Glycocinnasperimicin D Synthetic Studies: Synthesis of Cinnamoyl Glycosides via Iodination-Heck Reaction Sequence Starting from Phenyl Glycosides

Article abstract of DOI:10.1055/s-2003-43376

A new approach for the synthesis of cinnamoyl glycoside has been developed via iodination-Heck reaction sequence starting from phenyl glycoside. Successful application of this procedure accomplished the construction of the right core structure of aminosug

Full text of DOI:10.1055/s-2003-43376

LETTER
89
Glycocinnasperimicin D Synthetic Studies: Synthesis of Cinnamoyl Glycosides
via Iodination-Heck Reaction Sequence Starting from Phenyl Glycosides
G
lycocinnasper
a
imicin D S
i
ynthetic
h
Studies ei Nishiyama, Yoshiyasu Ichikawa,* Minoru Isobe
Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Fax +81(52)7894100; E-mail: ichikawa@agr.nagoya-u.ac.jp
Received 9 September 2003
During our synthetic endeavor, we soon recognized that
Abstract: A new approach for the synthesis of cinnamoyl glycoside
glycosylation of a highly functionalized pyranose, such as
2,4-diamino-2,4,6-trideoxy-D-glucopyranose or its equiv-
has been developed via iodination-Heck reaction sequence starting
from phenyl glycoside. Successful application of this procedure ac-
alents, with p-hydroxycinnamic acid derivatives is quite
problematic due to a poor nucleophilic nature of the phe-
nol bearing an electron-withdrawing group.4 To circum-
vent this problem, we developed a synthetic plan which
involves a new approach for the synthesis of cinnamoyl
glycosides (Scheme 1).
complished the construction of the right core structure of amino-
sugar antibiotic, glycocinnasperimicin D.
Key words: antibiotics, cinnamoyl glycoside, glycosylation, Heck
reaction, palladium
In 1985, Umezawa et al. reported the isolation of a novel
antibiotic, glycocinnasperimicin D, from the fermentation
broth of Nocardia strain.1 Its structure was elucidated by
spectroscopic studies as represented in Figure 1, which
clarified that this aminosugar antibiotic belongs to a mem-
ber of glycocinnamoylspermidine. The more complex
relative with an additional 2,4-diaminopentose is LL-
BM123b [cinodine b, (2)], which was isolated and identi-
fied at Lederle Laboratories.2 Glycocinnasperimicin D (1)
has demonstrated broad antibacterial spectrum and sever-
al unique structural features; the left portion is 2-ureido-
pentose and the right part is 2,4-diamino-2,4,6-trideoxy-
a-D-glucopyranose with p-cinnamoyl spermidine agly-
son. These two amino sugars are joined with urea glycosyl
linkage. The interesting structure and small availability of
1 from natural sources promoted us to pursue the synthetic
work of 1.3 In this manuscript, we describe a new
approach to cinnamoyl glycosides and its application for
the synthesis of right segment of 1.
Scheme 1
Starting from a-phenyl glycoside I, initial efforts focused
on the deoxygenation of C-6 hydroxy group.5 Iodination
of the resulting phenyl 6-deoxy-glycoside II followed by
the Heck reaction with acrylamide containing spermidine
moiety would offer a highly convergent tactic to the right
subunit of 1. In our initial attempts to explore this strategy,
we focused on the synthesis of cinnamoyl a-D-galactopy-
ranoside (Scheme 2).
Phenyl a-D-galactopyranoside 4 was readily prepared by
Lewis acid catalyzed glycosylation of pentaacetate 3 with
phenol in 47% yield after recrystallization.6 A screen of
several iodination agents revealed that cerium (IV)-pro-
moted iodination is an optimal solution.7 In practice, treat-
ment of 4 with ceric ammonium nitrate (CAN) and iodine
salt (n-Bu4NI) in MeCN at 70 °C for 24 h furnished io-
dophenyl galactoside 5 in 95% yield. The Heck reaction
of 5 with methyl acrylate [Pd(OAc)2, P(o-tol)3, CH3CN,
70 °C] proceeded smoothly to furnish a-cinnamoyl galac-
toside 6 in 88% yield.8
Figure 1
SYNLETT 2004, No. 1, pp 0089–0092
Advanced online publication: 4.12.2003
DOI: 10.1055/s-2003-43376; Art ID: U17903ST
© Georg Thieme Verlag Stuttgart · New York
0
5.
0
1.
2
0
0
4
We examined the generality of this cinnamoyl glycoside
synthesis using a variety of phenyl glycosides (Table 1).

90
T. Nishiyama et al.
LETTER
Table 1 Cinnamoyl Glycoside Synthesis Using a Variety of Phenyl
Glycosides
Entry Phenyl glycoside
Iodination Heck
yield (%)
reaction (%)
Scheme 2
Ready availability of each phenyl glycoside and good
overall yield over two steps make this approach highly
acceptable.9
A
92
92
87
89
84
87
With an efficient route to cinnamoyl glycoside estab-
lished, we turned our attention to the right core synthesis
of glycocinnasperimicin D (Scheme 3).
B
C
D
E
96
94
96
93
Glycosylation of glucosamine derivative 12 with phenol
catalyzed with tin (IV) chloride in CH2Cl2 proceeded
smoothly to afford a 4:1 anomeric mixture of phenyl gly-
cosides (87%).10 Following purification of a-anomer 13
by chromatography, hydrolysis of acetyl groups in 13
(Et3N, MeOH, H2O) and selective tosylation (TsCl, pyri-
dine) of the triol 14 furnished tosylate 15 (61% in two
a CAN (3.0 equiv), n-Bu4NI (1.5 equiv), CH3CN, 70 °C, 24 h.
b Methyl acrylate (3.0 equiv), 30 mol% Pd(OAc)2, 50 mol% P(o-tol)3,
Et3N (5.0 equiv), CH3CN, 70 °C, overnight.
steps). Acetylation of two hydroxy groups in 15 (Ac2O,
pyridine) followed by the SN2 displacement (n-Bu4NI,
NaI, DME) produced iodide 17 (91% yield over two
steps). Reductive hydrogenolysis of 17 (H2, 10% Pd-C,
Et3N, EtOAc) then furnished 6-deoxy pyranose 18 in
good yield (90%). Finally, iodination of phenyl glycoside
18 followed by the Heck reaction with acrylylspermidine
successfully constructed the right core structure of glyco-
cinnasperimicin D, and the product, 2-amino-6-deoxy-a-
D-glucocinnamoyl spermidine 19, was isolated in 75%
yield.11
Scheme 3
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LETTER
Glycocinnasperimicin D Synthetic Studies
91
During these synthetic works, we recognized that io-
dophenyl glycosides, prepared from readily available phe-
nyl glycosides by high-yielding iodination process, are
particularly attractive synthons for the synthesis of substi-
tuted phenyl glycosides (Scheme 4). In fact, introduction
of 1-dodecyne onto the phenyl ring in 20 was achieved
efficiently by the Sonogashira cross-coupling reaction
[1-dodecyne, PdCl2(PPh3)2, CuI, Et3N, benzene] to pro-
vide a useful amphilic carbohydrate derivative 21 for the
nonionic detergents in 75% yield.12 This example demon-
strates synthetic potential of iodophenyl glycosides.13
Acknowledgment
This research was financially supported by a Grant-In-Aid for
Scientific Research from the Ministry of Education, Science, Sports
and Culture.
References
(1) Dobashi, K.; Nagaoka, K.; Watanabe, Y.; Nishida, M.;
Hamada, M.; Takeuchi, T.; Umezawa, H. J. Antibio. 1985,
1166.
(2) Ellestad, G. A.; Cosulich, D. B.; Broschard, R. W.; Martin,
J. H.; Kunstmann, M. P.; Morton, G. O.; Lancaster, J. E.;
Fulmor, W.; Lovell, F. M. J. Am. Chem. Soc. 1978, 100,
2515.
(3) For the synthetic studies of LL-BM123b, see the references:
(a) Araki, K.; Miyazawa, K.; Hashimoto, H.; Yoshimura, J.
Tetrahedron Lett. 1982, 23, 1705. (b) Araki, K.; Kawa, M.;
Saito, Y.; Hashimoto, H.; Yoshimura, J. Bull. Chem. Soc,
Jpn. 1986, 59, 3137. (c) Araki, K.; Hashimoto, H.;
Yoshimura, J. Carbohydr. Res. 1982, 109, 143.
(4) (a) Oyama, K.; Kondo, T. Synlett 1999, 1627; and references
therein. (b) See also ref.3c
(5) We avoid glycosylation with iodophenol, because our
preliminary experiments showed that catalytic
hydrogenolysis of 6-iodo-glycopyranose is the most simple
and high-yielding method for multigram synthesis of 6-
deoxy glycopyranose. For recent examples of C6-
deoxygenation: Medgyes, A.; Farkas, E.; Liptak, A.;
Pozsgay, V. Tetrahedron 1997, 53, 4159.
Scheme 4
In conclusion, a new approach for the synthesis of cin-
namoyl glycoside was established, and successful appli-
cation of this method accomplished the construction of
the right core structure found in glycocinnasperimicin D.
Furthermore, palladium-catalyzed reaction successfully
demonstrated synthetic potential of iodophenyl glyco-
sides.
(6) This acid-catalyzed glycosylation initially led to the
formation of an anomeric mixture of phenyl galactosides.
Prolonged reaction time (4 d) resulted in a gradual decrease
of the b-isomer proportion and concomitant increase in the
formation of a-anomer.
(7) Sugiyama, T. Bull. Chem. Soc. Jpn. 1981, 54, 2847.
(8) (a) Bromination of b-phenyl glucoside 9 (Br2, CH2Cl2, –5
°C) and the Heck reaction of the resultant brominated
glycosylated aromatic with alkenes has been reported by
Lepoittevin et al.: Mabic, S.; Lepoittevin, J.-P. Tetrahedron
Lett. 1995, 36, 1705. (b) In our case, bromophenyl
glycosides, prepared (NBS, DMF, r.t.) in good yields, were
found to be poor substrates for the Heck reaction.
(9) Although cinnamoyl glycosides are known as important
natural products, their synthesis suffer from the low
nucleophilicity of p-hydroxycinnamic acid derivatives. For
example: Takada, N.; Kato, E.; Ueda, K.; Yamamura, S.;
Ueda, M. Tetrahedron Lett. 2002, 43, 7655.
General Procedure for the Synthesis of Cinnamoyl Glycosides
via Iodination-Heck Reaction Sequence
A solution of phenyl galactoside 4 (500 mg, 1.18 mmol), tetra-n-bu-
tylammonium iodide (654 mg, 1.77 mmol) and CAN (1.94 g, 3.54
mmol) in MeCN (20 mL) was heated at 70 °C for 24 h. The resulting
yellow solution was poured into sat. aq NaHCO3, and the aq layer
was extracted with EtOAc. The combined organic extracts were
washed with water and brine, dried over anhyd Na2SO4, and then
concentrated. The resulting residue was purified by silica gel chro-
matography (stepwise gradient of 25% to 30% EtOAc–hexane) to
afford the iodophenyl galactoside 5 (613 mg, 1.11 mmol, 95%) as a
white solid.
(10) We have found the reversal of selectivity in this
glycosylation using TMSOTf and Et2O (Scheme 5).
A dry Schlenk flask was charged with 5 (80 mg, 0.15 mmol), methyl
acrylate (40 mL, 0.44 mmol), tri-o-tolylphosphine (18 mg, 0.073
mmol), Et3N (0.10 mL, 0.73 mmol), and MeCN (2.0 mL). The so-
lution was degassed by two freeze-thaw cycles. After cooling the
Schlenk flask at –78 °C, palladium(II) acetate (9.0 mg, 0.040 mmol)
was placed on the resulting solidified reaction mixture. The Schlenk
flask was evacuated and then heated at 70 °C overnight. After cool-
ing to r.t., the reaction mixture was poured into sat. aq NH4Cl, and
the aq layer was extracted with EtOAc. The combined organic ex-
tracts were washed with brine, dried over Na2SO4, concentrated,
and purified by silica gel chromatography (stepwise gradient of
25% to 30% EtOAc–hexane) to furnish a-cinnamoyl galactoside 6
(65 mg, 88%) as a white crystalline mass.
Scheme 5
(11) Spectroscopic data of 19; [a]D26 = +98.9 (c 1.09, CHCl3). 1H
NMR (CDCl3, 300 MHz): d = 1.17 (d, J = 6.5 Hz, 3 H), 1.40–
1.90 (m, 6 H), 1.44 (s, 9 H), 1.48 (s, 9 H), 2.05 (s, 3 H), 2.07
(s, 3 H), 3.08–3.25 (br s, 4 H), 3.25–3.40 (br s, 4 H), 3.64 (s,
3 H), 3.93 (dq, J = 10.5, 6.5 Hz, 1 H), 4.18 (td, J = 10.5, 3.5
Hz), 4.50–4.70 (br s, 1 H), 4.94 (dd, J = 10.5, 9.5 Hz, 1 H),
5.11 (d, J = 10.0 Hz, 1 H), 5.37 (dd, J = 10.5, 9.5 Hz, 1 H),
Synlett 2004, No. 1, 89–92 © Thieme Stuttgart · New York

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T. Nishiyama et al.
LETTER
(13) For recent examples of the Sonogashira reacton using
5.54 (d, J = 3.5 Hz, 1 H), 6.37 (d, J = 15.5 Hz, 1 H), 7.04–
7.10 (3 H), 7.44–7.52 (2 H), 7.57 (d, J = 15.5 Hz, 1 H). 13
NMR (CDCl3, 75 MHz): d = 17.1, 20.47, 20.53, 25.5, 27.2,
27.5, 28.19, 28.23, 35.6, 39.9, 43.2, 46.5, 52.3, 53.9, 66.3,
70.7, 73.1, 79.0, 79.7, 95.6, 116.4, 120.2, 129.2, 129.8,
139.4, 156.0, 156.5, 157.0, 166.1, 169.7, 171.2.
C
iodophenyl a-D-mannopyranoside for the efficient synthesis
of sugar-rods and cyclodextrin-based cluster mannosides,
see: (a) Roy, R.; Das, S. K.; Santoyo-Gonzalez, F.;
Hernandez-Mateo, F.; Dam, T. K.; Brewer, C. F. Chem.–
Eur. J. 2000, 6, 1757. (b) Ortega-Caballero, F.; Gimenez-
Martinez, J. J.; Vargas-Berenguel, A. Org. Lett. 2003, 14,
2389.
(12) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 23, 4467. (b) Takahashi, S.; Kuroyama, Y.;
Sonogashira, K.; Tohda, Y.; Hagihara, N. Synthesis 1980,
627.
Synlett 2004, No. 1, 89–92 © Thieme Stuttgart · New York