Radical triquinanes

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. 

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. 

A convenient route to triquinanes is based on a strategy of silyl radical addition to conjugated dienes to form allylic type radicals and their subsequent intramolecular addition to C=C double bonds. By exposure of 10 to (TMS)3SiH and AIBN at 80 °C (Reaction 7.16) the triquinane 11 is obtained with an unoptimized 51 %> yield [26]. 

The same process shown in Scheme 88 starting from different 2-substituted oxetanes and using biphenyl as the electron-carrier catalyst under THF reflux has been used to prepare regioselectively substituted primary alcohols. On the other hand, the combination of a DTBB-catalyzed ca 20%) lithiation with triethylaluminium in TFIF at —78 °C has been used for the transformation of strained oxetanes to substituted di- and triquinanes through a rearrangement process . An example is given in Scheme 89 for the transformation of oxetane 299 into the product 302 through radicals 300 and 301. 

Pattenden and coworkers have designed and performed a cascade of radical reactions towards the synthesis of angular triquinanes72. Irradiation of the refluxed benzene solution containing a 1 1 mixture of diastereomers of bromide 7 and (TMS SiH gave the corresponding triquinane oxime 8 as a 1 1 mixture of a- and /J-methyl diastereomers in 38% yield. 

An acyl radical formed from Se-Ph selenoester, can be used for the construction of a polycyclic skeleton in one-pot reaction [315, 316]. In this way, triquinane (+)-... 

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. 

Radical tandem reactions and in a wider context radical dominos or cascades have attracted a lot of attention because of their intrinsic elegance and the construction of a broad and sometimes unique array of molecular architectures they allow. Contrary to a long-standing idea, efficiency and selectivity requirements can also be met. A good illustration is the one-pot assembly of hnear triquinane 2 from acychc precursor 1 (Scheme 1) [1]. In this ten-elementary radical step process, five C - C bonds are created as well as three quaternary centers and four stereogenic centers, almost all completely controlled. 

Briggs et al. proposed a new strategy for the synthesis of tricyclic structures using acyl xanthates as precursor for acyl radicals [121]. Irradiation with visible light of a solution of acyl xanthate in presence of 1,6-diene 126 afforded czs-fused bicyclic compound 127 in a good yield (Scheme 38). Radical reduction of xanthate and subsequent aldol condensation leads to the formation of [5.5.5]-fused ring systems similar to those of the triquinane terpene family. 

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. 

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]. 

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... 

The angular triquinane ( )-6-silphiperfolcne is prepared by a related tandem radical cyclization sequence92,93. The precursor (4i /S)-3-(3-butenyl)-4-[( )-3-bromo-2-methyl-2-butenyl]-4-mcthyl-2-cyclopentenone is rapidly assembled (three steps) from 3-ethoxy-2-cy-clopentenone in 45 % overall yield. Radical cyclization of the precursor provided a 3 1 mixture of isomers in 66% yield. In the major stereoisomer, the methyl group is orientated / , opposite to that required in the target product. 

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... 

Although 0-stannyl ketyl radical anions are intermediates only recently developed for synthetic applications, they already provide ready access to carbonyl-alkene cyclizations, ring scissions, and tin(IV) enolates. Unlike standard radical reactions, these transformations provide an alcohol or ketone after workup that can be further synthetically manipulated. Finally, the intermediates can be applied to natural product skeletons such as the triquinanes. 

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