Asymmetric preparation

The allenyl carboxylate 35 was obtained in an enantiomerically enriched form by the palladium-catalyzed reduction of the racemic phosphate 34 using a chiral proton source [53]. The two enantiomers of the (allenyl)samarium(III) intermediate are in rapid equilibrium and thus dynamic kinetic resolution was achieved for the asymmetric preparation of (i )-35 (Scheme 3.18). 

The catalytic asymmetric preparation of a-chiral amines, by addition of organo-metallic reagents to C=N bonds, is one of the most important reactions in homogeneous catalysis [26]. However, the catalytic asymmetric addition of simple alkylmetals has been achieved only in recent years. 

An asymmetric preparation of alkenylcyclopropanes has also been realized by the use of palladium(O) complexes carrying chiral ferrocenylphosphine ligands (equation 22)38. The requisite rt-allyl palladium intermediates can also be generated from allene and meth-ylenecyclopropane derivatives, 1839 and 1940, in the presence of palladium(O) complex and alkenyl or aryl halide (equations 23 and 24). The cobalt complexes, 20, similarly afford the corresponding alkenylcyclopropanes upon exposure to LDA (equation 25)41. 

A tandem palladium-catalyzed reaction can effect a similar transformation to produce 2-vinyl-substituted heterocyclic systems as in Eq. 8E.11. By varying the amino acid moiety of the ligand, 83% ee could be obtained from the use of the glycine-derived ligand 129 [161]. A maximum enantioselectivity of 65% ee has been recorded for this type of reaction in an earlier study with BINAP as ligand [ 162]. Because both ( )- and (Z)-isomers gave the same enantioselectivity, attack on the rapidly interconverting 7t-allyl intermediates seems to determine the selectivity. Modest enantioselectivities have been reported for the related asymmetric preparation of 2-vinylpiperazine and 1,4-benzodioxane derivatives [163,164],... 

Interestingly, the use of optically active alcohol 51 in this protocol leads, after cleavage of the benzylic ether in the initial adduct 52, to the enantiomerically enriched homoallylic alcohol 26. This approach appears to be the first asymmetric preparation of homoallylic alcohols via open-chain acetal derivatives (Scheme 13.19). 

Under optimized reaction conditions this two step synthesis for asymmetric preparation of /1-lactams is performed as follows. First, the organocatalyst 46 is added as a shuttle base to a solution of the acid chloride, 47, and the proton sponge , 49, at low temperature. Within a few minutes the soluble ketene and the hydrochloride salt, 49 HC1, as a white precipitate, are formed. Subsequently, the imino ester 44 is added to this solution at —78 °C, which results in the asymmetric formation of the /Mactam. Thus, the alkaloid 46 acts both as a dehydrohalogena-tion agent and as an organocatalyst for subsequent lactam formation [49, 52]. 

In conclusion, a catalytic asymmetric Horner-Wads worth-Emmons reaction using chinchona derivatives as organocatalysts has recently been realized. Because enantioselectivity is currently low to modest, improvement of the reaction to make this route attractive for asymmetric preparation of enantiomerically pure enones of type 77 is certainly a major issue. 

Many types of pericyclic and cycloaddition reactions have been documented. Although there are no general guidelines for the asymmetric preparation, reagents such as chiral catalysts are providing more general routes. Many of the reactions discussed rely on the use of low temperature. Although it is expensive to conduct low temperature reactions on an industrial scale, reactions that need temperatures of down to -105°C can be conducted. It should be noted that at such temperatures only stainless steel vessels, which require neutral or basic conditions, can be used at these extreme temperatures. In addition, reactions that involve the use of a metal can cause contamination problems in wastewater or the product. 

Fu has also achieved the addition of 2-cyanopyrrole to arylalkylketenes, again using PPY 4c (2 mol%) as catalyst in toluene at rt, and with similarly high selectivity and yield [59]. Additionally, related processes have been developed for the asymmetric preparation of /Mactams [67] and /Mactones [63] by the formal [2+2]-cycloaddition of N-tosylaldimines and aryl aldehydes, respectively, to Ice-... 

Remarkably, there is a noticeable lack of general methods for the asymmetric preparation of chiral sulfoxides from sulfides. The most satisfactory method would be a generally applicable enantioselective sulfoxidation reaction which would allow the preparation of sulfoxides from any prochiral sulfide with high ee s and in which the sulfoxide would be amenable to enantioselective preparation in both senses. 

Preparation. A number of methods have been reported for both the racemic and asymmetric preparations of l-amino-2,3-dihydro-lH-inden-2-ol (1), most commonly starting from inexpensive and readily available indene. These methods have been described in detail in recent reviews. The valuable properties of 1 as both a component of a medicinally active compound and as a chirality control element, derive primarily from its rigid and well-defined stereochemical structure. As a result, the compound is most desirable in enantiomerically pure form. One of the most efficient asymmetric syntheses of 1, which may be employed for the synthesis of either enantiomer of the target molecule, involves an asymmetric epoxidation (89% yield, 88% ee) of indene to give epoxide 2 using the well-established Jacobsen catalyst. This is followed by a Ritter reaction using oleum in acetonitrile resulting in conversion to the oxazoline (3) which is subsequently hydrolysed to the amino alcohol. Fractional crystallization with a homochiral diacid permits purification to >99% ee (eq 1). ... 

Houk control concerns electrophilic attack on alkenes, enolates and the like. The alkylation of enolate 56 would be an example if it were not held in a ring by chelation. It can in fact be difficult to tell whether chelation is involved or not with many enolates and the outcome of the reaction may tell which. Chamberlin s asymmetric preparation of both pyrrolidine 2,3-dicarboxylic acids 141 and 142 from natural aspartic acid illustrates this perfectly. The key to the stereochemical control is the very large protecting group 9-phenylfluorenyl-143 introduced by Rapoport.22... 

Because cyanohydrins are versatile intermediates, various methods for their asymmetric preparation have been worked out [46] (cf. Chapter 29). The chiral dipeptide catalysts allow the use of HCN but their application is restricted to aromatic aldehydes. Generally, 2% catalyst is needed and best optical yields are obtained at room temperature or below. As summarized by North [46], the pattern and the nature of substitution strongly affects the enantioselectivity (Table 5). Recently, the application to the synthesis of chiral side chains for Hq-uid crystal polymers was described [44]. 

Auxiliary 16 has also been used in the asymmetric preparation of P-homoaryl-glydnes [13, 17]. The reactions yielded 63-68% and gave diastereomeric ratios from 85 15 to 93 7. 

One of the most common substrates is vinyl acetate, leading to 2-acetoxypropanal with up to 98% ee125 if the reaction is carried out in the presence of orthoformate. Vinyl propionate and vinyl benzoate can also be used (see Table 7)75,167. All these substrates are prostereogenic building blocks, e.g, as precursors for the asymmetric preparation of a-amino acids, such as threonine. 

Asymmetric preparations of homoallylic alcohols have also appeared,... 

A more sophisticated target, for which an asymmetric preparation had not existed at the onset of our study, was pancratistatin 52, a promising antitumor agent in short supply from natural sources. This target was approached by a completely new strategy, a part of a systematic approach to alkaloids and oligosaccharides from vinylaziridine 47 and vinylepoxide 48, both derived from bromobenzene as shown in Figure 10 (X = Br, H). 

The asymmetric synthesis of cyclopropanes has attracted continual efforts in organic synthesis, due to their relevance in natural products and biologically active compounds. The prevalent methods employed include halomethylmetal mediated processes in the presence of chiral auxiliaries/catalysts (Simmons-Smith-type reactions), transition-metal-catalyzed decomposition of diazoalkanes, Michael-induced ring closures, or asymmetric metalations [8-10,46], However, the asymmetric preparation of unfunctionahzed cyclopropanes remains relatively undisclosed. The enantioselective activation of unactivated C-H bonds via transition-metal catalysis is an area of active research in organic chemistry [47-49]. Recently, a few groups investigated the enantioselective synthesis of cyclopropanes by direct functionalization reactions. 

The a-aminonitrile intermediates resulting from these MC Strecker strategies have been found useful for the synthesis of more complex and interesting structmes [106]. This is the case of Fitch and coworkers, who developed an efficient two-pot synthesis for the asymmetric preparation of benzothiadia-zine-substituted tetramic acids 83 (Scheme 10.37) [107],... 

The reduction of quinolines was applied to the asymmetric preparation of the anti-bacterial agent (/ )-flumequine 18 [85, 86], starting from quinoline 12a and generating the key tetrahydroquinoline intermediate 14a for the total synthesis and using 17 as catalyst (Scheme 6) [87]. 

In the last decade, increasing efforts have been devoted to the asymmetric preparation of structurally diverse P-amino acids (for selected reviews, see [219— 222]), due to their involvement in the synthesis of peptidomimetics and as valuable budding blocks. 

The use of amide-directed ip -arylation has been successfully utilized in the asymmetric preparation of unnatural a-amino acids (Schane 3.25). " Treatment of electron-deficient phthalimide protected a-amino amides with Pd(TFA)2 and aryl iodides led the formation of novel phenylalanine derivatives in high yield and excellent chemoselectivity. The method displays robnst tolerance for amnltitnde of substituted aromatics with varying electronic properties. Suppression of fcis-arylation was excellent under the reported conditions. This method was also extended toward the preparation homoarylated phenylalanines affording novel aryl differentiated moieties with excellent diastereoselectivities. 

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