Decarboxylation Krapcho

Nucleophilic decarboxylation of (3-ketoesters, malonate esters, a-cyanoesters, or a-sulfonylesters. 

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Chloride is a poor nucleophile, but it is more reactive in DMSO by which it cannot be solvated. And, as soon as the carboxylate is substituted, the high temperature encourages (entropy again) irreversible decarboxylation, and the other by-product, MeCl, is also lost as a gas. The decarboxylation (in fact, removal of a C02Me group, not CO2) is known as the Krapcho decarboxylation. Because of the S 2 step, it works best with methyl malonate esters. 

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 first enantioselective formal total synthesis of paeonilactone A was reported by J.E. Backvall who used a palladium(ll)-catalyzed 1,4-oxylactonization of a conjugated diene as the key step. The lactonization precursor diene acid was obtained from an enantiopure dimethyl malonate derivative via sequential Krapcho decarboxylation and ester hydrolysis. 

The Krapcho decarboxylation is the nucleophilic decarboxylation of malonate esters, p-ketoesters, a-cyanoesters, a-sulfonylesters, and related compounds. The reaction is done in dipolar aprotic solvents in the presence of salt and/or water at high temperatures.1... 

The Krapcho decarboxylation has found wide application in organic synthesis.8-11 Its primary utility has been to convert malonate or acetoacetate derivatives to the corresponding carbonyls.12-16 As malonates have found tremendous use in many areas of synthesis, the Krapcho has also found wide utility. 

The Krapcho decarboxylation was also utilized as a beneficial side reaction in the key step in the Deslongchamps synthesis of (+)-maritimol.18 In this asymmetric synthesis, the Lewis acid mediated intramolecular Diels-Alder reaction of 11 to produce 12 was followed by thermal decarboxylation to yield 13. The thermal Diels-Alder reaction of 11 was then tested and found to proceed in slightly higher yield and resulted in decarboxylation occurring in the same pot. Remarkably, the complete diastereo- and enantiocontrol in this reaction is directed by the remote nitrile stereocenter. Additional... 

A second methodology relies on the use of unsaturated malonates as electrophiles in conjugate addition reactions, thus necessitating removal of the ancillary ester group. Enders and co-workers24 have shown a general method for preparation of semialdehyde derivatives, such as 40, which utilized the Krapcho decarboxylation reaction. In this case, conjugate addition of SAMP-hydrazone 36 proceeded with excellent selectivity to... 

Malonate and related activated methylene compounds have also been used as the nucleophile in conjugate addition/Michael reactions. Taylor and co-workers have developed a new methodology that utilizes (salen)aluminum complexes such as 43 as a catalyst to effect the enantioselective conjugate addition to a,p-unsaturated ketones by a variety of nucleophiles.25 For example, nitriles, nitroalkanes, hydrazoic acids, and azides have found utility in this reaction. Additionally, cyanoacetate (42) has been demonstrated to undergo a highly enantioselective conjugate addition to 41. The Krapcho decarboxylation is then necessary to produce cyanoketone 44, an intermediate in the synthesis of enantioenriched 2,4-cw-di substituted piperidine 45. 

Activated methylene compounds such as dimethyl malonate have found substantial utility in palladium catalyzed allylic substitution reactions. Accordingly, the Krapcho decarboxylation is often used in conjunction with these reactions. As an example, the first total synthesis of enantiomerically pure (-)-wine lactone has utilized the sequence of reactions.27 First, the allylic substitution reaction of 2-cyclohexen-l-yl acetate (49) with alkali sodium dimethylmalonate yielded 51 with high enantioselectivity, as a result of the use of chiral phosphine ligand 50. The malonate was then subjected to Krapcho decarbomethoxylation using NaCl, H2O, and DMSO at 160 °C to yield 52. This reaction has been used similarly following the allylic substitution reaction with other malonate derivatives.28-30... 

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