Macrocyclization under radical conditions

Most of the kinetic models predict that the sulfite ion radical is easily oxidized by 02 and/or the oxidized form of the catalyst, but this species was rarely considered as a potential oxidant. In a recent pulse radiolysis study, the oxidation of Ni(II and I) and Cu(II and I) macrocyclic complexes by SO was studied under anaerobic conditions (117). In the reactions with Ni(I) and Cu(I) complexes intermediates could not be detected, and the electron transfer was interpreted in terms of a simple outer-sphere mechanism. In contrast, time resolved spectra confirmed the formation of intermediates with a ligand-radical nature in the reactions of the M(II) ions. The formation of a product with a sulfonated macrocycle and another with an additional double bond in the macrocycle were isolated in the reaction with [NiCR]2+. These results may require the refinement of the kinetic model proposed by Lepentsiotis for the [NiCR]2+ SO/ 02 system (116). 

Aprotic solvents mimic the hydrophobic protein interior. However, a functional artificial receptor for flavin binding under physiological conditions must be able to interact with the guest even in competitive solvents. As found by spectroscopic measurements with phenothiazene-labeled cyclene, the coordinative bond between flavin and Lewis-acidic macrocyclic zinc in methanol was strong enough for this function. Stiochiometry of the complex was proved by Job s plot analysis. Redox properties of the assemblies in methanol were studied by cyclic voltammetry which showed that the binding motif allowed interception of the ECE reduction mechanism and stabilisation of a flavosemiquinone radical anion in a polar solvent. As a consequence, the flavin chromophore switched from a two-electron-one-step process to a two-step-one-electron-each by coordination. 

Cyclic ketones. 1,5-Dienes undergo silylcarbonylation and cyclization in tandem in the presence of CO. Macrocyclic ketolactones are acquired from (o-iodoalkyl acrylates by an intramolecular radical Michael reaction under similar conditions. 

The free radical addition of a thiol to carbon-carbon double or triple bonds is a well-established reaction. It represents one of the most useful methods of synthesizing sulfides under mild conditions. Since its discovery [5] and its much later formulation as a free-radical chain reaction (Scheme 1) [6], the anti-Markovnikov addition of thiols to unsaturated compounds has been the subject of many reviews [8, 9]. These reactions were originally initiated by thermal decomposition of peroxides or azocompounds, by UV irradiation or by radiolysis [10]. (An example of addition of 1-thiosugar to alkenes initiated by 2,2 -azobisisobutyronitrile (AIBN) [11] is reported in equation (1)). More recently, organoboranes have been used as initiators and two examples (Et3B and 9-bora-bicyclo [3.3.1.] nonane) are reported in equations (2) and (3) [12,13]. Troyansky and co-workers [14a] achieved the synthesis of macrocycles like 12- and 13-membered sulfur-containing lactones by the double addition of thiyl radical to alkynes. An example is depicted in equation (4). The same approach has also been applied to the construction of 9- and 18-membered crown thioethers [14b]. The radical chain addition of thiyl radicals to differently substituted allenes has been considered in detail by Paste and co-workers [15], who found that preferential attack occurs at the central allenic carbon and gives rise to a resonance-stabilized ally radical. The addition of benzenethiol to allenic esters has been reported and the product formation has been similarly inferred (equation (5)) [16]. 

It has long been known that thiyl radicals add reversibly to double bonds (cf. Scheme 1) [17]. The (Z)-( ) interconversion of olefins by the addition-elimination sequence of thiyl radicals [18] is now an established methodology in chemical synthesis [19] and has been applied successfully as the key step in the synthesis of elaborate molecules such as the antifungal macrocyclic lactone (-)-gloeosporone [20a] and the antibiotic-antitumor agent (+)-hitachimycin [20b]. The E/Z ratio after equilibration generally reflects the thermodynamic stability of (Z)- and ( )-alkenes. It has recently been shown that equilibrium Z/E-18/82) for ( )- and (Z)-hexen-l-ol is reached with PhS radical in 1 h at 80°C [21]. Comparatively, the same isomeric composition is reached in 4h and lOh with Bu3Sn and (TMS)3Si respectively under similar conditions. 

In the presence of catalytic amounts of vitamin B12, it has been possible to couple 1,1-disubstituted alkenes with defined regiochemistry under mild conditions in environmentally benign solvent system such as ethanol/water (Table 1). The mechanistic studies led the authors to conclude that organic free radicals are formed in this reaction. In the current process, the rate of combination of two radicals is increased by removing the persistent Co(ll) radical with Ti(in) or Zn. This is in contrast to cobalt-catalyzed free-radical chain transfer and cobalt-mediated living radical polymerization in which the cobalt macrocycle s role is to reduce the steady-state concentration of free radicals (Equation (33)). ... 

Michael reaction of macrocyclic ketene silyl acetals or a-enones occurs smoothly under electron-transfer conditions whereas the reaction of 6-membered analogs is more sluggish, indicating the importance of ring flexibility to enable the a,/8-carbon-carbon bonds of both reaction components to rotate when the radical species are generated [72c]. 

Exposure of 14 (m = 3, R = rcrf-Bu) to cyclohexyl iodide, allyltributylstannane, and AIBN leads to a macrocycle 15 with two new stereogenic centers. The allyl group provides additional functionality for further transformations and also creates a new stereocenter in the process. In order to effect the desired macrocyclization, addition of the first-formed radical to the proximal acrylamide moiety must be faster than addition to the chain transfer agent allyltributylstannane, a requirement that can be fulfilled under appropriate reaction conditions. Premature chain transfer in this particular system, under conditions that discourage bimolecular reaction between two templates, leads to two simple n = 1 products (vide infra). 

Exploration of the template controlled free-radical oligomerization of other activated olefins began with standard monomers utilized in bulk polymer synthesis and the template 63. Vinyl acetate and acrylonitrile led only to uncontrolled polymerization, while vinylene carbonate did not react under the standard experimental conditions. More exotic monomers, such as vinyl trifluoroacetate and rert-butyl acrylate, were also unsuccessful. Only methyl acrylate polymerization was arrested by template 64 to provide the macrocyclized product 96 in modest yield as a mixture of five diastereomers (Scheme 8-25). Subsequent studies with the more effective thiophenyl-bearing template 63 at lower temperatures improved this yield to 35%. The diastereomer distribution was reminiscent of the methyl methacrylate-derived product, although no stereochemical assignments were made in this case either. 

Although ESR data for chlorin and BPheo cation radicals provide clear evidence of macrocycle distortions consonant with crystallographic results for the parent compounds[21,33,34], it would obviously be more instructive to examine the solution properties of distorted porphyrins under conditions where the conformations observed in the crystalline state are maintained in solution. We have therefore examined a series of synthetic porphyrins in which different peripheral substituents were added in order to deliberately introduce steric crowding that would be maintained in solution[32,35,36]. An example of this approach is shown... 

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