Total Synthesis of an Oxepine Natural Product, (±)-Janoxepin

Abstract

The total synthesis of (±)-janoxepin, a novel antiplasmodial d-leucine derived oxepine-pyrimidinone-ketopiperazine isolated from the fungus Aspergillus janus, is described. The cornerstones of the synthetic route are pyrimidinone preparation, ring-closing metathesis, aldol introduction of the enamide, and dihydro-oxepine elaboration. This synthetic route proved very efficient for the formation of a number of janoxepin analogues, including dihydro-janoxepin and tetrahydro-janoxepin.

Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors

“…A solution of Boc-Phe-NCCN (5.0 g, 16.5 mmol) in formic acid (5 mL) was stirred for 16 h and then concentrated under vacuum to give COO . Phe-NCCN as an oil which was used in the next step without further purification: yield 90% [ 38 ].…”

ChemInform Abstract: Amine‐Free Approach Toward N‐Toluenesulfonyl Amidine Construction: A Phosphite‐Mediated Beckmann‐Like Coupling of Oximes and p‐Toluenesulfonyl Azide.

“…Finally, quenching of 6 yields amidine 8, which after undergoing a 1,3-phosphoryl shift provides the observed amidine 3. This mechanism is commensurate with a Beckmann-like ligation event involving a stereospecific [1,2] shift and nitrilium cation capture. While there are a number of methods for phosphoramide cleavage, dephosphorylation without amidine hydrolysis represents a significant synthetic challenge.…”

“…However, the addition of PhSO 2 NH 2 yielded exclusively the azide ligation product 3 b in 85 % yield (Table 3, entry 2). This mechanism is commensurate with a Beckmann-like ligation event involving a stereospecific [1,2] shift and nitrilium cation capture. [11b] However, 3 b and 5 a, likely arising from carboxylic acid addition to a nitrilium cation intermediate and subsequent hydrolysis, were obtained in a 3:1 ratio.…”

“…Exposure of 1 j and TsN 3 to ClP(dmp-ol) and Et 3 N in PhMe at 0 8C yielded the N-sulfonyl phosphoramidine 3 j in 58 % yield as a single regio-and stereoisomer. [18] It is important to note that under the reaction conditions, a epimerization of the chiral oxime is not observed, and the retention of absolute configuration at the site of migration is consistent with a concerted [1,2] shift.…”

“…In recent years they have become a common synthetic building block in heterocycle construction [1] and the synthesis of biologically active natural products. [2] They also have emerged as a key functional group in pharmaceutical drug design. [3] Despite their growing biological significance, [4] the use of amidines as bioorthogonal chemical reporters is notably absent.…”