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Diastereoselective manipulations and conformational calculations of enantiomerically pure bicyclo(M.1.0)alkan-2-ones and bicyclo(M.1.0)alk-3-en-2-ones.
AuthorGregg, Timothy Morgan.
Committee ChairMash, Eugene A. Jr.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractMedium- and large-sized cycloalkanones with adjacent fused cyclopropyl rings are excellent substrates for highly diastereoselective reactions. We attribute the high selectivity of these reactions to local conformational rigidity around the stereo genic cyclopropane ring in these otherwise flexible systems. Addition of a variety of nucleophiles to these compounds, where the large ring ranged from eight- to 16-membered, gave cyclopropyl carbinols with >20:1 stereoselectivity. Crystallographic analysis of the products in several cases confirmed that the favored approach of the nucleophile is anti to the geometry of the ring fusion. This ability of the cyclopropyl ring to direct stereoselective reactions at carbonyl was extended to carbon atoms further around the parent ring. In initial studies, alkylations of bicyclo[6.1.0]nonan-2-one lithium enolate gave single a-alkyl ketone diastereomers. These and other bicyclic ketones have been converted to the respective α,β-unsaturated ketones and extremely high diastereoselectivity in 1,2-additions to these compounds was observed, giving the respective allylic cyclopropyl carbinols. Additionally, Michael and cuprate additions to these enones gave 1,4-adducts in good yield, with diastereoselectivity dependent on the specific reaction and the ring size. Molecular mechanics calculations were performed to model the ground state conformations of the starting ketones and enones in these reactions. In the large ensemble of conformers found in each ring size, conformers lowest in energy all tended to expose one face of the carbonyl to the surroundings. For enones, anchoring of the olefin resulted in conformers exhibiting both s-cis and s-trans configurations. For reactions where assumption of early transition states is appropriate, ground state conformers can be used as general, predictive models for diastereoselection. The generalization of these computational results makes our approach to medium and large ring functionalization a powerful tool for the synthesis of medium and large carbocyclic natural products.