Atom-Economical Synthesis of the N(10)−C(17) Fragment of Cyclotheonamides via a Novel Passerini Reaction−Deprotection−Acyl Migration Strategy¹

Abstract

[reaction: see text]. A novel variant of the atom-economical Passerini reaction between suitably protected argininal, dipeptide isonitrile, and proline components afforded adduct 13. Orthogonal N-deprotection of 13 led, via a smooth O- to N-acyl migration, to 14, which constitutes the N(10)-C(17) fragment of the cyclotheonamide family of serine protease inhibitors. Each reaction in this three-step protocol proceeds in good yield and under very mild conditions.

Asymmetric Multicomponent Reactions (AMCRs): The New Frontier

“…The use of trifluoroacetic acid in the presence of excess pyridine led to an increase in the diastereoselectivity up to 75:25 (Scheme 25). [98] This protocol was evaluated in the synthesis of bestatin, which is a potent inhibitor of aminopeptidases and prolyl endopeptidases, [99] as well as of eurystatin A [100] and the N10-C17 fragment of cyclotheonamides, [101] without racemization of the a-aminoaldehyde moiety. The use of chiral isocyanides derived from glucosyl compounds and chiral aldehydes did not improve the previously mentioned stereoselectivity.…”

Chemistry and Biology Of Multicomponent Reactions

“…Respective PADAM sequences of thrombin inhibitors have been performed on a kg scale to obtain material for (pre)clinical development. 43b …”

Application of the O-N Intramolecular Acyl Migration Reaction in Medicinal Chemistry

“…Thus, this rearrangement has been applied in the synthesis of peptidomimetics: including -secretase inhibitors [127,128], prolyl endopeptidase inhibitor eurystatin A [129], HIV-protease inhibitors [130], and many others [131][132][133][134][135][136][137]. An O-N intramolecular benzoyl migration was effectively used to obtain the paclitaxel side chain, phenylisoserine [138].…”