HALOGENATED BIOGENIC AMINES IN BIOCHEMISTRY AND PHARMACOLOGY

生物胺在神经传递中起关键作用， 代谢，并控制各种生理过程。 使用各种合成方法，包括新颖的 我们开发的程序，我们已经准备了一系列的生物 在各个环位置上被氟取代的胺。这些 环氟化的生物胺继续在 大量的研究，包括对 运输、储存、释放、代谢和作用方式 这些胺。特别重要的是， 6-氟诺啡肽是一种选择性α-肾上腺素能激动剂， 2-氟诺啡肽是一种选择性β-肾上腺素能激动剂。因为 我们以前的FNE合成产生外消旋物质，我们 已经研究了纯R-对映体的路线。不对称 产生的氟苯乙烯前体的氨羟基化 对映体富集的氟化的菲乙醇胺，尽管具有适度的 对映选择性高对映选择性羰基还原 具有手性硼催化剂的氟化氯酮中间体 （化学酶），其次是侧链的阐述，提供了一个 以良好的产率获得R-FNE。对映选择性氰醇 通过手性Salen催化剂催化形成，然后还原， 是我们开发的第二个程序。最后一次隔离后， 纯化后，纯R-和S-异构体的受体结合将被 进行评估立体异构对受体的影响 选择性。为了有可用的替代生物 2-FNE和6-FNE的前体，我们以前合成 苏型-2-和6-氟二羟基苯基丝氨酸（氟-DOPS） 外消旋形式，但发现这些类似物是差的底物 芳香族氨基酸脱羧酶我们准备了钥匙 氟化DOPS的2S，3R-异构体的前体， 对映选择性羟醛缩合策略。嘌呤的氟化类似物和 嘧啶碱基作为潜在的P-位点 磷酸二酯酶抑制剂，并作为潜在的NMR探针， DNA结构与功能

Biogenic amines play key roles in neurotransmission, metabolism, and in control of various physiological processes. Using a variety of synthetic methodologies, including novel procedures developed by us, we have prepared a series of biogenic amines with fluorine substituted at various ring-positions. These ring-fluorinated biogenic amines continue to find applications in a multitude of studies, including research on the mechanisms of transport, storage, release, metabolism, and modes of action of these amines. Of particular significance was the discovery that 6-fluoronorepinephrine is a selective a-adrenergic agonist and 2-fluoronorepinephrine is a selective b-adrenergic agonist. Because our previous syntheses of FNEs produced racemic material, we have investigated routes to the pure R-enantiomers. Asymmetric aminohydroxylation of fluorostyrene precursors produced enantio-enriched fluorinated phenethanolamines, albeit with modest enantioselectivities. Highly enantioselective carbonyl reductions of fuorinated chloroketone intermediates with chiral boron catalysts (chemzymes), followed by side-chain elaboration, have provided a route to R-FNEs in good yield. Enantioselective cyanohydrin formation catalyzed by chiral salen catalysts, followed by reduction, is a second procedure we have developed. After final isolation and purification, receptor binding of the pure R- and S-isomers will be carried out to assess the effects of stereoisomerism on receptor selectivities. In order to have available alternate biological precursors for 2-FNE and 6-FNE, we previously synthesized threo-2- and 6-fluorodihydroxyphenylserine (fluoro-DOPS) in the racemic form, but found these analogues to be poor substrates for aromatic amino acid decarboxylase. We have prepared key precursors to the 2S,3R-isomers of fluorinated DOPS using Evans enantioselective aldol strategy. Fluorinated analogs of purine and pyrimidine bases are being prepared as potential P-site phosphodiesterase inhibitors, and as potential NMR probes for DNA structure and function.