Enantioselective synthesis optically active compounds

The enantioselective 1,4-addition addition of organometaUic reagents to a,p-unsaturated carbonyl compounds, the so-called Michael reaction, provides a powerful method for the synthesis of optically active compounds by carbon-carbon bond formation [129]. Therefore, symmetrical and unsymmetrical MiniPHOS phosphines were used for in situ preparation of copper-catalysts, and employed in an optimization study on Cu(I)-catalyzed Michael reactions of di-ethylzinc to a, -unsaturated ketones (Scheme 31) [29,30]. In most cases, complete conversion and good enantioselectivity were obtained and no 1,2-addition product was detected, showing complete regioselectivity. Of interest, the enantioselectivity observed using Cu(I) directly in place of Cu(II) allowed enhanced enantioselectivity, implying that the chiral environment of the Cu(I) complex produced by in situ reduction of Cu(II) may be less selective than the one with preformed Cu(I). 

Brunner, H., Enantioselective Synthesis of Organic Compounds with Optically Active Transition Metal Catalysts in Substoichiometric Quantities, 18, 129. 

Enzymes are widely recognized as valuable tools for the synthesis of optically active compounds [22]. Thus, lipase-catalyzed acylation or deacylation is one of the most efficient methods for the preparation of optically active alcohols, acids, and esters. Because lipases retain activity and selectivity in non-conventional media such as organic liquids, their use as biocatalysts in enantioselective synthetic reactions has considerably increased. 

Asymmetric cyclization using chiral ligands offers powerful synthetic methods for the preparation of optically active compounds [39]. After early attempts [40,41], satisfactory optical yields have been obtained in a number of cases. Synthesis of the optically active cA-decalin system [42] was carried out with high enantioselectivity based on the differentiation of enantiotopic C=C double bonds [43]. The cyclization of the triflate 93 gave the cA-decalin 94 with 95% ee in 78% yield using (i )-BINAP. A mixture of 1,2-dichloroethane and f-BuOH is the best solvent, and the asymmetric synthesis of vemolepin (96) via Danishefsky s key intermediate 95 has been achieved [44]. 

Enantioselective Synthesis of Organic Compounds with Optically Active... 

Chiral auxiliaries are optically active compounds which are used to direct asymmetric synthesis. The chiral auxiliary is temporarily incorporated into an organic synthesis which introduces chirality in otherwise racemic compounds. This temporary stereocentre then forces the asymmetric formation of a second stereocentre. The synthesis is thus diastere-oselective, rather than enantioselective. After the creation of the second stereocentre the original auxiliary can be removed in a third step and recycled. E. J. Corey in 1975, B. M. Trost in 1980 and J. K. Whitesell in 1985 introduced the chiral auxiliaries 8-phenylmenthoT (1.40), chiral mandelic acid (1.41) and frans-2-phenyl-l-cyclohexanoT (1.42), respectively. 

There are three methods available for the enantioselective synthesis of pheromones (1) derivation from enantiopure natural products, (2) enantiomer separation (optical resolution), and (3) chemical or biochemical asymmetric synthesis. Practitioners of enantioselective synthesis must be familiar with the analytical methods for the determination of enantiomeric purity of an optically active compound. These basic methods will be explained briefly in this section, and discussed in depth through examples in the later sections of this chapter. 

Until fairly recently, primarily transition metal complexes and enzymes were utilized as catalysts for enantioselective synthesis [17]. Nicolaou and Sorensen wrote the following statement in their book published in 1996 [18] In a catalytic asymmetric reaction, a small amount of an enantiomerically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. ... 

Since cis-3, trans-3, and trans-2 bis-adducts of 50 with identical addends are chiral as a result of inherently chiral functionalization patterns [10, 44-46], it was of interest to explore whether Bingel macrocyclizations with bismalonates bridged by non-racemic tethers would provide an enantioselective synthesis of these compounds. An overall enantioselective synthesis of optically active Cgg bis-adducts had been achieved previously by asymmetric Sharpless bis-osmylation [77] however, this sequential bis-func-tionalization lacks the regioselectivity of the Bingel macrocyclization, and therefore requires tedious regioisomer separations. 

The chemistry of natural products encompasses their isolation, structure elucidation, partial and total synthesis, elucidation of their biogenesis, and the biomi-metic synthesis of N. p. Major breakthroughs in analysis were, e.g., the structural clarifications of morphine, lignin, insulin, estrones, and cholesterol as well as the elucidation of the biosyntheses of terpenoids, morphine, penicillin, chlorophyll, and vitamin B 2. Major advances in synthetic chemistry were, e.g., the total syntheses of camphor, hemin, quinine, saccharose, tropine, stryehnine, chlorophyll, vitamin B 2, erythromycin, taxol and palytoxin. Numerous N. p. of the so-ealled ehiral pool are used as starting materials for the synthesis of optically active compounds or serve (in the form of their derivatives) as catalysts for enantioselective syntheses. 

Enzymes are optimized catalysts for the synthesis of the optically active compounds needed in nature. To-day enzymes are also extensively used for the synthesis of optically active compounds needed in industry. However, for substrates which differ from the enzymes natural substrates usually a drop in reactivity and enantioselectivity is observed. In addition, there are many reactions which are not accessible to enzyme catalysis or in which enzymes are decomposed. 

The attempts to achieve enantioselective synthesis of cycloadduct compounds by using a chiral Lewis acid associated with achiral cobaltoxime resulted in moderate Another approach is to replace the dimethylglyoxime ligand set by salen ligands. Cobalt(ii) salen complexes synthesized in achiral form showed good results in Diels-Alder reactivity. In the chiral salen complex, the corresponding optically active dienylcobalt complexes 189 have been obtained by the reaction of optically active cobalt(ll) salen complexes 188 with allenic compounds (Equation (28)). 

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. ... 

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