Still–Gennari Olefination and its Applications in Organic Synthesis

Abstract

The Still–Gennari olefination is a widely applied modification of the Horner–Wadsworth–Emmons reaction, allowing access to Z‐olefins by carbonyl group transformation. Its synthetic utility is undoubtedly of great significance for organic chemistry, as can be illustrated by the number of citations of the original report by W. C. Still and C. Gennari which up to date has been cited over 1000 times. In 2008 Nobel prize winner Ei‐ichi Negishi indicated the Still–Gennari olefination as one of the crucial methods for tolefin synthesis, complementary to palladium‐catalyzed alkenylations. Surprisingly, so far there is no review concerning this popular and valuable transformation. Therefore, we aim to comprehensively systematize achievements in this field and to present the scope of applications of the Still–Gennari olefination along with recent examples in the total synthesis of biologically active compounds. Our review is intended to be of interest for the general chemical community as well as to be a helpful source of information for synthetic organic chemists.magnified image

Applications of the Horner–Wadsworth–Emmons Olefination in Modern Natural Product Synthesis

“…An unusual 9-BBN complexation of free carboxylic acid allowed successful Julia olefination with sulfone 212 to give 213. Lactonization was employed to complete the total synthesis of (-)-lasonolide A (6).…”

“…In 1983 Still and Gennari modified the HWE reaction to obtain almost exclusively Z-selective alkenes. 5,6 This transformation was achieved by using electrophilic bis(trifluoroethyl) phosphonoacetate in combination with a strong dissociating base, such as potassium bis(trimethylsilyl)amide (KHMDS) and 18-crown-6 in THF, which allowed highly stereoselective formation of Zunsaturated esters. Ten year later, Ando reported that the use of ethyl diphenylphosphonoacetate results in an almost exclusive formation of Z-alkenes by using Still´s conditions [KHMDS/ 18-crown-6] and benzyltrimethylammonium hydroxide (Triton B) as a base.…”

Enantioselective Michael addition to vinyl phosphonates via hydrogen bond-enhanced halogen bond catalysis

“…Phosphorus compounds are an important class of molecules in organic synthesis both as valuable reagents and end targets. 15 More specifically, (chiral) organophosphonates and their phosphonic acid derivatives can be used in the much-acclaimed Horner–Wadsworth–Emmons reaction 16 and are also valuable biomolecules. 17 Therefore, the asymmetric synthesis of organophosphonates has received significant attention over the years.…”

A Straightforward, Purification-Free Procedure for the Synthesis of Ando and Still–Gennari Type Phosphonates

“…7 Many protocols for the synthesis of Still-Gennari and Ando type reagents were developed and improved in recent years. 6,8 Although reagents and procedures enabling synthesis of Z-,-unsaturated carboxylic acids, ketones, nitriles, amides, sulfones, phosphonates etc. were presented, synthesis of Z-,-unsaturated esters remains the most useful application of these reagents.…”

“…were presented, synthesis of Z-,-unsaturated esters remains the most useful application of these reagents. 6,9 Because of the low nucleophilicity of tris (2,2,2-trifluoroethyl) phosphite and bis (2,2,2-trifluoroethyl) phosphite in the Arbuzov or Michaelis-Becker reaction with alkyl halides, respectively, most procedures for the synthesis of Still-Gennari type reagents are based on transesterification of dialkyl phosphonates (Scheme 1) or functionalization of bis (2,2,2-trifluoroethyl) methylphosphonate. Nevertheless, there are a few examples of the synthesis of Still-Gennari type phosphonates via Arbuzov or Michaelis-Becker reactions and a few other approaches, as presented in our recent review.…”