Part I: A facile approach towards eight-membered N-heterocycles: aza-Wittig/retro-Claisen rearrangement. Part II: Studies towards the total synthesis of (-)-Nakadomarin A

An improved approach towards the synthesis of (-)Nakadomarin A is described herein. As part of these studies, a one-pot aza-Wittig/retro-Claisen rearrangement methodology that allows for facile formation of enantiomerically pure azocines has been developed. Utilizing this novel methodology, the bottom portion of the natural product, containing five-membered ring D and eight membered ring E, was prepared in a 10-step sequence in overall 12.9% yield. This sequence features two key transformations developed in Boeckman group: formation of highly functionalized cyclobutane adduct 144 via diastereoselective SN2' cyclization and the subsequent one-pot aza-retro-Claisen-rearrangement of the corresponding aldehyde 94 to enantiomerically pure azocine 58. The chirality which is relayed in our approach originates from a Corey-Bakshi-Shibata (CBS) reduction of enone 96.; Treatment of azocine 58 with LDA and diphenyl phosphorochloridate, followed by the addition of another portion of LDA, famished phosphate 153 in 79% yield. Exclusive C-phosphonation was observed. The phosphate 153 was thereafter elaborated to (Z)-carbomethoxymethylene lactam 93 through a Homer-Wadsworth-Enunons reaction with greater than 14:1 selectivity.; Finally, among the two attempted approaches towards the construction of piperidine ring A, 1,3-dipolar cycloaddition of (Z)-carbomethoxymethylene lactam 93 and azomethine ylides (R)-182 was successfully realized. Further studies involving installation of the furan moiety, ring expansion reaction followed by formation of ring B and ring F are discussed.