Total synthesis of Pamamycin-607

Abstract

Pamamycin-607 would be dissected into $C_{1``}-C_{11``}$ subunit 73 and $C_1-C_{18}$ subunit 74. $C_{1``}-C_{11``}$’subunit 73 has been synthesized starting from 86 and 102. Diol 86 was converted into aldehyde 80 via regioselective reductive cleavage of benzylidene acetal and Swern oxidation, and 101 was derivatized into sulfone 81 via Mitsunobu reaction. Aldehyde 80 was coupled with sulfone 81 to give δ-triethylsilyloxyolefin 75. 75 was cyclized stereoselectively by iodoetherification to give syn-2,5-disubstituted tetrahydrofuran 105. Reduction of iodide and debenzylation yielded $C_{1``}-C_{11``}$ subunit 108. Synthesis of $C_1-C_{18}$ subunit 74 was accomplished in two different pathways. In the first approach, Roush’s boronation was used for introduction of the hydroxy methyl functional groups in the main chain. Wittig reaction of phosphonium salt 197 and aldehyde 226 gave 229 and iodoetherification was performed with perfect stereoselectivity to yield syn-2,5-disubstituted tetrahydrofuran 230 as the left part of $C_1-C_{18}$ subunit. 230 was converted into δ -triethylsilyloxyolefin 246 via regioselective epoxide-ring opening and Wittig reaction with aldehyde 80. 246 was cyclized stereoselectively and $C_1-C_{18}$ subunit 253 for coupling with $C_{1``}-C_{11``}$ subunit 108 was obtained via chemoselective Mitsunobu reaction and Jones oxidation. Coupling reaction of 108 and 253 by Yamaguchi conditions and subsequent copper ion promoted macrolactonization of S-2-pyridyl thiolate gave pamamycin-607 1. In the second approach, aldol condensation was used for introduction of the hydroxy methyl functional groups in the main chain and double cyclization was accomplished. Aldehyde 271 was prepared from 266 and 267 via olefination, and subjected to aldol condensation with oxazolidinone 265 with exclusive diastereoselectivity. Weinreb amide 260 was prepared via second aldol condensation and coupled with iodide 261, which was generated from aldehyde 80 and sulfone 2...