Keto esters, total synthesis, asymmetric

C.H. Heathcock and co-workers devised a highly convergent asymmetric total synthesis of (-)-secodaphniphylline, where the key step was a mixed Claisen condensation. In the final stage of the total synthesis, the two major fragments were coupled using the mixed Claisen condensation] the lithium enolate of (-)-methyl homosecodaphniphyllate was reacted with the 2,8-dioxabicyclo[3.2.1]octane acid chloride. The resulting crude mixture of (3-keto esters was subjected to the Krapcho decarboxylation procedure to afford the natural product in 43% yield for two steps. 

A highly exo-selective asymmetric hetero Diels-Alder reaction was the key step in D.A. Evans total synthesis of (-)-epibatidine. The bicyclic cycloadduct was then subjected to a fluoride-promoted fragmentation that afforded a (f-keto ester, which was isolated exclusively as its enol tautomer. The removal of the ethoxycarbonyl functionality was achieved using the Krapcho decarboxylation. Interestingly, the presence of a metal salt was not necessary in this transformation. Simply heating the substrate in wet DMSO gave rise to the decarboxylated product in quantitative yield. 

A general synthetic route toward the marine metabolite eunicellin diterpenes was developed by G.A. Molander and co-workers.The power of this method was demonstrated by the completion of the asymmetric total synthesis of deacetoxyalcyonin acetate. A tricyclic (3-keto ester intermediate was methylated in the y-position with complete diastereoselectivity using dianion chemistry and the crude product was subjected to the Krapcho decarboxylation. This was one of the rare cases when the transformation did not only remove the methoxycarbonyl group, but at the same time epimerized the newly formed stereocenter to yield a separable mixture of methyl ketones. 

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. 

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). 

Moreover, the protocol could be used for a vinylogous Mukaiyama aldol addition and offered a solution to the problem of the asymmetric acetoacetate aldol reaction. Thus, 2 mol% of the catalyst 198 is enough to promote the addition of silyl dienolate 214 to various aldehydes to give, after desilylation, O-protected P-keto-5-hydroxy esters [113]. The protocol is illustrated for an addition to P-stannylpropenal 213. Depending on the enantiomer of the catalyst 198 or ent-198 chosen to mediate the aldol addition, enantiomeric products 215 and ent-215 were obtained in 92% ee. In an elegant convergent total synthesis, both enantiomers were incorporated into macrolactin A, as shown in Scheme 5.65 [114,115]. 

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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