Synthetic and Mechanistic Investigations on the Rearrangement of 2,3‐Unsaturated 1,4‐Bis(alkylidene)carbenes to Enediynes

Abstract

Abstract The synthesis of 3,4‐ene‐1,5‐diynes, the key structural moiety present in several naturally occurring antitumor antibiotics, from 1,2‐enedialdehydes under two different experimental conditions is reported. One method involves the dibromomethylenation of dialdehydes under Corey–Fuchs conditions (CBr 4 , Ph 3 P, and Zn) and treatment of the resulting tetrabromides with n BuLi or LDA to afford enediynes. The second method involves a base‐mediated reaction of enedialdehydes with diethyl (1‐diazo‐2‐oxopropyl)phosphonate (Bestmann–Ohira reagent) and subsequent transformation of the bis(diazo) compounds generated in situ to enediynes. While the transformation of bis(diazo) compounds to enediynes could take place exclusively through alkylidenecarbenes, generated in situ by geminal elimination of N 2 , an alternative pathway, involving the vicinal elimination of HBr to afford an intermediate bromoalkyne and its subsequent metal‐halogen exchange and protonation during workup, exists for the bis(dibromoalkylidenes). However, our deuterium‐labeling experiments with a model substrate, deuterated p ‐methoxybenzylidene dibromide, established the predominance of the alkylidenecarbenes, generated in situ by metal‐halogen exchange and elimination, for this substrate and, by analogy, for the tetrabromides as well. The scope of this novel methodology was extended to the synthesis of various heteroatom‐based (S, Se, and P) enediynes by quenching the acetylides with suitable electrophiles. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)