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