Hirsutic acid

Reduction of the ketone (147), followed by elimination gave the olefin (148). The olefin (148) was subjected again to a second annelation, and as expected, dichloroketene addition, ring expansion and zinc reduction gave the tricyclic compound (149). Compound (149) could be converted to ( )-hirsutic acid C (150) 52K... 

A rather unusual "reconnection" is found in the retrosynthetic analysis of hirsutic acid by Trost [26], in which two methyl groups are reconnected to an unsaturated six-membered ring. 

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]. 

Strategies based on reconnections which have been applied succesfully to sesquiterpenes, such as caryophyllene, isocaryophyllene and hirsutic acid, as well as to Cecropia juvenile hormone. 

Trost and co-workers relied on the Michael and the Stetter reaction to set the relative stereochemistry for the core of hirsutic acid C (Scheme 22) [95], The Stetter reaction was accomplished in 67% yield with 2.3 equiv. of 3,4-dimethyl-5-(2 -hydroxyethyl) thiazolium iodide 54 and 50 equiv. of triethylamine. 

The first stereocontrolled synthesis of ( )-hirsutic acid (720) was achieved by Trost In this work, four of the seven asymmetric centers are fixed in the correct relative stereochemistry in bridged bicyclic compound 721 which in turn is formed by... 

More recently, the same group achieved a simple, highly stereocontrolled total synthesis of (+)-hirsutic acid (Scheme LXXIX) ". This chirally directed effort developed subsequent to reaction of dl-728 with (+)-di-3-pinanylborane, alkaline hydrogen peroxide oxidation, chromatography, PCC oxidation, and hydrogenolysis. The dextrorotatory hydroxy ketone 729 was nicely crafted into keto aldehyde 730 from which 720 was readily obtained. Once again, the Wacker oxidation played an instrumental role in annulation of the third five-membered ring. The remainder of the asymmetric synthesis was completed as before. 

Helminthogermacrene, 304 Hirsutene, 153 Hirsutic acid, 117 26-Hydroxy cholesterol, 151... 

In contrast to the well documented conjugate addition of carbon nucleophiles to activated alkenes, similar intermolecular attempts with activated alkynes with non-cuprate reactants are typically non-productive due to competing multiple addition processes.87 6 However, protic intramolecular conjugate additions of ketones as shown for the syntheses of griseofulvin and hirsutic acid,222 are successful. Recently, several aprotic intramolecular conjugate additions to activated alkynes have been reported, as... 

Banwell MG, Austin KAB et al (2007) Chemoenzymatic total syntheses of the linear triquinane-type natural products (+)-hirsutic acid and (—)-complicatic acid from toluene. Tetrahedron 63 6388-6403... 

The p-bromophenylacyl ester of hirsutic acid (36, Scheme 24) shows a dramatic topotactic rearrangement induced by the x-ray irradiation [72]. The reactant lattice is preserved in the conversion of 36 to a 2 3 ratio of 36 and its keto form, 37. 

The stereospecific conversion of the synthetic tricyclic ketone (157)73 into ( )-hirsutic acid (159) has been accomplished74 by the short reaction sequence shown in Scheme 21. 

As part of their studies of the synthesis of hirsutic acid C, Lansbury and co-workers developed a stereoselective synthesis of norhirsutanes (Scheme 52).333 Model experiments involved the addition to ketone 333 of Grignard reagents derived... 

Their more directed approach to hirsutic acid utilized 341 as starting material (Scheme 53).335 This diketo ester was the major product obtained from alkylation of the pyrrolidine enamine of340 with 3-bromo-2-butanone and aldolization in aqueous base. Reesterification with diazomethane and catalytic hydrogenation generated the cis-fused bicyclooctane nucleus. The subsequent Claisen alkylation of 342 proved to be stereoselective, affording 343 as the major product. Cyclization as before furnished 344 whose further transformations are currently being examined. 

Hirsutic acid C has been observed to rearrange to a biologically active isomer called hirsutic acid N or isohirsutic acid which has been formulated as 348. A convergent, stereocontrolled sythesis of this molecule has also been described by Lans-bury (Scheme 54).336) Claisen alkylation of 342 with 345 again proved to be site-... 

Cyclopentanone annelation (10, 139-140) - The iterative cyclopentenone anne-lation has been extended to a synthesis of hirsutic acid (7) starting with the ester I. This alkene surprisingly does not react with chloromethylketene, but does react stereoselectively with dichloroketene to give 2 as the major product One of the chlorine atoms was replaced by methyl by treatment with (CH,) CuLi (3 equiv. ) and then with CH,I and HMPT. Ring... 

Undoubtedly one of the major sesquiterpenoid synthetic achievements of the year has been the synthesis of hirsutic acid C (288) (Scheme 42). Intramolecular Michael reactions were used to generate the key tricyclic ketone (287) with the correct relative stereochemistry at four of the chiral centres. The ethylene bridge was then cleaved to create the two requisite methyl groups. Interestingly the first intramolecular Michael reaction [(285) (286)] could be achieved with (-)-... 

In the final step of the total synthesis of ( + )-hirsutic acid C, enone 11 was epoxidized with alkaline hydrogen peroxide to give selectively epoxide 12, which was converted in situ to the final product72. 

Asymmetric hydroboration using IpC2BH was also applied in the stereocontrolled synthesis of a linearly fused triquinane, (+)-hirsutic acid (eq 1) ... 

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). ... 

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