A short, high-yield, stereoselective synthesis of racemic exo- and endo-brevicomin

Abstract

Stereoselective reduction and cycl ization of 6 -methyl -2propionyl-2,3d i hyd ro -4Hpyran provides brevicomin in quantitative yield as a 86:14 or a 17:83 mixture of exo and endo isomers through DIBAH reduction in ether at reflux or Zn(BH,), in the presence of ZnCI, in ether at 0 "C, respectively.

Introduction of Bicyclic Ketal Chemistry: Synthesis and Transformation Reaction of 6,8-Dioxabicyclo[3.2.1]octane Skeletal System

“…19 MVK dimer 2 was methylated using enamine alkylation and reduced using DIBALH or Zn(BH 4 ) 2 with ZnCl 2 to give 86:14 or 17:83 mixture of exo-and endo-brevicomin respectively after acidic work-up (Scheme 2). 16 The mouse pheromone has been isolated from urine of the male mouse of the species Mus musculus 20 and synthesized in a low yield. 21 We utilized the stereoselective synthesis of exo-brevicomin for the mouse pheromone synthesis.…”

“…31 Enamine alkylation is known to favor the less substituted position because of steric effects 32 and we used this methodology for the brevicomin synthesis. 16 The regioselective methylation at the more substituted position in the bicyclic ketal system has been observed in very low yield (20%) by using the trityl anion. 33 Several bases were used for this enolate methylation and we found that NaH and t-BuONa gave better yields of thermodynamic product 20 than KH, t-BuOK, LHMDS, KHMDS, NaOMe, and LDA.…”

“…The reduction with LiAlH 4 or NaBH 4 did not show any critical selectivity and gave 60:40 mixtures of threo and erythro-alcohols respectively, and the result could be explained by the Bartlett model 15 D which showed the comparable bulkiness between the ring oxygen and the ring methylene towards the hydride attack. This methodology has been utilized in the stereoselective synthesis of exo-and endo-brevicomin, 16 and the pheromone of mouse Mus musculus. 17…”