Triquinanes radical cyclizations

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. 

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. 

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. 

The extention of radical cyclization of (bromomethyl)dimethylsilyl allyl ethers to propargyl analogs 17 has been studied by Malacria and coworkers. The intermediate exocyclic vinyl radical 18 can be either trapped by the hydrogen atom to give, after simple chemical transformations, the trisubstituted alkene 19 (equation 25) or can be added intramolecularly to give cyclic products when suitably located double bonds are present (equations 26 and 27). An attempt to apply this methodology to the stereoselective synthesis of angular and linear triquinane has also been performed. When = t rt-butyl,... 

Triquinanes 137 serve as good examples of a challenging framework in natural product synthesis [53]. In 2012, a domino radical cyclization to give vinylogous carbonates and carbamates was developed by Gharpure and coworkers [54], which involves an unprecedented, highly stereoselective formation of heterocyclic rings (Scheme 5.28). 

Hollingworth, G. J., Pattenden, G. and Schulz, D. J. (1995) Cascade Radical Cyclization-Fragmentation-Transannular-Ring Expansion Reactions Involving Oximes. A New Approach to Synthesis of Angular Triquinanes, Aust. J. Chem. 48, 381-399. 

Fraser-Reid s group have described further examples of the use of serial radical cyclization to prepare di- and triquinane natural products. The previously-reported intermediate (4) (Vol. 23, p. 264) has been ring-opened by a Vasella-Bernet reaction, and hence converted to the triquinane (5) with the silphinene skeleton (Scheme 2). Similar initial steps were involved in the conversion of (6) into silphiperfolene (7), and to transform (8) (Vol. 23, p. 265) into (-)-a-pipitzol (9) (mannose carbons numbered). ... 

Malacria and co-workers developed a synthetic route to linear triquinanes by transannular radical cyclizations of the , -cycloundeca-4,8-dien-l-yne 114. Upon radical initiation, the primary radical 115 underwent the 5-exo-dig cycli-zation to give 116 (Scheme 20.31), which in turn participated in tandem transannular radical cyclzations to give a single diasteromeric triquinane 119. This was followed by the Tamao oxidation to give 120 in 60% yield. 

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. 

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. 

Clearly, there was no reason to stop at / -silyl radical 21. An access to linear and angular triquinanes 24 and 27 was open by adding a new 5-exo cyclization from intermediate radicals 25 and 28. This just required us to work with substrates 26 and 29 bearing three unsaturations (Scheme 10). 

In conclusion, it is now possible to assemble highly functionalized linear triquinanes from acyclic precursors with high diastereocontrol. The sequence mixing intramolecular cyclizations and a [3-f2] radical annulation appears as the strategy of choice. To probe its versatility, this strategy will have to materialize into total syntheses of natural products. 

While studying the stereochemical outcome of the cyclization of an cu-iodo substituted link in disubstituted cyclooctadienic precursors, Winkler reported that the tra 5-disubstituted cyclooctadiene 105 led to the formation of a 1 1 mixture of cis-anti-cis and cis-syn-cis triquinanes 107 in 28% global yield and, as major products, trans- and cw-bicyclo[6.3.0]undecenes 108 (Scheme 31). This example reveals a complete lack of stereocontrol during the first 5-exo cyclization from radical 106 an exactly 1 1 trans, exjunction stereoselectivity is obtained [47],... 

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