Phenethylamine moiety

Through the modification of the known L-type VDCC inhibitors verapamil and its desmethoxy analog emopanil, Eli Lilly identified a novel series of amino acid containing phenylalkylamines which demonstrate submicromolar inhibition of neuronal non-L-type VDCC while showing markedly decreased activity on L-type channels. They initially investigated the modification of the phenethylamine moiety and found that chain elongation and incorporation of a second phenyl substituent (compound 1) markedly shifted activity away from L-towards non-L-type inhibition. 

Yamashita, T., Yasuda, M., Isami, T., Nakano, S., Tanabe, K., and Shima, K. (1993) Synthesis of phenethylamine moiety by photoamination of styrene derivatives with ammonia. Tetrahedron Letters, 34, 5131-5134. 

A jS-phenethylamine moiety was incorporated into the trans-decalin ring system (45)... 

We have analyzed (14J the molecular structures of these semirigid chiral ligands and, in both, we have identified a common chiral pharmacophore, namely a phenyl ring and a nitrogen atom, uniquely juxtapositioned one to the other, which is contained in an extended phenethylamine moiety. We have since shown that the same pharmacophore is present in the DAR antagonist (+)-octo-clothepin,III,as well as in several other DAR ligands (19). 

Butaclamol s activity was ascribed to the presence of the neuroleptic pharmacophore within its extended phenethylamine moiety. Inspection of the structure of isobutaclamol reveals no such phenethylamine moiety, but instead, shows the presence of a phenyl propyl amine moiety. It thus appears that butaclamol and isobutaclamol are incapable of presenting the same pharmacophore to the DAR. We have therefore studied the molecular structures of butaclamol and isobutaclamol more closely with a view to resolving this apparent anomaly. 

An efficient introduction of the phenethylamine moiety was envisioned from reduction of an enamide intermediate, but the formation of the enamide proved somewhat problematic. Initial attempts to form the enamide from the oxime 43 resulted in closure to the cyclic imine 45, presumably via the intervention of a nitrene intermediates (Scheme 5.20). ... 

Among the most commonly applied chiral moiety for nitrones (2) is the N-a-methylbenzyl substituent (Scheme 12.6) (18-25). The nitrones 8 with this substituent are available from 1 -phenethylamine, and the substituent has the advantage that it can be removed from the resulting isoxazolidine products 9 by hydrogeno-lysis. This type of 1,3-dipole has been applied in numerous 1,3-dipolar cycloadditions with alkenes such as styrenes (21,23), allyl alcohol (24), vinyl acetate (20), crotonates (22,25), and in a recent report with ketene acetals (26) for the synthesis of natural products. Reviewing these reactions shows that the a-methylbenzyl group... 

The structures of all currently approved gastric acid secretion inhibitors that act as inhibitors of the sodium-potassium pump consists of variously substituted pyiidylsulfonyl-benzimidazoles. A structurally very distinct compound based on a pyrimidine moiety has much the same activity as the benzimidazole-based drugs. In yet another convergent synthesis, reaction of (3-phenethylamine (53) with acetic anhydride affords amide 54. Treatment with polyphosphoric acid (PPA) then leads to ring closure to form the dihydroisoquinoline (55). Sodium borohydride then reduces the enamine function to afford fragment 56. 

Like BINOL, salicylaldehyde imines have become very important in asymmetric catalysis and a variety of polydentate ligands prepared from chiral monoamines and diamines are employed in oxidation reactions, carbenoid reactions and Lewis acid catalyzed reactions. As in the previous section, this section emphasizes the effect of the phenol moiety on the asymmetric catalysis. An imine derived from a chiral 1-phenethylamine and salicylaldehyde was employed in the copper catalyzed asymmetric cyclopropanation by Nozaki, Noyori and coworkers in 1966, which is the first example of the asymmetric catalysis in a homogeneous system . Salicylaldehyde imines with ethylenediamine (salen) have been studied extensively by Jacobsen and Katsuki and their coworkers since 1990 in asymmetric catalysis. Jacobsen and coworkers employed the ligands prepared from chiral 1,2-diamines and Katsuki and coworkers sophisticated ligands possess chirality not only at the diamine moiety but also at the 3,3 -positions. 

Compounds structurally related to the endogenous sympathomimetic amines epinephrine and norepinephrine have classically been employed as appetite suppressants. These agents, of which amphetamine [300-62-9], C9H13N, is the prototypical example, generally retain the phenethylamine, but lack the catechol moiety present in the natural substances. As a consequence, they are well absorbed after oral administration and readily distribute into the central nervous system where they exert their anorectic effects at hypothalamic appetite control centers. A component of their efficacy in promoting weight... 

Since its discovery the Pictet-Spengler cyclization has formed the basis of numerous syntheses of alkaloids containing aromatic subunits. This high-yielding reaction involves, in its broadest sense, nucleophilic attack on an iminium ion by the Tr-electrons of a tethered aromatic moiety. In the classical reaction a substituted P-phenethylamine is condensed with an aldehyde under acidic conditions to produce a te-trahydroisoquinoline (Scheme 16). A useful variant of the Pictet-Spengler reaction, which provides tetr ydro-(3-carbolines and their derivatives, involves the condensation of a tryptamine derivative and an aldehyde (Scheme 16). Whether nucleophilic attack on the resulting iminium ion occurs initially at the a- or -indole carbon is a topic of current debate and, indeed, there is evidence to suggest that the mechanistic pathway could be substrate dependent. ... 

To showcase this method, the antibiotic fumaramidmycin (64), was synthesized in two steps from commercially available phenethylamine. Oxidation alpha to the nitrogen of the amide moiety was accomplished in high yield and high selectivity. 

In another example, variation in one of the starting components by using the carboxylic salt of a-epoxide in reaction with P-phenethylamine (dopamine) under the Pictet-Spengler conditions was used for the synthesis of trimethoquinol. This compound is one of a small group of compounds devoid of an aminoalcohol moiety that acts as a P-adrenergic agonist investigated as a potent bronchodilator. ... 

Until the early 1990s, there was no practical use of the hydroxychlorination of alkenes. Recently, Dai and co-workers have enhanced the synthetic utility of this reaction by employing allylic amines and sulfides as the substrate. When a combination of DMF or THF with H2O is used as the solvent, the hydroxychlorination of these substrates proceeds smoothly and regioselectively to give chlorohydrins in high yields (Scheme 3). The product chlorohydrins serve as the precursors of epoxides. Unfortunately, with allyl amines bearing chiral moieties such as (/ )-phenethylamine, the diastereoselectivities of... 

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