Aluminum- and boron-mediated c-glycoside synthesis from 1,2-anhydroglycosides.

Article abstract of DOI:10.1021/ol006286u

[reaction: see text]This letter describes a single flask strategy to the synthesis of alpha-C-glycosides from glycals. This protocol couples a glycal epoxidation reaction with a C-2 alkoxy-directed carbon-carbon bond-forming reaction.

Full text of DOI:10.1021/ol006286u

ORGANIC
LETTERS
2
000
Vol. 2, No. 17
707-2709
Aluminum- and Boron-Mediated
C-Glycoside Synthesis from
2
1,2-Anhydroglycosides
Jon D. Rainier* and Jason M. Cox
Department of Chemistry, The UniVersity of Arizona, Tucson, Arizona 85721
rainier@u.arizona.edu
Received July 1, 2000
ABSTRACT
This letter describes a single flask strategy to the synthesis of r-C-glycosides from glycals. This protocol couples a glycal epoxidation
reaction with a C-2 alkoxy-directed carbon−carbon bond-forming reaction.
Due to their increased stability to hydrolysis as well as their
presence in a number of interesting natural products, C-
glycosides have received a great deal of attention from the
become attractive is that they can be generated from the
reaction of the corresponding glycal with dimethyldioxirane
under very mild conditions. This enables one to bypass the
isolation of relatively unstable glycosides containing ano-
meric leaving groups, as it is not necessary to isolate the
epoxide prior to the addition of carbon nucleophiles (Scheme
1).
4
1
synthesis and medicinal chemistry community. While this
attention has led to a number of elegant approaches to their
synthesis, to the best of our knowledge there is no readily
available method that enables one to predictably generate
R- or â-C-glycosides from a single glycosyl donor.
Among the many glycosyl donors that have been utilized
in C-glycoside synthesis, 1,2-anhydroglycosides have re-
ceived a significant amount of attention of late. This is largely
due to their utility in the synthesis of C-glycosides having a
trans-relationship between the C-2 hydroxy group and the
anomeric C-C bond through their coupling with carbon
nucleophiles.2 Another reason that these epoxides have
Scheme 1
,3
(1) (a) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Elsevier
Science: Tarrytown, New York, 1995. (b) Postema, M. H. D. C-Glycoside
Synthesis; CRC Press: Boca Raton, Florida, 1995.
(2) For anti-selective epoxide openings, see ref 3 and (a) Klein, L. L.;
McWhorter, W. W., Jr.; Ko, S. S.; Pfaff, K.-P.; Kishi, Y.; Uemura, D.;
Hirata, Y. J. Am. Chem. Soc. 1982, 104, 7362. (b) Bellosta, V.; Czernecki,
S. J. Chem. Soc., Chem. Commun. 1989, 199. (c) Best, W. M.; Ferro, V.;
Harle, J.; Stick, R. V.; Tilbrook, D. M. G. Aust. J. Chem. 1997, 50, 463.
(d) Timmers, C. M.; Dekker, M.; Buijsman, R. C.; van der Marel, G. A.;
Ethell, B.; Anderson, G.; Burchell, B.; Mulder, G. J.; Van Boom, J. H.
Bioorg. Med. Chem. Lett. 1997, 7, 1501. (e) Guo, J. S.; Duffy, K. J.; Stevens,
K. L.; Dalko, P. I.; Roth, R. M.; Hayward, M. M.; Kishi, Y. Angew. Chem.,
Int. Ed. 1998, 37, 187. (f) Evans, D. A.; Trotter, B. W.; C oˆ t e´ , B. Tetrahedron
Lett. 1998, 39, 1709. (g) Evans, D. A.; Trotter, B. W.; Coleman, P. J.;
C oˆ t e´ , B.; Dias, L. C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999,
In the course of our recently completed formal total
synthesis of hemibrevetoxin B using C-glycoside technology
5
5, 8671.
3) (a) Rainier, J. D.; Allwein, S. P. J. Org. Chem. 1998, 63, 5310. (b)
Rainier, J. D.; Allwein, S. P. Tetrahedron Lett. 1998, 39, 9601.
(4) (a) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6661. (b) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377.
(
1
0.1021/ol006286u CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/28/2000

we found that trimethylaluminum efficiently transferred a
methyl group to bicyclic epoxide 4 in a syn-fashion to
Table 1
5-7
provide 5 (eq 1). While the reaction proceeded reasonably
well in a number of solvents, we were intrigued by the
observation that the highest coupling yields occurred when
the reaction was carried out in nonpolar solvents. This led
us to suspect that the transfer of a methyl group from an
intermediate aluminate complex might be important.
We set out to explore the scope of this chemistry, as it
would complement the aforementioned anti-selective addition
of other carbon nucleophiles to glycal epoxides. That is, if
the aluminum chemistry proved to be general we would be
able to construct either R- or â-C-glycosides from a single
glycal epoxide by simply varying the counterion on the
nucleophile.
With these goals in mind, we set out to investigate the
coupling of 3,4,6-tri-O-benzyl-D-glucal epoxide 2 with alkyl,
aryl, alkynyl, vinyl, and allyl aluminum reagents (Table 1).
As had occurred in the 4 f 5 transformation, the transfer of
3
a methyl group from Me Al occurred from the same face as
9
the C-2 alkoxy group and resulted in a syn relationship
high yield when coupled with 2. Interestingly, while both
8
11
between the newly formed C-O and C-C bonds (entry 1).
dimethylalkynyl aluminum and trimethyl aluminum trans-
As the addition of dimethyl cuprate to 2 gives the corre-
sponding anti-addition product, this experiment effectively
ferred alkynyl and methyl groups, respectively, at low
temperature, the transfer of a vinyl group from dimethylvinyl
9
8
demonstrates that it is possible to control the C-glycoside
stereochemistry by simply varying the counterion on the
nucleophile.
aluminum required relatively elevated temperatures to effect
transfer in moderate yields. Unfortunately, at elevated
temperatures methyl transfer became competitive with vinyl
transfer (entry 4). These problems were circumvented by
turning to trivinylaluminum. R-Vinyl glycoside 8 was
isolated in 76% yield when 6 equiv of trivinyl aluminum
were used, and the reaction was allowed to warm from -65
The aluminum chemistry was also applicable to other
10
nucleophiles; the corresponding alkynyl, vinyl, phenyl, and
furyl aluminum reagents also provided R-C-glycosides in
(
5) Rainier, J. D.; Allwein, S. P.; Cox, J. M. Org. Lett. 2000, 2, 231.
1
2
°
C to room temperature (entry 6). f Fewer equivalents of
(6) We are aware of one other report of the addition of trimethyl
aluminum to glycal epoxides giving the product from syn-facial epoxide
opening. See Bailey, J. M.; Craig, D.; Gallagher, P. T. Synlett 1999, 132.
trivinylaluminum gave lower yields of 8 with significant
quantities of oligomeric sugars (entry 5). By using the
conditions that were optimized for the vinyl addition, the
transfer of phenyl from triphenyl aluminum and 2-furyl from
trifuryl aluminum gave the corresponding R-C-glycosides 9
and 10 in 79% and 85% yield, respectively (entries 7 and
(7) For syn-selective epoxide opening reactions with acetylide anion in
the presence of ZnCl2 see: Leeuwenburgh, M. A.; Timmers, C. M.; van
der Marel, G. A.; van Boom, J. H.; Mallet, J.-M.; Sinay, P. G. Tetrahedron
Lett. 1997, 38, 6251.
(8) Procedure for the addition of trimethylaluminum to 2: To a solution
of 3,4,6-tri-O-benzyl-D-glucal (50 mg, 0.12 mmol) and CH2Cl2 (1.5 mL)
at 0 °C was added dimethyldioxirane (1.8 mL of a 0.1 M solution in acetone,
1
2
8
). In our hands, allyl transfer from triallyl aluminum has
0
.18 mmol) dropwise. After 10 min the reaction mixture was concentrated.
The resulting white solid was taken up in CH2Cl2 (6.0 mL) and cooled to
90 °C. To this solution was added AlMe3 (0.060 mL of a 2.0 M solution
been more problematic and has yielded mixtures of R- and
-
in hexanes, 0.12 mmol) quickly. After 5 min the reaction was quenched
with 0.5 M HCl (2 mL) and allowed to warm to room temperature. The
mixture was extracted with CH2Cl2 (5 × 5 mL), washed with brine (1 × 5
mL), dried (Na2SO4), and concentrated. Flash chromatography (5:1 hexanes:
ethyl acetate) afforded 44 mg (82%) of alcohol 6 as a colorless oil.
(11) The aluminum reagents were prepared by coupling commercially
available aluminum chlorides (Me2AlCl or AlCl3) with the appropriate
Grignard or lithium reagent. See: Paley, R. S.; Snow, S. R. Tetrahedron
Lett. 1990, 31, 5853.
(
9) The relative stereochemistry from epoxide opening was established
(12) Procedure for the addition of trivinyl aluminum to 2: A solution of
2 (0.12 mmol) and CH2Cl2 (2 mL) at 0 °C was added to a solution of
1
8
by comparing the C-1, C-2 H NMR J values for the â- and R-C-glycosides
of the C-2 alcohols or the corresponding C-2 acetates. For the â-C-
glycosides, J1,2 ranged from 9.2 to 10 Hz. (a) ref 3. (b) Rainier, J. D.;
Allwein, S. A.; Cox, J. M. Unpublished results). For the corresponding
R-C-glycosides, J1,2 ranged from 4.2 to 5.9 Hz.
trivinylalane (0.72 mmol) and CH2Cl2 (12.0 mL) dropwise over 1 h at -60
°C. After warming to room temperature and stirring for an additional 1 h,
the reaction mixture was cooled to 0 °C and quenched with HCl (0.5 N
(aq), 2 mL). The mixture was extracted with CH2Cl2 (5 × 5 mL), washed
with brine (5 mL), dried (Na2SO4), and concentrated. Flash chromatography
(5:1 hexanes:ethyl acetate) afforded 42 mg (76%) of alcohol 8 as a colorless
oil.
(10) We have been unable to generate the corresponding â-alkynyl
glycoside from the addition of acetylide anions to 4. Van Boom has
generated R-alkynyl glycosides from alkynyl zinc additions. See ref 7.
2708
Org. Lett., Vol. 2, No. 17, 2000

â-allyl glycosides (entry 9). Presumably, â-allyl products
come from a competitive intermolecular allyl transfer reac-
tion.13
Scheme 2
We were of the opinion that the presence of MgCl
2
from
the synthesis of triallylaluminum was responsible for the
1
3
somewhat disappointing results with triallylaluminum. In
an effort to overcome these problems, we targeted the transfer
of allyl from triallylborane. We were attracted to boron for
two reasons. First, when reacting with 2, it should transfer
its ligands intramolecularly via a “borate” complex. Second,
triallylborane can be purified.14 In the event, we were
extremely pleased to find that the exposure of 2 to freshly
distilled triallylborane at -60 °C resulted in a 13:1 mixture
of R- and â-allyl-glycosides respectively in 70% yield (eq
of aluminum or boron reagents to glycal epoxides. These
coupling reactions nicely complement the previously reported
anionic couplings to these same epoxides and represent the
first examples of the predictable formation of R- or â-C-
glycosides from a single glycosidic donor. Current efforts
are focused on the continued examination of these reactions
as well as their application to the synthesis of fused
polyether-containing natural products.
2).
Acknowledgment. The authors are grateful to the Na-
tional Institutes of Health, General Medical Sciences
(GM56677), Research Corporation, and the donors of the
Petroleum Research Fund, administered by the American
Chemical Society, for support of this research. We would
also like to thank Dr. Neil Jacobsen and Dr. Arpad Somagyi
for help with NMR and mass spectroscopy experiments,
respectively.
The syn addition reactions appear to be occurring via the
mechanism outlined in Scheme 2. Aluminum or boron
complexation to the epoxide is followed by oxonium ion
formation to provide 13. Intramolecular ligand transfer to
the oxonium ion then gives the isolated products after
hydrolysis.
To conclude, we have demonstrated that C-glycosides
having a cis relationship between a C-2 alkoxy group and a
C-1 carbon-carbon bond can be generated via the addition
Supporting Information Available: Spectroscopic data
for compounds 6-11 and the corresponding C-2 acetates.
This material is free of charge via the Internet at http://
pubs.acs.org.
(13) We believe that the intermolecular addition is occurring from an
aluminum “ate” complex (possibly chlorotriallyl aluminate). Thus far, we
have not been able to purify triallyl aluminum.
(14) Brown, H. C.; Racherla, U. S. J. Org. Chem. 1986, 51, 427.
OL006286U
Org. Lett., Vol. 2, No. 17, 2000
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