Eudesmane synthesis

An example, where two C-C-bonds are formed and one C-C-bond is broken is the synthesis of the tricycle 3-285, which has some similarity with the eudesmane framework 3-286, developed by Kilburn and coworkers (Scheme 3.72) [113]. Thus, exposure of the easily accessible methylenecyclopropyl-cyclohexanone 3-281 to samarium(II) iodide led to the generation of ketyl radical 3-282, which builds up a six-membered ring system with simultaneous opening of the cyclopropane moiety. Subsequent capture of the formed radical 3-283 by the adjacent alkyne group afforded the tricycle 3-285 via 3-284 as a single diastereoisomer in up to 60% yield. It should be noted that in this case the usual necessary addition of HMPA could be omitted. 

The sesquiterpenes (+)-10-epijuneol466, (4.54) and ( )-calameon467) (4.55) have been obtained via addition of 6-isopropyl-3-methyl-2-cyclo-hexenone to cyclobutene derivatives. A similar sequence has been applied for the synthesis of an eudesmane precursor (4.56)468). 

In one of the earliest applications of this type of process to complex molecule synthesis, Corey and Hortmann, in their synthesis of dihydrocostunolide 38, found that photolysis of 36 afforded a photostationary state of 36 and 37 (Scheme 9)19. Hydrogenation of this mixture then gave 38. A recent modification of this synthesis, which avoids the photostationary equilibrium between eudesmane (36) and germacrane (37) forms, was realized using a modified substrate, 3920. Irradiation of 39 provided a 77% yield of a mixture of diastereomeric ketones 41 these are produced via tautomerization of the intially produced trienol 40. Dienone 41 was then easily converted to 38 via a series of conventional steps (Scheme 9). 

The trans-cis isomerization process observed in the eudesmane/germacrane ring system has been utilized for the synthesis of the c/s-fused sesquiterpene occidentalol, 48a, and its 7-epi isomer, 48b (Scheme ll)22. Photolysis of the traws-fused diene 45 at —78°C afforded triene 46, which upon warming underwent disrotatory electrocyclization to give 47a and 47b as a 1 2 mixture of diastereomers. Apparently, the carboalkoxy group imparts... 

The extrapolation of the vinylcyclopropane-cyclopentene rearrangement to a vinyl-cyclobutaiie-cyclohexene synthesis begins to create new insights into the synthesis of six membered ring natural products. The eudesmane sesquiterpene (—)-P-selinene, 217 illustrates such a strategy as summarized in Scheme 14 80). A suitable cyclohexene... 

The construction of the tricyclo[5.2.0.02,6]nonane (26, n = 1) and tricyclo[6.2.0.02,7]decane (26, n = 2) frameworks involved the [2 4- 2] cycloaddition of readily accessible31,32 l,2-bis(trimethyl-siloxy)cyclobutene and cnone 25, n = 1 or 2, respectively.33 The yields (75-80%) were good for adducts 26a, c, e, and g. Lower yields (40-50%) were observed for adducts 26b and 26f, while adduct 26d was only isolated in a trace amount. The most interesting and important reaction, related to the total synthesis of eudesmane sesquiterpenes, was the photochemical reaction of (-)-piperitone (25g) with l,2-bis(trimethylsiloxy)cyclobutene, which gave c/.v,(5wf/u W-2/j,7/i-dimethyl-4/ -isopropyl-l f ,8Jf -bis(triniethylsiloxy)tricyclo[6.2.0.0z 7]dec-3-one (26g) with the relative cis configuration of the methyl (R2) and isopropyl (R3) groups.33,34 Some of the other photochemical [2 + 2] cycloaddition reactions utilizing l,2-bis(trimethyl-siloxy)cyclobutene are shown by the formation of 2735,36 and 28.37... 

The construction of a key intermediate for use in the synthesis of the eudesmane sesquiterpenes starting from 2-methylfuran has been reported (74H(2)639). Metallation of... 

Fig. 38 Examples of molecules prepared following new concepts in total synthesis (a) intricarene (220) generated by protective group-free synthesis and (b) late-stage site-selective C-H oxidations to generate eudesmane-type terpenes like 222 or (c) to prepare the hydroxylated artemisinin derivative 223...

The utility of this stepwise C3 - C4 - C6 ring expansion has been demonstrated by the synthesis of the optically active eudesmane sesquiterpene (—)- 3-selinene 295 starting from the commercially available (—)-perillaldehyde 2871S3). Thus, addition of the 1-lithio-l-methoxycyclopropane 136 (vide supra. Sect. 4.6.3, Eq. (44)) to 287,... 

A new method of constructing isopropylidene functionality has been illustrated recently in the synthesis of 4(14),7(ll)-selinadiene (202), a eudesmane derivative present in hops.92 Interest continues in the isolation, structural elucidation, and... 

In the past, synthetic routes to the eudesmane skeleton have involved a Robinson annelation sequence in the construction of the bicyclic framework. Although this procedure has enjoyed moderate success in the synthesis of certain members of this class, the associated small yields and stereochemical problems have been major drawbacks. Huffman and Mole have developed an alternative approach... 

In the synthesis of occidentalol (ref. 13), a eudesmane-type compound consisting of a cis-fused decalin containing a homoannular 1,3-diene system, dihydrocarvone was converted by a typical Robinson annellation reaction to the basic reguired bicyclic structural unit. (It is of interest that a related bicyclic methyldecalenone structure, the Wieland-Miescher ketone, has been employed for the synthesis of longifolene (ref.14), copaene (ref.15) and sativene (ref.16) by three totally different strategies outside the present concept of the semi-synthetic approach). 

Transannular cyclizations of cyclodecadiene monoepoxides have been studied in exhaustive detail, particularly amongst natural germacranolides, because of their relevance to biogenetic models for the synthesis of eudesmane- and guaiane-type sesquiterpenes. " A full discussion of this topic is beyond the scope of this chapter, but the examples collected in equations (54-64) provide the reader with an in-... 

Michael addition. TiCl4 was used to effect addition of the silyl enol ether I to 2 to obtain 3. Base could not be used because of the extreme sensitivity of 2. The product was used for synthesis of several eudesmane sesquiterpenes containing an a-methylene-y-butyrolactone unit, such as //-epiatlantolactone (4).5... 

When the alkene is part of an edge fused bicyclic system (bicyclo[m.n.0] systems), the regio- and stereoselectivity is influenced by the conformation of the molecule and the relative stereochemistry of the substituents. Hydroboration of 31, in Heathcock s synthesis of eudesmanes, led to a 66 34 mixture of boranes with attack from the top face predominating (giving 32). 19,15... 

Huffman and Mole have published full details of their synthetic approach to the basic eudesmane skeleton. In the past the synthetic strategy for the construction of this bicyclic ring system has been largely restricted to standard reaction sequences involving at some stage a Robinson annelation procedure. Schwartz et have now developed a new approach to this problem, culminating in the synthesis of ( )-junenol (251) as outlined in Scheme 24. From the... 

Successful application of the Mitsonobu epimerization procedure to an eudesmanic alcohol 44 to bring about inversion of configuration at C(l) is the crucial step in the Harapanhalli synthesis of erivanin (50) from santonin (Scheme 7) [16]. Reduction of enone 43, prepared from santonin in 10 steps, with sodium borohydride furnished the )8-alcohol 44 as the sole product. This product results from the approach of the hydride anion from the less hindered Of-face of the molecule. The chemical modification of the C(3)-C(4) double bond to give a 3a-hydroxy-A4-i4 rnoiety was accomplished via the epoxide 46 and its rearrangement in a basic medium. Epoxidation of 44 with MCPA yielded only one product without any directing effect exerted by the homoallylic alcohol. Treatment of 46 with lithium diisopropylamide (EDA) afforded l-e/>/-erivanin (47). For the synthesis of erivanin (50), epimerization at C(l) prior to the A -modification sequence was required. Attempts to epimerize this carbon atom in 44 by acetolysis of the tosyl derivative 45 were unsuccessful as they led to eliminated product 13 (Scheme 3). 

Eriolanin (104) is a novel antileukemic seco-eudesmane and was isolated by Kupchan and co-workers [45]. It possesses significant activity in vivo against P-388 leukaemia in mice and in vitro against cell cultures derived from human carcinoma of the nasopharynx (KB). Grieco developed an ingenious synthesis[46] of eriolanin (104), which has been depicted in "Fig (9)". 

The latter are formed as stress metabolites after infection by fungi or bacteria such as Erwinia carotovora and Phytophthora infestans together with other compounds such as phytuberin. Compounds (3), (4), (5), and (6) in the given order are precursors in the biosynthesis of the phytoalexin rishitin. The V. are formed biosynthetically from eudesmane type sesquiterpenes. Lit. J. Am. Chem. Soc. 120, 1747 (1998) (synthesis) Tetrahedron Lett. 37, 8703 (1996). 

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