Stereoselective Synthesis of Dysoxylactam A

Abstract

The first report on the stereoselective synthesis of dysoxylactam A is disclosed. The five stereogenic centers of the fatty acid chain are created by utilizing Merck-Carreira and Marshall’s propargylation reaction, Evans’ alkylation methodology, and Noyori’s transfer hydrogenation protocol.

Total Synthesis of Dysoxylactam A

“…The unique biological and structural features of dyxoxylactam A are in good accordance with our continuing interest in natural-product-oriented explorations . Herein we describe a concise and stereocontrolled total synthesis of dysoxylactam A …”

Synthesis of Dysoxylactam A Using Iterative Homologation of Boronic Esters

“…Such esterifications are notoriously difficult, [15] with this step being highlighted as problematic in previous syntheses of dysoxylactam A; [2–4] which was our experience too. Using a modification of Chandankar's DCC/DMAP conditions, we obtained the desired ester 8 in moderate yield, but with a significant amount of epimerisation [2] . The use of HOAt or HOBt did not prevent this epimerisation, but fortunately separation of diastereoisomers was possible.…”

“…Such was the interest in this natural product, that even though it was only reported in 2019, three total syntheses of dysoxylactam have already appeared (Figure 1). Chandankar completed the first synthesis in 16 steps [2] using a combination of Carreira and Marshall propargylation reactions, Evans alkylation methodology and Noyori transfer hydrogenation to control the stereochemistry present in the fatty acid chain. The macrocycle was formed via a macrolactamisation.…”

“…With the alcohol 3 in hand, we explored the esterification of the hindered secondary alcohol with N-Boc-l-valine. Such esterifications are notoriously difficult, [15] with this step being highlighted as problematic in previous syntheses of dysoxylactam A; [2][3][4] which was our experience too. Using a modification of Chandankar's DCC/DMAP conditions, we obtained the desired ester 8 in moderate yield, but with a significant amount of epimerisation.…”

“…Using a modification of Chandankar's DCC/DMAP conditions, we obtained the desired ester 8 in moderate yield, but with a significant amount of epimerisation. [2] The use of HOAt or HOBt did not prevent this epimerisation, but fortunately separation of diastereoisomers was possible. Ozonolysis-oxidation procedure converted the alkene to the corresponding carboxylic acid 9 cleanly and in one-pot.…”