Ring‐Closing Metathesis and Photo‐Fries Reaction for the Construction of the Ansamycin Antibiotic Kendomycin: Development of a Protecting Group Free Oxidative Endgame

Abstract

Two convergent total syntheses of the ansa-polyketide (-)-kendomycin (1) are described. The syntheses benefit from the use of readily available and cheap starting materials. Highly complex diastereoselective Claisen-Ireland rearrangements were used to introduce the (E)-double bond and the C16-Me group. The ring closure of the strained ansa macrocycle was achieved by ring-closing metathesis and a highly efficient combination of macrolactonization and photo-Fries reaction. A protecting group free endgame via an unstable o-quinone is presented. Additionally some unsuccessful synthetic efforts towards the total synthesis of 1 are described.

Total synthesis of natural products containing benzofuran rings

“…The total synthesis was interrupted through the route reported by Mulzer and co-workers. 194 However, the subsequent ring contraction reported by these authors via a photo-Fries rearrangement 195 could be also occurred (Scheme 37).…”

Total Synthesis of the Antibiotic Kendomycin: A Macrocyclization Using the Tsuji–Trost Etherification

“…This elimination process was accelerated by the addition of a small amount of water. The compound 23 has the same skeleton as intermediates obtained by the groups of Lee7a and Mulzer 7e,f. Finally, the selective removal of the phenolic TBS group, oxidation, and acidic rearrangement of the resulting o ‐quinone, with the simultaneous TBS removal, accomplished the total synthesis of kendomycin.…”

“…The macrocyclic carbon framework of 1 represents a major challenge for an efficient chemical synthesis. Among all the achieved total syntheses and formal total syntheses, several macrocyclization strategies, including C‐glycosydation,7a ring‐closing metathesis (RCM),7b,c,e,f, 8 the Barbier reaction,7d photo‐Fries rearrangement,7e,f Dötz benzannulation,7g and Prins reaction7h have been reported, albeit in modest yields. We have attempted an RCM strategy for the macrocyclization at the C13C14 double bond of 1 8.…”

Recent Advances in Total Synthesis via Metathesis Reactions

“…From these alkynes, in the cases of enigmazole A, polycavernoside A, and kendomycin, a transannular pyran (for enigmazole A) and a furan ring (for polycavernoside A and kendomycin) were efficiently constructed by means of activation of the alkyne with goldbased catalysts 436-438 217 to provide compounds 439-441. In the cases of polycavernoside A and kendomycin, the syntheses were formal, having been described their total synthesis by Lee and Woo 218 and Mulzer and co-workers 219 from advanced precursors 440 and 442, respectively. On the other hand, for the synthesis of lytharanidine (431), formation of a piperidine ring was required, which was achieved by a sequence of redox isomerization, followed by transannular aza-Michael addition from macrocyclic alkyne 435 (Schemes 52 and 53).…”