A Novel Approach toward the Synthesis of Kendomycin:  Selective Synthesis of a C-Aryl Glycoside as a Single Atropisomer

Abstract

[reaction: see text] A convergent and concise route to an advanced precursor 2b of kendomycin (1) has been developed by applying a S(N)1 ring cyclization as a key step. The resulting C-aryl glycoside was initially isolated as a rotameric mixture, but after MOM protection of the o-hydroxyl of the phenol, the conformation was frozen to the desired kendomycin-like atropisomer.

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

“…In approaches B and C using compounds 7 and 9, respectively, as RCM precursors, the tetrahydropran ring should be generated by diastereoselective S N 1 reaction of the C9-OH with an in situ generated benzylic cation at C5. [9] The final approach (D) focuses on the macrolactonization of compound 8 followed by a photo-Fries reaction, and the tetrahydropyran should be formed by C5-carbonyl reduction and S N 1 cyclization. It should be noted at this point, that only approaches C and D have been successful, in contrast to route A where the RCM did not work and B, where the RCM precursor 7 could not be made at all.…”

“…In the first approach (A), we intended to combine olefinic carbons C9 and C10 of compound 6 through RCM, followed by an addition of C5‐OH to C9 for tetrahydropyran ring formation. In approaches B and C using compounds 7 and 9 , respectively, as RCM precursors, the tetrahydropran ring should be generated by diastereoselective S N 1 reaction of the C9‐OH with an in situ generated benzylic cation at C5 9. The final approach (D) focuses on the macrolactonization of compound 8 followed by a photo‐Fries reaction, and the tetrahydropyran should be formed by C5‐carbonyl reduction and S N 1 cyclization.…”

“…Colvin’s one carbon chain elongation11 afforded the corresponding alkyne, which was alkylated with MeI and converted to 10 by hydrozirconation/iodination. Iodide 11 was prepared from known compound 14 9 via a two step standard procedure. Pd 0 ‐assisted Negishi coupling12 of iodides 10 and 11 , followed by deprotection gave ( E )‐olefin 15 which was converted to 1,4‐diene 16 via IBX oxidation and Wittig methylenation (Scheme ).…”

In Pursuit of a Competitive Target: Total Synthesis of the Antibiotic Kendomycin

“…The second approach from the Mulzer group [10] (Scheme 4) was centered around a ring-closing metathesis (RCM) of diene 16 for the C13ÀC14 connection. Tetrahydropyran formation should be achieved by a S N 1 cyclization via carbenium intermediate 17 wherein the aryl group would adopt an equatorial position.…”

Einem kompetitiven Zielmolekül auf den Fersen: Totalsynthese des Antibiotikums Kendomycin

“…Der zweite Ansatz von Mulzer et al 10. (Schema ) konzentrierte sich auf eine C13‐C14‐Verknüpfung durch Ringschlussmetathese (RCM) des Diens 16 .…”