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
Asymmetric Organocatalysis
Albrecht Berkessel, Harald Gröger
Hardcover, 440 Pages
First Edition, 2005
ISBN: 3-527-30517-3 - Wiley-VCH
Recent Literature
A P-cyclohexyl substituted ferrocenophane catalyst affords high levels of
asymmetric induction in the organocatalytic [3 + 2] annulation reaction between
allenes and electron-poor olefins.
A. Voituriez, A. Panossian, N. Fleury-Brégeot, P. Retailleau, A. Marinetti, J. Am. Chem. Soc., 2008,
130, 14030-14031.
A highly efficient and enantioselective Hantzsch ester mediated conjugate
reduction of β-nitroacrylates is catalyzed by a Jacobsen thiourea catalyst. The
reaction is a key step in a new route to optically active β2-amino
acids.
N. J. A. Martin, X. Chen, B. List, J. Am. Chem. Soc., 2008,
130, 13862-13863.
A phosphine-catalyzed annulation of modified allylic ylides with various
aromatic imines gives 3-pyrrolines in moderate to very good yield. The presence
of a substituent (R) in the allylic compound is crucial for this reaction.
S. Zheng, X. Lu, Org. Lett.,
2008,
10, 4481-4484.
N-Heterocyclic carbenes catalyze the oxidation of unactivated aldehydes to
esters with manganese(IV) oxide in excellent yield under mild conditions. The reaction proceeds
through a transient activated alcohol generated in situ and
preserves stereochemical integrity. Various esters can be
synthesized using a broad range of alcohols and unactivated
aldehydes.
B. E. Marki, K. A. Scheidt, Org. Lett.,
2008,
10, 4331-4334.
The use of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as solvent and catalyst
allows a simple and efficient, chemoselective mono-N-Boc protection of
various structurally diverse amines with di-tert-butyl dicarbonate. The
catalyst can be readily recycled. No competitive side reactions such as
formation of isocyanates, ureas, and oxazolidinones from α-amino alcohols were
observed.
A. Heydari, S. Khaksar, M. Tajbakhsh, Synthesis, 2008,
3126-3130.
TEMPO-derived reagents tagged with multiple perfluoroalkyl chains and
triazole moieties promote the oxidation of alcohols to aldehydes in organic
solvent/water mixtures with reaction rates comparable to homogeneous TEMPO
reagents, but can be easily recovered by liquid/emulsion filtration.
A. Gheorghe, T. Chinnusamy, E. Cuevas-Yańez, P. Hilgers, O. Reiser, Org. Lett.,
2008,
10, 4171-4174.
An enantioselective addition of alcohols to imines proceeds in the presence of a
catalytic amount of a chiral phosphoric acid catalyst to give the respective
chiral N,O-aminals in excellent yield and enantioselectivity.
G. Li, F. R. Fronczek, J. C. Antilla, J. Am. Chem. Soc., 2008,
130, 12216-12217.
A chiral bifunctional multiple hydrogen-bonding-donor amine-thiourea catalyzes a
highly anti-selective and enantioselective nitro-Mannich reaction for a
broad spectrum of substrates. Multiple hydrogen-bonding donors play a
significant role in accelerating reactions and improving yields,
diastereoselectivities, and enantioselectivities.
C.-J. Wang, X.-Q. Dong, Z.-H. Zhang, Z.-Y. Xue, H.-L. Teng, J. Am. Chem. Soc., 2008,
130, 8606-8607.
With an easily accessible cinchona alkaloid catalyst, efficient enantioselective
peroxidation and epoxidation have been successfully developed. Employing readily
available α,β-unsaturated ketones and hydroperoxides, this novel reaction will
open new possibilities in the asymmetric synthesis of chiral peroxides and
epoxides.
X. Lu, Y. Liu, B. Sun, B. Cindric, L. Deng, J. Am. Chem. Soc., 2008,
130, 8134-8135.
NHC-catalyzed direct amidation of a variety of aryl, alkyl, alkenyl, and
heterocyclic aldehydes with nitroso compounds is a powerful method for the
synthesis of N-arylhydroxamic acids in excellent yields. This chemistry
was also extended to a three-component reaction for the synthesis of N-arylaziridines.
F. T. Wong, P. K. Patra, J. Seayad, Y. Zhang, J. Y. Ying, Org. Lett., 2008,
10, 2333-2336.
A mild and efficient interconversion from silyl ethers to sulfonates esters
proceeds readily in acetonitrile at room temperature in the presence of p-toluenesulfonyl
fluoride and a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7ene (DBU). This
method can be used with trimethysilyl (TMS), triethylsilyl (TES) and tert-butyldimethylsilyl
(TBDMS) ethers.
V. Gembus, F. Marsais, V. Levacher, Synlett, 2008,
1463-1466.
Triphenylphosphine is a suitable organocatalyst for the chemoselective O-tert-butoxycarbonylation
of phenols under neutral and neat conditions.
R. Chebolu, S. V. Chankeshwara, A. K. Chakraborti, Synthesis, 2008,
1448-1454.
Chiral primary amine salts catalyze highly enantioselective epoxidations of
cyclic enones with hydrogen peroxide.
X. Wang, C. M. Reisinger, B. List, J. Am. Chem. Soc., 2008,
130, 6070-6071.
The peptide H-D-Pro-Pro-Glu-NH2 is a highly effective catalyst for
conjugate addition reactions between aldehydes and nitroethylene to obtain
γ-nitroaldehydes and, after reduction, monosubstituted γ-nitroalcohols in
excellent yields and optical purities. The products can be readily converted
into γ2-amino acids that were previously only accessible by the use
of chiral auxiliaries.
M. Wiesner, J. D. Revell, S. Tonazzi, H. Wennemers, J. Am. Chem. Soc., 2008,
130, 5610-5611.
Enantioselective organocatalytic Michael addition of aldehydes to
nitroethylene catalyzed by (S)-diphenylprolinol silyl ether provides
β-substituted-δ-nitroalcohols in nearly optically pure form. The Michael adducts
bear a single substituent adjacent to the carbonyl and can be efficiently
converted to protected γ2-amino acids.
Y. Chi, L. Guo, N. A. Kopf, S. H. Gellman, J. Am. Chem. Soc., 2008,
130, 5048-5049.
Triphosphazene (TAPC) was found to be an efficient catalyst for the Beckmann
rearrangement of various ketoximes to lactams.
M. Hashimoto, Y. Obora, S. Sakaguchi, Y. Ishii, J. Org. Chem., 2008,
73, 2894-2897.
A basic functionalized ionic liquid, 1-butyl-3-methylimidazolium hydroxide ([bmim]OH),
catalyzed the three-component condensation reaction of acid chlorides, amino
acids, and dialkyl acetylenedicarboxylates in water to afford functionalized
pyrroles in high yields.
I. Yavari, E. Kowsari, Synlett, 2008,
897-899.
A direct asymmetric iodination reaction of aldehydes with NIS catalyzed by a
novel axially chiral bifunctional amino alcohol represents a rare example of a
highly enantioselective synthesis of optically active α-iodoaldehydes.
T. Kano, M. Ueda, K. Maruoka, J. Am. Chem. Soc., 2008,
130, 3728-3729.
N-Heterocyclic carbenes (NHCs) catalyze the silyl transfer from trialkylsilyl
ketene acetals to ketones. A series of enolizable ketones as well as
cyclohexanecarboxaldehyde were efficiently converted into the corresponding
silyl enol ethers at 23°C in THF.
J. J. Song, Z. Tan, J. T. Reeves, D. R. Fandrick, N. K. Yee, C. H. Senanayake, Org. Lett., 2008,
10, 877-880.
Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic
acid efficiently catalyzed the Mannich-type reactions of aldehydes with α-imino
esters under mild conditions and afforded anti-Mannich products with high
diastereo- and enantioselectivities.
H. Zhang, S. Mitsumori, N. Utsumi, M. Imia, N. Garcia-Delgado, M. Mifsud, K.
Albertshofer, P. H.-Y. Cheong, K. N. Houk, F. Tanaka, C. F. Barbas, III, J. Am. Chem. Soc., 2008,
130, 875-886.
A chiral N-heterocyclic carbene catalyzed the Staudinger reaction of
arylalkylketenes with a variety of N-tert-butoxycarbonyl arylimines to
give the corresponding cis-β-lactams in good yields with good
diastereoselectivities and excellent enantioselectivities.
Y.-R. Zhang, L. He, X. Wu, P.-L. Shao, S. Ye, Org. Lett., 2008,
10, 277-280.
The bifunctional chiral phosphine Lewis base
(R)-2‘-diphenylphosphino-[1,1‘-binaphthalene]-2-ol is an effective
organocatalyst in the asymmetric aza-MBH reaction of ethyl (arylimino)acetates with
alkyl vinyl ketones to give the corresponding adducts in good yields
and high enantiomeric excesses under mild conditions.
M. Shi, G.-N. Ma, J. Gao, J. Org. Chem., 2007,
72, 9779-9781.
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