An alternative and convenient synthesis of oct-7-enal, a naturally-occurring aldehyde isolated from the Japanese thistle Cirsium dipsacolepis

ARTICLE

An alternative and convenient synthesis of oct-7-enal, a naturally-occurring aldehyde isolated from the Japanese thistle Cirsium dipsacolepis

Andrea B. J. Bracca; Teodoro S. Kaufman^*

Instituto de Química Rosario and Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina

ABSTRACT

A new synthesis of oct-7-enal, a naturally-occurring unsaturated aldehyde isolated from the Japanese thistle Cirsium dipsacolepis, is reported. The natural product was prepared in five steps and with good overall yield from pentane-1,5-diol.

Keywords: chemical synthesis, oct-7-enal, Cirsium dipsacolepis, natural product

RESUMO

Esse trabalho descreve a síntese do oct-7-enal, um aldeído natural, isolado do cardo japonês Cirsium dipsacolepis. O produto natural foi preparado em cinco etapas com bom rendimento, partindo-se do pentano-1,5-diol.

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.¹ We have recently reported that tricyclic analogs of the stephaoxocanes bearing their 1,9-oxaazaphenalene motif exhibit interesting acetylcholinesterase inhibitory activity.²

In the course of our studies³ 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 7⁴ 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).⁵ Known as yamagobo, this is a perennial herb that grows in Japan on dry plains, which is the source of bioactive compounds⁶ 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-octadiene⁹ and biochemical oxidation of this diene with Pseudomonas oleovorans monooxygenase.¹⁰ Also, copper (I) and lead (IV)-catalyzed oxidative ring opening of cyclooctanol¹¹ 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 ºC¹⁴ or on a copper catalyst.¹⁵

However, 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 by-products,¹³ sometimes the aldehyde 8 being only a minor product.¹¹

The reactivity of 8 as a model in the selective reduction of carbonyls, mediated by 2-propanol in supercritical fluids, has been studied.¹⁶ Interestingly, 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.¹⁸ In 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.²⁰ The 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/Al₂O₃; the same oxidation was also successfully carried out in 78% yield, employing Dess-Martin periodinane in anhydrous CH₂Cl₂. Spectral data of the synthetic compound were in agreement with the literature.⁷

In 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.

Experimental

General procedures

FT-IR spectra were determined with a Shimadzu IR Prestige 21 spectrophotometer. The ¹H and ¹³C NMR spectra were acquired in CDCl₃ 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 oven-dried 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.

5-(tert-Butyl-dimethyl-silanyloxy)-pentan-1-ol (10)

A solution of pentane-1,5-diol (1000 mg, 9.62 mmol) in anhydrous THF (20 mL) was treated with NaH (50% in mineral oil, 462 mg, 9.62 mmol); after stirring at room temperature during 1 h, a solution of tert-butyl dimethylsilyl chloride (1452 mg, 9.62 mmol) in THF (10 mL) was added dropwise and the reaction was left to proceed for 3 h at room temperature. Then, brine (10 mL) was added and the reaction products were extracted with EtOAc (3 × 25 mL). The combined organic extracts were washed once with brine (5 mL), dried over Na₂SO₄, concentrated under reduced pressure and chromatographed, furnishing monoprotected diol 10 (1495 mg, 60%), as an oil. IR (KBr) ν_max/cm^-1: 3354, 2950, 2858, 1473, 1389, 1258, 1101, 1006, 836 and 775; ¹H NMR δ 0.05 [s, 6H, Si(CH₃)₂], 0.89 [s, 9H, C(CH₃)₃], 1.40-1.59 (m, 6H, H-2, H-3 and H-4), 3.64 (dt, 4H, J 5.4 and 7.0, H-1 and H-5); ¹³C NMR δ -5,40 [2C, Si(CH₃)₂], 18.26 [C(CH₃)₃], 21.92 (C-3), 25.86 [3C, C(CH₃)₃], 32.39 (2C, C-2 and C-4), 62.84 (C-5)^* and 63.00 (C-1).^* MS (CI), m/z (%): 219 [(M + 1)⁺, 100], 201 [(M – H₂O + 1)⁺, 32], 155 (6), 127 (4), 85 (12) and 69 (24).

5-(tert-Butyl-dimethyl-silanyloxy)-pentyl-4-methylbenzenesulfonate (11)

Triethylamine (1.05 mL, 7.56 mmol) and DMAP (50 mg, 0.41 mmol) were added to a solution of alcohol 10 (1104 mg, 5.04 mmol) in CH₂Cl₂ (16 mL). The solution was cooled in an ice-water bath and then treated portionwise with tosyl chloride (1059 mg, 5.55 mmol). After stirring overnight at room temperature, a saturated solution of NH₄Cl was added (10 mL) and the reaction products were extracted with CH₂Cl₂ (3 × 25 mL). The organic extracts were combined, washed with brine (10 mL), dried (Na₂SO₄), concentrated under reduced pressure and chromatographed, furnishing tosylate 11 (1618 mg, 86%), as an oil. IR (KBr) ν_max/cm^-1: 2954, 2858, 1599, 1472, 1362, 1257, 1189, 1098, 962, 835, 776 and 664 ; ¹H NMR δ 0.04 [s, 6H, Si(CH₃)₂], 0.87 [s, 9H, C(CH₃)₃], 1.30-1.39 (m, 2H, H-3), 1.40-1.51 (m, 2H, H-4), 1.66 (dt, 2H, J 6.6 and 14.7, H-2), 2.45 (s, 3H, ArCH₃ of Ts), 3.55 (t, 2H, J 6.2, H-5), 4.03 (t, 2H, J 6.6, H-1), 7.34 (d, 2H, J 8.5, ArH-3 and ArH-5 of Ts) and 7.79 (d, 2H, J 8.5, ArH-2 and ArH-6 of Ts); ¹³C NMR δ -5,45 [2C, Si(CH₃)₂], 18.20 [C(CH₃)₃], 21.50 (ArCH₃ of Ts),^* 21.68 (C-3),^* 25.82 [3C, C(CH₃)₃], 28.52 (C-2), 31.93 (C-4), 62.61 (C-5), 70.45 (C-1), 127.76 (2C, Ar-2 and Ar-6 of Ts), 129.68 (2C, Ar-3 and Ar-5 of Ts), 133.16 (Ar-1 of Ts) and 144.49 (Ar-4 of Ts). MS (CI), m/z (%): 373 [(M + 1)⁺, 78], 315 (10) and 201 (100).

tert-Butyl-dimethyl-oct-7-en-1-yloxy-silane (12)

Anhydrous copper (I) iodide (255 mg, 1.34 mmol) was added to a solution of tosylate 11 (100 mg, 0.27 mmol) in anhydrous Et₂O (1 mL); the resulting suspension was cooled to –20 ºC and treated with freshly prepared 1.83 mol L^-1 solution of allylmagnesium bromide in Et₂O (1.46 mL, 2.68 mmol). The reaction was left to warm to room temperature and further stirred for 4.5 h, when a saturated solution of NH₄Cl (10 mL) was added and the reaction products were extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine (10 mL), dried (Na₂SO₄), concentrated in vacuo and chromatographed, providing silyl ether 12 (60 mg, 92%) as an oil. IR (KBr) ν_max/cm^-1: 2955, 2858, 1641, 1473, 1388, 1256, 1102, 910, 836, 774 and 661; ¹H NMR d 0.05 [s, 6H, Si(CH₃)₂], 0.89 [s, 9H, C(CH₃)₃], 1.25-1.45 (m, 6H, H-3, H-4 and H-5), 1.51 (bt, 2H, J 6.8, H-6), 2.04 (bq, 2H, J 6.6, H-2), 3.60 (dd, 2H, J 5.5 and 7.5, H-1), 4.92 (bdd, 1H, J 2.0 and 9.0, H-8), 4.98 (bdd, 1H, J 2.0 and 18.4, H-8) and 5.79 (dddd, 1H, J 6.8, 6.8, 9.0, and 18.4, H-7); ¹³C NMR d -5,38 [2C, Si(CH₃)₂], 18.26 [C(CH₃)₃], 25.56 (C-3), 25.87 [3C, C(CH₃)₃], 28.81 (2C, C-4 and C-5), 32.72 (C-2), 33.63 (C-6), 63.16 (C-1), 114.04 (C-8) and 139.02 (C-7). MS (CI), m/z (%): 243 [(M + 1)⁺, 12], 185 (15), 127 (25), 111 (80) and 99 (39), 85 (69), 71 (84), 57 (100) and 43 (82).

Oct-7-enol (13)

A solution of silyl ether 12 (704 mg, 2.91 mmol) in Et₂O (10 mL), was treated with 1M TBAF in THF (5.2 mL, 5.2 mmol). After stirring overnight at room temperature, the solvent was removed under reduced pressure and the remaining oil was chromatographed, furnishing 13 (368 mg, 99%), as an oil. IR (KBr) ν_max/cm^-1: 3554, 2928, 2857, 1641, 1435, 1254, 1057, 908, 837 and 783; ¹H NMR d 1.30-1.44 (m, 6H, H-3, H-4 and H-5), 1.57 (quintet, 2H, J 6.6, H-2), 2.05 (bq, 2H, J 7.2, H-6), 3.63 (t, 2H, J 6.6, H-1), 4.94 (ddt, 1H, J 1.2, 2.2 and 10.2, H-8), 5.00 (dq, 1H, J 2.0 and 17.4, H-8) and 5.81 (ddt, 1H, J 6.6, 10.2 and 17.4, H-7); ¹³C NMR δ 25.46 (C-3), 28.73 (C-4),^* 28.75 (C-5),^* 32.60 (C-2), 33.57 (C-6), 62.83 (C-1), 114.11 (C-8) and 138.91 (C-7). MS (CI), m/z (%): 129 [(M + 1)⁺, 3], 111 (8), 73 (100), 69 (19) and 55 (7).

Oct-7-enal (8)

Anhydrous sodium acetate (32 mg) and PCC/Al₂O₃ (562 mg) were successively added to a solution of alcohol 13 (25 mg, 0.20 mmol) in CH₂Cl₂ (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 CH₂Cl₂ (2 mL) and the solvent was distilled off, affording 8 (25 mg, 80%), as an oil. IR (KBr) ν_max/cm^-1: 2926, 2855, 1726, 1639, 1462, 1258, 1078, 910, 837 and 783; ¹H NMR δ 1.30-1.46 (m, 4H, H-4 and H-5), 1.55-170 (broad quintet, 2H, J 6.8, H-3); 2.09 (bq, 2H, J 6.8, H-6), 2.45 (dt, 2H, J 1.6 and 7.3, H-2), 4.97 (ddt, 1H, J 1.6, 2.0 and 10.1, H-8), 5.00 (ddt, 1H, J 1.6, 2.0 and 17.1, H-8), 5.80 (ddt, 1H, J 6.6, 10.1 and 17.1, H-7) and 9.77 (t, 1H, J 1.9, CHO); ¹³C NMR δ 21.77 (C-3), 28.44 (C-4), 29.55 (C-5), 33.35 (C-6), 43.68 (C-2), 114.34 (C-8), 138.53 (C-7) and 202.62 (C-1). MS (EI), m/z (%) 125 (5, M⁺-H), 97 (12, M⁺-CHO), 83 (20, M⁺-C₂H₃O), 82 (37, M⁺-C₂H₄O by McLafferty rearrangement), 73 (11), 67 (43), 60 (37), 55 (100, C₃H₅O⁺, cleavage at C-3 – C-4), 54 (28) and 51 (7); these results are in good agreement with the literature data.⁷

Acknowledgments

The authors gratefully acknowledge CONICET, ANPCyT and Fundación Josefina Prats for financial support and A.B.J.B. is also thankful to CONICET for her fellowship. Thanks are due to Drs. V. Minkin (Rostov State University, Russia) and D. A. Bianchi (Technical University of Vienna, Austria) for helping with literature, and Drs. F. Arrighi and A. Bardón (National University of Tucumán, Argentina) are acknowledged for providing mass spectral data.

References

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Received: December 21, 2007

Web Release Date: July 14, 2008

Publication Dates

• Publication in this collection
  22 Sept 2008
• Date of issue
  2008

History

• Accepted
  14 July 2008
• Received
  21 Dec 2007