A Novel Intermediate to the Synthesis of 4-5-5 Fused Tricarbocyclic Core Present in Terpenic Natural Products

Este trabalho refere-se à síntese enantiosseletiva da dienona (5R)-4,8-dimethylbicyclo[3.3.0]oct1(8),3-dien-2-one. Este intermediário, pode ser reconhecido como um bloco de construção versátil para a síntese de uma grande variedade de compostos com esqueleto biciclo[3.3.0]octano. A estratégia sintética empregada aqui faz uso da reatividade invertida de um precursor cianoidrina TMS-éter, como equivalente de ânion acila, para promover uma reação de alquilação intramolecular. A síntese formal do (-)-kelsoeno foi realizada pela preparação do intermediário avançado (1R,5S,8R)-4,8dimethylbicyclo[3.3.0]oct-3-en-2-one, a partir da hidrogenação seletiva do composto intitulado (5R)4,8-dimethylbicyclo[3.3.0]oct-1(8),3-dien-2-one.


Introduction
There is currently considerable interest in the synthesis of optically active bicyclo[3.3.0]octanecontaining one or more functional group(s) at suitable position(s) for synthetic purposes, as these compounds have been widely accepted as an efficient chiral building block or intermediate for preparing both natural and nonnatural biologically active compounds. 1The tricyclo[6.2.0.0 2,6 ] decane framework 1, constituted through the linear fusion of 4-5-5-membered carbocyclic rings, has been encountered only sporadically among natural products. 2mong the very few known examples of terpenoid natural products based on this ring system are sulcatine G (2), from a Basidiomycetes fungus, 3,4 poduran (3), from the springtail Podura aquatica 5 and kelsoene 4, from the marine sponge Cymbastela hooperi 6 as well as from the liverworts Ptychanthus striatus, 7 Calypogeia muelleriana 8 and Tritomaria quinquedentata. 9n 1999, Nabeta et al., on the basis of 1 H NMR experiments carried out on two diastereomeric substances derived from (+)-kelsoene, concluded that the natural product has the absolute configuration (-)-4 (Figure 1). 10 However, in 2001, Schultz 11 and Mehta 12 independently demonstrated, on the basis of synthetic studies, that this conclusion was incorrect and that, in fact, the absolute configuration of natural (+)-kelsoene is as depicted in 4.
5][16] The intermediate 8 in turn could be accessed from the acyclic keto aldehyde precursor 9 by aldol condensation and silyloxy nitrile conversion of the resulting cyclic aldehyde.[19][20]

Results and Discussion
9][20] (-)-Limonene epoxide 10 reacts cleanly with HOCl to afford 10-chlorolimonene oxide 11. 18 Subsequent acid-catalyzed hydrolysis of epoxyde function to diol 12, followed by oxidative cleavage with sodium metaperiodate, leads to the keto aldehyde (-)-9 in 48% overall yield from (-)-10. 19,20ldehyde 13 was obtained from (-)-9 by aldol condensation with piperidine-acetic acid, in 44% yield. 20he unstable conjugated aldehyde 13 thus obtained was cleanly converted to the cyanohydrin TMS ether 8 by addition of Me 3 SiCN in the presence of catalytic amount of KCN/18-crown-6 complex.5][16] In our case, we found higher yield performing the cyclization reaction at lower temperature and reduced excess of base.The crude product 14 was treated with tetra-n-butylammonium fluoride in aqueous THF at room temperature for 3 days to give only (-)-6 with the endocyclic C3-C4 double bond, after chromatographic purification.Attempts to isolate thermodynamically less stable exocyclic olefin isomer 7 resulted in failure.When the decyanation of 14 was conducted at shorter reaction time and lower temperature, Scheme 1. Retrosynthetic analysis for (R)-6 from (-)-limonene oxide.rapid isomerization took place, as observed by 1 H NMR spectroscopy.
Pentalenone (-)-6 was them subjected to catalytic hydrogenation at 1 atm over 10% Pd/C in EtOH at 25 o C and the reaction course was examined by 1 H NMR spectroscopy and CG analysis.Running the hydrogenation reaction for 24 h, formation of 5 and 15 was observed in a ratio of approximately.1.7:1.The rapid isomerization of 6 to 15 during the hydrogenation reaction is supported by 1 H NMR data comparisons between isolated 6 and the mixture containing 5 and 15.The singlet olefinic signal H-3 in the mixture containing 5 and 15 appears at δ 5.81 and 5.68 ppm, respectively, while the corresponding resonance in 6 is at 5.88 ppm.In the 1 H NMR spectrum of 6, the signals assigned to vinyl methyl hydrogens were observed at δ 2.08 (s, 3H) and 2.10 ppm (s, 3H).In the mixture of 5 and 15, two vinyl methyl protons were observed at 2.01 and 2.04 ppm for each compound and a doublet observed at 1.02 ppm (6.8 Hz) is assigned to C-8 methyl hydrogens.After 35 h reaction, the conversion of 15 to 5 was essentially complete.At this stage, the reaction was quenched by filtration over celite to afford the crude product in 89% yield.Because of experimental difficulties, the volatile enone 5 was not purified. 1H NMR spectroscopy and CG analysis of the crude product presents approximately 78% of 5.The assignments of 1 H and 13 C in the NMR spectra of the crude product containing 5 are further supported by reported data described in the literature. 13The addition of hydrogen to both (-)-6 and 15 is favored by the convex upper face of the molecule; on this basis, the major hydrogenation product, which is the same in the two cases, is endo methyl enone 5.][23] Running the hydrogenation reaction with the same catalyst at 810 kPa of hydrogen pressure in EtOH at 25 o C, for 24 h, gave a mixture of the saturated ketone 16 and a minor saturated product which was not separable by chromatography on silica gel.The structure of 16 was supported by the assignments of its 1 H and 13 C NMR data and comparison with those described in the literature 24 while the minor saturated component which was not fully characterized in this work is presumably formed by the addition of hydrogen from the more sterically encumbered face of (-)-6.

Scheme 2.
poduran (3).Intermediate (-)-6 was obtained in seven steps and 15.6% overall yield from (-)-limonene oxide (10).The scaffolding potential of this new building block is currently under study and will be reported in due course.

Experimental
Melting points were measured on an Electrothermal IA 9100 digital melting point apparatus.IR spectra were measured on a Mattson Galaxy Series FT-IR 3000 (model 3020). 1 H and 13 C NMR spectra were obtained on a Varian VXR-200.Chemical shifts are expressed as δ (ppm) relative to TMS as an internal standard and J values are given in Hz.The products were analyzed by GC on a Shimadzu GC-17A Gas Chromatograph, equipped with a FID detector.GC parameters for achiral analysis: injector 230 °C; detector 300 °C; oven 80 °C for 5 min then 15 °C min -1 for 5 min until 300 °C; column pressure 20 kPa, column flow 6.3 mL min -1 ; linear velocity 53.1 cm s -1 ; total flow 138 mL min -1 ; split ratio 1:20; column DB1 15 m × 0.53 mm (internal diameter).GC parameters for chiral analysis: injector 250 °C; detector 300 °C; oven 60 °C for 10 min then 1 °C min -1 until 220 °C; column pressure 100 kPa, column flow 1.1 mL min -1 ; linear velocity 27.9 cm s -1 ; total flow 41 mL min -1 ; split ratio 1:27; column β-cyclodextrin 30 m × 0.25 mm (internal diameter).Optical rotations were measured in a Perkin-Elmer 341 polarimeter with a 0.1 dm cell at a temperature of 20 °C.
Purification by column chromatography was carried out on silica gel 60 (70-230 mesh).Analytical thin-layer chromatography (TLC) was conducted on Merck aluminum plates with 0.2 mm of silica gel 60F-254.
(5:1, 3 x 50 mL) and dried over anhydrous Na 2 SO 4 .Removal of the solvent left an oil containing essentially the bicyclic cyanohydrin TMS ether 14.Subsequently, the resulting oil was dissolved in 43 mL of 10% aqueous Et 2 O, and 3.3 mL of 1mol L -1 n-Bu 4 N + F -in THF was added to this mixture.The resulting mixture was stirred at room temperature for 3 days.After this time, water (10 mL) was added and the mixture was extracted with Et 2 O (3 x 25 mL).The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give 540 mg of the crude product as a yellowish foam.Purification of the residue by chromatography afforded 391 mg (2.65 mmol, 75% based over three step from starting aldehyde 13) of (-)-6.