Locked conformations for proline pyrrolidine ring: synthesis and conformational analysis of cis- and trans-4-tert-butylprolines.
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 (Cgamma) 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 trans-substitution, 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-Boc-trans-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.
Koskinen
Ari M P
AM
Laboratory of Organic Chemistry, Department of Chemical Technology, Helsinki University of Technology, P.O. Box 6100, FIN-02015 HUT, Finland. ari.koskinen@hut.fi
Helaja
Juho
J
Kumpulainen
Esa T T
ET
Koivisto
Jari
J
Mansikkamäki
Heidi
H
Rissanen
Kari
K
D018360:Crystallography, X-Ray; D008968:Molecular Conformation; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry*; D013237:Stereoisomerism
D011759:Pyrrolidines; D011392:Proline; C032519:pyrrolidine