Organocatalysis uses small organic molecules predominantly composed of C, H, O, N, S and P to accelerate chemical reactions. The advantages of organocatalysts include their lack of sensitivity to moisture and oxygen, their ready availability, low cost, and low toxicity, which confers a huge direct benefit in the production of pharmaceutical intermediates when compared with (transition) metal catalysts.
In the example of the Knoevenagel Condensation, it is believed that piperidine forms a reactive iminium ion intermediate with the carbonyl compound:
Another organocatalyst is DMAP, which acts as an acyl transfer agent:
Thiazolium salts are versatile umpolung reagents (acyl anion equivalents), for example finding application in the Stetter Reaction:
All of these organocatalysts are able to form temporary covalent bonds. Other catalysts can form H-bonds, or engage in pi-stacking and ion pair interactions (phase transfer catalysts). Catalysts may be specially designed for a specific task - for example, facilitating enantioselective conversions.
|An early example of an enantioselective Stetter Reaction is shown below: :||
model explaining the facial selectivity
Enantioselective Michael Addition using phase transfer catalysis:
The first enantioselective organocatalytic reactions had already been described at the beginning of the 20th century, and some astonishing, selective reactions such as the proline-catalyzed synthesis of optically active steroid partial structures by Hajos, Parrish, Eder, Sauer and Wiechert had been reported in 1971 (Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615; U. Eder, G. Sauer, R. Wiechert, Angew. Chem. Int. Ed. 1971, 10, 496, DOI). However, the transition metal-based catalysts developed more recently have drawn the lion’s share of attention.
Hajos-Parrish-Eder-Sauer-Wiechert reaction (example)
The first publications from the groups of MacMillan, List, Denmark, and Jacobson paved the way in the year 1990. These reports introduced highly enantioselective transformations that rivaled the metal-catalyzed reactions in both yields and selectivity. Once this foundation was laid, mounting interest in organocatalysis was reflected in a rapid increase in publications on this topic from a growing number of research groups.
Proline-derived compounds have proven themselves to be real workhorse organocatalysts. They have been used in a variety of carbonyl compound transformations, where the catalysis is believed to involve the iminium form. These catalysts are cheap and readily accessible:
A general picture of recent developments: V. D. B. Bonifacio, Proline Derivatives in Organic Synthesis, Org. Chem. Highlights 2007, March 25.
Books on Organocatalysis
Albrecht Berkessel, Harald Gröger
Hardcover, 440 Pages
First Edition, 2005
ISBN: 3-527-30517-3 - Wiley-VCH
A chiral primary amine-thiourea catalyst based on dehydroabietic amine enables a highly enantioselective Michael addition of nitroalkanes to α,β-unsaturated ketones to yield γ-nitro ketones with excellent enantioselectivities (up to 99% ee) and in up to 96% yield. This protocol was successfully applied in asymmetric syntheses of (R)-baclofen and (R)-phenibut.
X.-T. Guo, J. Shen, F. Sha, X.-Y. Wu, Synthesis, 2015, 47, 2063-2072.
A highly enantioselective organocatalytic peroxidation of enals enabled an enantioselective route toward the core structure of interesting anticancer natural products including a cyclization cascade of a chiral bis(epoxy)hydroperoxide and should be applicable to the enantioselective synthesis of a broad range of chiral 1,2-dioxolanes and 1,2-dioxanes.
L. Hu, X. Lu, L. Deng, J. Am. Chem. Soc., 2015, 137, 8400-8403.
Pyrrolidinine-thioxotetrahydropyrimidinone derivatives were tested for their catalytic properties in various asymmetric organic transformations. These catalysts could efficiently catalyze the reactions in brine, without the use of organic solvent, and by employing an almost stoichiometric amount of reagents. Thus, the products were isolated by simple extractions in excellent yields, diastereoselectivities, and enantioselectivities.
N. Kaplaneris, G. Koutoulogenis, M. Raftopoulou, C. G. Kokotos, J. Org. Chem., 2015, 80, 5464-5473.
A photo-organocatalytic enantioselective α- and γ-alkylation of aldehydes and enals with bromomalonates occurs under illumination by a fluorescent light bulb in the presence of a commercially available aminocatalyst without any external photoredox catalyst. Mechanistic investigations reveal the ability of transiently generated enamines to directly reach an electronically excited state while reactive radical species from the organic halides are formed.
M. Silvi, E. Arceo, I. D. Jurberg, C. Cassani, P. Melchiorre, J. Am. Chem. Soc., 2015, 137, 6120-6123.
A cooperative catalyst system enhances both yield and selectivity of an enantioselective N-heterocyclic carbene (NHC)-catalyzed β-protonation providing a broad range of aryl-oxobutenoates and highly enantioenriched succinate derivatives. The method demonstrates the benefits of combining different activation modes in organocatalysis.
M. H. Wang, D. T. Cohen, C. Benjamin Schwamb, R. K. Mishra, K. A. Scheidt, J. Am. Chem. Soc., 2015, 137, 5891-5894.
A direct enantioselective α-hydroxymethylation of aldehydes employing an α,α-diarylprolinol trimethylsilyl ether organocatalyst enables efficient access to β-hydroxycarboxylic acids and δ-hydroxy-α,β-unsaturated esters via an intermediate lactol in good yields, excellent enantioselectivity, and compatibility with a broad range of functional groups in the aldehyde.
R. K. Boeckman, K. F. Biegasiewicz, D. J. Tusch, J. R. Miller, J. Org. Chem., 2015, 80, 4030-4045.
Highly efficient nBu3P-catalyzed desulfonylative [3 + 2] cycloadditions of allylic carbonates with arylazosulfones enable the synthesis of pyrazole derivatives in very good yields under mild conditions.
Q. Zhang, L.-G. Meng, K. Wang, L. Wang, Org. Lett., 2015, 17, 872-875.
The direct asymmetric α-benzoyloxylation of β-ketocarbonyls catalyzed by a chiral primary amine demonstrates excellent enantioselectivity for a broad range of substrates, which allows convenient access to highly enantioenriched α-hydroxy-β-ketocarbonyls.
D. Wang, C. Xu, L. Zhang, S. Luo, Org. Lett., 2015, 17, 576-579.
Umpolung enables a facile synthesis of α-methylene-β-lactams. Under the catalysis of triphenylphosphine, a number of 2-propiolamidoacetates or α-propiolamido ketones underwent cyclization to afford the corresponding 4-substituted 3-methyleneazetidin-2-ones in high yields.
L. Zhu, Y. Xiong, C. Li, J. Org. Chem., 2015, 80, 628-633.
N-Heterocyclic Carbene Catalyzed Highly Chemoselective Intermolecular Crossed Acyloin Condensation of Aromatic Aldehydes with Trifluoroacetaldehyde Ethyl Hemiacetal
B. T. Ramanjaneyulu, S. Mahesh, R. V. Anand, Org. Lett., 2015, 17, 6-9.
Quaternary ammonium derivatives of cinchona alkaloids are highly efficient catalysts for asymmetric nitro-Mannich reactions of amidosulfones. A very broad substrate generality was observed, and both enantiomers of the products can be synthesized in high enantio- and diastereoselectivity.
B. Wang, Y. Liu, C. Sun, Z. Wei, J. Cao, D. Liang, Y. Lin, H. Duan, Org. Lett., 2014, 16, 6432-6435.
In a useful synthesis of phenols from arylboronic acids, hydrogen peroxide is generated in situ by aerobic photooxidation using visible-light irradiation and easily handled 2-chloroanthraquinone as an organocatalyst. The mild, metal- and base-free conditions enable an environmentally benign approach to the synthesis of phenols from arylboronic acids.
K. Matsui, T. Ishigami, T. Yamaguchi, E. Yamaguchi, N. Tada, T. Miura, A. Itoh, Synlett, 2014, 25, 2613-2616.
A relay strategy, in which ring-closing metathesis and bifunctional chiral amine (thio)urea-catalyzed Michael addition reactions proceed in a one-pot fashion, offers an alternative approach to the synthesis substituted cyclopentanes in good yields and good enantioselectivities.
Y. Zhang, X. Song, X. Chen, A. Song, S. Zhang, W. Wang, Synthesis, 2014, 46, 2601-2607.
A continuous-flow protocol for the light-induced fluorination of benzylic compounds in very good isolated yields in residence times below 30 min uses Selectfluor as the fluorine source and xanthone as an inexpensive and commercially available photoorganocatalyst. The flow photoreactor is based on transparent fluorinated ethylene propylene tubing and a household compact fluorescent lamp with black-light irradiation.
D. Cantillo, O. de Frutos, J. A. Rincón, C. Mateos, C. O. Kappe, J. Org. Chem., 2014, 79, 8486-8490.
Efficient, asymmetric conjugate addition-protonation reactions of thiols to α-substituted vinyl ketones are catalyzed by a chiral primary-tertiary diamine derived from l-phenylalanine. This organocatalyst promotes the sulfa-Michael addition-protonation reactions with good to excellent enantioselectivity.
N. Fu, L. Zhang, S. Luo, J.-P. Cheng, Org. Lett., 2014, 16, 4626-4629.
A readily synthesized chiral sulfinamide based organocatalyst enables an asymmetric ring-opening (ARO) reaction of meso epoxides with anilines in high yields of with excellent enantioselectivity at room temperature. A probable mechanism for the catalytic ARO reaction is envisaged by 1H and 13C NMR experiments.
M. Kumar, R. I. Kureshy, S. Saravanan, S. Verma, A. Jakhar, N.-u. H. Khan, S. H. R. Abdi, H. C. Bajaj, Org. Lett., 2014, 16, 2798-2801.
2,2,2-trifluoroacetophenone is an efficient organocatalyst for a cheap, mild, fast, and environmentally friendly epoxidation of alkenes. Various olefins, mono-, di-, and trisubstituted, are epoxidized chemoselectively in high to quantitative yields utilizing low catalyst loadings and H2O2 as a green oxidant.
D. Limniois, C. G. Kokotos, J. Org. Chem., 2014, 79, 4270-4276.
In a synergistical combination of photoredox catalysis and organocatalysis for the direct β-alkylation of saturated aldehydes, photon-induced enamine oxidation provides an activated β-enaminyl radical intermediate, which readily combines with a wide range of Michael acceptors to produce β-alkyl aldehydes in a highly efficient manner. This redox-neutral, atom-economical C–H functionalization can be achieved both inter- and intramolecularly.
J. A. Terrett, M. D. Clift, D. W. C. MacMillan, J. Am. Chem. Soc., 2014, 136, 6858-6861.
The asymmetric Payne oxidation of N-sulfonyl aldimines catalyzed by a P-spiro chiral triaminoiminophosphorane enables a practical synthesis of optically active N-sulfonyl oxaziridines with high efficiency and an excellent level of enantioselectivity. The versatility of this method was demonstrated by the diastereoselective kinetic oxidation of racemic α-chiral N-sulfonyl imines.
R. Tsutsumi, S. Kim, D. Uraguchi, T. Ooi, Synthesis, 2014, 46, 871-878.
The use of [bis(trifluoroacetoxy)iodo]benzene as stoichiometric oxidant and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone as organocatalyst enables a convenient oxidation of isochromans. A further reaction with grignard reagents or amides affords the corresponding isochroman derivatives.
W. Muramatsu, K. Nakano, Org. Lett., 2014, 16, 2042-2045.
Challenges in controlling the proline-catalyzed asymmetric aldol reaction between aliphatic aldehydes and acetone include side reactions such as aldol condensation and self-aldolization. Recently optimized conditions enable high yields of the desired addition product and good to excellent enantioselectivities.
A. Martínez, K. Zumbansen, A. Döhring, M. van Gemmeren, B. List, Synlett, 2014, 25, 932-934.
Pyrrolidine as an organocatalyst enables a general and efficient biomimetic method for the synthesis of aldimines from aldehydes and compounds bearing an amino group. This nucleophilic catalysis proceeds via iminium activation with outstanding yields in the absence of acids and metals under simple conditions. The method has been applied to the synthesis of N-sulfinyl, N-sulfonyl imines, N-phosphinoyl, N-alkyl, and N-aryl imines.
S. Morales, F. G. Guijarro, J. L. G. Ruano, M. B. Cid, J. Am. Chem. Soc., 2014, 136, 1082-1089.
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