An efficient synthesis of the protected carbohydrate moiety of Brasilicardin A

Article abstract of DOI:10.1021/ol2013704

A synthesis of the protected carbohydrate moiety 2 of Brasilicardin A starting from l-rhamnose and d-glucosamine is described. The disaccharide was synthesized using a TMSOTf-mediated glycosylation of the 2-phthalimido-2- deoxyglucose donor 5 and the 3-hydroxyl group of the protected l-rhamnose derivative 4, which already bears the 3-hydroxybenzoate unit. The imidate 2 was coupled via TMSOTf-mediated glycosidation with cholesterol as a model aglycone followed by the selective cleavage of all the acetate groups to give the Brasilicardin A analogue 16.

Full text of DOI:10.1021/ol2013704

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3710–3713
An Efficient Synthesis of the Protected
Carbohydrate Moiety of Brasilicardin A
Michael E. Jung* and Pierre Koch
Department of Chemistry and Biochemistry, University of California, Los Angeles, 405
Hilgard Avenue, Los Angeles, California 90095, United States
jung@chem.ucla.edu
Received May 20, 2011
ABSTRACT
A synthesis of the protected carbohydrate moiety 2 of Brasilicardin A starting from L-rhamnose and D-glucosamine is described. The disaccharide
was synthesized using a TMSOTf-mediated glycosylation of the 2-phthalimido-2-deoxyglucose donor 5 and the 3-hydroxyl group of the protected
L-rhamnose derivative 4, which already bears the 3-hydroxybenzoate unit. The imidate 2 was coupled via TMSOTf-mediated glycosidation with
cholesterol as a model aglycone followed by the selective cleavage of all the acetate groups to give the Brasilicardin A analogue 16.
Brasilicardin A (1, Figure 1), isolated from the cultured
broth of the actinomycete Norcardia brasiliensis IFM0406,
is a tricyclic terpenoid consisting of an anti/syn/anti perhy-
drophenanthrene skeleton with a sugar moiety and an
amino acid side chain attached.1 The carbohydrate moiety
is a dissacharide consisting of an L-rhamnose with a β-N-
acetylglucosamine unit attached to the 3-hydroxyl and a
3-hydroxybenzoate unit attached to the 4-hydroxyl. This
unusual carbohydrate is also a key structural feature of the
related natural product Brasilicardin B.2 Based on both
1HÀ C and 1HÀ H coupling constants, the stereochem-
istry at each anomeric position of the sugar moieties
was assigned: R at the anomeric position of rhamnose
and β on the N-acetylglucosamine.1 Brasilicardin A was
found to exhibit immunosuppressive as well as cyto-
toxic activity against several different cell lines.1À3
StructureÀactivity relationship (SAR) studies on ana-
logues of 1 revealed the importance of the glucosamine
and 3-hydroxybenzoate substituents at the 3- and
13
1
Figure 1. Structure of Brasilicardin A (1).
4-positions of the rhamnose for immunosuppressive
activity.3
Our synthetic strategy toward Brasilicardin A (1) is
illustrated in Scheme 1. We planned to introduce the
sugar moiety in one of the last steps of the synthesis of 1
via the TMSOTf-promoted glycosylation of the glyco-
syl donor 2 and the protected terpenoid aglycone 3
via the method of Schmidt.4 In order to minimize the
length of the synthesis, we opted to use acetates as the
(1) Shigemori, H.; Komaki, H.; Yazawa, K.; Mikami, Y.; Nemoto,
A.; Tanaka, Y.; Sasaki, T.; In, Y.; Ishida, T.; Kobayashi, J. J. Org.
Chem. 1998, 63, 6900–6904.
(2) Komatsu, K.; Tsuda, M.; Shiro, M.; Tanaka, Y.; Mikami, Y.;
Kobayashi, J. Bioorg. Med. Chem. 2004, 12, 5545–5551.
(3) (a) Komatsu, K.; Tsuda, M.; Tanaka, Y.; Mikami, Y.; Kobayashi,
J. Bioorg. Med. Chem. 2005, 13, 1507–1513. (b) Komaki, H.;
Nemoto, A.; Tanaka, Y.; Takagi, H.; Yazawa, K.; Mikami, Y.;
Shigemori, H.; Kobayashi, J.; Ando, A.; Nagata, Y. J. Antibiot. 1999,
52, 13–19.
(4) (a) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. 1980, 19,
731–732. (b) Zhu, X; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48,
1900–1934.
r
10.1021/ol2013704
Published on Web 06/16/2011
2011 American Chemical Society

protecting group for the five hydroxyl functions even
though there was a possible problem in retaining the
integral benzoate moiety of the final product while
cleaving the acetates. However, we reasoned that the
benzoate group, being situated between two equatorial
groups, would be quite hindered toward nucleophilic
attack and thus likely to survive acetate removal, which
would significantly shorten the synthesis. The donor 2
would arise from TMSOTf-mediated coupling of the
known 2-phthalimido-2-deoxyglucose donor 55 and the
protected L-rhamnose derivative 4. As the protecting
group for the 2-amine of glucosamine, we chose the
phthaloyl group since it is known to selectively afford
β-glycosides in couplings with alcohols in the presence
of a Lewis acid.6,7 Compound 4 could be synthesized in
four steps from the commercially available L-rhamnose
monohydrate.
but used as a mixture. Acylation with 3-acetyloxybenzoic
acid, which was prepared according to Zhang et al.,8
using DCC/DMAP coupling conditions furnished the
ester 8 in 88% yield. Treatment of 8 with a 1:1:3 mixture
of THF/water/acetic acid at 21 °C resulted in the
regioselective ring opening of the acid labile ortho ester
to afford the desired 2-acetyloxy 3-hydroxy derivative 4
in 98% yield.9 This acetyloxy group is required to
ensure neighboring group participation in the later
glycosylation, which favors the formation of the de-
sired 1,2-trans linked product.7 The 1H NMR of 4
clearly indicated a downfield shift of the H-2 signal
from 3.95 ppm in the 1H NMR spectrum of compound
6 to 5.11 ppm caused by the acetyloxy substituent at this
position.
Scheme 2. Synthesis of the Glycosyl Acceptor 4
Scheme 1. Synthetic Strategy for the Preparation of 1
Scheme 3 shows the synthesis of the 2-phthalimido-2-
deoxyglucose donor 5. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-
phthalimido-β-D-glucopyranose (9) was synthesized
from commercially available D-glucosamine HCl in
two steps and 61% yield via the method of Minuth et
al.10 Selective anomeric deacetylation of 9 was achieved
in 69% yield using ethylene diamine and acetic acid,
following the protocol of Zhang and Kovac.11 The
hemiacetal 10 was activated by treatment with trichlor-
oacetonitrile and DBU to give the trichloroacetimidate
5 in 81% yield.
In the first step in the synthesis of the L-rhamnose
acceptor 4 (Scheme 2), the anomeric position of the
L-rhamnose was protected with an allyl group to give 6 in
87% yield. The allyl R-L-rhamnopyranoside (6) was trans-
formed into the 2,3-ortho ester 7 by reaction with triethyl
orthoacetate in the presence of a catalytic amount of
10-camphorsulfonic acid in 84% yield. Compound 7 was a
mixture of two diastereomers, which were not separated
(8) Zhang, B.-S.; Wang, W.; Shao, D.-D.; Hao, X.-Q.; Gong, J.-F.;
Song, M.-P. Organometallics 2010, 29, 2579–2587.
(5) (a) Grundler, G.; Schmidt, R. R. Carbohydr. Res. 1985, 135, 203–
218. (b) Grundler, G.; Schmidt, R. R. Liebigs Ann. Chem. 1984, 1826–
1847.
(6) Banoub, J.; Boullanger, P.; Lafont, D. Chem. Rev. 1992, 92, 1167–
1195.
(9) (a) Paulsen, H.; Lorentzen, J. P. Liebigs Ann. Chem. 1986, 1586–
1599. Carbohydr. Res. 1987, 165, 207–337. (b) King, J. F.; Allbutt, A. D.
Tetrahedron Lett. 1967, 8, 49–54. Can. J. Chem. 1970, 48, 1754–1769.
(10) Minuth, T.; Irmak, M; Groschner, A; Lehnert, T; Boysen,
M. M. K. Eur. J. Org. Chem. 2009, 997–1008.
(7) Paulsen, H. Angew. Chem., Int. Ed. 1982, 21, 155–173.
(11) Zhang, J.; Kovac, P. J. Carbohydr. Chem. 1999, 18, 461–469.
Org. Lett., Vol. 13, No. 14, 2011
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Scheme 3. Synthesis of the Glycosyl Donor 5
Scheme 4. Synthesis of the Trichloroacetimidate 2
The synthesis of the desired protected carbohydrate
moiety 2 of Brasilicardin A (Scheme 4) involved the
coupling of the 2-phthalimido glucosamine donor 5 and
the glycosyl acceptor 4 in dichloromethane at À78 °C,
mediated by a catalytic amount of TMSOTf, to afford the
disaccharide 11 in 94% yield. Under these conditions, only
the formation of the desired β-anomer was observed (the
NMR spectra showed 3J1,2 = 8.4 Hz, indicating that H-1 is
in the R-orientation). The phthaloyl group was removed
from 11 by treatment with ethylene diamine inn-butanol at
85 °C followed by acetylation with acetic anhydride in
pyridine to furnish compound 12 in 83% yield for the two
steps. The ester bond of the benzoate group was stable
under these hydrolysis conditions. To our surprise, the
signal of the methyl group of the acetamido moiety showed
a dramatic upfield shift in the proton NMR (δ=1.14ppm).
Removal of the allyl protecting group on the anomeric
oxygenwasachieved ingood yield by heating the allyl ether
12 with 0.5 equiv of Pd(PPh3)4 in acetic acid at 80 °C.
Finally, the hemiacetal 13 was converted to the desired
trichloroacetimidate 2 using trichloroacetonitrile and
DBU. The structure of compound 2 was proven by
X-ray crystallographic analysis12 (Figure 2). The X-ray
structure clearly confirms the stereochemistry at both
anomeric positions, namely R for the rhamnose and β for
the glucosamine unit. Moreover, the X-ray data offer a
good explanation for the upfield shift of the methyl group
of the NHAc moiety, namely that it lies below the phenyl
ring of the 3-acetyloxybenzoate moiety and is thus de-
shielded. This orientation is supported by an intramolecu-
lar hydrogen bond between the NÀH group of the amide
and the CdO group of the acetyl protecting group of the
3-hydroxybenzoate moiety. The length of the hydrogen
˚
bond interaction is 2.13 A.
For the synthesis of Brasilicardin A (1), we would need
to couple this disaccharide unit and then deprotect the
acetate protecting groups without any unforeseen pro-
blems arising, especially deprotection of the benzoate
Figure 2. Ortep plot of imidate 2.
group. Therefore we decided to test the coupling of the
imidate 2 on a model aglycone using a TMSOTf-mediated
(12) We thank Dr. Saeed Khan (UCLA) for the X-ray structural
analysis.
3712
Org. Lett., Vol. 13, No. 14, 2011

R-anomer 15 was thus obtained in 73% yield. The
R-stereochemistry at the anomeric center was determined
1
13
Scheme 5. Coupling of 2 with Cholesterol (14) and Deprotection
by the direct HÀ C coupling constant of C-1 of the
rhamnose unit (1JCH = 170.5 Hz).13 Finally, under mild
conditions, i.e., addition of 1 equiv of acetyl chloride to a
solution of compound 15 in 1:1 MeOH/dichloromethane
(to generate an equiv of HCl), selective cleavage of all of the
acetate groups in the presence of the benzoate was achieved.14
In this manner, we were able to isolate the desired Brasi-
licardin A analogue 16 in 65% yield as a pure compound.
In summary, we have described the synthesis of the
carbohydrate moiety of Brasilicardin A in a protected
form, compound 2, in nine steps and in an overall yield
of 38% from commercial L-rhamnose. Coupling of this
imidate 2 to a model aglycone was achieved in good yield
with the desired R-anomer as the major product. Investiga-
tion of the biological activity of 16 and the synthesis of
both Brasilicardin A and its simpler analogues are cur-
rently in progress.
Acknowledgment. P.K. gratefully acknowledges sup-
port by the Deutsche Forschungsgemeinschaft (KO
4111/1-1). We also thank CNSI-Abraxis (UCLA) for
financial support of this research. The authors thank Dr.
Saeed Khan for obtaining and analyzing the X-ray crystal-
lographic data and Dr. John Greaves, Director, Mass
Spectrometry Facility, University of California, Irvine,
for the HRMS data.
Supporting Information Available. Experimental pro-
cedures and proton and carbon NMR for all new com-
pounds and X-ray crystallographic data (cif file) for
compound 2. This material is available free of charge
via the Internet at http://pubs.acs.org.
glycosylation. As the model aglycone, we chose the com-
mon steroid cholesterol (14) since it has a secondary
equatorial hydroxyl group like the Brasilicardin A agly-
cone, e.g., 3. The addition of TMSOTf was carried out at
0 °C, and the reaction was stirred for 1 h at 21 °C to furnish
a mixture of the desired R-anomer 15 and its β-anomer in a
ratio of 9:1 (Scheme 5). Both anomers could be separated
via flash chromatography on silica gel, and the desired
(13) Kasai, R.; Okihara, M.; Asakawa, J.; Mizutani, K.; Tanaka, O.
Tetrahedron 1979, 35, 1427–1432.
(14) Yeom, C.-E.; Lee, S. Y.; Kim, Y. J.; Kim, B. M. Synlett 2005,
1527–1530.
Org. Lett., Vol. 13, No. 14, 2011
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