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Application of the taraxerane–oleanane rearrangement to the synthesis of seco-oleanane triterpenoids from taraxerone

Phan Minh Gianga, Vu Minh Trangab, Phan Tong Sona & Katsuyoshi Matsunamic

a Faculty of Chemistry, VNU University of Science, Vietnam National University, Hanoi, 19 Le Thanh Tong Street, Hanoi, Viet Nam

b VNU University of Education, Vietnam National University, Hanoi, 144 Xuan Thuy Road, Hanoi, Viet Nam

c Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan Published online: 15 Sep 2014

To cite this article: Phan Minh Giang, Vu Minh Trang, Phan Tong Son & Katsuyoshi Matsunami

(2015) Application of the taraxerane–oleanane rearrangement to the synthesis of seco-oleanane triterpenoids from taraxerone, Natural Product Research: Formerly Natural Product Letters, 29:1, 64-69, DOI: 10.1080/14786419.2014.958737

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Application of the taraxerane – oleanane rearrangement to the synthesis of seco-oleanane triterpenoids from taraxerone

Phan Minh Gianga*, Vu Minh Trangab, Phan Tong Sonaand Katsuyoshi Matsunamic

a

Faculty of Chemistry, VNU University of Science, Vietnam National University, Hanoi, 19 Le Thanh Tong Street, Hanoi, Viet Nam;bVNU University of Education, Vietnam National University, Hanoi, 144 Xuan Thuy Road, Hanoi, Viet Nam;cGraduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan

(Received 19 June 2014; final version received 21 August 2014)

Synthetic oleananes and seco-oleananes form a group of promising anti-inflammatory and cancer chemopreventive agents with an excellent safety profile These compounds are usually prepared by semi-synthesis from natural oleanane triterpenoids Since a taraxer-14-ene was reported to be rearranged into an olean-12-ene under mild reaction conditions, a rapid synthesis of seco-oleananes from taraxerone, which is a readily available starting material, was explored by us Treatment of taraxerone with m-chloroperoxybenzoic acid gave 14,15-epoxy lactones, which underwent the taraxerane – oleanane rearrangement leading to new seco-oleanane triterpenoids

Keywords: taraxerone; Baeyer – Villiger oxidation; taraxerane – oleanane rearrangement; 3,4-seco-oleanane

1 Introduction

Numerous natural pentacyclic compounds arise from squalene through a variety of cyclisation modes under the catalytic action of oxidosqualene cyclases The pentacyclic triterpenoids are divided into many subgroups based on their carbon skeleton, of which lupane, oleanane and ursane are distinguished classes because of their widespread occurrence and biological, pharmacological or medicinal activities (Honda et al 2000; Laszczyk 2009) A number of publications have highlighted structure – activity relationships of oleananes, showing the importance of chemical modifications in improving potency of the natural oleananes (Sun et al

2006; Kazakova et al.2014) Several 100 synthetic oleananes and seco-oleananes have been synthesised and they are proved to be non-cytotoxic agents in the treatment of inflammatory diseases and cancer chemoprevention (Finlay et al.1997; Maitraie et al.2009; Liby & Sporn

2012) In most reports, these compounds were semi-synthesised from natural oleananes The rearrangement of 2a,14a-diepoxytaraxerane into olean-12-ene-2a,3b,15a-triol under mild reaction conditions reported by Banerji et al (1999) inspired a new synthetic approach

As taraxerone (1) is a readily available taraxerane triterpenoid and possesses a C-14/C-15 double bond, new seco-A-ring oleananes can be prepared from 1 by the Baeyer – Villiger oxidation, followed by the facile taraxerane – oleanane rearrangement described above Oxidation of the carbonyl group and epoxidation of the C-14/C-15 double bond give an epoxy lactone, which can subsequently undergo the taraxerane – oleanane rearrangement and lactone-ring opening, leading to seco-oleanane products (Scheme 1) We report herein the first synthesis of 3,4-seco-oleanane triterpenoids from taraxerone

q 2014 Taylor & Francis

*Corresponding author Email:phanminhgiang@yahoo.com

Natural Product Research, 2015

Vol 29, No 1, 64–69, http://dx.doi.org/10.1080/14786419.2014.958737

2 Results and discussion

Treatment of taraxerone (1) with m-chloroperoxybenzoic acid (MCPBA) in CH2Cl2solution at room temperature led to the epoxidation of C-14/C-15 double bond and Baeyer – Villiger oxidation of C-3 ketonic group The HR-ESI-MS of the epoxy lactone product 2 showed a peak

at m/z 479.3493 ([Mþ Na]þ), determining its molecular formula as C

30H48O3 The1H and13C NMR determined the introduction of the C-14/C-15 epoxide ring [dH3.04 (1H, br d, J¼ 6.5 Hz);

dC57.2 and 68.6] on comparison with the NMR data of 14,15-epoxyepitaraxerol (Scheme S1) The A-ring lactone was determined by the chemical shifts of two C-4 methyl groups [dH1.43 (3H, s) and 1.46 (3H, s)], C-4 (dC86.2) and the lactone carbonyl group (dC174.9) (Maitraie et al

2009; Tu et al.2009)

The lactone ring of 2 was cleaved by treatment with a catalytic amount of H2SO4in MeOH to yield product 3 An acid-catalysed transesterification of 2 with MeOH might occur first, followed

by dehydration of C-4 tertiary hydroxyl group at room temperature Independently, the skeletal taraxerane – oleanane rearrangement took place to give 3 as the final product Mechanistically, the 14,15-epoxide ring was protonated, followed by epoxide ring opening to generate a carbocation at C-14 and C-15 hydroxymethine Then 1,2-migration of C-13 methyl group to C-14, followed by the cleavage of a H-12 proton afforded 3 (Scheme 2) The structure of 3 was characterised by NMR spectroscopic data, which revealed the presence of a methyl ester [dH3.65 (3H, s);dC51.6 and 174.5] and C-4/C-23 double bond [dH 4.68 (1H, s) and 4.88 (1H, s); dC 113.6 and 147.3] Characteristic signals of the C-12/C-13 double bond of the olean-12-ene [dH 5.31 (1H, t,

J¼ 3.0 Hz);dC123.2 and 145.9] (Seo et al.1975) and a secondary hydroxymethine [dH4.22 (1H, dd, J¼ 11.5 Hz, 5.0 Hz);dC68.4] were observed in the NMR spectra of 3

On the other hand, the formation of 14,15-epoxy-3,4-seco-taraxerane (4) could be achieved

by treatment of 1 with MCPBA in a mixture of CH2Cl2and CH3OH Carbon-13 signals of B, C,

D and E rings were similarly observed for 2 and 4; however, A-ring was cleaved by transesterification reaction, resulting in the appearance of two methyl groups at C-4 [dH 1.23 (3H, s) and 1.28 (3H, s)] and a methyl ester group [dH3.66 (3H, s);dC51.7 and 175.6] in the1H and13C NMR spectra of 4 Compound 4 was then converted into its corresponding hydroxy acid

5 To prevent the possible dehydration of C-4 tertiary alcohol, 4 was hydrolysed in 5%

O O

a

1

H3CO2C

OH b

2

HO

HO2C

OH HO

H3CO2C

O

4

c

d,e

3

5

1 2

3

4 5 6 7 8 9 10

13 14

17 18

22

23 24

27

28

41.9%

99.3%

Reagents: (a) MCBPA, CH2Cl2; (b) H2SO4, MeOH; (c) MCPBA, CH2Cl2, MeOH; (d) KOH, MeOH; (e) HCl, H2O

Scheme 1 Synthesis of 3 and 5 from 1

Natural Product Research 65

methanolic KOH (Tu et al.2009) Then quick acidification of the hydrolysis product with 10% aqueous HCl caused the taraxerane – oleanane rearrangement to afford 15-hydroxyolean-12-ene (5) The NMR spectra of 5 showed signals of C-3 carboxylic acid (dC176.3), hydroxy-bearing C-4 (dC75.7), two C-4 methyl groups [dH1.25 (3H, s) and 1.29 (3H, s);dC27.5 and 33.4] (Tu

et al 2009), C-12/C-13 double bond of the newly formed olean-12-ene [dH 5.31 (1H, t,

J¼ 3.0 Hz);dC 123.6 and 145.8] and C-15 hydroxymethine [dH 4.18 (1H, dd, J¼ 11.5 Hz, 5.5 Hz);dC68.3]

Since the 14,15-epoxide rings of 2 and 4 area-oriented due to facile approach of the reagent from the more exposeda-phase (Banerji et al.1999), the ring opening led to thea-oriented C-15 secondary hydroxyl group In the NOESY spectrum of 4 (Scheme S2), a NOESY correlation was observed between H-15 (dH3.04) and H3-26 (dH1.15) As an evidence for the stereochemistry, H-15b of 3 and 5 gave a typical diaxial coupling constant (J ¼ 11.5 Hz) with axial H-16a Subsequently, methyl migration from C-13 to C-14 occurred from the samea-phase, leading to thea-orientation of C-14 methyl group

3 Experimental

3.1 General experimental procedures

All reagents were products for synthesis Taraxerone (1) was obtained by chromatographic isolation from Euphorbia hirta and Mallotus barbatus plants Optical rotations were measured

on a Jasco P-1030 digital polarimeter (Jasco, Tokyo, Japan) FT-IR spectra were recorded on a Horiba FT-710 spectrophotometer (Horiba, Kyoto, Japan) HR-EI-MS were measured on a Jeol JMS-T100GCV mass spectrometer (Jeol, Tokyo, Japan) HR-ESI-MS and HR-APCI-MS were measured on an Applied Biosystems QSTAR XL mass spectrometer (Applied Biosystems, Foster City, CA, USA).1H (500 MHz) and13C NMR (125 MHz) spectra were recorded on a Bruker Avance 500 NMR spectrometer (Bruker, Billerica, MA, USA) Silica gel (0.040 – 0.063 mm) (Merck, Darmstadt, Germany) was used for column chromatography (CC) Thin-layer chromatography (TLC) was carried out on Merck TLC silica gel 60 F254aluminium plates (Merck, Darmstadt, Germany)

3.2 Baeyer – Villiger oxidation of taraxerone (1)

A mixture of 1 (97.2 mg, 0.229 mmol) and MCPBA (119 mg, 0.69 mmol) in CH2Cl2(8 mL) was stirred at room temperature for 72 h The mixture was washed with aqueous NaHCO3 and

O

O O

2

H3CO2C

OH

H3CO2C

OH H

H3CO2C

O

H3CO2C

O

−CH 3 OH

H

CΗ 3 OH2

3

−CH 3 OH2

CH3OH

H3CO2C

OH

H

CH3OH

H

Scheme 2 Plausible synthetic pathway of 3 from 2

66 P.M Giang et al

extracted with CH2Cl2 (20 mL£ 5) The CH2Cl2 extract was concentrated under reduced pressure to give a crude product The crude product was purified by CC on silica gel using n-hexane – EtOAc 30:1, 19:1 and 9:1 to give 2 (66.6 mg, 0.146 mmol, 63.8%)

14,15-Epoxy-3,4-seco-taraxerane-3,4-lactone (2): white amorphous powder; ½a
25

D þ 58.9 (c¼ 0.14, CHCl3); IR (nmax, cm21): 1718, 1456, 1386, 1290, 1108;1H NMR (CDCl3):d0.79 (3H, s, 30-CH3), 0.86 (3H, s, 29-CH3), 1.05 (3H, s, 28-CH3), 1.08 (3H, s, 25-CH3), 1.12 (3H, s, 26-CH3), 1.18 (3H, s) (27-CH3), 1.43 (3H, s, 24-CH3), 1.46 (3H, s, 23-CH3), 3.04 (1H, br d,

J¼ 6.5 Hz, H-15);13C NMR (CDCl3):d16.9 (C-25), 17.8 (C-11), 22.5 (C-6), 23.4 (C-27), 23.6 (C-26), 24.5 (C-30), 25.8 (C-23), 30.1 (C-16), 30.9 (C-20), 31.2 (C-28), 31.9 (C-2), 32.4 (C-24), 32.9 17), 33.1 7), 33.5 29), 33.9 12), 34.5 21), 36.4 13), 37.4 1), 37.6 (C-22), 39.2 (C-19), 39.6 (C-8), 40.9 (C-10), 46.2 (C-9), 49.5 (C-18), 54.9 (C-5), 57.2 (C-15), 68.6 (C-14), 86.2 (C-4), 174.9 (C-3); Positive-ion HR-ESI-MS: m/z 479.3493 (Calcd for C30H48O3Na 479.3496)

3.3 Synthesis of methyl 15-hydroxy-3,4-seco-olean-4(23),12-dien-3-oate (3)

Compound 2 (36.4 mg, 0.08 mmol) was dissolved in MeOH (5 mL) Concentrated H2SO4(1 drop) was added and the reaction mixture was stirred at room temperature for 24 h The mixture was concentrated under reduced pressure, washed with aqueous NaHCO3solution and extracted with CH2Cl2(20 mL£ 5) The CH2Cl2extract was concentrated under reduced pressure to give

a crude product The crude product was purified by CC on silica gel using n-hexane – EtOAc 50:1, 30:1 and 9:1 to give 3 (23.3 mg, 0.05 mmol, 62.5%)

Methyl 15-hydroxy-3,4-seco-olean-4(23),12-dien-3-oate (3): white amorphous powder;

½a
24

D þ 102.7 (c ¼ 0.47, CHCl3); IR (nmax, cm21): 3444, 1734, 1636, 1465, 1384, 1299, 1176;

1

H NMR (CDCl3):d0.87 (3H, s, 28-CH3), 0.88 (6H, s, 29-CH3, 30-CH3), 0.95 (3H, s, 25-CH3), 1.09 (3H, s, 26-CH3), 1.18 (3H, s, 27-CH3), 1.75 (3H, s, 24-CH3), 2.20 (1H, m, H-2a), 2.37 (1H, ddd, J¼ 16.0 Hz, 10.0 Hz, 6.0 Hz, H-2b), 3.65 (3H, s, -OCH3), 4.22 (1H, dd, J¼ 11.5 Hz, 5.0 Hz, H-15), 4.68 (1H, s, H-23a), 4.88 (1H, s, H-23b), 5.31 (1H, t, J¼ 3.0 Hz, H-12);13C NMR (CDCl3):d17.4 26), 19.5 25), 19.8 27), 23.5 24), 23.6 30), 23.8 11), 24.7 6), 28.5 1), 28.9 28), 30.9 20), 33.1 8), 33.3 29), 34.0 7), 34.6 2), 34.7 (C-21), 36.7 (C-16), 37.7 (C-9), 37.8 (C-22), 39.3 (C-10), 40.9 (C-14), 46.3 (C-19), 47.8 (C-18), 48.1 (C-17), 50.1 (C-5), 51.6 (-OCH3), 68.4 (C-15), 113.6 (C-23), 123.2 (C-12), 145.9 (C-13), 147.3 (C-4), 174.5 (C-3); HR-EI-MS: m/z 470.37525 (Calcd for C31H50O3470.37599); Positive-ion HR-ESI-MS: m/z 493.3650 (Calcd for C31H50O3Na 493.3652); Positive-ion HR-APCI-MS: m/z 471.3824 (Calcd for C31H51O3471.3833)

3.4 Synthesis of methyl 14,15-epoxy-4-hydroxy-3,4-seco-taraxeran-3-oate (4)

A mixture of 1 (1 g, 2.358 mmol) and MCPBA (1.22 g, 7.07 mmol) in a mixture of CH2Cl2and

CH3OH (8 mL) was stirred at 08C for 40 min., then at room temperature for 72 h The mixture was washed with aqueous NaHCO3and extracted with CH2Cl2(20 mL£ 5) The CH2Cl2extract was concentrated under reduced pressure to give a crude product The crude product was purified twice by CC on silica gel using n-hexane – EtOAc 30:1, 19:1 and 9:1 and n-hexane – EtOAc 15:1 and 9:1 to give 4 (482.1 mg, 0.988 mmol, 41.9%)

Methyl 14,15-epoxy-4-hydroxy-3,4-seco-taraxeran-3-oate (4): white amorphous powder;

½a
25

D þ 28.8 (c ¼ 0.16, CHCl3); IR (nmax, cm21): 3497, 1723, 1445, 1386, 1204, 1177;1H NMR (CDCl3):d0.79 (3H, s, 30-CH3), 0.86 (3H, s, 29-CH3), 1.01 (1H, m, H-19a), 1.04 (1H, m, H-7a), 1.05 (2H, m, H-9, H-22a), 1.05 (3H, s, 28-CH3), 1.06 (3H, s, 27-CH3), 1.08 (3H, s, 25-CH3), 1.09 (2H, m, H-6a, H-12a), 1.15 (3H, s, 26-CH3), 1.18 (1H, m, 16a), 1.21 (1H, m, H-19b), 1.23 (1H,

m, H-7b), 1.23 (3H, s, 24-CH3), 1.25 (1H, m, H-12b), 1.28 (3H, s, 23-CH3), 1.37 (1H, m, H-5),

Natural Product Research 67

1.43 (1H, m, H-21a), 1.45 (1H, m, H-22b), 1.47 (1H, m, H-6b), 1.49 (1H, m, H-11a), 1.62 (1H,

m, H-2a), 1.64 (1H, m, H-11b), 1.97 (1H, m, H-18), 2.01 (1H, d, J¼ 10.5 Hz, H-16b), 2.14 (1H,

m, H-1a), 2.17 (1H, m, H-21b), 2.38 (1H, ddd, J¼ 15.5 Hz, 10.5 Hz, 4.5 Hz, H-2b), 2.53 (1H, ddd, J¼ 15.5 Hz, 10.5 Hz, 4.5 Hz, H-1b), 3.04 (1H, br d, J ¼ 6.5 Hz, H-15), 3.66 (3H, s, -OCH3);13C NMR (CDCl3):d17.2 (C-11), 20.7 (C-25), 22.1 (C-6), 23.4 (C-27), 23.7 (C-26), 24.4 (C-30), 27.4 (C-24), 28.9 (C-1), 30.1 (C-16), 30.9 (C-20), 31.3 (C-28), 32.9 (C-17), 33.2 (C-12), 33.6 (C-29), 33.9 (C-23), 34.11 (C-7), 34.14 (C-2), 34.6 (C-21), 36.5 (C-13), 37.6 (C-22), 39.2 (C-19), 39.6 (C-8), 41.8 (C-18), 42.3 (C-10), 46.1 (C-9), 51.5 (C-5), 51.7 (-OCH3), 57.2 (C-15), 68.8 (C-14), 75.8 (C-4), 175.6 (C-3); Positive-ion HR-ESI-MS: m/z 511.3752 (Calcd for C31H52O4Na 511.3758)

3.5 Synthesis of 4,15-dihydroxy-3,4-seco-olean-12-en-3-oic acid (5)

Compound 4 (50 mg, 0.102 mmol) in 5% methanolic KOH (9.5 mL) was stirred at room temperature for 72 h The reaction mixture was concentrated under reduced pressure, added with distilled water (18 mL), 10% aqueous HCl to pH 1 and extracted with CH2Cl2(20 mL£ 5) The

CH2Cl2extract was concentrated under reduced pressure to give 5 (48.2 mg, 0.102 mmol, 99.3%) 4,15-Dihydroxy-3,4-seco-olean-12-en-3-oic acid (5): white amorphous powder;

½a
25

D þ 30.7 (c ¼ 0.12, CHCl3); IR (nmax, cm21): 3482, 3219, 1698, 1457, 1383, 1276, 1224,

1201, 1180;1H NMR (CDCl3þ CD3OD):d 0.87 (3H, s, 28-CH3), 0.88 (6H, s, 29-CH3,

30-CH3), 1.07 (3H, s, 25-CH3), 1.12 (3H, s, 26-CH3), 1.16 (3H, s, 27-CH3), 1.25 (3H, s, 24-CH3), 1.29 (3H, s, 23-CH3), 2.31 (1H, m, H-2a), 2.48 (1H, m, H-2b), 4.18 (1H, dd, J¼ 11.5 Hz, 5.5 Hz, H-15), 5.31 (1H, t, J¼ 3.0 Hz, H-12);13

C NMR (CDCl3þ CD3OD):d17.5 (C-26), 19.7 (C-27), 19.9 25), 22.8 6), 23.4 11), 23.7 30), 27.5 24), 28.9 28), 29.1 1), 31.1 (C-20), 33.1 (C-8), 33.3 (C-29), 33.4 (C-23), 34.4 (C-2), 34.7 (C-21), 35.3 (C-7), 36.8 (C-16), 37.6 (C-22), 39.0 (C-9), 41.0 (C-14), 41.3 (C-10), 46.4 (C-19), 47.8 (C-18), 48.2 (C-17), 51.4 (C-5), 68.3 (C-15), 75.7 (C-4), 123.6 (C-12), 145.8 (C-13), 176.3 (C-3); Positive-ion HR-ESI-MS: m/z 497.3597 (Calcd for C30H50O4Na 497.3601)

4 Conclusion

In addition to the traditional synthetic methodology of oleananes, a new approach to oleananes from taraxeranes can be explored By applying the facile taraxerane – oleanane rearrangement, taraxerone was successfully converted into new seco-oleanane triterpenoids The application of this method to expand the existing library of synthetic oleananes is the subject of ongoing investigations

Supplementary material

Synthesis of 14,15-epoxytaraxerol, Schemes S1 and S2 and spectra of compounds 3 – 5 relating

to this article are available online

Funding

This research was funded by Vietnam National Foundation for Science and Technology Development (NAFOSTED) [grant number 104.01-2012.10]

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