Amino-alcohols coupling ketones with

Cross-coupling reactions of nitrones with aldehydes and ketones make it possible to synthesize vicinal amino alcohols, which are common in natural products. These transformations have been performed by a new method of reduction... 

Reductive cross-dimerization has been established with ketones and 0-meth-oximes upon reduction in isopropanol with a Sn cathode as a convenient route to yS-amino alcohols, diastereoselectivities of up to 85 15 were obtained. A chiral ligand was obtained this way from the coupling of (-) - menthone with O-methyl acetaldoxime. Similarly, ketones could be coupled to hydrazones and nitrones. Also, intramolecular couplings were achieved with good yields and diastereoselectivity (Fig. 56) [308]. 

Intermolecular coupling between ketones and 0-methyl oximes, hydrazones and nitrones is achieved on reduction at a tin cathode in isopropanol [105]. It is not clear which of the reacting species accepts the initial electron in these processes. The reaction with 0-methyloximes, followed by catalytic reduction of the first formed O-methylhydroxylamine, is a convenient synthetic route to 2-amino-alcohols. 

Starting from enantiomerically pure 4,5-dihydroisoxazoles5 s-22-26-31 -34,37-43 Ljjjs methodology, coupled with subsequent transformation, allows the preparation of 1,3-amino alcohols and /3-hydroxy ketones of high diastereomeric and enantiomeric purity. 

The first step in the overall synthetic scheme (Scheme 6) is the condensation of an appropriate carboxylic acid with trifluoroacetaldehyde. The carboxylic acid is chosen to impart specificity for the target enzyme. In one example,[28 the dianion of cyclohexanepropanoic acid (29) was formed by the addition of LDA and then quickly condensed with trifluoroacetaldehyde to form the p-hydroxy acid 30 as a racemic mixture of erythro- and threo-isomers. The p-hydroxy acid 30 is then protected with TBDMSOTf forming 31. Diphenyl phosphorazidate, TEA, and benzyl alcohol were then utilized in a Curtius rearrangement of the protected alcohol 31, which proceeds through an isocyanate intermediate that yields the protected amino alcohol 32 upon reaction with benzyl alcohol. In order for this step to occur at an appreciable rate, a second equivalent of triethylamine had to be added. The amino alcohol 32 was then deprotected and coupled with Boc-Phe-Leu-OH to give the trifluoromethyl alcohol 33, which was oxidized to the corresponding trifluoromethyl ketone 34 as a 1 1.2 mixture of diastereomers using the Dess-Martin periodinane procedure. Thus far, the compound shown in Scheme 6 is the only compound that has been synthesized by this method, but it is reasonable to assume that many other similar fluoro ketones can be produced by this scheme. 

The 1,3-dipolar cycloaddition of nitrones to alkenes is a useful route to isoxazolidine derivatives, the reductive cleavage of which furnishes a range of compounds such as fi-hydroxy ketones, /S-amino alcohols, etc. [29]. Although Lewis acids are known to promote the cycloaddition [29,30], some nitrones, especially aliphatic nitrones, are unstable under these conditions and lower yields are sometimes obtained. The three-component coupling reaction of benzaldehyde, A/-benzylhydroxylamine, and A-phe-nylmaleimide proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3, to afford the corresponding isoxazolidine derivative in a good yield with high diaster-eoselectivity (Eq. 12) [31]. 

Chiral oxazolines Stille carbonylative coupling,4 Pd-catalyzed carbonylative coupling of Inflates of ketones and phenols with chiral amino alcohols provides )3-hydroxy amides, which cyclize to chiral oxazolines when treated with thionyl chloride. 

Meyers and colleagues described the palladium-catalyzed carbonylative synthesis of oxazolines as early as 1992 [268]. Aryl or enol triflates made from the corresponding ketones and phenols, and also aryl halides, were used as starting materials and coupled with amino alcohols to give chiral a,)S-unsaturated or aryl oxazolines in good yields. Later on, Perry s group performed systematic studies on this one-pot, two-step process for the preparation of oxazolines (Scheme 2.37) [269, 270]. 

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