B-endo Cyclization

The endo(Q) cyclizations are highly useful in natural product syntheses. Solenopsin B can be prepared via the endo(B)-endo cyclization in two steps from a simple acyclic precursor (equation 28). Analogous endo(B) cyclizations have been utilized as key steps in synthetically important transformations (equations 29 and 30). ... 

An easy, silica gel-promoted 6-endo cyclization of y-epoxy alcohol 32 to pyran 33, followed by acid-catalyzed spiroketalization of the keto diol 34, afforded the common tricyclic spiroketal fragment 35 of lituarines A, B, and C (Scheme 8.8) [20b],... 

All these reactions are examples of oxidative cyclocarbonylation-alkoxy-carbonylation. However, the Pdh/KI catalytic system turned out to be a very efficient catalyst also for promoting cyclization-alkoxycarbonylation processes. In fact, optimal conditions were found for selectively converting 4-yn-l-ols into tetrahydrofuran derivatives (Eq. 41) [107] through 5-exo-dig cyclization followed by alkoxycarbonylation (Scheme 19, path a). This kind of process was not possible for the propynyl, 3-yn-l-ol, and 2-ethynylaniline substrates, seen before, for stereoelectronic reasons [302], With the latter substrates, the endo cyclization mode (Scheme 19, path b), although in principle stereo electronically allowed, was not observed. 

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]. 

Free-radical reaction of vinyl iodides having dienoate function in the presence of (TMS)3SiH and AIBN in refluxing benzene caused a tandem cyclization reaction to produce (4 - -1) and (4 - - 2) annulated compounds [94]. Reaction (7.83) shows the transformation resulted from a tandem 5-exo, 6-endo cyclization to give the isoindole skeleton where the stereogenic centres were highly controlled, whereas Reaction (7.84) proceeded via a tandem 6-exo, 5-exo cyclization to furnish a (4 -b 1) cycloadduct. 

Some mechanistic aspects of the above cascade reaction deserve comment. Thus, after the intermolecular addition of the nucleophilic acyl radical to the alkene, the electrophilic radical adduct A, instead of undergoing reduction, reacts intramolecularly at the indole 3-position (formally a 5-endo cyclization) to give a new stabilized captodative radical B, which is oxidized to the fully aromatic system. (For a discussion of this oxidative step, see Section 1.5.)... 

The extension of the above regioselective 6-endo cyclization to appropriately substituted substrates provided a novel synthetic entry to the pyrido[4,3-b]carbazole skeleton of the indole alkaloid olivacine, which resulted in a concise total synthesis of its tetrahydro derivative ( )-guatambuine <6 IT 160 67CJC89>. 

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>. 

Grande s group has studied the titanocene-promoted intramolecular addition of epoxides to activated alkenes in both 5-exo and 6-endo cyclization modes as a new way of preparing polycyclic b-lactam antibiotics [ 110-112]. 

The efficient activation of oxime sulfonates by organoaluminum reagents enables the intramolecular cyclization of alkenic oxime mesylates, which involves the electrophilic addition of the intermediate ni-trilium ion to the double bond. This results in the direct formation of a wide variety of structurally diverse carbocyclic and heterocyclic systems. Four distinct cyclization modes, i.e. endo(B)-endo, endo(B)-exo, exo(B)-endo and exo(B)-exo are possible, as shown in Scheme 4P The values in parentheses refer to the yields obtained using SnCU. 

The similar endo(B)-exo cyclizations have been effected with phosphorus pentoxide and more recently with trimethylsilyl polyphosphate (equation 32 and 33). The starting alkenic oximes are readily obtainable by the alkylation of the oxime dianion. Hence the overall process provides convenient access to the stereospecific synthesis of various heterocycles bearing substituents in the desired positions. 

Tricyclizations including seven-membered ring closure are rarely described. Initiation of the reaction by a tetramethylallylic cation leads to a six-six-seven-membered ring system via a b-endo-b-endo-l-endo cyclization according to Markovnikov s rule. Two diastereomers are formed due to the lack of remote stereocontrol by the initiating cation66. 

Bennasar M-L, Roca T, Feirando F (2006) Regioselective 6-endo cyclizations of 2-indoly-lacyl radicals total synthesis of the pyrido[4,3-b]carbazole alkaloid guatambuine. J Org Oiem 71 1746-1749... 

A ruthenium-catalyzed intramolecular olefin hydrocarbamoylation for the regiodivergent synthesis of indolin-2-ones and 3,4 dihydroquinolin-2-ones was disclosed by Chang and coworkers (Eq. (7.3)) [8]. The reactions underwent smoothly without requiring external CO atmosphere. In the presence of combined catalysts of Ru3(CO)i2/Bu4NI, a 5-exo-type cyclization proceeds favorably to form indolin-2-ones as a major product in good to excellent yields in DMSO/toluene cosolvent (catalytic system A). When the reaction was conducted in the absence of halide additives in NAf-diniethylacetamide (DMA)/PhCl (catalytic system B), 3,4-dihydroquinolin-2-ones were obtained in major in moderate to high yields via a 6-endo cyclization process. An excellent level of regioselectivity was observed with a variety of substrates to deliver 5-exo- or 6-endo-cyclized lactams. 

Two mechanistic pathways, which differed in the way of ruthenium-mediated initial cleavage of formyl C-H or amido N-H bond, were proposed for the catalytic cycle. As shown in Scheme 7.3, an irreversibly cleavage of formyl C-H bond by the active ruthenium complex was followed by reversible insertion of the olefin into the Ru-H bond, which afforded either six-membered or seven-membered ruthenacycle. After reductive elimination, indolin-2-ones or 3,4-dihydroquinolin-2-one was formed. According to isotopic studies, pathway leading to six-membered lactams is postulated to be less favored. Another cyclization process initiated by Ru-catalyzed oxidative addition of formyl N-H bond (Scheme 7.4) was similar to Carreira s proposal for their hydrocarbamoyla-tion reaction of allylic formamides under similar ruthenium catalysis conditions [7]. The 6-endo cyclization process is proposed to be favored under the catalytic system B. 

Two approaches to convergent steroid syntheses are based on the thermal opening of benzocyclobutenes to the o-quinodimethane derivatives (see p. 80 W. Oppolzer, 1978 A) and their stereoselective intramolecular Diels-Alder cyclizations. T, Kametani (1977 B, 1978) obtained (+ )-estradiol in a six-step synthesis. The final Diels-Alder reaction occurred regio- and stereoselectively in almost quantitative yield, presumably because the exo transition state given below is highly favored over the endo state in which rings A and D would stcrically inter-... 

Rctrosynthetic path a corresponds to Pd-catalysed exo-trig cyclization of o-halo-JV-allylanilines. Path b involves the endo-trig cyclization of o-halo-JV-vinyl anilines. Path c is a structurally similar cyclization which can be effected photochemically in the absence of an o-substituent. Retrosynthetic path d involves intramolecular Friedel-Crafts oxyalkylation followed by aromatiz-ation. 

Other possible cyclizations may involve 5-epoxy alcohols such as the generic compound 2. In this case, two pathways are theoretically possible a more favored 6-exo cydization mode (Route c) giving rise to a THP ring, or an alternative 7-endo cydization mode providing an oxepane ring (Route d) (Eq. b, Scheme 8.1) [7]. 

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