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

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, Ph3P, and Zn) and treatment of the resulting tetrabromides with nBuLi 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 alkylidene-carbenes, generated in situ by geminal elimination of N2, 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.