Template-controlled cyclizations

An attractive way to overcome the problem described above is the use of templates [26]. According to Bush, a template organizes an assembly of atoms, with respect to their loci, in order to achieve a particular linking of atoms [27]. 

Lindsey s group used the same methodology for the synthesis of a hexameric wheel of porphyrins that shows in the presence of appropriate guest molecules interesting light-harvesting properties [29]. Its synthesis starting from 67 and 

An interesting precoordination of bisacetylenes was reported by Bauerle and coworkers. Reaction of the terthiophene diyne 71 with ds-Pt(dppp)Cl2 (72) yielded the metallacycle 73 in 91 % yield after chromatography [30], Treatment of 73 with iodine led, with reductive 1,1-elimination, to the formation of the macrocycle 

74 in 54% isolated yield. Interestingly, this cyclic dimer was not observed when 71 was cydized in a statistical reaction under high-dilution conditions. 

The macrocycle formation proceeds via the intermediate compound A that can undergo two different reactions either intramolecular cyclization towards the desired macrocycle M or intermolecular reaction with additional A to produce the 

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COMPLEXES WITH NR,NH- AND NH,NH-NHCS BY TEMPLATE-CONTROLLED CYCLIZATION REACTIONS... 

Scheme 9.10 Template-controlled cyclization of 2-hydroxyphenyl isocyanide followed by Af-alkylation.

Complexes bearing protic NHC ligands are accessible by various synthetic routes such as the deprotonation of azoles followed by reaction with a transition metal complex, the template-controlled cyclization of functionalized isocyanides, and the oxidative addition of different azoles to transition metal complexes. The complexes with simple monodentate NR,NH-NHCs often tend to tautomerize to give the N-bound azoles. This type of tautomerization is prevented in complexes with donor-functionalized NR,NH-NHCs. Recent smdies demonstrate that complexes with protic NHCs obtained from C2-H azoles are formed by an oxidative addition/reductive elimination reaction sequence. The N—H group in complexes with protic NR,NH-NHCs can serve as a hydrogen bond donor and thus as a molecular recognition unit and may enable various types of bifunctional catalysis. Recent smdies indicate that even biomolecules such as caffeine can be C8-metallated. It... 

Much simpler than the template-controlled generation of p-functionalized isocyanides is their direct use. 2-Hydroxyalkyl isocyanide 59, where the nucleophilic group and the isocyanide are linked together, spontaneously cyclizes upon activation of the isocyanide by coordination to an electron-poor metal center under... 

Although the mechanism of the base-induced formation of calixarenes has been studied in some detail, the reaction pathways remain uncertain. The most intuitively reasonable proposal is that the immediate precursor of any particular calixarene, regardless of size, is the linear oligomer carrying the requisite number of aryl residues. Another proposal, however, postulates that calix[8]arenes, for example, arise from intermolecularly hydrogen-bonded dimers (hemicalixarenes) formed from a pair of crescent-shaped, intramolecularly hydrogen-bonded linear tetramers. Calix[4]arenes, formed under considerably more strenuous conditions, have been postulated to be the result not of direct cyclization of the linear tetramer but of reversion of the calix[8]arene. The cyclic octamer is viewed as the product of kinetic control, and the cyclic tetramer is viewed as the product of thermodynamic control. The particular efficacy of KOH and RbOH for the formation of calix[6]arenes suggests that the hexamer is the product of template control. 

Generally, isocyanides can be attacked by proton bases HX (X = OR, RNH) in a nucleophilic reaction that leads to acylic heterocarbene complexes [27, 28] The use of functionalized isocyanides containing both the isocyanide group and the nucleophile in the same molecule gives access to complexes with heterocyclic carbene ligands via an 1,2-addition across the C=N triple bond [29]. A number of research groups have been active in the development of nucleophile-functionalized isocyanides, which could subsequently be cyclized in metal template-controlled reactions. 

Five years later, Ley and coworkers [149] reported the total synthesis of tetronasin based on a biosynthetically inspired metal-templated polyene cyclization reaction of open chain precursor 310 (Scheme 1.49). By this transformation, Ley installed simultaneously four new stereocenters and obtained Yoshii s intermediate 312 with complete stereochemical control. 

The radical is generated on the sugar template using mostly the tin hydride method and halo derivatives [72,87,89], thionocarbonate [90-91], or selenium derivatives [91,94, 95]. Again, in these reactions, the kinetically controlled 5-exo cyclization is always... 

Control experiment indicated that template effect (in the presence of different metal salts) [108] was not operating for this transformation. The presence of NH function in 86 that could potentially form a H-bond with oxazole ring, thus preorganizing the cyclization precursor [109], was not an obligation. Indeed, compound 86 (R = H) and 87 (R = Et, Fig. 2) was obtained in essentially identical yield. Aliphatic diamines are suitable substrates, as cyclophane 88 and 89 can be prepared in reasonable yield. It is interesting to note that a 47% yield of 89 meant 88% yield per chemical bond created, including the macrocyclization step. 

Few examples have been reported demonstrating enantioselective cyclization methodology. One known example, however, is similar to the diastereoselective cyclization of 175, which uses a menthol-derived chiral auxiliary and a bulky aluminum Lewis acid (see Eq. (13.55)). The enantioselective variant simply utilizes an achiral template 188 in conjunction with a bulky chiral binol-derived aluminum Lewis acid 189 (Eq. (13.59)) [75]. Once again the steric bulk of the chiral aluminum Lewis acid complex favors the s-trans rotamer of the acceptor olefin. Facial selectivity of the radical addition can then be controlled by the chiral Lewis acid. The highest selectivity (48% ee) was achieved with 4 equivalents of chiral Lewis acid, providing a yield of 63%. 

One approach to oligomer control in a free-radical polymerization utilizes bound monomers and relies on templated radical macrocyclization reactions. Successful execution of this strategy requires that cyclotelomerization effectively compete with intermo-lecular chain transfer. Scheme 8-2 in Section 8.1 depicts this chemistry schematically wherein radical addition (A), cyclization (C), and chain transfer (T) provide an =3 telomer. The key macrocyclizations (cyclotelomerizations) must precede chain transfer. These transformations are well precedented by systematic investigations of free-radical macrocyclizations that appeared in the 1980s [19-23] and by the seminal contributions of Kammerer, Scheme 8-4 [24-34]. 

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