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 |
Recent Literature
An achiral amine in combination with a catalytic amount of a chiral Brønsted
acid can accomplish an aldol addition-dehydration-conjugate reduction-reductive
amination with 2,6-diketones to provide cyclohexylamines as potential
intermediates of pharmaceutically active compounds in good yields and excellent
enantioselectivities.
J. Zhou, B. List, J. Am. Chem. Soc., 2007,
129, 7498-7499.
A thiourea-catalyzed transfer hydrogenation
of various aromatic as well as aliphatic aldimines through hydrogen-bonding activation with Hantzsch 1,4-dihydropyridine
as the hydrogen source gives the respective amines under acid- and metal-free reaction
conditions.
Z. Zhang, P. R. Schreiner, Synlett, 2007,
1455-1457.
1-Methoxy-2-methyl-1-(trimethylsiloxy)propene, a neutral π-nucleophile, is able
to efficiently catalyze cyanosilylations and cyanocarbonations of various
aldehydes and ketones.
X. Wang, S.-K. Tian, Synlett, 2007,
1416-1420.
Singly occupied molecular orbital (SOMO) catalysis allows an enantioselective
organocatalytic α-enolation of aldehydes. A chiral secondary amine catalyst
reacts with aldehydes to form transient enamines that undergo selective
one-electron oxidation to generate SOMO-activated electrophilic radical cations
which are susceptible to attack by ketone-derived enol silanes.
H.-Y. Jang, J.-B. Hong, D. W. C. MacMillan, J. Am. Chem. Soc., 2007,
129, 7004-7005.
METHOX: A New Pyridine N-Oxide Organocatalyst for the Asymmetric Allylation of Aldehydes with Allyltrichlorosilanes
A. V. Malkov, M. Bell, F. Castelluzzo, P.
Kocovsky, Org. Lett., 2005,
7, 3219-3222.
A highly chemo- and enantioselective epoxidation of conjugated cis-enynes
using readily available glucose-derived ketones as catalysts and Oxone as
oxidant forms cis-propargyl epoxides in high ee's. The interaction
between the alkyne substrate and the oxazolidinone moiety of the ketone catalyst
are important for the stereodifferentiation.
C. P. Burke, Y. Shi, J. Org. Chem., 2007,
72, 4093-4097.
α-Imino esters derived from aryl and alkyl keto esters could be reduced
to the corresponding α-amino esters in excellent yields and in high enantiomeric
excesses using 5 mol-% of a chiral phosphoric acid as catalyst, Hantzsch ester
as hydride donor, and toluene as solvent.
G. Li, Y. Liang, J. C. Antilla, J. Am. Chem. Soc., 2007,
129, 5830-5831.
Highly strained β-sultams, sulfonyl analogues of β-lactams, were prepared
enantio- and diastereoselectively by tertiary amine catalyzed [2 + 2]
cycloaddition reactions. β-Sultams are practical precursors of highly
enantioenriched β-aminosulfonyl derivatives of biological interest.
M. Zajac, R. Peters, Org. Lett., 2007,
9, 2007-2010.
Conjugate addition of dimethyl alkenylboronates to α,β-unsaturated ketones in the presence of catalytic amounts of 3,3'-disubstituted binaphthols provides alkenylation products in good yields and
high enantioselectivities.
T. R. Wu, J. M. Chong, J. Am. Chem. Soc., 2007,
129, 4908-4909.
Acetals react with allyltrimethylsilane in the presence of a catalytic amount of
sulfonic acids to give the corresponding homoallylic ethers in high yields. The
scope of the reaction is broad and both aromatic as well as aliphatic acetals
can readily be used.
D. Kampen, B. List, Synlett, 2006,
2589-2592.
An organocatalytic highly enantioselective formation of vinyl-substituted
all-carbon quaternary stereocenters proceeds in good yield via nucleophilic
vinylic substitution of various α-substituted-α-cyanoacetates with
α-chloroalkenones using a dimeric cinchona alkaloid phase-transfer catalyst.
M. Bell, T. B. Poulsen, K. A. Jørgensen, J. Org. Chem., 2007,
72, 3053-3056.
A N,N′-bis[3,5-bis(trifluoromethyl)phenyl]thiourea-catalyzed tetrahydropyran and
2-methoxypropene protection of hydroxyl groups is broadly applicably to acid-sensitive substrates such as aldol
products, hydroxy esters, acetals, silyl-protected alcohols, and cyanohydrins.
A mechanistic interpretation of the high catalytic efficiency is given.
M. Kotke, P. R. Schreiner, Synthesis, 2007,
779-790.
In the presence of only 0.5 mol % of
an N-heterocyclic carbene, various aldehydes and 2,2,2-trifluoroacetophenone underwent Mukaiyama aldol reactions in THF with
a trimethylsilyl ketene acetal as well as with a trimethylsilyl enol ether to afford aldol
adducts in good yields. These conditions are extremely mild and operationally
simple and tolerate various functional groups.
J. J. Song, Z. Tan, J. T. Reeves, N. K. Yee, C. H. Senanayake, Org. Lett., 2007,
9, 1013-1016.
Different aldehydes and amines react with acyl cyanides in the presence of a
catalytic amount of the Schreiner thiourea catalyst to give the corresponding N-acyl amino nitriles in high yields. The scope of the reaction is broad and
allows the use of both aromatic and aliphatic aldehydes and amines.
S. C. Pan, B. List, Synlett, 2007, 318-320.
A hydrogen-bond-catalyzed, acid- and metal-free direct reductive amination of aldehydes uses thiourea as organocatalyst and the
Hantzsch ester for transfer-hydrogenation. This methods allows for the high-yielding
synthesis of diverse amines.
D. Menche, F. Arikan, Synlett,
2006, 841-844.
(S)-3-[2-(Diphenylphosphino)phenyl]BINOL is an efficient asymmetric
bifunctional organocatalyst for the aza-Morita-Baylis-Hillman reaction. The
Brønsted acid and Lewis base functionalities cooperate in substrate activation
to promote the reaction with high enantiocontrol.
K. Matsui, S. Takizawa, H. Sasai, Synlett,
2006, 761-765.
A highly enantioselective catalytic alkylation of cyanoacetates was
achieved using a chiral phase-transfer catalyst to give α,α-disubstituted
α-cyanoacetates which have a chiral quaternary carbon.
K. Nagata, D. Sano, T. Itoh, Synlett, 2007, 547-550.
Asymmetric reduction of ketimines with trichlorosilane can be catalyzed by
N-methylvaline-derived Lewis-basic formamides with high enantioselectivity
and low catalyst loading at room temperature in toluene. Appending a fluorous
tag to the catalyst simplifies the isolation procedure and allows the catalyst
to be recycled.
A. V. Malkov, M. Figlus, S. Stončius, P. Kočovský, J. Org. Chem., 2007,
72, 1315-1325.
A highly enantioselective Mannich reaction with in situ generation of
carbamate-protected imines from stable α-amido sulfones catalyzed by an organic
catalyst provides a concise and highly
enantioselective route converting aromatic and aliphatic aldehydes into
optically active aryl and alkyl β-amino acids.
J. Song, H.-W. Shih, L. Deng, Org. Lett., 2007,
9, 603-606.
An asymmetric vinylogous Mannich reaction of α,α-dicyanoolefins and
N-Boc
aldimines is promoted by a simple chiral bifunctional thiourea-tertiary amine
organocatalyst. The reaction was highly efficient, regio-, and stereoselective
at room temperature for a broad range of substrates.
T.-Y. Liu, H.-L. Cui, J. Long, B.-J. Li, Y. Wu, L.-S. Ding, Y.-C. Chen, J. Am. Chem. Soc., 2007,
129, 1878-1879.
Please cite and link this page as follows:
Organocatalysis ( URL: http://www.organic-chemistry.org/topics/organocatalysis.shtm )
Friday, 16-May-2008 08:35:22 CEST
