Triquinanes cyclization

Hirsutene (1) and A9(,2,-capnellcnc (2), the parent members of the hirsutane and capnellane families of triquinane natural products, respectively, are isomeric molecules that possess four contiguous stereogenic centers, one of which is quaternary. The linearly fused tricyclopentanoid frameworks of compounds 1 and 2 are obviously very similar, differing only with respect to the positions of the three methyl groups. An asset of Curran s tandem radical cyclization strategy is that it provides a unified entry into a wide variety of linear condensed cyclopentanoid natural products. As a result, it is possible to devise nearly identical retrosynthetic pathways for these structurally related molecules. 

Si-directed Nazarov cyclization (13, 133-134). Denmark2 has extended the Si-directed cyclization of (i-silyl divinyl ketones to preparation of linear tricycles (triquinanes). These cyclizations proceed very readily even at low temperatures, and the position of the double bond is controlled by the silyl group. The reactions... 

A radical tandem cyclization, consisting of two radical carbocyclizations and a heterocoupling reaction, has been achieved by electrolysis of unsaturated carboxylic acids with different coacids. This provides a short synthetic sequence to tricyclic products, for example, triquinanes, starting from carboxylic acids which are accessible in few steps (Scheme 6) [123]. The selectivity for the formation of the tricyclic, bi-cyclic, and monocyclic product depending on the current density could be predicted by applying a mathematical simulation based on the proposed mechanism. 

Electroreduction of y- and 5-cyano ketones in isoPrOH with a Sn cathode gave a-hydroxyketones with good diastereo-selectivities as cyclization products. The reaction has been used as a key step for the synthesis of, for example, guaiazulene, triquinanes, and dihydrojasmone. Similarly, the corresponding intermolecular couplings were realized [315]. 

Reductive cyclization.1 Reduction of the unsaturated aldehyde 1 with Sml2 in THF/HMPT (20 1) at 0° effects a tandem radical cyclization of the fram-3,5-disubstituted cyclopentene system to a linear triquinane unit (2) with surprisingly high cw-ann-di-stereoselectivity. 

For example, ( )-hirsutene, a member of the triquinane class of natural products, has been prepared by tandem radical cyclization as shown in equation 132801. Also, in a key step in the synthesis of silphiperfolene, the tricyclic ketal precursor oxosilphiperfolene was generated by a tandem cyclization process (equation 133)805. The desired enantiomer was generated in a 5 2 excess over the unwanted one. 

Some double-bond shifts and isomerizations have been observed previous to the PKR. Sometimes 1,6 enynes have reacted partially as 1,7 enynes, or 1,8-enynes have isomerized to 1,7-enynes prior to the PKR [59,60,133]. In some intermolecular examples strained alkenes have isomerized totally before the cyclization giving unexpected products. An example, in the synthesis of triquinanes like 120, depicted in Scheme 33, the starting alkene 118 was isomerized to 119 prior to the reaction with 117 [134,135]. 

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 potential of sequential radical addition as a powerful method to achieve the formation of five-membered rings was fully realized in the tandem radical cyclization strategy devised by Curran for the synthesis of triquinanes. In the case of linearly fused triquinanes, such as hirsutene 90 (Scheme 3.40), this strategy implies the retrosynthetic disconnection of the tricyclic framework by the application of two sequential radical cyclization transforms at rings A and... 

More sophistication was required to elaborate the pathway applicable for the synthesis of triquinane 165, a known precursor for the preparation of hypnofilin 166. The presence of a hydroxyl group in ring A of 166 dictated the use of a modified substrate for the tandem radical cyclization and an entirely different method for its triggering. A one-electron reduction of the aldehyde carbonyl in 167 by Sml2 proved to be the method of choice in this case. It is worthwhile to note that adduct 160, already utilized in the synthesis of 154, also turned out to be useful as an advanced intermediate for the preparation of 167. 

Mehta has examined relative stereocontrol in an approach to the carbocyclic nucleus of ophiobolins. Cyclization of the triquinane (11) gave two products, (12) and (13), in a 4 1 ratio (Scheme 14). These products arise from opposite rotatory pathways as shown. Surprisingly, the major product arises from conrotation to the concave face of the diquinane unit. Finally, Nazarov has provided an interesting example of both fused and spiro mode annulations in equation (10). ... 

In an imaginative construction of the angular triquinane ( )-hirsutene (158), Oppolzer and Robyr reported the carbonylative closure of allylic carbonate 155 to yield bicyclooctanes 156 and 157 (Scheme 6-27) [57]. In this multistep transformation, a alJylpalladium intermediate arising from the allylic carbonate 155 undergoes intramolecular Heck insertion of the pendant alkyne. Carbonylation of the resulting vinylpalladium intermediate, another Heck cyclization, and a second carbonylation then provide a mixture of acids, which after esterification yield esters 156 and 157 in good yield. 

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]. 

During the enantioselective total synthesis of (-)-coriolin, I. Kuwajima and co-workers used a Darzens-type reaction to construct the spiro epoxide moiety on the triquinane skeleton. Interestingly, the usual Darzens condensation where the a-bromoketone was condensed with paraformaldehyde yielded a bromohydrin in which the hydroxymethyl group was introduced from the concave face of the molecule. This bromohydrin upon treatment with DBU gave the undesired stereochemistry at C3 (found in 3-ep/-coriolin). To obtain the correct stereochemistry at C3, the substituents were introduced in a reverse manner. It was also necessary to enhance the reactivity of the enolate with potassium pinacolate by generating a labile potassium enolate in the presence of NIS. The in situ formed iodohydrin, then cyclized to the spiro epoxide having the desired stereochemistry at C3. 

During the synthetic studies toward the natural product kalmanol, L.A. Paquette and co-workers prepared the CD diquinane substructure by using an intramoiecuiar Pauson-Khand reaction. The use of an A/-oxide promoter for the cyclization resulted in very mild conditions and afforded the desired triquinane in good yieid and as a single diastereomer. 

The capnellene and hirsutene marine sesquiterpenes are ideal candidates for radical cyclizations and both have been elaborated via carbonyl-alkyne cyclizations (equations 141-143). Thus treatment of the ketone (117) with the sodium naphthalene radical anion gives the triquinane (118). Subsequent allylic... 

---