Coriolin, synthesis

For his synthesis of the anti-tumour compound diketo-coriolin, Danishefsky needed (9) with its two fused five-membered rings, Enone disconnection suggests two possible precursors. 

These catalysts have been applied to D-A reactions that are parts of several important synthetic routes, thereby making them enantioselective.96 For example, key intermediates in the synthesis of cortisone and coriolin were prepared in enantiomeri-cally pure form using catalyst B. 

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]. 

Khand annulations (extremely efficient in the synthesis of polyquinanes and cyclopentanoid sesquiterpenes -triquinacene, coriolin, etc.-, among many others). 

Coriolin (689), a metabolite of the Basidiomycete Coriolus consors, has attracted widespread interest because of its unusual anti-tumor activity and highly functionalized triquinane structure. Accordingly, a number of syntheses of689 have appeared on the scene. One of the earliest, due to Tatsuta, et al., begins with epoxide 690, whose preparation had been earlier realized in connection with their work on hirsutine (see Scheme LXIII). Deoxygenation of 690, hydrolysis, and cis-hydroxy-lation provided keto triol 691 (Scheme LXXII) The derived acetonide was transformed via 692 into tetraol 693 which could be selectively acetylated and dehydrated on both flanks of the carbonyl group. Deacetylation of 694 followed by epoxidation completed the synthesis. 

In a manner paralleling somewhat their strategy for carbaprostaglandin synthesis (Scheme LX), Ikegami, et al., have realized a coriolin total synthesis starting from 1,3-cyclooctadiene. With 701 in hand, they proceeded to elaborate the functionalized... 

This unnatural acid is used as a chiral intermediate for the synthesis of a number of products. Chemical asymmetric synthesis was very difficult and so the stereoselective synthetic properties of enzymes were exploited to carry out a selective reduction reaction. The stereoselective hydrolysis of protein amino acid esters had already been commercialised by Tanabe in Japan using immobilised aminoacylase, and selective reduction reactions using whole yeast cells are already used in a number of processes, such as the selective reduction of the anti-cancer drag Coriolin. 

Diels-Alder reaction. The Diels-Alder reaction of 1 with 2 provides a key step in a total synthesis of alternative mode, the less stable trans-fusion ol the bicyclopcntanc system is formed. The product is converted in two steps into... 

The final step in Danishefsky s synthesis of the sesquiterpene coriolin (2)3 required bis epoxidation of 1. All attempts to effect this reaction in one step resulted in a mixture of the desired diepoxide (2) and epicoriolin (3) in about equal parts under best conditions. However, a two-step epoxidation procedure (1 >4 and 5 ->-6) resulted in a stereoselective synthesis of 2. 

Methyleneeyclopentane annelation (9,454-455). The mesylate (2) of 1 has been usedasan electrophilic equivalent of trimethylenemethane for methyleneeyclopentane annelation of a cyclopentanone in a synthesis of coriolin (7).2 Thus, reaction of the enolate of 4, a protected equivalent of 3, reacts with 2 to give 5, which after oxidation to the disulfone is cyclized by fluoride ion to the tricyclic methyleneeyclopentane derivative 6. The product is converted into 7 by several known transformations. 

Methylenecyclopentanes.2 Trost and Curran have used 1 as an electrophilic synthon for trimethylenemethane. Thus 1 reacts with the anion of 2 to give 3 in 72% yield. This product was oxidized to the disulfone, which was then cyclized to 4 by F. Various transformations are possible for the exocyclic methylene group. For the synthesis of coriolin (6), the group was converted to a pem-dimethyl group by cyclopropanation and hydrogenolysis. The product (5) was converted in several more steps into 6. 

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). 

The anti-cancer compound coriolin 23 has three fused five-membered rings and two epoxides. Notice that the 3/5 and both 5/5 ring fusions are cis. There have been many syntheses of coriolin, most using stereochemistry from folded precursors.7 We shall feature a couple of examples. Matsomoto s synthesis involves the hydroboration of alkene 24. The addition of borane is cis 25 and the boron is replaced by OH with retention of configuration to give 26. The hydroboration occurred on the outside of the molecule, on the same face as the ring junction hydrogens.8... 

This concept has been applied for the synthesis of the structurally complex and highly oxyfunctionalized triquinane (—)-coriolin (Sch. 31) [61]. Two carbonyl groups, both in the right position for 1,2-acyl shift were present in the trimethyl-functionalized bicyclo[2.2.2]octenone 58. With a site-selectivity of 85% the expected regioisomeric tricyclic dione 59 was formed as a mixture of epimers (Sch. 31). Subsequent transformations involving the annulations of the third five-membered ring as well as epoxidation and hydroxylation steps led to the desired natural product... 

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. 

Koreeda and Mislankar reported that the reaction of the dianion of 3-isobutoxycyclopent-2-en-l-one with 3-iodo-2,2-dimethylpropanal leads to a dual C—C bond-forming reaction at both the C4 and C5 carbons, giving the corresponding bicyclic compound (Scheme 21)33. This [3 + 3]-type annulation product was used as a key building block in the synthesis of dZ-Coriolin. 

Magnus was the first to develop extensive synthetic applications of the Pauson-Khand preparation of the bicyclo[3.3.0]oct-l-en-3-one system. His efforts amply demonstrate the degree to which the high level of functionality in the Pauson-Khand products can be directly utilized in building more complex structures. A formal synthesis of the antitumor sesquiterpene coriolin illustrates a very efficient sequence for construction of the third ring in the linearly fused triquinane series in the presence of considerable functionality (Schemes 10 and 18). A synthesis of the related triquinane hirsutic acid utilizes the observation that the proper stereochemical relationship between the substituents at C-7 and the ring-fusion carbon (C-5) of the bicyclo[3.3.0]oct-l-en-3-one system, while not controllable in the cycloaddition reaction itself, may be readily established by acid- or base-catalyzed equilibration (equation 54 and Scheme 19). ... 

A stereoselective Li-NHs reduction of a cyclopentenone has been employed in two different syntheses of the cytotoxic sesquiterpene coriolin (69 Scheme 2). In one synthesis, tricyclic ketone (70) was reduced stereoselectively to alcohol (71) using Li-NHs-methanol. In the second synthesis, tetracyclic enone (72) was converted in a single step to (71). This reduction proceeds by initial cleavage of the cyclopropyl ketone unit of (72) to give ketone (70), which is then reduced to (71). 

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