Two-component coupling process

The asymmetric total synthesis of prostaglandin Ei utilizing a two-component coupling process was achieved in the laboratory of B.W. Spur. The hydroxylated side-chain of the target was prepared via the catalytic asymmetric reduction of a y-iodo vinyl ketone with catecholborane in the presence of Corey s CBS catalyst. The reduction proceeded in 95% yield and >96% ee. The best results were obtained at low temperature and with the use of the B-n-butyl catalyst. The 6-methyl catalyst afforded lower enantiomeric excess and at higher temperatures the ee dropped due to competing non-catalyzed reduction. 

This palladium-catalyzed three-component coupling reaction leading to the formation of aryl-substituted allylic amines was recently adapted to solid-phase synthesis (Scheme 8.23). Amines were chosen to attach to a solid support (Rink resin) in this three-component coupling process and were reacted with a variety of aryl halides and linear or cyclic non-conjugated dienes, the reaction being carried out at 100 °C for two days in the presence of palladium acetate and diisopropylethyl-amine. A wide variety of aryl-substituted allylic amines were then obtained after cleavage from the solid support by trifluoroacetic acid [60],... 

An instructive and useful process is the two-component coupling of an alkene with an electrophilic radical the latter will of course not react with the protonated heterocycle, but after addition to the alkene, a nucleophilic radical is generated, which will react. ... 

The potential of one-pot three-component coupling reaction was further explored by the same group for the synthesis of substituted tetrahydropyranols 207 Ishikawa [96]. As for the two previous examples, the isolation of the Michael products A in suitable yields is only allowed when the addition of the different starting materials proceeds in a well-established order, thus avoiding undesired side reactions. Furthermore, this three-component coupling process could be successfully combined with an additional nucleophilic addition step to allow an asymmetric one-pot four-component coupling reaction to give rise to tetrahy-dropyrans 208 that are present in many natural products (Scheme 2.70). 

In 2005, Tanaka et al. [41] reported a four-component coupling process involving two acetylenes, a nitrile, and a divalent titanium tJkoxide reagent, Ti(OiPr), /2-iPrMgCl, for the synthesis of pyridines. Chiral pyridines could be synthesized by using chiral nitrile precursors. The yields were good. 

In the older literature and in papers by some industrial azo chemists up to the 1960s it was claimed that (Z)-diazoates react in azo coupling processes. This belief can be traced back to the paper by Schraube and Schmidt (1894), who discovered the (Z)/(ii)-isomerism of diazoates (see Sec. 1.1). The most important tool used by Schraube and Schmidt for distinguishing between the two isomers was the (correct) observation that only one of the isomers reacted with coupling components, forming the same azo dye as when diazonium salt solutions were used. The apparent reactivity of the (Z)-diazoate is due to the fact that its equilibrium with the diazonium ion is relatively rapid, whereas the diazonium ion is produced only very slowly from the (ii)-diazoate (see Sec. 7.1). 

Acyl residues are usually activated by transfer to coenzyme A (2). In coenzyme A (see p. 12), pantetheine is linked to 3 -phos-pho-ADP by a phosphoric acid anhydride bond. Pantetheine consists of three components connected by amide bonds—pantoic acid, alanine, and cysteamine. The latter two components are biogenic amines formed by the decarboxylation of aspartate and cysteine, respectively. The compound formed from pantoic acid and p-alanine (pantothenic acid) has vitamin-like characteristics for humans (see p. 368). Reactions between the thiol group of the cysteamine residue and carboxylic acids give rise to thioesters, such as acetyl CoA. This reaction is strongly endergonic, and it is therefore coupled to exergonic processes. Thioesters represent the activated form of carboxylic adds, because acyl residues of this type have a high chemical potential and are easily transferred to other molecules. This property is often exploited in metabolism. 

Two closely related reports of pyrazole generation by condensation of substituted hydrazines with enamino carbonyl compounds have appeared. In situ formation of an enaminoketone, by treatment of a diketone with dimethylformamide dimethyl acetal, was followed by tandem Michael addition-elimination/cyclodehydration under aqueous conditions in sealed microwave vessels (Scheme 3.12)17. Isoxazoles and pyrimidines were also prepared by replacing the substituted hydrazine with hydroxylamine or amidines, respectively (see Chapter 5, Section 5.3.2). The overall process may be regarded as another example of a multi-component coupling. In a similar fashion, enamino propenoates were condensed with substituted hydrazines to afford substituted pyrazoles (see Chapter 5, Section 5.3.2) (Scheme 3.12)18. 

Closer examination of tetrahydropyrans 173 clearly reveals that two molecules of aldehyde 174 have been appended onto allylsilane 171 via a novel three-component coupling reaction. Marko et al. proposed the mechanism depicted in Scheme 13.61 [65], Formation of heterocycles 173 is described as a sequence of two processes an initial ene-type reaction [80] which leads to alcohol 177 via the chair-like transition state 176, in which both the aldehydic R-group and the OTMS substituent assume an equatorial position. The high regio- and stereoselectivity observed in this ene-reaction can be nicely explained by considering the stabilizing /(-silicon effect and the repulsive 1,3-diaxial interactions. Transition state 176 contains no 1,3-diaxial interactions and benefits fully from the stabilizing /(-silicon effect [81, 82] (for more detailed transition-state discussion see ref. [63]). 

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