Carbohydrates in Organocatalysis
Stereospecific reactions are of immense importance to the field of synthetic organic chemistry. Two enantiomers can have very different biological activity and Thalidomide, a racemic drug, is a infamous example of this. The drug was licenced for sale in the late 1950's and its primary purpose was to alleviate "morning sickness" during pregnancy. (R)-Thalidomide had the desired sedative properties but its enantiomer caused catastrophic foetal defects. Many of the affected did not survive until birth or even early their childhood and those that did, survived with physical deformities. It has received recent media attention with survivors groups in Ireland seeking government compensation. This was a watershed event which highlighted the need for stricter testing being required for drugs before licensing.5 There is no doubt that there is increasing demand for enantiomerically pure compounds in pharmaceutical, fine chemical, fragrances, agrochemical and the material science industries.
An increasing number of stereospecific reactions can be accelerated by chiral organic molecules. Organocatalysis is the process of acceleration of chemical reaction with a substoichiometric amount of an organic compound which does not contain a metal atom.1 Organic molecules have been used as catalysts from the early age of synthetic Chemistry.2 The earliest example of an organocatalyst was accidentally stumbled upon by Justus von Liebig in 1860,2 but the novel area of enantioselective organocatalysis hadn't emerged as a major topic in organic chemistry until recently.3,4 This is because the efficiency and selectivity of organocatalyzed reactions began to meet the standards of established organic reactions.4
Until recently, the catalysts utilized by chemists for enantioselective synthesis of organic compounds were either transition metal catalysts or enzymes.6 Chemists commonly use transition metal-based catalysts,7 and the development of enantioselective chiral transition metal complexes enabled the synthesis of enantiomerically pure compounds. Transition metal-based catalysts have been utilized in organic synthesis for many years and its importance was emphasized with the awarding of the Nobel Prize in 2001 to William S. Knowles, Ryoji Noyori and K. Barry Sharpless for their collective work on chirally catalyzed reactions.6 Transition metal-based catalysts are extremely useful in syntheses but large scale industrializations of these processes face certain obstacles. The relatively high costs of metal catalysts and popular chiral diphosphine ligands make industrial scale preparations unviable. Due to the toxicity of most transition metals the purification, especially for pharmaceuticals, is a significant factor that must be addressed. Other difficulties with transition metal-based catalysts must also be overcome, such as catalyst recovery, pollution and waste management, before industrial-scale preparations may be attempted.
Enzymes and chemists have often tried to emulate Organocatalysts
o Types of organocatalyst, Mode of action of each
Most organocatalysts can be generally classified as Lewis bases, Lewis acids, Brønsted bases, and Brønsted acids.7
The general catalytic cycles proposed by List7 are shown in Scheme 1. Accordingly, Lewis base catalysts (B:) initiate the catalytic cycle via nucleophilic addition to the substrate (S). The resulting complex undergoes a reaction and then releases the product (P) and the catalyst for further turnover. Lewis acid catalysts (A) activate nucleophilic substrates (S:) in a similar manner. Brønsted base and acid catalytic cycles are initiated via a (partial) deprotonation or protonation, respectively. Lewis base catalyst initiates the catalytic cycle by nucleophilic attack on the substrate. The resulting complex undergoes reaction and releases product and the catalyst for the further turn over. Lewis acid catalysts also activate substrates in a similar manner. Bronsted base and acid catalysis is initiated by the partial protonation or deprotonation, respectively. The following report illustrates the case studies of organocatalysts exploring Lewis basicity or Lewis acidity in catalyzing organic reactions.
An ideal organocatalyst should possess (i) easy availability; (ii) accessibility of both the enantiomers with comparable price, (iii) low molecular weight, (iv) easy separation from the product, (v) easy recovery after work-up, without racemization.
Organocatalyst can perform reactions under aerobic atmosphere with wet solvents. The catalysts are inexpensive and some of them are by-products from the other organic reactions. They are stable at ambient conditions. They can be easily separated from the products without racemization. They can be anchored to a solid support and be reused without losing catalytic activity.
o reactions, etc.
* Carbohydrates advantages from review paper
Carbohydrates have only lately been recognized as versatile staring materials for organocatalysts.8
Carbohydrate derived Organocatalysts
Prominent Shi Ketone
(1) Pracejus, H.; Matje, H. Journal Fur Praktische Chemie 1964, 24, 195.
(2) Dalko, P. I. Enantioselective Organocatalysis: Reactions and Experimental Procedures; Wiley-VCH, 2007.
(3) Dalko, P. I.; Moisan, L. Angewandte Chemie-International Edition 2001, 40, 3726.
(4) Dalko, P. I.; Moisan, L. Angewandte Chemie-International Edition 2004, 43, 5138.
(5) Heaton, C. A. Chemical Industry, 1994.
(6) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis; WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2005.
(7) Seayad, J.; List, B. Organic & Biomolecular Chemistry 2005, 3, 719.
(8) Boysen, M. M. K. Chemistry-a European Journal 2007, 13, 8649.