Locked Conformations for Proline Pyrrolidine Ring: Synthesis and Conformational Analysis of <i>cis-</i> and <i>trans</i>-4-<i>tert</i>-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 (Cγ) 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.