o-Quinodimethanes: Efficient Intermediates in Organic Synthesis.

Desulfonylation reactions: Recent developments

Cancer is a major killer disease all over the world and more than six million new cases are reported every year. Nature is an attractive source of new therapeutic compounds, as a tremendous chemical diversity is found in millions of species of plants, animals, and microorganisms. Plant-derived compounds have played an important role in the development of several clinically useful anti-cancer agents. These include vinblastine, vincristine, camptothecin, podophyllotoxin, and taxol. Production of a plant-based natural drug is always not up to the desired level. It is produced at a specific developmental stage or under specific environmental condition, stress, or nutrient availability; the plants may be very slow growing taking several years to attain a suitable growth phase for product accumulation and extraction. Considering the limitations associated with the productivity and vulnerability of plant species as sources of novel metabolites, microorganisms serve as the ultimate, readily renewable, and inexhaustible source of novel structures bearing pharmaceutical potential. Endophytes, the microorganisms that reside in the tissues of living plants, are relatively unstudied and offer potential sources of novel natural products for exploitation in medicine, agriculture and the pharmaceutical industry. They develop special mechanisms to penetrate inside the host tissue, residing in mutualistic association and their biotransformation abilities opens a new platform for synthesis of novel secondary metabolites. They produce metabolites to compete with the epiphytes and also with the plant pathogens to maintain a critical balance between fungal virulence and plant defense. It is therefore necessary that the relationship between the plants and endophytes during the accumulation of these secondary metabolites is studied. Insights from such research would provide alternative methods of natural product drug discovery which could be reliable, economical, and environmentally safe.

Endophytic fungi: novel sources of anticancer lead molecules

Podophyllotoxin, steganacin and combretastatin: Natural products that bind at the colchicine site of tubulin

Cyclobutarenes and Related Compounds

(–)-Podophyllotoxin of 98% optical purity has been synthesized in eight steps and in 15% overall yield. The key step, Diels–Alder addition of the o-quinonoid pyrone 2 [6,7-methylenedioxy-1-(3,4,5-trimethoxyphenyl)-2-benzopyran-3-one] to the chiral dienophile 5 [5-(–)-menthyloxyfuran-2(5H)-one], proceeds with very high regio-, endo- and facial selectivity.

Asymmetric total synthesis of (–)-podophyllotoxin

(–)-Podophyllotoxinof 98% optical purity is synthesised in eight steps and in 15% overall yield from the pyrone 2 and the chiral dienophile 3.

At 80 °C 1a-acetyl-l-phthalimido-1a,6b-dihydrobenzofuro[2,3-b]azirine 1(X = Ac) transfers phthalimidonitrene to a series of traps: Me2SO, 2-methoxynaphthalene, indene, methyl methacrylate, methyl crotonate, mesityl oxide, cis- and trans-stilbene and cyclohexene. Oxidation of N-aminophthalimide with lead tetraacetate in the presence of these traps gives the same major products (ref. 2a). With 1,3-dimethoxybenzenes, the reagent 1(X = Ac) provides 2H- and 3H-azepines e.g.25a and 24a as the major products with N-phthalimidoanilines e.g.18 formed to a lesser extent. On the other hand Pb(OAc)4 oxidation of N-aminophthalimide in the presence of 1,3-dimethoxybenzenes gives N-phthalimidoanilines and no detectable 2H- or 3H-azepines. Small quantities of acetic or benzoic acid present during the dissociation of 1(X = Ac) in the presence of 1,3-dimethoxybenzenes cause marked increases in the formation of N-phthalimidoanilines compared with azepines. The unusually stable and isolable 2H-azepines 25 rearrange to 3H-azepines 24 only on heating and 5,7-dimethoxy-3-methyl-2-phthalimido-2H-azepine 25d is characterised by X-ray crystal structure analysis.

Mild thermal route to phthalimidonitrene and its reaction with activated benzenes to give 2H- and 3H-azepines; X-ray crystal structure analysis of an isolable 2H-azepine

Thermolysis of 4a (X = H) gives 6a and 6b (X = H) in a ratio of 1∶4 whereas 4b (X = SO2Ph) gives more of the trans-ring junction product 6a (X = SO2Ph) suitable for the synthesis of pisiferol [ratio 6a∶6b (X = SO2Ph) = 1.5∶1]. Base catalysed elimination of the phenylsulfonyl group from 6a (X = SO2Ph) gives 18 which is hydrogenated to 6a (X = H), an intermediate in the synthesis of pisiferol. Both 6a and 6b (X = SO2Ph) have ring B in a half-boat conformation.

Control of stereochemistry in an intramolecular Diels–Alder reaction by the phenylsulfonyl group; an improved synthesis of pisiferol

The 2-benzopyran-3-one (7) is a stable, isolable, and useful Diels–Alder diene; its adduct (10) formed with dimethyl fumarate is transformed in three steps into methyl epipodophyllate (14) which gives epipodophyllotoxin (2)(81%) by direct lactonisation (ZnCl2–tetrahydrofuran–4 A molecular sieves).

David W. Jones

Papers

Asymmetric total synthesis of (–)-podophyllotoxin

Asymmetric total synthesis of (–)-podophyllotoxin

Mild thermal route to phthalimidonitrene and its reaction with activated benzenes to give 2H- and 3H-azepines; X-ray crystal structure analysis of an isolable 2H-azepine

Control of stereochemistry in an intramolecular Diels–Alder reaction by the phenylsulfonyl group; an improved synthesis of pisiferol

Synthesis of podophyllum lignans via an isolable o-quinonoid pyrone