Tertiary radical cyclization

The key features of Curran s productive and elegant tandem radical cyclization strategy are illustrated in a retrosynthetic analysis for hirsutene (1) (see Scheme 27). The final synthetic event was projected to be an intermolecular transfer of a hydrogen atom from tri-rc-butyltin hydride to the transitory tricyclic vinyl radical 131. The latter can then be traced to bicyclic tertiary radical 132 and thence to monocyclic primary radical 133 through successive hex-5-enyl-like radical cyclizations. It was anticipated that the initial radical 133 could be generated through the abstraction of the iodine atom from... 

The N,0- and N,S-heterocyclic fused ring products 47 were also synthesized under radical chain conditions (Reaction 53). Ketene acetals 46 readily underwent stereocontrolled aryl radical cyclizations on treatment with (TMSlsSiH under standard conditions to afford the central six-membered rings.The tertiary N,0- and N,S-radicals formed on aryl radical reaction at the ketene-N,X(X = O, S)-acetal double bond appear to have reasonable stability. The stereoselectivity in hydrogen abstractions by these intermediate radicals from (TMSlsSiH was investigated and found to provide higher selectivities than BusSnH. 

Radical cyclization to macrolides.111 Cyclization of iodoalkyl acrylates (1) by reaction with Bu3SnH (1 equiv.) in the presence of AIBN is useful for formation of macrolides (2) containing 11 or more members. Similar cyclization of iodoalkyl fumarates (3) results in two macrolides with the endo-product predominating except when n is 16 or higher. Tertiary iodides undergo this free radical cyclization more... 

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... 

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. 

Birch reduction-alkylation of 5 with 2-bromoethyl acetate was carried out with complete facial selectivity to give 57. This tetrafunctional intermediate was converted to the bicyclic iodolactone 58 ( > 99% ee) from which the radical cyclization substrate 59 was prepared. The key radical cyclization occurred with complete regio- and facial-selectivity and subsequent stereoselective reduction of the resulting tertiary radical gave 60 with the required trans BC ring fusion.The allylic alcohol rmit of (+)-lycorine was obtained by a photochemical radical decarboxylation, 62 63. 

In this case, the intermediate vinyl radical (cf Scheme 9) underwent a remarkable [1,51-hydrogen abstraction from the non-activated C—H bond of the proximal isopropyl group. Furthermore, the resulting primary alkyl radical underwent a unique, stereoselective 5-endo-trig cyclization onto the adjacent double bond to generate a tertiary radical, which is a precursor of the highly substituted cyclopentanols 22 and 23. The reaction with Bu3SnH as radical mediator totally reversed the products ratio obtained in 88% yield, i.e. 22 23 = 19 81. 

Bromo-enamides have been reported to give radical cyclization in excellent yields (82-99%) to p-lactams using catalytic amounts (30%) of tripyridylamine (TPA) copper halide complex [184]. The p-lactam developed under mild conditions via 4-exo bromine atom transfer and subsequent elimination of the tertiary bromide that could be readily achieved by reaction with DBU (Scheme 83). 

In Kuehne s total synthesis of vincadifformine (89), the pentacyclic natural product was obtained when tetracyclic phenylselenide 88 was treated with 2.5 equivalents of n-Bu SnH and the radical initiator AIBN in refluxing benzene [52]. The stereochemistry of the phenylselenyl substituent in the tetracyclic precursor had no impact on the product yield. After the tertiary radical intermediate 90 was generated (Scheme 17), the 5-exo-trig cyclization was prohibited... 

The utility of tandem oxidative cyclizations is clearly demonstrated in substrates in which both additions are to double bonds [12]. Oxidative cydization of 20 with two equivalents of Mn(OAc)3 and of Cu(OAc)2 in acetic acid at 25 °C affords 86 % bicyclo[3.2.1]octane 25. Oxidation affords the a-keto radical 21, which cyclizes exclusively 6-endo in the conformation shown to afford the tertiary radical 22 with... 

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... 

The presence of a quaternary carbon atom is frequently encountered in sesquiterpene natural products and it often creates a synthetic challenge when two or more quaternary carbon atoms are present contiguously. The synthetic strategies for the construction of quaternary carbon centers involve sigmatropic rearrangements/ intramolecular cycloaddition/ and the reaction of tertiary carbon nucleophiles with a carbon electrophile. Recently, radical cyclization strategies turned out to be very effective for this purpose. For example, Srikrishna utilized the radical cyclization reaction to prepare tricyclo[6.2.1.0 - ]undecane system, which is present in several sesquiterpenes such as zizaenes and prelacinanes, and Chen demonstrated that a tandem radical cyclization approach is an efficient method for constructing the two quaternary carbon centers in the cedrene skeleton. ... 

---