Asymmetric variant of the

These initial reports demonstrated that a catalytic asymmetric variant of the Simmons-Smith reaction could be developed. Although good yields and selectivities were obtained, the lack of a clear understanding of the origin of activation, the limited structural information on the active species and the absence of a stereochemical model made rational improvements difficult at best. The next... 

The Gabriel-Cromwell aziridine synthesis involves nucleophilic addition of a formal nitrene equivalent to a 2-haloacrylate or similar reagent [29]. Thus, there is an initial Michael addition, followed by protonation and 3-exo-tet ring-closure. Asymmetric variants of the reaction have been reported. N-(2-Bromo)acryloyl camphor-sultam, for example, reacts with a range of amines to give N-substituted (azir-idinyl)acylsultams (Scheme 4.23) [30]. 

A similar but asymmetric variant of the reaction, involving the radical addition of alkyl iodides and trialkylboranes to chiral azirine esters derived from 8-phenyl-menthol and camphorsultam, in the presence of a Cu(i) catalyst, has subsequently been reported [64]. The diastereoselectivity of the addition is variable (0-92% de)... 

Almost 20 years after the initial report of the Stetter reaction, Ciganek reported an intramolecular variant of the Stetter reaction in 1995 with thiazolium precatalyst 74 providing chromanone 73 in 86% yield (Scheme 10) [64]. This intramolecular substrate 72 has become the benchmark for testing the efficiency of new catalysts. Enders and co-workers illnstrated the first asymmetric variant of the intramolecnlar Stetter reaction in 1996 utilizing chiral triazolinylidene pre-catalyst 14 [65]. Despite moderate selectivity, the implementation of a chiral triazolinylidene carbene in the Stetter reaction laid the fonndation for future work. 

Considerable interest has been shown in developing asymmetric variants of the Si-H insertion. The chiral auxiUary (Jl)-pantolactone has performed quite well in this chemistry, as illustrated in the formation of 169 in 79% diastereomeric excess (Eq. 19) [28]. A wide variety of chiral catalysts have been explored for the Si-H insertion chemistry of methyl phenyldiazoacetate [29, 117-119]. The highest reported enantioselectivity to date was obtained with the rhodium prolinate catalyst Rh2(S-DOSP)4, which generated 170 with 85% enantiomeric excess (Eq. 20) [120]. 

These two mechanistic modes have an impact on the development of asymmetric variants of the Tsuji-Trost Reaction. 

A successful asymmetric variant of the imino-Stetter reaction has recently been presented by Miller et al., who employed chiral peptidic thiazolium salts similar to compound 43 (see Fig. 9.6) [51]. 

On the other hand, lithium enolates derived from substituted endocyclic ketones have largely been exploited in the synthesis of steroids since the regioselectivity of their deprotonation can be controlled and high levels of 1,2- and 1,3-stereoselection occur9,418. The control is steric rather than electronic, with the attack directed to the less substituted ji-face of the enolate for conformationally rigid cyclopentanones, whereas stereoelectronic control becomes significant for the more flexible cyclohexanones. Finally, an asymmetric variant of the formation of a-branched ketones by hydration of camphor-derived alkynes followed by sequential alkylation with reactive alkyl halides of the resulting ketones was recently reported (Scheme 87)419. 

The most successful asymmetric variants of the Abramov reaction employ chiral substrates, either chiral carbonyl compounds or aldimines, or chiral phosphorus(III) reagents.5,51,86,88 However, the Pudovik reaction using chiral catalysts is a superior route for the asymmetric synthesis of a-hydroxy- and a-aminophosphonates (Section 6). 

Scheme 5. Asymmetric variants of the amino acid synthesis according to Strecker (Bn = Benzyl).

Considerable efforts have been made to develop asymmetrical variants of the classical Pauson-Khand reaction. Initial investigations have shown that compounds derived from cobalt complexes of type 1, in which a carbonyl ligand is replaced by a chiral phosphane (glyphos), react with high enantioselectivity [22], However, the procedure is too complex to be of preparative value. The concept of Kerr et al., who achieved significant enantioselectivities (max. 44 % ee) in intermolecular Pauson-Khand reactions by... 

Recently, the asymmetric variants of the Stetter [114-118], crossed-benzoin [114, 117-120], and transeslerification [121] reactions have attracted great interest as asymmetric nucleophilic acylation processes. A prerequisite for asynunetric catalysis is the availability of a chiral catalyst. Introduction of chirahty into the thiamin framewoik follows the same principles as that for the related imidazoUum systems, mainly the introduction of a chiral centre next to the nitrogen atom of the thiazole ring [117]. 

In the area of speciality chemicals, asymmetric hydroformylation will be thoroughly investigated in the future. This reaction offers a convenient and waste-free way to introduce chirality into molecules by a C-C bond formation step. The recent successes in this area will replace the earlier Pt catalysts which suffer from extensive side reactions such as hydrogenation and isomerization. The ligands used so far are expensive (some are more highly priced than the rare catalyst metals) and difficult to synthesize. Improvements in their synthesis along with new concepts, for instance in the area of phosphorus/heteroatom ligands, will make commercial realization of the asymmetric variant of the oxo reaction more probable. 

The asymmetric variant of the Pomeranz-Fritsch reaction was used by D. Rozwadowska and co-workers in the total synthesis of (-)-salsolidine. ... 

The Darzens reaction (tandem aldol-intramolecular cyclization sequence reaction) is a powerful complementary approach to epoxidation (see Chapter 5) that can be used for the synthesis of a,P-epoxy carbonyl and a,p-epoxysulfonyl compounds (Scheme 8.32). Currently, all catalytic asymmetric variants of the Darzens reactions are based on chiral phase-transfer catalysis using quaternary ammonium salts as catalysts. 

The first investigations in the field of heterazolium-catalyzed asymmetric nucleophilic acylation go back to Sheehan et al. (Scheme 2) [24], who tried to devise an asymmetric variant of the benzoin reaction, which was known to be catalyzed by thiazolium salts from the work of Ukai et al. [25,26] and of Mizuhara et al. 

In general, the unsatisfactory yields obtained in the asymmetric variants of the thiazolium-catalyzed benzoin reaction are probably caused by the low inherent activity of the thiazolium salts, which is aggravated by the steric bulk accumulated in the neighborhood of the active site. 

The first attempts to develop a heterazolium-catalyzed asymmetric variant of the Stetter reaction were carried out by our group [44,45,46], employing the chiral thiazolium salt 9 to catalyze the addition of butanal to chalcone. The resultant 1,4-dicarbonyl compound 10 was obtained in 29% yield with enantiomeric excesses up to 30% (Scheme 6). 

Acetate-derived silyl ketene acetals (11, 13 and 14) react with aldehydes with good stereoselectivity (equation 10) significant results are reported in Table 5. Removal of the auxiliary, with methanolic KOH, gave the corresponding (3-hydroxy acids in good enantiomeric excess (ee). The asymmetric variants of the Mukaiyama reaction also helped to solve the long-standing problem of an efficient anti selec-... 

A very efficient asymmetric variant of the oxidative coupling reaction of /(-naphthol using a copper(II) complex with (S)-amphetamine as a chiral reagent has been developed 14, giving the binaphthol with 95% ee. 

Consequently, chemists must have at their disposal simple, effective, efficient, and stereoselective synthetic methods to construct the necessary frameworks. Development of catalytic asymmetric variants of the phospho-aldol reaction provides, arguably, the most versatile such process for the simultaneous construction of the [P-C] bond and associated a-carbon functionality with control over the stereochemistry at the newly generated alpha-carbon site. 

The direct oxidation of unfunctionahsed alkanes in an asymmetric fashion is a formidable challenge. However, oxidation of C—H bonds adjacent to suitable functional groups gives a handle on which to operate. In particular, the aUyKc oxidation of cyclic alkenes utilising asymmetric variants of the Kharasch—Sosnovsky reaction has received considerable attention. The reaction is catalysed by copper salts and requires a perester to give the allylic ester as product. 

Significant advances in the development of a catalytic asymmetric variant of the aldol reaction have been developed recently. Both enantiomericaUy pure Lewis acids and Lewis bases have been applied to the addition of silyl enol ethers to aldehydes and ketones and highly diastereoselective and enantioselec-tive additions have been achieved. Often, the mode of diastereoselectivity can be rationalised from a consideration of the relevant open or closed transition states. 

Thus the asymmetric variant of the Euler method is area preserving, even though the standard Euler method is not. 

Han, Ryu, and Yang reported later a facile method for the highly regioselec-tive cross acyloin condensations between aromatic aldehydes and acetaldehyde (10 equiv. in order to suppress the self-acyloin products from aromatic aldehydes) using properly chosen NHC catalysts. An asymmetric variant of the reaction between para-chlorobenzaldehyde and acetaldehyde was also demonstrated, with moderate enantioseleetivity (41% yield and 60% ee) (Seheme 7.11). 

Asymmetric variants of the Pd-catalyzed allylic substitution reaction have enjoyed considerable attention since the first stoichiometric example reported in 1973J The reaction has been the subject of several reviews, and in some cases, the levels of enantioselec-tivity have reached in excess of 99% ee. 

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