Transannular cyclization

Scheme 3.21. Domino radical macro-cyclization/transannular-cyclization procedure for the synthesis of the taxane skeleton.

Surprisingly few examples in this category of nine-membered ring radicals are devoted to the synthesis of polycyclic frameworks through a radical cascade involving transannular closures. We have previously mentioned the capacity of the car-yophyllene radical to cyclize transannularly (Scheme 28), but this example of a unique radical cyclization step was not applied in cascade strategies [45]. 

Large ring heterocyclic radicals are not particularly well known as a class. Their behavior often resembles that of their alicyclic counterparts, except for transannular reactions, such as the intramolecular cyclization of 1-azacyclononan-l-yl (Scheme 1) (72CJCH67). As is the case with alicyclic ethers, oxepane in the reaction with r-butoxy radical suffers abstraction of a hydrogen atom from the 2-position in the first reaction step (Scheme 2) (76TL439). 

By using various trapping reagents, it has been deduced that the transannular fragmentation is rapidly reversible. The cyclization of the fragmented radical C is less favorable, and it is trapped at rates which exceed that for recyclization under most circumstances. " Radicals derived from ethers and acetals by hydrogen abstraction are subject to fragmentation, with formation of a ketone or ester, respectively. 

Schopf et al. 188,189) observed that -tetrahydroanabasine salts contain a molecule of water or methanol. According to infrared spectra, they exist as 2-hydroxy- or 2-methoxy-3-(2-piperidyl)piperidine salts (97). Salt 99, obtained by a transannular cyclization reaction taking place on neutralization of bicyclic amino ketone 98, also belongs to this group 181). 

The mercuric acetate dehydrogenation of carbomethoxydihydro-cleavacine (177) yields immonium salt 178, which undergoes transannular cyclization to give a mixture of coronaridine (180, R = Et, R, = H) and dihydrocantharanthine (180, R = H, Ri = Et). The reaction is accompanied... 

As attractive as the transannular bridging of bis(thiolactones) to bicyclic bis(oxepane) frameworks is, our inability to convert the disulfide bridging product (see 25, Scheme 5) to a mmv-fused bre-vetoxin-type bis(oxepane) (see 28) necessitated the development of a modified, stepwise strategy. This new stepwise approach actually comprises two very effective methods for the construction of cyclic ethers the first of these is the intramolecular photo-induced coupling of dithioesters, and the second is the reductive cyclization of hydroxy ketones. We will first address the important features of both cyclization strategies, and then show how the combination of the two can provide an effective solution to the problem posed by trans-fused bis(oxepanes). 

The reaction in Entry 5 was used in the syntheses of linetin, which is an aggregation pheromone of the ambrosia beetle. In Entry 6, a transannular 5-exo cyclization occurs. Entry 7 is an example of formation of a lactone by carboxylate capture. In this case, the product was isolated as the mercurochloride. 

The most widely exploited photochemical cycloadditions involve irradiation of dienes in which the two double bonds are fairly close and result in formation of polycyclic cage compounds. Some examples of alkene photocyclizations are given in Scheme 6.9. Entry 1 is a transannular cyclization. The preference for the observed product over tricyclo[4.2.0.02,5]octane does not seem to have been analyzed in detail. Entries 2, 3, and 4 involve photolysis in the presence of Cu03SCF3. Entries 5 and 6 are cases in which the double bonds are in close proximity and can cyclize to caged structures. 

Catalyst 70 is very effective for the reaction of terminal alkenes, however 1,1-disubstituted olefins provide hydrosilylation products presumably, this is due to steric hindrance [45]. When a catalyst with an open geometry (78 or 79) is employed, 1,1-disubstituted alkenes are inserted into C-Y bonds to give quaternary carbon centers with high diastereoselectivities (Scheme 18). As before, initial insertion into the less hindered alkene is followed by cyclic insertion into the more hindered alkene (entry 1) [45]. Catalyst 79 is more active than is 78, operating with shorter reaction times (entries 2 and 3) and reduced temperatures. Transannular cyclization was possible in moderate yield (entry 4), as was formation of spirocyclic or propellane products... 

A well-known characteristic of medium-sized rings (8- to 11-membered) is their ability to undergo facile transannular reactions. Cere et al. found that acid-catalyzed transannular cyclizations of 8-10-membered 7,5-unsaturated cyclic sulfides yield fused bicyclic sulfonium salts independently of the geometry of the double bond <1998J(P2)977>. 

The same group reported the trimethylsilyl iodide-promoted transannular cyclization of the eight-memebered cyclic sulfide, rra r-4,5-dihydroxythiocane 46 <1997JOC8572>. As expected this intramolecular Sn2 reaction gave only one product, o-4-hydroxy- r-thioniabicyclo[3.3.0]octane iodide 47, as shown in Equation (15). 

Transannular cyclizations of nine-membered cyclic sulfides provided a novel route to thioanalogues of swainsonine derivatives. Treatment of the enantiopure polyhydroxylated thiacyclononane derivative 48a with trimethylsilyl iodide yielded the bicyclic sulfonium salt 49a as a single diastereomer, as shown in Equation (16) <2003JOC3311 >. The presence of a C2-axis and the complete regio- and stereoselectivity of the transannular substitution led to a single configurationally homogeneous product irrespective of the fact that the sulfur atom would attack C-5 or C-6. 

Lithium aluminum hydride reduction of 31 in the presence of benzylamine affords a 70% yield of l-benzylamino-2-oxaadamantane.154 This approach is patented as a general method for the preparation of N-substituted 2-oxa-adamantyl-l-amines.155 Transannular cyclization of 31 or 35 in the presence... 

Upon treatment with Me3SiOTf, the 2,5-dihydrofuran-containing 14-membered marine cembranoid sarcophytoxide was converted to a 10-membered ring product as shown below <06OL2957>. Presumably, the Lewis acid promoted the cleavage of the dihydrofuran ring to provide a transient allylic cation, leading to a transannular cyclization. 

Iodoetherification (vide supra) of ( )-aIlyl alcohols 99 followed by transannular radical cyclization in a 5-exo-trig mode was reported to provide ci s-fused bicyclic acetals with high diastereoselectivities. To illustrate, an example is given below <00SL1193>. 

High oxidation state alkylidene complexes in which a heteroatom is bound to the alkylidene carbon atom are extremely rare [41]. Since the approach shown in Eq. 43 failed, the related approach shown in Eq. 44 was taken to prepare the medium-sized ring subunits [222]. The latter product was formed in good yield when n=2, R H, R2=Et, but only poor yield when n=2, R =Et, R2=H, possibly due to unfavorable interactions between the ethyl substituent and transannular groups in the transition state for cyclization of the allyl ether [222]. Ruthenium catalysts either failed or gave low yields, presumably because of the steric hindrance associated with ring-closing dienes of this type. 

Another report by Rychnovsky et al. explored the potential of chirality transfer in the transannular cyclization of cyclodecene 45 [42], They proposed a radical deoxygenation of 45, which produces an intermediate cyclodecenyl radical that can cyclize in a 5-exo fashion to yield 5,7-fused bicycle 48 (Scheme 13). The potential for the optically enriched radical precursor 45 to undergo enantioselective cyclization is dependent on the rate of transannular cyclization. That is, if the radical generated from optically pure... 

Scheme 11.IS Application of transannular cyclizations in the total synthesis of 7,8-epoxy-4-basmen-6-one (48) [72]. a)The yield of 47 refers to macrocycle 45 as starting material.

The bicyclic aminoalkene l-azabicyclo[4.4.4]tetradec-5-ene (32) behaves actually like an enamine96. It is oxidized more readily than its saturated analogues. Protonation does not occur on the nitrogen atom but at the double bond accompanied by transannular cyclization (32 — 33). 

Another example of a transannular cyclization that occurs in the solid state is provided by the epoxy alcohol 31. This compound is stable when dissolved in organic solvents and in 0.25N sulfuric acid. However, the crystals transform rapidly to 32. Although the process is accompanied by partial melting, it appears to be a true solid-state one. Interestingly, the reaction is slowed down appreciably when the dry crystals are covered with ether. Hydrogen bromide is eliminated in the reaction and it may be that an acid-catalyzed process is also occurring in the presence of solvent this process may be slowed down by the dissolution of the decomposition products in the solvent (77). 

C. Deprotonation of Bicyclo[3.2.1]alkadiene, Some Other Cycloalkadienes and Cyclooctatetraene Bishomoaromaticity and Transannular Cyclization... 

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