C O M M U N I C A T I O N S
Scheme 2 a
Acknowledgment. Dedicated to Professor Robert H. Grubbs
for his seminal work in olefin metathesis. We thank NSERCC for
generous financial support from AstraZeneca (Mo¨lndal Sweden)
through the Medicinal Chemistry Chair Program. We appreciate
the enthusiastic support given by Dr. David Rees and Dr. Kenneth
Granberg (AstraZeneca). We also thank Elaine Fournelle for HPLC
analyses and Dr. Michel Simard for X-ray analyses. M.T. acknowl-
edges scholarships from NSERC and FCAR.
Supporting Information Available: Experimental procedures of
key reactions, NMR, and X-ray and other data (PDF). This material is
References
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a Reagents and conditions: (a) TBDPSCl, imidazole, DMF; 90%. (b)
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Scheme 3 a
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successful cyclization of 17 to the pyrroline 18 in 90% yield.18
A
series of well-precedented transformations gave 20 which was
definitively characterized by single-crystal X-ray analysis of the
corresponding N-acetyl derivative 20a.
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proline esters varies with the nature of the Lewis acid, the nucleophile,
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The acyclic peptide chain 22 was prepared as shown in Scheme
3 from D-leucine and 2-O-methyl-D-glyceraldehyde easily available
from D-mannitol.19 Peptide coupling between 14 and 22 afforded
23 which was hydrolyzed to the free acid. A second peptide
coupling with 20 proceeded in good overall yield to give 24, which
was desilylated to the alcohol 25. Treatment of 25 with pyridine-
SO3 complex in dichloromethane in the presence of a catalytic
quantity of dibutyltin oxide20 afforded the corresponding sulfate
ester. Hydrolysis of the N-Boc group with TFA in dichloromethane,
followed by isolation of the crude product and purification by
reverse phase HPLC afforded dysinosin A as a white solid, identical
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1
in all respects to the natural product (HPLC, H,13C NMR, FAB
(19) Nicolaou, K. C.; Piscopio, A. D.; Bertinato, P.; Chakraborty, T. K.;
and electrospray mass spectrometry).
Minowa, N.; Koide, K. Chem. Eur. J. 1995, 1, 318.
(20) Lubineau, A.; Lemoine, R. Tetrahedron Lett. 1994, 35, 8795. (b) Sanders,
W. J.; Manning, D. D.; Koeller, K. M.; Kiessling, L. L. Tetrahedron 1997,
53, 16391. (c) Martinelli, M.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar,
N. K.; Dhokte, U. P.; Doecke, C. W.; Zollars, L. M.; Moher, E. D.; Khau,
V. V.; Kosmrlj, B. J. Am. Chem. Soc. 2002, 124, 3578.
The total synthesis of dysinosin A by an enantioselective route
provides definitive evidence for its structural and configurational
identity. It also represents the first total synthesis of a hitherto
unknown member of the aeruginosin family of marine antithrombin
natural products, with inhibitory activity against Factor VIIa.
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