The asymmetric synthesis of the potent immunosuppressive agent (−)-pateamine A isolated from
the marine sponge Mycale sp. is described. A key strategy employed in the synthesis was a β-lactam-based
macrocyclization to form the 19-membered dilactone macrolide. The synthesis confirms the relative and absolute
stereochemistry as 3R,5S,10S,24S and sets the stage for studies into the mechanism of action of pateamine A.
Other studies and findings made in the course of the synthesis and described herein include the following: (1)
a Stille coupling can be competitive with π-allyl formation, (2) SmI2 effects a mild N−O cleavage of
N-benzyloxy-β-lactams, (3) the synthesis of a pateamine A-dexamethasone hybrid molecule for use in a yeast
three-hybrid assay was accomplished, and (4) IC50 values were determined for synthetic and natural pateamine
A and related compounds in the interleukin 2 reporter gene assay.
[reaction: see text] The use of Cp(2)Fe(PR(2))(2)PdCl(2) (R = i-Pr and t-Bu) in Suzuki coupling reactions were illustrated using a high throughput screening approach. The di-tbpfPdCl(2) catalyst was shown to be the more active catalyst for unactivated and sterically challenging aryl chlorides. Comparison studies using the commercial catalysts dppfPdCl(2), (Ph(3)P)(2)PdCl(2), (Cy(3)P)(2)PdCl(2), DPEPhosPdCl(2), dppbPdCl(2), dppePdCl(2), Pd(t-Bu(3)P)(2), and [Pd(mu-Br)(t-Bu(3)P)](2) were also done for selected cases to demonstrate the superior activities of di-tbpfPdCl(2) and di-isoppfPdCl(2).
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