Catalytic Enantioselective Diels-Alder Reactions Chwee T.S 1 and Wong M.W 2

Transcription

1 Catalytic Enantioselective Diels-Alder Reactions Chwee T.S 1 and Wong M.W 2 Department of Chemistry,Faculty of Science, National University of Singapore 10 Kent Ridge Road, Singapore Abstract Theoretical studies were performed on B 3,BF 3 and BLA acting as catalysts in the [4+2] cycloaddition reaction of cyclopentadiene and methacrolein. All three catalysts are effective in catalyzing the reaction by lowering the LUM energy of the dienophile. BLA, in particular, is an enantioselective catalyst specifically designed for α-substituted dienophiles. The enantioselectivity of the catalyst could be understood from the transition state assembly, proposed separately by Corey and Yamamoto and calculations show that Corey s model leads to an energetically preferred pathway. Introduction: In the hierarchy of carbon-carbon bond construction, the Diels-Alder reaction has attained a preeminent position. This cycloaddition process allows for the stereoselective formation of cyclohexene rings possessing as many as four stereogenic centers.the reaction facilitates the rapid development of molecular complexity and has been duly exploited in organic synthesis and hence the search for enantioselective variants of this process has captured the attention of numerous researchers. Although chiral auxiliarybased reactions retain a position of central importance, complementary catalytic variants are developing rapidly. Among these, Lewis acid that selectively activate one component while providing a stereo-defined environment are being used as effective catalysts. The Bronsted acid is essential for both the high reactivity of the Lewis acid and the high enantioselectivity. A theoretical study was performed to investigate the effect of Lewis acid on the rate and enantioselectivity of Diels-Alder reactions. Method: Initial structures were generated and optimized using Spartan 5.0 while Gaussian 98 was used for all subsequent calculations. Transition structures were characterized by an imaginary vibrational mode that corresponds to the C-C bond forming process. The Diels-Alder reaction were examined by four levels of theory: AM1,F/ST-3G,F/3-21G and B3LYP/6-31G*//F/3-21G. The latest corresponds to the best level of theory in this study. Results: + B 3 BF 3 *BLA Cyclopenta-1,3-diene C 3 s-cis methacrolein *Exo-product is formed exclusively

2 Uncatalyzed Diels-Alder Reaction between Cyclopentadiene and methacrolein Transition state AM1 ST-3G 3-21G F3-21G//B3LYP6-31G* 1 S-cis-exo transition state Activation 2 S-cis-endo transition state Activation 3 S-trans-exo transition state Activation 4 S-trans endo transition state Activation Catalyzed Diels Alder Reaction between Cyclopentadiene and methacrolein by B 3 and BF 3 B 3 -s-trans-methacrolein (exotransition energy/kjmol -1 B 3 -s-trans-methacrolein (endo-transition (a)b 3 -s-cis-methacrolein (exotransition B 3 -s-cis-methacrolein (endotransition state Activation energy/kjmol =1 BF 3 -s-trans-methacrolein (exotransition (b)bf 3 -s-trans-methacrolein (endo-transition BF 3 -s-cis-methacrolein (exotransition BF 3 -s-cis-methacrolein (endotransition AM1 ST-3G 3-21G B3LYP 6-31G*//F-321G

3 3 B BLA complexed with methacrolein Complexation Energy AM1 ST-3G/ kjmol G/kJmol -1 B3LYP 6-31G*/kJmol -1 (c)bla Yamamoto s s- trans//kjmol -1 BLA + Yamamoto s s-cis//kjmol BLA + Corey s s- trans (d)bla + Corey s s-cis (a) (b) Bronstedacid assisted Lewis acid BLA Lewis Acid F 3 B Bronsted Acid B C3 B C 3 (c) (d) Energy AM1/hartree ST-3G/hartree 3-21G/hartree B3LYP 631G*//F 3-21G/hartree Yamamoto s s-trans Activation Corey s s-cis Activation Energy/kJmol -1 Activation Energy = Yamamoto s s-trans transition state Corey s s-cis complex Yamamoto s s- trans complex Corey s s-cis transition state Activation energy = Reaction Coordinate

4 Discussion In this study, catalysis by Lewis acids in the Diels-Alders reaction has led to two primary effects, namely, increased rate of reaction and asynchronicity in the concerted reaction. The increase in rate is due to the lowering of the LUM energy of the dienophie firstly from conjugation and further from the allyl-like character of the dienophile which is enhanced by coordination to the Lewis acid. The asynchronicity of the reaction is exemplified in the transition state where the two C-C bond forming distance differs considerably. This can be understood from the effect of Lewis acid on the orbital coefficients of the LUM. The increased orbital coefficients on the β-carbon causes one C-C bond formation to be more advanced than the other leading to asynchronicity and in extreme cases, intermediates can be isolated. The ability of B 3, BF 3 and BLA to function as catalyst are evidenced by the lowered activation energy of all the reactions compared to the uncatalyzed one and in particular, BLA, is an enantioselective catalyst that specifically forms the exo-enantiomer, Formyl hydrogen bonding, pi stacking and steric screening serve to organize the substrate bounded to the catalyst. The complex first formed between methacrolein and BLA favours the prelude to the transition state proposed by Yamamoto. owever, the calculated transition state shows that Corey s proposed model is lower in energy. The combined effects suggest that the pathway leading to Corey s transition state assembly is the preferred route to the formation of the enantiomer. Acknowledgements I am especially indebted to A/P Richard Wong Ming Wah for offering me the opportunity to work on this project and his constant supervision despite his very tight schedule. References: ethylene butadiene Allyl cation 1. Corey,E.J,;Rohde,J.J Tetrahedron Letters,1997,Vol.38, Corey,E.J;Rohde J.J;Fischer;Azimioara,Tetrahedron Letters,1997,Vol 38, Ishihara,K;Yamamoto,. J.Am.Chem.Soc,1994,116, Ishihara,K;Kurihara,;Yamamoto,. J.Am.Chem.Soc,1994,116, R.Noyori,Asymmetric Catalysis in rganic Synthesis,Wiley,New York,1994;Catalytic Asymmetric Synthesis,Wiley,VC, New York, Gaussian 98,Revision A.11, M,J. Frish et al

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