Formal Total Synthesis of Quadrone

The utility of electroreductive cyclization chemistry is demonstrated quite nicely in its application to a formal total synthesis of quadrone (59) [41]. This fungal metabolite isolated from Aspergillus terreus, displays in vivo and in vitro cytotoxicity. One approach focuses upon three transformations, two involving 

Controlled potential reduction of 60 in the presence of dimethyl malonate as a proton donor afforded a mixture of two products, the y-hydroxy ester 65 and lactone 66, in a combined yield of 89% each was converted to a common intermediate, 67. 

One can attribute the selective formation of materials with the ester and allyl units trans to one another, to the preference for the allyl unit to occupy a pseudoequatorial rather than a pseudoaxial orientation in the product-determining transition state. Compare, for example, transition state formulation 68 with 69. This stereochemical outcome is fortunate, as later on in the sequence, it is necessary for the allyl unit (after functional group modification) to swing across the top face of the cyclopentyl ring system during the conversion of 62 to 63. Were the substituents cis to one another, this would not be possible. 

Keto ester 67 was converted to the unsaturated nitrile 70 in a routine manner. The latter proved to be an exceptionally useful intermediate. Concern that the significant steric demands which are associated with the formation of a sigma bond to the fully substituted beta carbon of the unsaturated nitrile would prevent reaction from occurring, were allayed by the discovery that the controlled potential reduction of 70 at —2.4 V in the presence of dimethyl malonate as the proton donor, alforded a 90% isolated yield of the requisite [3.2.1] adduct 71. This material was subsequently converted to enone 72 [42], a convergent point with an existing synthesis of quadrone (59). 

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A successful formal total synthesis of ( )-quadrone (218) via a route in which a divinylcyclopropane rearrangement played a key role was achieved by employing the substrate (228 Scheme 32). This material is readily prepared from the ketone (227) and, in contrast to compounds (219) and (224), undergoes smooth Cope rearrangement to the tricyclic diene acetal (229), which is easily transformed into the keto acetal (230). A rather lengthy sequence of reactions effects conversion of (230) into the keto aldehyde (221), which, as mentioned previously, has served as an intermediate in a total synthesis of ( )-quadione (218)."... 

Sowell, C.G., Wohn, R.L., and Little, R.D., Electtoreductive cyclization reactions. Stereoselection, creation of quaternary centers in bicychc frameworks, and a formal total synthesis of quadrone. Tetrahedron Lett., 31, 485, 1990. 

Carbon-carbon bond formation resulting in ring closure is important in synthesis, especially so if the process is general. A potentially very useful method whereby silyl enol ethers undergo palladium(n)-mediated intramolecular cycliz-ation with alkenes is therefore noteworthy (Scheme 26). Although we illustrate just one example in the Scheme, many others were investigated, including an application for the formal total synthesis of ( )-quadrone. ... 

A demonstration of the utility of the electroreductive cyclization reaction is provided by the formal total synthesis of the antitumor agent quadrone (16, Scheme 4) [17]. The first stage of the synthesis involved a controlled potential reduction of (9) in the presence of dimethyl malonate as the proton donor. An efficient cyclization ensued, leading to the formation of the y-hydroxy ester (10)... 

The utility of electroreductive cyclization (ERC) reaction is demonstrated by the formal total synthesis of the antitumor agent quadrone (120) that is outlined in Scheme 13 [35]. The reaction serves to link the -carbon of an electron deficient alkene to the carbonyl carbon of an aldehyde or ketone tethered to it. The transformation plays a pivotal role in the key carbon-carbon bond forming events leading to 124 and 122, and en route to quadrone (120). 

In Kende s formal total synthesis of the antitumor agent quadrone , a late stage intermediate, prior to closure of the third carbocyclic ring, was prepared using the method of Stille. The reaction appears to be exceedingly slow, even when HMPA is used as the solvent (equation 95). This points to the fact that transfer of simple alkyl groups from tin to the acylpalladium complex is not facile. No mention was made of alternative nucleophiles for this transformation such as dimethylcuprate or methylmagnesium chloride. 

Funk and Abelman used the Ireland-Claisen rearrangement in a formal synthesis of the tetracyclic terpenoid quadrone (Scheme 4.140) [136]. Treatment of the lactone under typical conditions resulted in facile rearrangement at or below room temperature to give the bicyclic acid after sUyl ester hydrolysis. Oxidative cleavage of the alkenes then intercepted an intermediate previously employed by Schles-singer in a total synthesis of quadrone. 

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