Three component strategy

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

White and Kawasaki have employed a three-component strategy to access an advanced dienyl fragment in their total synthesis of (+)-latrunculin A 102 (Scheme... 

ZHU-SALZMAN, K., KOlWA, H., SALZMAN, R.A., SHADE, R.E., AHN, J.E., Cowpea bruchid Callosobruchus maculatus uses a three-component strategy to overcome a plant defensive cysteine protease inhibitor. Insect Molec. Biol, 2003, 12, 135-145. 

Saha et al. [103] developed an efficient and one-pot three-component strategy for synthesizing highly functionalized quinazoline derivatives 70. A mixture of 2-ami-nobenzophenone, aromatic aldehyde, and ammonium acetate in the presence of I2 provides desired products in excellent yields even at moderate temperature (40 °C), with no need of chromatographic purification (Scheme 10.52). 

Chemoselective carbonylation of a vinyl iodide 34 with alcohol containing a vinyl bromide moiety 35 has been successfully employed for the solid-phase synthesis of a macrosphelide precursor 36 [43]. After the 4-methoxyphenylmethyl (MPM) group was removed, the palladium-catalyzed carbonylative macrolactonization of the vinyl bromide 37 achieved the synthesis of the macrosphelide-supported derivative 38 (Scheme 9.13). The combinatorial synthesis of a 122-member macrosphelide library has been performed by the three-component strategy based on the palladium-catalyzed chemoselective carbonylation/macrolactonization reaction. 

Scheme 11.61 Prostaglandin synthesis according to a three-components strategy in which both side chains are installed as organocuprate reagents.

Scheme 5. Larock s palladium-promoted, three-component coupling strategy for prostaglandin synthesis.

In a defensive strategy that is based on the detection of a chemical/biological agent in order to initiate a response, the time required for authorities to respond to an attack has three components the inherent response time of the detection system, the time required to verify the validity of a detector alarm, and the time required to decide on what action to take in response to the alarm. These three elements are discussed in more detail below. 

Scheme 2.1 Three-components coupling strategy for 1 by medicinal chemists.

It should be also noted that, in a very recent publication, Liu and coworkers were successful in applying microwave radiation within their domino approach towards the synthesis of pyrrolo[2,l-fc]quinazoline alkaloids such as deoxyvasicinone, 8-hy-droxydeoxyvasicinone, mackinazolinone and isaindigotone, which exhibit a promising broad spectrum of biological activities. In the case of isaindigotone, the authors were able to extend their strategy to a three-component procedure, which comprises the domino conversion of anthranilic acids and Boc-protected amino acids into the tricyclic core skeleton [43]. 

During the last decade, a substantial number of novel (sometimes even stereoselective) strategies for the preparation of allenic prostaglandins have been devised. The approach used by Patterson involves a three-component coupling via a 1,4-addi-tion of the organocopper compound 121 to the enone 120, followed by alkylation of the enolate formed with the bromide 122 (Scheme 18.40) [121]. However, due to the notoriously low reactivity in the alkylation of the mixed copper-lithium enolate formed during the Michael addition [122], the desired product 123 was obtained with only 28% chemical yield (the alkylation was not even stereoselective, giving 123 as a 1 1 mixture of diastereomers). 

Scheme 9.7. An asymmetric, three-component synthetic strategy for / -lactam synthesis.

A vast array of piperidine containing cores, both natural and synthetic, are of biological and medicinal interest. These heterocyclic scaffolds have been the subjects of considerable synthetic efforts, especially for the construction of optically active compounds. In this context, Khan et al. reported a catalytic bromodi-methylsulfonium bromide (BDMS) three-component reaction of 1,3-dicarbonyls with aromatic aldehydes and aromatic amines for a facile access to highly functionalized piperidines (Scheme 24) [104]. This strategy is an interesting illustration of... 

Another example of a MCR-based strategy for the synthesis of pyridines was reported by Kantevari et al. in 2007. Thus, the three-component condensation of enaminones, 1,3-dicarbonyls, and ammonium acetate in the presence of a catalytic amount of a tangstocobaltate salt as heterogeneous catalyst, either in refluxing solvent or under solvent-free conditions, allowed the regioselective formation of 2,3,6-trisubstituted pyridines and 2,7,7-trisubstituted tetrahydroquinolin-5-ones (Scheme 55) [155]. This methodology combines shorter reaction times and... 

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