Barton method radical cyclizations

Carbon-centered radicals generated by Barton s thiohydroxamate method can also participate in ring-forming reactions (see Scheme 26).52b,s3 For example, irradiation of 129 results in the formation of compound 130 (82% yield). The outcome of this transformation is reminiscent of Stork s elegant radical cyclization/trapping processes (see Schemes 7 and 8), in that/botn alkene carbon atoms have become functionalized. / I... 

Recent work by Newcomb has resulted in the emergence of a second method for the cyclizations of amminium radical cations that shows good synthetic potential.175-176 As illustrated in Scheme 42, AMiy-droxypyridine-2-thione carbamates can be generated and cyclized by analogy to the Barton method (which uses thione esters). In Scheme 42, the preparation of the precursors and two variants on the cyclization, reductive trapping and thiopyridyl trapping are illustrated. 

Alkoxyl radicals can be generated by a variety of methods including peroxide reduction, nitrite ester photolysis, hypohalite thermolysis, and fragmentation of epoxyalkyl radicals (for additional examples of alkoxyl radical generation, see Section 4.2.S.2). Hypohalites are excellent halogen atom donors to carbon-centered radicals, and a recent example of this type of cyclization from the work of Kraus is illustrated in Scheme 43.182 Oxidation of the hemiketal (57) presumably forms an intermediate hypoiodite, which spontaneously cyclizes to (58) by an atom transfer mechanism. Unfortunately, the direct application of the Barton method for the generation of alkoxyl radicals fails because the intermediate pyridine-thione carbonates are sensitive to hydrolytic reactions. However, in a very important recent development, Beckwith and Hay have shown that alkoxyl radicals are formed from N-alkoxypyridinethiones.183 Al-... 

The Liu synthesis of Aa-methyl-A18-isokoumidine (137) (214) starts from L-tryptophan (138), which was transformed to intermediate 139 in six steps. The Dieckmann condensation of 139 afforded the /3-ketoester 140. Oxidative free radical cyclization of /3-ketoester 140, initiated with Mn(0Ac)3, H20/Cu/(0Ac)2 H2O, followed by the removal of the Na-protecting group, led almost quantitatively to 141. Hydrolysis and decarboxylation using the Barton method afforded, via compound 142, intermediate 143. Treatment of 143 with (CH3)2S = CH2/dimethyl sulfoxide (DMSO) THF yielded the epoxy derivative 144, which was reduced with A1H2C1 in THF to the, not yet naturally found, jVa-methyl-A18-isokoumidine (137) (Scheme 12). 

A useful modification of the Barton deoxygenation of secondary alcohols involves the use of O-phenylthionocarbonates developed by Robins et al. [15]. Application of this method for the generation and cyclization of a hex-5-ynyI radical is shown is Scheme 5. The precursors are readily prepared from D-ribose by a Grignard addition, followed by selective alcohol derivatizations. The major exo-isomer has been converted into carba-a-D-ribofuranose [16]. 

Sequences in which addition precedes cyclization are not as straightforward to conduct as the reverse however, they are very important because a net annulation results (that is, a new ring is formed by the union of two acyclic precursors in one experimental step). The intermediate radical is differentiated from the other radicals provided that the cyclization reaction is rapid, but it can be difficult to differentiate the initial radical from the final radical. As illustrated in Scheme 57, this is particularly true in the tin hydride method because many different types of radicals react with tin hydride at similar rates. Reaction of (69) under standard radical addition conditions produces (70), which results from a sequence of addition/cy-clization/addition.233 That the last C—C bond is formed actually results from a lack of selectivity the initial and final radicals are not differentiated and they must undergo the same reaction. Of course, this lack of selectivity is of no consequence if the product contains the desired skeleton and the needed functionality for subsequent transformations. Such sequences are very useful for forming three carbon-carbon bonds, and they can also be conducted by Barton s thiohydroxamate method.234 Structural modifications are required to differentiate the initial and final radicals, and, as illustrated by the conversion of (71) to (72), phenyl groups can provide the needed differentiation (probably by retarding the rate of addition more than they retard the rate of hydrogen abstraction). Clive has demonstrated that phenyl-substituted vinyl radicals also provide the needed selectivity, as illustrated by the second example in Scheme 57.233... 

Fig. 1.42. Cyclization of a 5-hexenyl radical intermediate from a Barton-McCombie defunctionalization as a method for cyclopentane annulation (cyclizing defunctionalization, in terms of Figure 1.2 this means a "substitution including a fragmentation and an addition ).

Fig. 1.35. Cyclization of a 5-hexenyl radical intermediate from a Barton-McCombie defunctionalization as a method for cyclopentane annulation.

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