Chiral tertiary alcohols asymmetric synthesis

Asymmetric Synthesis of Chiral Tertiary Alcohols in High Enantiomeric Excess... 

The subsequent epoxidation of these in situ formed allylic tertiary alcohols yielded the corresponding syn-e oxy alcohols with high levels of diastereo- and enantioselectivity, thus providing a novel one-pot asymmetric synthesis of acyclic chiral epoxyalcohols via a domino vinylation epoxidation reaction (Scheme 4.17). ... 

Two principal approaches to the synthesis of an optically pure chiral secondary or tertiary alcohol from the reaction of an organometallic reagent with an aldehyde or ketone respectively are of current interest. In the first approach an alkyllithium or dialkylmagnesium is initially complexed with a chiral reagent which then reacts with the carbonyl compound. In this way two diastereo-isomeric transition states are generated, the more stable of which leads to an enantiometic excess of the optically active alcohol. This approach is similar in principle to the asymmetric reductions discussed in Section 5.4.1 (see also p. 15). Two chiral catalysts may be noted as successful examples, (10) derived... 

Addition to unsaturated centres (C=0, C=N, C=C) adjacent to the diene can occur in a diastereoselective fashion, and asymmetric synthesis can be carried out if the diene complex is optically active. As Fe(CO)3 coordinates from one face of the unsymmetrically substituted conjugated dienes, the complexes are chiral and can be resolved to the optically active forms 93 and 94, which are used for asymmetric synthesis. The optically active acetyldiene complex 95, obtained by the acetylation of the optically active diene complex 94, reacts diastereoselectively with PhLi to give 96. The optically active tertiary alcohol 97 is obtained by its decomplexation. The enantiomer 100 can be synthesized by the opposite operation namely the benzoylation of 94 to give 98, and subsequent reaction of MeLi gives 99. The enantiomer 100 is obtained by decomplexation [16]. 

Akiyama, Y, Ishikawa, K, OzaM, S, Asymmetric synthesis of functionalized tertiary alcohols by diastereoselective aldol reaction of silyl enol ether and ketene silyl acetals with a-keto esters bearing an optically active cyclitol as a chiral auxihary, Synlett, 275-276, 1994. 

Chiral auxiliary-bound substrates have also been used for the asymmetric process. The aldol reaction of chiral pyruvates such as 46 is a reliable method for highly enantioselective synthesis of functionalized tertiary alcohols (Scheme 10.38) [112]. The Lewis acid-catalyzed aldol-type reactions of chiral acetals with silyl enolates are valuable for the asymmetric synthesis of -alkoxy carbonyl compounds ]113, 114]. 

Stereoselective allylic substitution reactions are very useful in the asymmetric synthesis of complex organic molecules. An important approach is to use readily available enantiopure allylic alcohols or their derivatives. The substitution products such like 129 and 130, containing tertiary or quaternary chiral centers, are obtained in excellent... 

Chiral amino alcohols are common structures in drug molecules for example, y-secondaiy aminoalcohols are key intermediates in the synthesis of several pharmaceuticals, examples of which are shown in Scheme 14.12. Zhang has shown that Rh-DuanPhos catalysts can be used to synthesise these key intermediates directly via asymmetric hydrogenation of the p-secondary amino ketone. Application to the synthesis of the antidepressant duloxetine is shown in Scheme 14.12. It should be noted that, to date, ruthenium catalysis has not been successfully applied to the reduction of secondary amino substrates a tertiary amino group is required resulting in a less efficient synthesis requiring extra S3mthetic steps. ... 

One of the pervasive problems in asymmetric synthesis has been the development of stereoselective acetate ester aldol reactions. Although a number of chiral auxiliaries perform superbly well in diastereoselective propionate aldol additions, these have, with rare exceptions, been unsuccessful in the corresponding additions of unsubstituted acetate-derived enolates [19, 63, 64). Braun s disclosure of a stereoselective acetate aldol addition reaction with 103 was an important milestone in the development of the field (Scheme 4.11) [63, 65]. The diol auxiliary can easily be prepared from mandelic acid esterification of the secondary alcohol is obsei ved, without interference from the tertiary counterpart. Its use has been showcased in a number of syntheses [53]. The high yield and diastereoselectivity generally obtained with 103 were highlighted by investigators at Merck in the construction of the chiral lactone fragment that is common in a number of HMG-CoA reductase inhibitors, such as compactin (105) [66]. 

One of the key pioneers in this area was Solladie, who thoroughly investigated the reactions of chiral sulfoxide carbanions [21], Their diastereoselec-tive additions to ketones and aldehydes are illustrative of the method (Scheme 13.16) [67]. Addition of 104 to cyclohexyl methyl ketone (105) thus furnished adduct 106. The sulfoxide, having fulfilled its role as an auxiliary, is subsequently subjected to reductive cleavage to afford hydroxy ester 107. After transesterification, alcohol 108 was produced in 95 % ee. Despite the numerous years that have transpired since these results were first published, such optically active tertiary alcohols remain otherwise difficult to prepare, a feature that attests to the potential value of chiral sulfoxide anions in asymmetric synthesis. 

A synthesis of the Inhoffen-Lythgoe diol (46.7, Scheme 2.46), a useful intermediate in the synthesis of Vitamin D derivatives, demonstrates the use of a chiral acetal in an asymmetric tandem cyclisation reaction.102 Once again, Lewis acid co-ordination to the less hindered oxygen of the acetal 46.1 initiated a Prins-like cyclisation that terminated by attack of the propargylsilane on an incipient tertiary carbocation. After removal of the chiral auxiliary, the allene function in the alcohol 46.4 was transformed into the side chain of 46.7 with the creation of two new stereogenic centres. 

Tanaka et al. developed a Rh-catalyzed asymmetric one-pot transesterification and [2+2+2] cyclotrimerization using nonracemic ligand 415 in the synthesis of enantio-enriched 3,3-disubstituted phthalides (R R ) (Scheme 2-39)P The chiral Rh complex with 415 efficiently desymmetrized dipropargyl alcohols 413 (R = R -OC-) in the reaction with 412 to give phthalides 414 (R = R -C=C-) in up to 87% yield and 93% ee. Also, the kinetic resolution of racemic tertiary propargylic alcohols... 

A number of other asymmetric enolate protonation reactions have been described using chiral proton sources in the synthesis of a-aryl cyclohexanones. These include the stoichiometric use of chiral diols [68] and a-sulfinyl alcohols [69]. Other catalytic approaches involve the use of a BlNAP-AgF complex with MeOH as the achiral proton source, [70] a chiral sulfonamide/achiral sulfonic acid system [71,72] and a cationic BINAP-Au complex which also was extended to acyclic tertiary a-aryl ketones [73]. Enantioenriched 2-aryl-cyclohexanones have also been accessed by oxidative kinetic resolution of secondary alcohols, kinetic resolution of racemic 2-arylcyclohexanones via an asymmetric Bayer-Villiger oxidation [74] and by arylation with diaryhodonium salts and desymmetrisation with a chiral Li-base [75]. 

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