Building blocks for (C15−C3)-modified epothilone D analogs

Bifurcated synthesis of methylene-lactone- and methylene-lactam-fused spirolactams via electrophilic amide allylation of γ-phenylthio-functionalized γ-lactams

“…Since the cyclization under acidic conditions led to the predominant formation of the methylene-lactam-fused spirolactam, we set another route toward 5 via cyclization of N-Boc-functionalized γ-hydroxymethacrylamide [26]. We initially treated the hydroxylactam prepared through CuBr-mediated hydroxylation of 3b with di-tert-butyl dicarbonate (Boc 2 O) in the presence of N,N-dimethyl-4-aminopyridine (DMAP), but a mixture of structurally unidentified products was formed.…”

Divergent Synthesis of Methylene Lactone- and Methylene Lactam-Based Spiro Compounds: Utility of Amido-Functionalized γ-Hydroxylactam as a Precursor for Cytotoxic N,O- and N,N-Spiro Compounds

“…Meanwhile, a regioisomeric N , O -spiro structure depicted as 4 , which was our original target in the previous work, should be highly attractive due to the fact that α-methylene-γ-butyrolactone shows more potent bioactivity and should work as a better Michael acceptor compared with the corresponding methylene lactam . Considering the highly functionalized molecular structure of 3 , compound 4 would be accessible through lactonization of the γ-hydroxy amide moiety, and such transformation has already been shown in many reports including our recent works, in which acidic or Boc-protection approaches were employed (Figure , methods A and B) . In this report, we describe a new pathway enabling a bifurcated synthesis of cytotoxic N , O -spiro compounds using amido-functionalized γ-hydroxylactam 3 as a key intermediate and a synthetic method for new methylene lactam-based N , N -spiro compounds.…”