RESUMO
Four chiral diphosphine ligands consisting of bis(2,5-diphenylphospholan-1-yl) groups connected by the sp(2) carbon linkers 2,3-quinoxaline ((S,S)-Ph-Quinox), 2,3-pyrazine ((S,S)-Ph-Pyrazine), maleic anhydride ((S,S)-Ph-MalPhos), and 1,1'-ferrocene ((S,S)-Ph-5-Fc) were synthesized, and their cationic [rhodium(I)(COD)] complexes were prepared. These complexes were tested in asymmetric hydrogenation of functionalized olefins. [((S,S)-Ph-Quinox)Rh(COD)]BF4 showed high activity and selectivity against itaconate and dehydroamino acid substrates. The corresponding (S,S)-Ph-Pyrazine and (S,S)-Ph-MalPhos complexes exhibited lower activities and selectivities. [((S,S)-Ph-5-Fc)Rh(COD)]BF4 showed high activity with low selectivity for these substrates, but high activity and selectivity against 2-C-substituted cinnamate salts, whereas rhodium complexes of (S,S)-Ph-Quinox and (R,R)-Ph-BPE showed low activity and selectivity against 2-C-substituted cinnamate salts.
Assuntos
Carbono/química , Reagentes de Ligações Cruzadas/química , Fenol/química , Fósforo/química , Catálise , Cinamatos/química , Hidrogenação , Ligantes , Espectroscopia de Ressonância Magnética , Anidridos Maleicos/química , Modelos Moleculares , Estrutura Molecular , Fenol/síntese química , Pirazinas/química , Quinoxalinas/química , Ródio/química , Estereoisomerismo , Succinatos/químicaRESUMO
This Account provides an overview of our activities in the area of asymmetric hydrogenation over the last 12 years. We discuss the manufacture of metal-containing precatalysts and their use in asymmetric hydrogenation processes. Many of the metal complexes have been made on a multikilogram scale for our own use and also provided to our customers. In addition, we review some of the applications that we have developed for our asymmetric hydrogenation catalysts, many of which have been operated on commercial scales. This all underlines that asymmetric hydrogenation is a mature technology that has been adopted for use in the pharmaceutical and fine-chemical industries.
Assuntos
Indústria Química/métodos , Catálise , Hidrogenação , Ródio/química , Rutênio/química , EstereoisomerismoRESUMO
Two methods to produce (2S)-5-amino-2-(1-n-propyl-1H-imidazol-4-ylmethyl)-pentanoic acid were investigated. Diastereoisomeric salt resolution, using the quinidine salt, gave the desired intermediate in 98% ee and 33% yield. Asymmetric hydrogenation of various substrates gave high conversions, with up to 83% ee. Integration of these two approaches via asymmetric hydrogenation of a quinidine salt substrate followed by crystallization provided the desired intermediate in 94% ee and 76% yield.
Assuntos
Aminoácidos/síntese química , Técnicas de Química Combinatória , Imidazóis/química , Ácidos Pentanoicos/síntese química , Quinidina/química , Aminoácidos/análise , Estrutura Molecular , Ácidos Pentanoicos/análise , Ácidos Pentanoicos/química , EstereoisomerismoRESUMO
[reaction: see text] The 11-oxa prostaglandin analogue AL-12182 1 has potent topical ocular hypotensive activity. A convergent and concise general synthesis of this class of prostanoid was developed employing a stereoselective coupling reaction between a tetrahydrofuran core electrophile and a nucleophilic omega side chain component, providing a route that should be suitable for commercial scale production. The tetrahydrofuran core was assembled from dimethyl d-malate using a stereoselective beta-hydroxy ester dianion alkylation reaction.
Assuntos
Prostaglandinas Sintéticas/síntese química , Ciclização , Estrutura Molecular , Prostaglandinas/química , Prostaglandinas Sintéticas/químicaRESUMO
A robust and scalable procedure for the palladium-catalyzed dynamic kinetic asymmetric transformation of 3,4-epoxy-1-butene into (2R)-3-butene-1,2-diol with water as the cosolvent is reported. Examination of the effects of solvent and temperature led to the identification of conditions that permitted use of 0.025 mol % catalyst, providing (2R)-3-butene-1,2-diol in 84% isolated yield and 85% enantiomeric excess. Subsequent Heck reactions with a diverse range of coupling partners are described and the influence of their electronic nature on maintaining the enantiopurity of the diol is discussed.
Assuntos
Glicóis/síntese química , Paládio/química , Catálise , Glicóis/química , Compostos Organometálicos/química , Estereoisomerismo , Tetra-Hidronaftalenos/síntese químicaRESUMO
The asymmetric hydrogenation of a selectively crystallised (E)-4,4-diaryl-3-butenoate with a rhodium-PhanePhos catalyst is described, providing an intermediate to the antidepressant sertraline.
Assuntos
Antidepressivos/síntese química , Butiratos/química , Sertralina/síntese química , Antidepressivos/química , Catálise , Hidrogenação , Estrutura Molecular , Ródio/química , Sertralina/químicaRESUMO
A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin 1 in excellent overall yield and purity.
Assuntos
Anticonvulsivantes/síntese química , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/síntese química , Proteínas de Bactérias , Hidrogenação , Pregabalina , Estereoisomerismo , Fatores de TranscriçãoRESUMO
The application of asymmetric hydrogenation to the manufacture of pharmaceutical intermediates has become increasingly prevalent in the past three to five years. This review focuses on the hydrogenation substrates and their use, rather than comparing the specific catalysts employed. The literature published between 2002 and 2003 is covered, with some pertinent examples from 2001, all of which demonstrate the increasing number of applications for this technology.
Assuntos
Hidrogenação , Preparações Farmacêuticas/síntese química , Especificidade por Substrato , Alcenos/síntese química , Aminoácidos/síntese química , Química Farmacêutica , Compostos Heterocíclicos/química , Iminas/síntese química , Cetonas/síntese química , Reino UnidoRESUMO
We examined the effect of 1R,4S-4-amino-cyclopent-2-ene-carboxylic acid (ACC), a reversible inhibitor of GABA transaminase, on the expression of conditioned place preference response to cocaine and nicotine in rats. Cocaine (20 mg/kg i.p.) and nicotine (0.4 mg/kg s.c.), but not vehicle or 300 mg/kg i.p. of ACC, produced a significant conditioned place preference response. Pretreatment of animals with 300 and 75 mg/kg i.p. of ACC significantly attenuated the expression of the cocaine- and nicotine-induced conditioned place preference responses, respectively. These results are the first to suggest that reversible inhibition of GABA transaminase may be useful in blocking cue-induced relapse to nicotine and cocaine.