Radical macrocyclization

As will be discussed later, the novel pentacyclic antitumor alkaloid roseophilin continues to attract much synthetic effort and several approaches relied on the venerable Paal-Knorr condensation for construction of the pyrrole moiety. For instance, Trost utilized this reaction upon diketone 1 to afford the tricyclic core 2 of roseophilin in a strategy featuring an enyne metathesis as a key step <00JA3801>, while another formal synthesis of this alkaloid utilized a radical macrocyclization to produce the ketopyrrole core <00JCS(P1)3389>. 

The field of alkyl radical macrocyclization reactions was further augmented with an n + 1) strategy, which incorporates a CO unit in the macrocycle [93], Thus, in the presence of highly diluted (0.005-0.01 M) (TMS)3SiH, co-iodoacrylates underwent an efficient three-step radical chain reaction to generate 10- to 17-membered macrocycles in 28-78% yields, respectively (Reaction 7.82). 

Radical macrocyclization to taxane ring system. Treatment of the iodotrienone 1 with Bu.iSnH/AlBN provides two epimers (2 and 3) of the taxane ring system. The ring system 2 corresponds to that present in taxol, the natural alkaloid found in the bark of yew trees. 

Scheme 51), Weavers utilized direct formation of the a-iodomethylene-y-butyrolactone 148 from the propiolate 147 via atom transfer cyclization. Alke-noyloxymethyl iodides and selenides were converted into lactones upon treatment with tributylstannane or tributylgermane [101], In the (—)-zearalenone (152) synthesis reported by Pattenden [102] (Scheme 52), the ester tether is a bystander in the radical macrocyclization. 

Two distinct but related strategies that rely on templates to control the number of monomers incorporated into an oligomeric product can be envisioned. One of these approaches, shown in Scheme 8-2, relies on templated radical macrocyclization reactions to control telomer size [14, 15]. This strategy requires attachment of all of the monomer units to the template backbone and uses macrocyclization, which faces competition from intermolecular chain transfer, to control the telomer length. The chain transfer agent T-I (i.e., telomerization terminator) is not attached to the template. 

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]. 

Pyrazolecarbinols can be dehydrated to vinylpyrazoles, (438) — (446) (72JHC1373), or transformed into chloromethyl derivatives (81T987). Compound (440 R = CH2C1) thus prepared is the starting material for the synthesis of the macrocycles (226)-(228) (Section 4.04.2.1.2(vi)). Vinyl- and ethynyl-pyrazoles have been extensively studied (B-76MI40402) and many vinylpyrazoles are polymerized by free radical initiators. 

Radical IV can be considered as a unique phosphorus radical species. Reduction of the parent macrocycle with sodium naphtalenide in THF at room temperature gave a purple solution. The FPR spectrum displayed a signal in a 1 2 1 pattern, with flp(2P)=0.38 mT. DFT calculations on radical IV models indicated a P-P distance of 2.763 A (P - P is3.256 A in the crystal structure of the parent compound and the average value of a single P-P bond is 2.2 A). According to the authors, the small coupling constant arises from the facts that the principal values of the hyperfine tensor are of opposite sign and that the a P P one electron bond results from overlap of two 3p orbitals [88]. 

Methylation of [Co(tmt)]2+ with Mel leads to the potent methyl carbanion donor trans-[Co(tmt)Me2]+ (186). Reaction of this complex with variety of methyl-lead(IV) compounds in MeCN is rapid, leading to the same monomethylcobalt(III) product, but resulting in different methylated Pb derivatives depending on the reaction stoichiometry and Pb compound.839 The same complex rapidly transfers Me groups to Zn2+ and Cd2+ in MeCN,840 or Pb2+ and Sn2+ in water.302,841 The kinetics of Co—C bond formation in the reactions with primary alkyl and substituted primary alkyl radicals has been found to be influenced more by the structure of the macrocycle than by the nature of the radicals.842... 

When multiple peripheral substituents, as in [Ni(2,3,5,7,8,10,12,13,15,17,18,20-dodecaphenyl-porphyrin)], [Ni(5,10,15,20-tetra(/-butyl)porphyrin)], [Ni(2,3,7,812,13,17,18-tetracyclohexenyl-5,10,15,20-tetraphenylporphyrin)], and [Ni(OETPP)], cause the macrocycles to become nonplanar,283,284 the HOMOs of the porphyrins are destabilized and the molecules become easier to oxidize.283,285 In accord with the general discussion above, these compounds are oxidized to tt cation radicals and remain so even at low temperatures in CH2C12. However, upon addition of... 

Pendent arm 1,4,7-triazacyclononane macrocycles (91) and (92) have been used to stabilize the zinc-to-phenoxyl bond allowing characterization of these compounds.477 The interest in the zinc complexes comes from the wide potential range in which it is redox stable allowing observation of the ligand-based redox processes, this allows study of the radical by EPR and the electronic spectra is unperturbed by d-d transitions. Macrocycles of the type l,4,7-tris(2-hydroxybenzyl)-1,4,7-triazacylononane form a bound phenoxyl radical in a reversible one-electron oxidation of the ligand. The EPR, resonance Raman, electronic spectra, and crystal structure of the phenoxide complexes were reported. This compound can be compared to a zinc complex with a non-coordinated phenoxyl radical as a pendent from the ligand.735... 

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