Winklers Total Synthesis of Manzamine

Synthetic studies towards manzamine A (1) commenced with exploration of routes to the essential building block 27 containing the final E-ring alkene bond, starting with commercially 

With this piece synthesized, the opportunity to install the stereo-genic center in 27 selectively through a diastereoselective alkylation reaction was now at hand. For this purpose, the Winkler group decided to enlist a widely applicable and useful method developed by Andrew Myers and co-workers at Harvard University for the synthesis of a-amino acids in which pseudoephedrine glycinamide (41), an inexpensive and commercially available material, serves as a chiral auxiliary capable of controlling the selectivity of nucleophile addition. Indeed, this synthetic technology proved highly efficacious as treatment of 41 with two equivalents of LDA in the presence of LiCl in THF at — 78°C, followed by the slow addition 

With both 27 and 28 in hand, these fragments were smoothly joined in a Michael addition simply by stirring at ambient tempera- 

which was immediately quenched with methyl cyanoformate (Mander s reagent). As one would expect, approach of this electrophile occurred from the more accessible convex face of the AB ring system, providing 20 with the absolute stereochemistry shown. Since this center would be destroyed later in the synthetic sequence, however, the selectivity of this operation was actually of no consequence. 

with conversion of the resultant alcohol into the corresponding mesylate (53) proceeding in 88 % yield. This newly installed leaving group was then immediately eliminated upon treatment with DBU at room temperature in benzene, affording a 1.5 1 mixture of the a,p- and p,y-unsaturated esters 54 and 19, with the minor isomer being the desired compound for the envisioned epox- 

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