Aristolactones

This ring contraction has been used to provide the ten-membered ring of the germacranolide aristolactone (4) from a 13-membered allylic propargylic ether. 

The pioneering work on enantioselective [2,3]-Wittig rearrangement was carried out by Marshall and Lebreton in the ring-contracting rearrangement of a 13-membered cyclic ether using lithium bis(l-phenylethyl) amide (63) as a chiral base (equation 34). Upon treatment with a (S,S)-63 (3 equivalents) in THF at —70 to —15 °C, ether 64 afforded the enantioenriched [2,3]-product 65 in 82% yield with 69% ee. The reaction was applied in the synthesis of (+)-aristolactone (66). 

Chiral lithium bases have been used for enantioselective deprotonation to yield configurationally stable a-oxy carbanions. This holds potential for asymmetric [2,3]-Wittig rearrangement in stereoselective synthesis. Thus, treatment of propargylic ether 72 with (S,S)-3 in THF at — 70 °C to —15 °C afforded propargylic alcohol 73 in 82% yield and in 69% ee of the shown enantiomer96,97. This product was successfully employed as a precursor of (-l-)-Aristolactone (Scheme 55). 

With only moderate dilution and without a template effect, the cyclic ether 24 which is an important precursor in the total synthesis of the racemic ger-macranolide-aristolactone (25) was obtained from the hydroxychloride 23 [35]. 

Figure 6.7. Natural products using the [2,3]-Wittig rearrangement as the key step (a) ant pheromone [58] (b) t aromycin A (J768) (c) Prelog-Djerassi lactone (J771) (d) aristolactone...

Over the last seventy years over sixty species of Aristolochia have been exploited for chemical examination by research groups throughout the world and a variety of compounds have been isolated. The spectrum of physiologically-active metabolites from Aristolochia species covers 14 major groups based on structure aristolochic acid derivatives, aporphines, amides, benzylisoquinolines, isoquinolones, chlorophylls, terpenoids, lignans, biphenyl ethers, flavonoids, tetralones, benzenoids, steroids, and miscellaneous. The aristolochic acid derivatives, host of phenanthrene derived metabolites were further classified into aristolochic acids, sodium salts of aristolochic acids, aristolochic acid alkyl esters, sesqui- and diterpenoid esters of aristolochic acids, aristolactams, denitroaristolochic acids, and aristolactones. The terpenoids can further be subdivided into 4 groups mono-, sesqui-, di- and tetraterpenoids. 

Moreover, sesquiterpenoids were widely distributed in the stems and roots of these species rather than in leaves. Seven sesquiterpenoids, madolin A-E (300, 299, 296, 295, 271) as new and aristolactone (278) and manshurolide (307) as known,were isolated from the stems and roots of A. cucurbitifolia, an endemic species of Taiwan... 

Aristolactones, the 10-oxygenated denirtoaristolochic acid derivatives can be viewed as a by-product of the biosynthesis of aristolactam from aristo- lochic acid [294], Thus the intermediate amino acid might tautomerize to the corresponding imine which could then be hydrolyzed to the lactone via hydroxyacid, Scheme (5). 

Applications of cyclocarbonylation to the preparation of natural products include the synthesis of ( )-aristolactone [12], (+ )-hamabiwa]actone B [13], (+ )-asimicin, and (+ )-bullatadn [14], all of which involve 4-hydroxybutenolide motifs (Scheme 2.4). 

Formation of lactones from alkenyl halides has also been reported as part of natural product syntheses, as in Marshall s approach to ( )-aristolactone,t or as a means to support stereochemical assignments. " So far, the reactions discussed have all involved attack of a free hydroxyl group on the acylpalladium species. A closely related approach involves attack of an 0-enolate, which is usually generated from the corresponding ketone. The concept is shown in Scheme 11. 

Aristolactone (Martin-Smith et al., 1964) is an essential oil obtained along with limonene vide supra) from the aerial parts of the woody vine Aristolochia gibertii (Aristolochiaceae), a plant with large calabash-shaped spotted flowers with an unpleasant odor. 

SCHEME 17.10. Synthesis of ( )-aristolactone 43 by a [2,3]-Wittig rearrangement-ring contraction of propargylic ether 41. 

Marshall JA, Lebreton J, DeHoff BS, Jenson TM. Total synthesis of the germacranolide ( )-aristolactone via [2,3]-Wit-tig ring contraction. Tetrahedron Lett. 1987 28(7) 723-726. 

Marshall JA, Lebreton J. Enantioselective synthesis of mac-rocyclic propargyUc alcohols by [2,3]-Wittig ring contraction. Synthesis of (-l-)-aristolactone and cembranoid precursors. 7 Arw. Chem. Soc. 1988 110(9) 2925 2931. 

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