Angularly fused triquinanes

The synthesis of other angularly fused triquinanes as well as linearly fused sesquiterpenes such as hirsutene and capnellene quickly followed. Many general methods for the synthesis of cyclopentanoid natural products emerged as a result of the target-oriented effort [6]. These accomplishments have been reviewed extensively on numerous occasions [7]. This chapter reviews the history of retigeranic acid from its isolation and structure determination to published approaches to its synthesis and the four total syntheses accomplished to date. 

Silphinene (750), an angularly fused triquinane isolated by Bohlmann and Jakupovic from Silphium perfoliatum in 1980 has a substitution pattern entirely different from that of isocomene and pentalenene. Entirely different synthetic protocols are consequently required. Two successful approaches to 750 have so far been devised. That due to Leone-Bay and Paquette makes use of an iterative annulation scheme... 

The cyclization provides a route to the angularly fused triquinane system of 3, which lacks two of the methyl groups present in the natural sesquiterpene isocomene (4). Cyclization of a suitably substituted enyne for synthesis of 4, however, proceeds in minute yield.3... 

The conversion of the cycloadducts (57) and (58) to isocomene proceeds accorditig to plan. Thermolysis of the former provides diene (89), which is also obtained from cycloadduct (58), presumably via a 1,3-alkyl shift which produces (57) as an intermediate. Partial hydrogenation of diene (89) affords isocomene in six steps from commercially available starting materisds. The brevity of this )i oach to such angularly-fused triquinanes is a further manifestation of the synthetic benefit arising from the complexity increase associated with the meta cycloaddition. 

Serratosa s entry into the angularly fused triquinanes, mentioned earlier (equation 33), succeeds for terminal but not internal propargyl ethers. The in situ alkene isomerization that precedes cycloaddition renders synthesis of the bicyclo[3.3.0]oct-l-ene isomer unnecessary, making this a most direct synthetic process in spite of the modest yields. ... 

Hua has used the products of Pauson-Khand cycloadditions for syntheses of optically active pental-enene and racemic pentalenolactone E methyl ester. The racemic ketone in the first case was converted to the necessary optically active intermediate by kinetic resolution via 1,4-addition of an optically active allyl sulfoxide anion. These represented the first synthesis of natural products containing the angularly fused triquinane skeleton from bicyclic Pauson-Khand products (equation 53 and Scheme 20). ... 

Since our direct route to angularly fused triquinanes from cycloaddition of l-(4-pentynyl)cyclopen-tenes is limited to trisubstituted alkenes and simple terminal alkynes, bisnorisocomene, but not iso-comene itself, could be prepared (Scheme 22). However, this limitation is not a factor for most other compounds in this class of natural products, and the steric interactions described earlier worked to our advantage in a diastereocontrolled synthesis of pentalenene (see structure. Scheme 20). The natural product was obtained by subjecting the product of Scheme 14 to the sequence i, Li, NH3, MeOH ii, MeLi, Et20 iii, p-TsOH, benzene, reflux. ... 

Intramolecular radical cyclizations are exceptionally useful and have found widespread use in organic synthesis [11,12]. Kolbe chemistry has been exploited in this manner providing access to the prostaglandin precursor 8 [13], and to ring systems (10) that are common to the angularly fused triquinane natural products [14]. 

In principle, substrates could be designed to allow an application of the tandem sequence to the synthesis of a variety of natural products, particularly the angularly fused triquinanes 53-56 illustrated in Figure 2. 

Silphinene (56) is a member of the angularly fused triquinane class of natural products, and has been the focus of many synthetic endeavours [66]. Yamamura and coworkers made excellent use of their intramolecular electrooxidative phenol cycloaddition chemistry as a key step in the assembly of this material [63,67]. It is noteworthy that the conversion of 269 to 270 is not thwarted by the fact that cycloaddition must occur with a sterically demanding trisubstituted double bond. 

Similar methodology was used in a total synthesis of the angularly fused triquinane pentalenene (53) [65]. The known phenol 271 was used as the starting material. In this and the previous instance (viz. with 269) constant-current electrolyses were performed, this time converting 271 to a mixture of the desired adduct 272 (64%) as well as a material epimeric at the CH20Ac-bearing carbon (16%). The major adduct corresponds to one wherein the original olefin stereochemistry has been maintained. Conversion of 272 to the natural product followed chemistry similar to that used in the synthesis of silphinene (56). 

This bicyclo[3.3.0]octenone preparation has been employed in numerous natural product syntheses. Scheme 5-4 shows an early adaption of one of the cycloadditions shown in Eq. (53) toward the synthesis of the linearly fused triquinane system in coriolin. The substitutional and stereochemical characteristics built in by the Pauson-Khand process lend themselves to a very efficient approach [120]. Angularly fused triquinanes have also been prepared by closing the third ring onto a bicyclic Pauson-Khand product [121]. 

In the synthesis of ( )-pentalenene, the PKR was used to construct the angularly fused triquinane ring system 77 from cyclopentene 76. 

Recently reported rearrangements of linear triquinanes (244) to their angularly fused isomers (247) have been envisaged to involve the formation and equilibration of the enolates (245) and (246) followed by an intramolecular Michael addition of the enolate ion in (246) to the cyclopentenone moiety see Scheme 62. It has been reported that treatment of l,10-dibromobicyclo[8.1.0]undecane-3,8-dione (248) with triethylamine in dichloromethane results in the formation of a novel cyclopenta[(>]pyran derivative (249). The mechanism outlined in Scheme 63 has been postulated to account for this unusual transformation. 

Cydopentenone 64 bearing a carbonyl group in the substitutent R may serve for the synthesis of the angularly fused triquinane skeleton 66 based on a double Michael addition to the cyclopentadienone generated via base-promoted elimination of the dialkylamine [45]. Spiro[4.4]nonenone 65 appears as the relevant intermediate from the first Michael addition. Biscyclopentannulated cyclobutane 67... 

Aminocarbonylation has been combined with the Pauson-Khand reaction to construct fused tricyclic alkaloid skeletons (see 00154). The tandem aminocarbonylation/Pauson-Khand reaction of haloalkynes with a chiral allylic amine promoted by Co2(CO)8 gave angular triquinanes as exemplified in Scheme 25. Thus, the reaction of l-chloro-2-phenylethyne 175 with Co2(CO)8 at 0°C gave alkyne-dicobalt complex 176, which was converted to enoyl-dicobalt complex 177 upon warming to 25 °C. The reaction of enoyl-dicobalt complex 177 with cyclopente-nylmethyl(l-phenylethyl)amine 179 yielded Pauson-Khand reaction product, angular triquinane 180, via A -allylic aminocarbonylated alkyne-dicobalt complex 178 (Scheme 25). ... 

The linear triquinane skeleton is easily accessible from methyl 8-oxotricyclo-[5.4.0.0] undecan-l-carboxylate 67 [64]. Photoreduction of 67 affords ring-expanded intermediate 67" which cyclizes to the linearly fused triquinane 68 (Scheme 29, eq 1). An extension of this reaction to the heterocyclic angular tricyclic compound 70 has also been achieved starting from keto lactone 69 (Scheme 29, eq 2) [75]. 

Triquinanes rank among the most important natural carbon frameworks [12, 19], Angular- and linear-fused carbon skeletons possess three five-membered rings which share one or two carbon-carbon bonds, respectively. Natural products from a wide array of biological sources produce these compounds with a considerable range of functionality. A new radical anion tandem process to prepare two triquinane skeletons, linear and angular, was initiated by the radical anion of strained ring systems... 

The skeieton of linear triquinane is easily accessible from the methyl 8-oxotricyclo I 5.4.0.0l undecan-l-carboxylate 150." Photoreduction of 150 implied the formation of a ring-expanded intermediate K which cyclized to produce the linearly fused triquinane 151 (Scheme 58). An extension of this reaction to heterocyclic angular tricyclic compounds has also been achieved (Scheme 59). This photofragmentation method has been ex-... 

Hwang, J.-T. and Liao, C.-C., Synthesis of angularly and linearly fused triquinanes via the common intramolecular Diels-Alder adduct of a masked o-benzoquinone. Tetrahedron Lett., 32,6583,1991. 

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