Final Report Summary - ISOCAT (Developing chiral isothioureas as asymmetric organocatalysts; synthesis, catalysis and mechanistic investigations)
Nucleophilic or Lewis-base catalysis encompasses a multitude of different catalyst types and reactions, and this area has been extensively reviewed (1). Despite intense interest within this field, there still exists a need to develop practical and efficient catalytic methodology that is capable of the stereocontrolled construction of carbon-carbon or carbon-heteroatom bonds, essential for the rapid assembly of complex molecules with biological and chemical value. Over the last 10 years there has been a huge increase in development and applications of organocatalysis in which the catalyst acts as a nucleophile. Amidines and guanidines and related isothiourea catalysts are often only thought of as strong organic bases, however, a number of small molecules containing basic functional groups have been shown to act as efficient nucleophilic catalysts. The structural diversity of accessable nucelophilic catalysts based on these motifs, including those containing stereocentres, makes these catalysts applicable to a wide range of achiral and stereoselective reactions. Within the literature, isothioureas and amidine derivatives have been used widely for asymmetric acyl transfer processes to alcohol and amines (2). However, applications of these catalyst architectures to the generation of ammonium enolates, typically formed from the interaction of a nucleophilic tertiary amine with ketenes (3) are extremely limited. An alternative but synthetically appealing strategy utilising the in situ organocatalytic generation of enolates directly from carboxylic acids has received little attention to date. In this area, Romo has elegantly shown that aldehyde- and keto-acids undergo intramolecular cyclisation using either cinchona alkaloids, 4-pyrrolidinylpyridine or homobenzotetramisole as the Lewis base promoter, giving the corresponding cyclic lactones in good yields and stereoselectivities (4). Building upon these precedents and focus on the central concept behind our research programme, isothioureas as catalysts in synthesis and their use as state of the art Lewis-bases in terms of catalytic efficiency and product enantioselectivity, we first prepared a range of enantiomerically pure, but stereochemically diverse, isothioureas. Established literature procedures were used to access the desired isothioureas, easily prepared from readily available enantiomerically pure materials (5). The effect of skeletal and stereochemical modification to the catalyst core upon catalyst efficiency and enantioselectivity was evaluated for direct generation of an isothiouronium enolates, from carboxylates, and their ability to catalyse the intramolecular subsequent intramolecular Michael cyclisation (6).
A range of enone-acid substrates were prepared as the Michael acceptors to afford indene and dihydrobenzofuran carboxylates after derivatisation. Tetramisole hydrochloride 4 proved a competent enantioselective precatalyst for the transformation, giving polycyclic lactones 2 with excellent diastereo- and enantiocontrol (13 examples; up to 95:5 dr and 97 % ee) (7). Screening of temperature, solvent effects and activating agent were also studied to allow correlation between enantioselectivity and catalyst structure, leading to maximise catalyst efficiency.
During the following months, the generality of this domino Michael addition-lactonisation process was also examined. Utilising the optimised conditions, the protocol allowed the incorporation of alkyl and both electronwithdrawing and -donating aryl substituents within the enone, substitution of the aromatic tether, as well as the use of aliphatic substrates, giving the desired polycyclic products in good yield with high dr.
Subsequent studies demonstrated the first asymmetric intermolecular version of this reaction process using isothiourea 5, transforming phenylacetic acid and beta,gamma-unsaturated-keto-esters 7 into lactones 8 in 72 % yield and 96 % ee.
To the best of our knowledge, these preliminary results represented the first time that a non-stoichiometric quantity of an isothiourea has been used in an asymmetric C-C bondforming reaction proceeding via an in situ generated ammonium enolate involving carboxylic acids. It offers huge potential for generating structurally diverse functionalised building blocks in a catalytic asymmetric fashion directly from readily available carboxylic acid starting materials. Building upon these promising preliminary results, new studies aimed to further the scope and generality of this intermolecular Michael addition-lactonisation process. Structural variation within the acid component and the nature of the acceptor functionality varied giving giving the lactones 8 with excellent diastereo- and enantiocontrol (21 examples; up to 98:2 dr and 97 % ee) (7).
The further application of this methodology to prepare dihydropyridones through Michael addition-lactonisation utilising aza-analogues were investigated. To date, the only intermolecular process using this strategy requires alpha-keto-beta, gamma unsaturated esters as the Michael acceptor, with chalcones being unreactive. To build upon this work, we envisaged that the electron-withdrawing N-sulfonyl group within N-tosyl-alpha, beta-unsaturated ketimine derivatives would facilitate intermolecular organocatalytic Michael / lactamisation, thus furnishing stereodefined dihydropyridones from arylacetic acids under isothiourea-mediated catalysis directly. During the following twelve months of this Intra-European Fellowship (IEF)-funded project, we lead our studies toward this goal and the coupling of this transformation with a new N- to C-sulfonyl photoisomerisation process and other derivatisation procedures for the efficient asymmetric synthesis of polysubstituted dihydropyridones, dihydropyridines, piperidines, and tetrahydropyrans with high stereocontrol (8).
We have completed most of the objectives within the multi-disciplinary research proposal with minor deviations. The optimised catalyst identification and application to numerous heterocyclic templates was achieved. In situ generation of isothiouronium enolates, from carboxylates succeeded, and subsequent intramolecular and intermolecular asymmetric organocatalytic reaction allowed a range of enantioenriched carbo- and heterocycles. Current research is directed toward the development of alternative uses of isothioureas and other Lewis bases in asymmetric catalysis and their corresponding mechanistic studies.
References:
(1) (a) S. E. Denmark, G. L. Beutner, Angew. Chem., Int. Ed., 2008, 47, 1560; (b) J. E. Taylor, S. D. Bull, J. M. J. Williams Chem. Rev. Soc. 2012, 41, 2109.
(2) For representative examples see V. B. Birman, E. W. Uffman, H. Jiang, X. Li, C. J. Kilbane, J. Am. Chem. Soc. 2004, 126, 12226; Y. Zhang, V. B. Birman, Adv. Synth. Catal. 2009, 351, 2525.
(3) For a review of the chemistry and reactivity of enolates derived from ketenes see D. H. Paull, A. Weatherwax, T. Lectka, Tetrahedron 2009, 65, 6771; (a) H. Wynberg, E. G. J. Staring J. Am. Chem. Soc. 1982, 104, 166; (b) S. France, A. Weatherwax, A. E. Taggi, T. Lectka Acc. Chem. Res. 2004, 37, 592; (c) G. C. Fu Acc. Chem. Res. 2004, 37, 542; (d) M. Dochnahl, G. C. Fu Angew. Chem., Int. Ed. 2009, 48, 2391.
(4) (a) G. S. Cortez, R. L.Tennyson D. Romo J. Am. Chem. Soc. 2001, 123, 7945; (b) V. C. Purohit, A. S. Matla, D. Romo J. Am. Chem. Soc. 2008, 130, 10478; (c) H. Nguyen, G. Ma, D. Romo Chem. Commun 2010, 46, 4803; (d) C. A. Leverett, V. C.; Purohit, D. Romo Angew. Chem., Int. Ed. 2010, 49, 9479.
(5) A range of enantiomerically pure beta-3-amino acids are commercially available that are readily reduced to give 3-substituted gamma-amino alcohols; beta-2-amino acids are readily available following the work of Gellman - see Y. Chi, E. P. English, W. C. Pomerantz, W. S. Horne, L. A. Joyce, L. R. Alexander, W. S. Fleming, E. A. Hopkins and S. H. Gellman, J. Am. Chem. Soc. 2007, 129, 6050; J. W. Yang, M. Stadler and B. List, Nature Protocols 2007, 2, 1937.
(6) Related intramolecular Michael addition-lactonization processes using NHCs to generate enolates from enals have been reported: (a) E. M. Phillips, M. Wadamoto, A. Chan, K. A. Scheidt Angew. Chem., Int. Ed. 2007, 46, 3107; (b) Y. Li, X.-Q. Wang, C. Zheng, S.-L. You Chem. Commun. 2009, 5823.
(7) D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin, A. D. Smith J. Am. Chem. Soc. 2011, 133, 2714.
(8) C. Simal, T. Lebl, A. M. Z. Slawin, A. D. Smith Angew. Chem., Int. Ed. 2012, 51, 3653.
A range of enone-acid substrates were prepared as the Michael acceptors to afford indene and dihydrobenzofuran carboxylates after derivatisation. Tetramisole hydrochloride 4 proved a competent enantioselective precatalyst for the transformation, giving polycyclic lactones 2 with excellent diastereo- and enantiocontrol (13 examples; up to 95:5 dr and 97 % ee) (7). Screening of temperature, solvent effects and activating agent were also studied to allow correlation between enantioselectivity and catalyst structure, leading to maximise catalyst efficiency.
During the following months, the generality of this domino Michael addition-lactonisation process was also examined. Utilising the optimised conditions, the protocol allowed the incorporation of alkyl and both electronwithdrawing and -donating aryl substituents within the enone, substitution of the aromatic tether, as well as the use of aliphatic substrates, giving the desired polycyclic products in good yield with high dr.
Subsequent studies demonstrated the first asymmetric intermolecular version of this reaction process using isothiourea 5, transforming phenylacetic acid and beta,gamma-unsaturated-keto-esters 7 into lactones 8 in 72 % yield and 96 % ee.
To the best of our knowledge, these preliminary results represented the first time that a non-stoichiometric quantity of an isothiourea has been used in an asymmetric C-C bondforming reaction proceeding via an in situ generated ammonium enolate involving carboxylic acids. It offers huge potential for generating structurally diverse functionalised building blocks in a catalytic asymmetric fashion directly from readily available carboxylic acid starting materials. Building upon these promising preliminary results, new studies aimed to further the scope and generality of this intermolecular Michael addition-lactonisation process. Structural variation within the acid component and the nature of the acceptor functionality varied giving giving the lactones 8 with excellent diastereo- and enantiocontrol (21 examples; up to 98:2 dr and 97 % ee) (7).
The further application of this methodology to prepare dihydropyridones through Michael addition-lactonisation utilising aza-analogues were investigated. To date, the only intermolecular process using this strategy requires alpha-keto-beta, gamma unsaturated esters as the Michael acceptor, with chalcones being unreactive. To build upon this work, we envisaged that the electron-withdrawing N-sulfonyl group within N-tosyl-alpha, beta-unsaturated ketimine derivatives would facilitate intermolecular organocatalytic Michael / lactamisation, thus furnishing stereodefined dihydropyridones from arylacetic acids under isothiourea-mediated catalysis directly. During the following twelve months of this Intra-European Fellowship (IEF)-funded project, we lead our studies toward this goal and the coupling of this transformation with a new N- to C-sulfonyl photoisomerisation process and other derivatisation procedures for the efficient asymmetric synthesis of polysubstituted dihydropyridones, dihydropyridines, piperidines, and tetrahydropyrans with high stereocontrol (8).
We have completed most of the objectives within the multi-disciplinary research proposal with minor deviations. The optimised catalyst identification and application to numerous heterocyclic templates was achieved. In situ generation of isothiouronium enolates, from carboxylates succeeded, and subsequent intramolecular and intermolecular asymmetric organocatalytic reaction allowed a range of enantioenriched carbo- and heterocycles. Current research is directed toward the development of alternative uses of isothioureas and other Lewis bases in asymmetric catalysis and their corresponding mechanistic studies.
References:
(1) (a) S. E. Denmark, G. L. Beutner, Angew. Chem., Int. Ed., 2008, 47, 1560; (b) J. E. Taylor, S. D. Bull, J. M. J. Williams Chem. Rev. Soc. 2012, 41, 2109.
(2) For representative examples see V. B. Birman, E. W. Uffman, H. Jiang, X. Li, C. J. Kilbane, J. Am. Chem. Soc. 2004, 126, 12226; Y. Zhang, V. B. Birman, Adv. Synth. Catal. 2009, 351, 2525.
(3) For a review of the chemistry and reactivity of enolates derived from ketenes see D. H. Paull, A. Weatherwax, T. Lectka, Tetrahedron 2009, 65, 6771; (a) H. Wynberg, E. G. J. Staring J. Am. Chem. Soc. 1982, 104, 166; (b) S. France, A. Weatherwax, A. E. Taggi, T. Lectka Acc. Chem. Res. 2004, 37, 592; (c) G. C. Fu Acc. Chem. Res. 2004, 37, 542; (d) M. Dochnahl, G. C. Fu Angew. Chem., Int. Ed. 2009, 48, 2391.
(4) (a) G. S. Cortez, R. L.Tennyson D. Romo J. Am. Chem. Soc. 2001, 123, 7945; (b) V. C. Purohit, A. S. Matla, D. Romo J. Am. Chem. Soc. 2008, 130, 10478; (c) H. Nguyen, G. Ma, D. Romo Chem. Commun 2010, 46, 4803; (d) C. A. Leverett, V. C.; Purohit, D. Romo Angew. Chem., Int. Ed. 2010, 49, 9479.
(5) A range of enantiomerically pure beta-3-amino acids are commercially available that are readily reduced to give 3-substituted gamma-amino alcohols; beta-2-amino acids are readily available following the work of Gellman - see Y. Chi, E. P. English, W. C. Pomerantz, W. S. Horne, L. A. Joyce, L. R. Alexander, W. S. Fleming, E. A. Hopkins and S. H. Gellman, J. Am. Chem. Soc. 2007, 129, 6050; J. W. Yang, M. Stadler and B. List, Nature Protocols 2007, 2, 1937.
(6) Related intramolecular Michael addition-lactonization processes using NHCs to generate enolates from enals have been reported: (a) E. M. Phillips, M. Wadamoto, A. Chan, K. A. Scheidt Angew. Chem., Int. Ed. 2007, 46, 3107; (b) Y. Li, X.-Q. Wang, C. Zheng, S.-L. You Chem. Commun. 2009, 5823.
(7) D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin, A. D. Smith J. Am. Chem. Soc. 2011, 133, 2714.
(8) C. Simal, T. Lebl, A. M. Z. Slawin, A. D. Smith Angew. Chem., Int. Ed. 2012, 51, 3653.