Template reaction ring-closing

Examples of template procedures in which the ring-closing condensation involves reaction at a centre other than a donor atom have been documented. In an early synthesis of this type, the reaction of bis-(dimethylglyoximato)nickel(n) (62) with boron trifluoride was demonstrated to yield the corresponding complex of the N4-donor macrocycle (63) (Schrauzer, 1962 Umland Thierig, 1962). In this reaction the proton of each bridging oxime linkage is replaced by a BF2+ moiety. X-ray... 

A great variety of aza macrocycle complexes have been formed by condensation reactions in the presence of a metal ion, often termed template reactions . The majority of such reactions have inline formation as the ring-closing step. Fourteen- and, to a lesser extent, sixteen-membered tetraaza macrocycles predominate, and nickel(II) and copper(II) are the most widely active metal ions. Only a selection of the more general types of reaction can be described here, and some closely related, but non metal-ion-promoted, reactions will be included for convenience. The reactions are classified according to the nature of the carbonyl and amine reactants. 

A library of vancomycin analogues has been prepared using ring closing metathesis reactions in aqueous solution (Nicolaou, K. C., Hughes, R., Cho, S. Y., Wissinger, N., Labischinski, H., Endermann, R. Chem. Eur. J. 2001, 7, 3824) a kinetic template effect was observed when the library was prepared in the presence of a dipeptide trap. 

Walters, M.A. et al.. Templates for exploratory library preparation. Derivatization of a functionalized spirocyclic 3,6-dihydro-2H-pyran formed by ring-closing metathesis reaction, J. Comb. Chem., 4,125, 2002. 

Figure 11 A general strategy to knot synthesis based on the combination of metal templating and the ring-closing metathesis reaction.

In 1997, a [2]catenane bearing Cgo was synthesized through Stoddart s methodology,exploiting n-n interactions between aromatic moieties. " The double Bingel addition of a [34]crown-10 bismalonate to Cgo was followed by a ring-closed reaction, where the electron-deficient cyclobis-(paraquat-p-phenylene) (CBPQT +) macrocycle recognizes the electron-rich hydroquinone template. 

A conceptually diHerent, convergent route was developed in 2006 by Nicolaou and Harrison [35, 146] for the enantioselective synthesis of 290 and 291. On the basis of an enantioselective Mg(II)-templated Diels-Alder reaction between chiral dienol 292 and methyl acrylate and on previous model studies to build the spirotetronic core [143c], Nicolaou prepared a ring-closing metathesis (RCM) precursor (296) that smoothly afforded atropoisomer 290 after oxidation and deprotection (Scheme 1.45). Nicolaou also observed that 290 and 291 participate in an acid-catalyzed intercorversion leading to equilibrium mixtures of various ratios depending on the acidic media. 

Nevertheless, self-assembling processes by nature rely on weak interactions and the isolation of chemically stable knots and links requires a final knotting step in which covalent bonds are formed. While irreversible reactions such as Williamson ether reactions" and ring closing methathesis are employed successfully to form knots and links, their template-directed syntheses have recently been enriched by the concept of dynamic covalent chemistry (DCC). DCC employs reversible covalent bond formation that allows equilibration of a system toward the most thermodynamically stable structures dictated by the sum of the non-covalent bonding interactions. 

The importance of indoloazocine scaffold in indole alkaloids has been supported by several methodologies and total syntheses published through the years. One example is the total synthesis of ( )-apparicine by the Re.nne.sar group (Scheme 4.1). Indeed, the indoloazocine scaffold was synthesized via an indole-template ring-closing metathesis reaction. Another key step was the Heck cycli-zation to finally assemble the bridged skeleton [27]. 

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