1. Locked conformations for proline pyrrolidine ring: synthesis and conformational analysis of cis- and trans-4-tert-butylprolines
Ari M P Koskinen, Juho Helaja, Esa T T Kumpulainen, Jari Koivisto, Heidi Mansikkamäki, Kari Rissanen 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.
2. Pentanidium-catalyzed enantioselective phase-transfer conjugate addition reactions
Ting Ma, Xiao Fu, Choon Wee Kee, Lili Zong, Yuanhang Pan, Kuo-Wei Huang, Choon-Hong Tan J Am Chem Soc. 2011 Mar 9;133(9):2828-31. doi: 10.1021/ja1098353. Epub 2011 Feb 11.
A new chiral entity, pentanidium, has been shown to be an excellent chiral phase-transfer catalyst. The enantioselective Michael addition reactions of tert-butyl glycinate-benzophenone Schiff base with various α,β-unsaturated acceptors provide adducts with high enantioselectivities. A successful gram-scale experiment at a low catalyst loading of 0.05 mol % indicates the potential for practical applications of this methodology. Phosphoglycine ester analogues can also be utilized as the Michael donor, affording enantioenriched α-aminophosphonic acid derivatives and phosphonic analogues of (S)-proline.
3. Synthesis of glycopeptides with phytoalexin elicitor activity--III. Syntheses of hexaglycosyl hexapeptides and a nonaglycosyl hexapeptide
T Takeda, T Kanemitsu, Y Ogihara Bioorg Med Chem. 1996 Nov;4(11):1873-80. doi: 10.1016/s0968-0896(96)00170-8.
A block synthesis of the model compound for the phytoalexin elicitor-active glycoprotein is described. Combination of the C-terminus free compounds, N-(9-fluorenylmethoxycarbonyl)-O-(tert-butyl)-L-seryl-L-proline (1) or N-(9-fluorenylmethoxycarbonyl)-(2,3,4,6-tetra-O-acetyl-beta-D-g luc opyranosyl) -(1-->6)-(2,3,4-tri-O-acetyl-alpha-D-mannopyranosyl)-(1-->6) -(2,3,4-tri-O-acetyl-alpha-D-mannopyranosyl)-L-seryl-L-proline (2) with the N-terminus free compounds, 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl -(1-->6)-(2,3,4-tri-O-acetyl-alpha-D-mannopyranosyl)-(1-->6)-(2,3,4-tri- O -acetyl-alpha-D-mannopyranosyl)-L-seryl-L-prolyl-L-seryl-L-proline methyl ester (4), O-(tert-butyl)-L-seryl-L-prolyl-(2,3,4,6-tetra-O-acetyl-beta-D -glucopyranosyl)-(1-->6)-(2,3,4-tri-O-acetyl-alpha-D-mannopyranosyl) -(1-->6)-(2,3,4-tri-O-acetyl- alpha-D-mannopyranosyl)-L-seryl-L-proline methyl ester (6) or 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranosyl -(1-->6)-(2,3,4-tri-O-acetyl-alpha-D-mannopyranosyl)-(1-->6) -(2,3,4-tri-O-acetyl-alpha-D-mannopyranosyl)-L-seryl-L-prolyl -(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-(1-->6) -(2,3,4-tri-O-acetyl-alpha-D-mannopyranosyl)-(1-->6) -(2,3,4-tri-O-acetyl-alpha-D-mannopyranosyl)-L-seryl-L-proline methyl ester (8), by use of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) gave three hexaglycosyl hexapeptides and a nonaglycosyl hexapeptide derivatives (9, 11, 14, and 17). These N-terminus free compounds were derived from triglycosyl tetrapeptides (3 and 5) or a hexaglycosyl tetrapeptide (7) on selective deblock reaction by morpholine. The hexaglycosyl hexapeptides (10, 13, and 16) and the nonaglycosyl hexapeptide (18) have been prepared by the convergent block synthesis.