An Alternative and Convenient Synthesis of Oct-7-enal , a Naturally-Occurring Aldehyde Isolated from the Japanese Thistle Cirsium Dipsacolepis

Stephaoxocanidine (1) and eletefine (2) are two members of the recently uncovered family of stephaoxocane alkaloids, isolated from Menispermaceae of the Far East and Brazil, respectively. We have recently reported that tricyclic analogs of the stephaoxocanes bearing their 1,9-oxaazaphenalene motif exhibit interesting acetylcholinesterase inhibitory activity. In the course of our studies towards the synthesis of desoxystephaoxocanidine (3) and its analogs, and taking into account the retrosynthetic approach shown in Scheme 1 for the elaboration of tricyclic ketone 4 through the intermediacy of benzocyclodecenyl alcohol 5, employing the known bromoaldehyde 7 and the related styrene derivative 6, we required a simple and efficient synthetic route towards oct-7-enal (8). Oct-7-enal is a naturally-occurring unsaturated aldehyde, isolated from the volatile oil of the thistle Cirsium dipsacolepis (Asteraceae). Known as yamagobo, this is a perennial herb that grows in Japan on dry plains, which is the source of bioactive compounds and which edible roots, once pickled, are used to accompany meat-based foods due to their extraordinary flavor. The unsaturated aldehyde has been synthesized in widely different scales and diverse purposes, by dihydroxylation of one of the double bonds of 1,8-nonadiene, followed by oxidative fission of the resulting diol, as well as by partial hydroboration-oxidation and further oxidation of 1,7-octadiene and biochemical oxidation of this diene with Pseudomonas oleovorans monooxygenase. Also, copper (I) and lead (IV)-catalyzed oxidative ring opening of cyclooctanol were employed for its synthesis, as well as copper (I)-assisted conjugate addition of 4-pentenylmagnesium bromide to acrolein diethyl acetal, followed by acid hydrolysis of the resulting enol ether, isomerization of cyclooctene oxide employing solid acids and bases, and isomerization of 2,7-octadien1-ol on copper, chromium and zinc composite catalysts at 180-250 oC or on a copper catalyst. However, these approaches are not exempt from serious drawbacks, such as low yields, use of harsh conditions, requirement of expensive starting materials, use of special or not readily available catalysts or co-factors, inconvenient separation conditions, such as preparative HPLC, and the concomitant production of unwanted byproducts, sometimes the aldehyde 8 being only a minor product. The reactivity of 8 as a model in the selective reduction of carbonyls, mediated by 2-propanol in supercritical fluids, has been studied. Interestingly, the use of an impure sample of oct-7-enal has also been informed.

Stephaoxocanidine (1) and eletefine (2) are two members of the recently uncovered family of stephaoxocane alkaloids, isolated from Menispermaceae of the Far East and Brazil, respectively. 1We have recently reported that tricyclic analogs of the stephaoxocanes bearing their 1,9-oxaazaphenalene motif exhibit interesting acetylcholinesterase inhibitory activity. 2n the course of our studies 3 towards the synthesis of desoxystephaoxocanidine (3) and its analogs, and taking into account the retrosynthetic approach shown in Scheme 1 for the elaboration of tricyclic ketone 4 through the intermediacy of benzocyclodecenyl alcohol 5, employing the known bromoaldehyde 7 4 and the related styrene derivative 6, we required a simple and efficient synthetic route towards oct-7-enal (8).
Oct-7-enal is a naturally-occurring unsaturated aldehyde, isolated from the volatile oil of the thistle Cirsium dipsacolepis (Asteraceae). 5Known as yamagobo, this is a perennial herb that grows in Japan on dry plains, which is the source of bioactive compounds 6 and which edible roots, once pickled, are used to accompany meat-based foods due to their extraordinary flavor.The unsaturated aldehyde has been synthesized in widely different scales and diverse purposes, by dihydroxylation of one of the double bonds of 1,8-nonadiene, followed by oxidative fission of the resulting diol, 7,8 as well as by partial hydroboration-oxidation and further oxidation of 1,7-octadiene 9 and biochemical oxidation of this diene with Pseudomonas oleovorans monooxygenase. 10Also, copper (I) and lead (IV)-catalyzed oxidative ring opening of cyclooctanol 11 were employed for its synthesis, as well as copper (I)-assisted conjugate addition of 4-pentenylmagnesium bromide to acrolein diethyl acetal, followed by acid hydrolysis of the resulting enol ether, 12 isomerization of cyclooctene oxide employing solid acids and bases, 13 and isomerization of 2,7-octadien-1-ol on copper, chromium and zinc composite catalysts at 180-250 ºC 14 or on a copper catalyst. 15owever, these approaches are not exempt from serious drawbacks, such as low yields, 7 use of harsh conditions, 13,14 requirement of expensive starting materials, 7,10,12 use of special or not readily available catalysts or co-factors, 10 inconvenient separation conditions, 14 such as preparative HPLC, 7 and the concomitant production of unwanted byproducts, 13 sometimes the aldehyde 8 being only a minor product. 11he reactivity of 8 as a model in the selective reduction of carbonyls, mediated by 2-propanol in supercritical fluids, has been studied. 16Interestingly, the use of an impure sample of oct-7-enal has also been informed. 17

Results and Discussion
Therefore, here we wish to report an alternative, straightforward and convenient synthesis of oct-7-enal in five steps, from the readily available pentane-1,5-diol (9).As shown in Scheme 2, this comprised the selective monoprotection of one of the hydroxyl groups of the starting material as tert-butyl dimethylsilyl (TBS) ether employing TBSCl and NaH in dry THF, which furnished 60% of compound 10, a yield that was similar to that achieved when TBSCl and imidazole in anhydrous DMF were used. 18In turn, alcohol 10 was transformed into the related sulfonic ester 11 (86% yield) with tosyl chloride and triethylamine, under conventional conditions, setting the stage for chain elongation.There are scattered precedents of the direct displacement of tosylates by the allyl Grignard; 19 however, it was considered convenient to employ copper (I) iodide assistance, a more established alternative. 20he need of several equivalents of low order cuprates to achieve high yields has been recognized as one of their major drawbacks; 21 therefore, use of excess allylmagnesium bromide was key for attaining high conversions from 11.Not unexpectedly, when a threefold excess of allyl Grignard was employed, 76% of 12 was obtained; this was improved to 84% upon use of a six-fold excess of the organometallic reagent and reached 92% when a ten times excess was added.
Next, the silyl ether was conveniently deprotected with TBAF in THF to smoothly provide almost quantitative yields of oct-7-enol (13), which was finally oxidized to the desired aldehyde 8 in 80%, employing PCC/Al 2 O 3 ; the same oxidation was also successfully carried out in 78% yield, employing Dess-Martin periodinane in anhydrous CH 2 Cl 2 .Spectral data of the synthetic compound were in agreement with the literature. 7n conclusion, an alternative and simple synthesis of the natural product oct-7-enal (8) was achieved in five steps and 38% overall yield, from commercially available pentane-1,5-diol.The synthesis involved differential protection of both hydroxyl groups of the diol with inclusion of a suitable leaving group, which after copper (I)-assisted displacement with an allyl Grignard furnished the required 8-carbon chain.Mild deprotection and functional group interconversion culminated in the synthesis of 8.The main advantages of the proposed sequence are simplicity, ease of purification of the intermediate products and ready accessibility of starting materials and reagents.Its application to the elaboration of analogs of stephaoxocanes will be reported in due course.

General procedures
FT-IR spectra were determined with a Shimadzu IR Prestige 21 spectrophotometer.The 1 H and 13 C NMR spectra were acquired in CDCl 3 employing TMS as internal standard, with a Bruker Avance 300 spectrometer operating at 300.13 and 75.46 MHz, respectively; coupling constants (J) are expressed in Hertz.The asterisk (*) indicates that assignments can be exchanged; mass spectra were acquired at the National University of Tucumán.The reactions were carried out under dry argon atmospheres, employing ovendried glassware.All new compounds gave single spots on TLC plates run in different hexane-EtOAc solvent systems.Spots were visualized by spraying with ethanolic p-anisaldehyde/ sulfuric acid reagent and careful heating.Visualization by exposure to UV light (254 and 365 nm), preceded spraying in case of compounds with suitable chromophors.Flash column chromatographies were carried out with silica gel 60 H, eluting with mixtures of hexane-EtOAc under positive pressure and employing stepwise gradient techniques.
Oct-7-enal (8)  Anhydrous sodium acetate (32 mg) and PCC/Al 2 O 3 (562 mg) were successively added to a solution of alcohol 13 (25 mg, 0.20 mmol) in CH 2 Cl 2 (2.5 mL), and the resulting suspension was stirred at room temperature until complete consumption of the starting alcohol.Then, the solids were filtered through a column of silica gel, washed with CH 2 Cl 2 (2 mL) and the solvent was distilled off, affording 8 (25 mg,