Transannular cyclizations

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... 

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... 

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

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. 

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... 

Transannular cyclization has also been observed in the bromofluorination of norbor-nadiene (49) using NBS in the presence of Et3N-3HF which led to a 3 2 mixture of... 

By comparison, the direction of halogenation of monomethyl-substituted bicyclo[4.3.0] nona-3,7-dienes depends" considerably on the position of the methyl group. For a diene lacking a substituent at C(3), the reaction proceeds with retention of the initial structure (equation 83), whereas in the case of the 3-methyl substituted diene, it occurs through transannular cyclization giving a brexane type monoiodo derivative (equation 84). 

Furthermore, the oxy-Cope rearrangement of allenic cycloheptane alcohol 47 (NaOEt, THF, 20 °C, 12 h, 80%) gave rise only to ring-enlarged product 48 without transannular cyclization (equation 15)29. The above transformations can be rationalized either by the fragmentation-recombination mechanism or by a concerted oxy-Cope mechanism29. 

Ionic hydrogenation of the same bicyclic diene 382 by Et3SiH in the presence of CF3COOH at room temperature or at 80 °C via ions 387 and 388 is accompanied by transannular cyclizations (equation 139)192. The behavior of diene 382 under Ritter reaction conditions (MeCN, H2SO4) reveals new possibilities to control the transannular cyclizations (equation 140)193. Depending on the sulfuric acid concentration, the reaction temperature and the presence of a nucleophilic solvent, these transformations can be directed to the formation of either the bicyclic amides 389 and 390 having the precursor structure or the tricyclic products 391193. 

A quite detailed review of transannular cyclizations was published201 wherein their important role in biomimetic syntheses of sesquiterpenes as well as explanation of the biogenetic formation of the polycyclic natural compounds from their monocyclic precursors is discussed. The great significance of these transformations for the synthesis of natural products is also emphasized in a series of reviews which describe the cyclizations to form terpene derivatives, e.g., of the germacrane and humulene systems202-206. 

In a related experiment, a radical intermediate derived from the oxidation of an activated methylene group was used to trigger a transannular cyclization across an eight-membered ring (Scheme 14) [26], After cyclization, the reaction... 

With cyclooctane, transannular cyclization (an intramolecular form of C5 cyclization) is especially favored (705). It gives bicyclo(3,3,0)octane... 

The acid-catalysed transannular cyclization of 8-10-membered y,5-unsaturated cyclic sulfides (59) or (60) yields c/x-fused bicyclic sulfonium salts (61) independently of the geometry of the double bond. The rate varies linearly with the acidity function -(Ho h with a slope of 1. The rate variations span a range of about 10 , the maximum rate difference being observed for the ( /Z)-thiacyclooct-4-ene pair. The data are consistent with the classical interpretation of the intramolecular reactivity in terms of internal strain of the substrate and/or of the transition state. ... 

The ionisation-induced cyclization sequence could be followed by a proton-induced cyclization (Scheme 3). Protonation of the double bond of 13 generates a dolabellyl cation (15) that is transformed into a dolastyl cation (16) by a transannular cyclization between and (dolabellane numbering). Subsequent deprotonation at (dolastane numbering) leads to the dolasta-1 (15),8-diene which is further functionalized by enzymatic oxidation. 

It is tempting to speculate that the neodolastane carbon skeleton (21) is biosynthesized by a transannular cyclization of a neodolabellyl cation (10) (Scheme 4). However, this assumption is only based on structural analogy. A detailed analysis of the biosynthesis has yet to be published. 

The apparently latest total synthesis of a dolastane diterpene was published by Williams and coworkers in 1993 as a short communication (Fig. 16) [91]. (-)-Clavulara-l(15),17-dien-3,4-diol (129) was synthesized using a strategy that relied on the availability of the enantiomerically pure building block 162 from (+)-9,10-dibromocamphor (163) (Fig. 16). Cornerstones of the synthesis are a macrocyclization that afforded the 11-membered (A+B)C-ring (160) and a transannular cyclization that converted a bicyclic into a tricyclic ring system. Two of the seven chirality centres in the synthetic clavu-... 

Scheme 30 Transannular cyclization as key transformation toward ent-129 (Williams 1993)...

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