Hydrogenation keto esters, total synthesis

Rychnovsky and his group have recently developed new synthetic methods that lead to the total syntheses of the polyene macrolides roxaticin [2], roflamycoin [3], and filipin III [4]. The polyol chains of all three natural products were constructed by iterative, stereoselective alkylation of lithiated cyanohydrin acetonides and subsequent reductive decyanation, illustrated here by the synthesis of the polyol framework of filipin III (1) (Scheme I). The bifunctional cyanohydrin acetonide 2, prepared by ruthenium/BINAP catalyzed enantioselective hydrogenation of the corresponding ) -keto ester (BINAP = [ 1,1 -binaphthyl]-2,2 -diylbis(diphenylphosphane)), is deprotonated with LiNEt2 and alkylated with 2-benzyloxy-l-iodoethane. The alkylation product 3 is converted by a Finkelstein reaction into the iodide 4, which is used to alkylate a second... 

The total synthesis of pentacyclic alkaloid (-)-haliclonadiamine was accomplished by D.F. Taber and co-workers. The Noyori asymmetric hydrogenation was used to prepare a bicyclic 3-hydroxy ester intermediate in enantiopure form from a racemic bicyclic P-keto ester via kinetic resolution. It was found that the hydrogenation only took place in the presence of added HCI and by optimizing the amount of HCI added, the proportion of the total reduced ketone could be controlled. About 87% of the "matched" ketone was reduced, while the other P-keto ester enantiomer was not significantly converted to the reduced product. Interestingly, the diastereoselectivity of the hydrogenation depended on the nature of the added acid with HCI, the trans diastereomer was the major product, while with AcOH the cis diastereomer was dominant. 

The third total synthesis of luciduline has been reported and is outlined in Scheme 2. The starting material is the same keto-nitrile (16) used in Heath-cock s lycopodine synthesis described above. Treatment of (16) with methanolic sodium hydroxide led directly to a mixture of the cis-lactam (31) and the corresponding tran -isomer (ratio 5 1). Condensation of (31) with ethyl tri-methylsilylacetate furnished the unsaturated ester (32), which was N-methylated to (33). Catalytic hydrogenation of (33) provided a 1 1 mixture of (34) and its C-5... 

As an extension of this work, a total synthesis of sulfobacin A, a von Willebrand factor receptor antagonist, was reported by the same group, in 2004. The key steps of this short route to sulfobacin A involved ruthenium-catalysed asymmetric hydrogenation reactions of a /i-ketoester and a /J-keto-a-amino ester hydrochloride to afford, respectively, the corresponding enantiomerically pure S-hydroxy ester and the enantio-enriched anti -hydroxy-a-amino ester hydrochloride through DKRs (Scheme 2.15). 

Asymmetric Hydrogenation of Keto Esters in the Total Synthesis Statins ° are effective inhibitors of 3-... 

Dolastatin 10 is a natural, cytotoxic antimitotic peptide with microtubule-inhibitory and apoptotic effects, isolated from the sea hare Dolabella auricularia. It has demonstrated in vitro and in vivo efficacy in the DU-145 human prostate cancer model. " Ratoveloma-nana-Vidal and Genet and co-workers proposed a total synthesis of dolastatin 10, where the three stereogenic centers were created by Ru(II)-catalyzed asymmetric hydrogenations of p-keto esters The reduction of P-keto ester 121 was accomplished with in situ generated [RuBr2(5)-SYNPHOS)] (1 mol%) as a catalyst under 12 bar hydrogen and at 50°C in EtOH. After 24 hours, it was achieved with complete conversion and good diastereoselectivity (3R) (3S) = 98 2. 

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