-[[2′,3′,4′-
tr is-O-(4-a zid obu ta n oyl)-6′-O-(ter t-bu tyld im eth ylsilyl)-â-D-
glu copyr an osyl]oxy]]-1′-bu tan oyl-â-D-glu copyr an osyl]oxy]-
1-bu ta n ol (21). This compound was prepared according to the
same procedure as 18. From 1.46 g (1.04 mmol) of 20 and 261
mg (1.15 mmol, 1.1 equiv) of DDQ was obtained 1.14 g (85%) of
21 as a white solid: mp 73-75 °C; Rf ) 0.24 (50% EtOAc/
hexane); [R]24D +7.47° (c 3.86, THF); 1H (CDCl3) δ 0.04, 0.06 (2s,
6H), 0.9 (s, 9H), 1.28 (d, 3H, J ) 6 Hz), 1.3 (d, 3H, J ) 6.4 Hz),
1.7-1.74 (m, 2H), 1.8-1.9 (m, 12H), 2.3-2.4 (m, 13H), 2.5 (dd,
1H, J ) 8, 16 Hz), 3.3-3.4 (m, 12H), 3.5-3.6 (m, 1H), 3.65-
3.75 (m, 6H), 4.0 (m, 1H), 4.1-4.2 (m, 3H), 4.6 (d, 1H, J ) 8.4
Hz), 4.64 (d, 1H, J ) 7.6 Hz), 4.9 (t, 1H, J ) 8.4 Hz), 4.96 (t, 1H,
J ) 8, 8.4 Hz), 5.0-5.1 (m, 2H), 5.15-5.2 (m, 2H); 13C (CDCl3)
δ 172.0, 171.9, 171.23, 171.2, 171.1, 171.0, 170.2, 100.7, 100.6,
76.2, 74.3, 73.6, 73.4, 73.0, 71.67, 71.63, 71.6, 68.8, 68.5, 62.1,
61.9, 59.2, 50.35, 50.31, 50.3, 50.27, 50.25 (one overlapping
carbon), 41.7, 39.1, 30.9, 30.8, 30.73, 30.7, 30.5 (one overlapping
carbon), 25.7, 24.0, 23.9, 23.88, 23.85, 23.8 (one overlapping
carbon), 21.8, 21.7, 18.2, -5.4, -5.5. Anal. Calcd for C50H80N18
20Si (1281.38): C, 46.87; H, 6.29; N, 19.68. Found: C, 47.14,
H, 6.23; N, 19.60.
-
O
Ma cr ola cton e 25. Into a 500 mL Parr flask was placed 99
mg (0.085 mmol) of 24, 55 mg of palladium on carbon, 10 mL of
THF, and 300 mL of distilled ethanol. The reaction mixture was
hydrogenated with a Parr hydrogenator overnight at rt. The
solution was filtered through a pad of Celite, washed with 200
mL of ethanol, and then heated to reflux for 4 h. Evaporation
of the solvent in vacuo left a pale yellow oil that was further
purified by column chromatography (30% MeOH/CHCl3) to give
22 mg (52%) of 25 as a white foamy solid: mp 135 °C dec; Rf )
(3S,3′S)-3-[[2,3,4-Tr is-O-(4-a zid obu ta n oyl)-6-[3′-[[2′,3′,4′-
tr is-O-(4-a zid obu ta n oyl)-6′-O-(ter t-bu tyld im eth ylsilyl)-â-D-
glu copyr an osyl]oxy]]-1′-bu tan oyl-â-D-glu copyr an osyl]oxy]-
1-bu ta n oic Acid (22). This compound was prepared according
to the same procedure as 19. From 1.5 g (1.18 mmol) of 21, 1.03
g (4.83 mmol, 4.1 equiv) of NaIO4, 15.4 mg (0.05 equiv) of RuCl3‚-
3H2O, 35 mL of CCl4, 20 mL of water, and 20 mL of acetonitrile
was obtained 1.2 g (77%) of 22 as a white solid: mp 75-77 °C;
Rf ) 0.12 (50% EtOAc/hexane); 1H (CDCl3) δ 0.04, 0.06 (2s, 6H),
0.9 (s, 9H), 1.3 (d, 3H, J ) 6 Hz), 1.32 (d, 3H, J ) 6.6 Hz), 1.8-
1.9 (m, 12H), 2.3-2.6 (m, 16H), 3.3-3.4 (m, 12H), 3.5-3.6 (m,
1H), 3.7-3.8 (m, 3H), 4.2 (m, 4H), 4.6 (d, 1H, J ) 8.1 Hz), 4.7
(d, 1H, J ) 7.8 Hz), 4.9-5.0 (m, 2H), 5.0-5.1 (m, 2H), 5.2-5.3
(m, 2H); 13C (CDCl3) δ 174.5, 172.0, 171.9, 171.3, 171.2, 171.1,
170.3, 101.0, 100.6, 74.3, 73.6, 73.5, 72.9, 71.7, 71.6, 71.4, 68.9,
68.5, 62.2, 61.9, 50.3, 41.7, 41.4, 30.9, 30.8 (overlapping carbons),
30.4, 29.6, 25.7, 23.9, 23.7, 21.7, 18.2, -5.4, -5.5. As this
compound was hygroscopic no elemental analysis could be
obtained.
1
0.30 (30% MeOH/CHCl3); H (pyridine-d5) δ 1.5 (d, 6H, J ) 5.6
Hz), 2.5 (dd, 2H, J ) 11.4, 13.4 Hz), 3.3 (dd, 2H, J ) 3.8, 13.4
Hz), 3.8 (t, 2H, J ) 9.2 Hz), 4.0 (m, 4H), 4.2 (t, 2H, J ) 8.8 Hz),
4.6 (t, 2H, J ) 10.8 Hz), 4.7 (m, 2H), 4.9 (dd, 2H, J ) 1.4, 11.4),
4.95 (d, 2H, J ) 8.0 Hz); 13C (pyridine-d5) δ 170.7, 102.3, 78.5,
74.9, 74.7, 72.5, 71.3, 66.1, 42.7, 22.0; FAB HRMS C20H33O14
calcd 497.1869, found 497.1864 (MH+) (1.2 ppm deviation).
Ack n ow led gm en t. We gratefully acknowledge the
Coalition to Increase Minority Degrees (CIMD) Program
for continued support, Professor Therese Markow Project
Director for the Minority Access to Research Careers
(MARC) (J .U.), and the National Science Foundation
(CHE-8813109) for a 300 MHz spectrometer. The
principal investigator is especially grateful to the Na-
tional Science Foundation for a Career Award (CHE-
9503260).
(3S,3′S)-3-[[2,3,4-Tr is-O-(4-a zid obu ta n oyl)-6-[3′-[[2′,3′,4′-
t r is-O-(4-a zid ob u t a n oyl)-â-D-glu cop yr a n osyl]oxy]]-1′-b u -
ta n oyl-â-D-glu cop yr a n osyl]oxy]-1-bu ta n oic Acid (23). This
compound was prepared according to the same procedure as 17.
From 383 mg (0.296 mmol) of 22 was obtained 300 mg (85%) of
1
23 as a viscous oil: Rf ) 0.12 (50% EtOAc/hexane); H (CDCl3)
δ 1.3 (d, 3H, J ) 6.5 Hz), 1.32 (d, 3H, J ) 6.0 Hz), 1.8-1.9 (m,
∼12H), 2.3-2.5 (m, ∼14H), 2.55-2.6 (m, 2H), 3.3-3.35 (m,
∼12H), 3.6 (m, 2H), 3.7 (m, 2H), 4.2-4.26 (m, 4H), 4.7 (2d, 2H,
J ) 8.0 and 8.0 Hz), 4.95 (m, 2H), 5.1 (m, 2H), 5.2 (m, 2H); 13C
(CDCl3) δ 174.5, 171.9, 171.8, 171.7, 171.3, 171.1, 170.2, 100.8,
99.7, 74.2, 73.8, 73.1, 73.0, 72.8, 71.5, 71.47, 71.3, 68.8, 68.4,
61.9, 61.3, 50.27, 50.26, 50.24, 50.23, 41.6, 41.4, 30.78, 30.76,
30.74, 30.72, 30.6, 30.4, 23.86, 23.85, 23.83, 23.82, 23.7, 21.6,
21.5; FAB HRMS C44H64O21N18 calcd 1180.4493, found 1203.4412
(M+ + Na), (-1.8 ppm deviation).
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H-
and 13C-NMR and HRMS spectra of compounds 23-25 (55
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O961623R