Synthesis of Chiral Ketones

Soderquist JA, Ramos J, Matos K (1997) Tetrahedron Lett 38 6639 Brener L, Brown, HC (1977) J Org Chem 42 2702 Brown HC, Garg CP, Liu K-T (1971) J Org Chem 36 387 Carlson BA, Brown HC (1993) Synth 776 

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Asymmetric synthesis of ketones and acids A new synthesis of chiral ketones and acids starts with the reaction of an anhydride or an acid chloride with either I-or li-ephedrin to form a chiral N,N-disubstituted amide (1) in almost quantitative yield. The amide (1) is then alkylated via the anion to give 2, which contains three asymmetric centers. Acid hydrolysis of 2 gives a carboxylic acid (3) with an optical yield of 75% (two examples). Cleavage of 2 with methyllithium gives a methyl ketone (4), in optical yields of 45-75%. 

Ketones. The follow-up steps for asymmetric synthesis of chiral ketones from W-acylbomane-10,2-sultams consist of thiolysis and Grignard reaction catalyzed with... 

Similarly to the asymmetric synthesis by imines and oxazoline, there is also a chiral hydrazone, (S)-l-amino-2-(methoxymethyl)pyrrolidine 51a, which gives chiral hydra-zones on reaction with aldehydes and ketones and is able to form an intermolecular chelate with the methoxy group. Enders and coworkers used this system for enantioselec-tive aldol reactionand for synthesis of chiral ketone and aldehyde (equation 30). 

A new synthesis of chiral ketones relies on the high levels of asymmetric induction observed in the hydroboration of olefins by monoisopino-campheyl-borane (Scheme 15). The optical and chemical yields are high, and the chiral auxiliary may be readily recovered and recycled. 

Yamamoto and Ishihara et al. have revealed that acidic protons in the optically active binaphthol (BINOL) or BINOL monomethyl ether are activated by coordination of SnCU to form a Lewis acid-assisted chiral Bronsted add (LBA) (43) and can be used a s a chiral proton source f or the synthesis of chiral ketones or carboxylic acids from silyl enol ethers or ketene bis (trialky Isilyl) acetals [44]. The chiral LBA system is also effective in the catalytic version with 5-10 mol% of the optically active BINOL monomethyl ether and SnCU in the presence of 2,6-dimethylphenol as a stoichiometric proton source (Scheme 10.22). Further details and backgrounds of the reactions using LBA are reviewed in the first edition of this series [12]. 

Chiral oxazolines have also been utilized for the synthesis of ehiral ketones bearing quaternary earbon stereoeenters. As shown below, reaetion of substituted oxazoline 30 with 2 equiv PhLi followed by treatment with benzyl bromide gives ketone 33 upon aeidie hydrolysis. This reaetion is believed to proeeed via addition of PhLi to keteneimine 31 to afford metalated enamine 32, whieh undergoes alkylation at the nueleophilie earbon to provide 33 after aqueous workup. ... 

The reduction of ketones, aldehydes, and olefins has been extensively explored using chemical and biological methods. As the latter method, reduction by heterotrophic microbes has been widely used for the synthesis of chiral alcohols. On the contrary, the use of autotrophic photosynthetic organisms such as plant cell and algae is relatively rare and has not been explored because the method for cultivation is different from that of heterotrophic microbes. Therefore, the investigation using photosynthetic organisms may lead to novel biotransformations. 

The usefulness of the carbonyl reductase from Candida magnoliae as an enzyme catalyst in the synthesis of chiral alcohol intermediates has been demonstrated by carrying out the reduction of several ketones on a preparative scale [56]. The isolated yields and enantiomeric excess of the product alcohols are summarized in Table 7.1, from which it can be seen that these chiral alcohols were obtained in essentially optically pure forms in excellent yields. These chiral alcohols are important intermediates in the synthesis of pharmaceuticals and agrichemicals. For example, optically active 2-hydroxy-3-methylbutyrate is an important chiral synthon... 

The development of chiral phosphorus ligands has made undoubtedly significant impact on the asymmetric hydrogenation. Transition metal catalysts with efficient chiral phosphorus ligands have enabled the synthesis of a variety of chiral products from prochiral olefins, ketones, and imines in a very efficient manner, and many practical hydrogenation processes have been exploited in industry for the synthesis of chiral drugs and fine chemicals. 

The enantioseiective hydrogenation of a-amino ketones has been applied extensively to the synthesis of chiral drugs such as the / -agonist SR 58611 (Sanofi Cie). m-Chlorstyreneoxide was obtained via carbene-induced ring closure of the amino alcohol. Epoxide-opening by a chiral amine obtained via a ruthenium-catalyzed hydrogenation of an enamide has led to the desired compound where... 

Enzyme reductions of carbonyl groups have important applications in the synthesis of chiral compounds (as described in Chapter 10). Dehydrogenases are enzymes that catalyse, for example, the reduction of carbonyl groups they require co-factors as their co-substrates. Dehydrogenase-catalysed transformations on a practical scale can be performed with purified enzymes or with whole cells, which avoid the use of added expensive co-factors. Bakers yeast is the whole cell system most often used for the reduction of aldehydes and ketones. Biocatalytic activity can also be used to reduce carbon carbon double bonds. Since the enzymes for this reduction are not commercially available, the majority of these experiments were performed with bakers yeast1 41. 

Enantioselective organic synthesis using modified skeletal catalysts has wide application in areas such as pharmaceutical production for example, synthesis of chiral alcohols from ketones [90], which is described in detail elsewhere in this book. 

A closely related reaction of ketones and ketoesters with chiral f-butyl (+)-(i )-p-toluenesulfinylacetate 50 was utilized for the synthesis of chiral (3-hydroxy acids as shown in Scheme 32 (317). The optical purities of the final reaction products varied from 8.5 to 91%. 

Iridium complexes are known to be generally less active in hydrosilylation reactions when compared to rhodium derivatives, although iridium-based catalysts with bonded chiral carbene ligands have been used successfully in the synthesis of chiral alcohols and amines via hydrosilylation/protodesilylation of ketones [46-52] and imines [53-55], The iridium-catalyzed reaction of acetophenone derivatives with organosubstituted silanes often gives two products (Equation 14.3) ... 

The same authors 83) used the chiral ketone (46) as substrate for the preparation of optically active cyclohexanol derivatives (47) which may be useful intermediates in the synthesis of chiral natural products, such as (—)-mesenbranoene, (+)-2-carene etc. 

Grotzinger, A. S. Demir, M. Pohl, Benzoylformate decarboxylase from Pseudomonas putida as stable catalyst for the synthesis of chiral 2-hydroxy ketones. Chem. Eur.J. 2000, 6, 1483-1495. 

The use of chiral auxiliary groups on the amide function permits the synthesis of chiral bicyclic ketones, e.g. 15, with enantioselectivity maximized with two chiral groups on the amide function.15... 

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