Asymmetric variant of the reaction

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)... 

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). 

The use of AlMe2Cl as a cocatalyst enables the intramolecular carbocyanation of alkenes which are too unreactive to undergo carbocyanation. It was shown that the turnover-limiting step of this reaction is not oxidative addition of a C-CN bond, but insertion of a tethered alkene [51]. A catalytic asymmetric variant of the reaction was also developed, generating valuable synthetic intermediates containing all-carbon quaternary stereogenic centers (Scheme 6.16) [51, 57]. 

The reaction was considered to proceed via hydrometal-lation/carbometallation/p-hydride elimination sequence followed in some cases by alkene transposition. Asymmetric variants of the reaction have been developed by the same group [59] and others [60], utilizing chiral phosphine ligands (Scheme 7.37), and concluded that the isomer ratios, ee s, and catalytic activity observed are dependent on 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... 

Asymmetric variants of these reactions are highly interesting since they provide access to chiral heterocycles. A recent comprehensive study by Stahl and coworkers reports the synthesis of various enantiopure [Pd( 4-C1)C1(NHC)]2 complexes and their application in asymmetric aza-Wacker cyclisations. The reactions generally proceed with low yields or enantioselectivity [43]. The best enantio-selectivity (63%) was achieved using complex 28 (Table 10.8). 

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

An asymmetric variant of this reaction was developed using chiral Pd complex 111 with either silanes or disiloxanes [66-68]. Both relative and absolute stereochemistries were controlled in this system and good yields (60-85%) were obtained after oxidation (Eq. 18). Formation of the silane-containing product was inhibited by the presence of water due to competitive formation of the palladium hydrides and silanols [68]. The use of disiloxanes as reductants, however, provided expedient oxidation to the alcohol products without decreasing the isolated yields enantioselectivity was 5-15% lower in this more robust system [66]. Benzhydryldimethylsilane proved to be a good compromise between high yield and facile oxidation [66]. Palladium com-... 

When 1,3-dienes containing a tethered alcohol are subjected to Wacker-type reactions, the initial intramolecular oxypalladation event creates a 7r-allylpalladium species, which can then undergo an additional bond-forming process to effect an overall 1,4-difunctionalization of the diene with either cis- or // -stereochemistry (Scheme 18).399 An array of substrate types has been shown to participate in this reaction to generate both five- and six-membered fused or ro-oxacycles.435-437 Employing chiral benzoquinone ligands, progress toward the development of an asymmetric variant of this reaction has also been recorded, albeit with only modest levels of enantioselectivity (up to 55% ee).438... 

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. 

The conjugate addition of organometallic reagents to a./i-unsaturated compounds is one of the basic methods in our repertoire for the construction of carbon-carbon bonds. These addition reactions have been used as key steps in the synthesis of numerous biologically active compounds, and show a broad scope due to the large variety of donor and acceptor compounds that can be employed. It is evident that a tremendous effort has been devoted over the last three decades to develop asymmetric variants of this reaction. ... 

A clean, high-yielding asymmetric Baylis-HiUman reaction has been reported employing Oppolzer s sultam,63ab it couples acrylates witii a variety of aldehydes at 0 °C, with >99% ee in all cases described.630 Another new, practical variant of the reaction employs a phosphine catalyst,64 and here the temperature effect is critical the rate increases in either direction from room temperature, with a dramatic improvement observed at 0 °C. This unusual observation is explained in tenns of a temperature-dependent equilibrium between efficient and inefficient intermediates. 

The initial a-addition adduct from the reaction of methyl (S)-2-isocyano-4-methylpentanoate 232 and protected (S)-alaninal 233 further reacted with benzoic acid to furnish 234 as a diastereomeric mixture. The stereochemistry of the resulting benzoyl-protected alcohol was inconsequent since the latter functionality is oxidized during the course of the synthesis using pyridinium dichromate to afford the a-oxoamide in the final target. In general, however, in isocyanide MCRs the control of the newly created stereogenic center is problematic and separation of diastereomeric mixtures cannot be avoided. A recent report by Denmark and Fan on a catalytic asymmetric variant of this reaction therefore represents an interesting development [119]. 

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

Not surprisingly, chiral formamides emerged as prime candidates for the development of an asymmetric variant of this reaction. A selection of the most efficient amide catalysts based on amino acids is shown in Figure 7.4 representative examples of enantioselective hydrosilylation are collected in Tables 7.7 and 7.8. Proline-derived anilide 82a and its naphthyl analogue 82b, introduced by Matsu-mura [3c], produced moderate enantioselectivity in the reduction of aromatic ketimines with trichlorosilane at 10 mol% catalyst loading (Table 7.7, entries 1 and 2). Formamide functionality proved to be crucial for the activation of the silane, as the corresponding acetamides failed to initiate the 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]. 

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). 

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. 

Since CIgSiH is known to be activated by DMF and other Lewis bases to effect hydrosilylation of imines (Scheme 4.2) [8], it is hardly surprising that chiral formamides, derived from natural amino adds, emerged as prime candidates for the development of an asymmetric variant of this reaction [8]. It was assumed that, if successful, this approach could become an attractive altemative to the existing enzymatic methods for amine production [9] and to complement another organo catalytic protocol, based on the biomimetic reduction with Hantzsch ester, which is being developed in parallel [5]. 

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-... 

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