Details

PROCESSING OF THE DIBAL ADDUCT OF A PROLINE-DERIVED ESTER TO GENERATE A SINGLE DIASTEREOMER OF AN ALLYL ALCOHOL FOR USE IN A NOVEL SYNTHETIC METHOD FOR PYRROLIZIDINES

by Zhao, Yang

Abstract (Summary)
Using the method of intramolecular carbolithiation in which the organolithium is generated by reductive lithiation of a phenyl thioether, annulations on to pyrrolidine derivatives have been accomplished to produce virtually enantiomerically and diastereomerically pure pyrrolizidines. However, the main part of the thesis involves mechanistic and theoretical studies of the highly diastereoselective process by which a key intermediate, (S,S)-2-pyrrolidinyl vinyl carbinol 6, in the synthesis of a hydroxylated pyrrolizidine, is generated from N-Boc-L-proline methyl ester. The process involves the treatment of this ester with DIBAL at -78 ¡ãC, warming to -20 ¡ãC, cooling to -78 ¡ãC, and treatment with vinylmagnesium bromide. It was demonstrated that there is virtually no stereoselectivity when the vinylmagnesium bromide is added to the corresponding aldehyde in the presence of di-isobutylaluminum methoxide, the products expected if the DIBAL-ester adduct decomposes before Grignard addition. Further evidence that an aldehyde is not involved was obtained when it could not be detected by 1H NMR in the solution after warm-up. The theoretical study was designed to test a postulated mechanism in which a mixture of diastereomeric adducts R1 and R2 of DIBAL and the ester, generated at -78 ¡ãC, undergoes equilibration by reversible ionization of the methoxide ion when warmed and that the isomer R1 greatly predominates at equilibrium. Both diastereomers are believed to involve a seven-membered ring, afforded by coordination of the Al atom of the adduct with the carbonyl oxygen atom of the Boc group, fused to the pyrrolidine. Reaction of the diastereomer R1 with vinylmagnesium bromide via a SNi mechanism would yield the observed diastereomer of the allylic alcohol. Calculations do indeed predict that R1 is substantially more stable than its diastereomer R2 providing evidence for the mechanism. As a bonus, it has been discovered that the same high stereoselectivity can be attained without raising the temperature by adding a catalytic amount of the Lewis acid ZnCl2 at -78 ¡ãC; the Lewis acid probably aids the ionization of the methoxide ion thus increasing the rate of equilibration, providing an additional piece of evidence for the mechanism as well as simplifying the experimental procedure.
Bibliographical Information:

Advisor:Scott Nelson; Toby Chapman; Theodore Cohen

School:University of Pittsburgh

School Location:USA - Pennsylvania

Source Type:Master's Thesis

Keywords:chemistry

ISBN:

Date of Publication:06/29/2006

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