Lignan lactones

Another anti-cancer agent in clinical use is podophyllotoxin (3-59) this has an aryl tetrahydronaphthalene lignan lactone skeleton, and demonstrates potent tubulin-binding, anti-mitotic properties (Scheme 3.16) [30]. The Sherburn group [31] prepared this molecule by a tris(trimethylsilyl)silane promoted conversion of thionocarbonate 3-55 into the lactone 3-58, which proceeded with a yield of 38 %. As intermediates, the radicals 3-56 and 3-57 can be assumed. 

Honda T, Kimura N et al (1994) Chiral synthesis of lignan lactones, (—)-hinokinin, (—)-deoxypodorhizone, (—)-isohibalactone and (—)-savinin by means of enantioselective deprotonation strategy. J Chem Soc Perkin Trans 1 1043-1046... 

Fig. 5 Naturally occurring lignan lactones and their 7-aza-analogues...

SnCU is also effective in the opening of cyclopropane rings to produce cationic intermediates useful in cyclization reactions. For example, the cyclization of aryl cyclopropyl ketones to form aryl tetralones, precursors of lignan lactones and aryl naphthalene lignans, is mediated by SnCU (Eq. 60) [93]. The reaction is successful in nitromethane, but not in benzene or dichloromethane. Analogous cyclizations with epoxides result in very low yields (2-5 %). 

There has been much interest in the synthesis of lignan lactones of the aryl tetralin type, induced by the antitumour activity of podophyllotoxin relatives, and some short oxidative routes into the series have been pursued. In a typical reaction, in which both Cp—Cp and Cp—Car couplings occur, the cinnamyl cinnamate (297) was treated for 30 s with chromium trioxide-fluoroboric acid in acetonitrile. Three tetracyclic products were obtained, the lactones (298 19%) and (299 7%), and ( )-isopodophyllotoxone... 

Justicidin E (15) selectively inhibited 5-lipoxygenase (LO), but did not inhibit the activity of humanl5-LO nor porcine 12-LO [112]. Naphthalenic lignan lactones... 

M Taafrout, F Roussac, IP Robin, RP Hicks, DD Shillady, AT Sneden. Neoisostegane, a new bisbenzoylcyclooctadiene lignan lactone from Steganotaenia araliacea. J Nat Prod 47 600-606, 1984. 

H Saito, H Yoshikawa, Y Nishimura, S Kondo, T Takeuchi, H Umezawa. Studies on lignan lactone antitumor agents.I. Synthesis of aminoglycosidic lignan variants related to podophyUotoxin. Chem Pharm Bull 34 3733-3740, 1986. 

N Chauret, C Li, Y Ducharme, LA Trimble, JA Yergey, C Ramachandran, DA Nicoll-Griffith. In vitro and in vivo biotransformations of the naphthalenic lignan lactone 5-lipoxygenase inhibitor, L-702,539. Drug Metab Dispos 23 65, 1995. 

Scheme 46 Syntheses of furofuranone lignan lactones and eburnamonine...

The resin product obtained by extraction of the dried roots and rhizomes of the North American plant Podophyllum peltatum L. (the American mandrake or mayapple) and of the related Indian species Podophyllum emodi Wall. Ex Royle is known as podophyllin and has long been known to possess medicinal properties. The major active substance in podophyllin is the lignan lactone podophyllotoxin (7) although a variety of other lignans and lignan glycosides have also been isolated from podophyllin. ... 

Bisbenzocyclooctadienes. The nonph lignan lactones is accomplished with Rc 0-... 

Bisbenzocyclooctadienes The nonphenolic coupling used in the synthesis of lignan lactones is accomplished with Re207 in TFA-TFAA media. 

This reaction was a key step in the synthesis of the (+)-form of the dibenzocyclooctadiene lignan lactone steganacin (5).°... 

Within the realm of natural products and bioactive compounds, the tri- or tetra-ort/w-substituted biaryl subunit is by far the most common form of atropisomerism. The Sj Ar reaction allows the formation of the backbone of important drugs with diverse biological activities such as (-)-steganone (1), a dibenzocyclooctadienyl lignan lactone exhibiting antileukemic activity [6] spirooxoindohnes... 

Vhh and /hh couplings have been determined by da Silva et to characterize three 7,7 -dihydroarylnaphtalene lignan lactones, and by Machida et alP to perform structural elucidation of four neolignan glycosides with enantiomeric aglycones from Osmanthus ilicifolius. 

Annapoorani K S, Damodaran C, Sekharan P C 1984 Solid-state fluorodensitometric quantitation of arylnaphthalene lignan lactones of Cleistanthus collinus. J Chromatogr 303 296-305... 

Hicks R P, Sneden A T 1983 Neoisostegane, a new bisbenzocyclooctadiene lignan lactone from Steganotaenia araliacea Hochst. Tetrahedron Lett 24 2987 - 2990... 

Hokanson G C 1979 The lignans of Poly gala polygama (Polygalaceae). Deoxypodophyllotoxin and three new lignan lactones. J Nat Prod 42 378-384... 

The reaction of enolates derived from lactones (121) with aromatic aldehydes has been used effectively in the synthesis of lignan lactones, e.g. (122) and... 

An alternative approach to structures similar to (122) involves initial construction of the saturated ring followed by a lactonization sequence. Meyers and Avila have described the conversion of naphthyloxazolines into lignan lactone derivatives with the same basic structure as (12 ). Bislactone lignans are obtained by the instantaneous oxidative dimerization of p-alkoxycinnamic acids with thallium(iii) trifluoroacetate or cobalt(iii) trifluoride. Although the yields are only between 12 and 54%, the method provides a convenient entry into these complicated structures. ... 

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