Scope and Limitations of Fmoc Chemistry SPPS-Based Approaches to the Total Synthesis of Insulin Lispro via Ester Insulin.

We have systematically explored three approaches based on 9-fluorenylmethoxycarbonyl (Fmoc) chemistry solid phase peptide synthesis (SPPS) for the total chemical synthesis of the key depsipeptide intermediate for the efficient total chemical synthesis of insulin. The approaches used were: stepwise Fmoc chemistry SPPS; the "hybrid method", in which maximally protected peptide segments made by Fmoc chemistry SPPS are condensed in solution; and, native chemical ligation using peptide-thioester segments generated by Fmoc chemistry SPPS. A key building block in all three approaches was a Glu[O-ß-(Thr)] ester-linked dipeptide equipped with a set of orthogonal protecting groups compatible with Fmoc chemistry SPPS. The most effective method for the preparation of the 51 residue ester-linked polypeptide chain of ester insulin was the use of unprotected peptide-thioester segments, prepared from peptide-hydrazides synthesized by Fmoc chemistry SPPS, and condensed by native chemical ligation. High-resolution X-ray crystallography confirmed the disulfide pairings and three-dimensional structure of synthetic insulin lispro prepared from ester insulin lispro by this route. Further optimization of these pilot studies could yield an efficient total chemical synthesis of insulin lispro (Humalog) based on peptide synthesis by Fmoc chemistry SPPS.

A Robust, Recyclable Resin for Decagram Scale Resolution of (±)-Mefloquine and Other Chiral N-Heterocycles.

Decagram quantities of enantiopure (+)-mefloquine have been produced via kinetic resolution of racemic mefloquine using a ROMP-gel supported chiral acyl hydroxamic acid resolving agent. The requisite monomer was prepared in a few synthetic steps without chromatography and polymerization was safely performed on a >30 gram scale under ambient conditions. The reagent was readily regenerated and reused multiple times for the resolution of 150 grams of (±)-mefloquine and other chiral N-heterocylces.

Paramagnetic palladacycles with Pd(III) centers are highly active catalysts for asymmetric aza-Claisen rearrangements.

A combination of spectroscopic and electrochemical methods--XANES, EXAFS, X-ray, (1)H NMR, EPR, Mössbauer, and cyclic voltammetry--demonstrate that the most efficient Pd catalysts for the asymmetric rearrangement of allylic trifluoroacetimidates unexpectedly possess in the activated oxidized form a Pd(III) center bound to a ferrocene core which remains unchanged (Fe(II)) during the oxidative activation. These are the first recognized Pd(III) complexes acting as enantioselective catalysts.