Stereocomplementary and Parallel Syntheses of Multi-Substituted (E)-, (Z)-Stereodefined α,ß-Unsaturated Esters: Application to Drug Syntheses.

Ubiquitous α,ß-unsaturated esters are well recognized as key structural olefin scaffolds in organic chemistry. (E)- and (Z)-steroselectivity is the most critical issue in their synthesis, however, (E)- and (Z)- stereocomplementary synthetic methods remain quite limited. The present account discloses general (E)-, (Z)-stereocomplementary syntheses of a variety of α,ß-unsaturated esters from highly accessible (E)-, (Z)-stereodefined enol tosylates derived from ß-ketoesters and α-formyl esters. Step 1 toward the stereocomplementary preparation of (E)-, (Z)-stereodefined enol tosylates is implemented by using inexpensive reagents under mild reaction conditions. Step 2 toward the highly stereoretentive synthesis of (E)- and (Z)-stereodefined α,ß-unsaturated esters involves Suzuki-Miyaura, Negishi, Sonogashira, Iron-catalyzed, Mizoroki-Heck, and Buchwald-Hartwig cross-coupling reactions. Notably, this strategy was successfully applied for parallel drug syntheses of (E)- and (Z)-zimelidine, (E)- and (Z)-tamoxifen, and Merck's cyclopropane pharmacophore. Representative successful utilizations by other groups are also introduced.

Total Syntheses of All Six Chiral Natural Pyrethrins: Accurate Determination of the Physical Properties, Their Insecticidal Activities, and Evaluation of Synthetic Methods.

Chiral total syntheses of all six insecticidal natural pyrethrins (three pyrethrin I and three pyrethrin II compounds) contained in the chrysanthemum (pyrethrum) flower were performed. Three common alcohol components [(S)-cinerolone, (S)-jasmololone, and (S)-pyrethrolone] were synthesized: (i) straightforward Sonogashira-type cross-couplings using available (S)-4-hydroxy-3-methyl-2-(2-propynyl)cyclopent-2-en-1-ones (the prallethrin alcohol) for (S)-cinerolone (overall 52% yield, 98% ee) and (S)-pyrethrolone (overall 54% yield, 98% ee) and (ii) traditional decarboxylative-aldol condensation and lipase-catalyzed optical resolution for (S)-jasmololone (overall 16% yield, 96% ee). Two counter acid segments [(1R,3R)-chrysanthemic acid (A) and (1R,3R)-second chrysanthemic acid precursor (B)] were prepared: (i) C(1) epimerization of ethyl (±)-chrysanthemates and optical resolution using (S)-naphthylethylamine to afford A (96% ee) and (ii) concise derivatization of A to B (96% ee). All six pyrethrin esters (cinerin I/II, jasmolin I/II, and pyrethrin I/II) were successfully synthesized utilizing an accessible esterification reagent (TsCl/N-methylimidazole). To investigate the stereostructure-activity relationship, all four chiral stereoisomers of cinerin I were synthesized. Three alternative syntheses of (±)-jasmololone were investigated (methods utilizing Piancatelli rearrangement, furan transformation, and 1-nitropropene transformation). Insecticidal activity assay (KD50 and IC50) against the common mosquito (Culex pipiens pallens) revealed that (i) pyrethrin I > pyrethrin II, (ii) pyrethrin I (II) > cinerin I (II) ≫ jasmolin I (II), and (iii) "natural" cinerin I ≫ three "unnatural" cinerin I compounds (apparent chiral discrimination).

Divergent Synthetic Access to E- and Z-Stereodefined All-Carbon-Substituted Olefin Scaffolds: Application to Parallel Synthesis of (E)- and (Z)-Tamoxifens.

A highly substrate-general synthesis of all-carbon-substituted E- and Z-stereodefined olefins is performed. The method comprises two sets of parallel and stereocomplementary preparations of (E)- and (Z)-α,ß-unsaturated esters involving two robust and distinctive reactions: 1) stereocomplementary enol tosylations using readily available TsCl/diamine/(LiCl) base reagents, and 2) stereoretentive Negishi cross-coupling using the catalysts [Pd(dppe)Cl2] (for E) and [Pd(dppb)Cl2] (for Z). The present parallel approach is categorized as both type I (convergent approach: 16 examples, 56-87 % yield) and type II (divergent approach: 18 examples, 70-95 % yield). The obtained (E)- and (Z)-α,ß-unsaturated ester scaffolds are successfully transformed into various E- and Z-stereodefined known and novel olefins (8×2 derivatization arrays). As a demonstration, application to the parallel synthesis of both (E)- and (Z)-tamoxifens, a representative motif of all-carbon-substituted olefins, is accomplished in a total of eight steps with an overall yield of 58 % (average 93 %) and 57 % (average 93 %), respectively.

(E)- and (Z)-stereodefined enol phosphonates derived from ß-ketoesters: stereocomplementary synthesis of fully-substituted α,ß-unsaturated esters.

A versatile, robust, and stereocomplementary synthesis of fully-substituted (E)- and (Z)-stereodefined α,ß-unsaturated esters 3 from accessible α-substituted ß-ketoesters 1via (E)- and (Z)-enol phosphonates was achieved. The present method involves two accessible reaction sequences: (i) (E)- and (Z)-stereocomplementary enol phosphorylations of a wide variety of ß-ketoesters 1 (24 examples; 71­99% yield, each >95: 5 ds), and (ii) (E)- and (Z)-stereoretentive Suzuki­Miyaura cross-coupling (16 examples; 71­91% yield, >81/19 ds) and Negishi cross-coupling (32 examples; 65­96% yield, >95 : 5 ds) using (E)- and (Z)-enol phosphonates 2. 1H-NMR monitoring for a key reactive N-phosphorylammonium (imidazolium) intermediate I and an application in the synthesis of both (E)- and (Z)-tamoxifen precursors 6 are described.

(E)-,(Z)-parallel preparative methods for stereodefined ß,ß-diaryl- and α,ß-diaryl-α,ß-unsaturated esters: application to the stereocomplementary concise synthesis of zimelidine.

Parallel and practical methods for the preparation of both (E)- and (Z)-ß-aryl(1)-ß-aryl(2)-α,ß-unsaturated esters 1 and (E)- and (Z)-α-aryl(1)-ß-aryl(2)-α,ß-unsaturated esters 2 are described. These methods involve accessible, robust, stereocomplementary N-methylimidazole (NMI)-mediated enol tosylations (14 examples, 70-99% yield), as well as stereoretentive Suzuki-Miyaura cross-couplings (36 examples, 64-99% yield). The highlighted feature of the present protocol is the use of parallel and stereocomplementary approaches to obtain highly (E)- and (Z)-pure products 1 and 2 by utilizing sequential enol tosylations and cross-coupling reactions. An expeditious and parallel synthesis of (E)- and (Z)-zimelidine (3), which is a highly representative selective serotonin reuptake inhibitor (SSRI), was performed by utilizing the present methods.