There are limited methods for establishing acyclic conformations which result in intramolecular cyclization to medium sized rings. Previous work has examined the relationship of alkyl group substitution, the Thorpe-Ingold, gem-dialkyl, a reactive rotamer effects, to ring closure in small and large rungs; but, these effects have not been evaluated in a systematic fashion for the synthesis of medium sized rings. This proposal will examine the steric and stereoelectronic directing effects of trialkylstannyl and -silyl groups on cyclization of 8-to-12 membered carbocyclic and heterocyclic rings. Preliminary data describing cyclization of alpha-alkoxystannyl dienes to 8-membered oxacycles by ring closing metathesis (RCM) is presented. Preliminary data describing cyclization of alpha-alkoxystannyl dienes to 8-membered oxacycles by ring closing metathesis (RCM) is presented. We will examine the """"""""tin effect"""""""" in relation to the known effects mentioned above. Direct comparison of rates of reactions for Sn, Si, and C substituted dienes in the synthesis of carbocycles and heterocycles by RCM will be obtained. We will investigate the stereoelectronic effect of heteroatoms in relation to acyclic conformational control of the tin substituted dienes in RCM to medium sized rings. We will extend this investigation to the synthesis of medium sized lactones, and carbocycles to lactonization and aldol reactions, respectively. In addition, the """"""""tin effect"""""""" will be examined for other transition metal mediated cyclization reactions such as carbopalladation, the Pauson Khand reaction and palladium catalyzed enzyme cycloisomerization. In addition to the conformational control studies, further work is proposed to assess the configurational stability of cyclic alpha-alkoxy lithio anions derived from 8- to 12- membered rings obtained via RCM of the stannyl substituted dienes. Nucleophilic addition reactions to 8- to 12- membered cyclic acetals, available by RCM of stannyl substituted diene acetals, will be examined in detail. These reactions have limited precedent and will be of considerable interest to the synthetic organic community. We also propose several applications of the new chemistry developed in this grant application. Carbocyclic systems will be produced via Ramberg Backlund ring contraction and 2,3-sigmatropic rearrangements of oxacyclic species. The total synthesis of laurencin, phoracantholide I, cephalosporolide C, and diplodialide C are also proposed as illustrations of this novel methodology. This proposal therefore presents an innovative method for the control of acyclic conformations which can lead to intramolecular cyclization reactions that cannot be realized without pre-existing conformational constraints. Furthermore, the use of functional groups, such as trialkylstannanes, allows for functional group conversion of the directing substituent via nucleophilic or electrophilic processes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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North Carolina State University Raleigh
Schools of Arts and Sciences
United States
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