Total Syn the sis of Kaempferol and Meth yl ated Kaempferol De riv a tives

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1 Jour nal of the Chi nese Chem i cal So ci ety, 2001, 48, Total Syn the sis of Kaempferol and Meth yl ated Kaempferol De riv a tives Yean-Jang Lee* ( ) and Tsao-Dong Wu ( ) De part ment of Chem is try, Na tional Changhua Uni ver sity of Ed u ca tion, Changhua, Tai wan Kaempferol (1), a nat u ral prod uct from var i ous plants, was syn the sized in which the lon gest lin ear se - quence is only seven steps in over all yields of 47% from com mer cially avail able 1,3,5-trimethoxybenzene (10). The meth yl ated kaempferols 2-5 were also pre pared by use of this con cise syn thetic meth od ol ogy. The key trans for ma tions in this syn the sis in volved the I 2 ox i da tive-promoting-cyclization and DD ox i da tive hydroxylation. Sev eral strat e gies to achieve 1 are pro vided. INTRDUCTIN The flavone nu cleus is part of a large num ber of nat u ral prod ucts and me dic i nal com pounds. 1 Kaempferol (1) 2 and other flavonoids are known as po ten tial antitumor agents and hu man im mu no de fi ciency vi rus (HIV) type 1 integrase in hib - i tors. 3 Kaempferol and its 3--glycoside de riv a tives have been iden ti fied in var i ous plants, veg e ta bles, fruits, and bev - er ages such as Tai wan Bau hinia, 4 Phyllanthus virgatus, 5 Chamaecyparis formosensis, 6 Inula bri tan nica, 7 French beans, 8 on ions, 9 as par a gus, 10 blue ber ries, 11 red rasp berry juice, 12 grape fruit juice, 13 teas, 14 and honey. 15 Pos sessing tyrosinase in hib i tory ac tiv ity, 16 kaempferol was ob served to in hibit the ox i da tion of L-3,4-dihydroxyphenylalanine cat a - lyzed by mush room tyrosinase with an ID50 of 67 g/ml (0.23 mm). In ad di tion, kaempferol was as sayed in mouse skin carcinogensis to show an antitumor-promoting ef fect 17 and the in hib i tory ac tiv ity of HIV pro te ase. 18 ur pre vi ous in ves ti ga tion in di cated that the flavonoid an a logues are ther - a peu ti cally use ful in anal ogy to the struc tural fea tures of CAPE. 19 We ex tend this as sump tion that kaempferol or other flavonoids per form in hib i tory ac tiv ity against HIV-1 inte - grase and tu mors. n the other hand, meth yl ated kaemperols 2-5 were iso lated from Alpinia, 20 Zingiber, 21 and Amomum Koenigii. 22 Amomum K., a mem ber of the Zingiberaceae, and many spe cies of this fam ily in clud ing gin ger, tur meric, and car da mom have been used as tra di tional Chi nese, Jap a nese and In dian med i cines. 23 Due to the me dic i nal im per a tives, the scar city of kaempferol and the clear need for a re li able sup - ply, we are stim u lated to syn the size these flavonoids. There are semisynthetic stud ies in the lit er a ture. 24,25 The re ported re sults 26 and our pre lim i nary study show that the fla vones can be syn the sized from o-hydroxy-ketones or chalcones us ing the Allan-Robinson 27 or Algar-Flym-yamada 28 re ac tion, but in poor yields. Herein we re port the syn the ses of kaempferol (1) and meth yl ated kaempferols 2-5. High lights of the syn - the sis in clude cross aldol con den sa tion, I2 ox i da tive pro mot - ing-cyclization re ac tion, and C-3 hydroxylation of flavone with dimethyldioxirane (DD). 29 R 4 kaempferol 1 R 3 RESULTS AND DISCUSSIN R 1 R 2 R 1 =R 2 =R 3 =R 4 =H R 1 =R 2 =R 3 =R 4 =Me R 1 =H,R 2 =R 3 =R 4 =Me R 3 =H,R 1 =R 2 =R 4 =Me R 1 =R 3 =H,R 2 =R 4 =Me Dis con nec tion of the tar get mol e cule 1 re sulted in two com mer cially avail able start ing ma te ri als (Scheme I). Two ap proaches will be pur sued to de ter mine which strat egy is vi - a ble. The first ap proach in volves the cross-aldol con den sa - tion re ac tion of ketone 6 and al de hyde 7 un der ba sic con di - tions, fol lowed by C-3 hydroxylation of flavone to af ford the de sired 1. The sec ond ap proach em ploys the Friedel-Crafts re ac tion of cinnamic acid 9 and phloroglucinol 8 cat a lyzed by Lewis acid to pro vide the pre cur sor flavone, fol lowed by C-3 hydroxylation of flavone to achieve 1. The ini tial pro posal was to use ke tones 6 and al de hydes 7 via cross aldol re ac tion for kaempferol syn the sis. The cross-aldol re ac tion showed only the start ing ketone 6 and the side prod ucts could be de - tected/iso lated from this re ac tion mix ture un der sev eral ba sic con di tions (K, Na, NaHC3, Na2C3, pyridine, and pyrrolidine). To over come these tech ni cal dif fi cul ties, we switched to us ing the Friedel-Crafts re ac tion. Starting with the com mer cially avail able 4-hydroxy -

2 202 J. Chin. Chem. Soc., Vol. 48, No. 2, 2001 Lee and Wu H Scheme I Retrosynthetic anal y sis of kaempferol (1) 1 H H 8 b Friedel-Crafts 9 a Aldol cinnamic acid (9) and thionyl chlo ride, the ex pected acyl chlo ride was ob tained. The fol low ing acylation of phloro - glucinol cat a lyzed by Lewis acid did n t pro vide tetra - hydroxy-chalcone. With the aim of de vel op ing a suc cess ful route to 1, the hydroxyl groups were first pro tected as a methoxy group to pro vide the more lipophilic sub stances. We then sought to em ploy the Friedel-Crafts re ac tion of tri - methoxy benzene 10 and 4-methoxycinnamic acid chlo ride 11 with AlBr3 as a cat a lyst to yield o-hydroxy-chalcone 12 in 35% yield (Scheme II). To op ti mize this re ac tion, we ap plied cross-aldol re ac tion of 13 and 14 to pro vide pen ta methyl - chalcone 15, fol lowed by ortho-demethylation of aceto - phenone cat a lyzed with AlCl 3 to af ford o-hydroxylchalcone 12 in high yield (two steps 87%). Com pound 13 was ob tained via ZnCl2-cat a lyzed acylation of 10 with acetyl chlo ride in ex cel lent yield (98%). Cyclization with I2/pyridine af forded the flavone 16 in good yield (74%). It is worth not ing that we failed to ob tain the cyclization prod uct by use of H 2 2 or H C 6 7 PhSSPh con di tions. 30 How ever, we could achieve the flavanone in very low yield (12%) by treat ment of K 2 C 3. The ad van tage of I2 ox i da tive cyclization is that the re ac tion can be ac com plished in a rel a tively high yield and af ford only the de sired prod uct 16 in an one-pot re ac tion. At this point, the fi nal step of the syn the sis was fo cused on the ox i da tive re ac tion of the C-3 flavone. How ever, this proved im pos si ble to ef fect lithiolation with LDA or LHMDS 31 (Scheme II). An al ter na tive method for C-3 hy - drox ylation was also ex am ined. x i da tive-hydroxylation of dimethyldioxirane (DD) has been re ported on sev eral fla - vones. 29 In the case of 16 we failed to pro vide C-3 hydroxyflavone since the free hydroxyl group of flavone also af fected the ox i da tive-hydroxylation with DD. The methylation of 16 with Me 2 S 4 to give the meth yl ated flavone 17, fol lowed by C-3 hydroxylation with DD gen er ated the ex pected flavonol 3 in 95% yield (Scheme III). The C-3 hydroxyflavone 3 un der went demethylation smoothly with BBr 3 to ac com plish the de sired prod uct 1 in ex cel lent yield (91%). n the other hand, it could be eas ily ma nip u lated from the com mer cially avail able flavanone 18. The ox i da tion of 18 with I2/pyridine was em ployed to ob tain flavone 19 in ex cel - lent yield (93%). The methylation of 19 with Me 2 S 4 to pro - vide the meth yl ated flavone 17 in very good yield (84%), which could be con verted to af ford 1 as well. The meth yl ated kaempferol de riv a tives 2-5 were also ac com plished un evenly (Scheme IV). The flavonol 3 was treated with Me2S4 to give 2 in ex cel lent yield (98%), and fol lowed by demethylation of 2 with 1 eq. BBr3 to reach 4 in 97% yield. Finally, com pound 4 was readily trans formed to 5 via demethylation with 1 eq. BBr 3 in ex cel lent yield (95%). Melting points and 1 H and 13 C NMR spec tra of the syn thetic prod ucts 1-5 are in agree ment Scheme II Me Me Me Me ZnCl 2 Cl 98% Me Me Me Me AlCl 3 I 2 91% 12 pyridine 74% Cl CH K Me 96% AlBr 3 PhN 2 35% 16 Me Me Me Me 12 Me Me Me 15 Me

3 To tal Syn the sis of Kaempferol J. Chin. Chem. Soc., Vol. 48, No. 2, H 3 Scheme III 16 Me 2 S 4 BBr 3 91% Me with those re ported for nat u rally de rived ma te ri als. 22,32 In con clu sion, we have de vel oped an ef fec tive strat egy to syn the size kaempferol (1) and its de riv a tives 2-5. The tac - tics in volv ing the Friedel-Crafts, cross-aldol con den sa tion, I 2 ox i da tive pro mot ing-cyclization, and DD ox i da tive re ac - tion pro vide an easy ac cess to syn the size other flavonoids as well. Fur ther bi o log i cal as says to eval u ate the ef fi cacy of these com pounds 1-5 as agents against tu mors are cur rently underway. EX PER I MEN TAL SEC TIN DD 94% Me 95% Scheme IV 18 Me 2S 4 acetone 98% 2 1 I 2/pyridine reflux 93% 17 H 1 eq. BBr 3 97% Me Me 2 S 4 84% Melting points were de ter mined on a Mel Temp II melt - ing point ap pa ra tus and are un cor rected. 1 H NMR and 13 C NMR spec tra were ob tained us ing a Bruker AC-200 spec - trom e ter. Chem i cal shifts are re ported in parts per mil lion (, ppm) us ing CHCl3 ( H 7.26) as an in ter nal stan dard. Sol vents were freshly dis tilled prior to use from phos pho rus pentoxide or CaH2. THF was dis tilled from so dium di phen yl ketyl. All re ac tions were car ried out un der ni tro gen at mo sphere un less oth er wise stated. Sil ica gel (sil ica gel 60, mesh, Merck) was used for chro ma tog ra phy. r ganic ex tracts were dried over an hy drous MgS 4. 2-Hydroxy-4,6,4 -trimethoxychalcone (12) Method (A): To a mix ture of phloroglucinol 10 (1.0 g, 5.9 mmol) and freshly pre pared acid chlo ride 11 (1.3 g, eq. BBr 3 95% mmol) in nitrobenzene (25 ml) was added AlBr 3 (1 M 7.1 ml, 7.1 mmol) so lu tion dropwise at room tem per a ture. The sus pen sion was stirred un der a ni tro gen at mo sphere for 24 h. The re sult ing so lu tion was quenched by add ing 1 N H2S4 (3 ml), and fol lowed by ex trac tion with ether. The sol vent was re moved in vacuo to give a solid mix ture which was sub - jected to col umn chro ma tog ra phy (Si 2, Ether:CH 2 Cl 2 1:1) to ob tain 12 (1.8 g, 35%) as solid: mp o C (lit. 33 mp o C); 1 H NMR (200 MHz, (CD3)2C) 4.04 and 4.13 (s, 9H), 6.23 (s, 2H), 7.14 and 7.82 (d, J = 8.7 Hz, 4H), 7.90 and 8.05 (d, J = 15.6 Hz, 2H); 13 C NMR (50 MHz, (CD3)2C): 56.1, 56.4, 56.8, 92.1, 95.0, 107.1, 115.6, 126.1, 129.3, 131.4, 143.6, 162.9, 164.0, 167.6, 169.5, Method (B): A so lu tion of 15 (2.5 g, 7.6 mmol) and an - hy drous AlCl 3 (1.1 g, 8.4 mmol) was stirred at room tem per a - ture un der a ni tro gen at mo sphere for 10 h. To this so lu tion was added 1 N H2S4 (2 ml), and the re sult ing mix ture was sub se quently ex tracted with ether. Evap o ra tion of the or ganic layer in vacuo gave a light brown solid which was sub jected to col umn chro ma tog ra phy (Si 2, Ether:pe tro leum ether 1:1) to give 12 (2.2 g, 91%). 2,4,6,4 -Tetramethoxychalcone (15) A mix ture of 2,4,6-trimethoxyacetophenone (2.0 g, 9.5 mmol) and 4-methoxybenzaldehyde (1.3 g, 9.5 mmol) in eth - a nol (50 ml) was stirred at room tem per a ture for 0.5 h. A so - lu tion of 50% K (38 ml, 330 mmol) was added dropwise, and then stirred at room tem per a ture for 6 h. A so lu tion of 4 N HCl was added and the re sult ing mix ture ex tracted with CH2Cl2. The or ganic layer was con cen trated and the res i due was sub jected to col umn chro ma tog ra phy (Si 2, EA:CH 2 Cl 2 1:3) to give 15 (3.0 g, 96%) as a yel low solid: mp o C (lit. 33 mp o C); 1 H NMR (200 MHz, (CD 3 ) 2 C) 3.90, 3.99 and 4.02 (s, 12H), 6.46 (s, 2H), 6.97 and 7.41 (d, J = 16 Hz, 2H), 7.12 and 7.73 (d, J = 8.9 Hz, 4H); 13 C NMR (50 MHz, (CD 3 ) 2 C) 56.1, 56.2, 56.5, 92.0, 113.2, 115.6, 128.4, 128.8, 131.2, 144.5, 159.8, 162.8, 163.5, Hydroxy-7-methoxy-2-(4-methoxyphenyl)chromen-4- one (16) A mix ture of 12 (2.00 g, 6.4 mmol) and I 2 (1 eq. 6.5 mmol) in pyridine (10 ml) were refluxed for 8 h. Af ter cool - ing, the solid was fil tered and the fil trate was sub jected to col - umn chro ma tog ra phy (Si2, Ether:CH2Cl2 1:1) to pro vide the de sired prod uct 16 (1.5 g, 74%) as a white solid: mp o C (lit. 34 mp 165 o C);. 1 H NMR (200 MHz, (CD 3 ) 2 C) 4.06 and 4.07 (s, 6H), 6.47 and 6.83 (d, J = 2.2 Hz, 2H), 6.85 (s, 1H), 7.27 and 8.18 (d, J = 9.0 Hz, 4H); 13 C NMR (50 MHz, CDCl 3 ) 55.5, 55.7, 92.5, 98.0, 104.2, 105.5, 114.4, 123.5,

4 204 J. Chin. Chem. Soc., Vol. 48, No. 2, 2001 Lee and Wu 128.0, 157.6, 162.1, 162.5, 164.0, 165.4, ,7-Dimethoxy-2-(4-methoxyphenyl)chromen-4-one (17) To a sus pen sion of 16 (0.54 g, 1.8 mmol) and K2C3 (2 eq g) in ac e tone (25 ml) was added Me 2 S 4 (0.19 ml, 1.99 mmol) dropwise at room tem per a ture, and then refluxed for 8 h. To the re sult ing so lu tion was added 25 ml H 2, and the mix ture was ex tracted with CH2Cl2. The or ganic layer was con cen trated in vacuo, and the res i due sub jected to col - umn chro ma tog ra phy (Si 2, Ether:CH 2 Cl 2 1:2) to pro vide 17 (0.53 g, 94%) as a yel low solid: mp o C (lit. 35 mp o C); 1 H NMR (200 MHz, (CD 3)2C) 4.02, 4.04, and 4.08 (s, 9H), 6.60 and 6.89 (d, J = 2.4 Hz, 2H), 6.63 (s, 1H), 7.23 and 8.09 (d, J = 9.0 Hz, 4H) 13 C NMR (50 MHz, (CD 3 ) 2 C) 56.2, 56.6, 56.8, 94.3, 97.2, , 115.6, 125.0, 128.8, 160.9, 161.2, 162.2, 163.4, 165.2, ,7-Dihydroxy-2-(4-hydroxyphenyl)chromen-4-one (19) A mix ture of 18 (2.00 g, 7.3 mmol) and I2 (1 eq. 7.3 mmol) in pyridine (10 ml) were refluxed for 4 h. Af ter cool - ing, the solid was fil tered and the fil trate was sub jected to col - umn chro ma tog ra phy (Si2, Ether:CH2Cl2 1:3) to pro vide the de sired prod uct 19 (1.85 g, 93%) as a white solid: mp o C (lit. 36 mp o C); 1 H NMR (200 MHz, DMS) 6.21 and 6.50 (d, J = 2.0 Hz, 2H), 6.79, 10.41, and (bs, 3 ), 6.94 and 7.93 (d, J = 8.8 Hz, 4H); 13 C NMR (50 MHz, CDCl3 DMS) 92.2, 97.2, 101.1, 102.2, 114.2, 119.6, 126.4, 155.7, 159.4, 159.9, 162.1, 162.4, Hydroxy-5,7-dimethoxy-2-(4-methoxyphenyl)chromen- 4-one (3) The re quired amount (26~126 ml) of the DD (pre - pared ac cord ing to Adam s pro ce dure 29 ) in ac e tone ( M), was added rap idly un der N 2 to a cooled so lu tion of flavone 17 (0.4 g, 1.3 mmol) in dried CH2Cl2 (100 ml). Stirring was con tin ued for 5-8 h. The re ac tion was mon i tored by TLC anal y sis. The sol vent was re moved and the res i due was sub jected to col umn chro ma tog ra phy to get the cor re - spond ing 3-hydroxyflavone 3 (0.4 g, 95%) as a solid: mp o C (lit. 37 mp o C); 1 H NMR (200 MHz, CDCl 3 ) 3.85, 3.90 and 3.97 (s, 9H), 6.33 and 6.54 (d, J = 1.9 Hz, 2H), 7.26 (s, 1H), 7.02 and 8.16 (d, J = 8.6 Hz, 4H); 13 C NMR (50 MHz, CDCl3) 55.3, 55.7, 56.3, 92.3, 95.6, 106.1, 113.9, 123.5, 128.8, 137.4, 142.2, 158.8, 160.4, 160.6, 164.2, ,5,7-Trihydroxy-2-(4-hydroxyphenyl)chromen-4-one (kaempferol 1) A sealed tube of 3 (0.40 g, 1.2 mmol) and BBr 3 (5 eq. 1 M 6.1 ml) in CH2Cl2 (10 ml) was refluxed for 24 h, and then cooled to room tem per a ture. The re sult ing mix ture was dis - solved in Me and sub jected to col umn chro ma tog ra phy (Si2, EA:Hex ane 1:2) to ob tain 1 (0.32 g, 91%) as a yel low solid: mp o C (lit. 4 mp o C); 1 H NMR (200 MHz, (CD3)2C) 6.41 and 6.68 (d, J = 2.0 Hz, 2H), 7.16 and 8.30 (d, J = 8.9 Hz, 4H) 13 C NMR (50 MHz, (CD 3 ) 2 C) 94.8, 99.5, 104.5, 116.7, 123.6, 130.8, 137.0, 147.4, 158.1, 160.6, 162.6, 165.4, ,5,7-Trimethoxy-2-(4-methoxyphenyl)chromen-4-one (2) To a mix ture of 3 (0.20 g, 0.6 mmol) and K2C3 (2 eq g) in ac e tone (25 ml) was added Me2S4 (63 L, 0.70 mmol) dropwise at room tem per a ture, and then refluxed for 8 h. The re sult ing so lu tion was cooled and was added H 2 (5 ml), and ex tracted with CH2Cl2. The or ganic layer was con - cen trated in vacuo, and the res i due was sub jected to col umn chro ma tog ra phy (Si 2, Me:CH 2 Cl 2 1:20) to pro vide 2 (0.20 g, 98%) as a yel low solid: mp o C (lit. 38 mp 165 o C); 1 H NMR (200 MHz, CDCl 3 ) 3.85, 3.87, 3.88, and 3.93 (s, 12H), 6.30 and 6.47 (d, J = 2.3 Hz, 2H), 6.98 and 8.04 (d, J = 9.1 Hz, 4H) 13 C NMR (50 MHz, CDCl3) 55.3, 55.7, 56.3, 59.8, 92.3, 95.6, 109.4, 113.8, 123.1, 129.7, 141.0, 152.6, 158.7, 160.9, 161.1, 163.8, Hydroxy-3,7-dimethoxy-2-(4-methoxyphenyl)chromen- 4-one (4) To a so lu tion of 2 (0.20 g, 0.58 mmol) in CH 2 Cl 2 (20 ml) was cooled to 0 o C for 30 min, and in tro duced BBr3 (1 eq. 1 M 0.58 ml) into the so lu tion dropwise. The or ange mix ture was stirred at 0 o C for 30 min, and then Me was added. The sol vent was re moved in vacuo, and the res i due was sub - jected to col umn chro ma tog ra phy (Si 2, Ether:Hex ane 1:1) to af ford 4 (0.19 g, 97%) as a yel low solid: mp o C (lit. 39 mp o C); 1 H NMR (200 MHz, CDCl3) 3.85, 3.86, and 3.89 (s, 9H), 6.33 and 6.43 (d, J = 2.4 Hz, 2H), 7.01 and 8.08 (d, J = 9.0 Hz, 4H) 13 C NMR (50 MHz, CDCl3) 55.4, 55.7, 60.1, 92.1, 97.8, 106.0, 114.0, 122.7, 130.1, 138.8, 155.9, 156.7, 161.6, 162.0, 165.4, ,5-Dihydroxy-7-methoxy-2-(4-methoxyphenyl)chromen- 4-one (5) To a so lu tion of 4 (15 mg, mmol) in CH2Cl2 (2 ml) was added BBr3 (1.2 eq. 1 M 55 L) at room tem per a - ture, and the re ac tion mix ture was refluxed for 4 h. The crude prod uct was dis solved in Me and sub jected to col umn chro ma tog ra phy (Si2, EA:CH2Cl2 1:5) to achieve 5 (14 mg, 95%) as a yel low solid: mp o C (lit. 40 mp o C); 1 H NMR (200 MHz, CDCl 3 ) 3.87 (s, 6H), 6.36 and 6.47 (d, J

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