Efficient and reliable amplification of chirality has borne its greatest fruit with transition metal-catalyzed reactions since enantiocontrol may often be imposed by replacing an achiral or chiral racemic ligand with one that is chiral and scalemic While the most thoroughly developed enantioselective transition metal-catalyzed reactions are those involving transfer of oxygen (epoxidation and dihydroxylation)1,2 and molecular hydrogen,3 the focus of this review is on the area of enantioselective transition metal-catalyzed allylic alkylations which may involve C-C as well as C-X (X ) H or heteroatom) bond formation4-9 The synthetic utility of transitionmetal-catalyzed allylic alkylations has been soundly demonstrated since its introduction nearly three decades ago10-21 In contrast to processes where the allyl moiety acts as the nucleophilic partner, we will limit our discussion to processes which result in nucleophilic displacements on allylic substrates (eq 1) Such reactions have been recorded with a broad

http://web4.uwindsor.ca/users/j/jlichaa/reference.nsf/0/10ff8b04ff3a317885256d88005720f6/$FILE/cr-1996-96-395-allylpd-asym.pdf

Asymmetric Transition Metal-Catalyzed Allylic Alkylations.

Metal-catalyzed enantioselective allylation, which involves the substitution of allylic metal intermediates with a diverse range of different nucleophiles or S(N)2'-type allylic substitution, leads to the formation of C-H, -C, -O, -N, -S, and other bonds with very high levels of asymmetric induction. The reaction may tolerate a broad range of functional groups and has been applied successfully to the synthesis of many natural products and new chiral compounds.

Metal-catalyzed enantioselective allylation in asymmetric synthesis.

Departament of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet, 1211 Geneve 4, Switzerland, Department of Organic Chemistry, Stockholm University, Arrhenius Laboratoriet, 106 91 Stockholm, Sweden, Organic Chemistry II, Dormund University of Technology, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany, and Departament de Quimica Fisica i Inorganica, Universitat Rovira i Virgili, C/ Marcel · li Domingo s/n, 43007 Tarragona, Spain

Enantioselective Copper-Catalyzed Conjugate Addition and Allylic Substitution Reactions

The Walden memorial at the Technical University in Riga is pictured in the frontispiece to mark the recent centennial of the Walden inversion. This is a rare public monument to key events from the first era of exploration in stereocontrolled synthesis, and may be the only such monument to use the language of organic chemistry expressed at the molecular level. The reaction of racemic substrates with chiral nucleophiles is one of many methods currently known to achieve kinetic resolution, a phenomenon that ranks as the oldest and most general approach for the synthesis of highly enantioenriched substances. The first nonenzymatic kinetic resolutions as well as the original forms of the Walden inversion were studied in the 1890s. All of these investigations were conducted within the first generation following the demonstration that carbon is tetrahedral, and provided abundant evidence that the principles and importance of enantiocontrolled syntheses were understood. However, a reliable, rapid technique to quantify results and guide the optimization process was still lacking. Many decades passed before this problem was solved by the advent of HPLC and GLPC assays on chiral supports, which stimulated explosive growth in the synthesis of nonracemic substances by kinetic resolution. The Walden monument is accessible to passers-by for hands-on inspection as well as for contemplation and learning. In a similar way, kinetic resolution is experimentally accessible and can be thought-provoking at several levels. We follow the story of kinetic resolution from the early discoveries through fascinating historical milestones and conceptual developments, and close with a focus on modern techniques that maximize efficiency.

Efficiency in nonenzymatic kinetic resolution.

Chiral tertiary alcohols and R-tertiary amines are important building blocks of naturally occurring and artificial biologically active molecules. Although there are catalytic asymmetric oxidation and amination reactions to access these chiral building blocks, the catalytic asymmetric addition of carbon nucleophiles to ketones and ketimines, which can simultaneously construct a carbon skeleton and tetrasubstituted stereogenic center, is synthetically more efficient (Scheme 1). Realizing the catalytic asymmetric addition to ketones and ketimines (tetrasubstituted carbon synthesis), however, is generally more challenging than addition to aldehydes or aldimines (trisubstituted carbon synthesis) for two main reasons: (1) ketones and ketimines are significantly less reactive than aldehydes and aldimines; (2) enantio-face differentiation of ketones and ketimines is more difficult due to the smaller steric and electronic differences between the two substituents on prochiral carbons. Therefore, asymmetric catalysts that promote C-C bond-formation to ketones and ketimines should have high catalyst activity and enantioselectivity.

Asymmetric Synthesis of Tertiary Alcohols and α-Tertiary Amines via Cu-Catalyzed C−C Bond Formation to Ketones and Ketimines

Sulfoximine-substituted bis(allyl)titanium complexes, which are configurationally labile at the Cα-atoms, have emerged as valuable reagents in asymmetric synthesis. Their highly selective reactions with aldehydes and N-sulfonyl imino esters allow the attainment of enantio- and diastereomerically pure sulfoximine-substituted homoallylic alcohols and homoallylic amines, respectively, which are valuable starting materials for the asymmetric synthesis of homopropargylic alcohols, 2,3-dihydrofurans, medium-sized carbocycles and lactones, unsaturated mono- and bicyclic prolines, β-amino acids, and vinyl oxiranes, respectively. The high synthetic versatility of the sulfoximine group stems from its ability to function as a chiral carbanion-stabilizing nucleofuge. © 2007 Wiley Periodicals, Inc. 18:472–481, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20331

Development of new methods for asymmetric synthesis based on sulfoximines

Racemic S-methyl-S-phenylsulfoximine (±)-1 can be resolved with only 0.6 equivalents of (+)-camphorsulfonic acid by avoiding any recrystallization to give (+)-1 of ⩾99% ee in 80% yield and (−)-1 of 97–99% ee in 74% yield. This procedure, which is based on the separation of the diastereomeric salt (+)-1/(+)-CSA and the sulfoximine (−)-1, should be suited for a large scale application.

An efficient resolution of (±)-S-methyl-S-phenylsulfoximine with (+)-10-camphorsulfonic acid by the method of half-quantities

The palladium-catalyzed asymmetric sulfonylation of allylic substrates rac- 7a,b and rac- 8a,b in the presence of the chiral phosphino-oxazoline ligand 3a gave the allylic sulfones 9a and 9b with ee-values of 59% and 88%, respectively, in high yield. In the presence of ligand ent- 3b the enantiomeric allylic sulfones ent- 9a and ent- 9b were obtained with ee-values of 57% and 93% in high yield.

Palladium-catalyzed asymmetric allylic sulfonylation

Regio- and Enantioselective Substitution of Primary Endocyclic Allylic Sulfoximines with Organocopper and Organocuprate Reagents. The Importance of Iodide for the Allylic Substitution with Organocopper Compounds

The acyclic and cyclic allylic tert -butyl sulfones 3 , ent - 3 , 11a , 11b and 15a–c of 89–98% ee were synthesized in 40–92% yield by a Pd-catalyzed reaction of the respective allylic acetates and carbonates rac - 1a , rac - 1b , rac - 10a , rac - 10b and rac - 14a–c with LiO 2 S t -Bu in the presence of the chiral ligands 2a , ent - 2b and 12 . Formation of the n -butyl sulfones 13a and 13b of 95% ee was observed. Reactions of rac - 1a and 1b / ent - 1b with LiO 2 S t -Bu in the presence of 2a and ent - 2b , respectively, in THF under heterogeneous conditions were accompanied by a kinetic resolution of the allylic substrates. The faster reacting allylic substrate and the preferentially formed sulfone had the same absolute configuration. The allylic tert -butyl sulfide 17 of 92% ee was obtained in 63% yield by the Pd-catalyzed reaction of rac - 1b with Me 3 SiS t -Bu in the presence of ent - 2b .

H.‐J. Gais

Papers

Development of new methods for asymmetric synthesis based on sulfoximines

An efficient resolution of (±)-S-methyl-S-phenylsulfoximine with (+)-10-camphorsulfonic acid by the method of half-quantities

Palladium-catalyzed asymmetric allylic sulfonylation

Regio- and Enantioselective Substitution of Primary Endocyclic Allylic Sulfoximines with Organocopper and Organocuprate Reagents. The Importance of Iodide for the Allylic Substitution with Organocopper Compounds

Pd-catalyzed asymmetric synthesis of allylic tert-butyl sulfones and sulfides: Kinetic resolution of the allylic substrate by a chiral Pd-complex