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.
The direct asymmetric conjugate addition of a-cyanoacetates to enones generating densely functionalized a-amino acid precursors with adjacent quaternary and tertiary stereocenters is described comparing monoand bis-palladacycle catalysts. This edge article features the complementary value of mono-and bimetallic catalysis in a case study using related catalyst systems. Different major diastereomers of the 1,4-addition products are formed by the use of the planar chiral mono-and bimetallic catalyst systems and provide access to epimeric amino acid derivatives. Both catalyst types require the use of a Brønsted acid (HOAc) as a co-catalyst to avoid an undesired b-hydride elimination. Kinetic studies show that the C-C bond forming step takes place almost instantaneously with the bis-palladium complex after productive substrate coordination. This extraordinarily high reactivity for an elementary step generating a sterically demanding linkage of a quaternary and a tertiary stereocenter stresses the cooperativity of both metal centers.
We have systematically explored three approaches based on Fmoc chemistry 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[Oβ(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 should yield an effective total chemical synthesis of insulin lispro (Humalog) based on peptide synthesis by Fmoc chemistry SPPS.
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.
The anchoring of well-defined molecular catalysts on a surface is an attractive strategy to develop sustainable catalytic processes. This article describes the first syntheses of monolith-supported ferrocene palladacycle catalysts. Monolithic supports were prepared via ring-opening metathesis polymerization (ROMP) using the ''1st generation Grubbs catalyst''. Fluorinated carboxylates were surface-grafted utilizing living Ru-termini. The immobilization of the palladacycles onto the monolithic support was accomplished by ligand substitution on the fluorinated carboxylates of the graft polymer. An investigation of these supported catalysts on the efficiency and reusability under different reaction conditions in a direct Michael addition generating a quaternary C-atom is reported. Whereas stereoselectivity was found to be significantly lower than in a comparable homogeneous system, Pd-leaching was not detected in all analyzed samples indicating a permanently immobilized catalyst system.
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