Synthesis of ( ± )-Africanol

Os compostos 1a e 1b, diastereoisômeros do africanol, foram obtidos como produtos exclusivos através de uma metodologia que empregou como etapa chave a reação de ciclização intramolecular, mediada por nBuLi, do iodeto vinílico 5. Utilizando processo de ciclização semelhante com o composto 19, obteve-se o álcool terciário 20 como único produto. O africanol pode ser obtido, juntamente com seus diastereoisômeros 1a e 1b, ao se efetuar a reação de ciclização intramolecular da cetona 21, em presença de iodeto de samário.


Introduction
Africanol 1, a tricyclic sesquiterpene alcohol, was isolated in 1974 from the soft coral Lemnalia africana collected around the island of Leti, province of Maluku, Indonesia 1 .The structure of africanol, including its absolute configuration, was established by X-ray crystallography 2 .Substance 1 is a member of the africanane group of sesquiterpenoids, which includes several other compounds such as isoafricanol 2, leptographiol 3 and isoleptographiol 4, all of which were isolated in 1986 from a sapwood staining ascomycete fungus, Leptographium lundbergii Lag.et Melin 3 .
There are four syntheses of africanol described in the literature [4][5][6][7] of which the one described by Fan and White 7 , is the shortest and most elegant.This route also provided the diastereomer isoafricanol 2. Our initial approach to the synthesis of africanol consisted of the construction of a five membered ring on the bicyclo[5.1.0]octanoneprecursor 6, employing methodology based on the intramolecular cyclization of a vinylic anion onto a carbonyl moiety 8 as the key step, as shown in the retrosynthetic analysis in Scheme 1.

General
Reagents and solvents were purified and dried using standard methods.Reactions involving organometallic reagents were carried out under argon in oven-dried or 5890 GC (FID, 25 m x 0.20 mm capillary column crosslinked with 5% phenyl methyl silicone).Conventional and flash column chromatography were carried out with 70-230 and 230-400 mesh silica gel (E.Merck), respectively.Radial chromatography purifications were performed using a Chromatotron ® model 7924 with plates of 1, 2 or 4 mm (silica gel 60, PF 254 with calcium sulphate, E. Merck 7749).Distillation temperatures, which refer to bulb-to-bulb (Kugelrohr) distillations, are uncorrected.IR spectra were recorded on a Perkin-Elmer 1710 spectrometer with internal calibration. 1H NMR were recorded on CDCl 3 solutions using Bruker AC-200 or WH-400 spectrometers.Chemical shifts (δ) are given in ppm and coupling constants (J) in Hz.Deuterated solvents were used as lock and reference signal ( 1 H NMR reference signal relative to the proton resonance resulting from incomplete deuteration of the CDCl 3 : δ 7.25). 13C NMR spectra were determined as solutions either in CDCl 3 or in C 6 D 6 with the spectrometers described above.The chemical shifts (δ) are reported in ppm relative to the center peak of CDCl 3 (δ 77.0) or C 6 D 6 (δ 128.0).Low and high resolution mass spectra were obtained on Kratos/AEI 50 or MS 902 mass spectrometers.Combustion analyses were obtained with a Carlo Erba 1106 C, H, N analyzer.

3,6-Dimethyl-2-cyclohexenone (9)
To a solution of diisopropylamine (18.14 g, 179.3 mmol) in THF (450 cm 3 ) at -78 o C was added n BuLi in hexanes (108 cm 3 , 171 mmol).After stirring for 30 min at 0 o C the solution was recooled to -78 o C followed by dropwise addition of 3-methyl-2-cyclohexenone (17.9 g, 163 mmol) in THF (100 cm 3 ).After 1 h at -78 o C iodomethane (69.4 g, 489 mmol) was added and the resulting mixture was stirred 1h at -78 o C and 3 h between -20 and -15 o C. Ether (600 cm 3 ) was added and the solution of the crude product was washed with water (2 x 100 cm 3 ) and saturated NaCl (2 x 70 cm 3 ), and dried over anhydrous MgSO 4 .The solvent and excess iodomethane were removed by rotary evaporation and the product was distilled at reduced pressure (17   (10)   To a flask containing copper (I) cyanide (5.64 g, 63.0 mmol) and THF (250 cm 3 ) at -78 o C was added MeLi in ether (43.0 cm 3 , 60.4 mmol).After stirring 20 min at -10°C the solution was recooled to -78 o C and a second portion of MeLi (43.0 cm 3 , 60.4 mmol) was added.After 30 min, chlorotrimethylsilane (13.69 g, 126.0 mmol) was added followed by addition of a solution of compound 9 (6.000 g, 48.32 mmol) and HMPA (22.58 g, 126.0 mmol) in THF (50 cm 3 ).The mixture was stirred 2 h at -78 o C and 3 h at room temp, then quenched with saturated aqueous NH 4 Cl/NH 4 OH (100 cm 3 , pH 8).After 10 h at room temp the phases were separated and the aqueous layer was extracted with Et 2 O (2 x 30 cm 3 ).The combined organic extracts were washed with water (2 x 30 cm 3 ) and concentrated under reduced pressure to 100 cm 3 .The product was then stirred with 1 mol.L -1 HCl (10 cm 3 ) for 2 h at room temp.Ether (100 cm 3 ) was added, the phases were separated, and the organic layer was The above mixture (3.000 g, 14.15 mmol) was dissolved in benzene (30 cm 3 ) and a solution of diethylzinc in hexanes (28 cm 3 , 28 mmol) was added at 40 o C followed by the dropwise addition of CH 2 I 2 (11.37 g, 42.45 mmol).After the addition was complete, a slow flow of O 2 was introduced into the headspace above the reaction mixture for 1 h.The resulting solid was removed by filtration over celite using hexane as eluent and the product was transferred to a separatory funnel containing ether (100 cm 3 ).The mixture was washed with saturated aqueous NH 4 Cl/NH 4 OH (2 x 30 cm 3 , pH 8) and water (1 x 30 cm 3 ), and dried over Na 2 SO 4 .The filtrate was concentrated under reduced pressure and purified by flash chromatography (petroleum ether/ether 92:8 v/v) to give compound 11 (2.72   12), 211 (64), 197 (15), 169 (16), 121 (20), 96 (30), 75 (39), 73 (100).

Results and Discussion
The cycloheptenone intermediate 7 was prepared as shown in Scheme 2, employing ring expansion of the silyloxybicyclo[4.1.0]heptane11 as the key step.
Thus, alkylation of 3-methylcyclohex-2-en-1-one 8 with methyl iodide, at low temperature, afforded compound 9 in good yield.Conjugate addition of the higher order dilithium dimethylcyanocuprate to the α,β-unsaturated ketone 9 was carried out in the presence of the additives HMPA/TMSCl [9][10][11] .A ratio ranging from 15:1 to 19:1 of the thermodynamic versus kinetic enol silyl ethers was achieved when ketone 10 was treated with trimethylsilyl iodide and hexamethyldisilazane in pentane 12 at -25ºC.Cyclopropanation of the resultant silyl enol ether mixture with diethylzinc and diiodomethane, in the presence of oxigen, gave 11 in high yield 13,14 .The ring expansion was then successfully carried out by treatment of compound 11 with FeCl 3 in pyridine/DMF 15 .
With the key precursor 7 in hand, a straightforward sequence of steps was employed to convert cycloheptenone 7 into bicyclic ketone 6 (see Scheme 3).
When ketone 7 was treated with ethylene glycol in the presence of PTSA in benzene, the ketal 12 was obtained as the only product.The migration of the double bond was confirmed by the 1 H NMR spectrum of 12, which showed a multiplet for the vinylic hydrogen.Ketal 12 was subjected to the cyclopropanation conditions as before (diethylzinc and diiodomethane in the presence of oxygen 13,14 ).Removal of the ketal protecting group of 13 by transketalization with PTSA in acetone generated bicyclic ketone 6.
Several reaction conditions were tried in unsuccessful attempts to alkylate ketone 6 directly with iodide 14, using LDA as base in THF/HMPA and varying the temperature of the reaction mixture from -78 o C to room temperature.This problem was surmounted by converting ketone 6 into its N,N-dimethylhydrazone derivative 16 , (see Scheme 4) and sequential treatment of the derivative 15 with LDA in THF and the alkyl iodide 14, yielding the desired alkylated product 16.After oxidative cleavage of the hydrazone with sodium periodate in phosphate buffer solution 17 , ketone 17 was obtained in 31% yield for the two steps.Vinyl iodide 5 was easily generated from vinylstannane 17 by treatment with a solution of iodine in methylene chloride 8 .The alkylation of hydrazone 15 occurred regioselectively and with high stereoselectivity (> 30:1 ratio as determined by GC) giving, as the major diastereomer, the product derived from alkylation of the ring on the same side as the adjacent methyl group.The synthesis of the tricyclic carbon skeleton was completed by treatment of the vinyl iodide with n BuLi to effect lithium-halogen exchange, with the resulting anion undergoing an intramolecular cyclization to 18.The relative configuration of the tricyclic alcohol 18 was assigned after hydrogenation of the exomethylene function, which gave compounds 1a and 1b, diastereomers of africanol.Pure samples of 1a and 1b could be obtained by chromatography of the mixture on silica gel.Compounds 1a and 1b exhibited 1 H NMR spectra data identical with those of the same two substances previously prepared by Tai and coworkers 6 .
In an analogous sequence of reactions, hydrazone 15 was alkylated with (Z)-1-bromo-3-iodo-2-butene, followed by cyclization to give compound 20 (see Scheme 5).The only product obtained displayed the trans ring junction.The product 20 exhibited a H 1 NMR spectrum identical with that of the same compound prepared by Paquette and Ham 5 .The results outlined above revealed that the n BuLi mediated cyclizations of the keto iodides 5 (Scheme 4) and 19 (Scheme 5) were higly stereoselective and produced only the corresponding trans fused alcohols 18 and 20, respectively.Thus, in each case, the intermediate alkenyllithium function (formed by lithium iodine exchange) attacks the carbonyl carbon from the side opposite to the cyclopropyl (angular) methyl group.It is evident from molecular modelling that, in each of the modes of cyclization that could lead to the cis-fused epimers of 18 and 20, the transition states for cyclization would experience significant steric hindrance (1,3-diaxial type interaction) between the alkenyl-lithium moiety and the angular methyl group.On the other hand, the transition states leading to 18 and 20 appear to be relatively free of steric compression.
In view of the results described above, it was decided to prepare compound 21 and treat it with samarium iodide in the presence of HMPA.It was expected that the samarium iodide would generate the ketyl radical which would be complexed with HMPA 18 , prior to attack on the terminal double bond.
Having made 21 by alkylation of the anion of 15 with 4-iodo-1-butene, the cyclization was attempted.The reaction produced a mixture of the compounds 1a and 1b, along with africanol, in a ratio of 1:0.6:1, respectively.The formation of isoafricanol was not observed.

Conclusion
The methodology presented herein was very effective up to the preparation of bicyclic ketone 6.The regioselective