Synthesis of C-3 coupled biflavonoids and C-3 coupled biflavonoid analoguesThe invention relates to methods for the preparation of an optically inactive and optically active compounds which are selected from the group consisting of C-3 coupled biflavonoids and C-3 coupled biflavonoid analogues from a starting material or intermediate which are respectively selected from the group consisting of optically inactive or optically active flavan-3-ols and optically active flavan-3-ones, the method comprising the steps of (a) providing an optically inactive or active compound having a fIavan-3-ol structure or a compound which is a flavan-3-one, (b) if a compound having a flavan-3-ol structure with a hydroxy group on the C-3 carbon is selected as starting material, converting the hydroxy group on the C-3 carbon of the compound having the flavan-3-ol structure to an oxo group to form a flavan-3-one of that compound, (c); providing a compound having a nucleophilic aromatic moiety, which compound is selected from the group of compounds having a nucleophilic aromatic moiety and which have flavonoid base structures and compounds having a nucleophilic aromatic moiety and which do not have a flavonoid base structure, (d) contacting the flavan-3-one provided by step (a) or obtained by step (b) with the compound containing the nucleophilic aromatic moiety in the presence of a Lewis acid; (e) forming a first intermediate compound wherein the oxo group on the C-3 carbon is converted to a hydroxy group by virtue of nucleophilic addition when the compound containing the nucleophilic aromatic moiety is contacted to the C-3 carbon of the flavan-3-one, (f) subjecting the first intermediate compound to dehydration so as to introduce a double bond between the C-3 carbon and C-4 carbon of the intermediate compound with the concomitant removal of the hydroxy group from the C-3 carbon to form an optically active flavene compound which is substituted by the nucleophilic aromatic moiety on the C-3 carbon, (g).Method by starting material or intermediate preparation compound; said compound is selected from the group of being made up of two flavonoid analogues of two flavonoids of c-3 coupling and c-3 coupling; said starting material or midbody are selected from by in flavan-3-alcohol and the group that flavane-3-ketone is formed, said method comprising the steps of:(a) the compound with flavan-3-alcohol structure or the compound of flavane-3-ketone are provided;(b) if the compound of selecting to have the flavan-3-alcohol structure that on c-3 carbon, has oh group as starting material, then changes into the flavane-3-ketone of oxo base to form this compound with the oh group on the c-3 carbon of said compound with flavan-3-alcohol structure;(c) compound that contains the nucleophilic aromatic part is provided, said compound is selected from by in the following group of forming: the compound and the compound that contains the nucleophilic aromatic part and do not have flavonoid substruction that contain the nucleophilic aromatic part and have flavonoid substruction;(d) make provide by step (a) or in the presence of lewis acidic, contact with the said nucleophilic aromatic compound partly that contains by said flavane-3-ketone that step (b) obtains;(e) when the said compound that contains the nucleophilic aromatic part contacts with the c-3 carbon of said flavane-3-ketone, form first midbody compound, wherein the oxo base on said c-3 carbon relies on nucleophilic addition(adn) to change into oh group;(f) said first midbody compound is dewatered so that between the c-3 of said midbody compound carbon and c-4 carbon, introduce two keys and remove oh group from c-3 carbon simultaneously, thereby be formed on the c-3 carbon by the substituted yellow ene compound of said nucleophilic aromatic part;the yellow ene compound that (g) randomly will obtain carries out hydroboration-oxidation hydration, removes said pair of key between c-3 carbon and the c-4 carbon thus, and introduces oh group at c-4 carbon place simultaneously, thereby forms second midbody compound;(h) further said second midbody compound of oxidation step (g) randomly; oh group with said c-4 carbon place changes into the oxo base thus, is formed on thus on the c-3 carbon by substituted pair of flavonoid of selected nucleophilic aromatic part or two flavonoid analogue;(i) further randomly, and as the alternative step of step (h), the said yellow ene compound that step (f) is obtained carries out oso 4dihydroxy reaction removes said pair of key between c-3 carbon and the c-4 carbon thus, and introduces simultaneously oh group at c-4 carbon place and introduce oh group at c-3 carbon place, thereby forms the 3rd midbody compound; with (j) said the 3rd midbody compound is dewatered; thereby remove the oh group at c-3 carbon place; and between c-3 carbon and c-4 carbon, introduce two keys; form the enol product thus and this enol product spontaneously reset, thus be formed on that its c-4 carbon place has the oxo base and on its c-3 carbon by substituted pair of flavonoid of selected nucleophilic aromatic part or two flavonoid analogue.
Ｃ－３ 결합 바이플라보노이드들 및 그것의 유사체들의 합성본 발명은 플라반-3-올(flavan-3-ol) 및 플라반-3-온(flavan-3-one)들로 이루어진 군으로부터 선택된 출발물질(starting material) 또는 중간체(intermediate)로부터, C-3 결합 바이플라보노이드들(biflavonoids) 및 C-3 결합 바이플라보노이드 유사체들로 이루어진 군으로부터 선택된 화합물을 제조하는 방법을 제공한다.플라반-3-올(flavan-3-ol) 및 플라반-3-온(flavan-3-one)들로 이루어진 군으로부터 선택된 출발물질(starting material) 또는 중간체(intermediate)로부터, C-3 결합 바이플라보노이드들(biflavonoids) 및 C-3 결합 바이플라보노이드 유사체들로 이루어진 군으로부터 선택된 화합물의 제조 방법으로서,(a) 플라반-3-올 구조를 가진 화합물 또는 플라반-3-온인 화합물을 제공하는 단계;(b) C-3 카본 상에 수산기를 가진 플라반-3-올 구조의 화합물이 출발물질로서 선택된 경우, 플라반-3-올 구조를 가진 화합물의 C-3 카본 상의 수산기를 옥소기(oxo group)로 변환시켜 상기 화합물의 플라반-3-온을 형성하는 단계;(c) 친핵성 방향족 부위를 가지고 있고 플라보노이드계 구조를 가진 화합물들과 친핵성 방향족 부위를 가지고 있지만 플라보노이드계 구조를 가지고 있지 않은 화합물들의 군으로부터 선택된 화합물인 친핵성 방향족 부위를 가진 화합물을 제공하는 단계;(d) 상기 단계(a)에서 제공되거나 단계(b)에서 생성된 플라반-3-온을 루이스 산 존재 하에서 친핵성 방향족 부위를 포함하는 화합물과 접촉시키는 단계;(e) 친핵성 방향족 부위를 함유하고 있는 화합물이 플라반-3-온의 C-3 카본과 접촉할 때, 친핵성 첨가 반응에 의해 C-3 카본 상의 옥소기가 수산기로 변환되는 제 1 중간체 화합물 형성하는 단계;(f) C-3 카본으로부터의 수산기의 제거를 수반하면서 중간체 화합물의 C-3 카본과 C-4 카본 사이에 이중 결합을 도입하기 위해 제 1 중간체 화합물을 탈수시켜, C-3 카본 상의 친핵성 방향족 부위에 의해 치환되는 플라빈 (flavene) 화합물을 형성하는 단계;(g) 선택적으로, 제조된 플라본 화합물을 수산화붕소첨가-산화(hydroboration-oxidation) 수화(hydration) 반응시켜, C-4 카본에서 수산기의 도입을 수반하면서 C-3 카본과 C-4 카본 사이에서 상기 이중 결합을 제거함으로써 제 2 중간체 화합물을 형성하는 단계;(h) 또한 선택적으로, 단계(g)의 제 2 중간체 화합물을 산화시켜 상기 C-4 카본의 수산기를 옥소기로 변환함으로써, C-3 카본 상의 선택된 친핵성 방향족 부위에 의해 치환되는 바이플라보노이드 또는 그것의 유사체를 형성하는 단계;(i) 또한 선택적으로, 그리고 단계(h)에 대신하여, 단계(f)의 플라빈 화합물을 OsO4 디하이드록실화(dihydroxylation) 반응시켜, C-4 카본에 대한 수산기의 도입과 C-3 카본에 대한 수산기의 도입을 수반하면서 C-3 카본과 C-4 카본 사이에 상기 이중 결합을 제거하여, 제 3 중간체 화합물을 형성하는 단계; 및(j) 제 3 중간체 화합물에 탈수를 행하여, C-3 카본의 수산기가 제거되고 C-3 카본과 C-4 카본 사이에 이중 결합이 도입됨으로써, 에놀(enol) 생성물을 형성하고, 그러한 에놀 생성물이 자발적으로 재배열 하도록 하여, C-4 카본에 옥소기를 가지고 있으며 C-3 카본에서 선택된 친핵성 방향족 부위에 의해 치환되는 바이플라보노이드 또는 바이플라보노이드 유사체를 형성하는 단계;를 포함하는 것을 특징으로 하는 제조 방법.