Cyclization, radicals transition states

It is important to note here that both of the 5-exo radical cyclizations (133—>132—>131, Scheme 27) must proceed in a cis fashion the transition state leading to a strained mms-fused bicy-clo[3.3.0]octane does not permit efficient overlap between the singly occupied molecular orbital (SOMO) of the radical and the lowest unoccupied molecular orbital (LUMO) of the alkene. The relative orientation of the two side chains in the monocyclic radical precursor 134 is thus very significant because it dictates the relationship between the two outer rings (i. e. syn or anti) in the tricyclic product. The cis-anti-cis ring fusion stereochemistry of hirsutene would arise naturally from a cyclization precursor with trans-disposed side chain appendages (see 134). 

It was proposed that the transition state requires approach of the radical directly above the site of attack and perpendicular to the plane containing the carbon-carbon double bond. An examination of molecular models shows that for the 3-butenyl and 4-pentenyl radicals (16, =1,2) such a transition state can only be reasonably achieved in < Xf>-cyclization (i.e. 16—> 15). With the 5-hexcnyl and 6-heptenyl radicals (16, w=3,4), the transition state for exo-cyclization (16- 15) is more easily achieved than that for enc/o-cyclization (i.e. 16 — 17). 

The rare [1,4] hydrogen transfer has been observed in radical cyclizations. With respect to [1,7] hydrogen shifts, the rules predict the thermal reaction to be antarafacial. Unlike the case of [1,3] shifts, the transition state is not too greatly strained, and such rearrangements have been reported, for example,... 

The multistep radical elimination may involve the generation of discrete intermediates, which for instance could be formed by a cyclization process7) such as 15- 16- 17e). Alternatively, there may be no intermediate involved in the elimination sequence, but the actual transition states 19, 22 are substantially lower in energy due to the anchimeric assistance of suitable functional groups9,10) (4). 

It can be assumed that in the domino process of, for example 5-3, a reactive radical cation intermediate 5-5 is initially formed [5]. The intramolecular cyclization then proceeds almost exclusively through a stable, chair-like, six-membered transition state 5-8 to give a distonic radical cation 5-9, which is trapped by the aromatic... 

Transition state effects communication of orthogonal orbitals in the transition state of radical-anionic cyclizations 23... 

Fig. 24 Relative energies for the transition states and radical products for the different cyclization pathways (benzannelated systems in parentheses).

The starting points for both C1-C5 and C1-C6 cyclizations are characterized using C1-C6 distances to stress that starting point for both cyclizations is the same enediyne radical-anion. However, for transition states and products of C1-C5 and C1-C6 cyclizations, the respective incipient bond length (C1-C5 or C1-C6) was used as the reaction coordinate... 

Models accounting for the observed selectivities can be obtained from simple analysis of transition structures, according to the work of Spellmeyer and Houk [37]. These authors have calculated the transition states for cyclizations of radicals to be those shown in Scheme 12.19, but with a hydrogen atom being replaced by the CH2OTiCp2Cl group. 

In an extensive investigation of the stereochemical memory effect, a series of six diastereomeric pairs of substrates was prepared to probe the effect of single, then multiple substituents on the 5-exo cyclization of amines onto alkene radical cations [144,145]. Overall, these cyclizations were highly dia-stereoselective and were accounted for by a transition-state model employing a chairlike transition state with attack of the nucleophilic amine on the opposite face of the alkene radical to the one shielded by the phosphate anion in the initial contact ion pair (Scheme 34), as exemplified in Schemes 35 and 36. 

The transition-state model for these cyclizations (Scheme 34) differs fundamentally from the well-established Beckwith-Houk transition model for radical cyclizations [130,146-148]. Thus, while both models invoke chairlike transition states, without excluding the possibility of twist boatlike systems in some instances, the Beckwith-Houk model involves full conformational... 

Scheme 28 explains the stereochemical outcome from the tandem radical cyclization in the presence of the [Yb(Ph-pybox)(OTf)3] (pybox = 2,6-bis(2-oxazolin-2-yl)pyridine). The ytterbium complex 107 is shown in an octahedral geometry (with one triflate still bound to the metal) where re-face cyclization is favored due to the steric interactions of the substrate and the ligand s phenyl groups. The 6-endo cyclization takes place via a chair-like transition state to yield a tertiary radical 108 followed by a ring flip and... 

Figure 11.5 Ball-and-stick transition state models for (i) the 5-dig-cyclization of the hexa-4,5-dien-l-yl radical (left) and the 5-exo-trig-cyclization of the hepta-5,6-dien-l-yl radical (right).

The tertiary a-ester (26) and a-cyano (27) radicals react about an order of magnitude less rapidly with Bu3SnH than do tertiary alkyl radicals. On the basis of the results with secondary radicals 28-31, the kinetic effect is unlikely to be due to electronics. The radical clocks 26 and 27 also cyclize considerably less rapidly than a secondary radical counterpart (26 with R = H) or their tertiary alkyl radical analogue (i.e., 26 with R = X = CH3), and the slow cyclization rates for 26 and 27 were ascribed to an enforced planarity in ester- and cyano-substituted radicals that, in the case of tertiary species, results in a steric interaction in the transition states for cyclization.89 It is possible that a steric effect due to an enforced planar tertiary radical center also is involved in the kinetic effect on the tin hydride reaction rate constants. 

Extensive mechanistic investigation of the ring expansion 33 —> 34 was performed in order to differentiate between a ring-opening reaction to give a silyl radical 39 (path a), followed by the 6-endo cyclization, or a pentavalent silicon transition state 40 (path b). It was clearly demonstrated that the ring expansion proceeds via a pentavalent silicon transition state (Scheme 6.10) [16]. 

The presence of a 4-methoxy substituent on the 2-phenylethyloxyl or 3-phenylpropyl-oxyl side chains radically altered the course of these cyclizations (Scheme 4). 31a and 31b afforded the spiro-fused ring systems 32 and 33 in 26 and 69% yields, respectively, as the only cyclization products. With this substituent, cyclization onto the activated ipso positions was favoured over direct attack, even where the strained transition state for Atj -5 cyclization of 31a to 32 was involved. Demethylation of the intermediate spirocyclohexa-dienyl cation is favoured over rearrangement in these cases. Kikugawa and coworkers effected the formation of 32 (82%) and 33 (39%) with reverse efficiencies using AgaCOs in TFA . 

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