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A robust synthesis of (5Z,8Z,11Z,13E)(15S)-15-hydroxyeicosa-5,8,11,13-tetraenoic acid (15(S)-HETE) sodium salt was established, utilising a biooxidation process. Treatment of arachidonic acid with soybean lipoxidase in 0.1 M sodium tetraborate buffer under oxygen pressure resulted in formation of the hydroperoxide, 15(S)-HPETE. Addition of sodium borohydride to the reaction mixture reduced the hydroperoxide to 15(S)-HETE, which was then purified by column chromatography. 15(S)-HETE sodium salt was prepared by treatment of an ethanol solution of HETE with aqueous sodium hydrogen carbonate. Multiple 10-g batches of 15(S)-HETE sodium salt with >98% enantiomeric excess and >98% chemical purity were prepared to support clinical trials.

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.

A synthesis of N-acetylcolchinol, a key intermediate in the synthesis of ZD6126, was developed. The enantiodifferentiating step required the catalytic asymmetric hydrogenation of an enamide. After screening a range of metal and ligand combinations it was found that (S,S)-iPr–FerroTANE Ru(methallyl)2 and [(S,S)-tBuFerroTANE Rh(COD)]BF4 gave both high enantioselectivity (>90% ee) and high catalyst utility (molar S/C = 1000).

A synthesis of (1R,2S)-dehydrocoronamic acid ethyl ester was developed employing a regio- and enantioselective palladium-catalysed nucleophilic ring-opening of 3,4-epoxy-1-butene with a glycine anion equivalent as the key enantiodifferentiating step. The desired selectivity was achieved using Trost’s naphthyl ligand. The subsequent activation of the free hydroxyl group and ring-closure by intramolecular SN2 reaction gave the desired amino acid ethyl ester.

Stoichiometric sodium borohydride is frequently used in the chemoselective reduction of ketones to racemic secondary alcohols. Catalytic homogeneous hydrogenation using (diphosphine)RuCl2(diamine) complexes provides a practical and economic alternative. A range of substrates were investigated and the optimum precatalyst identified in each case. Norcamphor was reduced with high diastereoselectivity using (Ph3P)2RuCl2(en); (E)-4-phenylbut-3-en-2-one was reduced with good chemoselectivity, and acetophenone was hydrogenated very efficiently using the same precatalyst. Isophorone and 3-dimethylaminopropiophenone were effectively hydrogenated using (dppf)RuCl2(en).

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.

A method for the coupling of acyl and imino substituents to the sterically encumbered 5-position of a 4-aminoquinazoline was developed. Starting with a 4-amino-5-iodoquinazoline, the method employs a facile intramolecular zinc-mediated transfer from the 4-amino group to the iodo-bearing carbon. The method was found to be effective for a variety of substituents, in particular a pyridyl group required for the synthesis of Pfizer’s prostate selective α1 antagonist candidate for the treatment of benign prostatic hyperplasia, UK-338,003.

Asymmetric hydrogenation is becoming an increasingly prevalent technology for the manufacture of complex pharmaceutical intermediates. Drawing from Chirotech's experience over the past eight years, this article emphasisesthe need for a diverse catalyst collection in providing practical solutions for a wide range of target compounds.

An extremely efficient route to highly enantiomerically enriched 2-methylsuccinamic acid via asymmetric hydrogenation has been developed. By using [(S,S)-Et-DuPHOS Rh COD]BF4 as the precatalyst und...

The practicalities of the asymmetric hydrogenation of acetophenone derivatives are addressed. The catalysts used, derived from the precatalysts [(xylylPhanePhos)RuCl2(DPEN)] (S)-(R,R)-1 and (R)-(S,S)-1, were shown to possess very high reactivity. 4‘-Fluoroacetophenone was hydrogenated at a molar substrate-to-catalyst ratio (S/C) of 100,000 with complete conversion effected in as little as 80 min (average turnover ∼1200 min-1, peak turnover ∼2500 min-1). The catalysts are tolerant of a range of commercial grade substrates, in most cases a S/C of 5000−10000 was achieved without the need to purify the ketone. Using precatalyst 1 enantioselectivities of 95 → 99% ee were achieved. The high selectivity and catalyst activity, plus the simplicity of the process, offers significant advantages over other enantioselective ketone reductions.

A concise synthesis of 5-hydroxy-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one utilising a novel selective desulfonylation protocol is described. This method provides facile access to a key intermediate for the asymmetric synthesis of calanolide A.

A commercial synthesis of the antiglaucoma agent, travoprost 2, is described. A total of 22 synthetic steps are required to provide the single enantiomer prostanoid, with the longest linear sequence being 16 steps from 3-hydroxybenzotrifluoride. The route is based upon a cuprate-mediated coupling of the single enantiomer vinyl iodide 13 and the tricyclic ketone 5, of high stereochemical purity, to yield the single isomer bicyclic ketone 15. A Baeyer−Villiger oxidation provides the lactone 16 as a crystalline solid, thus limiting the need for chromatographic purification. DIBAL-H reduction, Wittig reaction, esterification, and silyl group deprotection complete the synthesis of travoprost.

A novel asymmetric route to 2-amino-1,2,3,4-tetrahydronaphthalenes has been demonstrated starting from phthalimidovinylglycinol (PVG). Functionalisation of PVG via Heck reaction, olefin hydrogenation and cyclisation provides the title products.

Dopaminergic activity in the mesocorticolimbic system is associated with reinforcing properties of psychostimulant drugs. We previously demonstrated that increased γ-aminobutyric acid (GABA)-ergic activity produced by γ-vinyl GABA [ d , l -4-amino-hex-5-enoic acid (Vigabatrin®)], an irreversible inhibitor of GABA-transaminase, attenuated cocaine, nicotine, heroin, alcohol, and methamphetamine-induced increases in extracellular nucleus accumbens dopamine as well as behaviors associated with these biochemical changes. In the present study, using in vivo microdialysis techniques, we compared three different strategies to increase GABAergic activity in order to modulate cocaine-induced increase in extracellular dopamine. Our data demonstrate that the anticonvulsant 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NNC-711), a GABA uptake inhibitor, dose and time dependently diminished increases in extracellular dopamine following acute cocaine challenge. Furthermore, we demonstrated that cyclized analogue of vigabatrin, a competitive reversible GABA-transaminase inhibitor, is a more potent inhibitor of cocaine-induced dopamine increase than vigabatrin. Our data suggest that in addition to irreversible inhibition of GABA transaminase, inhibition of GABA uptake represent another potentially effective, indirect strategy for the treatment of cocaine abuse.

A synthetic strategy for the preparation of tetronasin 1, an acyltetronic acid ionophore demonstrating antibiotic, antiparasitic and growth promotion in ruminants is described. The key step involves a metal mediated cyclization reaction which creates two rings and four new stereocentres in a highly efficient manner. The configurations of three of these stereocentres are as required for the synthesis of tetronasin. The remaining stereocentre is readily epimerised to the natural configuration at a later stage of the synthesis.

A convenient synthesis of 11,12-diamino-9,10-dihydro-9,10-ethanoanthracene (1) is described. A Diels-Alder reaction between fumaryl chloride and anthracene provides an acid chloride. Conversion into an acyl azide followedby a thermal Curtius rearrangement and saponification affords the racemic diamine. Diastereoisomeric salt resolution provides the single enantiomer products, which are used as the chiral backbone of several ligands in asymmetric catalysis, including the Trost asymmetric allylic alkylation ligand 2.

The asymmetric hydrogenation of 1-aryl-2-imidazol-1-yl-ethanones offers a concise route to homochiral 1-aryl-2-imidazol-1-yl-ethanols. Catalytic asymmetric transfer hydrogenation with formic acid using [(R,R)-TsDPEN]Ru(Cymene)Cl as precatalyst was shown to be effective in this transformation. Preliminary process development showed that the hydrogenation could be carried out under mild conditions at a molar substrate-to-catalyst (S/C) ratio of 1000−2000.

Six deuterium labelled N-acylcysteamine polyketide derivatives (3) – (8) have been prepared as putative precursors for incorporation in studies of the biosynthesis of the ionophore antibiotic tetronasin (1). The route to these compounds was designed to be flexible and to maximise the use of common synthetic fragments.

Side-chains corresponding to phenylalanine, tyrosine and tryptophan are introduced onto a steroid template in a highly efficient manner via a condensation of the appropriate lithium acetylide with a steroidal ketone. The subsequent acetylene functionality can be selectively reduced in the presence of a modified benzyl ether and steroid ring unsaturation.

Non-peptide ligands are described that are rationally derived from dipeptides known to be key in binding to the appropriate peptide receptors. These derivatives are shown to exhibit affinity and selectivity for the receptors under study and may be designated as chemical leads for further exploitation in the design of potential therapeutic agents.

The preparation of seven deuterium labelled N-acetyl cysteamine thioesters ( 2a ), ( 2b ), ( 3a ), ( 3b ), ( 4 ), ( 5 ) and ( 6 ) as putative biosynthesis precursors of the acyl tetronic acid ionophore tetronasin is described.

An approach to the total synthesis of the ionophore antibiotic tetronasin ( 1 ) is reported, in which the key step is a novel base catalysed cascade cyslisation of an activated polyene ( 2 ). This establishes two rings and four stereogenic centres in one step. A related polyene ( 16 ) has been cyclised in a similar fashion, illustrating the generality of the procedure.

Two highly efficient and complementary synthetic routes to the C19C26 tetrahydrofuran fragment ( 2 ) of the novel acyltetronic acid ionophore antibiotic tetronasin (ICI 139603) ( 1 ) are described to provide multigramme quantities of the required product.

Synthesis of derivatives and carbocyclic analogues of adenosine-2′-monophosphate, a substrate for bovine inositol monophosphatase, shows that the 1-purine heterocycle and the 4-hydroxymethyl are not required for binding to the enzyme. In contrast, the cyclic ether oxygen is necessary for efficient phosphate hydrolysis.

The effectiveness of cyclooctadiene and norbornadiene precatalysts of the type [Rh(DuPHOS)(diolefin)]BF 4 in catalytic asymmetric hydrogenation of various prochiral olefins has been examined. In some of the systems studied, the NBD complex gave rise to the catalytically active species more rapidly than the corresponding COD complex, as expected. However, as catalyst loadings were reduced to levels more conducive to economic manufacture, the difference between the use of COD and NBD precatalysts became increasingly insignificant. This was conveniently highlighted by the formation of low enantiomeric excess products upon using an equimolar mixture of ( S , S ) and ( R , R ) precatalysts, bearing COD and NBD respectively. With other substrates, the system displayed no induction time for either precatalyst and identical reaction profiles were observed.

Molecular superimposition studies have led to the design and synthesis of 2β,4α-dihydroxy-6α-[5-(2-hydroxyphenyl)pentyloxy]-1β-phosphoryloxycyclohexane, a potent inhibitor of inositol monophosphatase.

Side-chains corresponding to phenylalanine, tyrosine and tryptophan are introduced onto a steroid template in a highly efficient manner via a condensation of the appropriate lithium acetylide with a steroidal ketone. The subsequent acetylene functionality can be selectively reduced in the presence of a modified benzyl ether and steroid ring unsaturation.

An efficient synthesis of racemic tert-leucine from trimethylpyruvic acid using a Leuckart type reaction is described. A facile resolution of an intermediate with α-methylbenzylamine allows entry into either (R)-or (S)-tert-leucine.

The single enantiomer title alcohols, useful as ω-side chain precursors for pharmaceutically important prostaglandin analogues were synthesised from the corresponding racemic alcohols by a convenient 4-step sequence. After enzymatic acylation of the alcohol with a vinyl carboxylate, the residual (S)-alcohol in the mixture was converted to the mesylate. Subsequent displacement with the corresponding carboxylate anion, followed by enzymatic deacylation gave the desired (R)-alcohol. In this way, all of the starting alcohol was utilised without the need for separation of the starting material and product after the bioresolution.

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.

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.

[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.

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.

The asymmetric hydrogenation of a dihydropyrrolo-benzothiadiazine dioxide 1 with a diphosphine ruthenium diamine catalyst has been used to synthesize the AMPA receptor positive modulator tetrahydropyrrolo-benzothiadiazine dioxide 2 (S 18986) in high enantiomeric excess. The use of factorial experimental design led to significant improvements in the process parameters and improved enantioselectivity.

A robust and scalable procedure for the palladium-catalyzed dynamic kinetic asymmetric transformation of 3,4-epoxy-1-butene into (2 R )-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 (2 R )-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.

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.

Asymmetric hydrogenation is becoming an increasingly prevalent technology for the manufacture of complex pharmaceutical intermediates. Drawing from Chirotech's experience over the past eight years, this article emphasisesthe need for a diverse catalyst collection in providing practical solutions for a wide range of target compounds.

A concise synthesis of a symmetrical biaryl diphosphine ligand bearing 3,5-dimethylphenyl substituents at phosphorus is described. The ruthenium catalysts [diphosphine RuCl 2 diamine] containing the new ligand Xyl-TetraPHEMP were found to be as active and as selective as the state-of-the-art catalysts for homogeneous asymmetric ketone hydrogenation.