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Catalytic homogeneous asymmetric hydrogenation – successes and opportunities

Chris S. G. Seo and Robert H. Morris

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Seo, C. S. G.; Morris, R. H. Organometallics 2019, 38, 47–65. . https://pubs.acs.org/doi/10.1021/acs.organomet.8b00774

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Catalytic homogeneous asymmetric hydrogenation – successes and opportunities

Chris S. G. Seo and Robert H. Morris*

Department of Chemistry, University of Toronto, M5S3H6

ABSTRACT: This is an overview of successes in the realm of catalytic homogeneous asymmetric hydrogenation of substrates primarily of interest in the synthesis of pharmaceuticals in order to identify important problems still to solve. First, tables are provided that list the successful reductions to over 90% enantiomeric excess of prochiral ketones to alcohols, imines to amines, and olefins to saturated carbon centers. Noted in the tables are the metal (including “green” metals Mn, Fe, Co) or enzyme, the class of ligand, the conditions of the medium and the scale of reduction, if over 1 kg of product, and the nature of the process, whether direct hydrogenation using H2 gas (DH), transfer hydrogenation (TH) or hydrogenation with dynamic kinetic resolution (DKR). Tables of representative pharmaceutical or fine chemicals products are provided for each class of substrate. With this overview, the opportunities for further research and development become clearer.

INTRODUCTION Catalytic asymmetric hydrogenation provides a convenient and practical method to prepare chiral alcohols, amines and alkanes from prochiral substrates. The use of hydrogen gas as the reductant (asymmetric direct hydrogenation, ADH) offers 100% atom economy and has a long track record of success in the industrial production of single enantiomer advanced pharmaceutical intermediates (API) 1-

12 as recognized by the Nobel prize to Knowles13 and Noyori.14 This has inspired a huge academic research effort which continues to this day that provides leads for future successful applications. Homogeneous processes are also considered that involve the transfer of hydrogen from an alcohol solvent or formic acid to the prochiral substrate (asymmetric transfer hydrogen, ATH).

The following tables provide a summary of important transformations of prochiral ketones, imines and alkenes by the reduction of substituted C=O, C=N or C=C bonds to alcohols, amines and alkanes in greater than 90% enantiomeric excess (ee). The bold text entries are for reactions conducted on scale (OS) with more than 1 kg of product formed. The green entries represent the use of abundant, benign (“green”) metals like iron, manganese and cobalt as opposed to the more well-studied, but more expensive, rare, and potentially harmful platinum metals (Ru, Rh, Pd, Os, Ir) that have lower acceptable metal contamination limits in API than Fe, Mn and Co. Some enzyme-catalyzed reductions are also highlighted in green; they are becoming more important and are sometimes judged to be superior to a metal-based catalyst.15-16 Not shown are other functional groups on these substrates which may direct the stereochemistry of the hydride addition or slow the reaction by competitive binding. In some cases several stereogenic centers can be installed when more than one olefin17-18

or ketone19 is present or when there is an epimerizable chiral center next to the site of hydride addition that allows the operation of dynamic kinetic resolution (DKR). 2,20-29

The optimization of the catalyst structure and the conditions of operation usually involves extensive exploration and screening, especially since an enantiomeric excess in the product of greater than 90% is generally desired. Several campaigns involving high throughput screening have been described in the

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literature to achieve this objective.5,7,9,12,15,30-33 The tables of general structures of the prochiral ketones, imines and olefins that are reduced (see below) list only the final outcome of this extensive experimentation along with a literature or patent reference. Each entry first provides the metal used. Then the class of ligand, usually chelating and enantiopure, is abbreviated as with phosphorus (P-P), nitrogen (N-N) or mixed donor (P-N, P-S, P-N-P, P-N-N-P, P-N-P-N, N-C, N-N-C, S-N-N-S, N-O) atoms. Ruthenium catalysts sometimes contain arene ligands or arenes strapped to a homochiral amide-amine moiety (denoted arene-N-N in the Tables). Monodentate ligands such as phosphines and N-heterocyclic carbenes (NHC) are also used including those with self-recognition elements such as complimentary hydrogen bonding;9,34-37 these are denoted by a (P,P) notation, for example. Even though the donor atoms may be the same, there is no unique, all-purpose ligand structure for highly enantioselective reactions; for example almost every example listed below with a P-P ligand involves a diphosphine with a different structure tailored for a particular application. In certain cases computational methods have been used to discover the optimum ligand structure.38-39 The nature of the medium (protic such as an alcohol, aprotic such as THF or CH2Cl2, acidic and basic) is noted since it bears on the mechanism of the reaction when considering the stability of intermediate hydride and dihydrogen complexes40 and on the tolerance of the system to other acid- or base-sensitive groups in the substrate. Certain catalysts allow the hydrogenation of acid-sensitive41-42 and base-sensitive43-44 substrates. Tables also present a few representative examples of pharmaceutically interesting compounds produced on scale from several of the substrate classes.

KETONES An inspection of Table 1 reveals that ruthenium-based systems dominate in the ADH and ATH of ketones. Noyori’s Nobel-prize winning ruthenium catalysts trans-RuCl2(diamine)(BINAP)14 with enantiomerically matched primary diamines and BINAP ligands in basic isopropanol45 have been employed to produce a variety of important alcohols used in the pharmaceutical industry (see Table 2). These include alcohols produced from prochiral ketones with simple aryl alkyl structures CO-1,19 alpha-aminoalkyl aryl structures CO-2,19 3,4-butan-2-ones CO-5 with dynamic kinetic resolution (DKR) at the 3 position,46 and cyclic ketones of general structure CO-6. These processes are often conducted under mild conditions (20 to 100 °C, 1 to 100 atm H2) and low catalyst loadings. The DKR step allows a second stereogenic carbon center to be set in one configuration, often in high dr (diastereomeric ratio), next to the site of hydride addition. For example, a ketone of structure CO-5 was converted via ADH/DKR to approximately 4 kg of an (R)-alcohol (94% ee) API for Taranabant (Table 2) using 20 g RuCl2((S)-xyl-BINAP)((S)-DAIPEN), 370 g KOtBu at 7 atm H2 and 0 °C in isopropanol.46 A sterically hindered ketone of structure CO-6 containing a pyridyl, ester and olefin was hydrogenated on scale to >98% ee (R) alcohol for a possible cholesteryl ester transfer protein (CETP) inhibitor (Table 2) using a RuCl2(BIBOP)(ampy) catalyst where BIBOP is a homochiral bisdihydrobenzooxaphosphole and ampy is 1-aminomethylpyridine at 3 atm H2, 25 °C in isopropanol with 10 mol% KOtBu.47 The high activity is linked to the proposed mechanism of the reaction, involving the heterolytic splitting of dihydrogen under basic conditions and the hydride attack of a trans-dihydride RuH2(diamine)(diphosphine) on the hydrogen-bonded carbonyl group (NH-O=C) with low activation energy barriers.48 The nature of the process where the substrate doesn’t coordinate to the metal results in a selectivity of carbonyl over olefin reduction and inertness to halide, trifluoromethyl, alkoxy, ester, nitro, amine and amide functional groups.19 A rhodium complex with a diphosphine with a modified pyrrolidine backbone (P-N-P ligand) was active for the hydrogenation of N-benzylphenylephrone to the precursor alcohol to phenylephrine (Table 2) in

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92% ee (R) at 20 bar H2, 50 °C in MeOH with NEt3 present.49 Neutral rhodium diphosphine complexes have also been used in the ADH of hindered ketones to produce, for example Mefloquine derivatives (Table 2).50 Recently some promising abundant metal (Fe, Mn, Cu) catalysts have been described for the ADH of simple ketones CO-1.51-56 In general bespoke P-N-P’ or P-N-N tridentate chiral ligands are used on iron (0.1% loading) and manganese (1% loading) while the copper systems use a mixture of an enantiopure diphosphine ligand (1-3% loading) and tris(3,5- xylyl)phosphine at relatively high loadings (1.5-6%).

The more acidic ketones of structures CO-4, CO-10 (with n = 1) and CO-11 of Table 1 are best reduced with ADH catalyzed by the Noyori ruthenium BINAP catalysts without diamines, or by other ruthenium diphosphine catalysts under protic or acidic conditions. For these ketones there have been at least three on scale reactions conducted. The hydrogenation of hydroxyacetone (CO-4) using a RuCl2(BINAP) system resulted in the production of (R)-1,2-propanediol on a large scale for the synthesis of the antibacterial levofloxacin (Table 2).14 A -ketoester of structure (CO-10) was converted to the (S)- -alcohol in 97% ee) on scale using the same catalyst system at 4 atm H2, 100 °C in ethanol; this alcohol was used in the synthesis of an HMG-CoA reductase inhibitor (Table 2).57 The mechanism for CO-10 is thought to involve the coordination of a protonated ketone as well as a functional group of the ketone via chelation to a cationic ruthenium hydride intermediate [RuHCl(BINAP)(H-ketone)]+.19 The tolerance of the hydride intermediates to acids can be understood by estimating the pKa of their protonated dihydrogen forms.40,58 The neutral dihydride intermediate RuH2(diamine)(BINAP) is easily protonated to give inactive cationic dihydrogen complexes (pKa

iPrOH > 10) while the monocationic [RuHCl(BINAP)(H-ketone)]+ are not easily protonated because they would give very acidic dicationic dihydrogen complexes (pKa

iPrOH < 0). An -amino--keto ester (CO-11) was converted into a carbapenam precursor alcohol (Table 2) on scale using the ruthenium binap system under AH/DKR conditions of 100 atm H2, 1% catalyst at 50 °C.8 Interestingly a nickel-based system with a diphosphine ligand catalyzes the ADH/DKR of such a substrate (CO-11) with a higher catalyst loading (5%) at 100 atm H2, 25 °C.59

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Table 1. Structures of ketones that have been hydrogenated to alcohols in greater than 90% ee using homogeneous catalysts.a

CO-1 R1 = aryl, heteroaryl, alkenyl, alkynyl; R2 = alkyl. Ru/P-P,N-N/base/DH,OS,1,5,7-8,14,19,60 Ru/P-N,P/base/DH,OS,61 Ru/arene,N-N/protic/TH,OS or enzyme/TH,OS,62 Ru/arene,N-O/base/TH,OS,7,63 Rh/Cp*,NN/base/TH,OS,64 Ru/P-P,N-N-C/base/DH,65 Ru and Os/P-P, C-N-N/base/TH,66-67 Ru/P-N-N-P/KOtBu/DH and TH,68 Ru/S-N-N-S/base/DH,69 Ir/P-N-N/base/DH,70-72 Rh/P-P/DH,73 Ru/arene,N-N/base/TH,20 Ru/arene-N-N/acid/TH.74-75 Cu/P-P/base/DH,51-52 Fe/P-N-P/base/DH,53-55 Fe/P-N-N-P/base/TH,76 Fe/P-N-P-N, CNR/protic/TH,77 Mn/P-N-N/KOtBu/DH,56 Enzyme/TH.78 CO-2 R1 = aryl; R2 = -aminoalkyl, -aminoalkyl, -aminoalkyl. Ru/P-P,N-N/base/DH,OS,8,19,79 Rh/P-N-P/aprotic/DH,OS,49 Ir/P-N-N/KOH/DH,80 Ru/P-P,N-N/KOH/DH,81 Rh/P-P/base/DH,49 Rh/P-P/acid/DH.1 CO-3 R1 = R2 = aryl, heteroaryl. Ru/P-P/acid/DH,OS,14 Rh/P-P/aprotic/DH,50 Rh/arene,N-N/acid/TH,20 Ru/P-N,P/NaOH/DH,82 Ir/P-N-N/base/DH,70 Ir/Cp*,N-N/protic/TH,64, Ru/arene-N-N/base/TH.75

CO-4 R1 = aryl; R2 = alkyl; X = Cl, Br, OAr, Oalkyl. Ru/P-P/acid/DH,OS,14 Rh/arene,N-N/acid/TH,20 Ru/P-N,P/NaOH/DH,82 Ir/P-N-N/base/DH,70 Ir/Cp*,N-N/protic/TH,64 Ru/arene-N-N/base/TH.75

CO-5 Ru/P-P,N-N/KOtBu/DH,DKR,OS,1,7,46 Ru/arene-N-N/base/TH,DKR,25 Ru/P-P/base/DH,DKR.2

CO-6 Ru/P-P,N-N/base/DH,OS,47 Rh/P-P/MeOH/DH,OS or Enzyme/TH,24 Rh/Cp,N-O/protic/TH,OS,83 Ru/S-N-N-S/base/DH,69 Ru/P-P,N-N/KOtBu/DH,44 Ru/arene-N-N/base/TH,75 Ru/arene,N-N/TH.23

CO-7 Ru/arene,N-N/acid/TH,DKR,25 Ru/arene-N-N/base/TH.75

CO-8 Ru/arene,N-N/NEt3,HCOOH/ATH. 84

CO-9 Ru/arene,N-N/protic/TH.20 Fe/PPNN/protic/TH.77

CO-10 n = 0-3; R1 = aryl; R2 = alkyl. Ru/arene,P-P/protic/DH,OS,57 Ru/arene,P-P/protic/DH,21 Ru/P-P/protic/DH,8,85-86 Ru/P-P/acid/DH,DKR,22 Ru/arene,N-N/iPrOH/TH,20 Os/arene,N-N/in living cell/TH.87

CO-11 R1 = aryl, alkyl; R2 = Me, Et; R3 = alkyl, OMe, NHCOCH3, CH2NHCOPh. Ru/P-P/CH2Cl2/DH,DKR,OS,8,88 Rh/arene,P-P/MeOH/DH,2,5 Ru/P-P/MeOH/DH,DKR.21 Ni/P-P/acid/DH.59

a The notation for the catalytic conditions is M/chiral ligand, additive/solvent, acidity/type of hydrogenation, where the ligand is an enantiopure nitrogen-based bidentate (N-N) or polydentate (arene-N-N), phosphorus-based monodentate P or P’, or bidentate (P-P, P-N) or tridentate (P-N-P, P-N-N) or tetradentate (P-N-N-P, S-N-N-S) and the type of asymmetric hydrogenation is direct with H2 (DH) or transfer (TH), sometimes on scale (OS, >1 kg product, in bold), with/without dynamic kinetic resolution (DKR). Entries in green use non platinum metal catalysts.

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Table 2. AH of ketones in pharmaceutical synthesis.

Class of substrate

Representative Pharmaceutical or Biologically Active Agent

Action Ref.

CO-1

Aprepitant

Orally active NK1 receptor antagonist for the prevention of vomiting and nausea during chemotherapy

63,89

CO-2

Phenylephrine

Sympathomimetic 49,90

CO-3

(R,S)-Mefloquine

Antimalarial 50,91

CO-4

Levofloxacin

Antibacterial 14,92

CO-5

Taranabant

Orally bioavailable cannabinoid-1 receptor (CB-1R) inverse agonist indicated for the treatment of obesity

46

CO-6

CETP inhibitor

Potential treatment of atherosclerosis and obesity

47

6

CO-10

Shared motif in HMG-CoA Reductase inhibitors

Therapy of hypercholesterolemia 57

CO-11

Carbapenem intermediate

A class of antibiotic agents 8,88,93

a The orange fragment represents the molecule produced by asymmetric hydrogenation and the red box

highlights the centers involved.

The asymmetric transfer hydrogenation (ATH) of ketones (CO-1)63,89 catalyzed by an arene ruthenium (1S,2R)-cis-1-aminoindan-2-olate complex to make an (R)-alcohol API for aprepitant (Table 2) and the rhodium-catalyzed transfer of hydrogen from basic isopropanol to ketone (CO-6)3 have also been employed on scale. In the second process, the acetone was continuously removed to prevent the enantioenriched tetrol product from reacting with acetone in a back reaction that would degrade the ee of the product. In the first process a ketone with an electron-withdrawing 3,5-(CF3)2C6H3 group was reduced in high enantioselectivity because the back reaction of acetone with the resulting alcohol is negligible.58 These catalysts also contain amine ligands that activate the ketone via NH-O=C hydrogen bonding but are more tolerant to acidicconditions than the ruthenium BINAP diamine catalysts discussed above. Enolizable ketones with electronegative substituents are often excellent substrates where ATH can be combined with DKR in order to install multiple chiral centers.28 The cyclic ketone CO-8 (Table 1) was reduced on a 400 g scale by ATH (to 99.7 ee) with DKR at the vinylogous position (>200:1 dr) to an API for a γ-secretase modulator BMS-932481, a candidate for the treatment of Alzheimer’s disease.84

Enzyme-catalyzed transfer hydrogenations can be competitive with these catalysts and there are examples of on scale ATH of ketones CO-162,78 and CO-624 catalyzed by engineered enzyme systems. Iron-based systems with tetradentate ligands furnished with phosphorus and nitrogen donors and with one carbonyl or isonitrile ligand are particularly active and promising for the ATH of ketones CO-176-77,94 and CO-9.77 Combining a lipase and ruthenium-based alcohol dehydrogenation/hydrogenation/racemization catalyst allows the biocatalytic production of -hydroxyketones from diketones CO-9.95 There is a recent report of an iron-based system efficiently carrying out the same, enantioselective monoreduction of CO-9.77 Such reductions must be carried out under neutral conditions to avoid racemizing the base-sensitive alcohol product. Nevertheless there are several interesting compounds with these structures including the farnesyl transferase inhibitors Kurasoin A and B (Table 2).96 The use of Noyori’s ATH catalyst RuCl((S,S)-Tsdpen)(p-cymene) allows the double reduction of diketones CO-9 to the (R,R)-diols in 99% ee, >19:1 dr using the reductant 1:1 formic acid:triethylamine.20

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IMINES Despite the prevalence of chiral amine and nitrogen-containing compounds in numerous bioactive compounds and drugs, asymmetric imine hydrogenation is underdeveloped in comparison to ketones and olefins. For the preparation of chiral amines, it is often preferable to perform hydrogenation across carbon-carbon double bond adjacent to an amino group (see the olefins section below), rather than carbon-nitrogen double bond due to inherent challenges encountered in imine hydrogenation.97 Imine compounds are prone to hydrolysis over time, and are unstable under acidic conditions. In the catalytic mixture, an imine may exist as a mixture of E-, Z-, and enamine isomers which can be a significant problem regarding stereoselective hydrogenation. Finally, the product amines may coordinate to the metal, poisoning the catalyst and impeding the catalytic activity.

Table 3 lists the common asymmetric imine hydrogenations reported to date. Three of the eight on scale processes involve the reduction of imine classes CN-1, CN-5 and CN-14 by iridium catalysts and iridium catalysts dominate in the other hydrogenation reactions (CN-6, CN-10 to CN-13 and CN-16). While quinolines (CN-10) tend to be reduced to the tetrahydroquinolines, substituted isoquinolines (not shown in Table 3) or their N-formate salts can be reduced at the C=N bond,98 or at the heterocycle completely.99-101 In this way an iridium diphosphine system was used for the reduction of a quinolinium salt to synthesize, on a small scale, the drug (+)-solifenacin.100 The adjacent aromatic ring of substituted isoquinolines and substituted quinoxalines can be selectively, completely and enantioselectively hydrogenated with ruthenium systems.102-103 The imine in a substituted benzothiazepine ring was reduced in high ee by an iridium diphosphine system in the synthesis of a bile acid transporter inhibitor.104 The most well known application of iridium-catalyzed AH of imines is that of the production of (S)-Metolachlor, the active ingredient in grass herbicide for maize agriculture, by asymmetric hydrogenation of an N-aryl dialkylimine precursor of the class CN-1 in Table 4.105 In a method developed by Ciba-Geigy (now Novartis), Ir-Xyliphos was used to reduce the to produce the (S)-metolachlor precursor with >1,000,000 TON, >200,000 h-1 TOF and 79% ee. This process has been operating on >10,000 tons per year since 1996, making it the largest scale enantioselective catalytic process to date.105

The conditions for many of the imine reductions are acidic or protic, conditions where a more easily reduced iminium ion can form.40 An achiral iron carbonyl complex, the Knölker complex, is tolerant to acid conditions and allows the ADH of N-aryl imines in the presence of a homochiral phosphoric acid.106 This was the first report of the ADH of a prochiral imine to an amine in high ee by an iron catalyst although the activity of the system was low for N-phenyl imines (TON 16-20 with respect to iron, TOF 1 h-1). This iron/organoacid based system was more effective for the ADH of N-protected imines of the type CN-2 with a diphenylphosphinyl group and the reduction of benzoxazine derivatives CN-8.107 This ADH catalyst and a more active ADH iron system with an unsymmetrical homochiral P-N-P’ ligand in THF with added KOtBu53 provide N-protected primary amines from imines CN-2 in high ee. ATH catalysts based on iron also give excellent results with these imines in basic isopropanol, 76,94,108-110 particularly the FeATHer-III catalysts.58,76 Primary amines without protection can be produced in certain cases by the direct ruthenium-catalyzed ATH75,111 or iridium-catalyzed ADH112 of (sometimes stable) NH imines CN-3. A “strapped” Noyori ruthenium catalyst reported by Wills et al.75 allows the production of the primary amine precursor to the Hepatitis C drug elbasvir by ATH (Table 4). One further example of an iron-based imine ADH system is the reduction of benzoxazinones (CN-9) using an ingenious relay system where an

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achiral iron carbonyl activates dihydrogen and passes the hydride to an organic hydride carrier and the proton to a chiral Brønsted base; these in turn pass the H+/H- equivalents to the imine substrate.113

Table 3. Structures of some imines that have been hydrogenated to amines in greater than 90% ee using homogeneous catalysts.a

CN-1 R1 = aryl, alkyl; R2 = alkyl. Ir/P-P/acid/DH,OS,105 Ru/N-N-N,P/base/DH,114 Ir/P-N,C-N/aprotic/DH.115-117 Fe/Knölker/acid/DH.106

CN-2 R1 = aryl, alkyl; R2 = alkyl. Fe/P-N-N-P/base/TH,76,110 Fe/Knölker/acid/DH,106,118 Fe/P-N-P’/base/DH.53

CN-3 R1 = aryl, R2 = aryl, CH2Ar. Ru/arene-N-N/NEt3,HCOOH, DCM/TH,75,111 Ir/P-P/protic/DH.112

CN-4 Ar = R = Ph Rh/Cp*,N-N/protic/TH,OS.119 Ar = 3,5-F2C6H3, R =H. Pd/P-P/MeOH/DH.120

CN-5 R= alkyl. Ir/P-P,I2/aprotic/DH,OS,121 Ru/arene,N-N/acid/TH,OS,121 Ir/P-P,I2/aprotic/DH,OS,122-123 Ir/P-P/aprotic/DH,124 Ir/P-P,I2/acid/DH,125 Ru/arene-N-N/acid/TH,75 Rh/Cp,N-N/TH.75

CN-6, n = 0, 1; R2 = pyridin-3-yl, R3 = H. Ir/P-N,I2/aprotic/DH.126 CN-7 n = 0; R1 = OMe, Me; R2 = aryl, alkyl; R3 = Me, cyclopentyl, cyclohexyl. Ru/arene, N-N/protic/DH.127

O

N Ph

CN-8 Fe/Knölker/acid/DH.107

CN-9, X = O, NMe. Fe/organic hydride/acid/DH.113

CN-10 X = CH; R1 = H, alkyl, halogen; R2 = alkyl, aryl, quinoxalin-2-yl; R3 = H, alkyl. Ir/P-P,HX/protic/DH,22 Ir/P-N,I2/aprotic/DH,128 Ru/arene,N-N/protic/DH.129 CN-11 X = N; R1 = alkyl, aryl; R2 = alkyl, quinolin-2-yl; R3 = H, alkyl. Ir/P-P,I2/aprotic/DH,22 Ir/P-P,HX/protic/DH,130 Ru/arene,N-N/protic/DH.129

CN-12 Ir/P-P,HX/protic/DH.130

CN-13 R1 = Ph; R2 = NBnCOCF3 Ir/P-P,HX/protic/DH.130-131

CN-14 R1 = aryl, alkyl; R2 = H, aryl. Ir/P-N,I2/protic/DH,OS,132 Ir/P-P,HX/protic/DH,133 Rh/Cp*/protic/TH.134

CN-15 R =2-(6-chlorobenzoxazole) Ru/arene,N-N/NEt3,HCOOH, DCM/TH.135

CN-16b R = H, alkyl, allyl, propargyl, Bn, CHPh2; R1 = alkyl, aryl; R2 = alkyl. Ru/P-P/NH4X/DH,136-137 Ru/P-P/NH3/NH4I/DH,138 Ir/P/Ti(OiPr)4/protic/DH,139-140 Ir/acid/DH.32 Enzyme.141

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a See the footnotes of Table 1 for the definitions of the abbreviations and notations. b This structure represents the product of a reductive amination.

Table 4. AH of imines in pharmaceutical and agrochemical synthesis.a

Class of substrate

Representative Pharmaceutical or Biologically Active Agent

Action Ref.

CN-1

Metolachlor

Herbicide 142

CN-3

Elbasvir

Treatment of hepatitis C

111

CN-4

API towards aza-ketolide macrocycle

Antibiotic 119

CN-5

a. Almorexant

N O

ON

b. Solifenacin

a. Orexin antagonist for the treatment of sleep disorders – development discontinued in 2011 b. Anticholinergic drug for the treatment of overactive bladder

a.121 b.122

10

CN-6

(S)- Nicotine

(S)-Anabasine

Suggested potential for Alzheimer’s disease, Parkinson’s disease and other conditions

126

CN-11

CETP inhibitor

Potential treatment of atherosclerosis and obesity

143-144

CN-13

(+)-CP-99,994 – nonpeptide antagonist of NK1 receptor

Prevention of vomiting and nausea during chemotherapy

131

CN-14

11β-hydroxysteroid dehydrogenase type 1 inhibitor

Therapeutic agent candidate for type 2 diabetes

132

CN-15

Suvorexant

Treatment of insomnia 135

CN-16

a. Sitagliptin

a. Dipeptidyl peptidase-4 (DPP-4) inhibitor to reduce blood glucose levels in patients with type 2 diabetes b. α-adrenergic receptor antagonist

a.136 b.139

11

b. (R)-Tamsulosin

a The orange fragment represents the molecule produced by asymmetric hydrogenation and the red box

highlights the centers involved.

The ATH of the N-protected imine CN-4 catalyzed by a cyclopentadienyl amidoamino rhodium catalyst provides an on scale solution for the production of (R,R)-pseudoephenamine glycinamide, a building block of macrolide antibiotic candidates (Table 4).119

The 1,2,3,4-tetrahydroisoquinoline structure is encountered in many compounds that exhibit bioactivity. In two notable scale-up studies, ruthenium and iridium catalysts were employed in the enantioselective reduction of dihydroquinoline compounds with aryl or alkyl group substituent at one position. Verzijl et al.121 developed both ADH using iridium and ATH using ruthenium methodologies in performing the enantioselective reduction of 1-alkyl-3,4-dihydroisoquinoline derivative (CN-5) towards a large scale synthesis of almorexant (Table 4). [Ir(COD)Cl]2-TaniaPhos showed the highest catalytic activity and enantioselectivity under 6 bar H2 with iodine as an additive, and the process was scaled up to a 750 kg batch that afforded 86% yield and >96% ee after recrystallization in toluene. An ATH process was performed on a 18 kg scale using Noyori’s ATH ruthenium arene amidoamine catalyst with an overall yield of 87% and 99.7% ee after recrystallization.121 On the other hand, in work by Ružič et al.,122 1-phenyl-3,4-dihydroisoquinoline was reduced in 200 g scale via asymmetric direct hydrogenation with [Ir(COD)Cl]2-(S)-P-Phos catalyst and 1.8 equiv. of H3PO4(aq) as additive under 20 bar of H2. They identified (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline as a key intermediate of solifenacin (Table 4). The large-scale reaction showed full conversion on HPLC (95% isolated yield after recrystallization) after 47 h with 97% ee. The significant amount of throughput screening needed to find the best conditions for these two imine reduction processes is noteworthy. Verzijl et al. performed initial screening with five classes of ligands including monodentate phosphoramidites, biaryl diphosphines and ferrocenyl diphosphines, and found the optimal ligand after screening through 28 ferrocenyl ligands. Ružič et al. 122 examined the activity and enantioselectivity imparted to the catalyst by 21 ligands, mainly consisting of the BINAP and P-Phos family.

Similarly a large screening campaign of 8 ruthenium catalysts, 20 rhodium catalysts and 35 iridium catalysts was required to find the optimum iridium-based catalyst for the on scale ADH of an N-benzylindenopyridinium bromide (CN-14) needed for the synthesis of a candidate drug to treat diabetes.132 The other catalysts were reported to have less-than-satisfactory activity and enantioselectivity towards the transformation. The best result was afforded using an [Ir(COD)Cl2]-MeO-BoQPhos catalyst system under 450 psi H2 with ~98% yield on HPLC assay and 70% ee. The pyridinum ring was reduced to the piperidine derivative on a 1.5 kg scale to afford the intermediate towards the total synthesis of an 11β-hydroxysteroid dehydrogenase type 1 inhibitor (Table 4).132 This transformation involves a series of hydride transfer, protonation and tautomerization steps.145

The ATH of the Suvorexant imine (CN-15) to produce the key (R)-diazepane ring is conducted on scale using a modified Noyori Ru(cymene)(arylamidoamido) catalyst with triethylamine/formic acid as the

12

reductant in wet DCM (Table 4).135 This first-of-a kind process represents a net asymmetric reductive amination: the condensation of a dialkylketone with an alkylamine followed by the ATH of the cyclic imine to the (R)-diazepane in 94% ee.

Table 3 provides examples of very desirable asymmetric reductive amination reactions (CN-16) which are still quite rare. An excellent ruthenium-catalyzed system has been reported that can convert prochiral ketones to enantioenriched primary amines using a mixture of ammonia and hydrogen;138 the ee are up to 87% but further improvement may be possible. Nevertheless this work represents a great advance, showing that the overalkylation of ammonia can be avoided when using the correct catalyst and conditions. In 2017, a reductive aminase from Aspergillus oryzae was discovered and shown to have high activity toward the coupling of carbonyl compounds with primary and secondary amines (CN-16 in Table 3).141

OLEFINS The rhodium diphosphine-catalyzed ADH of prochiral olefins in methanol is the best established and most prevalent asymmetric reduction in pharmaceutical synthesis as recognized by the Nobel prize to Knowles.13,146 Table 5 shows that many of the classes of prochiral olefins are reduced to the saturated compound in high ee with cationic complexes of rhodium(I)/(III) with the appropriate diphosphine ligand (P-P). In particular there are several examples on scale of the N-acyl-dehydroamino acids and esters CC-1 for the production of enantiopure amino acids utilizing such rhodium systems,1,5,146-147 with at least one example of a ruthenium(II) diphosphine system.1 It should be noted that the high price of rhodium compared to the other platinum metals means that efforts are made to substitute a rhodium catalyst with one with a cheaper metal such as ruthenium or even iridium. It is interesting that cobalt diphosphine complexes have also recently been found to be active for such reductions, although not yet on scale.148-150 Several important amino acid derivatives produced from CC-1 lead to drug molecules (e.g. Table 6). A Cathepsin S inhibitor151 and an intermediate to L-DOPA146 were obtained from AH in alcohol solvents using a rhodium diphosphine complex while levetiracetam148 could be prepared using a mixture of CoCl2, a suitable diphosphine and zinc in methanol. The production of non-natural amino acids are of particular interest since they confer metabolic stability to a peptide-like drug.35

Similarly both rhodium and cobalt diphosphine systems can be used in the ADH of N-acyl enamines CC-2 with on scale examples for rhodium only so far. Three drug molecules are listed for CC-2 in Table 6, all being produced using ADH with a suitable rhodium diphosphine catalyst. One method to overcome the expense of a rhodium catalyst is to immobilize and reuse it. For example a gem-disubstituted olefin CC-2 was successfully hydrogenated on scale to an API for a JAK2 kinase inhibitor with high TON with a cationic rhodium diphosphine supported on a polyoxotungstate which in turn was supported on alumina.152

Ruthenium(II) diphosphine systems are active for the ADH of a phthalazine enamide CC-3 (on scale), cyclic N-acylenamines and carbamates CC-4 (on scale toward the production of etamicastat)153 and a variety of prochiral acrylic acids CC-5 (on scale, Table 5). Both a ruthenium diphosphine catalyst154 and a rhodium system with mixed monodentate ligands discovered via high throughput screening155 have been used to make useful API compounds starting from CC-5 compounds (Table 6). The acrylate esters CC-6 are typically reduced with rhodium or iridium diphosphines with on scale examples in Table 5 for each. Interestingly a nickel-based diphosphine system33 and metal-free ene-reductases16,156 have been

13

discovered for the ADH and ATH reduction of compounds in the class CC-6. The ene-reductase was used to make an advanced Pregabalin precursor in perfect enantiopurity (Table 6).16

As the olefins become more hindered but with fewer heteroatom groups, cationic iridium catalysts with P-N 157-158 or C-N42 donor ligands with non coordinating anions (e.g. B(3,5-C6H3(CF3)2)4

-) in CH2Cl2 become important (see CC-4, CC-6 to CC-10, CC-13, CC-15, CC-17 and CC-18). Here the weakly coordinating olefin can outcompete the solvent and counteranion for access to the iridium center in order to receive one hydride equivalent and then a proton equivalent by reductive elimination or hydrogenolysis. Catalyst death can be prevented by designing the ligands so that they prevent bridging of the hydride intermediates, a known deactivation pathway of Crabtree-like iridium catalysts.72 However the iridium system that operated on scale was a more economical cationic iridium diphosphine combination, found by high throughput screening for the ADH of CC-7.159 The screening turned up an unexpected ligand for the problem, the quite flexible (S,S)-2,5-MeCH(PPh2)CH2CH(PPh2)Me. Normally quite rigid ligands such as the Josiphos ligand of the metolachlor process, for example, are required in order to obtain high ee in the reductions. Despite the utility of iridium catalysts, most of the more hindered systems that have been reduced on scale (CC-5, CC-10, CC-19) utilize ruthenium diphosphine catalysts under acidic conditions. A fragrance molecule, Hedione produced using ruthenium160 is included in Table 6. Thus the olefin of CC-5 is reduced without interference of its carboxylic acid.161-162 The hindered olefinic groups in substituted pyrroles163-164 (not included in Table 5) and indoles related to CC-14 163 undergo very enantioselective AH using certain ruthenium or palladium diphosphine catalysts. Ruthenium complexes with homochiral NHC ligands are very effective for the AH of hindered olefins including substituted benzofurans (CC-12),165 indolizines,166 quinoxalines,103 thiophenes and benzothiophenes,167 flavones and chromones,168 vinylthioethers169 and isocoumarins.170 Certain other ruthenium,171 rhodium172 and iridium173-174 catalysts are also effective for the AH of substituted furans (not shown in Table 5) and benzofurans (CC-12). The AH of aromatic heterocycles with multiple heteroatoms has been reviewed recently.175

Perhaps cobalt complexes with diphosphine ligands will prove advantageous in the AH of hindered olefins now that they have been shown to catalyze the ADH of minimally functionalized di- and tri- (CC-8), tri- and tetra-substituted (C-17 and C-18) olefins. A rhodium walphos system provided an API in 99% ee by the hydrogenation of an ammonium fluoroolefin substrate CC-20.176

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Table 5. Structures of some olefinic groups that have been hydrogenated to saturated stereogenic centers in greater than 90% ee using homogeneous catalysts.a

CC-1 R1 = H, Me; R2, R3 = H, alkyl, aryl; R4 = H, R5 = COR. Rh/P-N/aprotic/DH,OS,5 Rh/P-

P/protic/DH,OS,1,146-147,151 Ru/P-P/base/DH,OSb,1,177 Rh/P-P/MeOH/DH,178-179 Rh/P-P/aprotic/DH,35,180-182Rh/P,P’/aprotic/DH,34 Ru/P-P/protic/DH,6,183 Ir/P-N/aprotic/DH.184 Co/P-P/MeOH/DH.148-150

CC-2 R1 = alkyl, aryl; R4 = H; R5 = COR, H; R2, R3 = H, alkyl.

Rh/P-P/protic/DH,OS,1 Rh/P-P/MeOH/DH,OS,185-188 Rh/P-P/ phosphotungstic acid-alumina/DH,OS,152 Rh/P-P/MeOH/DH.189-190 Co/P-P/MeOH/DH.149-150 CC-3 phthalazine enamide Ru/P-P/protic/DH,OS. 50

CC-4 X = CH2, O. R1 = Ac, SO2R. R2 = H, Br, OMe, alkyl. Ru/P-P/base/DH,191 Ru/P-P/protic/DH,192 Ir/P-N/aprotic/DH.193-195

CC-5 R1 = alkyl, aryl; R2, R3 = H, alkyl, aryl, OAc; R4 = H . Ru/arene,P-P/base/DH,OS,154 Rh/P-P/acid/DH,OS,196 Ru/P-P/MeOH/DH,6,50 Rh/P-P/base/DH,197 Ir/P-N/base/DH,198-199 Rh/P,P/protic/DH,155 Rh/P-P/aprotic/DH.200 R4 = Na. Rh/P-P/NaOH,MeOH/DH.201 CC-6 R1, R4 = alkyl, aryl, heteroaryl; R2, R3 = H, alkyl, aryl, OR, CN) Ru/P-P/aprotic/DH,OS,161 Ru/P-P/acid/DH,OS,162 Ru/P-P/protic/DH, OS,202 Rh/P-P/aprotic/DH,200 Ir/P-N/aprotic/DH,203-204 Ir/P,py/aprotic/DH.205 Ni/P-P,Bu4NI/MeOH/DH,33 Ene-reductase.16,156

CC-7 Ir/P-P/protic/DH,OS. 159

CC-8 R1, R2 = aryl, alkyl, heteroaryl, Bpin. Rh/P-P/aprotic/DH,18 Ir/P-N/CH2Cl2/DH,157,195 Ir/P-S/CH2Cl2/DH,39 Ir/P-C/CH2Cl2/DH,41 Ir/C-N/CH2Cl2/DH.42,206 Co/N-N-N/aprotic/DH. 207 CC-9 R1 = CF3, R2 = OAc Rh/P-P/aprotic/DH,OS.208

CC-10 R1, R2, R3 = aryl, alkyl; R1 = alkenyl, R2 = CH2NHBoc, R3 = Ar; R1 , R2 = Bpin, R3 = H. Ru/P-P/acid/DH,OS,183 Rh/P-P/base/DH,6 Ru/P-P/MeOH/DH,6,50 Ru/P-P/DH,8 Ru/P-P/base/TH,209 Ir/P-N/CH2Cl2/DH,17,157,195,204,210-212 Ir/P-N/acid/DH,213 Ir/P-S/CH2Cl2/DH,39 Ir/P-C/CH2Cl2/DH,41 Ir/C-N/CH2Cl2/DH.42,206 Co/P-P/aprotic/DH.149-150,214

CC-11 X = O, NBoc; R = alkyl, aryl. Ru/P-P/base/DH.191

CC-12 X = O; R1, R2 = alkyl, aryl. Ru/NHC/aprotic/DH,171 Ir/P-N/DCM/DH 173 CC-13 X = SO2; R1, R2 = alkyl, aryl. Ir/P-N/CH2Cl2/DH.215 CC-14 X = NH. Ru/arene,N-N/protic/DH,127,216 Pd/P-P/acid/DH.217

CC-15 n = 1,2; R1, R2 = H, alkyl, aryl. Ir/P-N/aprotic/DH,218 Ir/P-N/CH2Cl2/DH.157,219-220 CC-16 Isocoumarin. Ru/NHC,N-N/NaOtBu/DH.170 CC-17 n = 2; R1 = NR2. Ir/P-S/CH2Cl2/DH,39 Ir/C-N/aprotic/DH,42 Ir/C-N/CH2Cl2/DH,41 Ru/N-N/aprotic/DH,221 Ru/NHC/KOtBu/DH,222 Ru/NHC/aprotic/DH,171Rh/P,P/CH2Cl2/DH.36 Co/P-P/aprotic/DH.150,214

CC-18 R1, R2, R3, R4 = aryl, alkyl. Ru/P-P/acid/DH,2 Ir/P-N/aprotic/DH,157 Rh/P-P/MeOH/DH.220 Co/P-P/aprotic/DH.150

CC-19 Ru/P-P/aprotic/DH,OS.160

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CC-20 Rh/P-P/protic/DH,OS.176

a See the footnotes of Table 1 for the definitions of the abbreviations and notations. b This is an N-sulfonamide.

Table 6. AH of olefins in pharmaceutical and fragrance synthesisa

Class of substrate

Representative Pharmaceutical or Biologically Active Agent

Action Ref.

CC-1

a. Cathepsin S inhibitor

b. L-DOPA

c. Levetiracetam

a. Potential autoimmune disease treatment b. Parkinson’s disease treatment c. Epilepsy treatment

a. 151 b. 146,223 c. 148

CC-2

a. Taranabant

b. Sitagliptin

a. Potential treatment obesity – development discontinued in 2008 b. Type 2 diabetes treatment c. Potential use in management of pain and inflammation

a.185 b.188 c.187

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c. Bradykinin B1 antagonist

CC-4

Terutroban

Antiplatelet agent 192

CC-5

a. Aliskiren

b. Prostaglandin D2 receptor (PGD2) antagonist

a. Direct renin inhibitor for treatment of hypertension b. Potential treatment for asthma and allergic rhinitis

a.155 b.154

CC-6

a. MK-1597 (ACT-178882)

a. Renin receptor inhibitor for potential treatment of hypertension b. Treatment of epilepsy, neuropathic pain and anxiety disorder c. Cardiovascular drug for treatment of heart failure

a. 161 b. 16 c. 202

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b. Pregabalin

c. Candoxatril

CC-10

a. Rozerem

b. Tipranavir

a. Treatment for insomnia without dependence b. Protease inhibitor for treatment of HIV infection

a. 224 b. 225

CC-19

methyl (+)-cis-dihydrojasmonate

Perfume ingredient 160

a The orange fragment represents the molecule produced by asymmetric hydrogenation and the red box

highlights the centers involved.

FUTURE OPPORTUNITIES FOR ASYMMETRIC HYDROGENATION DEVELOPMENT With high throughput discovery methods12,29,148,226 well established, screening for new catalysts and reactions will continue at an accelerated pace. This progress will be driven by even more productive experiments enabled by:

new metal precursors for screening and synthesis, especially those of the earth-abundant 3d metals particularly manganese, iron, cobalt, nickel and copper.150,214,227

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better mechanistic understanding of 3d metal catalysis, 58,148,150 and the general causes of catalyst poisoning by dioxygen,217,228 substrate functionality (e.g. nitrile, pyridyl, carboxylic acid, halogen, etc.) 229 and common impurities.

modular components for rapid ligand covalent synthesis with diverse electronic and steric properties in a few steps from commercially available homochiral compounds.26,54,75,123,157-

158,170,195,212,220,230-231 modular self-recognizing monodentate ligands for combinatorial catalyst synthesis.34-35,37 combinatorial ligand and substrate libraries for screening.226 new, commercially-available catalyst precursors and ligands in both enantiomeric forms in

quantities suitable for on scale applications. computational guidance in catalyst, substrate, and experiment design, increasingly with the

application of artificial intelligence techniques.232-233 on stream optimization in flow.32,152,234-236 new catalyst supports for flow applications.152,234-235 further advances in biotechnology and the directed evolution of enzymes (Nobel Prize, 2018).237

These advances will speed the discovery of the correct catalyst structure and conditions for the substrate of interest, since we recognize that there is no one metal-ligand solution for all ADH. The catalyst components are required to be easy to prepare in high yield and purity, and easy to handle.130 They should be readily activated and have high activity, productivity and enantioselectivity.

As noted above, while the use of earth-abundant metals is desirable from a cost, sustainability, health, and environmental point of view, the 3d metals present their own challenges. Without proper ligand scaffolding they tend to be unstable and sensitive to oxygen, particularly when paramagnetic. For related complexes, the 4d and 5d metals typically have larger HOMO/LUMO gaps than the 3d metals and are less likely to go high spin. The scarcity of 3d metal catalysts represented in Tables 1, 3 and 5 shows that much work needs to be done to define the limits of what is achievable in the reduction of the other classes of functional groups listed. There are no large scale applications of such homogeneous catalysts to date although the cobalt-based systems reported recently by the Merck/Princeton groups31,148-149 look promising for applications in the ADH of olefins. While 3d metal catalysts may be superior in terms of turn over frequency than their noble metal competitors,76 the productivity of the catalysts still needs to be improved. New, different types of air-stable 3d metal precursor complexes with labile ligands would be useful for screening applications and catalyst synthesis. The pros and cons in using metals for asymmetric hydrogenation versus enzymes or even stoichiometric reagents have been discussed.5,11,238

While conventional homochiral diphosphines provided a solution to the cobalt-catalyzed ADH of olefins, in general, bidentate ligands with 3d metals have not yet been successfully applied to the ADH of C=O and C=N bonds. Instead specific tridentate53-56,239 (including cyclopentadienyl-type106,110,113) and tetradentate58,76-77,240 ligands have proven successful so far. These ligands or catalysts are not yet commercially available for on scale applications although samples of the FeATHer-II catalyst can be purchased.58 It is important to have both enantiomers of the ligand available since usually enantiomeric drugs have to be evaluated in both forms.

There are several classes of substrate not shown in the Tables 1,3 and 5 that are still a challenge for any ADH system. Prochiral ketones and imines with only alkyl substitution have only rarely been

19

hydrogenated to products in >90% ee.241 Prochiral aromatic rings without heteroatom substitution are very challenging. Some progress has been made in the ADH of carbocyclic arenes using ruthenium catalysts 103,242 but further work is needed. Even imines that form part of a heteroaromatic structure often require harsh conditions (elevated H2 pressure and temperature with low substrate to catalyst loading). The report of the reduction of the pyridine rings of bisquinolines129 opens the possibility of ADH providing ligands for new catalysts for asymmetric synthesis, much like the way Fryzuk and Bosnich used a rhodium catalyst to “breed” its own chiral precursor. 243

Also not shown in the table is the scope of each hydrogenation, particularly whether other functional groups such as silyl, nitro, nitrile, imine, amine, olefin, aldehyde, thiophene or halogen can be tolerated or even left intact. High selectivity for the predictable reduction of one or more type of functional group is a desirable catalyst property. Often the presence of such groups causes noble metal catalyst deactivation or side reaction but usually how they affect catalysis is not known or understood.229 It is interesting to note that a nickel-catalyzed ADH of olefins was tolerant to the presence of imine, thioether, chlorides and bromides33 and an iron-catalyzed ATH of ketones and imines was tolerant to the presence of imine, thiophene, furans and olefins suggesting that 3d metals have promise for such applications.

Ketone substrates CO-1 to CO-9 are usually hydrogenated under basic conditions although there are exceptions where base sensitive substrates such as esters in alcohol solvent were successfully used. 43-

44,48,68,77,244 Imine and olefin substrates are often hydrogenated under acidic conditions using noble metal catalysts. There are only a few known systems involving a 3d metal that are tolerant to acidic conditions – the Knölker iron system106 and an iron-tricarbonyl system.113 More work is needed in this direction. The use of aprotic solvents such as CH2Cl2 can allow the ADH of acid sensitive-substrates such as enol-ethers and Boc-protected allylic alcohols with the correct iridium-based catalyst.41-42 Only CN-2, CN-8 and CN-9 have been reduced using iron-based systems and the products have not yet been incorporated into API. The complete reduction of prochiral heterocyclic rings like CN-13 and CN-14 remains a challenging problem.

Tri- and tetrasubstituted olefins with no groups that can act to direct the attack on the olefin are still a challenge, particularly unfunctionalized tetrasubstituted cycloalkenes. A mixture of E- and Z- isomers in the starting olefin or imine structure can be problematic. In fact for tri-substituted olefins the two isomers often lead to alkanes of opposite chirality with a low ee for the resulting mixture.231 Catalysts that provide the same high ee for both isomers are needed.

There are many advantages to conducting asymmetric hydrogenation in a flow system. This allows more robotic control of the conditions, enhanced catalyst reusability, high effective catalyst concentration (charge), and the safe use of higher pressures and temperatures. Reliable methods of homogeneous catalyst immobilization are still needed. If the catalyst and intermediates are all positively or negatively charged, then electrostatic absorption to solid supports such as polyoxometallate-coated alumina has proven to be effective. 152,234 Neutral catalysts can be supported using polymer-attached diphosphines.245

Asymmetric hydrogenation will remain an important reaction in the tool box of pharma research, development and production and in academia. It solves the problem of making a homochiral structure in a reliable, prompt and economical fashion, all of which are critical considerations in the time-sensitive synthesis of API.

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AUTHOR INFORMATION

Corresponding Author

*Email for R.H.M.: rmorris@chem.utoronto.ca

ORCID

Robert H. Morris: 0000-0002-7574-9388

Chris S. G. Seo: 0000-0002-5519-4127

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS

R.H.M. thanks NSERC for a Discovery Grant.

REFERENCES

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