Silyl Imine Electrophiles in Enantioselective Catalysis: A Rosetta Stone for Peptide Homologation, Enabling Diverse N-Protected Aryl Glycines from Aldehydes in Three Steps

Abstract

We report that N-(trimethylsilyl)imines serve in the Bis(AMidine)-catalyzed addition of bromonitromethane with a high degree of enantioselection. This allows for the production of a range of protected α-bromo nitroalkane donors (including Fmoc) for use in Umpolung Amide Synthesis (UmAS). Hence, peptide homologation with nonnatural aryl glycine amino acids is achieved in three steps from aromatic aldehydes, which are plentiful and inexpensive. Epimerization during the homologation step is circumvented by avoiding an α-amino acid intermediate.

DFT-Based Stereochemical Rationales for the Bifunctional Brønsted Acid/Base-Catalyzed Diastereodivergent and Enantioselective aza-Henry Reactions of α-Nitro Esters

“…As a result, we hypothesized that high diastereoselectivity is achieved by differences in catalyst− nitronate binding. 47 Given this premise and our previously reported model for stereoselection in C 2 -symmetric H,Quin-BAM Brønsted acid catalysis, we sought a deeper understanding of C 1 -symmetric H,Quin-BAM Brønsted acid catalysis. Specifically, the manner in which nitronate facial selectivity is achieved is concomitant with the preservation of azomethine facial selectivity.…”

“…anti-(2S,3S)-TS). 47 That the catalyst−imine binding determines enantioselection is a unifying principle supported by all BAM-catalyzed aza-Henry reactions, 19−31 for which the correlation between product amine configuration and catalyst antipode is currently without exception.…”

A New Wave of Amide Bond Formations for Peptide Synthesis

“…The obtained silyl amine intermediate was subsequently functionalized by a range of protecting groups including Fmoc, Cbz and Alloc groups. 95 Unfortunately, these methods remained limited to -aryl side chains. Interestingly, a homogenous organocatalyst 93 that displayed compatibility with bromo nitromethane granted an enantioselective aza-Henry addition to N-Boc-protected amino acid surrogates with aliphatic side chains in S-configuration 92 (Scheme 35).…”

Tandem N,N-Dialkylation Reaction of N-Trimethylsilyl α-Iminoesters Utilizing an Umpolung Reaction and Characteristics of the Silyl Substituent: Synthesis of Pyrrolidine, Piperidine, and Iminodiacetate

“…The advantage of metalloimines is that they can easily be transformed into unprotected N–H derivatives with only hydrolysis . In particular, silylimine is known to exhibit intriguing reactivity as nucleophiles and electrophiles …”