A novel class of potent and selective non-peptide bradykinin (BK) B2 receptor antagonists and agonists was designed and synthesized. The unique screening lead (9) was discovered by a two-step directed random screening process. Systematic chemical modification of 9 elucidated the structural requirements essential for the B2 binding affinity, leading to the identification of the basic framework of this new series of B2 antagonists. A molecular modeling study suggested the key role of the N-methylanilide moiety at the 3-position of the 2, 6-dichlorophenyl ring to allow these compounds to adopt the characteristic active conformation. It was further revealed that the 4-substituent of the quinoline moiety is the key pharmacophore to determine the agonist/antagonist profiles. During these studies, we discovered the orally active non-peptide B2 antagonist, FK 3657 (2), which is undergoing clinical development, and potent B2 agonists represented by FR 190997 (5) and FR 198100 (6).
Lodenosine, [9- (2, 3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl) adenine, FddA, 1] is an acid-stable purine nucleoside analog with activity against human immunodeficiency virus (HIV). There are two possible approaches to 1 - the glycosylation of a nucleoside base with a fluorinated sugar or direct nucleoside fluorination. However, both methods have drawbacks in terms of the number of steps, the use of toxic agents and low overall yields. In this review article, we describe two industrial synthetic approaches to 1 via 6-chloropurine riboside and 6-chloropurine 3'-deoxyribo-side, the latter being derived from inosine, a readily available starting material produced by fer-mentation. Several deoxygenation and fluorination methods are compared considering reaction yields, cost, safety and environmental concerns.
Free radical reactions leading to carbon-carbon bond formation have emerged as a powerful tool in organic synthesis. We have been investigating the fluoroalkylation of organic molecules using radical species. The main subjects in our study are how to generate fluorinated alkyl radicals, and how to control the radical reaction. The photochemical reaction of fluoroalkyl iodide with ditin was found to be a good method for the generation of fluorinated radicals, and the generated fluorinated radicals could be effectively introduced into olefinic compounds. By the use of this method, efficient synthesis of fullerene dimers containing a fluoroalkyl group and oxygenative fluoroalkylation of styrenes were accomplished. One-electron reduction of fluorinated alkyl halides using SmI2 or Na2S2O4 was also investigated. Simultaneous introduction of fluorinated radical with other radical species such as oxygen, or fluorinated radical with electrophiles into olefinic compounds could be performed by using fluorinated alkyl halides with one-electron reducing reagent.
Enantioselective allylation of carbonyl compounds and aldol reaction are powerful and essential tools for synthesizing optically active homoallylic alcohols and β-hydroxy carbonyl compounds, respectively. We have found that BINAP·AgOTf complex is an excellent catalyst for asymmetric allylation of aldehydes with allyltributyltin as well as the asymmetric aldol synthesis of tributyltin enolates with aldehydes, and can furnish the corresponding nonracemic products with high diastereo- and enantioselectivities. These reactions are useful with respect to reactivity and selectivity. Later, we developed an alternative BINAP·AgOTf-catalyzed asymmetric aldol reaction of an alkenyl trichloroacetate employing a catalytic amount of trialkyltin methoxide. Asymmetric Sakurai-Hosomi allylation of aldehydes with allylic trimethoxysilanes and Mukaiyama-type aldol reaction of trimethoxysilyl enolates have been also achieved using BINAP·AgF as a chiral catalyst in methanol or using a mixture of BINAP·AgOTf and KF·18-crown-6 as bifunctional chiral cata-lysts in THF. BINAP·Ag (I) complexes are also known to catalyze enantioselective nitroso aldol reaction between trialkyltin enolates and nitrosobenzene.
The Rh-catalyzed enantioselective hydrogenation of N-acylated dehydroamino acids or their esters, initiated by Kagan, constitutes now a standard tool for the synthesis of natural and unnatural amino acids of high enantiomeric purity. The reaction proceeds via the unsaturate-dihydride mechanism in which the oxidative addition of hydrogen to Rh-enamide complex is the rate-limiting and stereodifferentiating step. In addition to this standard pathway, alternative dihydrideunsaturate mechanisms have also been reported. The formation of a RhH2 may precede the olefin-Rh interaction, depending on the chiral ligands and reaction conditions. Reactions using BINAP-Ru (II) complexes (BINAP = 2, 2'-bis (diphenylphosphino) -1, 1'-binaphthyl), find a wider synthetic scope, allowing asymmetric hydrogenation of a range of functionalized olefins and ketones. Interestingly, the Rh and Ru complexes with the same BINAP ligand exhibit an opposite sense of asymmetric induction in hydrogenation of dehydroamino acid derivatives. This review summarizes some mechanistic studies in this hydrogenation catalyzed by diphosphine-Rh and-Ru complexes.
We report here the characteristics of the weak nonbonded interactions formed by a divalent selenium atom; i.e., Se…N, Se…O, Se…F, Se…Cl, …and Se…Br interactions. Seven series of 2-substituted benzeneselenenyl compounds [2-C6H4(SeY)CH2X; X = NRR', OH, F, Cl, etc.; Y = Cl, Br, CN, etc.], some of which were labeled with an NMR active stable isotope, were synthesized. The intramolecular Se…X interactions were characterized by 1H, 15N, 17O, 19F, 77Se and synthesized. NMR spectroscopy in solution as well as by quantum chemical calculation and natural bond orbital (NBO) analysis. It was found that the strength of the Se…X interactions decreases with decreasing the basicity of the X atom, i.e., in the order of X = N, O, F, Cl, Br. The trend demonstrated the importance of the hypervalent nature of selenium for formation of the Se…X interactions. Convenient correlations were proposed for estimation of the strength of Se…X interaction from the 77Se NMR chemical shift or the nonbonded Se…X atomic distance.