Applications of nitroalkene (4+2); cycloaddition chemistry. The asymmetric synthesis of substituted pyrrolidines and the total synthesis of mesembrine
Marcin, Lawrence R.
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https://hdl.handle.net/2142/20131
Description
Title
Applications of nitroalkene (4+2); cycloaddition chemistry. The asymmetric synthesis of substituted pyrrolidines and the total synthesis of mesembrine
Author(s)
Marcin, Lawrence R.
Issue Date
1996
Doctoral Committee Chair(s)
Denmark, Scott E.
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Organic
Language
eng
Abstract
A general route for the preparation of 2,2-disubstituted 1-nitroalkenes has been developed. Conjugate 1,4-addition of zinc cuprates (RCu(CN)ZnI) to easily obtained (E)-1-nitroalkenes, followed by trapping with phenylselenenyl bromide, and subsequent oxidative elimination afforded the corresponding 2,2-disubstituted 1-nitroalkenes in 76-88% yield as E/Z isomeric mixtures ($\sim$1.0/1.5, E/Z). 2,2-Disubstituted-1-nitroalkenes were found to undergo Lewis acid-promoted (4+2) cycloadditions with n-butyl vinyl ether to afford cyclic nitronates in 76-90% yield. The resulting nitronates were reduced with hydrogen in the presence of platinum oxide to afford 3,3-disubstituted pyrrolidines which were isolated in 70-83% yield as their N-tosyl derivatives. Similarly, cycloadditions of (E)-2-nitrostyrene with 2-substituted enol ethers provided for the stereoselective synthesis of cis- and trans-3,4-disubstituted pyrrolidines.
(E)-2-Substituted 1-nitroalkenes undergo highly diastereoselective (4+2) cycloadditions with the chiral vinyl ethers derived from (R)-2,2-diphenylcyclopentanol and (1R,2S)-2-phenylcyclohexanol to afford nitronates in high yields. The resulting nitronates were reduced to afford enantiomerically enriched pyrrolidines in good yields. A series of 3-substituted pyrrolidines (71-97% ee) were prepared, as well as (3S,4R)-4-methyl-3-phenyl-N-(p-tolylsulfonyl)pyrrolidine (92% ee) and (3S,4S)-3,4-diphenylpyrrolidine (99% ee).
The total synthesis of ($-$)-mesembrine was accomplished in seven steps and 19% yield from a functionalized 2,2-disubstituted 1-nitroalkene, which was prepared in six steps and 34% yield from ethyl 3-bromopropionate. The quaternary, stereogenic center of the natural product was established in 26/1 selectivity through an asymmetric (4+2) cycloaddition with a chiral vinyl ether derived from (1R,2S)-2-(1-methyl-1-phenylethyl)cyclohexanol.
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