Asymmetric Synthesis of the Fully Elaborated Pyrrolidinone Core of Oxazolomycin A

Abstract

The asymmetric synthesis of the key pyrrolidinone core, including a highly elaborated exocyclic carbon chain, of the γ-lactam β-lactone antibiotic oxazolomycin A is described. Principal features include the Birch reduction of an aromatic pyrrole nucleus, a late stage RuO(4) catalyzed pyrrolidine oxidation, and a highly diastereoselective organocerium addition to an aldehyde.

Asymmetric Total Synthesis of (−)-(3R)-Inthomycin C

“…As part of our ongoing efforts to prepare oxazolomycin B, , we required an efficient synthesis of (−)-(3 R )-inthomycin C and sought to differentiate our approach by avoiding the use of the stoichiometric organotin reagents on which all previous syntheses rely. Initial investigations on the biological activity of synthetic (−)-(3 R )-inthomycin C and structural analogues on human cancer cell lines are also described for the first time.…”

Diastereoselective intramolecular aldol ring closures of threonine derivatives leading to densely functionalised pyroglutamates related to oxazolomycin

“…1) 1 and have established that Dieckmann 2 and aldol 3 ring closures may be used to access such systems. While a number of other groups have developed methodology to provide the relevant lactam-lactone spirocyclic and inthomycin subsets of the natural product, [4][5][6][7][8][9][10][11] we have established that some smaller structural mimics exhibit antibacterial activity [12][13][14] and therefore sought routes providing rapid access to other skeletal subsets of oxazolomycin which might similarly provide antibacterially active libraries. We recently reported that a biomimetic intramolecular aldol reaction using malonamide 2 (R 1 ¼ H, R 2 ¼ H, X ¼ OMe) derived from oxazolidine template 1 may be used to generate densely functionalised pyroglutamates of type 3, possessing two contiguous quaternary chiral centres.…”

Advances toward the Synthesis of Functionalized γ-Lactams

“…63 The synthesis commenced with Rivas and Ling N-protection of the the commercially available pyrrole 228, followed by partial Birch reduction and quenching with iodomethyl pivalate. Ester reduction afforded compound 229, which was treated with a lipase enzyme to desymmetrate the compound.…”

“…Deprotection of the methoxymethyl (MOM) group, followed by oxidation to the corresponding carboxylic acid, provided compound 234 (Scheme 48). 63 Protection of the acid 234 with a silyl group, removal of the acetate group, and oxidation led to the desired aldehyde. The resultant aldehyde was subjected to the Nozaki-Hiyama-Kishi reaction, which is a nickel/chromium-mediated coupling reaction between an aldehyde and a vinyl halide.…”