Quadrone synthesis

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 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... 

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). 

Some illustrative examples from the field of polyquinanes are the synthesis of some derivatives of bicyclo[3.3.0]octane 6 (Scheme 6.7) [12] [15] -which have been used in the total syntheses of coriolin, hirsutic acid and quadrone- and the synthesis of triquinacene 7 and some of its derivatives. The retrosynthetic analysis of perhydrotriquinacene-l,4,7-trione (7a) is shown in Scheme 6.7bis. In the actual synthesis the hydroxy groups must be protected either as trialkylsilyl ethers or more conveniently as benzyl ethers [16] [17]. 

Interest in the total synthesis of the Aspergillus terreus derived quadrone fi06), an antitumor agent has been very intense. Success was first realized in Danishefsky s laboratory Once 601 was reached, its sidechain was elaborated and ring closure effected (Scheme LII). Condensation of 602 with 1-tert-butoxy-l-tcrt-butyl-dimethylsiloxyethylene in the presence of titanium tetrachloride and subsequent desilylation resulted in introduction of an angular acetic acid moiety. The two sidechains were next connected by intramolecular alkylation and the resulting keto add was subjected to selenenylation in order to produce 603. The a, P-unsaturated double bond was used to force enolization to the a position. Indeed, 604 was... 

An interestingly short total synthesis of quadrone was developed by Kende and coworkers who made application of Pd(II)-mediated cycloalkenylation of silyl enol ethers (Scheme LV) Their point of departure was 609 which was converted directly to 610, Reaction of this silyl enol ether with palladium acetate in acetonitrile gave predominantly 6JI which could be cyclized to 612. From this intermediate, it was possible to prepare the known keto acid. 

A synthesis of descarboxylquadrone (621) has been described The presence of the a, p-unsaturated carbonyl system causes this substan< to be biologically active, presumably in parallel with the latent a-methylene cyclopentanone functionality believed responsible for the cytotoxic activity of quadrone. 

In contrast, the closely related palladium acetate-promoted intramolecular alkylation of alkenes by tri-methylsilyl enol ethers (Scheme 4)6,7 has been used to synthesize a large number of bridged carbocyclic systems (Table 1). In principle, this process should be capable of being made catalytic in palladium(II), since silyl enol ethers are stable to a range of oxidants used to carry the Pd° -> Pd11 redox chemistry required for catalysis. In practice, catalytically efficient conditions have not yet been developed, and the reaction is usually carried out using a full equivalent of palladium(II) acetate. This chemistry has been used in the synthesis of quadrone (equation 2).8 With the more electrophilic palladium(II) trifluoroace-tate, methyl enol ethers underwent this cyclization process (equation 3).9... 

An elegant application of this chemistry to the formal synthesis of ( )-quadrone has been reported by Piers and coworkers.78a l2la Decomposition of ethyl diazoacetate in the presence of the bicyclic structure (119) resulted in selective cyclopropanation to form (120). Further modification of (120) generated the /ram-divinylcyclopropane (121), which on thermolysis followed by desilylation produced the tricyclic system (122). Conversion of (122) to the ketone (123) completed the formal synthesis because (123 Scheme 24) had been previously converted to ( )-quadione.l2lb... 

The first enantiomerically pure synthesis of the antitumor compound quadrone has been developed by Smith and coworkers103, via photoaddition of isobutylene to 218 followed by epimerization affording the desired photoproduct 219a in 5 1 ratio with its diastereomer in 74% yield. The synthesis of (+)-enantioquadrone was completed via kinetic resolution of 219a (Scheme 47). 

Intermolecular cyclopropanation reactions with ethyl diazoacetate have been employed for the construction of the cyclopropane-containing amino acid 7 (equation 25) Thus, rhodium(II) acetate catalysed decomposition of ethyl diazoacetate in the presence of d-cbz-vinylglycine methyl ester 5 afforded cyclopropyl ester 6 in 85% yield. Removal of the protecting group completed the synthesis of 7. Another example illustrating intermolecular cyclopropanation can be found in Piers and Moss synthesis of ( )-quadrone 8" (equation 26). Intermolecular cyclopropanation of enamide or vinyl ether functions using ethyl diazoacetate has also been used in the synthesis of eburnamonine 9", pentalenolactone E ester 10" and ( )-dicranenone A11" (equations 27-29). 

An entirely different approach for the synthesis of quadrone was chosen by Yoshii et al Yoshii s group started the assemblage of 62 from cyclohexenone 73 (Scheme 3.17), as a precursor of ring C. The synthetic sequence consisted of only 12 steps and was accomplished in an overall yield of 2.6%. The key steps in this synthesis, involving intermediates 74-78, are shown in Scheme 3.17. 

The cycloadduct of indane and vinyl acetate (136) has also figured in a clever synthesis of decarboxy-quadrone (145 Scheme 19) reported by Mehta. For this target the cycloadduct is reduced and solvol-yzed to provide alcohol (142). Dimethylation and rearrangement provides the required tricyclic subunit of the target. 

The cytotoxic sesquiterpenoid (-)-quadrone, isolated from the fungus Aspergillus terreus, possesses the constitution and absolute stereochemistry shown in (218). The tricyclic carbon skeleton of this interesting natural product is the same as that found in compound (198), which, as described above (Scheme 28), is readily prepared by thermolysis of the tricyclic diene (197). Thus, it appeared that the Cope rearrangement of a suitably substituted and functionalized derivative of (197) might serve effectively as a key intermediate in a total synthesis of ( )-quadione (218) that is, successful Cope rearrangement of a substrate, such as (219), would provide, stereoselectively, the tricyclic substance (220). Presumably, the intermediate (220) could then be converted into the keto aldehyde (221), which had already been transformed into ( )-quadrone (218). ... 

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)."... 

The anion radicals were generated by cathodic reduction, providing yields of cyclized product as high as 87 %. In a total synthesis of quadrone, efficient reductive cyclizations were used at two dilferent stages of the synthesis (Scheme 73) [121]. 

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). 

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