Modular reaction sequences

Abstract In the past decade, it has been extensively demonstrated that multicomponent chemistry is an ideal tool to create molecular complexity. Furthermore, combination of these complexity-generating reactions with follow-up cyclization reactions led to scaffold diversity, which is one of the most important features of diversity oriented synthesis. Scaffold diversity has also been created by the development of novel multicomponent strategies. Four different approaches will be discussed [single reactant replacement, modular reaction sequences, condition based divergence, and union of multicomponent reactions (MCRs)], which all led to the development of new MCRs and higher order MCRs, thereby addressing both molecular diversity and complexity. 

Fig. 7 Schematic representation of the modular reaction sequence (MRS) strategy to scaffold diversity...

Scheme 9 Modular reaction sequence involving the 1-azadiene SCR as initial MCR, to which several fourth components were added...

Scheme 10 Modular reaction sequences reported by Zhu and co-workers, involving an initial bis-amino oxazole MCR...

FIGURE 1.5 Modular reaction sequence approach in MCRs. 

MRS modular reaction sequences SMS silyl-modified Sakurai... 

Based on the application of three iterative halogenation/cross-coupling reaction sequences Handy et al. developed a modular synthesis of the lamellarin G trimethyl ether <04JOC0000>. 

An impressive reaction sequence for the modular synthesis of tetraarylated alkenes involving two directed Mizoroki-Heck reactions is outlined in Scheme... 

Recently, multistep enzyme-catalyzed reactions have attracted the attention of chemists and biotechnologists, as they can be combined in a modular manner and often lead to high-value compounds. All naturally occurring metabolic pathways are basically cascade reactions. Based on natural principles, synthetic chemists search for universal multistep processes applicable to a vast number of chemical compounds. Multistep enzyme-catalyzed reactions involving nonphysiological substrates and selective enzymes are of particular interest because they may lead to tailor-made complex molecules with desired properties. Moreover, one of the most important advantages of multistep enzyme-catalyzed reaction sequences... 

By applying the same postglycosylation/deprotection reaction sequence on tetrasaccharide 94, the remaining cleistetroside-5 was prepared in three steps. In addition, the revised route was also used to prepare two previously unknown analogs, cleistetroside-9 and -10. This was accomplished in a range of one to three steps by modular application of the postglycosylation reactions (dihydroxylation, acylation, and chloro-acylation) (Scheme 1.17). 

Ellman utilized the Suzuki coupling twice between a support-bound vinyl bromide and an alkyl 9-BBN derivative in a solid-phase synthesis of E- and F-series prostaglandins. The Suzuki reaction was performed in situ, with the hydroboration of a terminal olefin being followed by the palladium-mediated step. This sequence is attractive in library synthesis because of the wide range of suitable commercially available alkenes. The inspiration behind this chemistry was the solution-phase work of Johnson and Braun, where the couplings of 35 with 2-iodo-4-(silyloxy)cyclopent-2-enone 36 went well at room temperature with PdCljCdppO-AsPhj as catalyst (Scheme 41). The modular chemistry demonstrated in this paper was clearly amenable to adaptation to a solid-phase strategy. 

NRPS-independent siderophore (NTS) synthetases constitute another class of biosynthetic enzymes that can be divided into three types according to their amino acid sequence.These types are proposed to be specific for different substrates. Thus, type A enzymes are specific for citric acid, type B enzymes are proposed to be specific for a-ketoglutaric acid, and type C enzymes are specific for derivatives of citric or succinic acid. The type C enzymes are further divided into modular and iterative subtypes depending on whether they catalyze one or multiple condensation reactions. Thus for novel NTS synthetase systems uncovered by genome sequencing, structural features of their metabolic products can often be predicted. 

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