Cationic cyclization, transannular

BIOSYNTHESIS OF DITERPENES BASED ON CATIONIC CYCLIZATIONS, 1,2-SHIFTS, AND TRANSANNULAR PROCESSES 281... 

Cationic cyclization is a common theme for the biosynthesis of a large number of polycyclic terpenoids and is partly responsible for the structural diversity of terpenoids that share the same poly-isoprene origin. Thus, it is not surprising that cationic transannular cyclization is also prominently featured in polycyclic terpenoids synthesis. 

One early example was reported by Chatteijee in 1979 for stereospecific synthesis of the sesquiterpene isocomene by transannular cationic cyclization. The acid-catalyzed cyclization of epoxide 152 through transannular participation of the remote double bond led to the formation of 153 (Scheme 20.37), which was further transformed to isocomene. The reaction was stereoselective since formation of any other diastereomers will lead to the formation of much strained polycyclic systems with trans-fased cyclopentanes. 

The transannular cationic cyclization was the key transformation for biomimetic synthesis of the linear triquinane A -capneUene by Birch and Pattenden. It involved treating the cycloocta-1,5-diene or its exo-methylene isomer (i.e., 154) with BF3-Et20 to initiate the transannular cycH-zations to give A -capnellene and the two isomers 157 and 158 (Scheme 20.38). These products were derived from the same carbocation intermediate 156 of the transannular cationic cyclization and the major product A -capnellene was also formed by the isomerization of the bridgehead capnellene 158. 

The transannular cationic cyclization was used by Shira-hama and co-workers for synthesis of bicyclohumule-none and africanol. Interestingly, different modes of... 

SCHEME 20.37. The transannular cationic cyclization in the synthesis of isocomene. 

SCHEME 20.39. The transannular cationic cyclizations in the syntheses of bicyclohumulenone and africanol. 

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. 

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. 

An elegant synthesis of the neurotoxic alkaloid anatoxin has exploited the electrocyclic opening of the dibromobicyclo[5.1.0]octane followed by transannular cyclization (Scheme 13).238 Similarly, the thermal electrocyclic opening of the dichlorocyclopropane followed by intramolecular trapping of the developing allylic cation by a suitably positioned amine has been used in a homoaporphine synthesis.238... 

The reactivity of different dienes towards 4-(N,N-dimethylamino)phenyl cation (6) has been studied, and for open-chain dienes, such as 2,5-dimethyl-2,4-hexadiene, only the trans-pentadienylaniline is found in a 52% yield [30], In the case of cyclic dienes, transannular cyclization takes place, leading to an arylnortricyclene from norbornadiene and to l-arylbicyclo[3.3.0]octanes from 1,5-cyclooctadiene in moderate yields (Scheme 10.18) [30]. 

When the substituent in 10 at C2 is a carboxaldehyde group, i.e. 10b, this cationic cyclopropana-tion reaction was accompanied by transannular cyclization to form a mixture of regiomeric olefins 12b. However, a selective reaction occurred with 10a on silylation with trimethylsilyl triflate in toluene at — 20 °C and subsequent desilylation with potassium fluoride in methanol a mixture of olefins 12a was obtained in 80% yield. Applying these conditions to 10b did not lead to 12 b. Instead, efficient transannular cyclization took place to form the 3,6-secoprotoil-ludane system. These reactions are examples of a regio- and stereoselective transformation of the humulene skeleton into cyclohumulanoids. 

When the C1-C2 double bond is deactivated, for instance by oxidation of the methyl group to an aldehyde group as in 11, opening of the oxirane ring by trimethylsilyl triflate provided a homoallyl carbenium ion which then underwent transannular Ti-cyclization but with participation of the C8-C9 double bond leading to a mixture of secoprotoilludane derivatives 12 and 13. In this case the rearrangement took place from a different C-C conformation, where in an intermediate step an additional Z/ isomerization of the C1-C2 double bond occurred. Reaction of the 8,9-epoxide of humulene with tin(IV) chloride led initially to formation of a cationic center at C9, but internal 7r-cyclization yielded an alcohol with a hydroazulene structure. ... 

The radical cations of diene systems in cyclic molecules are also capable of reaction as demonstrated by Demnth, Roth and their coworkers. They have studied the influence of phase on the photochemical reactivity of some naturally occurring dienes. Thns the irradiation of the diene 10 in homogeneous solution (acetonitrile/water) in the presence of an electron-accepting sensitizer such as cyanonaphthalene (CN) or DCB brings about fraws,cw-isomerization only. However, when the electron transfer reaction is carried out in the presence of sodinm dodecyl sulphate, transannular hydrogen abstraction reactions yield the two prodncts 11 and 12. Similar reactivity is observed with frans-geranyl acetate 13 and all-trawi-famesyl acetate 14. The authors report that these cyclizations are the flrst examples of biomimetic processes brought about under SET conditions. 

A transannular 6-endo reaction takes place in the boron trifluoride-diethyl ether complex induced cyclization of a bicyclic aldehyde. After the Markovnikov-orientated ring-closure step, a tertiary cation is generated, which is stabilized by //-proton loss and tetracycle 18, bearing a cyclopropyl unit, is formed in 67% yield24. In this case an ene reaction is impossible. 

Stereoselective transannular cyclizations to hydroazulene systems are also described. These reactions are initiated by ionization of cyclodecenol to form an allylic cation or by oxirane ring opening in cyclodecadiene monoepoxides. 

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