Diastereoselective hydrogenation ketones

In the hydrogenation of optically active azomethines (prepared from chiral a-phenylcthyl-amine and ketones), the effect of reaction parameters, i.e., catalyst dispersion, mass and solvent polarity, on the diastereoselectivity has been studied20. The diastereoselective hydrogenation of several related chiral imines using nonchiral or chiral diphosphane ligands/rhodium has been reported to yield the corresponding amines with diastereomeric ratios up to 99.7 0.3 141. 

This situation was faced when the sertraline precursor rac. ketone 4 was reduced (Scheme 7.7). Two diastereomers were separated by crystallization and the right diastereomer (li ,4S)-6 converted to sertraline via the (4S )-ketone 4, then the imine, and finally c/s-diastereoselective hydrogenation was carried out. 

An attractive alternative to these novel aminoalcohol type modifiers is the use of 1-(1-naphthyl)ethylamine (NEA, Fig. 5) and derivatives thereof as chiral modifiers [45-47]. Trace quantities of (R)- or (S)-l-(l-naphthyl)ethylamine induce up to 82% ee in the hydrogenation of ethyl pyruvate over Pt/alumina. Note that naphthylethylamine is only a precursor of the actual modifier, which is formed in situ by reductive alkylation of NEA with the reactant ethyl pyruvate. This transformation (Fig. 5), which proceeds via imine formation and subsequent reduction of the C=N bond, is highly diastereoselective (d.e. >95%). Reductive alkylation of NEA with different aldehydes or ketones provides easy access to a variety of related modifiers [47]. The enantioselection occurring with the modifiers derived from NEA could be rationalized with the same strategy of molecular modelling as demonstrated for the Pt-cinchona system. 

Table6 Highly syn-diastereoselective intermolecular Rh-catalyzed hydrogenative aldol coupling of vinyl ketones through the tri-2-furylphosphine effect3...

The conversion of anomerically linked enol ethers 29 into either the cis- or trans-substituted pyranyl ketones with high diastereoselectivity and yield involves a Lewis acid-promoted O —> C rearrangement (Scheme 19) <00JCS(P1)2385>. Under similar conditions, homoallylic ethers 30 ring open and the oxonium ions then recyclise to new pyran derivatives 31. Whilst the product is a mixture of alkene isomers, catalytic hydrogenation occurs with excellent diastereoselectivity (Scheme 20) <00JCS(P1)1829>. 

Other functional groups which have a heteroatom rather than a hydroxyl group capable of directing the hydrogenation include alkoxyl, alkoxycarbonyl, carboxylate, amide, carbamate, and sulfoxide. The alkoxy unit efficiently coordinates to cationic iridium or rhodium complexes, and high diastereoselectivity is induced in the reactions of cyclic substrates (Table 21.3, entries 11-13) [25, 28]. An acetal affords much lower selectivity than the corresponding unsaturated ketone (Table 21.3, entries 14 and 15) [25]. 

In the hydrogenation of cyclic / -keto esters (ketones substituted with an al-koxycarbonyl moiety), Ru(II)-binap reduced a racemic substrate in DCM with high anti-diastereoselectivity to give a 99 1 mixture of the trans-hydroxy ester (92% ee) and the ds-hydroxy ester (92% ee), quantitatively [Eq. (18)] [119, 120]. 

The hydrogenation of a-amino ketones was also a key step for the synthesis of three more pharma actives (Fig. 37.25). Roche [95] divulged a pilot process involving the hydrogenation/dynamic kinetic resolution of a cyclic a-amino ketone using an optimized MeO-biphep ligand. The Ru-catalyzed reaction was carried out on a 9-kg scale with excellent enantio- and diastereoselectivities, and very... 

The reduction of a-hydroxy ketones 43 to 1,2-diols 44 was achieved in good yield and high diastereoselectivity in favour of the anti product by using ClsSiH and photolytic conditions [56]. In the proposed mechanism of Scheme 5.8, the addition proceeded via the intermediate adduct 45, which participated in the stereo-controlled hydrogen donation, and via the a-silylether 46, affording 1,2-diols in a preferential anti conformation. 

A study of the alkylation of the trimethylsilyl enol ether of octahydro-1 (2//)-naphthalenone reveals that the diastereoselectivity of the reaction is similar to that of the methylation of the corresponding lithium enolate (see Section 1.1.1.3.1.1.2 1.)89. Lewis acid cataly2ed phenyl-thioalkylations of the type indicated (i.e., 3 -> 4) have been used for a-alkylations of several cyclic and acyclic ketones, as well as aldehydes89. The easy removal of the phenylthio group by catalytic hydrogenation completes this convenient procedure for a-alkylation of carbonyl compounds89. 

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