Locked Conformations for Proline Pyrrolidine Ring: Synthesis and Conformational Analysis of cis- and trans-4-tert-4Butylprolines

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A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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Date
2005
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Language
en
Pages
6447-6453
Series
Journal of organic chemistry, Volume 70
Abstract
The motional restrictions of the proline pyrrolidine ring allow this secondary amine amino acid to act as a turn inducer in many peptides and proteins. The pyrrolidine ring is known to exhibit two predominant pucker modes (i.e., C-4 (Cç) exo and endo envelope conformers whose ratio can be controlled by proper substituents in the ring). In nature, the exo puckered 4(R)-hydroxy-L-proline plays a crucial role as a building block in collagen and collagen-like structures. It has been previously concluded that the electronegativity of the 4-cis-substituent increases the endo puckering while the electronegativity of the 4-trans-substituent favors the exo puckering. Here, we have introduced a sterically demanding tert-butyl group at C-4 in trans- and cis-configurations. In the case of transsubstitution, the induced puckering effect on the pyrrolidine ring was studied with X-ray crystallography and 1H NMR spectral simulations. Both cis- and trans-4-tert-butyl groups strongly favor pseudoequatorial orientation, therebycausing opposite puckering effects for the pyrrolidine ring, cis-exo and trans-endo for L-prolines, in contrast to the effects observed in the case of electronegative C-4 substituents. The syntheses and structural analysis are presented for the conformationally constrained 4-tert-butylprolines. The prolines were synthesized from 4-hydroxy-L-proline, substitution with t-BuCuSPhLi being the key transformation. This reaction gave N-Boctrans-4-tert-butyl-L-proline tert-butyl ester in 94% ee and 57% de. Enantioselectivity was increased to 99.2% ee by crystallization of N-Boc-trans-4-tert-butyl-L-proline in the final step of the synthesis.
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Keywords
conformational analysis, cuprate reagent, tert-butylproline
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Citation
Koskinen , A M P , Helaja , J , Kumpulainen , E T T , Koivisto , J , Mansikkamäki , H & Rissanen , K 2005 , ' Locked Conformations for Proline Pyrrolidine Ring: Synthesis and Conformational Analysis of cis- and trans-4-tert-4Butylprolines ' , Journal of Organic Chemistry , vol. 70 , pp. 6447-6453 . https://doi.org/10.1021/jo050838a