Fenestrane synthesis

Another elegant fenestrane synthesis, discovered by Keese, is described in Chapter 6. 

An illustrative example for the usefulness of the Weiss reaction for the construction of complex cyclopentanoid carbon skeletons is the synthesis of the all -cis [5.5.5.5]fenestrane 7 after Cook et al., starting from the a-diketone ... 

Scheme 3.77. Domino radical cyclization for the synthesis of fenestranes.

The Pauson-Khand reaction is the Co-induced formation of cyclopentenones from ene-ynes and CO. One impressive example of a domino Pauson-Khand process is the synthesis of fenestrane 6/4-15, as reported by Keese and colleagues [278]. The transformation is initiated by a double Grignard reaction of 4-pentynoic acid 6/4-12, followed by protection of the formed tertiary hydroxyl group to give 6/4-13. The Co-induced polycyclization of 6/4-13 led directly to the fenestrane 6/4-15... 

Chung and coworkers [280] combined a [2+2+1] with a [2+2+2] cycloaddihon for the synthesis of multi-ring skeletons, angular triquinanes, and fenestranes. For the preparation of tetracyclic compounds such a 6/4-17, these authors used diynes as 6/4-16 and CO as substrates (Scheme 6/4.5). Fully substituted alkynes gave low yields, and 1,5- as well as 1,7-dialkynes, did not react... 

The first claimed synthesis of a fenestrane precursor follows a similar route460a) (4.48). In general such intramolecular cycloadditions represent an efficient way of synthesizing centropolycyclanes 460b). 

A domino Pauson-Khand-Reaction was developed by Keese et al. starting from enediyne 155 leading to the shortest synthesis of a fenestrane 157 (scheme 31).1791... 

Scheme 31. Synthesis of fenestranes by domino Pauson-Khand reaction...

The synthesis of [4.4.4.4]fenestrane or windowpane has become an active area of research due to the aesthetic appeal of the hydrocarbon and the nature of its central quaternary carbon atom which is expected to be distorted from normal tetrahedral geometry . Ongoing investigations have generated a number of ring-expanded triquinane and tetraquinane ([5.5.5.5]fenestrane) homologs. These molecules form the subject matter of the discussion which follows. 

This strategy has been successfully employed for the construction of [5,5,5,5]-fenestranes (Equation (36)), as well as for the synthesis of complex natural products such as terpenoids, for example, hirsutene (Equation (37)). ... 

These intramolecular meta-addition processes were utilized in the key steps for the total synthesis of a-cedrene [245], isocomene [246], hirsutene [247], coriolin [248], silphinene [249], rudmollin [250], laurenene [251], and fenestranes [252-254], which were synthesized by Wender s and Keese s groups (Scheme 58). 

These allylpalladation-acylpalladation cascade bicyclization reactions have been applied mainly by Oppolzer to the synthesis of various natural products including (zb)-pentalenolactone E methyl ester [152], 3-isorauniti-cine [153], ( )-coriolin [154], and ( )-hirsutene [155]. Their application to the syntheses of [5.5.5.5]fenestrane derivatives by Keese [156,157] (Scheme 63) is also noteworthy. 

A spectacular application allowed the synthesis of fenestranes by a three-step sequential action of cobalt nanoparticles and a palladium catalyst [131]. The cascade reaction started with a PKR of enyne 105, accomplished by the cobalt catalyst giving 106, followed by the formation of allyl-7r3 palladium complex 107 which reacted with a nucleophile derived from diethyl malonate, to give enyne 108. The final step was a second PKR that gave 109 in good yield. They used cobalt nanoparticles as with Co/charcoal the third step did not take place, apparently due to damage in this catalyst after the allylation step (Scheme 31). 

Scheme 31 Three-step one pot synthesis of fenestranes from an enyne and an alkyne...

Several groups have developed the combination two or more PKR or PK-type reactions in the same reaction step. The multiplication of the synthetic power of this transformation has found immediate application for the synthesis of natural [S.5.5.5] systems called fenestranes. Starting materials have been enediynes that give two [2 + 2 + 1] cycloadditions. The extension of the reaction to triynes has led to interesting tandem processes that may include [2 + 2 + 2] cyclizations. Other cycloadditions like the Diels-Alder have also been combined with the PK. 

Keese envisioned the use of a tandem PKR for the synthesis of fenestranes. The second cycloaddition was in principle problematic as it involved an al-kene conjugated with a ketone. They were surprised when they observed the direct formation of the tetracyclic unit 136 from the endiyne 135 although with low yield [ 148]. Further studies from this group led to a mechanistic proposal that explained this result. It was clear from the fact that compound 140 failed to react, that the second PKR had to start from an intermediate metal-lacycle rather than from the uncomplexed final cyclopentenone. Thus, cobalt complex 137 would lead to 138 were both metal clusters would interact giving intermediate 139 which would evolve in the usual way to the final product (Scheme 42) [149]. These systems have been obtained later by Chung s group using cobalt nanoparticles as commented above (Sect. 2.4) [131]. 

Scheme 53 Tandem [2 + 2 + l]/[4 + 2] cycloaddition of diendiynes for the one pot synthesis of fenestranes...

However, in another contribution, Chung and coworkers realized the one-pot synthesis of [ S.5.5.6] fenestranes 42 via intramolecular cobalt-catalyzed tandem Pauson-Khand/Diels-Alder reactions of dienediynes 41 [44] (Scheme 21). 

Finally, sequential Pauson-Khand reactions (domino reactions) are possible [36, 37]. A particular fascinating application of this concept is the synthesis of a fenestrane by Keese and coworkers (Scheme 13) [36],... 

Scheme 13. Synthesis of a fenestrane by domino Pauson-Khand reaction according to Keese.

It is also relevant to add that while the experimental studies in this area have actually originated from rather abstract considerations advanced by organic chemists, the fenestrane-like design had been employed in Nature for a long while in the creation of the framework of several natural compounds (such as laurenene 146). What their functions are and how (or if) the functions are related to the specificity of their structure are still questions to be answered. It is also worth noting that synthesis of 146 was achieved rather easily (see refs, in 22b) by employing the methods elaborated in the course of studies aimed at the preparation of the fenestrane framework. 

Intramolecular cycloaddition of the enone (5) affords the adduct (6), which was used as the key intermediate in the synthesis of (7). Photocyclization of the enone (8) affords the tricyclononanone (9) this was used as an intermediate in the synthesis of the fenestrane (10). Irradiation of a mixture of the... 

The photo-Wolff rearrangement has proved of particular value in the synthesis of compounds containing four-membered rings. The first [4.4.4.5]fenestrane derivative (64) to be characterized was obtained in this way by irradiation of the diazocyclopentanone (65) in methanol, and the 4-diazopyrrolidine-2,3-diones (66) have similarly served as useful precursors in a novel approach to /3-lactams (67) and penams. " The related ring contraction... 

The first naturally occurring member of the class of fenestranes is the diterpene lauren-l-ene (27), isolated in 1979 from the essential oil of Dacrydium cupressinum. The intermediate (26) for Wender s stereocontrolled synthesis of (27) is readily accessible by attack of KOH on the tosyloxy ketone (25) to give, via fragmentation, a carboxylate anion which undergoes immediate ring closure to the lactone (26 Scheme 12). 

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