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 bifunctional organocatalyst enables a 1,3-addition of silyl-dienol ethers to nitroalkenes to provide Rauhut-Currier type products with tri- and tetrasubstituted double bonds. The process takes place under smooth, nonanionic conditions, and with high enantiomeric excess. A rational mechanistic pathway is presented based on DFT and mechanistic experiments.
M. Frias, R. Mas-Ballesté, S. Arias, C. Alvarado, J. Alemán, J. Am. Chem. Soc., 2017, 139, 672-679.
A 2,2,2-trifluoroacetophenone-catalyzed oxidation of allyloximes enables a green and efficient synthesis of isoxazolines utilizing H2O2 as the oxidant. A variety of substitution patterns, both aromatic and aliphatic moieties, are well tolerated, leading to isoxazolines in good yields.
I. Triandafillidi, C. G. Kokotos, Org. Lett., 2017, 19, 106-109.
A N-heterocyclic carbene-catalyzed [2 + 4] annulation of α-bromoenals and α-cyano-β-methylenones enables a direct and efficient approach to 1,3,5-trisubstituted benzenes. The reaction worked well for both aryl- and alkylenones.
C.-L. Zhang, S. Ye, Org. Lett., 2016, 18, 6408-6411.
A highly stereoselective one-pot intramolecular Mannich reaction using 2-oxopropyl-2-formylbenzoates and anilines as substrates, catalyzed by a secondary amine, provides 4-aminoisochromanones bearing two adjacent stereocentres in good yields with excellent cis-stereoselectivities and ee values.
F. Vetica, J. Fronert, R. Puttreddy, K. Rissanen, D. Enders, Synthesis, 2016, 48, 4451-4458.
In situ aerobic dual oxidation with asymmetric organocatalysis enables an enantioselective synthesis of α-hydrazino aldehydes from alcohols and N-Boc hydrazine instead of the conventional combination of aldehydes with azodicarboxylates. This reaction tolerates various substituents on the alcohol component and features excellent enantiocontrol, cheap starting materials, operational simplicity, and scalability.
Z. Cui, D.-M. Du, Org. Lett., 2016, 18, 5616-5619.
The use of diacyl disulfide as an acylation reagent enables an efficient ester formation under DMAP catalysis. A site-selective acylation of phenolic and primary aliphatic hydroxyl groups greatly expands the scope of protecting group chemistry. Diacyl disulfides offer excellent moisture tolerance, high efficiency, and potential in synthetic chemistry and biologically meaningful natural product modification.
H.-X. Liu, Y.-Q. Dang, Y.-F. Yuan, Z.-F. Xu, S.-X. Qiu, H.-B. Tan, Org. Lett., 2016, 18, 5584-5587.
A highly enantioselective Michael addition of malonates to enones is catalyzed by dipeptide-derived multifunctional phosphonium salts. This catalytic system offers wide substrate scope and gram scale-up synthesis of adducts with both excellent yield and enantioselectivity.
D. Cao, G. Fang, J. Zhang, H. Wang, C. Zheng, G. Zhao, J. Org. Chem., 2016, 81, 9973-9982.
A metal-free photoredox system, consisting of an acridinium photocatalyst, an organic base, and molecular sieve (MS) 4 Å, promotes chemoselective photooxidation of aryl alkenes in the presence of oxygen. This oxo-acyloxylation of aryl alkenes provides a green, practical, and metal-free protocol for a wide range of α-acyloxy ketones.
Q.-B. Zhang, Y.-L. Ban, D.-G. Zhou, P.-P. Zhou, L.-Z. Wu, Q. Liu, Org. Lett., 2016, 18, 5256-5259.
A modular aerobic oxidation of amines to imines has been achieved using an ortho-naphthoquinone (o-NQ) catalyst. Whereas the cooperative catalyst system of o-NQ and Cu(OAc)2 provided homocoupled imines from benzylamines, the presence of TFA helped the formation of cross-coupled imines in excellent yields. The oxidation of secondary amines to imines or ketimines is facilitated with the help of Ag2CO3 as cocatalyst.
Y. Goriya, H. Y. Kim, K. Oh, Org. Lett., 2016, 18, 5174-5177.
Chiral phosphine-catalyzed coupling of two readily available partners, γ-aryl-substituted alkynoates and alcohols, under mild conditions enables the enantioselective synthesis of benzylic ethers via internal redox reaction of the alkynoate partner.
D. T. Ziegler, G. C. Fu, J. Am. Chem. Soc., 2016, 138, 12069-12072.
A chemoselective oxidation of α-hydroxy acids to α-keto acids is catalyzed by 2-azaadamantane N-oxyl (AZADO), a nitroxyl radical catalyst. The use of molecular oxygen as a cooxidant enables the desired chemoselective oxidation to α-keto acids, that are labile and can easily release CO2 under oxidation conditions.
K. Furukawa, H. Inada, M. Shibuya, Y. Yamamoto, Org. Lett., 2016, 18, 4230-4233.
A photocatalytic direct decarboxylative hydroxylation of carboxylic acids enables the conversion of various readily available carboxylic acids to alcohols in good yields under extremely mild reaction conditions using molecular oxygen as a green oxidant and visible light as a driving force.
H.-T. Song, W. Ding, Q.-Q. Zhou, J. Liu, L.-Q. Lu, W.-J. Xiao, J. Org. Chem., 2016, 81, 7250-7255.
Highly acidic confined imino-imidodiphosphate (iIDP) Brønsted acids catalyze the asymmetric Prins cyclization of both aliphatic and aromatic aldehydes. Diverse functionalized 4-methylenetetrahydropyrans are obtained in very good yields and with high regio- and enantioselectivities.
L. Liu, P. S. J. Kaib, A. Tap, B. List, J. Am. Chem. Soc., 2016, 138, 10822-10825.
A class of axially chiral pyridoxamines bearing a lateral amine arm exhibited high catalytic activity and excellent enantioselectivity in asymmetric transamination of α-keto acids, to give various α-amino acids in very good yields and with high ee's. The lateral amine arm likely participates in cooperative catalysis as the Lys residue does in biological transamination and enhances both the activity and the enantioselectivity.
Y. E. Liu, Z. Lu, B. Li, J. Tian, F. Liu, J. Zhao, C. Hou, Y. Li, L. Niu, B. Zhao, J. Am. Chem. Soc., 2016, 138, 10730-10733.
Catalytic amounts of phosphine and triethylamine enable an efficient protocol for the synthesis of highly functionalized furans via intramolecular Wittig reaction. Silyl chloride as the initial promoter activates the phosphine oxide for reduction, while decomposition of Et3N·HCl resulted in regeneration of base, which mediated formation of phosphorus ylide.
C.-J. Lee, T.-H. Chang, J. K. Yu, G. M. Reddy, M.-Y. Hsiao, W. Lin, Org. Lett., 2016, 18, 3758-3761.
Helical peptide foldamers catalyze Michael addition reactions of nitroalkanes or dialkyl malonates to α,β-unsaturated ketones to give Michael adducts with high enantioselectivities. The amide protons at the N terminus in the α-helical peptide catalyst are crucial for activating Michael donors, while the N-terminal primary amine activates Michael acceptors through the formation of iminium ion intermediates.
A. Ueda, T. Umeno, M. Doi, K. Akagawa, K. Kudo, M. Tanaka, J. Org. Chem., 2016, 81, 6343-6356.
Amidine-based catalysts, particularly homobenzotetramisole and its analogues, achieve high enantioselectivities and yields in a reagent-free catalytic transformation of α,β-unsaturated thioesters into 2-substituted thiochromenes with carbon dioxide as the only byproduct.
N. A. Ahlemeyer, V. B. Birman, Org. Lett., 2016, 18, 3454-3457.
In systematic investigations to develop an efficient enantioselective synthetic method for α-alkyl-alanine by catalytic phase-transfer alkylation, the alkylation of 2-naphthyl aldimine tert-butyl ester in the presence of RbOH and O(9)-allyl-N-2',3',4'-trifluorobenzylhydrocinchonidinium bromide as catalyst at -35°C showed the highest enantioselectivities.
S.-s. Jew, B.-S. Jeong, J.-H. Lee, M.-S. Yoo, Y.-J. Lee, B.-s. Park, M. G. Kim, H.-g. Park, J. Org. Chem., 2003, 68, 4514-4516.
A carbene-catalyzed reaction enables a dynamic kinetic resolution of α,α-disubstituted carboxylic esters with up to 99:1 er and 99% yield.
X. Chen, J. Z. M. Fong, J. Xu, C. Mou, Y. Lu, S. Yang, B.-A. Song, Y. R. Chi, J. Am. Chem. Soc., 2016, 138, 7212-7215.
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