Organocatalysis
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:
T. Ooi, D. Ohara, K. Fukumoto, K. Maruoka, Org. Lett., 2005,
7, 3195-3197.
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. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold, S. V. Ley, Org.
Biomol. Chem., 2005,
3, 84-96.
Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima, M. Shoji, Angew. Chem. Int. Ed., 2006,
45, 958-961.
Kumaragurubaran, K. Juhl, W. Zhuang, A. Gogevig, K. A. Jorgensen, J. Am. Chem. Soc., 2002,
124, 6254-6255.
A general picture of recent developments: V. D. B. Bonifacio, Proline Derivatives in Organic Synthesis, Org. Chem. Highlights 2007, March 25.
Books on Organocatalysis
Asymmetric Organocatalysis
Albrecht Berkessel, Harald Gröger
Hardcover, 440 Pages
First Edition, 2005
ISBN: 3-527-30517-3 - Wiley-VCH
Recent Literature
Aryl iodides are efficient catalysts in an organocatalytic syn
diacetoxylation of alkenes. A broad range of substrates, including electron-rich
as well as electron-deficient alkenes, furnish the desired products in
very good yields with high diastereoselectivity.
W. Zhong, S. Liu, J. Yang, X. Meng, Z. Li, Org. Lett., 2012,
14, 3336-3339.
Confined chiral Brønsted acids catalyze asymmetric oxidations of a broad range
of sulfides to sulfoxides with hydrogen peroxide. The wide generality and high
enantioselectivity of the developed method is comparable even to the best
metal-based systems.
S. Liao, I. Čorić, Q. Wang, B. List, J. Am. Chem. Soc., 2012,
134, 10765-10768.
A direct reductive amination of ketones using the Hantzsch ester in the presence
of S-benzyl isothiouronium chloride as a recoverable organocatalyst
converts a wide range of ketones as well as aryl amines to the expected products
in good yields.
Q. P. B. Nguyen, T. H. Kim, Synthesis, 2012,
1977-1982.
An organocatalytic Dakin oxidation of electron-rich arylaldehydes to phenols can
be performed under mild, basic conditions using flavin catalysts. Catechols are
readily prepared and the oxidation of 2-hydroxyacetophenone was achieved.
S. C. M. S. Hoassain, F. W. Foss, Jr, Org. Lett., 2012,
14, 2806-2809.
The in situ generation of α-amino aldehydes followed by reaction
with
dimethyloxosulfonium methylide under Corey-Chaykovsky reaction conditions gives 4-hydroxypyrazolidine derivatives in high yields
with excellent enantio- and diastereoselectivities. This organocatalytic
sequential method enables an efficient synthesis of
anti-1,2-aminoalcohols.
B. S. Kumar, V. Venkataramasubramanian, A. Sudalai, Org. Lett., 2012,
14, 2468-2471.
Ozonolysis in the presence of pyridine directly generates ketones or aldehydes
through a process that neither consumes pyridine nor generates any detectable
peroxides. The reaction is hypothesized to involve nucleophile-promoted
fragmentation of carbonyl oxides via formation of zwitterionic peroxyacetals.
R. Willand-Charnley, T. J. Fisher, B. M. Johnson, P. H. Dussault, Org. Lett., 2012,
14, 2242-2245.
A bifunctional organocatalyst efficiently catalyzed not only enantioselective
conjugate addition of aromatic ketones to nitroolefins in good yields with
excellent enantioselectivities but also enantioselective conjugate addition of
acetone to nitroolefins in excellent yields with high enantioselectivities.
Z.-W. Sun, F.-Z. Peng, Z.-Q. Li, L.-W. Zhou, S.-X. Zhang, X. Li, Z.-H. Shao, J. Org. Chem., 2012,
77, 4103-4110.
Organocatalytic stereospecific dibromination of various functionalized alkenes
was achieved using a simple thiourea catalyst and 1,3-dibromo
5,5-dimethylhydantoin as a stable, inexpensive halogen source at room
temperature. The procedure was extended to alkynes and aromatic rings and to
dichlorination reactions by using the 1,3-dichloro hydantoin derivative.
G. Hernández-Torres, B. Tan, C. F. Barbas III, Org. Lett., 2012,
14, 1858-1861.
A nitroxyl-radical-catalyzed oxidation using diisopropyl azodicarboxylate
(DIAD) allows the conversion of various primary and secondary alcohols to their
corresponding aldehydes and ketones without overoxidation to carboxylic acids.
1,2-Diols are oxidized to hydroxyl ketones or diketones depending on the amount
of DIAD used.
M. Hayashi, M. Shibuay, Y. Iwabuchi, J. Org. Chem., 2012,
77, 3005-3009.
An enantioselective synthesis of γ-nitroesters by a one-pot asymmetric Michael
addition/oxidative esterification of α,β-unsaturated aldehydes is based on an
enantioselective organocatalytic nitroalkane addition followed by an N-bromosuccinimide-based
oxidation. The γ-nitroesters are obtained in good yields and
enantioselectivities, and the method provides an attractive entry to optically
active γ-aminoesters, 2-piperidones, and 2-pyrrolidones.
K. L. Jensen, P. H. Poulsen, B. S. Donslund, F. Morana, K. A. Jørgensen, Org. Lett., 2012,
14, 1516-1519.
A simple chiral primary amine catalyses a highly efficient reaction for the
synthesis of both Wieland-Miescher ketone and Hajos-Parrish ketone as well as
their analogues in high enantioselectivity and excellent yields. This procedure
represents one of the most efficient methods for the synthesis of these
versatile chiral building blocks even in gram scale with 1 mol% catalyst loading.
P. Zhou, L. Zhang, S. Luo, J.-P. Cheng, J. Org. Chem., 2012,
77, 2526-2530.
The of silica-coated magnetic nanoparticles allowed the construction of
magnetically recoverable organic hydride compounds. Magnetic
nanoparticle-supported BNAH (1-benzyl-1,4-dihydronicotinamide) showed efficient
activity in the catalytic reduction of α,β-epoxy ketones. After reaction, the
catalyst can be separated by simple magnetic separation and can be reused.
H.-J. Xu, X. Wan, Y.-Y. Shen, S. Xu, Y.-S. Feng, Org. Lett., 2012,
14, 1210-1213.
Activation of diphenylsilane in the presence of a catalytic amount of an
N-heterocyclic carbene (NHC) enables hydrosilylation of carbonyl derivatives
under mild conditions. Presumably, a hypervalent silicon intermediate featuring
strong Lewis acid character allows dual activation of both the carbonyl moiety
and the hydride at the silicon center. Some interesting selectivities have been
encountered.
Q. Zhao, D. P. Curran, M. Malacria, L. Fensterbank, J.-P. Goddard, E. Lacôte, Synlett, 2012,
433-437.
A bifunctional squaramide catalyzes a sulfa-Michael/aldol cascade reaction
between 1,4-dithiane-2,5-diol and chalcones with a low catalyst loading to yield
trisubstituted tetrahydrothiophenes with three contiguous stereogenic centers in
a highly stereocontrolled manner.
J.-B. Ling, Y. Su, H.-L. Zhu, G.-Y. Wang, P.-F. Xu, Org. Lett., 2012,
14, 1090-1093.
A phosphinite derivative that can be easily prepared in two steps from
commercially available aminoindanol is an effective catalyst for
enantioselective acylation of diols. For the asymmetric desymmetrization of
meso-1,2-diols, the corresponding monoester was obtained in high
enantioselectivity.
H. Aida, K. Mori, Y. Yamaguchi, S. Mizuta, T. Moriyama, I. Yamamoto, T.
Fujimoto, Org. Lett., 2012,
14, 812-815.
Commercially available and very inexpensive benzoic acids catalyze an efficient
and simple isomerization of readily prepared allylic alcohols to yield cyclic
products, unusual enyne, and dienols. The catalysts can be tuned for reactivity
and substrate sensitivity.
J. A. McCubbin, S. Voth, O. V. Krokhin, J. Org. Chem., 2011,
76, 8537-8542.
Cinchona-alkaloid-thiourea-based bifunctional organocatalysts enable a
straightforward asymmetric cycloetherification of ε-hydroxy-α,β-unsaturated
ketones for the synthesis of tetrahydrofuran rings. This catalytic process
represents a highly practical cycloetherification method that provides excellent
enantioselectivities, even with low catalyst loadings at ambient temperature.
K. Asano, S. Matsubara, J. Am. Chem. Soc., 2011,
133, 16711-16713.
Enantioenriched N,S-acetals can be prepared using chiral BINOL phosphoric
acids. The reaction combines electron-rich and electron-deficient aromatic N-acyl
imines with broad range of aliphatic and aromatic thiols to generate products in
excellent yield and enantioselectivity. The addition reaction could also be
achieved with an exceptional substrate to catalyst (S/C) molar ratio.
G. K. Ingle, M. G. Mormino, L. Wojtas, J. C. Antilla, Org. Lett., 2011,
13, 4762-4765.
1-Alkyl-3-methylimidazolium cation based ionic liquids efficiently catalyze
N-tert-butyloxycarbonylation of amines with excellent chemoselectivity. The
catalytic role of the ionic liquid is envisaged as electrophilic activation of
di-tert-butyl dicarbonate (Boc2O) through bifurcated hydrogen
bond formation with the C-2 hydrogen of the 1-alkyl-3-methylimidazolium cation.
A. Sarkar, S. R. Roy, N. Parikh, A. K. Chakraborti, J. Org. Chem., 2011,
76, 7132-7140.
A biomimetic proton transfer catalysis with a chiral organic catalyst enabled an
enantioselective olefin isomerization of a broad range of mono- and
disubstituted β,γ-unsaturated butenolides into the corresponding chiral
α,β-unsaturated butenolides in high enantioselectivity and yield. Mechanistic
studies have revealed the protonation as the rate-determining step.
Y. Wu, R. P. Singh, L. Deng, J. Am. Chem. Soc., 2011,
133, 12458-12461.
3,3′-Br2-BINOL catalyze the enantioselective asymmetric
propargylation of ketones using allenyldioxoborolane as nucleophile, in the
absence of solvent, and under microwave irradiation to afford
homopropargylic alcohols in good yields and high enantiomeric ratios.
Diastereoselective propargylations using chiral racemic allenylboronates result
in good diastereoselectivities.
D. S. Barnett, S. E. Schaus, Org. Lett., 2011,
13, 4020-4023.
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