Enantioselective asymmetric synthesis

Asymmetric Hydroboration. Hydroboration—oxidation of (Z)-2-butene with diisopinocampheylborane was the first highly enantioselective asymmetric synthesis (496) the product was R(—)2-butanol in 87% ee. Since then several asymmetric hydroborating agents have been developed. Enantioselectivity in the hydroboration of significant classes of prochiral alkenes with representative asymmetric hydroborating agents is shown in Table 3. 

Preparation of Chiral Sulfinates. Optically active sulfinates can be prepared by reaction of a symmetrical sulfite with t-Butylmagnesium Chloride in the presence of an optically active amino alcohol. The best enantioselectivity has been observed using quinine as the optically active amine (eq 2)3 An alternative approach to this new enantioselective asymmetric synthesis of alkyl t-butylsulfinates would be reaction of a racemic sulfinate with r-butylmagnesium chloride complexed by optically active alkaloids (eq 3). In this case, kinetic resolution of the racemic sulfinate leads to an optically active sulfinate and an optically active sulfoxide. 

Asymmetric synthesis is pCTformed on an achiral substrate with the help of a chiral auxiliary which is temporarily bound to the substrate or whidi is external to it (in the reagent or the catalyst). The first case is named diastereoselective asymmetric synthesis, and the second one enantioselective asymmetric synthesis to define the product being formed as a mixture of diastereomers and a mixture of enantiomers, respectively. The two processes are indicated in Rgure 1. 

Some achiral precursors in enantioselective asymmetric synthesis are indicated in Figure 2. In order to be used in diastereoselective asymmetric syntheses they need to bear a functional group able to give a temporary linkage to the chiral auxiliary. The asymmetric synthesis is a process of dessymmetrization of an achiral precursor (removal of all the elements of symmetry reflection, eg Sn elements). 

The first enantioselective asymmetric synthesis with ee in the range of 90% was the asymmetric hydroboration of alkenes desoibed in 1961 by H. C. Brown et al. In this cl sic study (Rgure 3), (R)-(-)2 butanol of 90% ee was isolated using ccmunercial (+)-a-pinene of about 90% ee. More recently, the authors prepared enantiopure a-pin ie and wo e able to produce 2-butanol with 98% ee. Asynunetric hydroboration became an established and an important class of asymmetric syntheses with very high ee s. 

The Mukaiyama aldol reaction has also been used in the enantioselective asymmetric synthesis of 5-hydroxy-P-keto ester derivatives. Katsuki and coworkers utilized the chiral Cr(salen) complex 69 for the catalysis of the aldol reaction in the presence of water or alcohol. The presence of alcohol in the reaction greatly increases the enantioselectivity of the aldol addition. In the reaction of the silyl enol ether 92 with the aldehyde 93 in the presence of the catalyst 69, triethylamine, and isopropanol yielded the aldol adduct 94 in high yield (87%) and excellent enantioselectivity (97% ee). 

Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic... 

Efficient enantioselective asymmetric hydrogenation of prochiral ketones and olefins has been accompHshed under mild reaction conditions at low (0.01— 0.001 mol %) catalyst concentrations using rhodium catalysts containing chiral ligands (140,141). Practical synthesis of several optically active natural... 

Asymmetric synthesis is a method for direct synthesis of optically active amino acids and finding efficient catalysts is a great target for researchers. Many exceUent reviews have been pubHshed (72). Asymmetric syntheses are classified as either enantioselective or diastereoselective reactions. Asymmetric hydrogenation has been appHed for practical manufacturing of l-DOPA and t-phenylalanine, but conventional methods have not been exceeded because of the short life of catalysts. An example of an enantio selective reaction, asymmetric hydrogenation of a-acetamidoacryHc acid derivatives, eg, Z-2-acetamidocinnamic acid [55065-02-6] (6), is shown below and in Table 4 (73). 

The variety of enzyme-catalyzed kinetic resolutions of enantiomers reported ia recent years is enormous. Similar to asymmetric synthesis, enantioselective resolutions are carried out ia either hydrolytic or esterification—transesterification modes. Both modes have advantages and disadvantages. Hydrolytic resolutions that are carried out ia a predominantiy aqueous medium are usually faster and, as a consequence, require smaller quantities of enzymes. On the other hand, esterifications ia organic solvents are experimentally simpler procedures, aHowiag easy product isolation and reuse of the enzyme without immobilization. 

Solladie-Cavallo has recently reported a two-step asymmetric synthesis of dis-ubstituted N-tosylaziridines from (R,R,R,Ss)-(-)-sulfonium salt 2 (derived from Eliel s oxathiane see Section 1.2.1.1) and N-tosyl imines with use of phosphazine base (EtP2) to generate the ylide (Scheme 1.42) [67], Although the diastereoselectiv-ity was highly substrate-dependent, the enantioselectivities obtained were very high (98.7-99.9%). The chiral auxiliary, although used in stoichiometric quantities, could be isolated and reused, but the practicality and scope of this procedure is limited by the use of the strong - as well as expensive and sensitive - phospha-zene base. 

Asymmetric epoxidations of alkenes have been intensively studied since Sharpless initial report on asymmetric epoxidation of allylic alcohols in 1980. This reaction, discussed in Section 9.1.3, has become one of the most widely employed reactions in asymmetric synthesis, due to its reliability and high enantioselectivity [2],... 

The development of Sharpless asymmetric epoxidation (SAE) of allylic alcohols in 1980 constitutes a breakthrough in asymmetric synthesis, and to date this method remains the most widely applied asymmetric epoxidation technique [34, 44]. A wide range of substrates can be used in the reaction ( ) -allylic alcohols generally give high enantioselectivity, whereas the reaction is more substrate-dependent with (Z)-allylic alcohols [34]. 

Another example of reagent-induced asymmetric synthesis is the enantioselective preparation of phosphoramides 6 by addition of dialkylzine reagents to A-diphenylphosphinoylimincs 4 in the presence of the enantiomerically pure 1,2-amino alcohols 5a or 5 b (diethylzinc does not add to A-silyl- or A-phenylimines)12. Phosphoramides 6 (crystalline solids) are obtained in moderate to good yield and good enantioselectivity. The latter can be enhanced by recrystallization. Acidic hydrolysis with dilute 3 M hydrochloric acid/tetrahydrofuran provides the corresponding amines 7 without any racemization. 

Diastereoselective and enantioselective [3C+2S] carbocyclisations have been recently developed by Barluenga et al. by the reaction of tungsten alkenylcarbene complexes and enamines derived from chiral amines. Interestingly, the regio-chemistry of the final products is different for enamines derived from aldehydes and those derived from ketones. The use of chiral non-racemic enamines allows the asymmetric synthesis of substituted cyclopentenone derivatives [77] (Scheme 30). 

The Rh2(DOSP)4 catalysts (6b) of Davies have proven to be remarkably effective for highly enantioselective cydopropanation reactions of aryl- and vinyl-diazoacetates [2]. The discovery that enantiocontrol could be enhanced when reactions were performed in pentane [35] added advantages that could be attributed to the solvent-directed orientation of chiral attachments of the ligand carboxylates [59]. In addition to the synthesis of (+)-sertraline (1) [6], the uses of this methodology have been extended to the construction of cyclopropane amino acids (Eq. 3) [35], the synthesis of tricyclic systems such as 22 (Eq. 4) [60], and, as an example of tandem cyclopropanation-Cope rearrangement, an efficient asymmetric synthesis of epi-tremulane 23 (Eq. 5) [61]. 

The first asymmetric synthesis of (—)-Y-jasmolactone, a fruit fiavor constituent, vas achieved via the enantioselective lactonization (desymmetrization) of a prochiral hydroxy diester promoted by porcine pancreas lipase (PPL) (Figure 6.23) [71]. 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

Imidazole and its derivatives continued to play an important role in asymmetric processes. Optically active pyrroloimidazoles 26 were prepared by the cycloaddition of homochiral imidazolium ylides with activated alkenes <96TL1707>. This reaction was used in the enantioselective preparation of pyrrolidines <96TL1711>. A review of the use of chiral imidazolidines in asymmetric synthesis was published <96PAC531> and the preparation and use of a new camphor-derived imidazolidinone-type auxiliary 27 was reported < 6TL4565> <96TL6931>. 

Hodous BL, Ruble JC, Fu GC (1999) Enantioselective addition of alcohols to ketenes catalyzed by a planar-chiral azaferrocene catalytic asymmetric synthesis of arylpropionic acids. J Am Chem Soc 121 2637-2638... 

Hoashi, Y., Yabuta, T., Takemoto, Y. (2004) Bifunctional Thiourea-Catalyzed Enantioselective Double Michael Reaction of y,5-Unsaturated fS-Ketoesterto Nitroalkene Asymmetric Synthesis of (—)-Epibatidine. Tetrahedron Letters, 45, 9185-9188. 

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