Selective methylation of kaempferol via benzylation and deacetylation of kaempferol acetates

Abstract

SummaryA strategy for selective mono-, di- and tri-O-methylation of kaempferol, predominantly on the basis of selective benzylation and controllable deacetylation of kaempferol acetates, was developed. From the selective deacetylation and benzylation of kaempferol tetraacetate (1), 3,4′,5,-tri-O-acetylkaempferol (2) and 7-O-benzyl-3,4′5,-tri-O-acetylkaempferol (8) were obtained, respectively. By controllable deacetylation and followed selective or direct methylation of these two intermediates, eight O-methylated kaempferols were prepared with 51–77% total yields from kaempferol.

Synthesis of icariin from kaempferol through regioselective methylation and para-Claisen–Cope rearrangement

“…Our synthetic approach to 1 commenced with the preparation of aglycone 3 , as illustrated in Scheme 1 . First, 7- O -benzylkaempferide ( 6 ) was easily obtained from kaempferol through tetraacetylation, followed by benzylation at C-7 and selectively methylation, according to our previously developed procedure [ 19 ]. In order to methylate exclusively the 4′-OH in kaempferol, we initially attempted to use methoxymethyl (MOM) as 7-OH protecting group, but this method could not provide an ideal yield in the 4′-OH selective methylation and in subsequent Claisen–Cope rearrangement.…”

“…With icaritin ( 3 ) in hand, the selective glycosylation was investigated ( Scheme 4 ). The alkylation of OH in kaempferol followed a specific reactivity order: 7 > 4′ > 3 >> 5 [ 19 ]. We initially attempted the 7-OH glycosylation with tetra- O -acetylglucopyranosyl bromide ( 15 ) [ 30 ] as the donor and SrCO 3 or AgNO 3 as an activator in pyridine or quinoline [ 15 , 31 ], but it was unsuccessful.…”

“…As a continuation of this program, herein we report a new approach to icaritin and then icariin through semi-synthesis from the commercially available natural product kaempferol. Our previously developed regioselective methylation of kaempferol [ 19 ], Europium(III)-catalyzed para -Claisen–Cope rearrangement and the bis-glycosylation are the key features of this linear synthesis. Previously, we succeeded in the selective methylation of 4′-OH in kaempferol.…”

C-7 modified flavonoids as novel tyrosyl-tRNA synthetase inhibitors

“…In comparison with 4 0 -OH, 7-OH shows 2 orders of magnitude decrease in pK a values of naringenin and genistein, [32][33][34] and alkylation of the hydroxyl groups occurs following a specic sequential position order: 7 > 4 0 . 35,36 The signals at about d 12.8 and 9.6 in b1-b6 were assigned to 5-OH and 4 0 -OH, respectively. [37][38][39] These facts suggested the selective O-alkylation of 7-OH.…”

A simple and effective preparation of quercetin pentamethyl ether from quercetin

“…PMFs can be synthesized from o -hydroxyacetophenone derivatives in several steps [27–28] or, more easily, from the corresponding phenolic flavones by conventional methylation, if the starting phenolic substrate is available [29–33]. Direct preparation of QPE ( 1 ) from quercetin ( 2 ) by per- O -methylation is difficult because the OH group at 5 position is resistant to alkylation due to its strong intramolecular hydrogen bonding with the carbonyl group at 4 position.…”