Enantioselective Total Synthesis of (+)- and (-)-Vittatalactone

Abstract

The asymmetric total synthesis of both enantiomers of (+)-and (-)-vittatalactone has been achieved using a desymmetrization strategy to create three methyl chiral centers. The key steps in these total syntheses are Myers asymmetric alkylation, coppercatalyzed alkylation, 2,2,6,6-tetramethyl-1-piperidinyloxyl-(diacetoxyiodo)benzene [TEMPO-PhI(OAc 2 )] promoted oxidation and p-toluenesulfonyl chloride mediated lactonization. The products are obtained in good overall yields employing linear synthetic sequences.Polydeoxypropionates are an important class of biologically active molecules and the development of methods for their synthesis has led to the discovery of new strategies. The use and application of pheromones is expected to grow more rapidly and widely in the coming years because of increasing concerns of consumers about residual chemicals from agricultural products. The chemical syntheses of such compounds will ensure ample supplies and facilitate their practical use in agriculture and forestry. Vittatalactone, a structurally unique pheromone, was isolated from the striped cucumber beetle, Acalymma vittatum by Francke 1 and coworkers in 2005. It contains a novel trans-configured b-lactone moiety and an all synconfigured tetramethyl substituted alkyl chain as structural features. Breit et al. 2 have assigned the relative and absolute configurations of natural (+)-1a and unnatural (-)-1b 3 vittatalactones through total synthesis. Figure 1 Structures of (+)-and (-)-vittatalactoneIn continuation of our research on synthetic pheromones, 4,5 and our ongoing studies on the synthesis of biologically active molecules by exploiting desymmetrization strategies, the interesting structural features and biological activity of vittatalactone have attracted our attention toward its synthesis. Two total syntheses of vittatalactone have been reported: as key steps, the method of Breit and coworkers involved an o-diphenylphosphinobenzoic acid (o-DPPB) directed allylic substitution, 2 whilst that of Schneider et al. utilized an iridium-catalyzed hydrogenation. 6 Our group previously accomplished the total synthesis of (+)-vittatalactone by using an enzymatic desymmetrization approach. 7 We herein report the total synthesis of both enantiomers of vittatalactone, (+)-1a and (-)-1b, by exploiting our previously developed desymmetrization strategy.Our retrosynthetic strategy is shown in Scheme 1 in which both enantiomers could be easily obtained from the common intermediate 5 by utilizing the appropriate chiral boron reagent.The synthesis of (+)-vittatalactone started from the known triol 3a 8 which was readily obtained from 5 using a desymmetrization approach. Protection of the 1,3-diol moiety was accomplished using 2,2-dimethoxypropane [Me 2 C(OMe) 2 ] 9 and a catalytic amount of p-toluenesulfonic acid in dichloromethane at 0 °C to afford 6a in 85% yield. The primary hydroxy group in 6a was converted into the corresponding iodide to give 7a 10 in 94% yield using triphenylphosphine, imidazole and iodine in toluene at room tempera...

Synthesis of the Acyclic Carbon Skeleton of Filipin III

“…The strategy which was envisioned to construct the macrocyclic core of filipin III, even if reported to be successful in the syntheses of several polyenic natural products, , proved to be inefficient in our case, probably due to the instability of the polyenic moiety during the last steps. Due to our previous failures in the synthesis of wortmannilactone (concomitantly realized to the synthesis of filipin III), we would like to stress avoiding the use of an oxidation/macrolactonization sequence at the last crucial step to access polyenic macrolactones.…”

“…Even under the mild Pinnick-Lindgren oxidation conditions (NaClO 2 , NaH 2 PO 4 , 2-methylbut-2-ene), which proved to be efficient in several syntheses of polyenic natural products, the aldehyde was transformed to a complex mixture due to the degradation of the polyenic moiety under these oxidative conditions. In addition, direct selective oxidation of the primary alcohol to the corresponding acid using Epp and Widlanski conditions [TEMPO, PhI­(OAc) 2 , MeCN/H 2 O = 1:1], which were also used in several total syntheses of complex molecules, led to the decomposition of compound 36 , and we were never able to obtain the desired carboxylic acid.…”

Desymmetrisation of meso‐2,4‐Dimethyl‐8‐oxabicyclo[3.2.1]‐oct‐6‐ene‐3‐ol and its Application in Natural Product Syntheses

“…2022, 22, 60 -95 metric alkylation, copper catalyzed alkylation, and TEMPO oxidation as key steps. [32] The synthesis of (+)-vittatalactone commenced from the triol 233 a which was obtained from 5.…”

“…In 2012, Yadav et al. synthesized both enantiomers of vittatalactone using desymmetrization strategy, Myers asymmetric alkylation, copper catalyzed alkylation, and TEMPO oxidation as key steps [32] . The synthesis of (+)‐vittatalactone commenced from the triol 233 a which was obtained from 5 .…”

The use of the lactone motif in chemical communication

“…12 Finally, a desymmetrization and auxiliary-controlled asymmetric alkylation strategy was used to obtain both enantiomers of 9. 13 Although no studies on the biosynthesis of b-lactones have been performed, it seems likely that they are formed via a fatty acid biosynthesis pathway employing propionate (methylmalonate) building blocks as the source of the methyl branches. A precursor acid such as 3-hydroxypentamethyl-undecanoic acid is then cyclized to form the b-lactone.…”