Contemporary Asymmetric Phase Transfer Catalysis: Large-Scale

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Contemporary Asymmetric Phase Transfer Catalysis: Large-Scale Industrial Applications Jiajing Tan, and Nobuyoshi Yasuda Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00304 • Publication Date (Web): 29 Sep 2015 Downloaded from http://pubs.acs.org on September 30, 2015

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Organic Process Research & Development

Contemporary Asymmetric Phase Transfer Catalysis: Large-Scale Industrial Applications Jiajing Tan* and Nobuyoshi Yasuda Department of Process Chemistry, Merck and Co., Inc. P.O. Box 2000, Rahway, NJ 07065 (USA) E-mail: [email protected] CONTENTS 1. Introduction 2. Alkylation 2.1 Intermolecular alkylation 2.2 Intramolecular alkylation 3. Conjugate addition 3.1 Intermolecular conjugate addition 3.2 Intramolecular conjugate addition 4. Epoxidation 5. Phosphorylation 6. Desymmetrization 7. Summary and outlook 1. INTRODUCTION Phase transfer catalysis, by definition, enables the rate enhancement of reactions between substrates partitioned in immiscible phases through using catalytic amounts of particular reagents (i.e. phase transfer catalysts), that transport one or multiple reactants across the interface between phases.1 Since its seminal disclosure in 1971 by Starks and co-workers,2 the paradigm has been widely exploited as a powerful synthetic tool characterized by both mild reaction conditions and simple experimental protocols.1,3 As water is often employed as a co-solvent and because such methods avoid the use of heavy metals, phase transfer catalysis is often regarded as an approach that is greener and more sustainable than alternative synthetic methodologies.3 Given these attractive features, phase transfer catalysis has been applied in industrial manufacturing processes, increasing operational efficiency, decreasing product costs, and reducing environmental impacts.1,3 The principle of phase transfer catalysis has also been applied to asymmetric synthesis. Large-scale asymmetric synthesis that does not rely on the availability of chiral pool materials or classical chiral resolutions has been largely enabled by the discovery and development of new catalytic methods and reagents. Current state-of-the-art industrial methods for catalytic asymmetric synthesis are dominated by metal-catalyzed and enzymatic stereoselective reactions,4 but asymmetric catalysis using organic molecules, including phase transfer catalysts has been constantly evolving as a complementary or alternative method, and thus has attracted increased attention in recent years.4,5 In particular, asymmetric phase transfer catalysis has shown great promise for constructing quaternary stereogenic 1 ACS Paragon Plus Environment


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centers, which has been and still is one of the most challenging problems faced in organic chemistry. Important advances in the field by research groups from both industry and academia have arisen from the development and application of more intricately designed phase transfer catalysts that provide vastly improved catalytic performance. Such work has given rise to the rapidly developing domain of catalyst design and reaction scope expansion within this field (Figure 1).6 Figure 1. Selected examples of chiral phase transfer catalysts

As a result of continuous development of phase transfer catalysis, excellent reviews on asymmetric phase transfer catalysis and book chapters on industrial applications of organocatalysis, including phase transfer catalysis, have been published.6,7 In light of the recent advances on the scale-up of this technology in asymmetric synthesis,7 it would be timely to provide a complementary review that specifically surveys the large-scale application of asymmetric phase transfer catalysis, especially those in industry. Inventions from industrial labs are often disclosed in patent applications and seldom published on journal publications in order to protect the corresponding intellectual property. Therefore, we have broaden our scope to include not only journal publications but also patent applications (through the end of 2014) as source materials, while most available reviews focus exclusively on examples from journal publications. The essential goal of this review is to provide a more comprehensive account of representative asymmetric phase transfer catalysis reports that are well-established or have the potential to be applied on large scale. Seminal reports on asymmetric phase transfer catalysis will also be covered with the

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purpose of providing a brief background. The rest of examples have been selected based on the following criteria: (a) implementation on a large scale (at least 100 mmol) (b) demonstration of a detailed experimental procedure. It is often difficult to ascertain the actual reaction scale from industrial patent applications, so representative examples from process chemistry departments are also included. Notably, even in the first asymmetric phase transfer-catalyzed alkylation reaction reported by Merck in 1984,8a the largest published scale was on 3.7 gram of substrate despite a successful demonstration of the process at pilot plant scale. We will discuss the advantages and limitations of asymmetric phase transfer catalysis and, in particular, emphasize its applications to large-scale synthesis in industry. We hope that this review will attract attention to this burgeoning field and inspire further interest in catalyst design as well as reaction development. For the sake of convenience, this review will be divided according to the reaction type in the table of contents. 2. ALKYLATION 2.1 Intermolecular alkylation In 1984, Dolling and co-workers at Merck published the ground-breaking example of using a cinchona alkaloid-derived quaternary ammonium bromide as the chiral phase transfer catalyst (PTC) for the construction of a synthetically challenging, all-carbon quaternary stereogenic center.8 With 10 mol% PTC 2 in a biphasic mixture of toluene (PhMe) and 50% aqueous sodium hydroxide (NaOH) solution, methylation of phenylindanone 1 afforded product 3 in 95% yield and 92% ee (Scheme 1). Compound 3 was the key intermediate in an asymmetric synthesis of (+)-indacrinone (4), a potent diuretic.9 The alkylation reaction was proposed to proceed through an ion-pair complex between the cinchoninium cation and the indanone anion, which was stabilized via hydrogen bonding and π−π stacking interactions, also shown in Scheme 1. The resulting stereochemistry could be explained by the electrophilic attack from the less hindered Si face of this complex.10 The detailed mechanistic studies on the effects of solvents, alkylating reagents, reaction temperatures and catalysts were then conducted by Hughes and co-workers at Merck.11 The results suggested that substrate 1 is deprotonated interfacially to form the sodium enolate while the catalysts are toluene-soluble dimers and could dissociate prior to complexation with the indanone anion, resulting in an order of 0.55 for the catalysts. β-Elimination was also found to be the main degradation pathway of the cinchona alkaloid-based PTCs. Under the reported reaction conditions, PTC 5 primarily decomposed to form enol ether 6, which was confirmed by comparison of the NMR data with independently prepared compound 6 (Scheme 1).



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Scheme 1. An asymmetric phase transfer-catalyzed alkylation reaction of indanone 1 and the catalyst decomposition pathway

Later, Bhattacharya and co-workers at Merck applied a similar catalyst system to the asymmetric phase transfer-catalyzed alkylation reaction of indanone 7 with 1,3-dichloro-2-butene (8) to prepare compound (S)-9 (Scheme 2).12a The pseudo-enantiomeric cinchonidine-derived PTC was then employed to synthesize the opposite enantiomer (R)-9 (99% yield, 78% ee), which was a key intermediate for synthesizing the drug candidate 11.12b Scheme 2. Asymmetric phase transfer-catalyzed alkylation reaction of 7 en route to 11


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Inspired by these pioneering reports, a large variety of structurally well-defined cinchona alkaloid-based quaternary ammonium salts have been studied as chiral PTCs for alkylation reactions over the past thirty years.7 As shown below, some of these methodologies have already found applications in large-scale productions, particularly for the enantioselective construction of quaternary stereocenters. For convenience, the rest of this section will be organized on the basis of substrate type. The alkylation of glycine Schiff base esters initiated by O’Donnell, Lygo and Corey’s early studies represents a significant body of work in asymmetric phase transfer catalysis, which provides an efficient access to chiral α-substituted and α,α-di-substituted amino acids.6 In 2004, Hulin and co-workers at Pfizer explored the asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester 12 with 2nitrobenzyl bromide 13 in the presence of Lygo/Corey type PTC 14a (Scheme 3). The resultant 2nitrophenylalanine derivative (S)-15 was obtained in 92% yield and 93% ee by using solid cesium hydroxide monohydrate (CsOH·H2O) as the base and dichloromethane (DCM) as the solvent.13 Further reductive cyclization led to (S)-16, a known potential inhibitor of glycogen phosphorylase, in great efficiency.13 A similar sequence was also reported for synthesizing the (R)-enantiomer of 16, using the pseudo-enantiomeric quinine-derived PTC 17. In 2012, this strategy was further applied by Dounay and co-workers at Pfizer to the synthesis of (S)-16 structural analogs.14 Scheme 3. Asymmetric synthesis of 16 via a phase transfer-catalyzed alkylation reaction of glycine ester Schiff base 12

Another notable example is the asymmetric synthesis of 4-fluoro-β-(4-fluorophenyl)-L-phenylalanine reported by Patterson and co-workers at GlaxoSmithKline (GSK).15 By using the cinchonine-derived PTC 17, the alkylation product 19, a key intermediate for a drug lead at GSK, could be prepared in 55% isolated yield and greater than 99% ee after direct crystallization from the reaction mixture at lab scale (Scheme 4). Unexpectedly, upon scale up, the desired product was obtained as a racemate. Further 5 ACS Paragon Plus Environment


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investigations indicated that it is crucial to add either the catalyst or base last to obtain the high levels of enantioselectivity observed at lab scale. Similar to the original discovery reported by Hughes and coworkers,9 the catalyst decomposition was found to be responsible for these less selective pathways. During the prolonged cooling period (0.5-1h) prior to the addition of 12 required for kilogram scale synthesis, the catalyst 17 irreversibly degraded through a Hofmann elimination under the basic reaction conditions to give the enol ether 20, which performed as an unselective catalyst (Scheme 4).9 This result was further supported by both MS and NMR studies. It must be noted that the order of reagents addition is important for scaled-up reactions employing cinchona alkaloid-based PTCs, despite the advantages of these catalysts with respect to low cost, bulk availability of raw materials and ease of catalyst syntheses. Scheme 4. Asymmetric alkylation of glycine ester Schiff base 12 and catalyst decomposition pathway

A similar asymmetric phase transfer alkylation strategy was applied to the synthesis of SC-84536 (28)16, a potential inhibitor of nitric oxide synthase originally developed by Santa Cruz Biotechnology (Scheme 5). During early studies of the alkylation of compound 22, an undesired elimination reaction of starting material 21 to form diene 23 was a major competing pathway, preventing the original route from being implemented on large scale.17a The stable electrophile 26 that was less prone to elimination was conceived as an alternative substrate to address this concern. With this strategy, the allylic alkylation product 27 could be prepared from glycine ester 25 and allylic acetate 26 in 95% yield and 75% ee by strategically combining the use of a chiral PTC 14b and a palladium complex.17 Consistent with prior independent reports from Takemoto and Gong on similar transformations, the oxidative addition of the palladium complex forms the active π-allylic fragment while the chiral PTC independently controls the stereoselectivity by forming a chiral ion pair with substrate 25.18 These reports represent the early applications of cooperative catalysis involving PTCs and metal catalysts, a concept should permit the creation of new asymmetric phase transfer-catalyzed transformations.6,19


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Scheme 5. Asymmetric synthesis of the carbon framework of SC-84536 (28)

Belyk and co-workers at Merck recently reported an asymmetric synthesis of a variety of (1R,2S)-1amino-2-vinylcyclopropanecarboxylic ethyl ester derivatives using phase transfer catalysis. Starting from (E)-N-phenylmethylene-glycine ethyl ester (29) and trans-1,4-dibromo-2-butene (30), the desired α,αdialkylation product 32 was obtained in 78% assay yield and 77% ee under phase transfer conditions, using 5 mol% PTC 31 (Scheme 6).20 Treating the protected amine 32 (>99% ee) with p-toluenesulfonic acid monohydrate (TsOH·H2O) in 2-propanol (i-PrOH) followed by crystallization gave the deprotection product directly as its tosylate salt 33 in 91% yield and greater than 99% ee. Later, Lou and co-workers at Bristol-Myers Squibb (BMS) as well as Aikawa and co-workers at Sumitomo Chemical Co., Ltd. also independently reported the asymmetric syntheses of aminoester 33 and its analogues via phase transfer-catalyzed cyclopropanation reaction.21 In fact, amino ester motifs such as 33 are key side chain intermediates for several potent hepatitis C virus (HCV) protease inhibitors including grazoprevir (34),22 vaniprevir (35),23 BILN 2061 (36, ciluprevir),24 ITMN-191 (37, danoprevir)25, BMS-650032 (38, asunaprevir)26 and GS 9451 (39)27, as shown in Figure 2. Scheme 6. Phase transfer-catalyzed enantioselective cyclopropanation of glycine ethyl ester 29



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Figure 2. Selected HCV NS3/4A protease inhibitors.

Another breakthrough in asymmetric phase transfer catalysis was reported 1999 by Professor Keiji Maruoka’s group at Kyoto University. They developed a structurally rigid, quaternary spiro-ammonium salt 40, derived from the commercially available chiral binaphthol 42, as a representative of a new class of C2-symmetric PTCs.28 Under phase transfer conditions, only 1 mol% 40 could catalyze the enantioselective alkylation of glycine ester 12 with benzyl bromides in excellent yields and enantioselectivities (Scheme 7). These chiral binaphthol-based PTCs are now referred to as Maruoka catalysts and have proven to be highly efficient catalysts in large-scale preparations of biologically active molecules.6,7


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Scheme 7. Maruoka’s seminal report on asymmetric phase transfer-catalyzed alkylation reaction

FTY 720 (43), an S1P receptor agonist, is a potential immunomodulator that was originally synthesized by Yoshitomi Pharmaceuticals (Figure 3).29 In a recent effort directed toward preparing the FTY 720 chiral analogue 44, Prasad and co-workers at Novartis reported the synthesis of the chiral amino acid subunit 48 using the Val-Ala derived Schöllkopf chiral auxiliary 46 (Scheme 8).30 However, the use of a stoichiometric chiral auxiliary 46 rendered this route less desirable for scale up. An alternative synthetic route was developed featuring an enantioselective alkylation reaction catalyzed by Maruoka catalyst 50. Starting from glycine ester 24 and alkyl iodide 49, the chiral amino acid 51 was prepared in 70% yield with 96% ee.30 Furthermore, an enrichment in product enantiopurity could be achieved by recrystallizing from ethanol and toluene. This improved synthesis enabled the kilogram scale synthesis of compound 44 in seven steps and an overall yield of 22%. Figure 3. FTY 720 and its chiral analogue



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Scheme 8. Asymmetric phase transfer-catalyzed alkylation reaction of 24 en route to 44

In 2009, Hayes and co-workers at Abbott reported a stereoselective, gram-scale route toward the synthesis of S1P1 agonist 58 (Scheme 9).31 An asymmetric phase transfer-catalyzed alkylation reaction was the key step to set the stereochemistry of the quaternary center. In the presence of compound 55, a simpler version of the first generation Maruoka catalyst, alkylation of an in situ generated racemic mono-alkylated glycine ester, followed by acidic deprotection gave the desired α,α-disubstituted amino acid ester 56 in 61% yield and 97% ee. Protection of the amine 56 as its Boc carbamate followed by the ring-closing metathesis using the Grubbs-Hoveyda second generation catalyst provided the desired amino ester 57 in good yield, which could be easily functionalized for potential structure-activity relationship (SAR) evaluation.


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Scheme 9. Asymmetric synthesis of α, α-dialkyl α-amino ester 56 via phase transfer catalysis

Despite the increasing prevalence of tertiary α-chiral amines as pharmaceutical and agrochemical targets, their asymmetric syntheses remain challenging due to the lack of practical methods for industrial scale manufacturing.32 Given the reported good overall yields and stereoselectivities for exemplified applications shown in Schemes 8 and 9, the asymmetric phase transfer-catalyzed alkylation based strategy could represent a practical solution to this persistent problem. Later, Seki and Kawase at Mitsubishi Tanabe Pharm Corporation disclosed a process for the asymmetric synthesis of pyrrolyl-succinic acid imide derivatives with spiro-quaternary stereogenic centers (Scheme 10).33 The conformationally rigid homo-chiral catalyst 61 promoted the asymmetric alkylation reaction of substituted cyanoacetic ester 59 with ethyl bromoacetate 60 to construct the tetra-substituted stereocenter of product 62 in quantitative yield and a modest 52% ee. Indeed, compound 62 was the key intermediate for the preparation of AS-320135 (63, ranirestat), a promising aldose reductase inhibitor being developed for the treatment of diabetic neuropathy by Sumitomo Dainippon Pharma and Kyorin Pharmaceutical Co. Ltd. Despite the potential for further elaboration, the use of α-cyanoacetates in asymmetric catalysis to construct quaternary stereogenic centers has been met with limited success.34



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Scheme 10. Enantioselective phase transfer-catalyzed alkylation of 59 using Maruoka catalyst 61

Odanacatib (68) is a potent, selective, and neutral cathepsin K inhibitor developed by Black and coworkers at Merck for the treatment of osteroporosis.36 Recently, Humphrey and co-workers, also at Merck, reported the enantioselective synthesis of amino ester 67 as the key intermediate in the synthesis of odanacatib (68), that relies on an asymmetric phase transfer-catalyzed alkylation strategy (Scheme 11).37 In this case, only 0.3 mol% Maruoka catalyst 50 was required to efficiently catalyze the alkylation reaction of glycine ester 64 with 3-chloro-2-methylprop-1-ene (65) to furnish the desired product 66 in 89% ee. The alkylation product 66 was then directly isolated as salt 67 in 92% yield and 89% ee by the deprotection/salt formation with 1,5-naphthalenedisulfonic acid tetra-hydrate (1,5-NDSA 4H2O) in a one-pot fashion. This through process was then applied to the gram-scale synthesis of compound 68.38 Scheme 11. Asymmetric phase transfer alkylation reaction catalyzed by Maruoka catalyst 50

Compared to the cinchona alkaloid-based PTCs, the commercially available Maruoka catalysts are typically more stable, even under strongly basic conditions. This observation is likely due to either the lack of β-hydrogens that could permit Hofmann elimination or the unique dihedral angle between the ammonium nitrogen and the β-hydrogens in the 3,3’-disubstituted binaphthyl chiral pocket.7 This 12 ACS Paragon Plus Environment

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enhanced robustness and the resulting opportunity to lower the catalyst loading (or even recycle the catalysts) offsets, to some degrees, the relatively high cost associated with their elaborate syntheses. In general, the cost-effectiveness and large-scale availability of Maruoka catalysts should be thoroughly evaluated before committing to industrial scale applications. Substituted oxindoles represent another widely explored substrate class for asymmetric phase transfercatalyzed alkylation reactions since 3,3-disubstituted oxindoles are the core structural motif in a large family of natural products and biologically active molecules (Figure 4).39 Taking their inspiration from the pioneering work of Dolling and co-workers,8 Wong and Lee at Hoechst-Roussel Pharmaceuticals developed the first catalytic asymmetric synthesis of a 3,3-disubstituted oxindole in 1991. 40 Treatment of oxindole 73 with chloroacetonitrile in the presence of PTC 74 provided the desired alkylation product 75 in 83% yield and 73% ee (Scheme 12). Further elaboration led to the formal total synthesis of the anticholinesterase natural product (-)-physostigmine (76). Figure 4. Representative examples of natural products and pharmaceutical molecules containing a oxindole core.

Scheme 12. Asymmetric alkylation reaction of oxindole 73 during the formal synthesis of 76

Since this seminal report, there have been many studies which expand upon this strategy for the enantioselective synthesis of 3,3-disubstituted oxindole based complex molecules.41 In 2013, Sun and 13 ACS Paragon Plus Environment


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co-workers at Xenox Pharmaceuticals Inc. reported an asymmetric synthesis of the spiro-oxindole 80, which had been disclosed as a potent treatment for human sodium channel-related diseases (Scheme 13).42 Their synthesis relied on the stereoselective phase transfer-catalyzed alkylation reaction, which was used to construct the all-carbon quaternary stereocenter of compound 79. After crystallization, the desired 3,3-disubstituted oxindole 79 was isolated in 69% yield and 99% ee. Scheme 13. Asymmetric alkylation reaction of oxindole 77 during the synthesis of 80

Indanones have also been extensively employed as substrates in asymmetric phase transfer-catalyzed intermolecular alkylation reactions.7 As part of a research program at Merck directed toward improving hormone replacement therapy (HRT),43 Huffman and co-workers reported an efficient asymmetric synthesis of compound 83, which was a selective estrogen receptor β-modulator for HRT.44 In the presence of PTC 2, intermediate 82 was prepared in 95% yield and 76% ee (Scheme 14). This key asymmetric alkylation step assembled the all-carbon stereogenic center of indanone 82, enabling the enantioselective synthesis of compound 83 in 34% yield and only eight steps from commercially available 2-fluoroanisole. Scheme 14. Asymmetric phase transfer-catalyzed alkylation of indanone 81

2.2 Intramolecular alkylation Although alkylations that proceed via intermolecular reactions are more common than their intramolecular counterparts in the asymmetric phase transfer catalysis literature, there are, nevertheless, examples of the latter that demonstrate intramolecular alkylation can be an efficient and scalable process. In 2010, Bulger and co-workers at Merck reported a novel enantioselective 14 ACS Paragon Plus Environment

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decarboxylative alkylation reaction for the preparation of spiro-oxindole 85, a key intermediate in the synthesis of the calcitonin gene-related peptide (CGRP) receptor antagonist 84.45 From the in situ generated 3,3-disubstituted oxindole 89, the desired cyclization product 91 bearing a chiral all-carbon quaternary spiro-stereocenter was attainable in 77% yield and 95% ee, which was otherwise difficult to be accessed via asymmetric catalysis (Scheme 15).46 This process was sufficiently robust to enable the multi-kilogram scale synthesis of compound 84. To the best of our knowledge, this report represents the only known phase transfer-catalyzed asymmetric decarboxylative alkylation reaction. Scheme 15. Retro-synthetic analysis and asymmetric decarboxylative alkylation reaction

More recently at Merck, Bell and co-workers identified compound 97 as a potent CGRP receptor antagonist.47 Like compound 84, the structure of antagonist 97 features a chiral spiro-quaternary center. Once again, asymmetric phase transfer catalysis was used to construct this challenging stereocenter. Xiang and co-workers at Merck identified the doubly quaternized cinchona alkaloid 94, which is alkylated at both the quinidine nitrogen and the quinoline nitrogen, to be the most effective catalyst for this spiro-cyclization reaction (Scheme 16). Using as low as 0.3 mol% PTC 94, the cyclization product 96 was obtained in 99% yield and 94% ee within 2 hours.48 PTC 94 could be readily prepared by treating the corresponding alkaloid 92 with excess 2-bromo-5-methoxy benzyl bromide (93) under reflux conditions. Aza-oxindole 96 was carried forward to prepare compound 97 on kilogram scale.



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Scheme 16. Asymmetric alkylation reaction of 95 catalyzed by doubly-quaternized PTC 94

The doubly-quaternized cinchona alkaloid-based PTCs demonstrated unprecedented reactivity and enantioselectivity for the spiro-cyclization reaction, as shown in Scheme 16. The installation of a second alkyl group on the quinoline nitrogen atom constitutes a new class of chiral PTCs that may provide fertile ground for new catalyst design and reaction development. However, the knowledge of these doubly quaternized PTCs is just emerging and requires further studies to better understand the structure, property and reactivity of these new molecular entities. 3 CONJUGATE ADDITION 3.1 Intermolecular conjugate addition Asymmetric conjugate addition reactions represented another important class of transformations in phase transfer catalysis.7 Shortly after the original work of Dolling and co-workers,8 Conn and coworkers at Merck demonstrated that cinchonidine-derived PTC 99 could catalyze the conjugate addition of indanone 7 onto methyl vinyl ketone (98).49 The desired adduct 100, a key intermediate for the preparation of the drug candidate 11, was obtained in 92% yield and 40% ee (Scheme 17). In contrast to the strategy shown in Scheme 2 toward the same synthesis target,12 Michael acceptor 98, in this case, was used as the alkylation reagent instead of its surrogate 1,3-dichloro-2-butene (8). Scheme 17. Asymmetric phase transfer-catalyzed Michael addition reaction of 7


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More recently, Scott and co-workers at Merck reported a practical asymmetric synthesis of the estrogen receptor β-selective agonist 105, employing a similar synthetic strategy as described above. The critical step of the process route is an enantioselective Michael addition of indanone 101 to set the all-carbon quaternary stereogenic center. The reaction relies on 15 mol% of cinchonine-derived PTC 102 (Scheme 18).50 During process development, it was found that a catalyst concentration of >8mg/mL (organic phase) was necessary to obtain reproducible levels of enantioselectivity (54-56% ee). This result could be achieved if compound 101 was stirred with PTC 102 in toluene and 50% aqueous NaOH solution for 14–16h under an inert atmosphere at room temperature, prior to the addition of 98. After phase cut and work-up, the crude mixture was subjected directly to the ring-closing aldol condensation reaction with acetic acid (AcOH) and pyrrolidine to give intermediate 104 in 85% isolated yield and 52% ee. This scalable synthetic route was demonstrated at 14 kg scale.51 Scheme 18. Asymmetric phase transfer-catalyzed Michael addition reaction of 101

In 2004, Mita and co-workers at Nippon Chemical Industrial Ltd. reported a new class of pest control agents, whose structures featured a unique 3,5-diaryl-5-(trifluoromethyl)-2-isoxazoline subunit (Figure 5).52a Over the past decade, compounds that share similar structural motifs have attracted enormous interest in both academia and industry, and have been disclosed as potential lead compounds for agrochemicals, insecticides and veterinary medicines.52 For instance, Bravecto (106, fluralaner) is an insecticide developed by Nissan Chemical Industries, Ltd. and Merck, which was approved by US Food and Drug Administration (FDA) in 2014 as a flea treatment in dogs.53 To address the synthetic challenge of this structural motif, an elegant cascade conjugate addition/cyclization approach54 was reported by Matoba at Nissan Chemical Industries, Ltd.55a By using the cinchona-derived PTC 108a, the desired trifluoromethyl-substituted 2-isoxazoline 109 was obtained in 94% yield and 54% ee from an E/Z isomeric mixture of 107 (Scheme 19). Later, the asymmetric synthesis of structurally similar compound 112 was reported by Toyama and co-workers also at Nissan Chemical Industries, Ltd. By using the different PTC 111, the desired cyclization product 112 was obtained in 97% yield and 94% ee (Scheme 19).55b Other related asymmetric syntheses of this class of 17 ACS Paragon Plus Environment


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molecules employing cinchona alkaloid-based PTCs can also be found in patent applications from Syngenta Ag56 and Zoetis LLC57. Figure 5. Structures of 3,5-diaryl-5-(trifluoromethyl)-2-isoxazolines

Scheme 19. Chiral 2-isoxazolines synthesis via cascade conjugate addition/cyclization reaction

3.2 Intramolecular conjugate addition Asymmetric intramolecular hetero-Michael additions can give rapid access to a large variety of enantiomerically enriched heterocycles.58 In early reports, asymmetric hetero-Michael addition reactions were enabled by chiral auxiliaries, chiral starting materials or stoichiometric quantities of external chirality source. The same challenge also applied to the asymmetric phase transfer catalyzed conjugate addition. For instance, the intramolecular oxo-1,4-conjugate addition reaction of 113 under phase transfer conditions reported by Wilhelm and co-workers in 2006 required a stoichiometric amount of cinchona alkaloid-based ammonium salt 14a in order to achieve good levels of enantioselectivities (Scheme 20).59 Even today, the catalytic asymmetric hetero-Michael addition reaction remains a significant challenge in organic synthesis.


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Scheme 20. Intramolecular oxo-Michael addition reaction

However, recent reports have shown promise that emerging technologies will enable the effective phase transfer-catalyzed intramolecular Michael addition. In 2014, Humphrey and co-workers at Merck reported a catalytic intramolecular enantioselective aza-Michael addition of guanidine 115 for the synthesis of letermovir (119), a phase III antiviral drug for the treatment of cytomegalovirus (CMV) infections (Scheme 21).60 In a mixture of toluene and aqueous tripotassium phosphate (K3PO4) solution, the intramolecular aza-Michael reaction of guanidine 115 with a doubly quaternized PTC 116 (3 mol%) proceeded smoothly to give the desired cyclization product 117 in quantitative conversion and 77% ee. The enantiomeric purity could be further upgraded to 99% by a one-pot salt formation protocol to give compound 118 in 85% yield and over 99% ee. This unprecedented aza-Michael addition method enabled the construction of the critical stereogenic center in 119 and served as the cornerstone of the commercial manufacturing process for this product.61 Scheme 21. Intramolecular conjugate addition reaction of guanidine 115 en route to 119

4. EPOXIDATION The catalytic asymmetric epoxidation of olefins is a powerful transformation in organic synthesis, as optically active epoxides are common motifs in biologically active compounds as well as important 19 ACS Paragon Plus Environment


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synthetic intermediates.62 Since Wynberg’s pioneering report in 1976,63 asymmetric phase transfer catalysis has been widely utilized for the enantioselective epoxidation of olefins, particularly α, βenones.7 However, there are only a few industrial applications of asymmetric phase transfer-catalyzed epoxidation reactions. In 2000, Rusinov and Chertorizhskii reported highly efficient phase transfercatalyzed epoxidations of steroid derivatives 120 and 121 (Scheme 22).64 In the presence of the chiral PTC 122, using the hydrogen peroxide/hexafluoroacetone complex as oxidant, the reaction provided the corresponding epoxidation products (123, 124) in good yields (91-97%) and diastereoselectivities (7.5:1 to 14.2:1), depending on the R group. This methodology was further applied to the synthesis of Mifeprex (125, mifepristone),65 which was originally developed by Roussel Uclaf as a synthetic steroid compound with both antiprogesterone and antiglucocorticoid properties. Scheme 22. Asymmetric phase transfer-catalyzed epoxidation reaction

5. PHOSPHORYLATION Despite the knowledge gained from the asymmetric phase transfer-catalyzed alkylation and conjugate addition mentioned above, the scale-up potential of asymmetric phase transfer catalysis has yet to be fully revealed. The expansion of reaction type is another factor that would be very beneficial for largescale applications. For instance, in 2003, Tamura and Ryukoku in Nippon Chemical Industrial reported the unprecedented phase transfer-catalyzed deracemization reaction for the synthesis of chiral phosphorous amides 128, which is a potent insecticide, miticide and nematicide (Scheme 23).66 In the presence of chiral PTC 14b, the phosphorylation reaction of thiazolidin-2-one (127) with racemic chlorophosphorothiolate 126 gave the desired product 128 in 93% yield with 53% ee using a biphasic mixture of toluene and 25% aqueous NaOH solution. This method constitutes a synthetic alternative to classical resolution methods. Although the reaction mechanism is not clear and the reported enantioselectivity is modest, this discovery may still open a new direction for expanding the scope of asymmetric phase transfer catalysis.


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Scheme 23. Asymmetric synthesis of phosphorous amide 128

6. DESYMMETRIZATION Recently, a novel phase transfer-catalyzed desymmetrization was reported by Kwok and co-workers at Schering Plough for the preparation of compound 131 (Scheme 24).67 The dihydropyrrole 131 is the key synthetic intermediate for Victrelis (132, boceprevir), which was approved by the FDA in 2011 for the treatment of chronic hepatitis C infections.68 In the presence of PTC 108b, the enantioselective elimination reaction of in situ generated prochiral N-chloroamine 130 gave the desired product 131 in 80% yield and 20% ee. This protocol has been further demonstrated at 100-gram scale. Although an enzyme-based asymmetric synthesis was later developed and utilized as the optimal manufacturing process for compound 132,69 this unique transformation is an example of the opportunities available for expanding the applications of asymmetric phase transfer catalysis. Scheme 24. Asymmetric phase transfer-catalyzed desymmetrization reaction of compound 130

7. SUMMARY AND OUTLOOK The aim of this review is to provide the reader with a realistic understanding of the current status of asymmetric phase transfer catalysis in industry by summarizing research progress from both journal publications and patent applications. Synthetic chemists have developed a wide variety of chiral PTCs, such as cinchona alkaloid-based catalysts, Maruoka catalysts, and Denmark catalysts,7 and as the quantity and variety of chiral PTCs have grown so too has the diversity of transformations that can be conducted with them. These asymmetric phase transfer catalyzed reactions have emerged as an alternative to transition metal catalysis and enzymatic methods for large-scale asymmetric synthesis, 21 ACS Paragon Plus Environment


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and the summarized industrial applications speak to their own usefulness in providing solutions to challenging synthetic problems, particularly the construction of quaternary stereogenic centers.70 Despite this level of pursuit, industrial applications of asymmetric phase transfer catalysis are still limited to a relatively narrow range of reactions. Accordingly, much work remains to unlock its full potential, and future research must include the development of scalable and cost-efficient methods, the improvement of chiral PTC availability in bulk quantities, the broadening of reaction scope, and the integration of phase transfer catalysis with other catalytic manifolds. It is our hope that this review will pique the interest of readers of Organic Process Research & Development in asymmetric phase transfer catalysis and provide inspiration for future discoveries in this exciting field. Acknowledgement We gratefully acknowledged the help from Dr. Michael Kress, Dr. Kevin Campos, Dr. Feng Xu, Dr. Guy Humphrey, Bangping Xiang, Dr. Zhijian Liu, Dr. David Thaisrivongs, Dr. Artis Klapars, Dr. Paul Bulger, Dr. Rebecca Ruck, Dr. Mark Huffman, Dr. Jacob Waldman and Dr. Alexie Kalinin. Reference: (1) Starks, C.; Liotta, C.; Halpern, M. Phase-Transfer Catalysis: Fundamentals, Applications and Industrial Perspectives; Chapman & Hall: New York, 1994. (2) Starks, C. M. J. Am. Chem. Soc. 1971, 93, 195. (3) For selected reviews on phase transfer catalysis, see: (a) Freedman, H. H. Pure Appl.Chem. 1986, 58, 857. (b) Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer Catalysis, 3rd Ed.; Wiley-VCH: Weinheim, 1993. (c) Handbook of Phase-Transfer Catalysis; Sasson, Y.; Neumann R. Eds.; Blackie Academic & Professional: London, 1997. (d) Makosza, M. Pure and Appl. Chem. 2009, 72, 1399. (4) (a) Chirality in Industry-The Commercial Manufacture and Applications of Optically Active Compounds; Collins, A. N.; Sheldrake G. N.; Crosby, J., Eds.; Wiley: New York, 1992. (b) Chirality in Industry II: Developments in the Manufacture and Applications of Optically Active Compounds; Collins, A. N.; Sheldrake, G. N.; Crosby, J. Eds.; Wiley: New York, 1997. (c) Asymmetric Catalysis on Industrial Scale; Blaser, H.-U.; Federsel, H.-J., Eds.; Wiley-VCH: Weinheim, Germany, 2011. (5) For selected reviews on asymmetric organocatalysis, see: (a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (b) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (c) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390. (d) Alemán, J.; Cabrera, S. Chem. Soc. Rev. 2013, 42, 774. (e) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis−From Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim, 2005. (f) Dalko, P. I. Enantioselective Organocatalysis; Wiley-VCH: Weinheim, 2007. (g) List, B. Asymmetric Organocatalysis; Springer: New York, 2009. (h) Pellissier, H. Recent Developments in Asymmetric Organocatalysis; RSC Publishing: UK, 2012. (i) Dalko, P. I. Comprehensive Enantioselective Organocatalysis, Vols. 1−3; Wiley-VCH: Weinheim, 2013. (6) For selected reviews on asymmetric phase transfer catalysis, see: (a) O’Donnell M. J. Catalytic Asymmetric Synthesis; Ojima, I. Ed.; Chemie: New York, 1993. (b) Nelson, A. Angew. Chem. 1999, 111, 1685; Angew. Chem., Int. Ed. 1999, 38, 1583. (c) O’Donnell, M. J. Catalytic Asymmetric Synthesis, 2nd 22 ACS Paragon Plus Environment

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ABSTRACT Asymmetric phase transfer catalysis has been recognized as an approach that is greener and more sustainable than synthetic alternatives and has evolved to be one of the most practical methods in challenging enantioselective synthesis. An overview of the current status of asymmetric phase transfer catalysis in industry is presented by summarizing research progress from both journal publications and patent applications.

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Contemporary Asymmetric Phase Transfer Catalysis: Large-Scale

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