Koskinen Ari M P, Helaja Juho, Kumpulainen Esa T T, Koivisto Jari, Mansikkamäki Heidi, Rissanen Kari
Laboratory of Organic Chemistry, Department of Chemical Technology, Helsinki University of Technology, P.O. Box 6100, FIN-02015 HUT, Finland.
J Org Chem. 2005 Aug 5;70(16):6447-53. doi: 10.1021/jo050838a.
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.
脯氨酸吡咯烷环的运动限制使得这种仲胺氨基酸在许多肽和蛋白质中充当转角诱导剂。已知吡咯烷环呈现两种主要的褶皱模式（即C-4（Cγ）外式和内式信封构象体，其比例可通过环中适当的取代基来控制）。在自然界中，外式褶皱的4（R）-羟基-L-脯氨酸作为胶原蛋白和类胶原蛋白结构的组成部分发挥着关键作用。先前已经得出结论，4-顺式取代基的电负性增加内式褶皱，而4-反式取代基的电负性有利于外式褶皱。在此，我们在C-4处以反式和顺式构型引入了空间位阻较大的叔丁基。在反式取代的情况下，通过X射线晶体学和1H NMR光谱模拟研究了对吡咯烷环的诱导褶皱效应。与电负性C-4取代基的情况相比，顺式和反式4-叔丁基都强烈倾向于假赤道取向，从而对吡咯烷环产生相反的褶皱效应，对于L-脯氨酸为顺式外式和反式内式。本文介绍了构象受限的4-叔丁基脯氨酸的合成和结构分析。脯氨酸由4-羟基-L-脯氨酸合成，用t-BuCuSPhLi进行取代是关键转化步骤。该反应以94%的对映体过量和57%的非对映体过量得到N-Boc-反式-4-叔丁基-L-脯氨酸叔丁酯。在合成的最后一步，通过N-Boc-反式-4-叔丁基-L-脯氨酸的结晶，对映选择性提高到了99.2%的对映体过量。
