Zwitterionic amino-Claisen rearrangement

The zwitterionic amino-Claisen rearrangement (41-44), a variant of the aza-Cope reaction (103-105), is another sigmatropic process which has been successfully employed in the synthesis of yohimbines. Mariano and his coworkers have presented designs for the synthesis of reserpine (2) and/or deserpidine (3) in which the target was envisioned as arising from jS-enaminoester 189 by... 

Model studies have demonstrated that the approach of Mariano and his coworkers does indeed permit rapid construction of the pentacyclic yohimbine skeleton (Scheme 129) (41, 42). For example, Diels-Alder reaction of dihydropyridine 193 with methyl vinyl ketone (194) afforded isoquinuclidene 195 which was sequentially ketalized, the nitrogen deprotected, and trypto-phylated to yield the model substrate 196. Treatment of 196 with t-butyl propiolate effected the crucial zwitterionic amino-Claisen rearrangement to efficiently provide the hexahydroisoquinoline 197 having the crucial cis-DE-ring fusion in place. Treatment of 197 under the Wenkert cyclization condi-... 

Clearly, this investigation demonstrated that the combined zwitterionic amino-Claisen rearrangement Wenkert cyclization methodologies constitute a rapid procedure for generating functionalized yohimbines. Moreover, the strategy is flexible and allows for the introduction of appropriate E-ring... 

An approach in constructing the basic reserpine skeleton via the amino Claisen rearrangement of zwitterionic vinylisoquinuclidenes has been investigated (256, 257). 

Presently, the zwitterionic aza-Claisen rearrangement has been developed as a reliable method to synthesize suitably protected non-natural a-amino acid derivatives, e.g., C-ahyl glycines of type 312 and 3-arylprohnes of type 313. 

The mechanistic rationale put forth for product formation involved ketene attack on the amine moiety followed by an amino Claisen rearrangement of the zwitterionic enolate. An analogous reaction is observed with methyl propiolate and fused azabicyclic systems [14]. 

A potentially useful route to reserpine alkaloids has been suggested by the application of the amino-Claisen reaction (Scheme 52) to the indolyl-substituted isoquinuclidine (268). Treatment of (268) with methyl propiolate gave the intermediate zwitterion (269) which rapidly rearranged to (270). This latter compound has all the necessary functionality for further elaboration into the reserpine ring system (B-82MI20700). 

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