Gloeosporone, synthesis

Although the precise mode of action of the binary RCM catalyst (i.e., (PCy3)2Cl2Ru=CHPh+H(OiPr)4) remains to be elucidated, its key role within the gloeosporone synthesis gives further credence to the notion that a transient and kinetically labile chelate complex acts as a crucial template which shapes the diene precursor and thereby provides internal bias for ring closure. 

RCM-based macrocyclization reactions as they potentially sequester the catalyst in an unproductive form. A recent total synthesis of gloeosporone 86 addresses this aspect and describes a simple, yet efficient way to overcome this limitation [31]. 

The final steps in a total synthesis of (+ )-gloeosporone (3, a natural germination inhibitor of a fungus) required oxidation of the acetylene group of 1 to a diketone group. The oxidation was carried out in 74% yield by the catalytic Ru02 procedure of Sharpless. On liberation (pyridine-HF) of the C7-hydroxyl group, the hydroxy... 

Seebach et al. [45] employed this procedure in the synthesis of the germination self-inhibitor gloeosporone (79). Treatment of seco acid 77 with 2 equiv of DEAD and 2 equiv of triphenylphosphine in benzene (0.005 M) for 10 min afforded the... 

A. Furstner and co-workers devised an efficient synthesis of (-)-gloeosporone, a fungal germination inhibitor. They utilized the Keck asymmetric allylation method to create the 7(R>homoallylic alcohol subunit. The reaction of the substrate aldehyde in the presence of the in situ generated catalyst provided the product with high yield and as the only diastereomer. It is important to note that it was essential to use freshly distilled Ti(/-OPr)4 for the preparation of the catalyst in order to get high enantioselectivity and reproducible results. 

The observation that thiyl radicals are able to isomerize alkenes was first made by Walling et al. many years ago [55] and, now the addition-elimination sequence of the phenylthiyl radicals is an established methodology in fine chemical synthesis [56]. It has been utilized as key step in the synthesis of biologically active compounds, such as (-)-gloeosporone [57a], (-l-)-hitachimycin [57b] and other naturally occurring macrolides [5b], as well as for preparing non-natural isomers of phospholipids [58]. 

Besides its extensive application in industrial processes, e.g., ROMP and ADMET, the alkene metathesis has been applied to drug discovery and peptide synthesis. Examples include the synthesis of antifungal lactone (-)-gloeosporone, the cross-metathesis of the amino acid homoallylglycine, the introduction of carbon-carbon cross-linkages into... 

Fiirstner and coworkers [31] have subsequently employed TilOi-Pr) as an additive during the preparation of a 14-membered macrocycle intermediate in the synthesis of (-)-gloeosporone (Scheme 12.17). When diene 55 was subjected to Ru-based catalyst 1 (3mol%) and Ti(Oi-Pr)4 (30mol%) in CH2CI2, the desired macrocycle 56 was obtained in 80% isolated yield (E Z = 2.7 1). 

It has long been known that thiyl radicals add reversibly to double bonds (cf. Scheme 1) [17]. The (Z)-( ) interconversion of olefins by the addition-elimination sequence of thiyl radicals [18] is now an established methodology in chemical synthesis [19] and has been applied successfully as the key step in the synthesis of elaborate molecules such as the antifungal macrocyclic lactone (-)-gloeosporone [20a] and the antibiotic-antitumor agent (+)-hitachimycin [20b]. The E/Z ratio after equilibration generally reflects the thermodynamic stability of (Z)- and ( )-alkenes. It has recently been shown that equilibrium Z/E-18/82) for ( )- and (Z)-hexen-l-ol is reached with PhS radical in 1 h at 80°C [21]. Comparatively, the same isomeric composition is reached in 4h and lOh with Bu3Sn and (TMS)3Si respectively under similar conditions. 

Two early examples disclosed by Fiirstner etal, ricinelaidic acid (60) and gloeosporone (63) (germination self-inhibitors isolated from Colktotrichum oeospo-rioide), were built by using [Ru]-I (Equations 1 and 2, Scheme 5.13). In the synthesis... 

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