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

Ari M.P. Koskinen, Juho Helaja, Esa T.T. Kumpulainen, Jari Koivisto, Heidi Mansikkamäki, Kari Rissanen

    Research output: Contribution to journalArticleScientificpeer-review

    32 Citations (Scopus)
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    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, thereby causing 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.
    Original languageEnglish
    Pages (from-to)6447-6453
    JournalJournal of organic chemistry
    Volume70
    DOIs
    Publication statusPublished - 2005
    MoE publication typeA1 Journal article-refereed

    Keywords

    • conformational analysis
    • cuprate reagent
    • tert-butylproline

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