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 catalytic, vicinal difluorination of olefins displays broad functional group tolerance, using inexpensive p-iodotoluene as the catalyst. Preliminary efforts toward the development of an enantioselective variant are reported.
I. G. Molnár, R. Gilmour, J. Am. Chem. Soc., 2016, 138, 5004-5007.
Upon exposure of enamides to aldehydes in the presence of a chiral NHC catalyst, C-C bond formation provides N-protected amines, bearing a quaternary carbon center, in good yields and with high enantioselectivities.
J. Wu, C. Zhao, J. Wang, J. Am. Chem. Soc., 2016, 138, 4706-4709.
With a suitable combination of N-heterocyclic carbene precatalyst, base, and fluorine reagent, a fluorination of alkynals proceeded smoothly to yield a wide range of α-fluoroallenoates with excellent chemoselectivity. α-Fluorinated allenoates are versatile synthetic intermediates toward other useful fluorine-containing building blocks.
X. Wang, Z. Wu, J. Wang, Org. Lett., 2016, 18, 576-579.
Catalytic enantioselective diboration of alkenes is accomplished with readily available carbohydrate-derived catalysts via the intermediacy of 1,2-bonded diboronates.
L. Fang, L. Yan, F. Haeffner, J. P. Morken, J. Am. Chem. Soc., 2016, 138, 2508-2511.
A highly para-selective halogenation of arenes bearing electron-donating coordinating groups in the presence of a dimidazolium salt rpovides p-haloarenes in good yields. A plausible mechanism for the catalytic reaction is proposed.
J. Chen, X. Xiong, Z. Chen, J. Huang, Synlett, 2015, 26, 2831-2834.
The reactivity of iodoarene amide catalysts in the α-oxytosylation of propiophenone is influenced by steric and electronic properties. A very reactive meta-substituted benzamide catalyst was employed in the α-oxytosylation of a series of substituted propiophenones to provide α-tosyloxy ketones in excellent isolated yield.
T. R. Lex, M. I. Swasy, D. C. Whitehead, J. Org. Chem., 2015, 80, 12234-12243.
An easily prepared recyclable TEMPO derived sulfonic salt catalyst, and mineral acids (NaNO2 and HCl) enable a selective aerobic oxidation of structurally diverse benzylic sp3 C-H bonds of ethers and alkylarenes to provide synthetically and biologically valued isochromanones and xanthones in good yields.
Z. Zhang, Y. Gao, Y. Liu, J. Li, H. Xie, H. Li, W. Wang, Org. Lett., 2015, 17, 5492-5495.
An N-heterocyclic carbene catalyzes a highly enantioselective [3 + 3] annulation reaction of N-hydroxyphthalimide (NHPI) 3,3-disubstituted acrylates and N-Ts ketimines, providing the desired chiral dihydropyridinone products bearing an all carbon quaternary stereogenic center in good yields with excellent enantioselectivities. The reaction demonstrates that NHPI acrylates are excellent substrates in NHC-catalysis.
Z. Zhang, X. Zeng, D. Xie, D. Chen, L. Ding, A. Wang, L. Yang, G. Zhong, Org. Lett., 2015, 17, 5052-5055.
Using a confined imidodiphosphate catalyst, a highly enantioselective intramolecular carbonyl-ene reaction of olefinic aldehydes delivers diverse trans-3,4-disubstituted carbo- and heterocyclic five-membered rings in high yields and with good to excellent diastereo- and enantioselectivities.
L. Liu, M. Leutzsch, Y. Zheng, M. W. Alachraf, W. Thiel, B. List, J. Am. Chem. Soc., 2015, 137, 13268-13271.
Coupling of benzaldehydes and benzyl chloride derivatives under basic conditions with an organocatalyst gives good yields of alkynes. The catalyst, a highly reactive sulfenate anion, is readily generated in situ from air-stable precursors. This method represents an attractive organocatalytic alternative to well-established stoichiometric approaches to alkynes and to transition-metal-based alkyne functionalization methods.
M. Zhang, T. Jia, C. Y. Wang, P. J. Walsh, J. Am. Chem. Soc., 2015, 137, 10346-10350.
Brřnsted acid catalysis enables highly efficient, regioselective, and enantioselective transfer hydrogenation of α-keto ketimines and reductive amination of diketones. A series of chiral α-amino ketones is prepared in high yields, excellent regioselectivities, and enantioselectivities.
W. Wen, Y. Zeng, L.-Y. Peng, L.-N. Fu, Q.-X. Guo, Org. Lett., 2015, 17, 3922-3925.
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.
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