Radical 6-exo-trig cyclization

The synthesis of tacamonine, an indole alkaloid of the Iboga type, was accomplished in both racemic and homochiral forms, by incorporating a classical 6-exo-trig radical cyclization in the key step of the synthesis (Reaction 7.57) [52], The cyclization produced piperidinone in a 72% yield as a diaster-eomeric mixture. 

Tacamonine, an indole alkaloid of the Iboga type, isolated from Tabermemontana eglandulosa, the root of which is used to treat snake bites in Zaire, bears structural similarity to the Hunteria alkaloids, eburnamonines, which possess vasodilator and hypotensive activities. Its synthesis in racemic and homochiral form was accomplished by incorporating a classic 6-exo-trig radical cyclization in the key step of the synthesis (Scheme 6)71. The radical precursor 6 was constructed in a 7-step synthesis by starting from racemic or chiral propane-1,3-diol. The radical cyclization of 6 produced the piperidinone in 72% yield as a diastereomeric mixture, which was then transformed into tacamonine. 

In 2001, tetracyclic 3.6.6.4 ring systems fused to a (3-lactam (IV, Fig. 6) have been reported to form via 6-exo-trig radical cyclization [252],... 

Scheme 23. Application of 6-exo-trig radical cyclization in Stork s approach to ( )-gelsemine...

Scheme 24. Six-membered lactones or lactals prepared using 6-exo-trig radical cyclization...

Scheme 27.6-exo-trig Radical cyclization with excellent 1,2-asymmetric induction... 

Scheme 32 illustrates an application of a 6-exo-trig radical cyclization in the total synthesis of ( )-mossambine (166) [68-69]. Indoloazepine 160 was obtained from tiyptamine in four steps (30% overall yield). Pyrolysis of 160 in refluxing toluene in the presence of 2-acetoxyacetaldehyde led to transient generation of an enamine acrylate 161, which stereoselectively formed the tetracyclic vinylogous urethane 162. Hydrolysis of the acetate... 

Diastereoselective 6-exo-trig radical cyclization of (—)-perhydro-l,3-benzoxazines 69, 71, 74 with Bu3SnH and AIBN gave a diastereomeric mixture of perhydropyrido[2,l-Z>][l,3]-benzoxazines 39, 70, and 72, 73, and 40, 75, respectively (00TA2809). 

Synthesis of (—)-Sibirine. Various types of alkaloids have been prepared by conjugate addition of carbon-centered radicals to unsaturated sulfones. This approach is used in the stereoselective synthesis of the Nitraria spirocyclic alkaloid (—)-sibirine, where a 6-exo-trig radical cyclization to an a,(3-unsaturated sulfone leads to the spirocyclic skeleton of the natural product (Eq. 153).263 The y-nitrogen-functionalized sulfone so obtained is then desulfonylated under dissolving-metal conditions. 

In summary, Wardrop developed a synthetic route to azatricycle 15 (16 steps), which Snider had previously transformed to 19. Accordingly, a formal synthesis of racemic desmethylamino FR901483 was achieved, the key steps being (i) formation of the azaspirodecane ring by an N-methoxy-A-acylnitrenium ion-induced spirocyclization (ii) construction of the bridge framework by a 6-exo-trig radical cyclization, and (iii) installation of the C(6) p-methoxybenzyl side chain by Lewis acid-mediated alkylation of a silyl enol ether. 

During their study on 6-exo-trig radical cyclizations of axially chiral a-halo-ortho-alkenyl anihdes, Curran and coworkers [40] prepared the tricyclic amide 93/94 in moderate yield (49-51%) and excellent chirality transfer (98-99%) via a 6-exo-trig/5-exo-trig sequence (Scheme 5.20). The reaction was proposed to be initiated by an attack at the carbon-bromide bond with BujSnH, providing a-amidyl radical 97 (Scheme 5.21). 

A radical cyclization approach for the synthesis of 5-lactones has also been reported by lhara et al. [104] (Scheme 59). Treatment of bromo ester 277 with tri- -butyltin hydride in the presence of AIBN under dilute conditions facilitated a 6-exo-trig radical cyclization to provide diastereomeric lactone 278 in 92 % yield. However, the reaction was found to be dramatically concentration dependent as it exclusively gave the reduced product 279 under concentrated conditions. Nevertheless, this problem was overcome by using tris(trimethylsilyl)silane, which exclusively led to the desired 5-lactone irrespective of the concentration of the reaction. 

In the total synthesis of the hesitine-type aconite alkaloid nominine, the C-ring was constructed by radical cyclization to form 118 from the enyne precursor 117. ° In the first step, the tin radical reacted with alkyne 117 to form a radical that underwent a 6-exo-trig radical cyclization. The resulting radical was trapped by BuaSnH to give a vinyl stannane, which afforded 117 after destannylation with SiOi (Scheme 25.56). 

---