Synthesis of racemic and chiral albicanol, albicanyl acetate and cyclozonarone: cytotoxic activity of ent-cyclozonarone

ARTICLE

Synthesis of racemic and chiral albicanol, albicanyl acetate and cyclozonarone: cytotoxic activity of ent-cyclozonarone

Virginia Delgado^I; Veronica ArmstrongI, ^*; Manuel Cortés^I; Alejandro F. Barrero^II

^IFacultad de Química, Pontificia Universidad Católica de Chile. Casilla 306, Correo 22, Santiago, Chile

^IIDepartamento de Química Orgánica, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain

ABSTRACT

The total synthesis of racemic cyclozonarone ((±)-3) was achieved from E,E-farnesol (4) in an eight-step sequence in 6.6% overall yield. Albicanol ((±)-1) and its acetate ((±)-2) are intermediates. A similar sequence starting from natural (-)-drimenol (5) gave (+)-albicanol (1) and (+)-cyclozonarone (3) (42% and 11% yield, respectively). The cytotoxic activity of (+)-cyclozonarone was assayed and showed some selectivity towards MS-1 (mice endothelial cells).

Keywords: albicanol, albicanyl acetate, cyclozonarone, total synthesis, chiral synthesis

RESUMO

A síntese completa da mistura racêmica do cyclozonarone ((±)-3), foi obtida a partir do E,E-farnesol (4) em uma seqüência de oito passos com um rendimento geral de 6,6%. O albicanol ((±)-1) e seu acetato ((±)-2) são intermediários. Uma seqüência inicial, similar a partir do produto natural (-)-drimenol (5), produziu o(+)-albicanol (1) e o(+)-cyclozonarone (3) com 42% e 11%, respectivamente. A atividade citotóxica do composto(+)-cyclozonarone foi avaliada e mostrou alguma seletividade para MS-1 (células endoteliais de camundongos).

Introduction

Synthetic efforts towards naturally occurring drimane sesquiterpenes have been constant due to their interesting biological activities.

The drimane-type alcohol albicanol ((+)-1) (Figure 1) was isolated from the liverworts Diplophyllum albilcans¹ and later from the dorid nudibranch Cadlina luteomarginata together with its acetate ((+)-2) which has a potent fish antifeedant activity.²

Banerjee^3,4 has previously synthesized racemic albicanol in an eight-step sequence, in 13% yield, starting from a drimane keto alcohol, which in turn has to be prepared by a several-step route, in 58% yield, from a commercially available octalone.^5,6 The total synthesis of racemic (1) and (2) had already been accomplished, as well, by Weiler⁷ through electrophilic cyclization of alkenic alkylsilanes, by a short three-step sequence in 30% yield, as a mixture of α and β isomers in C-9. Several asymmetric approaches to chiral 1 and 2 have been reported;^8-12 starting from higher terpenes with the trans decaline feature already constructed, such as manool, ⁸ or by routes involving optical resolution^9-11 and/or diasteroselective key steps, as reported by Shishido.¹²

Natural (-)-cyclozonarone (3) (Figure 1) has been isolated by Kurata et al.¹³ from the Pacific brown algae Dictyopteris undulata and possesses a potent feeding-deterrent activity toward young abalones. We have previously established the absolute configuration of natural (-)-(5R,10R)-cyclozonarone ((-)-3) through a six-step route, starting from natural (-)-polygodial, leading us to the synthetic enantiomer (+)-(5S,10S)-cyclozonarone ((+)-3).¹⁴ Later, (-)-cyclozonarone (3) was synthesized by Seifert et al.¹⁵ starting from (+)-albicanol (1), which in turn was prepared in 9 steps from b-ionone.¹⁶

Results and Discussion

Our strategy started with E,E-farnesol where the cyclization of 4 led to (±)-drimenol (5) according to Welzel's procedure; Scheme 1.¹⁷ Acetylation of drimenol ((±)-5) was performed as usually using Ac₂O and pyridine. The key step of the synthesis was the selenocatalytic allylic chlorination of drimenyl acetate ((±)-6);¹⁸ leading to an inseparable mixture of two chlorinated epimers (7a and 7b) which was subjected to reduction with Zinc dust, to furnish racemic albicanyl acetate ((±)-2) and unchanged β- chlorinated epimer ((±)-7b). Treatment of the previous mixture ((±)-2 and(±)-7b) with methanolic K₂CO₃ afforded (±)-1 and(±)-8 which were isolated and characterised by spectroscopic data analysis.

The more concluding data to establish (±)-8 as the 7-β-chlorinated epimer, was the double doublet centred at 1.95 ppm for H-5, the constants (J 3.1 and 9.1 Hz) are corresponding to axial-equatorial and axial-axial couplings with each H-6. The signal centred at 2.29 ppm for H-6 eq (ddd, J 2.6, 5.0 and 12.6 Hz) evidenced an axial-equatorial coupling with H-5 and H-7ax, besides the geminal coupling. Moreover, the coupling constants for H-7 (signal centred at 4.35 ppm) suggest an axial disposition for this proton. Thus, confirming the equatorial disposition for the chloro atom in (±)-8. On the basis of a similar analysis for H-5, H-6 and H-7 on both chlorinated albicanyl acetate (7a and 7b) the major epimer was assumed to have an axial chloro in C-7, while the minor epimer should correspond to the equatorial chloro in C-7.

The lack of reactivity for the equatorial chloro epimer towards Zn could be attributed to esteric hindrance for effective overlapping. Nevertheless, the ability of 7b to react with Zn was confirmed submitting a sample of pure 7b to the same experimental conditions as the epimeric mixture, although the reaction seems to be slower.

The possibility of readily preparing diene 9 from (±)-1 prompted us to assay a different approach to (±)-cyclozonarone. (±)-Albicanol (1) was dissolved in pyridine and added to a mixture of Tf₂O in pyridine, the reaction yielded 62% of diene 9. Racemic cyclozonarone was obtained from (±)-9 and benzoquinone as previously described¹⁴ (Scheme 2). Since racemic drimenol ((±)-5) has been previously resolved in its enantiomers¹⁹ the sequence described represents a formal synthesis of both enantiomers of cyclozonarone.

Starting from natural (-)-drimenol (5), ²⁰ (+)-albicanol 1 and ent-cyclozonarone ((+)-3) were also prepared following the same sequence depicted in Schemes 1 and 2.

Our continuous interest in synthetic methods for cyclozonarone is grounded in the biological activities both enantiomers exhibit. Previously, the effect of ent-cyclozonarone ((+)-3), prepared in these laboratories, on the growth of T. cruzi epimastigotes, Tulahuen strains, was studied together with that of the reference drugs nifurtimox and benznidazole (made by Roche under the trade names Radanil^TM, Rochagan^TM or Roganil^TM).²¹ Compound (+)-3 resulted ten times more active than the reference drugs. Recently, we have assayed cytotoxic activity of ent-cyclozonarone against cell lines A-549 (human lung carcinoma), HT-29 (human colon carcinoma), H-116 (human colon carcinoma), MS-1 (mice endothelial cells) and PC-3 (human prostate carcinoma), following the method reported by Bergeron et al.²² The IC 50 obtained for the five mentioned cell lines are shown in Table 1, resulting that the activity against MS-1 cells is 10-50 times higher than towards other cell lines tested.

Conclusions

Here, we have described a short total synthesis of racemic albicanol ((±)-1) (five steps, in 23% yield) and cyclozonarone ((±)-3) (eight steps, in 6.6% overall yield), starting from commercially available E,E farnesol. The key steps are the protonic cyclization of farnesol and the selenocatalytic allylic chlorination of drimenyl acetate ((±)-6)¹⁸to accomplish double bond isomerization. A similar sequence starting from natural (-)-drimenol (5) gave enantiopure (+)-1 and (+)-3 (42% and 11% respectively). Moreover, we have tested ent-cyclozonarone cytotoxic activity obtaining interesting IC50 values against all the cell lines assayed particularly MS-1 (the highest activity) and HT-29.

Experimental

General procedures

Melting points were determined on a Stuart Scientific SMP3 apparatus and are uncorrected. IR spectra were recorded on a Bruker Vector 22-FT in KBr disc or film. Optical rotations were obtained for CHCl₃ solutions in an Optical Activity, Ltd instrument in a 1 dm cell and their concentrations are expressed in g per mL. NMR spectra were recorded on a Bruker AC 200P (200.13 MHz for ¹H, 50.13 MHz for ¹³C) in CDCl₃ solutions with TMS as internal standard. Carbon multiplicity was established by a DEPT pulse sequence and signals were assigned based on 2D experiments. All two-dimension spectra were acquired with a Bruker AVANCE 400 Spectrometer with a Bruker inverse 5 mm Z gradient probe. The HMBC spectra were obtained using the inv4gplrndqf pulse sequence in the Bruker software. HRMS were determined on a MAT 95XP, Thermo Finnigan spectrometer. Chromatographic separations were carried out on Merck silica gel 60 (230-400 Mesh) using hexane-ethylacetate gradients of increasing polarity. All organic extracts were dried over magnesium sulfate and evaporated under reduced pressure, below 65ºC.

(±)-Drimenol(5)

HSO₃F (0.08 mL, 1.35 mmol) was added, at –78 ºC, to a solution of (E,E)-farnesol (4) (300 mg, 1.35 mmol) in a mixture of nitropropane:CH₂Cl₂, 12:1 (13 mL). After stirring for 30 min the reaction mixture was quenched with (C₂H₅)₃N (0.25 mL), diluted with water and extracted with EtOAc. The organic phase was dried (MgSO₄), filtered and the solvent was removed by simple distillation. The product was purified by column chromatography (hexane/EtOAc 8:2) to give (±)-5 (156 mg, 52%) as a colourless oil. Spectroscopic characteristics (NMR) being identical to those of natural (-)-drimenol; IR (KBr) ν_max/cm^-1: 3356, 1032; HRMS (M⁺) Found:222.19815. Calc. for C₁₅H₂₆O:222.19837.

(±)- Drimenyl acetate(6)

A mixture of (±)-5 (474 mg, 2.1 mmol), pyridine (5 mL) and acetic anhydride (0.2 mL, 2.5 mmol) was stirred for 3 h at room temperature. The mixture was diluted with H₂O and extracted with EtOAc. The organic phase was washed with saturated aqueous solution of KHSO₄, dried (MgSO₄) and the solvent was evaporated. The residue was purified by column chromatography to afford (±)-6 (513 mg, 91%) as a colourless oil, with identical spectroscopic characteristics as previously described for (+)-drimenyl acetate from natural (-)-drimenol.²³

7α and 7β-chloro-albicanyl acetate((±)-7a and (±)-7b)

Drimenyl acetate (±)-6 (262 mg, 0.99 mmol) was added to a solution of commercially available phenylselenyl chloride (19 mg, 0.099 mmol) in CH₂Cl₂ (6 mL). N-chlorosuccinimide (146.38 mg, 1.1 mmol) in CH₂Cl₂ (5 mL) was added to the previously prepared mixture. After stirring for 2 h at room temperature, the solvent was removed and the residue was suspended in diethyl ether. The organic layer was decanted from the solid, washed with H₂O and brine, dried (MgSO₄) and the solvent was removed under reduced pressure. The resulting crude was purified by column chromatography to afford an inseparable C-7 epimeric mixture of (±)-7a and(±)-7b (204 mg, 69%). Signals assignable to the major epimer: ¹H NMR (CDCl₃, 400 MHz) δ 0.74 (s, 3H), 0.80 (s, 3H), 0.87 (s, 3H), 2.02 (s, CH₃COO, 3H), 2.60-2.66 (ddd, J 1.9 Hz, J 3.8 Hz and J 8.7 Hz, 1H), 4.09-4.19 (dd, J 8.7 Hz and J 11.3 Hz, 1H, H-11), 4.31-4.39 (dd, J 3.9 Hz and J 11.3 Hz,1H, H-11), 4.72 (d, J 1.7 Hz,1H, H-12), 4.84-4.87 ( dd, J 2.8 Hz, 1H, H-7), 5.15 ( d, J 1.7 Hz, 1H, H-12); ¹³C NMR (CDCl₃, 100 MHz) δ 33.4 (CH₂, C-1), 19.0 (CH₂, C-2), 38.6 (CH₂, C-3), 32.9 (C, C-4), 47.4 (CH, C-5), 41.7 (CH₂, C-6), 65.5 (CH, C-7), 145.6 (C, C-8), 49.0 (CH, C-9), 38.7 (C, C-10), 60.9 (CH₂, C-11), 111.6 (CH₂, C-12), 33.1 (CH₃, C-13), 21.8 (CH₃, C-14), 14.6 (CH₃, C-15), 171.2 (C=O, OAc), 21.6 (CH₃, CH₃COO). Signals assignable to the minor epimer: ¹H NMR (CDCl₃, 400 MHz) δ 0.78 (s, 3H), 0.83 (s, 3H), 0.92 (s, 3H), 2.02 (s, CH₃COO, 3H), 2.24-2.34 (ddd, J 2.5 Hz, J 5.1 Hz and J 12.5 Hz, 1H, H-6eq), 4.08-4.26 ( dd, J 5.0 Hz and J 12.3 Hz, 1H, H-7), 4.17-4.27 ( dd, J 9.1 Hz and J 11.2 Hz, 1H, H-11), 4.33-4.82 ( dd, J 4.0 Hz and J 11.2 Hz,1H, H-11), 4.83 (d, J 1.4,1H, H-12), 5.51 (d, J 1.4, 1H, H-12); ¹³C NMR (CDCl₃, 100 MHz) δ 35.9 (CH₂, C-1), 19.0 (CH₂, C-2), 38.6 (CH₂, C-3), 33.6 (C, C-4), 54.6 (CH, C-5)*, 41.7 (CH₂, C-6), 63.5 (CH, C-7), 144.1 (C, C-8), 54.9 (CH, C-9)*, 38.7 (C, C-10), 61.1 (CH₂, C-11), 108.9 (CH₂, C-12), 33.5 (CH₃, C-13), 21.1 (CH₃, C-14), 15.1 (CH₃, C-15), 171.3 (C=O, OAc), 21.6 (CH₃, CH₃COO). *Signals may be interchanged. HRMS (M⁺) (mixture of epimers) Found: 298.16976 . Calc. for C₁₇H₂₇ClO₂ : 298.16996.

(±)-Albicanol(1)

Zn dust (433 mg, 6.62 mmol) was added to a solution of the mixture of epimers (±)-7 (241 mg, 0.81 mmol) in HOAc (4.05 mL), THF (5.6 mL) and H₂O (2.3 mL). This mixture was stirred at room temperature for 6 h. The solution was diluted with diethyl ether and the organic phase was decanted from the solid, washed with saturated NaHCO₃ aqueous solution, water and dried (MgSO₄); the solvent was removed under reduced pressure. After column chromatography on silica gel, 192 mg of an inseparable mixture of albicanyl acetate ((±)-2) and the β chlorinated epimer ((±)-7b) was obtained. Saponification of the former mixture with K₂CO₃/ MeOH and usual work up, gave after column chromatography 40 mg of 7β-chloro-albicanol ((±)-8); ¹H NMR (CDCl₃, 400 MHz) δ 0.73 (s, 3H), 0.80 (s, 3H), 0.90 (s, 3H), 1.05-1.65 (m, 8H, H-1, H-2, H-3, H-6ax and H-9), 1.94-1.97 (dd, J 3.1 Hz and J 9.1 Hz, 1H, H-5), 2.26-2.32 (ddd, J 2.6 Hz, J 5.0 Hz and J 12.6 Hz, 1H, H-6eq), 3.80-3.85 (dd, J 8.1 Hz and J 10.3 Hz, 1H, H-11), 3.87-3.91 ( dd, J 3.7 Hz and J 10.3 Hz, 1H, H-11), 4.33-4.37 (dd, J 5.0 Hz and J 12.6 Hz, 1H, H-7ax), 4.92 (bs, 1H, H-12), 5.58 (bs, 1H, H-12). ¹³C NMR (CDCl₃, 100MHz) d 38.5 (CH₂, C-1), 19.0 (CH₂, C-2), 41.7 (CH₂, C-3), 33.6 (C, C-4), 58.8 (CH, C-5), 36.1 (CH₂, C-6), 63.6 (CH, C-7), 145.0 (C, C-8), 55.1 (CH, C-9), 38.6 (C, C-10), 58.5 (CH₂, C-11), 108.0 (CH₂, C-12), 33.4 (CH₃, C-13), 21.6 (CH₃, C-14), 15.3 (CH₃, C-15) and 128 mg (71% from mixture of epimers 7) of (±)-albicanol (1); mp 68.2-68.8 ºC (hexane) (lit² mp 68-69 ºC); ¹H NMR (CDCl₃, 200 MHz) δ 0.69 (s, 3H), 0.78 (s, 3H), 0.85 (s, 3H), 1.94-2.04 (m, 2H, H-7ax, H-9), 2.38-2.45 ( ddd, J 2.4 Hz, J 4.2 Hz and J 12.9 Hz, 1H, H-7eq), 3.70-3.76 (d, J 11.0 Hz, 1H, H-11), 3.80-3.87 (dd, J 4.0 Hz and J 11.0 Hz, 1H, H-11), 4.64 (d, J 1.7 Hz, 1H, H-12), 4.94 (d, J 1.7 Hz, 1H, H-12); ¹³C NMR (CDCl₃, 50 MHz) δ 39.1 (CH₂, C-1), 19.2 (CH₂, C-2), 41.9 (CH₂, C-3), 33.5 (C, C-4), 55.2 (CH, C-5), 24.2 (CH₂, C-6), 37.9 (CH₂, C-7), 147.9 (C, C-8), 59.1 (CH, C-9), 39.0 (C, C-10), 58.8 (CH₂, C-11), 106.3 (CH₂, C-12), 33.6 (CH₃, C-13), 21.8 (CH₃, C-14), 15.3 (CH₃, C-15). HRMS (M⁺) Found : 222.19726. Calc. for C₁₅H₂₆O : 222.19863.

(±)-Albicanyl acetate(2)

(±)-Albicanol (1) was acetylated as described for (±)-drimenol to give 220 mg (83%) of (±)-2 as an oil with identical spectroscopic characteristics as previously described for natural (+)-albicanyl acetate.² HRMS (M⁺) Found: 264.20887. Calc. for C₁₇H₂₈O₂: 264.20893.

Diene(±)-(9). A solution of triflic anhydride (0.22 mL) in pyridine was added dropwise to a solution of albicanol ((±)-1) (63 mg, 0.3 mmol) in pyridine (10 mL) at 0 ºC. The mixture was stirred for 40 min at room temperature. An ice-water mixture was added and the solution was neutralized with NaHCO₃ and extracted with ethyl ether. The organic layer was dried (MgSO₄) and the solvent was removed in vacuum. The crude was purified by column chromatography to afford an oily product (38 mg, 62%) as a mixture of endo and exo dienes (1:4). Spectral data of the major isomer is in good agreement with those reported for exo-diene (9).¹⁴

(±)-Cyclozonarone(3)

Benzoquinone (27.5 mg, 0.25 mmol) was added to a solution of diene (±)-9 (1:4 mixture of endo and exo dienes) (40 mg, 0.19 mmol) in benzene (10 mL) and the mixture was refluxed under N₂ atmosphere for 28 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 21 mg of quinone 10, which was eluted after the unchanged endo-diene. Quinone 10 was dissolved in benzene (10 mL) and DDQ (15 mg, 0.062 mmol) was added. The mixture was refluxed for 4 h and after removing the solvent under reduced pressure and column chromatography, (±)-cyclozanorone (3) 18.2 mg, (46% overall yield from (±)-9) was obtained as a yellow oil, with identical spectroscopic characteristics as previously described for natural (-)-cyclozonarone.¹³ The same protocol was used for the synthesis of (+)-cyclozonarone (3) starting from natural (-)-drimenol.²⁰

(+)-Drimenyl acetate(+)-6

Acetylation of (-)-drimenol (1.5 g, 6.76 mmol) using standard condition furnished drimenyl acetate as colourless oil (1.53 g, 86%). Physical and spectroscopic characteristics were in good agreement with those previously described.²³ [α]²⁸_D + 7.69 (c 5.2, CHCl₃).

7α and 7β-chloro-albicanyl acetate(7a and 7b)

Allylic chlorination of (+)-drimenyl acetate (200 mg, 0.09 mmol) gave an inseparable mixture of 7α and 7β-chloro-albicanyl acetate (7a and 7b) (160.2 mg, 71%) as a white solid; mp 76.9-82.7 ºC; [α]²²_D – 57.8 (c 6.4, CHCl₃); IR ν_max/cm^-1 (KBr pellets): 1731, 1241, 918, 721; HRMS (M⁺) Found: 298.16808. Calc. for C₁₇H₂₇ClO₂: 298.16995.

Mixture of 7-β-chloro-albicanyl acetate(+)-7b and albicanyl acetate(+)-2

Reduction with Zn/HOAc/H₂O of 7 (mixture of epimers) (106 mg, 0.36 mmol) afforded 77 mg of a mixture of albicanyl acetate ((+)-2) and unchanged 7β-chloro-albicanyl acetate (7b), as an oil. Isolation by preparative TLC afforded 53 mg (66.3 %) of (+)-albicanyl acetate (2); [α]²²_D + 24.8º (c 4.83, CHCl₃); IR ν_max/cm^-1 (film KBr): 2928, 1740, 1235 ; and 23mg ( 28.8 % ) of unchanged 7β-chloro-albicanyl acetate ((+)-7b); [α]²²_D + 25.2º (c 1.59, CHCl₃); IR ν_max/cm^-1 (KBr pellets): 2942, 1731, 1240, 907.

(+)-Albicanol(+)-1

Saponification of the reduction mixture (250 mg) followed by column chromatography gave 170 mg of (+)-albicanol (1) as colourless needles; mp 67.5-68.3 ºC (lit² mp 68-69 ºC); [α]²²_D + 9.1º (c 2.21, CHCl₃) (lit² [α]²⁵_D + 13.0º (c 0.5, CHCl₃); HRMS (M+) Found: 222.19726. Calc. for C₁₅H₂₆O: 222.19836; IR ν_max/cm^-1 (KBr pellets): 3371, 2941, 1691, 1644, 880; and 7-β-chlorol-albicanol ((-)-8) (52 mg) as colourless needles; mp 89.7-91.6 ºC; [α]²⁸_D – 2.8º (c 3.6, CHCl₃); IR (KBr): ν_max/cm^-1 3265, 2925, 1650, 1460.

Diene (9)

Dehydration of (+)-albicanol (1) (94.1 mg, 0.42 mmol) afforded 52 mg, (60%) of diene 9 (mixture of exo and endo diene 1:4) as an oily product. Spectral data of the major isomer is in good agreement with those formerly reported by us for exo-diene (9).¹⁴

(+)-Ent-cyclozonarone

Diels Alder reaction of diene mixture (52 mg, 0.25 mmol) with p-benzoquinone (35.13 mg, 0.33 mmol) followed by oxidation of the corresponding quinone with DDQ (27.4 mg, 0.12 mmol) gave (+)-ent-cyclozonarone (35.3 mg, 45%) as oil. IR(KBr): ν_max/cm^-1 2924, 1669, 1600, 1460; ¹H-NMR and ¹³C NMR spectra identical to those of natural (-)-cyclozonarone.¹³

Acknowledgments

V. D. gratefully acknowledges Vicerrectoria Adjunta de Investigación y Doctorado, Pontificia Universidad Católica de Chile for VRAID fellowship. Authors are grateful to Dirección de Investigación y Postgrado, Facultad de Química, Pontificia Universidad Católica de Chile, for financial support, to MECESUP grant UCH 0116 de la Red Nacional de Doctorado en Química for HRMS analyses and to Dr. Luis Espinoza for valuable help with spectroscopic assignments.

Supplementary Information

Available free of charge at http://jbcs.org.br, as PDF file.

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Received: December 1, 2007

Web Release Date: August 1, 2008

Supplementary Information

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Publication Dates

• Publication in this collection
  03 Oct 2008
• Date of issue
  2008

History

• Accepted
  01 Aug 2008
• Received
  01 Dec 2007