Synthesis of ent-9 α , 15 α-cyclokaurene from grandiflorenic acid

Grandiflorenic acid (ent-kaura-9(11),16-dien-19-oic acid) has been converted into ent9,15-cyclokaurene, a speculative biogenetic precursor to 9,15-cyclogibberellin A9 in prothallia of the fern Anemia mexicana. The synthetic sequence involved selective ozonolysis of the 16-ene function, allylic bromination at C-12, intramolecular alkylation by the enolate derived from the 16-one group, and Wittig methylenation; entkaura-9(11),16-ene was also prepared. In one approach to the reduction of the 19carboxyl to a methyl group via stannane treatment of a 19-yl xanthate, the carbon skeleton was rearranged as a consequence of a presumed 1,5-hydrogen shift from C-20 to C-19. This step was followed by cylisation of the resulting homoallylic radical to a 9,20-cyclokauren-11-yl radical then fragmentation to give two 20-nor-B-homo-kaurene isomers. The alternative Wolff-Kishner reduction of a 19-al derivative proved to be satisfactory, however.


Introduction
A number of naturally occurring gibberellin ("GA") derivatives isolated from the prothallia of several fern species belonging to the Schizaeaceae (one of the most primitive fern families) 1,2 have been shown to promote the formation of antheridia and balance of material was a 3:1 mixture of isomers, the 1 H NMR spectrum of which showed the loss of a methyl group.Since the analogous saturated 19-chloro kaurane derivative was reduced without incident in 95% yield (see Experimental Section), we concluded that, for the 9(11)-ene, the intermediate 19-yl radical 14 had undergone a 1,5-transannular shift 14 to form the 20-yl radical 15 (Scheme 5), which then isomerised to 17 via the cyclopropycarbinyl radical 16. 15 The 1,5 shift could also have occurred in the saturated substrate, but could not have led to rearrangement and would therefore not have been apparent.

Scheme 5
The desired enone 19 was eventually obtained in more satisfactory yield by applying the Huang-Minlon modification 16 of the Wolff-Kishner reduction to aldehyde 18, and the sequence through to the cyclokaurene 1 then completed (Scheme 6) as for the corresponding ester 7 (see above).Unfortunately, the synthetic material showed no resemblance to the natural material.In view of the occurrence of 9,11-didehydro-GA 9 in the related genus Lygodium, 17 diene 20 was considered also to be a possible candidate for the unknown hydrocarbon and was therefore prepared from the Wittig methylenation of 19, but again no match was obtained.Both ester 10 and hydrocarbon 1 were decomposed by brief exposure to acid, and even chromatography on silica gel afforded rearranged products.Molecules of this type are unlikely, therefore, to have survived standard isolation and purification procedures.
Nevertheless, although the structure of the hydrocarbon isolated from A. mexicana remains unknown, the preparation of 1 and 20 narrows the options for the correct structure and one or other of these compounds may well yet prove to correspond to a natural product.was cooled to -78˚C for 5 min, then ozone was then bubbled through the solution for 9
To this powder, a solution of alcohol 11 (133 mg, 0.4 mmol) and 4-(dimethylamino)pyridine (5 mg) in THF (12 ml) was added via cannula and washed with THF (2 ml).The resulting mixture was stirred at 75˚C (oil bath) for 3 h, followed ISSN 1424-6376 Page 50 © ARKAT USA, Inc by addition of carbon disulphide (0.15 ml, 2.5 mmol, 6.0 eq.) via a syringe.The reaction mixture was then stirred at 75˚C (oil bath) for 4 h.Methyl iodide (0.15 ml, 2.4 mmol, 6.0 eq.) was introduced and the reaction was continued for a further 2 h at 75˚C (oil bath).The reaction mixture was then diluted with ether (100 ml), washed with water (3×25 ml) and brine (30 ml).The combined aqueous phase was extracted with diethyl ether (30 ml).The organic phase was combined and dried over sodium sulfate.
After filtration, the solvent was removed under reduced pressure and the residue was ent-16,16-Ethylenedioxy-17-norkauran-19-ol.As already described for the preparation of 11, lithium aluminum hydride (57 mg, 1.5 mmol, 1.5 eq.) was added to a solution of the acetal derived from 5 (370 mg, 1.0 mmol) in THF (20 ml) and the reaction suspension stirred at room temperature for 20 h.The excess of LiAlH 4 was then decomposed by addition of ethyl acetate (10 ml).The resulting mixture was diluted with ethyl acetate (150 ml) and washed with 10% NaOH aqueous solution (2×25 ml), water (2×30 ml) and brine (30 ml).The combined aqueous phase was extracted with ethyl acetate (30 ml).The organic phase was combined and dried over sodium sulfate.
Scheme 6 Procedures.Low resolution EI mass (l.r.m.s.) spectra (70 eV) and high resolution accurate mass measurements (h.r.m.s.) were recorded on a VG Autospec double focussing mass spectrometer.Infrared (i.r.) spectra (νmax) were recorded on a Perkin-Elmer 683 Infrared spectrophotometer in 0.25 mm NaCl solution cells or recorded on a Perkin-Elmer 1800 Fourier Transform Infrared spectrophotometer in KBr plates. 1 H-and 13 C-NMR spectra were recorded on a Varian Gemini 300 spectrometer at 300 and 75.5 MHz, respectively.Chemical shifts are reported as δ values in parts per million (ppm) relative to tetramethylsilane or the residual peak of CHCl 3 (7.25 ppm) while the central peak of CDCl 3 (77.0ppm) was used as the reference for carbon spectra.Distortionless enhancement by polarisation transfer (d.e.p.t.) and the attached proton test (a.p.t.) were used in the assignment of carbon spectra.Analytical thin layer chromatography (t.l.c.) was carried out on Merck aluminum t.l.c.plates precoated with silica KG60 F 254 and flash on Merck Kieselgel 60 silica.Tetrahydrofuran (THF), diethyl ether (ether), toluene and benzene were purified by ent-16-Oxo-17-norkaur-9(11)-en-19-oic Acid (6) and ent-16-Oxo-17-nor-kauran-19oic Acid (5).The acid mixture 4 (1 g) in pyridine (1 ml) and dichloromethane (250 ml)