Selenoesters radical cyclization

Attention was centered on radical precursors in which the 3-pyridyl moiety was attached at the indole-3-position with the aim of directly producing the pyrido[4,3-b]carbazole skeleton of ellipticine by regioselective cyclization upon the 4-position of the pyridine ring. Satisfactorily, A-methyl and A-benzyl selenoesters 52a and 52b led to the ellipticine quinones 53a and 53b in acceptable yields (60 and 42% yield, respectively), after the radical cyclization and the in situ oxidation at the interannular methylene group. The cyclization was clearly less efficient from A-(methoxymethyl) selenoester 52c and no reaction was observed... 

A few radical annulation approaches to fused indoles have been reported. 2-Indolylacyl radicals generated from selenoesters provided ellipticine quinones <05JOC9077>. A radical cyclization of haloacetamide derivatives was applied to the preparation of indolo[2,l-rf][l,5]benzodiazocines <05T941> and indolo[3,2-d][l]benzazepin-6-ones <05T5489>. 3,3-... 

Most studies have been directed toward the use of selenoesters and thioesters as radical precursors to generate acyl radicals in radical cyclizations [43]. However, selenoesters and thioesters as radical traps have not been well studied [40a]. Since the cyclization step is much slower than direct reduction by n-BusSnH, the use of (n-Bu3Sn)2 is required. Intramolecular cyclization of thioester 17 furnished cyclo-... 

Crich and Batty [39] further extended the studies with cis and tram 4,5-dioxygen-substituted (as acetonide) hept-6-enoyl radicals and found that in the tram isomer 154 the 1-endo mode was suppressed when compared to that in the cis isomer 150 for conformational reasons. It was further extended to a tandem 1-endo trig - 5-exo dig radical cyclization sequence starting from the selenoester 158 to generate the perhydroazulenes 159. 

Evans and Roseman [40] explored the 1-exo trig acyl radical cyclization for the generation of cyclic ethers 161 and 162 starting from the selenoesters 160. The efficiency and the diastereoselectivity of these reactions were found to increase when tristrimethylsilylsilane was used instead of BusSnH. The generality of this reaction was further established with the corresponding vinylsulfones (instead of acrylates) and also with the corresponding vinyl bromides (instead of selenoesters). 

Shishido and coworkers [42] have employed a highly stereoselective 1-endo trig radical cyclization reaction for the construction of a key intermediate 174 in their synthesis of a pseudoguanolide (-l-)-confertin starting from the selenoester 173. 

Radical cyclizations. When heated wi selenoesters bearing an alkenyl side chain giv... 

Radical cyclizations. When heated with tin hydride in benzene, thioesters and selenoesters bearing an alkenyl side chain give cyclic products. The side chain participates... 

Radical cyclization. Acyl radicals are generated from selenoesters on treatment with (Me3Si)jSiH in the presence of Et3B at or below room temperature. Such a radical can add to a juxtaposed conjugated ester to form a cyclic ketone with an acetic ester side chain. Substituents at the y and 5 positions of the ester unit have great influences on the cyclization mode. -- Triorganotin hydrides can also be used, but a higher temperature is required. 

Cyclization of an acyl radical generated from a carbohydrate-derived hept-6-enoic acid selenoester (to a cyclohexanone) has been studied even though the full potential of this reaction is yet to be established [38],... 

Generation of 3-indolylacyl radicals from the selenoesters 149, using either /j-Bu3SnH or tris(trimethylsilyl)silane (TTMSS) followed by reaction with various alkenes, offers a route to 3-acylindoles 150. On the other hand, the use of n-Bu Sn2 under irradiation gave cyclopent[6]indole derivatives such as 151 via a cascade involving initial addition of the acyl radical to the alkene, and a subsequent oxidative cyclization at the indole C-2 <02JOC6268>. 

Satisfactorily, the 1-endo closure became the predominat route when a temporary substituent was introduced at the 6-exo position of the alkene acceptor, a tactic previously used in similar 1-endo cyclizations involving aryl <4TL2335>, vinyl <05JOC519> or alkyl <06OL831> radicals. Hence, cyclization of selenoester 30b, which incorporates a 2-bromo-2-propenyl instead of an allyl moiety, led to the tricyclic substructure of mersicarpine 32 in a synthetically acceptable 62% yield, pyridoindole 31 being now the minor product (19%). The excess hydride ensured the final reductive removal of the bromine atom after the cyclization step <07JOC4562>. 

In contrast with the clean 1-exo cyclization of benzoyl radicals (e.g., selenoester 9, n = 3), no cyclization was observed from 2-indolylacyl radicals derived from selenoesters 33-35. Only the respective indole-2-carbaldehydes were isolated from the reaction mixtures, indicating that both exo and endo ring closures leading to 7- or 8-membered carbocycles fused to the indole ring are too slow for the radical chain to be productive <04OL759 07JOC4562>. 

On the other hand, 5-aza-7-octenoyl radicals derived from selenoester 39 behaved in a different way, leading to 1-exo and 8-endo cyclized products in ratios that were dependent on the hydride concentration. When working as above at 0.02 M, a 3 1 mixture of endo-exo products 40 and 41 was obtained, along with notable amounts of aldehyde 42. Interestingly, the use of more concentrated hydride solutions (0.14 M) not only resulted in a predictable... 

As the azocinoindole 40 constitutes the tricyclic substructure of the indole alkaloid apparicine , we attempted to improve the cyclization yield. Satisfactorily, the regioselectivity was completely switched to the 8-endo mode when the alkene acceptor was substituted at the internal position by a bromine atom. Thus, cyclization of selenoester 43 led to the desired target 40 as the only reaction product in 75% yield. Clearly, the bromine atom not only sterically prevented the competitive 1-exo attack, but also benefited the cyclization by activation of the double bond. It should be noted that similar halogen-controlled 8-endo cyclizations are known in the literature, but involving amidyl-type radicals <06OL2647>. 

The reductive cyclization protocol was then applied to a suitably A-protected radical precursor to allow further access to the alkaloid calothrixin B. Satisfactorily, 2-indolylacyl radicals derived from A-(methoxymethyl) selenoester 57 underwent cyclization under TTMSS-AIBN conditions with an even higher efficiency than their A-methyl counterparts. The reaction nevertheless followed a different course as, after the radical addition and quinoline rearomatization, pentacyclic phenol 58, a fully aromatic tautomeric form of ketone P, was isolated in 90% yield. The same phenol 58 was isolated although in lower yields (50-70%) using either stannane-AIBN or AIBN-irradiation protocols. 

Boger and Mathvink [36] explored the 1-exo trig cyclization of acyl radicals using selenoesters as precursors. Reaction of the selenoesters 126 and 128 with BusSnH and AIBN furnished exclusively the benzocycloheptanones 127 and 129, respectively. 

The methodology was also extended for the synthesis of cyclic ethers [38]. Reaction of the selenoester 142 with BuaSnH and AIBN furnished a mixture of 1-endo and 6-exo cyclized products 143 and 144. Interestingly the selenoester 145 furnished the 1-endo trig cyclized product 146 and the perhydrobenzofuran 147 obtained via decarbonylation of the initial radical followed by a 5-exo trig cyclization. Once again the presence of two sp carbons in the chain, e.g. benzannulated system 148, completely retarded the 1-endo mode and only 6-exo cyclization was observed leading to the formation of ketones 149. 

Phenylselenoesters 31 have been reported as precursors to acyl radicals and can be utilized in tandem processes (Scheme 12) . When an alkyl substituent is positioned at the C-5 in the starting selenoester, a clean 6-endo-ing cyclization occurs thus giving the... 

Pattenden et al. applied his expertise in polycyclic ring constructions based on radical-mediated cyclizations of polyolefin selenyl esters for the total synthesis of cytotoxic ( )-spongian-16-one, isolated from both New Zealand and Australian specimens of the sponge Chelonaplysilla viola-cea (Scheme 25.38). Treatment of selenoester 85 with Bu3SnH led to tetracycle lactone 86, which after methyle-nation gave the corresponding exocyclic methylene (not shown) in 42% overall yield. 

A 5-exo-trig acyl radical-alkene cyclization of selenoester 87 was used to introduce the fused cyclopentanone and complete the preparation of the tricyclic ansa-bridged azafiilvene core of e r-roseophilin in 83% yield (Scheme 25.39). Compound 88 is not only the most... 

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