Short and Efficient Syntheses of Protoberberine Alkaloids using Palladium-Catalyzed Enolate Arylation

A concise synthesis of the biologically active alkaloid berberine is reported, and a versatile palladium‐catalyzed enolate arylation is used to form the isoquinoline core. The overall yield of 50 % is a large improvement over the single, previous synthesis. By design, this modular route allows the rapid synthesis of other members of the protoberberine family (e.g., pseudocoptisine and palmatine) by substitution of the readily available aryl bromide and ketone coupling partners. Moreover, by combining enolate arylation with in situ functionalization, substituents can be rapidly and regioselectively introduced at the alkaloid C13 position, as demonstrated by the total synthesis of dehydrocorydaline. The avoidance of electrophilic aromatic substitution reactions to make the isoquinoline allows direct access to analogues possessing more varied electronic properties, such as the fluorine‐containing derivative synthesized here

Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists

A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (c log P 116 μg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA2 <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom log D7.4 (2.4), high LE (0.43), and solubility (152 μg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation

Heavier Alkaline Earth Catalyzed Ene-yne Cyclizations: Atom-Efficient Access to Tetrahydroisoquinoline Frameworks

Tetrahydroisoquinoline frameworks may be accessed with 100% atom efficiency through the alkaline earth catalyzed addition of primary amines to ene-yne substrates through a sequence of intermolecular alkene and intramolecular alkyne hydroamination steps

Heavier Alkaline Earth Catalysts for the Intermolecular Hydroamination of Vinylarenes, Dienes, and Alkynes

The heavier group 2 complexes [M­{N­(SiMe₃)₂}₂]₂ (<b>1</b>, M = Ca; <b>2</b>, M = Sr) and [M­{CH­(SiMe₃)₂}₂(THF)₂] (<b>3</b>, M = Ca; <b>4</b>, M = Sr) are shown to be effective precatalysts for the intermolecular hydroamination of vinyl arenes and dienes under mild conditions. Initial studies revealed that the amide precatalysts, <b>1</b> and <b>2</b>, while compromised in terms of absolute activity by a tendency toward transaminative behavior, offer greater stability toward polymerization/oligomerization side reactions. In every case the strontium species, <b>2</b> and <b>4</b>, were found to outperform their calcium congeners. Reactions of piperidine with <i>para</i>-substituted styrenes are indicative of rate-determining alkene insertion in the catalytic cycle while the ease of addition of secondary cyclic amines was found to be dependent on ring size and reasoned to be a consequence of varying amine nucleophilicity. Hydroamination of conjugated dienes yielded isomeric products via η³-allyl intermediates and their relative distributions were explained through stereoelectronic considerations. The ability to carry out the hydroamination of internal alkynes was found to be dramatically dependent upon the identity of the alkyne substituents while reactions employing terminal alkynes resulted in the precipitation of insoluble and unreactive group 2 acetylides. The rate law for styrene hydroamination with piperidine catalyzed by [Sr­{N­(SiMe₃)₂}₂]₂ was deduced to be first order in [amine] and [alkene] and second order in [catalyst], while large kinetic isotope effects and group 2 element-dependent Δ<i>S</i>^⧧ values implicated the formation of an amine-assisted rate-determining alkene insertion transition state in which there is a considerable entropic advantage associated with use of the larger strontium center