Total Synthesis of the Novel, Immunosuppressive Agent (−)-Pateamine A from Mycale sp. Employing a β-Lactam-Based Macrocyclization

Moreover, these studies have recently culminated in the synthesis of agents that exert cell and target specific responses. 2 Pateamine A (1) is a structurally novel and potent immunosuppressive natural product isolated fromMycale sp.by Munro and Blunt off the coasts of New Zealand. 3 It uniquely combines a thiazole ring and anE,Z-dienoate within a bis-lactone macrocycle bearing an all-E trienylamine side chain. This novel array of functionality makes pateamine A structurally dissimilar to other known immunosuppressants. As a first step toward elucidating the origins of its cellular effects, we now report a convergent, stereochemically flexible route to pateamine A, 4 wherein a â-lactam ring was strategically implemented to introduce the C3 amino group and to serve as an activated acyl group for macrocyclization. 5 We have previously described the synthesis of the C18-C24 fragment of pateamine A which aided in the determination of the C24 absolute stereochemistry in collaborative studies with Munro and co-workers. 6 Importantly, this assignment in conjunction with molecular modeling, extensive NMR studies, and further chemical derivitization by the New Zealand group provided a tentative stereochemical assignment of ( -)-pateamine A as 3R, 5S, 10S, 24S.7 With this information in hand, we embarked on a total synthesis that has now verified the stereochemical assignment and has enabled the synthesis of derivatives for further biological studies. Several issues guided our retrosynthetic plan (Figure 1). These included the known lability of the C3 amino group, 3 the isomerization-proneE,Z-dienoate, the desire to incorporate and liberate the polar amino groups at a late stage in the synthesis, the flexibility of attaching various side chains to the macrocyclic core structure, and finally the uncertainty of the stereochemical assignment. With this last consideration in mind and due to the distance between stereocenters, we resolved to introduce the four stereocenters by reagent control. In addition, we realized that some inherent flexibility was built into the synthetic plan since the stereochemistry at C10 could be readily retained (acylation) or inverted (Mitsunobu 8) during the joining ofâ-lactam4 and enyne acid5. The end-game strategy would rely upon a â-lactambased macrocyclization to esterify the C24 alcohol and a Stille coupling to append the trienylamine side chain. Concise and efficient syntheses ofâ-lactam 4, enyne acid5,9 and the dienylamino stannane 6 were required at the outset. The dienylamino stannane 6was readily prepared in two steps from enyne alcohol 7 (Scheme 1). 10 A one-pot tosylation and displacement with dimethylamine provided the enyne amine 8.11 Stannylcupration of this alkyne by the method of Oehlschlager gave the desired stannane 6 as a mixture of regioisomers which could be enriched in the desired isomer (9:1). 12