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Importance of the Nature of alpha-Substituents in Pyrrolidine Organocatalysts in Asymmetric Michael Additions

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Title Importance of the Nature of alpha-Substituents in Pyrrolidine Organocatalysts in Asymmetric Michael Additions
 
Creator PATIL, MP
SHARMA, AK
SUNOJ, RB
 
Subject density-functional theory
polarizable continuum model
diels-alder reaction
generalized gradient approximation
secondary orbital interactions
ab-initio calculations
aldol reactions
enantioselective organocatalysis
alpha,beta-unsaturated aldehydes
1,4-conjugate addition
 
Description The fundamental factors contributing toward the stereoselectivity in organocatalyzed asymmetric Michael reaction between aldehydes (propanal and 3-phenyl propanal) and methyl vinyl ketone (MVK) are established by using density functional theory methods. Three of the most commonly employed a-substituted pyrrolidine organocatalysts are examined. Several key stereochemical modes of addition between (i) a model enamine or (ii) pyrrolidine enamines derived from aldehydes and secondary amine to MVK are examined. Among these possibilities, the addition of (E)-enamine to cis-MVK is found to have a lower activation barrier. The stereochemical outcome of the reaction is reported on the basis of the relative energies between pertinent diastereomeric transition states. Moderate selectivity is predicted for the reaction involving pyrrolidine catalysts I and II, which carry relatively less bulky alpha-substituents dimethylmethoxymethyl and diphenylmethyl, respectively. On the other hand, high selectivity is computed in the case of catalyst III having a sufficiently large alpha-substituent (diarylmethoxymethyl or diphenylprolinol methyl ether). The enantiomeric excess in the case of 3-phenyl propanal is found to be much higher as compared to that with unsubstituted propanal, suggesting potential for improvement in stereoselectivity by substrate modifications. The computed enantiomeric excess is found to be in reasonable agreement with the reported experimental stereoselectivities. A detailed investigation on the geometries of the crucial transition states reveals that apart from steric interactions between the alpha-substituent and MVK, various other factors such as orbital interactions and weak stabilizing hydrogen-bonding interactions play a vital role in stereoselectivity. The results serve to establish the importance of cumulative effects of various stabilizing and destabilizing interactions at the transition state as responsible for the stereochemical outcome of the reaction. The limitations of commonly employed qualitative propositions, relying on the steric protection of one of the prochiral faces of enamines offered by the bulky alpha-substituent, are presented.
 
Publisher AMER CHEMICAL SOC
 
Date 2011-07-14T07:33:19Z
2011-12-26T12:48:16Z
2011-12-27T05:47:32Z
2011-07-14T07:33:19Z
2011-12-26T12:48:16Z
2011-12-27T05:47:32Z
2010
 
Type Article
 
Identifier JOURNAL OF ORGANIC CHEMISTRY, 75(21), 7310-7321
0022-3263
http://dx.doi.org/10.1021/jo101592b
http://dspace.library.iitb.ac.in/xmlui/handle/10054/3896
http://hdl.handle.net/10054/3896
 
Language en