Decarboxylative protonation

The Rouden group utilized 121 and 124 as organic bases for the asymmetric decarboxylative protonation of cyclic, acyclic, and bicyclic N-acylated a-amino hemimalonates [290]. The introduced protocol suffered from high catalyst loading... 

Scheme 6.135 Typical products obtained from the 121- and 124-catalyzed asymmetric decarboxylative protonation of N-acylated a-amino hemimalonates.

A novel system for the enantioconvergent decarboxylative protonation of racemic /3-kclo esters has been developed.48 The reaction tolerates a variety of substitution and functionality and delivers products of high enantiopurity in excellent yield. The enan-tioinduction in the observed protonated products is consistent with the intermediacy of an enolate that is intimately associated with a chiral Pd complex. 

This addition is followed by the decarboxylation of pyruvate. The positively charged ring of TPP acts as an electron sink that stabilizes the negative charge that is transferred to the ring as part of the decarboxylation. Protonation yields hydroxy ethyl-TPP. 

Scheme 7.18 Proposed mechanisms of enantioseiective decarboxylative protonation.

The enantioselective decarboxylative protonation, which is directly related to the venerable malonic add synthesis, has not shown the major advances in terms of selectivity that we could have expected for the oldest methodology used to carry out enantioselective protonations (Marckwald, 1904). The use of this reaction and, in particular, of its organocatalyzed version for the synthesis of compounds of biological significance is now emerging. This highlights the synthetic potential of this low-cost and operationally simple reaction, notably in the context of sustainable chemistry. However, this asymmetric reaction is not yet mature. Further investigations... 

Formation of chiral a-amino acids from aminomalonic acids via decarboxylative protonation is readily accomplished in the presence of thiourea 1 (ex quinidine)/ The diaster-eomeric 2 (ex quinine) has been employed to generate monomethyl esters in chiral form by methanolysis meso-cydic anhydrides ... 

Interestingly, the sense of stereoinduction (S) observed following decarboxylative protonation is opposite to that observed in our previous report, using Meldrum s acid as the BU source, with isoflavanone substrates without oxygenation at the 7-position of type 3 (Scheme 5.1). Intrigued by this finding, we reinvestigated... 

Following the previous successful application of the asymmetric decarboxylative protonation reaction in the catalytic asymmetric synthesis of isoflavanones we hoped to expand the scope of this work to the catalytic asymmetric synthesis of tertiary a-aryl cyclohexanones and, in particular, cyclopentanones given the dearth of reported methods for their direct asymmetric synthesis to date (see Sect. 4.6). 

General Procedure for the Racemic Decarboxylative Protonation Reaction (7 and 24)... 

The same catalyst 14 was found to promote enantioselective decarboxylative protonation reaction. Recent computational study used DFT/PM3... 

Scheme 3.25 Hybrid thiourea-cinchona-catalyzed asymmetric decarboxylative protonation. (Data from Blanchet, J. et al., Eur. ]. Org. Chem., 5493,2008.)...

Amere, M. Lasne, M. C. Rouden, J. Highly Enantioselective Decarboxylative Protonation of a-Aminomalonates Mediated by Thiourea Cinchona Alkaloid Derivatives Access to Both Enantiomers of Cyclic and Acyclic a-Aminoacids. Org. Lett. 2007, 9, 2621. 

Sengupta, A. Sunoj, R. B. Mechanistic Insights on Organocatalytic Enantioselective Decarboxylative Protonation by Epicinchona-Thiourea Hybrid Derivatives. J. Org. Chem. 2012,77,10525-10536. 

SCHEME 31.1. Marckwald s first enantioselective decarboxylative protonation and Duhamel and Plaquevent s enantioselective lithium enolate protonation. 

Blanche J, Baudoux J, Amere M, Fasne MC, Rouden J. Asymmetric malonic and acetoacetic acid s3mtheses-A century of enantioselective decarboxylative protonations. Eur. J. Org. Chem. 2008 5493-5506. 

Amere M, Lasne MC, Rouden J. Highly enantioselective decarboxylative protonation of a-aminomalonates mediated by thiourea cinchona alkaloid derivatives access to both enantiomers of cyclic and acyclic a-aminoacids. Org. Lett. 2007 9 2621-2624. 

Marinescu SC, Nishimata T, Mohr JT, Stoltz BM. Homogeneous Pd-catalyzed enantioselective decarboxylative protonation. Org. Lett. 2008 10 1039-1042. 

Mohr JT, Nishimata T, Beheima DC, Stoltz BM. Catalytic enantioselective decarboxylative protonation. J. Am. Chem. Soc. 2006 128 11348-11349. 

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