Total synthesis of (-)-galanthamine by remote asymmetric induction
Total synthesis of (-)-galanthamine by remote asymmetric induction
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DOI：
10.1002/anie.200353636
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发表时间：
2004-01-01
影响因子：
16.6
通讯作者：
Node, M
中科院分区：
文献类型：
--
作者：
Kodama, S;Hamashima, Y;Node, M
（N）-加兰他敏（Galanthamine，1）[1]是一种从石蒜科植物中分离出来的生物碱，由于其在阿尔茨海默病的临床治疗中作为选择性乙酰胆碱酯酶抑制剂而引起了合成化学家的注意。[2]其有限的供应和与从天然来源分离该化合物相关的高成本[3]是需要有效合成的两个令人信服的原因。（N）-加兰他敏（1）通常通过中间体（N）-那维定（2）的结晶诱导不对称转化[3，4]在工业上制备。[5]由于后一种化合物具有高度致敏性，化学家在使用它时必须非常小心，这强调了合成（α）-1的更安全和更有效方法的必要性。除了在金属氧化剂存在下的经典和仿生酚氧化偶联[4a，B，6]之外，不对称烯丙基烷基化和分子内Heck反应序列也已用于（C1）-1的优异合成策略中。[7]最近，我们改进了含有连苯三酚部分的降贝拉定型衍生物I的酚氧化偶联，并将其应用于（α）-2和（β）-1的合成。[8]本文报道了一种新的不对称合成（N）-加兰他敏（1）的方法，通过手性咪唑啉酮辅助的苯丙氨酸远程不对称诱导。我们的不对称合成（III）-1的策略涉及通过使用苯基碘（iii）双（三氟乙酸盐）（PIFA）作为“清洁”氧化剂来修改我们先前的外消旋合成[8]，如方案1所示。该合成的不对称版本中的关键步骤是偶联产物II的分子内迈克尔加成，得到环醚III。该步骤需要对称二烯酮部分的一个烯烃上的酚氧原子优先进攻。因此，我们通过在环中N原子的苄基位置引入α-氨基酸，将构象限制设计到II中的七元环中。更确切地说，手性咪唑烷酮A的偶联产物B中的七元环的构象将受到稠合五元环的限制。可以推断，通过这种新型的远程不对称诱导，B的分子内迈克尔加成然后将进行非对映选择性地得到环醚C。通过基于用于构象分析的Monte Carlo技术的半经验PM 3计算，[9]我们计算了中间体B的最稳定构象（R1= H，R2= Bn，R3= COCF 3）。酚性O原子与Cβ1的距离（2.61）比O原子与Cβ2的距离（3.15）短0.55。分子内迈克尔加成应该是高度区域选择性和非对映选择性的，从而导致所需的对应于（N）-加兰他敏的对映体。对于偶联反应中的底物，我们选择d苯丙氨酸作为手性助剂，因为其庞大的取代基（R2=苄基）预期在对应于A的手性咪唑烷酮的非对映选择性形成中是有效的。在脱水剂N-乙基-N '-（3-二甲基氨基丙基）碳二亚胺盐酸盐（EDC· HCl）存在下，（R）-N-Boc-d-苯丙氨酸（3，R= Bn）与酪胺缩合。然后除去N-Boc基团，得到92%产率的胺4a（经两步;方案2）。
(À)-Galanthamine (1),[1] an alkaloid isolated from the Amaryllidaceae family, has attracted the attention of synthetic chemists because of its use as a selective acetylcholinesterase inhibitor in the clinical treatment of Alzheimer's disease.[2] Its limited supply and the high costs associated with isolating this compound from natural sources [3] are two compelling reasons for the need for an efficient synthesis.(À)-Galanthamine (1) has usually been prepared industrially through the crystallization-induced asymmetric transformation [3, 4] of the intermediate (Æ)-narwedine (2).[5] As the latter compound is highly allergenic, chemists must be extremely careful when working with it, which underscores the necessity for safer and more efficient methods for the synthesis of (À)-1. In addition to the classical and biomimetic phenolic oxidative coupling [4a, b, 6] in the presence of metal oxidants, an asymmetric allylic alkylation and intramolecular Heck reaction sequence has also been used in an excellent synthetic strategy toward (À)-1.[7] We recently improved the phenolic oxidative coupling of norbelladine-type derivatives I, which contain a pyrogallol moiety, and applied it in a synthesis of (Æ)-2 and (Æ)-1.[8] Herein we report a new asymmetric synthesis of (À)-galanthamine (1), through remote asymmetric induction with a chiral imidazolidinone auxiliary derived from phenylalanine. Our strategy for the asymmetric synthesis of (À)-1 involved the modification of our previous racemic synthesis [8] by using phenyliodine (iii) bis (trifluoroacetate)(PIFA) as the “clean” oxidant, as shown in Scheme 1. The key step in this asymmetric version of the synthesis is the intramolecular Michael addition of the coupling product II to give the cyclic ether III. This step requires the preferential attack by the phenolic oxygen atom on one olefin of the symmetrical dienone moiety. Therefore, we designed conformational restriction into the seven-membered ring in II by introducing an α-amino acid at the benzylic position, α to the N atom in the ring. More precisely, the conformation of the sevenmembered ring in the coupling product B of the chiral imidazolidinone A would be restricted by a fused fivemembered ring. It could be reasoned that the intramolecular Michael addition of B would then proceed diastereoselectively to afford the cyclic ether C by this new type of remote asymmetric induction. Through semiempirical PM3 calculations based on the Monte Carlo techniques for conformer analysis,[9] we calculated the most stable conformer of the intermediate B (R1= H, R2= Bn, R3= COCF3). The distance between the phenolic O atom and Cβ1 (2.61) is 0.55 shorter than that between the O atom and Cβ2 (3.15). The intramolecular Michael addition should be highly regio-and diastereoselective, thus leading to the desired enantiomer corresponding to (À)-galanthamine. For the substrate in the coupling reaction, we chose dphenylalanine as the chiral auxiliary, as its bulky substituent (R2= benzyl) was expected to be effective in the diastereoselective formation of the chiral imidazolidinone corresponding to A.(R)-N-Boc-d-phenylalanine (3, R= Bn) was condensed with tyramine in the presence of the dehydrating agent N-ethyl-N’-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC· HCl). Removal of the N-Boc group then gave the amine 4a in 92% yield (over two steps; Scheme 2).