Multi-Component Transformations

Domino reactions present a modern approach in organic synthesis since they allow the preparation of complex molecules starting from simple substrate in a few steps and in many cases with high stereoselectivity. Moreover, as multi-component transformation they are highly suitable for combinatorial chemistry and give access to libraries of great diversity. 

Bienayme H, Huhne C, Oddon G et al (2000) Maximizing synthetic efficiency multi-component transformations lead the way. Chem Eur J 6(18) 3321-3329 Syamala M (2005) A decade of advances in three-component reactions. A review. Org Prep Proced Int 37(2) 103-171... 

Undoubtedly, there are still many metal-mediated multi-component transformations waiting to be discovered in this challenging and appeahng area of research. 

This improvement of the original Morita protocol provided a viable synthetic method, for this multi-component transformation formed a unique C-C bond and afforded functionality conducive to further derivatization in an atom economical manner albeit suffering long reaction times from days to weeks. In the early 1980s, the synthetic organic chemistry community realized the utility of this reaction and has continued into the 21 century. Thus, the reaction has been the subject of numerous reviews. Because of these recent reviews, this chapter will highlight only some literature examples of the last several years. 

The Biginelli reaction involves an one-pot reaction between aldehyde 1, 1,3-dicarbonyl 2, and urea 3a or thiourea 3b in the presence of an acidic catalyst to afford 3,4-dihydropyrimidin-2(l//)-one (DHPM) 4. This reaction is also referred to as the Biginelli condensation and Biginelli dihydropyrimidine synthesis. It belongs to a class of transformations called multi-component reactions (MCRs). 

Johnson GR, BF Smets, JC Spain (2001) Oxidative transformation of aminodinitrotoluene isomers by multi-component dioxygenases. Appl Environ Microbiol 67 5460-5466. 

Smith and co-workers have employed NHC 81 to catalyse the 0- to C-carboxyl transfer of a range of oxazolyl carbonates 80, forming 82 with the generation of a C-C bond at a quaternary centre with good catalytic efficiency [27], This transformation presumably proceeds via the generation of an intermediate carboxyazolium species, and has been utihsed as a component of domino multi-component reactions [28], as well as the rearrangement of indolyl and benzofuranyl carbonates (Scheme 12.15) [29]. 

Abstract Recent advances in the metal-catalyzed one-electron reduction reactions are described in this chapter. One-electron reduction induced by redox of early transition metals including titanium, vanadium, and lanthanide metals provides a variety of synthetic methods for carbon-carbon bond formation via radical species, as observed in the pinacol coupling, dehalogenation, and related radical-like reactions. The reversible catalytic cycle is achieved by a multi-component catalytic system in combination with a co-reductant and additives, which serve for the recycling, activation, and liberation of the real catalyst and the facilitation of the reaction steps. In the catalytic reductive transformations, the high stereoselectivity is attained by the design of the multi-component catalytic system. This article focuses mostly on the pinacol coupling reaction. 

It is important to select stoichiometric co-reductants or co-oxidants for the reversible cycle of a catalyst. A metallic co-reductant is ultimately converted to the corresponding metal salt in a higher oxidation state, which may work as a Lewis acid. Taking these interactions into account, the requisite catalytic system can be attained through multi-component interactions. Stereoselectivity should also be controlled, from synthetic points of view. The stereoselective and/or stereospecific transformations depend on the intermediary structure. The potential interaction and structural control permit efficient and selective methods in synthetic radical reactions. This chapter describes the construction of the catalytic system for one-electron reduction reactions represented by the pinacol coupling reaction. 

The delayed light emission as observed from the Bolonian stone is now classified as phosphorescence. We know now that these stones contain barium sulfate with traces of bismuth and manganese, and that the corresponding reducing process concerns the transformation of sulfate into sulfur. It is now well known that alkaline earth metal sulfates emit phosphorescence that strongly increases when traces of heavy metals are present. The so-called inorganic multi-component compounds phosphor and crystallophosphor are in fact polycrystalline substances containing traces of some ionic activators of luminescence. 

Domino reactions increasingly gain importance in the search for new drugs. Especially appropriate is the use of multi-component reactions in solution combinatorial chemistry. In such a process described by Wessel et al.1231 an alkoxy-nitroenone 48 was treated with different anilines 49 to give ketene-NO-acetals which in the presence of aromatic aldehydes and TfOH are transformed into 50 (scheme 10). The substrate 48 is readily available by oxidation of the nitrosugar 47. 

A new methodology for the construction of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives 166 by combining the Ugi multi-component reaction with [2 + 2] enone-olefin photochemical transformations was recently reported [132] (Fig. 32). The additional functional groups are in this case an enone (165) and a C=C double bond. Although the overall sequence is capable of creating up to five stereocentres, in most cases only two diastereomers are observed, which are epimeric at the exocyclic stereogenic centre. 

In 1983, Sasaki et al. obtained rough first approximations of the mid-infrared spectra of o-xylene, p-xylene and m-xylene from multi-component mixtures using entropy minimization [83-85] However, in order to do so, an a priori estimate of the number S of observable species present was again needed. The basic idea behind the approach was (i) the determination of the basis functions/eigenvectors V,xv associated with the data (three solutions were prepared) and (ii) the transformation of basis vectors into pure component spectral estimates by determining the elements of a transformation matrix TsXs- The simplex optimization method was used to optimize the nine elements of Tixi to achieve entropy minimization, and the normalized second derivative of the spectra was used as a measure of the probability distribution. 

A general way to improve synthetic efficiency, which in addition also gives access to a multitude of diversified molecules in solution, is the development of multi-component domino reactions which allow the formation of complex compounds starting from simple substrates. Domino reactions are defined as processes of two or more bond-forming reactions under identical conditions, in which the subsequent transformation takes place at the functionalities obtained in the former transformation thus, it is a time-resolved process [la,c,f,3]. The quality and importance of a domino reaction can be correlated to the number of bonds formed in such a process and the increase of complexity. Such reactions can be carried out as a single-, two- or multicomponent transformation. Thus, most of the known multicomponent transformations [4], but not all, can be defined as a subgroup of domino transformations. 

It is dear from the variety of natural products described in this chapter that multi-component reaction strategies encompass a very broad scope of synthetic transformations. The development of new MCRs constantly generates new opportunities, and it is likely that the application of these powerful processes in natural product synthesis is still in its infancy. Appealing characteristics of MCR strategies such as convergence and step-economy are expected to draw more and more synthetic chemists to design and implement MCRs in the total synthesis of complex natural products. 

Like most multi-component fats, milk fat exhibits monotropic polymorphism. Only one polymorph is stable (Bailey, 1951). Molecular rearrangements result in polymorphic transformations from the less to the more thermodynamically stable forms (Hagemann, 1988). Figure 7.5 shows the polymorphic transformations that occur in edible fats. 

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