Synthesis of Chiral Piperazinones Using Amphoteric Aziridine Aldehyde Dimers and Functionalized Isocyanides

Abstract

We have evaluated a range of functionalized isocyanides in the aziridine aldehyde-driven multicomponent synthesis of piperazinones. High diasteroselectivity for each isocyanide was observed. A theoretical evaluation of the reaction course corroborates the experimental data. Moreover, the reactivity of cis- and trans-configured aziridine aldehyde dimers has been compared. This study further probes the dimer-driven mechanism of cyclization and enables an efficient access to a wide range of chiral piperazinones bearing functionalized side chains.

A Mechanistic Model for the Aziridine Aldehyde-Driven Macrocyclization of Peptides

“…Emerging from the calculations was the finding that syn -addition modes Z -pro­( S ) 2a and E -pro­( R ) 2a , wherein isocyanide addition occurs proximal (i.e., syn to) to the l -proline amide carbonyl oxygen, corresponded to the favored stereofacial modes of addition (Figure ). Notably, this result is consistent with our previous investigations of the disrupted Ugi reaction of l -prolinium ions, , despite the increased complexity of the system and the presence of a proline-amide, rather than a proline-carboxylate, directing group.…”

“…We have previously reported a computational study on the mechanism of the reaction between the aziridine aldehyde dimer (( R )- 1 ), l -proline ( 6 ), and t Bu-isocyanide ( 3 ) to form a chiral piperazinone ( 7 ) (Figure a). , Therein, the computations revealed that the observed high diastereoselectivity originated from transition state assembly Z -pro­( S ) (Figure b), involving a carboxylate directed isocyanide addition to a kinetically favored Z -iminium ion formed between l -proline and an aziridine aldehyde dimer. A distinct nitrilium ion intermediate was not observed, and the concerted asynchronous process of isocyanide addition and carboxylate attack was deduced to be the driving force behind the high diastereoselectivity.…”

α-Amino Acids as Synthons in the Ugi-5-Centers-4-Components Reaction: Chemistry and Applications

“…In particular, the use of L-valine produced two different oxomorpholines 203 and 204 and a seven-membered lactone 205, in contrast to D-valine, which gave a mixture of syn-and anti-configured 2-oxomorpholines 207. L-amino acids were used by Yudin A. et al as starting material with isocyanides and aziridine aldehydes for piperazinone synthesis [48][49][50]. Piperazinone products 211 and 212 were obtained in all cases as a single diasteroisomers without formation of linear product (Scheme 54).…”

“…Piperazinone products 211 and 212 were obtained in all cases as a single diasteroisomers without formation of linear product (Scheme 54). A detailed analysis through X-ray crystallography and NOESY NMR studies revealed that diastereoselectivity L-amino acids were used by Yudin A. et al as starting material with isocyanides and aziridine aldehydes for piperazinone synthesis [48][49][50]. Piperazinone products 211 and 212 were obtained in all cases as a single diasteroisomers without formation of linear product (Scheme 54).…”

Stereoselective Multicomponent Reactions in the Synthesis or Transformations of Epoxides and Aziridines

“…In the case of the chiral primary amino acid, this transformation was selective for the trans -substituted products 90 while the chiral secondary or protected amino acids afforded cis -products. Besides this, a diverse range of functionalized isocyanides were screened in the disrupted Ugi reaction to obtain chiral piperazinones in high stereoselectivities [78].…”