An efficient multi-gram synthesis of (1R,2S,5S)-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate, a key chiral bicyclic proline fragment employed in the construction of the potent anti-HCV drug boceprevir, has been presented. The synthetic route commences with the readily available cis-cypermethric acid, a cheap source of the cyclopropane ring required in the targeted compound, and utilizes the cis-orientation of the 2,2-dichlorovinyl and carboxylic acid side arms, already present in the starting material, to effect a diastereoselective construction of the proline moiety.

A formal synthesis of the antiasthma drug montelukast sodium is described, wherein the key chiral diol intermediate was accessed with greater convergence of the C− C bond-forming steps as compared to previous routes. Improved synthetic efficiency was achieved by deploying homogeneous metal-based catalysis in two pivotal steps. In the first, a tandem Mizoroki−Heck reaction and double-bond isomerization between a previously known allyl alcohol intermediate and a hindered 2-(2-halophenyl)propan-2-ol secured direct access to the 3-(2-(2-hydroxypropan-2-yl)phenyl)-1phenylpropan-1-one moiety in the product. In the second step, asymmetric hydrogenation of the ketone functionality in the Mizoroki−Heck reaction product provided a convenient method to introduce the benzylic alcohol chiral center and obtain the desired chiral diol precursor of montelukast sodium. A detailed catalyst screening led to the identification of ((R)-XylBINAP)((R,R)-DPEN)RuCl2 as a catalyst that afforded an enantioselectivity of 99% ee in the hydrogenation step on a multigram lab scale at a molar substrate:catalyst loading of 5000:1. ■ INTRODUCTION Developed by Merck Frosst Canada in the 1990s as a part of a drug discovery program to elucidate a selective LTD4 antagonist, montelukast sodium 1 (Singulair) (Figure 1) is today a widely prescribed medication for the treatment of asthma and symptoms of seasonal allergies. The efforts of Merck Frosst, leading to the discovery and eventual commercialization of Singulair (a once $4.5 billion-a-year drug before the expiry of its patent in 2012), has often been cited as a “case study in modern drug discovery and development”. However, there remains scope both to hone existing strategies and to develop novel ones which address shortcomings in known synthetic routes to 1. A synthetic route generally representative of processes used for 1 is shown in Scheme 1. This employs a Mizoroki−Heck reaction of allylic alcohol 3 with methyl 2-iodobenzoate in a key C−C bond-forming step, followed by asymmetric reduction of ketone 4. A significant drawback of this approach is the methyl Grignard reagent addition to the aryl ester 5 that leads to the dimethyl aryl carbinol 6. This requires the use of anhydrous cerium chloride and a large excess of reagent and involves a tedious workup procedure on account of emulsion formation during the solvent extraction process. We reasoned that the methyl Grignard addition step could be avoided, and additionally a more streamlined overall route realized by employing a halide 10 bearing a preformed dimethyl aryl carbinol moiety in the Mizoroki−Heck reaction step, to provide the key intermediate 9, from which the diol 6 could be accessed via asymmetric reduction of the ketone functionality (Scheme 2). This reordering, while superficially straightforward, poses significant challenges in both key steps involved. First, the Mizoroki−Heck reaction employs, in place of reactive methyl 2-iodobenzoate, the hindered and less reactive 2-(2halophenyl)propan-2-ol 10. Second, a highly enantioselective Received: January 28, 2015 Figure 1. Structure of montelukast sodium 1. Article

In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic α-amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent-1-enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona-derived phase-transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol% in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost-effective preparation of pharmaceuticals.

A formal synthesis of the antiasthma drug montelukast sodium is described, wherein the key chiral diol intermediate was accessed with greater convergence of the CC bond-forming steps as compared to previous routes. Improved synthetic efficiency was achieved by deploying homogeneous metal-based catalysis in two pivotal steps. In the first, a tandem Mizoroki-Heck reaction and double-bond isomerization between a previously known allyl alcohol intermediate and a hindered 2-(2-halophenyl)propan-2-ol secured direct access to the 3-(2-(2-hydroxypropan-2-yl)phenyl)-1-phenylpropan-1-one moiety in the product. In the second step, asymmetric hydrogenation of the ketone functionality in the MizorokiHeck reaction product provided a convenient method to introduce the benzylic alcohol chiral center and obtain the desired chiral diol precursor of montelukast sodium. A detailed catalyst screening led to the identification of ((R)-Xyl-BINAP)((R,R)-DPEN)RuCl2 as a catalyst that afforded an enantioselectivity of 99% ee in the hydrogenation step on a multigram lab scale at a molar substrate:catalyst loading of 5000:1.

Dehydrocoronamic acid can be racemised by dehydration of an N-acyl derivative to an azlactone, which undergoes facile racemisation. For the N-trifluoroacetyl derivative, the racemisation process was combined with an enzymatic resolution, to achieve a dynamic kinetic resolution process by which the racemate can be converted to either enantiomer.

A synthetic route to an N-BOC D-phenylalanine pharmaceutical intermediate suitable for rapid scale-up to 150-kg scale was required. A seven-step route based on asymmetric hydrogenation of an N-acetyl dehydroamino-acid was developed. Starting with terephthalic dialdehyde, monoreduction of one aldehyde group, Erlenmeyer condensation, and ring-opening/O-deacetylation with methanol provided the 4-(hydroxymethyl)-substituted dehydrophenylalanine hydrogenation substrate. Asymmetric hydrogenation of this enamide using [((R,R)-Ethyl-DuPhos)Rh(COD)]BF(4) proceeded in high enantiomeric excess. Subsequently, the cis-2,6-piperidyl group was introduced by mesylation/displacement, the BOC group was introduced, and acetyl and methyl ester groups were removed by basic hydrolysis. This route was used to manufacture 150 kg of the BOC amino acid 1.

Two complementary and scalable approaches have been used to manufacture multikilogram quantities of N,O-protected-(S)-2-methylserine. The first approach uses a diastereomeric salt resolution of 2-methylserine methyl ester as the (1S)-(+)-camphorsulfonate salt, and was used to rapidly access 15 kg of (S)-3-tert-butoxycarbonyl-2,2,4-trimethyl-1,3-oxazolidine-4-carboxylic acid with > 99% ee. The second approach involves a stereoselective enolate methylation of a chiral cyclic L-serine derivative under cryogenic conditions. The four-step telescoped process, starting from L-serine methyl ester, was used to manufacture 20 kg of (2R,4S)-2-tert-butyl-3-tert-butoxycarbonyl-4-methyl-1,3-oxazolidine-4-carboxylic acid in 52% overall yield and 98% ee. The advantages and disadvantages for scale-up of both approaches are discussed.

A series of seven bis(2,5-diphenylphospholane) ligands has been evaluated for utility in rhodium-catalyzed asymmetric hydroformylation. The ligands differ in the nature of the moiety that bridges the two phospholane rings. Hydroformylation of styrene, vinyl acetate, and allyl cyanide was performed in tandem using parallel pressure vessels. Significant differences in rate, regioselectivity, and enantioselectivity were observed between catalysts. Ligands with two-carbon bridges exhibited selectivities comparable to the ethylene-bridged (S,S)-Ph-BPE. Electron-deficient heterocyclic bridges (pyrazine and quinoxaline) gave increased rates over (S,S)-Ph-BPE. Bis(2,5-diphenylphospholane) ligands with -CH2-, -CH2CH2CH2-, and 1,1'-ferrocenyl bridges led to significantly lower selectivities and rates than (S,S)-Ph-BPE. X-ray crystal structures of [(SS`)-Ph-Quinoxaline]Rh(acac), [(R,R)-Ph-BPM]Rh(acac), and [(SS)-Ph-5-Fc]Rh(acac) are reported. The P-Rh-P bite angles in these complexes are 87.46(3)degrees, 74.10(5)degrees, and 99.06(3)degrees, respectively. As with asymmetric olefin hydrogenation using bis-phospholane ligands, the maximum enantioselectivity in asymmetric hydroformylation was found with bis-phospholanes that adopt P-Rh-P bite angles near 85 degrees.

Chiral shift 31P NMR spectroscopy allows the identification of ligand leads in asymmetric catalyst systems for ZnMe2 addition to ArCHNP(O)Ph2. Subsequent GC-based optimisation shows [RhCl(CH2CH2)2]2 and (R,R)-MeDuPhos to be the optimal pre-catalyst combination (product in 78–93% ee). Transmetallation of [(MeDuPhos)Rh{N(P(O)Ph2–CHMeAr}] with ZnMe2 appears to be the rate limiting step of the catalytic cycle as competing coordination by the imine starting material leads to Ph2P(O)NHCH2Ar via MVP hydrogen-transfer. This limitation can largely be overcome by the slow addition of the imine.

Four chiral diphosphine ligands consisting of bis(2,5-diphenylphospholan-1-yl) groups connected by the sp2 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.

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 S(N)2 reaction gave the desired amino acid ethyl ester. (c) 2006 Elsevier Ltd. All rights reserved.

ChemInformVolume 36, Issue 30 Natural Products A Convergent Synthesis of the 11-Oxa Prostaglandin Analogue AL-12182(I). Martin E. Fox, Martin E. Fox Dowpharma, Chirotech Technol. Ltd., Cambridge Sci. Park, Cambridge CB4 0WG, UKSearch for more papers by this authorMark Jackson, Mark Jackson Dowpharma, Chirotech Technol. Ltd., Cambridge Sci. Park, Cambridge CB4 0WG, UKSearch for more papers by this authorIan C. Lennon, Ian C. Lennon Dowpharma, Chirotech Technol. Ltd., Cambridge Sci. Park, Cambridge CB4 0WG, UKSearch for more papers by this authorRaymond McCague, Raymond McCague Dowpharma, Chirotech Technol. Ltd., Cambridge Sci. Park, Cambridge CB4 0WG, UKSearch for more papers by this author Martin E. Fox, Martin E. Fox Dowpharma, Chirotech Technol. Ltd., Cambridge Sci. Park, Cambridge CB4 0WG, UKSearch for more papers by this authorMark Jackson, Mark Jackson Dowpharma, Chirotech Technol. Ltd., Cambridge Sci. Park, Cambridge CB4 0WG, UKSearch for more papers by this authorIan C. Lennon, Ian C. Lennon Dowpharma, Chirotech Technol. Ltd., Cambridge Sci. Park, Cambridge CB4 0WG, UKSearch for more papers by this authorRaymond McCague, Raymond McCague Dowpharma, Chirotech Technol. Ltd., Cambridge Sci. Park, Cambridge CB4 0WG, UKSearch for more papers by this author First published: 19 July 2005 https://doi.org/10.1002/chin.200530190Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume36, Issue30July 26, 2005 RelatedInformation

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.