Synthesis of the macrolactone disaccharide subunit of tricolorin A

Full text of DOI:10.1021/jo960655b

5208
J . Org. Chem. 1996, 61, 5208-5209
Sch em e 1a
Syn th esis of th e Ma cr ola cton e
Disa cch a r id e Su bu n it of Tr icolor in A
Daniel P. Larson and Clayton H. Heathcock*
Department of Chemistry, University of California,
Berkeley, California 94720
Received April 16, 1996
Farmers in the southeastern intertropical Mexican
state of Morelos make extensive use of Ipomoea tricolor
as a cover crop during the fallow period in sugar-cane
fields. This tuberous plant has the useful property of
suppressing the growth of other plants, including inva-
sive weeds. In 1993, Pereda-Miranda and co-workers1
reported the isolation of tricolorin A (1), the actual
compound responsible for the biological activity of this
plant. Compound 1 also demonstrated significant cyto-
toxicity against cultured P-388 and human breast cancer
cells. We chose tricolorin A as a synthetic target because
of the unique challenge in forming the macrolactone in
this molecule. We now report the synthesis of a protected
fucosyl â-D-glucoside that incorporates the 19-membered
lactone characteristic of tricolorin A.
a
Key: (a) (i) LiNH2, NH3, -33 °C; (ii) C9H19I, THF, -33 f 25
°C; (b) KAPA, THF; (c) TBSCl, imidazole, DMF; (d) KMnO4, HOAc,
H2O, pentane; (e) H2SO4, MeOH.
Sch em e 2a
a
Key: (a) 2,2-dimethoxypropane, p-TsOH; (b) t-BuCOCl, pyri-
dine, DMAP, 70 °C; (c) 50 psi H2, Pd(OH)2, EtOAc; (d) Cl3CCN,
Cs2CO3, CH2Cl2; (e) 7, TMSOTf, CH2Cl2; (f) NaOMe, MeOH,
MeOAc.
hydrogenation of the benzyl ether. Activation of the
fucose derivative for glycoside formation was achieved
by treatment with Cl3CCN and Cs2CO3 to furnish
The synthesis of the hydroxy acid aglycone is sum-
marized in Scheme 1. The (S)-propargylic alcohol 22 was
deprotonated with LiNH2 and the resulting lithioalkyne
treated with 1-iodononane to obtain 3 in 94% yield.
Treatment of 3 with KNH(CH2)3NH2 (KAPA)3 provided
terminal alkyne 4 in 79% yield. Protection of the alcohol
with tert-butyldimethylsilyl chloride, followed by oxida-
tive cleavage of the alkyne to the corresponding acid,4
and subsequent Fisher esterification gave the methyl
ester. Additionally, the acidic esterification reaction
conditions conveniently cleaved the TBS ether to give the
desired hydroxy ester 7 in good overall yield.
The fucose unit was prepared from the known benzyl
R-D-fucopyranoside (Scheme 2).5 Selective protection of
the C-3 and C-4 hydroxyl groups as the acetonide
followed by protection of the C-2 hydroxyl group as the
pivaloyl ester gave the fully protected intermediate 10.
The anomeric position was then unmasked by catalytic
6
trichloroacetimidate 12.
Coupling of hydroxy ester 7 and the crude trichloro-
acetimidate occurred smoothly in CH2Cl2 with catalytic
TMSOTf7 to give the desired â-glycosidic linkage in 79%
yield. The C-2 hydroxyl group was exposed by cleavage
of the pivaloyl ester with NaOMe in a MeOH/MeOAc
cosolvent to give coupling partner 14. A large excess of
NaOMe was employed in this reaction to allow the
reaction to proceed at a practical rate. We found that
use of MeOAc in this step greatly minimized saponifica-
tion of the methyl ester functionality in the molecule by
a minor amount of hydroxide present in the NaOMe
reaction solution.
As shown in Scheme 3, the glucose unit preparation
began by protection of the known glucopyranose 158 to
form the triacetyl compound 16. Formation of the amino
glycoside by treatment with BnNH2 followed by selective
hydrolysis with dilute aqueous acid9 furnished pyranose
(1) Pereda-Miranda, R.; Mata, R.; Anaya, A. L.; Wickramaratne, D.
B. M.; Pezzuto, J . M.; Kinghorn, A. D. J . Nat. Prod. 1993, 56, 571.
(2) Hashimoto, S.; Kase, S.; Suzuki, A.; Yanagiya, Y.; Ikegami, S.
Synth. Commun. 1991, 21, 833.
(3) (a) Brown, C. A.; Yamashita, A. J . Am. Chem. Soc. 1975, 97,
891. (b) Midland, M. M.; Halterman, R. L.; Brown, C. A.; Yamaichi, A.
Tetrahedron Lett. 1981, 22, 4171.
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42, 3749.
(5) Heyns, K.; Baron, A. L.; Paulsen, H. Chem. Ber. 1964, 97, 921.
(6) Urban, F. J .; Moore, B. S.; Breitenbach, R. Tetrahedron Lett.
1990, 31, 4421.
(7) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212.
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Soc. 1957, 79, 1986.
(9) (a) Sim, M. M.; Kondo, H.; Wong, C.-H. J . Am. Chem. Soc. 1993,
115, 2260. (b) Helferich, B.; Portz, W. Chem. Ber. 1953, 86, 604.
S0022-3263(96)00655-X CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 16, 1996 5209
Sch em e 3a
of the three ester groups in disaccharide 19 with LiOH
gave the macrolactonization precursor 20 in good yield.
Following the Yonemitsu protocol,12 the acid diol lacton-
ized at the C-3 hydroxyl position of the glucose ring with
a high degree of selectivity over the C-2 position to give
the target lactone 21 in 71% yield.
In summary, the target lactone disaccharide has been
synthesized in a total of 17 steps, with a longest linear
sequence of 10 steps and an overall yield of 18%. We
are currently exploring the synthesis of a suitable rham-
nosyl R-L-rhamnopyranoside to use as a glycosyl donor
for converting 21 into tricolorin A.
Ack n ow led gm en t. This work was supported by a
research grant from the United States Public Health
Service (GM 46057).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for all compounds (9 pages).
J O960655B
a
Key: (a) Ac2O, Et3N, DMAP, CH2Cl2; (b) (i) BnNH2, THF, (ii)
1 N HCl; (c) Cl3CCN, Cs2CO3, CH2Cl2; (d) 14, AgOTf, CH2Cl2; (e)
LiOH, THF, H2O; (f) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP,
benzene.
(10) Compounds 16 and 17 have been previously reported in the
literature, but were prepared by different methods and no modern
spectral data is available. For compound 16, see: Zervas, L. Chem.
Ber. 1931, 64, 2289. For compound 17, see: Korytnyk, W.; Mills, J . A.
J . Chem. Soc. 1959, 636.
(11) Douglas, S. P.; Whitfield, D. M.; Krepinsky, J . J . J . Carbohydr.
Chem. 1993, 12, 131.
(12) (a) Evans, D. A., Ng, H. P.; Rieger, D. L. J . Am. Chem. Soc.
1993, 115, 11446. (b) Hikota, M.; Sakurai, Y.; Horita, K.; Yonemitsu,
O. Tetrahedron Lett. 1990, 31, 6367.
17 in 87% yield.10 Glycosyl donor 18 was obtained by
treatment of 17 with Cl3CCN and Cs2CO3.
Treatment of alcohol 14 with the crude trichloroace-
timidate and anhydrous AgOTf11 in CH2Cl2 gave an 84%
yield of the â-disaccharide. Simultaneous saponification