The First Total Synthesis of Phebaclavin A and C

Chinese Journal of Chemistry, 2005, 23, 1453—1456 Full Paper

* E-mail: [email protected] Received November 25, 2004; revised March 16, 2005; accepted June 7, 2005. Project supported by the National Natural Science Foundation of China (No. 20472025) and QT Program (No. 20021001).

© 2005 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

The First Total Synthesis of Phebaclavin A and C

ZHANG, Yu(张宇) LIU, Dong(刘冬) LI, Yang(李洋) CAO, Xiao-Ping*(曹小平)

State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China

Phebaclavin A (1) and C (2) were synthesized in 60% and 58% total yields over 5 steps from commercially available starting meterials respectively. The synthesis feature was usage of the Wittig reaction twice and sol-vent-free cyclizing reaction as the key steps.

Keywords phebaclavin A, phebaclavin C, solvent-free cyclizing reaction, Wittig reaction

Introduction

3-Prenylated coumarins are a unique class of natu-rally occurring coumarins, characterized by the presence of a prenylated side chain in the coumarin skeleton. It was reported that they have been widely used in the fields of biology, medicine and polymer science.1 In continuation of our systematic research on this class of coumarins, we now attempt to synthesize a series of new phebaclavin A—H family, which were recently isolated from the aerial parts of phebalium clavatum by Muyard et al.,2 with a view to evaluated their biological properties. Moreover, because of Muyard proposing the biosynthetic homogeneity of all the phebaclavins, the prenyl side chains at C(3) of phebaclavin D—H can be considered as arising from bio- or chemical oxidation of that present at the same position in phebaclavin A and C. In the literature, there are only a few general strategies for the construction of the 3-substituted coumarin and its derivative. Kapil utilized 7-prenyloxycoumarins by abnormal Claisen rearrangement to obtain 3-alkenyl-coumarins.3 Larock reported the reaction of o-iodophenol and internal alkynes in the presence of 0.1 MPa of CO and palladium catalyst to produce 3,4-disubstituted coumarins.4 Mali and co-workers pre-pared a series of 3-allylcouma- rins realized by Wittig reaction and photochemical cyclisation.5 Because the Wittig reaction is the more convenient and efficient ap-proach than other methods, we chose it for the construc-tion of skeleton of the coumarins. Herein we presented the first total syntheses of two new coumarins, pheba-clavin A (1) and phebaclavin C (2).

Results and discussion

As shown in Scheme 1, 2,3-dihydroxy-4-methoxy- benzaldehyde (3) and 2,4-dihydroxybenzaldehyde (4) were chosen as the starting materials. Treatment of 3

with t-butyldimethylsiyl chloride (TBDMSCl) in the presence of imidazole in anhydrous CH2Cl2 gave the monosilylated product aldehyde 5a in 93% yield. This aldehyde was treated with Ph3P＝C(CH2CH＝CH2)- CO2Me,6 followed by solvent-free cyclizing reaction7 of the resulting ester to afford the 3-allylcoumarin (6a) in over 88% yield. With ample amounts of the key inter- mediate 6a in hand, oxidative cleavage of 6a was first tried by the osmium tetraoxide catalyzed periodate,8 but the yield was undesirable. Therefore ozonolysis followed by reduction with dimethyl sulfide of 6a provided aldehyde 7a9 in 85% yield. Then Wittig reaction of 7a with Ph3P＝C(Me)CO2Me in dry benzene gave the ester 8a as a single product. 1H NMR spectrum of 8a showed the signal due to the olefinic proton (H-2') at δ 6.89. This fact agreed with the E-configuration for 8a.10 Compound 8a was treated with tetrabutylammonium fluoride (TBAF) in THF to provide the phebaclavin A (1) as the sole product with the yield of 94%. On the other hand, The aldehyde 4 was protected selectively with methoxymethyl group (MOM) by treatment of it with chloromethyl methyl ether (MOMCl) to form 5b11 in the yield of 86%. In our experiment, however, protection of 3 with MOM was in poor selectivity. It is because the phenolic hydroxyl groups of C(2) and C(3) in 3 have similar reaction activity. Compound 5b underwent the similar reaction sequence as the description above to generate the E-configuration 8b (the olefinic proton at δ 6.89) in total yield of 72%. Finally, compound 8b was refluxed in the presence of conc. HCl (cat.) in MeOH to provide the desirable phebaclavin C (2) in good yield (93%). The spectral data (1H NMR, 13C NMR, MS and HRMS) measured on our synthetic sample were in very good agreement with the reported data.2 Especially comparing the 13C NMR data of target molecules 1 and 2 with those of natural product pheba clavin A and C, it was observed that there are only 16 resonance singals

1454 Chin. J. Chem., 2005, Vol. 23, No. 10 ZHANG et al.


Scheme 1 Synthesis of phebaclavin A and C

Reagents and conditions: (a) TBDMSCl, CH2Cl2, imidazole, 93%; (b) Ph3P＝C(CH2CH＝CH2)CO2Me, benzene, then N2, 180 °C, 88% for 6a

and 90% for 6b; (c) O3, CH2Cl2/MeOH＝3∶2 (V∶V), –78 °C, then Me2S, 85% for 7a and 86% for 7b; (d) Ph3P＝C(Me)CO2Me, benzene, 91%

for 8a and 93% for 8b; (e) TBAF, THF, 94%; (f) MOMCl (0.8 eq.), K2CO3, acetone, 86%; (g) conc. HCl (cat.), MeOH, 93%

in 1 and 15 resonance singals in 2 with the biggest error of chemical shift less than 0.18. These facts confirmed the E-configuration of target molecules, and also indi-cated the good stereoselectivity of this synthetic route.

Conclusion

In summary, the total synthesis of phebaclavin A and phebaclavin C was reported for the first time. The syn-thetic transformation utilized readily available aldehyde as starting materials. The yields were satisfactory, the synthesis routes were facile and could be extended to prepare other members of phebaclavin family. To the best of our knowledge, the Wittig reaction was the fast-est and most efficient approach to prepare 3-prenylated coumarins. The synthesis of all phebaclavin A—H and the investigation of their biological activity are in pro-gress.

Experimental

General procedures and materials

IR spectra were recorded on a Nicolet NEXUS 670 FTIR spectrometer, the 1H NMR and 13C NMR data were on a Mercury Plus 300 MHz spectrometer, and mass spectra were recorded on a ZAB-HS spectrometer. HRMS data were obtained on an APEXII47e spectrometer. Flash column chromatography was generally

performed on silica gel (200—300 mesh) eluting with petroleum ether/ethyl acetate and TLC inspections on silica gel GF254 plates with petroleum ether/ethyl acetate, if not noted especially below.

4-Methoxy-3-(tert-butyldimethylsilanyloxy)-2-hydroxybenzaldehyde (5a): A solution of 3 (1.03 g, 6.15 mmol) in dry CH2Cl2 (30 mL) was added to a solution of imidazole (0.50 g, 7.35 mmol) and TBDMSCl (0.93 g, 6.15 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 2 d, and evaporation of the sol-vent gave a white solid, which was further purified by silica gel column chromatography (petroleum ether∶ethyl acetate, 4∶1, V∶V) to afford 5a (1.61 g, 93%). m.p. 115 ℃; 1H NMR (CDCl3, 300 MHz) δ: 0.18 (s, 6H), 1.02 (s, 9H), 3.88 (s, 3H, OCH3), 6.55 (d, J＝8.7 Hz, 1H, H-5), 7.14 (d, J＝8.7 Hz, 1H, H-6), 9.72 (s, 1H, CHO), 11.05 (s, 1H, OH); 13C NMR (CDCl3, 75 MHz) δ: －4.6, 18.7, 25.7, 55.7, 103.6, 116.4, 127.7, 154.0, 157.7, 195.0. HRMS (ESI) calcd for C14H23O4Si ([M＋

H]＋) 283.1360, found 283.1352. 4-Methoxymethoxy-2-hydroxybenzaldehyde (5b):

A solution of 4 (0.28 g, 2 mmol) in dry acetone (30 mL) was added to a suspension of K2CO3 (0.33 g, 2.4 mmol) and MOMCl (0.16 g, 2 mmol) in dry acetone (15 mL). The mixture was stirred at room temperature for 4 h, filtered, and evaporation of the solvent gave a white solid, which was further purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100∶1,

Phebaclavin A and C Chin. J. Chem., 2005 Vol. 23 No. 10 1455


V∶V) to produce 5b11 (0.31 g, 86%). m.p. 49 ℃; 1H NMR (CDCl3, 300 MHz) δ: 3.48 (s, 3H, OCH3), 5.22 (s, 2H, OCH2O), 6.60 (d, J＝2.4 Hz, 1H, H-3), 6.66 (dd, J=8.4, 2.4 Hz, 1H, H-5), 7.45 (d, J＝8.4 Hz, 1H, H-6), 9.73 (s, 1H, CHO), 11.37 (s, 1H, OH); 13C NMR (CDCl3, 75 MHz) δ: 56.4, 94.0, 103.3, 109.0, 115.9, 135.3, 164.0, 164.3, 194.6; MS (EI) m/z (%): 182 (M＋, 16), 151 (3.8), 123 (1.6).

General proceduce for the preparation of 3-allyl- coumarins (6a, 6b): A solution of o-hydroxybenzaldehyde derivative 5a or 5b (1 mmol) and Ph3P ＝

C(CH2CH＝CH2)CO2Me (1.2 mmol) in benzene (20 mL) was stirred at room temperature for 8 h. Evapora-tion of the solvent gave the crude product, which was further purified by silica gel column chromatography to yield the esters. Then these esters were heated at 180 ℃

under nitrogen for 3 h. The residue was further purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100∶1 and 4∶1, V∶V) to provide 6a or 6b.

Compound 6a: 0.30 g, 88% yield, yellow colour oil; 1H NMR (CDCl3, 300 MHz) δ: 0.22 (s, 6H), 1.07 (s, 9H), 3.28 (d, J＝6.9 Hz, 2H, 2×H-1'), 3.87 (s, 3H, OCH3), 5.20—5.23 (m, 2H, 2×H-3'), 5.92—6.01 (m, 1H, H-2'), 6.80 (d, J＝8.7 Hz, 1H, H-6), 6.98 (d, J＝8.7 Hz, 1H, H-5), 7.39 (s, 1H, H-4); 13C NMR (CDCl3, 75 MHz) δ: －4.5, 18.7, 25.7, 34.5, 55.9, 108.0, 114.2, 117.8, 119.3, 124.6, 132.2, 134.3, 139.1, 145.5, 153.1, 161.3. HRMS (ESI) calcd for C19H27O4Si ([M＋H]＋) 347.1673, found 347.1670.

Compound 6b: 0.22 g, 90% yield, yellow colour oil; 1H NMR (CDCl3, 300 MHz) δ: 3.29 (d, J＝6.9 Hz, 2H, 2×H-1'), 3.49 (s, 3H, OCH3), 5.18—5.24 (m, 2H, 2×H-3'), 5.23 (s, 2H, OCH2O), 5.90—6.02 (m, 1H, H-2'), 6.95 (dd, J＝8.7, 2.2 Hz, 1H, H-6), 7.00 (d, J＝2.2 Hz, 1H, H-8), 7.39 (d, J＝8.7 Hz, 1H, H-5), 7.45 (s, 1H, H-4); 13C NMR (CDCl3, 75 MHz) δ: 34.3, 56.2, 94.4, 103.4, 113.3, 113.9, 117.9, 124.9, 128.1, 134.0, 138.9, 154.4, 159.4, 161.7. HRMS (ESI) calcd for C14H15O4 ([M+H]+) 247.0965, found 247.0973.

General proceduce for the preparation of 2'-oxoethylcoumarins (7a, 7b): Ozone-containing oxygen from an ozone generator was bubbled through a stirred solution of 6a or 6b (1 mmol) in CH2Cl2 (18 mL) and MeOH (12 mL) at －78 ℃ until reaction was completed, then methyl sulfide (1 mL) was added to the reaction mixture. The resulting mixture was allowed to warm gradually to room temperature and stirred for 24 h. The residue was further purified by silica gel column chromatography (petroleum ether/ethyl acetate, 8∶1 and 6∶1, V∶V) to yield 7a or 7b.

Compound 7a: 0.29 g, 85% yield, yellow colour semi-solid; 1H NMR (CDCl3, 300 MHz) δ: 0.22 (s, 6H), 1.07 (s, 9H), 3.63 (s, 2H, 2×H-1'), 3.91 (s, 3H, OCH3), 6.84 (d, J＝8.7 Hz, 1H, H-6), 7.02 (d, J＝8.7 Hz, 1H, H-5), 7.54 (s, 1H, H-4), 9.82 (s, 1H, CHO); 13C NMR (CDCl3, 75 MHz) δ: －4.5, 18.7, 25.7, 44.7, 55.9, 108.3, 113.8, 117.5, 119.8, 142.7, 153.8, 161.3, 197.8. HRMS

(ESI) calcd for C18H25O5Si ([M＋H]＋) 349.1466, found 349.1475.

Compound 7b: 0.21 g, 86% yield, yellow colour semi-solid; 1H NMR (CDCl3, 300 MHz) δ: 3.49 (s, 3H, OCH3), 3.66 (s, 2H, 2×H-1'), 5.23 (s, 2H, OCH2O), 6.97 (d, J＝8.4 Hz, 1H, H-6), 7.02 (s, 1H, H-8), 7.38 (d, J＝8.4 Hz, 1H, H-5), 7.59 (s, 1H, H-4), 9.82 (s, 1H, CHO); 13C NMR (CDCl3, 75 MHz) δ: 44.7, 56.3, 94.3, 103.5, 113.7, 117.9, 128.5, 142.3, 154.9, 160.1, 161.7, 197.6. HRMS (ESI) calcd for C13H13O5 ([M+H]+) 249.0757, found 249.0761.

General proceduce for the preparation of esters (8a, 8b): A solution of 2'-oxoethylcoumarin 7a or 7b (1 mmol) and Ph3P＝C(Me)CO2Me (1.2 mmol) in benzene (20 mL) was stirred at room temperature for 8 h. Evaporation of the solvent gave a yellow color oil, which was further purified by silica gel column chro-matography (petroleum ether/ethyl acetate, 8∶1 and 7∶1, V∶V) to produce 8a or 8b.

Compound 8a: 0.38 g, 91% yield; 1H NMR (CDCl3, 300 MHz) δ: 0.22 (s, 6H), 1.07 (s, 9H), 1.95 (s, 3H, 3'-CH3), 3.42 (d, J＝7.5 Hz, 2H, 2×H-1'), 3.76 (s, 3H, CO2CH3), 3.88 (s, 3H, OCH3), 6.82 (d, J＝9.0 Hz, 1H, H-6), 6.89 (t, J＝7.5 Hz, 1H, H-2'), 6.99 (d, J＝9.0 Hz, 1H, H-5), 7.37 (s, 1H, H-4); 13C NMR (CDCl3, 75 MHz) δ: －4.5, 12.5, 18.7, 25.7, 29.4, 51.9, 55.8, 108.1, 114.0, 119.4, 123.0, 130.2, 132.2, 137.1, 139.3, 145.5, 153.3, 161.2, 168.3. HRMS (ESI) calcd for C22H31O6Si ([M＋ H]＋) 419.1884, found 419.1870.

Compound 8b: 0.29 g, 93% yield; 1H NMR (CDCl3, 300 MHz) δ: 1.95 (s, 3H, 3'-CH3), 3.42 (d, J＝7.5 Hz, 2H, 2 × H-1'), 3.49 (s, 3H, OCH3), 3.77 (s, 3H, CO2CH3), 5.23 (s, 2H, OCH2O), 6.89 (t, J＝7.5 Hz, 1H, H-2'), 6.95 (dd, J＝8.1, 2.2 Hz, 1H, H-6), 7.00 (d, J＝2.2 Hz, 1H, H-8), 7.35 (d, J＝8.1 Hz, 1H, H-5), 7.42 (s, 1H, H-4); 13C NMR (CDCl3, 75 MHz) δ: 12.5, 29.3, 51.9, 56.2, 94.4, 103.5, 113.5, 113.8, 123.5, 128.2, 130.4, 136.9, 139.0, 154.5, 159.6, 161.6, 168.2. HRMS (ESI) calcd for C17H22NO6 ([M＋NH4]

＋) 336.1442, found 336.1445.

Phebaclavin A (1): To a solution of 8a (16 mg, 0.04 mmol) in dry THF was added TBAF (13 mg, 0.04 mmol). The mixture was stirred at room temperature for 2 h then diluted with CH2Cl2 (30 mL), washed with HCl (1 mol•L－1, 45 mL) and brine (45 mL), dried (MgSO4), filtered and concentrated in vacuum. The residue was further purified by silica gel column chromatography (petroleum ether∶ethyl acetate, 1∶1, V∶V) to afford 1 (11 mg, 94%) as an amorphous solid. 1H NMR (CDCl3, 300 MHz) δ: 1.95 (s, 3H, 3'-CH3), 3.43 (d, J＝7.5 Hz, 2H, 2×H-1'), 3.77 (s, 3H, CO2CH3), 3.98 (s, 3H, OCH3), 6.85 (d, J＝8.7 Hz, 1H, H-6), 6.89 (t, J＝7.5 Hz, 1H, H-2'), 6.98 (d, J＝8.7 Hz, 1H, H-5), 7.40 (s, 1H, H-4); 13C NMR (CDCl3, 75 MHz) δ: 12.6, 29.4, 51.9, 56.5, 107.8, 113.9, 118.2, 123.4, 130.5, 132.6, 136.8, 139.4, 141.2, 148.9, 161.0, 168.3. MS (FAB) m/z: 305.1 ([M＋H]＋).

Phebaclavin C (2): To a solution of 8b (50 mg, 0.16

1456 Chin. J. Chem., 2005, Vol. 23, No. 10 ZHANG et al.


mmol) in MeOH (20 mL) was added five drops of conc. HCl. The mixture was stirred at room temperature for 2 h and diluted with EtOAc (100 mL). The organic layer was washed with saturated NaHCO3 solution (100 mL) and water (50 mL), dried (MgSO4), filtered and concentrated in vacuum. The residue was further purified by silica gel column chromatography (petroleum ether∶ethyl acetate, 2∶1, V∶V) to afford 2 (41 mg, 93%) as an amorphous solid. 1H NMR (CDCl3, 300 MHz) δ: 1.96 (s, 3H, 3'-CH3), 3.42 (d, J＝7.5 Hz, 2H, 2×H-1'), 3.79 (s, 3H, CO2CH3), 6.82 (dd, J＝8.4, 2.4 Hz, 1H, H-6), 6.87 (t, J＝7.5 Hz, 1H, H-2'), 6.94 (d, J＝2.4 Hz, 1H, H-8), 7.30 (d, J＝8.4 Hz, 1H, H-5), 7.43 (s, 1H, H-4); 13C NMR (CDCl3, 75 MHz) δ: 12.6, 29.3, 52.1, 102.9, 112.8, 113.5, 122.3, 128.7, 130.3, 137.3, 139.8, 154.7, 159.3, 162.5, 168.6. MS (EI) m/z (%): 274 (M+, 1.7), 242 (9.5), 222 (9.9), 215 (7.5), 214 (22).

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(E0411252 ZHAO, C. H.)

Documents

The First Total Synthesis of Phebaclavin A and C