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
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.
Hexamethyldisilazane sodium salt (NaHMDS) is a highly active Lewis base catalyst
for the Staudinger reaction with disubstituted ketenes and imines. This
organocatalyst gave highly substituted β-lactams in nearly quantitative yield in
a very short time of five minutes even at temperatures as low as -78°C.
O. Sereda, R. Wilhelm, Synlett, 2007,
3032-3036.
A mild, efficient, and general aromatization of Hantzsch 1,4-dihydropyridines
with oxygen was realized at room temperature with 5 mol % of
9-phenyl-10-methylacridinium perchlorate as photocatalyst, which could be easily
recovered and reused.
X. Fang, Y.-C. Liu, C. Li, J. Org. Chem., 2007,
72, 8608-8610.
Bisphosphine-catalyzed mixed double-Michael reactions between amino-acid-derived
pronucleophiles as Michael donors and electron-deficient acetylenes as acceptors
afford β-amino carbonyl derivatives of oxazolidines, thiozolidines, and
pyrrolidines in excellent yields and with high diastereoselectivities under
operationally simple and mild conditions.
V. Sriramurthy, G. A. Barcan, O. Kwon, J. Am. Chem. Soc., 2007,
129, 12928-12929.
Organocatalysts derived from l-leucine and l-valine afforded the direct
syn-aldol reactions of a wide scope of aldehydes with various ketones with
excellent diastereomeric ratios and enantioselectivities.
X.-Y. Xu, Y.-Z. Wang, L.-Z. Gong, Org. Lett., 2007,
9, 4247-4249.
Phase-transfer-catalyzed alkylation of glycinate Schiff base with racemic
secondary alkyl halides proceeded with excellent levels of syn- and
enantioselectivities under the influence of a chiral quaternary ammonium bromide
and 18-crown-6. The alkylation product can be selectively converted to the
corresponding anti isomer, allowing the preparation of all the stereoisomers of
β-alkyl-α-amino acid derivatives.
T. Ooi, D. Kato, K. Inamura, K. Ohmatsu, K. Maruoka, Org. Lett., 2007,
9, 3945-3948.
An organocatalytic asymmetric cascade Michael reaction of α,β-unsaturated
aldehydes with bromomalonates, efficiently catalyzed by chiral diphenylprolinol
TMS ether in the presence of base 2,6-lutidine, gives cyclopropanes in high
enantio- and diastereoselectivities. Using NaOAc as base, a spontaneous
ring-opening of cyclopropanes leads to (E) α-substituted malonate
α,β-unsaturated aldehydes.
H. Xie, L. Zu, H. Li, J. Wang, W. Wang, J. Am. Chem. Soc.,
2007,
129, 10886-10894.
An enantioselective synthesis of α,α-disubstituted cyclopentenes proceeds via a
chiral enol generated in situ from an α,β-unsaturated aldehyde and a chiral N-heterocyclic
carbene catalyst. This reactive enol undergoes addition to one of two
enantiotopic ketones to afford an optically active β-lactone. Depending on the
substitution, a decarboxylation produces the cyclopentene products in high ee.
M. Wadamoto, E. M. Philipps, T. E. Reynolds, K. A. Scheidt, J. Am. Chem. Soc.,
2007,
129, 10098-10099.
An axially chiral dicarboxylic acid has been applied to a highly
enantioselective Mannich reaction of arylaldehyde N-Boc imines and diazo
compounds as a new class of chiral hydrogen-bonding catalyst.
T. Hashimoto, K. Maruoka, J. Am. Chem. Soc., 2007,
129, 10054-10055.
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