Diastereoselective Synthesis of Pentasubstituted γ‐Butyrolactones from Silyl Glyoxylates and Ketones through a Double Reformatsky Reaction

Abstract

The prevalence of g-butyrolactone substructures in natural products continues to stimulate interest in the development of concise and selective methods for their preparation. The assembly of g-butyrolactones that contain multiple stereocenters typically requires the synthesis of complex precursors through specialized routes. [1] Modular assembly strategies that circumvent this limitation would be welcome additions to the synthetic toolbox. Herein, we report diastereoselective reactions of Reformatsky reagents, silyl glyoxylates, and ketones that provide densely functionalized pentasubstituted g-butyrolactones containing three contiguous stereocenters. The reactions collectively constitute a rare example of the diastereoselective generation of vicinal stereogenic tertiary alcohols through aldolization. [2] Silyl glyoxylates are conjunctive reagents that participate in coupling reactions initiated by hydrides and nonstabilized carbon nucleophiles. [2c, 3] We examined the use of enolates and their equivalents in an effort to expand the range of nucleophilic promoters in transformations based on silyl glyoxylates. The projected transformation, outlined in Scheme 1, involves aldol addition to the silyl glyoxylate 2 to expose, after a [1,2]-Brook rearrangement, [4,5] a new enolate 3 capable of a second aldol reaction with an aldehyde or ketone electrophile. Lactonization would then provide g-butyrolactone 5.Initial experiments with magnesium and lithium enolates provided complex product mixtures; the desired lactones or their acyclic precursors were formed in low yield. We speculated that moderation of the enolate reactivity might be necessary and screened Reformatsky reagents under standard conditions. [6][7][8] The use of zinc enolates in combination with the appropriate reaction temperature facilitated the development of a workable experimental protocol (Scheme 2). The hydroxysilane 8 was isolated as the predominant product when the reaction was conducted at À20 8C. This result reflects an inability of the initial zinc aldolate to undergo Brook rearrangement at this temperature [Scheme 2, Eq. (1)]. [9] We took advantage of this finding by forming the initial adduct between the Reformatsky reagent and the silyl glyoxylate at À20 8C prior to the introduction of the ketone electrophile. Once the initial reaction between the silyl glyoxylate and the zinc enolate was complete, the addition of the ketone, followed by warming to À10 8C for 30 min, gave the desired product 7 in 33 % yield; however, 8 was still the major product [Scheme 2, Eq. (2)]. Optimal conditions involved this stepwise addition of the reagents, with an initial reaction temperature of À30 8C; the reaction mixture was then warmed to room temperature and stirred at this temperature for 1 h to afford the desired product in 73 % yield along Scheme 1. Three-component lactone synthesis. Bn = benzyl, TBS = tertbutyldimethylsilyl.Scheme 2. Optimization of the double Reformatsky reaction. General conditions for all reactions: enolate (1.5 equiv), ketone (2.0 e...