Enantioselective decarboxylative protonation

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

Conformational studies revealed numerous minima in the 15 kcal/mol range. Mechanistic studies were performed with the conformer with si/n-orientation of the N-H groups (relative free energy with respect to the conformational minimum 3.06 kcal/mol), since the simultaneous availability of two hydrogen bond donor N-H groups implies more effective substrate binding. 

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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... 

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. 

Scheme 3.2 First enantioselective decarboxylative protonation under thermal conditions...

Scheme 3.3 Pioneering works in enantioselective decarboxylative protonation...

Scheme 3.4 Enantioselective, decarboxylative protonation of 3-ketoacid in tetralone series...

Scheme 3.5 Enantioselective decarboxylative protonation of 2-hydroxymethyl-2-methyl hemimalonate...

Scheme 3.7 Enantioselective decarboxylative protonation of 2-cyano-2-phenylpropionic add...

Scheme 3.8 Enantioselective decarboxylative protonation of iV-acetylaminomalonic acid...

The enantioselective decarboxylative protonation of aminomalonic acid derivatives has been also extensively investigated by Rouden et al. [17]. Their first contribution in this area aimed at preparing enantioenriched pipecoUc esters by decarboxylation of A7-acetyl piperidinohemimalonate 24 [17]. Among the different cinchona alkaloids investigated, the best result was obtained by means of 9-ep/-cinchonine-benzamide 19b, previously developed by Brunner [14, 16]. Pipecolic ester 25 was obtained in up to 52% ee when conducting the reaction in THF at room temperature for 24 h. Various bis-cinchona alkaloids such as (DHQDj AQN 26 or (DHQDj Pyr 27 were also evaluated providing modest enantiomeric excesses not exceeding 24% ee. Most of the results outlined in this study were obtained in the presence of a stoichiometric amount of the chiral base. The few attempts to carry out experiments under catalytic conditions seem to... 

Scheme 3.9 General catalytic pathway for the enantioselective decarboxylative protonation of malonates cateilyzed by a chiral Br0nsted base (B )...

Scheme 3.10 Enantioselective decarboxylative protonation of iV-acetyl piperidinohemimalonate...

Scheme 3.11 Enantioselective decarboxylative protonation of iV-benzoyl substituted piperidinohemimalonates...

A further important advance was also achieved by Rouden et al. [17] who developed the use of thiourea cinchona alkaloids 33-34 in the enantioselective decarboxylative protonation of a-aminomalonates (Scheme 3.12). The basic idea in using these bifunctional catalysts was to take advantage of the good hydrogen-bond donor properties of the thiourea moiety to promote further interactions between the chiral proton source and the prochiral enolate intermediate. Bifunctional catalyst 33 in quinidine series turned out to be especially efficient with a large range of substrates... 

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