Total Synthesis of Kaempferol and Methylated Kaempferol Derivatives

Abstract

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 sequence 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 I2 ox i da tive-promoting-cyclization and DDO ox i da tive hydroxylation. Sev eral strat e gies to achieve 1 are pro vided. IN TRO DUC TIONThe 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 hibi tors. 3 Kaempferol and its 3-O-glycoside de riv a tives have been iden ti fied in var i ous plants, veg e ta bles, fruits, and bever 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 alyzed 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 Our pre vi ous in ves ti ga tion in di cated that the flavonoid an a logues are thera 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 integrase and tu mors. On 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 supply, 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-Oyamada 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 -

Kaempferol – A dietary anticancer molecule with multiple mechanisms of action: Recent trends and advancements

“…Chemically, KMF is synthesized by complex reaction having many steps: (a) cross aldol condensation of 2,4,6trimethoxyacetophenone (6) and 4-methoxybenzaldehyde (7) with KOH, (b) ortho-demethylation of 2,4,6,4 0 -tetramethoxychalcone (8) in the presence of AlCl 3 , (c) I 2 -mediated oxidative cyclization of 2-hydroxy-4,6,4 0 -trimethoxychalcone (9), (d) methylation of 5-hydroxy-7-methoxy-2-(4-methoxyphenyl)chromen-4-one by Me 2 SO 4 (10), (e) oxidative hydroxylation of 5,7-dimethoxy-2-(4methoxyphenyl)chromen-4-one (11) catalysed by DDO, (f) BBr 3 controlled catalytic demethylation of 3-hydroxy-5,7-dimethoxy-2 -(4-methoxyphenyl)chromen-4-one (12) (Lee & Wu, 2001) (Fig. 3A).…”

Novel Neolignan from Penthorum chinense

“…To determine the active components responsible for the pharmacological effects, further chemical study on the whole plants of P. chinense was carried out. A new neolignan, (7′ E )‐2′,4,8‐trihydroxy‐3‐methoxy‐2,4′‐epoxy‐8,5′‐neolign‐7′‐en‐7‐one ( 1 ) was isolated, together with lupeol ( 2 ; Mochammad et al 1980), betulinic acid ( 3 ; Salimuzzaman et al 1988), glyceryl monopalmitate ( 4 ; Shang et al 2002), β‐sitosterol ( 5 ), palmitic acid ( 6 ), ursolic acid ( 7 ), 2β,3β,23‐trihydroxy‐urs‐12‐ene‐28‐oic acid ( 8 ; Huang et al 1988), glyceryl monolaurate ( 9 ), scopoletin ( 10 ; Hiroshi et al 1980), (–)syringaresinol ( 11 ; Aiko et al 1994), 9,9′‐ O ‐diferuloyl‐(–)‐secoisolariciresionl ( 12 ; Hiroyuki et al 1995), pinocembrin ( 13 ; William et al 1977), apigenin ( 14 ; Sinha et al 1981), kaempferol ( 15 ; Lee and Wu 2001), luteolin ( 16 ; Shen et al 1997), β‐daucosterol ( 17 ), quercetin ( 18 ), 1‐ O ‐(β‐ D ‐glucopyranosyl)‐(2 S ,2′ R ,3 R ,4 E ,8 E )‐2‐(2′‐hydroxyhexadecanoylamino)‐4,8‐octdecadiene‐1,3‐diol ( 19 ; Masanori et al 1998), gallic acid ( 20 ; Yi et al 2002), pinocembrin‐7 ‐O‐ β ‐D‐ glucoside ( 21 ; Nobutoshi et al 1980), and quercetin‐3‐ O ‐β ‐D‐ glucoside ( 22 ).…”

New Triterpenoids and Anti-Inflammatory Constituents from Glinus oppositifolius

“…The known isolated compounds were readily determined by a comparison of physical and spectroscopic data ( 1 H-NMR, 13 C-NMR, MS, UV, and IR) with the literature values or corresponding authentic samples, and this included four flavonoids, kaempferol ( 4 ) [ 12 ], 6, 8-dimethyl-5, 7, 4′-trihydroxyflavone ( 5 ) [ 13 ], 5,7-dihydroxy-6,8-dimethylflavone ( 6 ) [ 14 ], and 5,4′-dihydroxy-7-methoxy-6,8-dimethylflavone ( 7 ) [ 15 ], and thirteen aromatics, 4-hydroxybenzoic acid ( 8 ) [ 16 ], 4-hydroxybenzaldehyde ( 9 ) [ 17 ], 4-hydroxyacetophenone ( 10 ) [ 17 ], methyl 4-Hydroxybenzoate ( 11 ) [ 17 ], p -anisic acid ( 12 ) [ 18 ], vanillin ( 13 ) [ 19 ], 4-hydroxy-3-methoxyacetophenone ( 14 ) [ 20 ], acetosyringone ( 15 ) [ 21 ], 4-hydroxy-3,5-dimethoxybenzaldehyde ( 16 ) [ 22 ], 4-hydroxybenzyl alcohol ( 17 ) [ 23 ], 2-(4-hydroxyphenyl)ethanol ( 18 ) [ 24 ], cinnamic acid ( 19 ) [ 25 ], and trans-ferulic acid ( 20 ) [ 26 ].…”