Radical bicyclic ring systems

Scheme 10.17 illustrates allylation by reaction of radical intermediates with allyl stannanes. The first entry uses a carbohydrate-derived xanthate as the radical source. The addition in this case is highly stereoselective because the shape of the bicyclic ring system provides a steric bias. In Entry 2, a primary phenylthiocar-bonate ester is used as the radical source. In Entry 3, the allyl group is introduced at a rather congested carbon. The reaction is completely stereoselective, presumably because of steric features of the tricyclic system. In Entry 4, a primary selenide serves as the radical source. Entry 5 involves a tandem alkylation-allylation with triethylboron generating the ethyl radical that initiates the reaction. This reaction was done in the presence of a Lewis acid, but lanthanide salts also give good results. 

Useful bicyclic ring systems are obtained by (TMS)3Si radical-mediated fragmentation of strained ketoalkene precursors. For example, the ketoalkene 64 reacted with 1.5equiv of silane to give 95% of hydrindanone 65 (Reaction 7.67) [78]. (TMS)3Si radical adds first to the terminal alkene and the carbon-centred radical can relieve the strain by cleaving the adjacent C—C bond. 

Another cyclic system was also constructed from the 4-hydroxyproHne derivative 29, which was subjected to the decarboxylation-iodination protocol (Scheme 17). Allylation at C-1 followed by a radical-mediated allylation at C-2 and ring-closing metathesis provided the bicyclic ring system 30 known from many naturally occurring alkaloids. 

Bicyclic ring systems containing three or four-membered rings have special bonding forces, which are reflected in their unusual chemistry. Their electron-transfer reactions have been studied in the gas, liquid, and solid phases, and the structure and reactivity of their radical cations have been the target of intense scrutiny. 

Intramolecular trapping of the radical produced by the PET fragmentation was utilized by Cossy et al. for the construction of bicyclic ring systems (Scheme 79) [335]. 

Annulated ring systems have as /1,7-substituents, when compared to annulated cyclopentyl radical systems, a stronger effect on the stereoselectivity than the corresponding combination of acyclic substituents. In all cases, attack tram to the /J.y-m-annulated ring is preferred. The stereoselectivity depends, furthermore, on additional substituents at the radical and the alkene, but it appears that the reactions of cyclohexyl radicals proceed less selectively than their cyclopentyl analogs. One frequently used route to these systems is sequential cyclization/ addi-tion reactions, in which the primary radical cyclizes to form the bicyclic ring system, followed by intermolecular addition to an alkene45,47 74. 

Samarium(II) iodide-promoted radical cydizations have also played a key role in the total synthesis of (-)-grayanotoxin III [43b]. Among the methods utilized for the synthesis of this molecule was an intramolecular ketyl olefin coupling reaction generating a bridged bicyclic ring system (Eq. 68). 

Scheme 19. Preparation of bicyclic ring systems by intramolecular addition of carbohydrate-based radicals onto C-linked acceptors...

The geometry of the bicyclic ring system in radical C directs the half-filled orbitals toward one another and its lifetime is less than 1 x 10 ° s. ... 

Davies and coworkers [55] disclosed a radical domino approach for the facile construction of bicyclic ring systems during their investigation on bis-vinyl ethers (Scheme 5.30). Thus, submitting the bis-vinyl ethers 142 to radical conditions (triphenyltin hydride/AIBN, refluxing benzene) led to the desired product 143 in moderate to good yields (33-81%) with up to 8 1 diastereoselectivity. 

The major factor identified in controlling the lifetimes of these radicals is the orientation of the singly occupied orbitals with respect to one another. In A, they are essentially parallel. This is a poor orientation for interaction. Diradical B is more flexible and rapidly reacts to give the coupling and fragmentation products. The geometry of the bicyclic ring system in radical C directs the half-filled orbitals... 

Reduction of an intermediate radical from the convex face of the cis-bicyclic ring system was to control stereochemistry at C20- Compound 163 was to be prepared from 164, which was to come from quinic acid (165) through a series of protections and oxidation state adjustments. 

Intermolecular trapping of this organosamarium with an appropriate electrophile produces branched cyclopentanol derivatives. In addition, the presence of intramolecular radical traps allows the rapid assembly of bicyclic ring systems with stereodefined double bonds, via an appropriate intramolecular cyclization. For example, reaction of iodopyranoside 82 with Sml2 in the presence of HMPA afforded bicyclic derivative 83 (Scheme 3.31) [67]. 

In general, the homo radical domino reaction is a powerful tool for the construction of complex molecules. Further examples are the synthesis of the BCD-Ring system of progesterone by Takahashi et al.,[521 the construction of bicyclic octanol derivatives by Sonoda et al.[531 and the total synthesis of (+)-claantholide and (-)-estafiatin by Lee et al.[541... 

Radical cyclizations catalyzed by 67a require the regeneration of the titanocene catalysts by a stoichiometric reductant, such as manganese. When 10 mol% of substituted cyclopentadienyltitanium complex 47e is applied instead truly catalytic cyclization sequences of epoxides 86 are possible (Fig. 25) [160]. Reductive radical generation from 86 promoted by titanocene chloride 67e and subsequent 5-exo cyclization of radical 86A generates a titanoxy cyclopentylalkyl radical 86B. Since the electron-poor titanocene chloride 67e reduces the tertiary radical 86B only sluggishly, its extended lifetime allows for a 1,5-SHi affording the bicyclic tetrahy-drofuran ring system 87. At the same time catalyst 67e is liberated. The reaction... 

In an extension of this chemistry, Molander and Harris have recently demonstrated that Smlj may additionally be employed in either one of an anionic/anionic or an anionic/radical sequential reaction for the stereocontrolled construction of complex bicyclic and tricyclic ring systems, which enhances even further the versatility and possibilities of this reagent [4, 5]. The Molander team, having greatly contributed to the popularity of this reagent over the last de-... 

Briggs et al. proposed a new strategy for the synthesis of tricyclic structures using acyl xanthates as precursor for acyl radicals [121]. Irradiation with visible light of a solution of acyl xanthate in presence of 1,6-diene 126 afforded czs-fused bicyclic compound 127 in a good yield (Scheme 38). Radical reduction of xanthate and subsequent aldol condensation leads to the formation of [5.5.5]-fused ring systems similar to those of the triquinane terpene family. 

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