Hirsutic acid synthesis

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]. 

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. 

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... 

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). ... 

The aprotic Bamford-Stevens reaction has been utilized for the development of a methodology towards 1,2-carbonyl transposition in natural product synthesis. The example in Scheme 8 illustrates the regiocontrolled alkene formation for the synthesis of hirsutic acid. ... 

Ethyl diazoacetate has been used extensively in the homologation of ketones to 3-keto esters. Lewis acid is required for the reaction (equation 23). ° There is a tendency for the least-substituted group to migrate, particularly if one group is fully substituted (equation 24). In a total synthesis of ( )-aplysin (20) this selective rearrangement was applied (Scheme 9), and a similar approach was used in a synthesis of (+)-hirsutic acid. Ethyl diazoacetate has also been used in the homologation of acyclic... 

Fused Five-membered Rings.—Structures based on the linear fusion of three five-membered rings are easily synthesized by intramolecular photocyclizations of dicyclopent-l-enylmethanes [viz. (75)], followed by in situ addition of methanol to the presumed intermediate bicyclo[2,l,0]pentanes (76) the general method has been applied in a synthesis of the hirsutane carbon skeleton (77) found in hirsutic acid and related natural sesquiterpenoids. 

With respect to the use of Cinchona alkaloid-derived organocatalysts, the first example of asymmetric Michel addition of ketones to enones appeared in 1979 when Trost illustrated, during the total synthesis of the sesquiterpene ( )-hirsutic acid C [101], a stereoselective (30% ee) quinine (59)-catalyzed intramolecular conjugate addition of an intermediate functionalized cyclohexanone (Scheme 2.32). 

Photoinduced epimerization reactions are sometimes encountered during the course of the ODPM rearrangement. Thus, it has been observed, as part of a study directed toward the total synthesis of (+)-hirsutic acid and (-)-complicatic acid, that triplet-sensitized irradiation of compound 97 affords the anticipated primary photolysis product 98, but this is accompanied by quantities of epimer 99. Sustained irradiation leads to increasing quantities of the thermodynamically favored isomer 99, presumably via either photoenolization of precursor 98 or through photoinduced C—C bond homolysis within the same compound followed by diradical recombination (to generate 99). 

Trost BM, Shuey CD, Dininno F, Mcelvain SS (1979) Stereocontrolled Total Synthesis of (-1-/—)-Hirsutic Acid C. J Am Chem Soc 101 1284... 

The past year has seen so many announcements of syntheses of complex carbocyclic natural products that the task of highlighting a few of them has been especially difficult. Clearly the stereocontrolled synthesis of the sesquiterpene hirsutic acid (1) by Trost and his co-workers merits special attention, as does the ingenious synthesis of its close relative hirsutene (2) by a group led by Tatsuta. No less meritorious is the synthesis of picrotoxinin (3) by Corey and Pearce or the syntheses of aphidicolin (4) by groups led by Trost and McMurry. Finally, mention must be made of the splendid single-handed effort by Still which resulted in the total synthesis of periplanone-B (5), the cockroach sex excitant pheromone. ... 

Cycloaddition reactions of cyclopropanes via cleavage of the C—C bond have been apphed to the synthesis of a wide variety of natural products, particularly terpenoids. For example, (-H)-dictamnol [5], (-H)-aphanamol I [6], (-H)-tremulenolide A [7], and (-l-)-lirondosin A [8] were synthesized through a [5-h2] cycloaddition reaction of vinylcyclopropanes with C—C unsaturated bonds. ( )-Hirsutene [9], ( )-pentalenene [10], ( )-asterisca-3(15),6-diene [10], ( )-hirsutic acid [11], and (-l-)-asteriscanohde [12] were synthesized via rhodium(l)-catalyzed [5-H2-H1] cycloaddition of vinylcyclopropanes with alkenes and carbon monoxide. Total syntheses of ( )-a-agarofuran [13], and ( )-pyrovellerolactone [14] were also achieved through cycloaddition reactions of cyclopropane derivatives. For these syntheses, reference to the papers should be made directly. 

A further stereocontrolled total synthesis of (-t-)-hirsutic acid has been reported. ... 

The dione (103) has also been employed as a precursor to coriolinj and it is worth noting that the first asymmetric total synthesis of hirsutic acid (104) has been achieved. ... 

Fused Five-membered Rings.—A number of biologically important terpenoids show structures based on the fusion of two or three five-membered rings, e.g. hirsutic acid, pentenolactone, coriolin, capnellane, and retigeranic acid, and efforts directed towards total synthesis of these structural types have burgeoned in the past few years. 

The tricyclic hydrocarbon hirsutene (94), isolated recently from Coriolus consors, is a probable precursor for coriolin (95), found in C. consors, and also for hirsutic acid (96), isolated from Stereum hirsutum. In a biogenetically patterned synthesis of hirsutene, Ohfume et al. have shown that treatment of the tricyclic hydrocarbon (92) with a catalytic amount of toluene-p-sulphonic acid leads to the endo-isomer (93), in 95% yield, which by manipulation of the double bond can be... 

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