Rates of carbonate bond formation: Implications for macrocyclization

High yields of cyclic oligomeric carbonates can be prepared using an amine-catalyzed reaction of bisphenol A–bischloroformate. We have studied the mechanistic aspets of this carbonate macrocyclization by the isolated study of key chemical events. Using stopped-flow FT-IR spectroscopy, we have found that the rate of carbonate formation between the intermediate acyl ammonium salt and 4-isopropylphenol is the same for the acyl ammonium salt derived from tri-n-butylamine, triethylamine and diethylmethylamine. Previously, we found that conversion of acyl ammonium salt to urethane was also insensitive to amine structure while the formation of acyl ammonium salt is profoundly dependent on amine structure. These results are consistent with a mechanism in which the selectivity toward macrocyclization versus linear oligomer or high polymer formation is related to acyl ammonium salt concentration.     

Design,Synthesis, and Characterization of Macrocyclic Inhibitors of the Proprotein Convertase Furin

The activation of viral glycoproteins by the host protease furin is an essential step in the replication of numerous pathogenic viruses. Thus, effective inhibitors of furin could serve as broad-spectrum antiviral drugs. A crystal structure of an inhibitory hexapeptide derivative in complex with furin served as template for the rational design of various types of new cyclic inhibitors. Most of the prepared derivatives are relatively potent furin inhibitors with inhibition constants in the low nanomolar or even sub-nanomolar range. For seven derivatives the crystal structures in complex with furin could be determined. In three complexes, electron density was found for the entire inhibitor. In the other cases the structures could be determined only for the P6/P5-P1 segments, which directly interact with furin. The cyclic derivatives together with two non-cyclic reference compounds were tested as inhibitors of the proteolytic activation and replication of respiratory syncytial virus in cells. Significant antiviral activity was found for both linear reference inhibitors, whereas a negligible efficacy was determined for the cyclic derivatives.     

Enhanced Permeability and Binding Activity of Isobutylene‐Grafted Peptides

We present a new peptide‐macrocyclization strategy with an isobutylene graft. The reaction is mild and proceeds rapidly and efficiently both for linear and cyclic peptides. The resulting isobutylene‐grafted peptides possess improved passive membrane permeability due to the shielding of the polar backbone of the amides, as demonstrated by NMR spectroscopy and molecular dynamics simulations. The isobutylene‐stapled structures are fully stable in human plasma and in the presence of glutathione. This strategy can be applied to bioactive cyclic peptides such as somatostatin. Importantly, we found that structural preorganization forced by the isobutylene graft leads to a significant improvement in binding. The combined advantages of directness, selectivity, and smallness could allow application to peptide macrocyclization based on this attachment of the isobutylene graft.     

大环多酰胺的合成进展

本文综述了近年来发展的合成大环四酰胺的方法,与先形成二酰胺二羧酸的衍生物再进行环化或者直接进行环化相比,先形成二酰胺二胺这种中间体,再进行环化的分步合成方法是一种较有效的途径。     

Site-Selective Peptide Macrocyclization

Cyclized peptides have seen a rise in popularity in the pharmaceutical industry as drug molecules. As such, new macrocyclization methodologies have become abundant in the last several decades. However, efficient methods of cyclization without the formation of side products remain a great challenge. Herein, we review cyclization approaches that focus on site-selective chemistry. Site selectivity in macrocyclization decreases the generation of side products, leading to a greater yield of the desired peptide macrocycles. We will also take an in-depth look at the new exclusively intramolecular N-terminal site-selective CyClick strategy for the synthesis of cyclic peptides. The CyClick method uses imine formation between an aldehyde and the N terminus. The imine is then trapped by a nucleophilic attack from the second amidic nitrogen in an irreversible site-selective fashion.     

One‐Pot Multi‐Component Synthesis and Solid State Structures of Functionally Rich Polyether Macrocycles

Densely functionalized polyether macrocycles can be prepared in one pot in yields up to 60% by the rhodium(II)‐catalyzed decomposition of methyl diazoacetoacetate in the presence of a variety of substituted or unsaturated 5‐ and 6‐membered ring cyclic ethers. A comprehensive analysis of the solid state conformations of the macrocyclic geometries is detailed as well as novel mechanistic insights about the multi‐component condensation reaction.

     

Rigid Peptide Macrocycles from On‐Resin Glaser Stapling

Peptide macrocycles are widely utilized in the development of high affinity ligands, including stapled α‐helices. The linear rigidity of a 1,3‐diynyl linkage provides an optimal distance (7 Å) between β‐carbons of the i,i+4 amino acid side chains, thus suggesting its utility in stabilizing α‐helical structures. Here, we report the development of an on‐resin strategy for an intramolecular Glaser reaction between two alkyne‐terminated side chains by using copper chloride, an essential bpy‐diol ligand, and diisopropylethylamine at room temperature. The efficiency of this ligation was illustrated by the synthesis of (i,i+4)‐, (i,i+5)‐, (i,i+6)‐, and (i,i+7)‐stapled BCL‐9 α‐helical peptides using the unnatural amino acid propargyl serine. Overall, this procedurally simple method relies on inexpensive and widely available reagents to generate low molecular weight 23‐, 26‐, 29‐, and 32‐membered peptide macrocycles.     

2-Mercaptopyridine — anchimerically-assisted activation of thiols,thioates and ketene thioacetals

The 2-mercaptopyridine reagent is reviewed with particular emphasis on a) recent developments, and b) comparison to alternative and sometimes superior methodologies. The useful application to macrocyclization or carboxyl activation is limited to special cases featuring additional functionalities. More recently, the reagent was utilized for the stereoselective synthesis of substituted β-lactones, β-lactames and carbohydrates