Stereoselective synthesis of megastigmatrien-3-one using catalytic olefin isomerization as key step

An unprecedented and efficient synthesis of megastigmatrien-3-one from readily available starting materials is reported. The transformation includes carbonyl group protection, reduction, oxidation, addition, elimination, and isomerization processes, which allows for the formation of resultant megastigmatrien-3-one with good purity and high stereoselectivity. This method features mild conditions and operational simplicity

8] Takazawa and co-workers developed a synthetic route towards megastigmatrien-3-one with the four isomers in the ratio 3:10:1:6, from isophorone (Scheme 2, route 1).The key steps involved an aldol-type reaction of dienoxysilanes and subsequent Lewis acid-catalyzed reaction with aldehyde. 6Demole and co-workers in Firmenich devised a synthesis from 2,6,6-trimethyl-4,4-ethylenedioxycyclohex-2-en-one.1,2-Addition with but-3-yn-2-ol of the resultant unsaturated ketoacetal then gave an acetylenic diol.Reduction and hydrolysis gave megastigmatrien-3-ones in 27% yield in the ratio 1:7:1.5:10. 9-10Trost and co-workers utilised dehydroionone as the starting material in a synthesis that included reduction, sulfenylation, and hydrolysis to give product in <25% yield (Scheme 2, route 2). 11The key step involved a [2,7]sigmatropic rearrangement of 3,4-dehydro-β-ionol, readily available from 3,4-dehydro-β-ionone.Although much has been achieved, the reported methods all resulted in low yields and involved harsh reaction conditions, difficulties with purification and suffered from low stereroselectivity.The four stereoisomers differ in odor.The isomer (E, E)-megastigmatrien-3-one is considered to be most typical of tobacco, while the (E, Z) and (Z, Z) isomers contribute little to the odor.As a consequence, the stereoselective synthesis of the isomers of megastigmatrien-3-one remains an important and challenging problem.

Scheme 2.
Representative examples of the synthesis of megastigmatrien-3-one.

Results and Discussion
To verify the possibility of our hypothesis, reaction ethyl 2,6,6-trimethyl-4-oxocyclohex-2-enecarboxylate with ethylene glycol in the presence of PPTS in toluene led to an 84% yield of the ketal 2, thus furnishing carbonyl protection (Scheme 3).Reduction of ketal 2 gave compound 3 in good yields.Alcohol 3 was oxidized to 4 in excellent yield under Swern oxidation conditions.Manganese dioxide in methylene chloride could also be used, however, the reaction time was long (2 days) and the yield lower (< 70%).Scheme 3. Initial protection, reduction, and oxidation processes.
Reaction of aldehyde 4 with allylmagnesium bromide gave diallyl alcohol intermediate 5, which underwent hydrolysis to triene 6.The two processes could be achieved without isolation of the intermediate 5, thus, the triene 6 was readily obtained.A complex mixture was obtained when the second dehydration step was conducted at higher temperature (Scheme 4).

Scheme 4. Addition and hydrolysis towards key triene intermediate.
With the desired triene mixture 6 in hand, we then turned our attention to the desired olefin isomerization.As shown in Table 1, several common Mukaiyama conditions 30 with iron and cobalt catalysts and varying solvents were screened.Little reaction occurred with several iron catalysts (Table 1, entries 1-3).The employment of cobalt catalyst system resulted in some improvement (Table 1, entries 4-5).Cobalt catalytic system Co(II) with different ligands L1-L4 and additives increased the yield of megastigmatrien-3-one (Table 1, entries 6-9).]  The transformation was sensitive to temperature, such that lower yields and stereoselectivity 7a:7b:7c:7d = 3:34:1:62 were obtained when the reaction was conducted at 40 o C, whereas only a trace amount of 7 was obtained at 80 o C (Table 1, entries 10-11).Scheme 5. Further application of megastigmatrien-3-one.
To further explore the application of the present conversion, the resultant megastigmatrien-3-one isomers were subjected to oxidation with MCPBA to give epoxide intermediates I (Scheme 5).Selective reduction of I gave 7-hydroxy-3,5-dienone 8 (3-oxo-β-ionol), which is a key intermediate towards important spices.

Conclusions
In conclusion, we have described an unprecedented synthesis of megastigmatrien-3-one from readily available starting material ethyl 2,6,6-trimethyl-4-oxocyclohex-2-enecarboxylate.This strategy features high stereoselectivity (with E, E isomer > 70%) over traditional methods with total yield of about 40%.The whole transformation sequence includes functional group protection, reduction, oxidation, and nucleophilic addition followed by hydrolysis.In the last step, the cheap and readily available metal catalyst delivers the desired product with low cost.Considering the excellent stereoselectivity and simple operation, the present method has potential to be further applied in organic synthesis and flavor industry.

Experimental Section
General.The NMR spectra were recorded on Bruker AC-500 spectrometer (500 MHz for 1 H NMR and 125 MHz for 13 C NMR) with CDCl3 as the solvent and TMS as internal reference. 1H NMR spectral data were reported as follows: chemical shift (δ, ppm), multiplicity, integration, and coupling constant (Hz). 13C NMR spectral data were reported in terms of the chemical shift.The following abbreviations were used to indicate multiplicities: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet.Low-resolution mass spectra were obtained on a Shimadzu LCMS-2010EV spectrometer in ESI mode and reported as m/z.High-resolution mass spectra (HRMS) were recorded on a Bruker Daltonics, Inc. APEXIII 7.0 TESLA FTMS instrument.GC analysis was caarriedout on an Agilent 8890B instrument.Melting points were obtained on a X-4 digital melting point apparatus without correction.Purification of products was accomplished by column chromatography packed with silica gel.Unless otherwise stated, all reagents were commercially purchased and used without further purification.