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DOI: 10.1055/s-0040-1706869
Building Complexity and Achieving Selectivity through Catalysis – Case Studies from the Pharmaceutical Pipeline
All the authors are current employees of Amgen Inc.
Publication History
Received: 15 May 2020
Accepted after revision: 30 May 2020
Publication Date:
23 July 2020 (online)
Dedicated to Prof. Barry M. Trost in recognition of his contributions to the advancement of transition-metal catalysis and his efforts in training the next generations of organic chemists.
Abstract
The last decade of small-molecule process development has witnessed a trend of increasing molecular complexity for clinical candidates. The continued advance of novel catalytic methods and subsequent translation to efficient and scalable processes has enabled process chemists to overcome the challenges associated with increasing complexity. This Account highlights several examples from the process chemistry laboratories at Amgen.
1 Introduction
2 The Evolution of Molecular Complexity
3 Catalysis as a Lever to Build Complexity
4 Ru(II)-Catalyzed Dynamic Kinetic Resolution Enabling the Manufacture of AMG 232
5 Application of Enzymatic Desymmetrization toward Scale-Up of the MCL-1 Inhibitor AMG 176
6 Synthesis of Fucostatin 1: Catalytic Asymmetric Transfer Hydrogenation
7 Manganese-Catalyzed Asymmetric Epoxidation To Prepare a Carfilzomib Intermediate
8 Asymmetric Reduction Strategies: Novel Apelin Receptor Agonists and AMG 986
9 Conclusions
#
Biographical sketches
Matthew G. Beaver joined the Process Development group at Amgen in 2012, where he is currently a Senior Scientist in Drug Substance Technologies, Pivotal and Commercial Synthetics. Matt earned his B.A. in chemistry from the College of the Holy Cross in 2005, followed by a Ph.D. in organic chemistry from the University of California, Irvine in 2010 under the guidance of Professor Keith A. Woerpel. He joined the group of Professor Timothy F. Jamison at MIT as an NIH postdoctoral fellow prior to the start of his industrial career at Amgen. In his current role, Matt has contributed to the technical advance of several clinical and commercial assets, with a recent focus on the implementation of continuous manufacturing to enable more efficient processes.
Seb Caille is currently a Senior Principal Scientist in Drug Substance Technologies, Pivotal and Commercial Synthetics. Seb has served as the drug substance team lead for multiple programs since joining the Amgen process development group in 2005, covering all phases of the commercialization lifecycle. He has also been mentoring junior program leads managing late-stage assets. He earned a Ph.D. in chemistry from the University of British Columbia in 2002, working under the guidance of Professor Edward Piers, and completed a postdoctoral fellowship at the University of California, Irvine, in 2004. Seb has authored 31 publications in refereed journals. He has also authored a book chapter and five patents. Finally, he has communicated his work externally in over ten conference presentations.
Robert P. Farrell is a Principal Scientist in Pre-Pivotal Drug Substance Technologies focusing on early clinical development programs. Since 2015, Bob has led four clinical programs as Drug Substance Team Leader. Bob has over 20 years of Process Research and Development experience in the pharma industry. Prior to joining Amgen in 2010, he was a member of the Chemical Development group at Roche, Palo Alto, CA, supporting early clinical development after starting his career on research into novel catalytic processes for commercial manufacturing at DSM-Catalytica, Mtn. View, CA. Bob has a B.S. degree in chemistry from SUNY-ESF in Syracuse NY.
Andreas R. Rötheli is currently a Process Development Scientist in Pre-Pivotal Drug Substance Technologies focusing on early clinical development programs. He joined Amgen in 2016 and has been involved in preclinical, clinical and commercial process development to aid the advancement of a variety of company assets ranging from cardiovascular to oncology indications. He is also a key member of Amgen’s small molecule catalysis group, which serves to support all phases of clinical development. Andreas is originally from Zürich, Switzerland and received his B.S. and M.S. degrees in chemistry from the Swiss Federal Institute of Technology in Zürich. At ETH Zürich, he performed undergraduate research in the laboratory of Prof. Erick M. Carreira, working on natural products total synthesis. He then received his Ph.D. from Harvard University working in the field of organocatalysis with Eric N. Jacobsen.
Austin G. Smith is currently a Process Development Senior Scientist in Drug Substance Technologies, Pivotal and Commercial Synthetics. Since joining Amgen in 2012, he has contributed to the scientific development and advancement of several clinical assets in Amgen’s portfolio, covering all phases of the commercialization lifecycle. Austin obtained his undergraduate degree in chemistry in 2006 from the College of the Holy Cross. He completed a Ph.D. in organic chemistry at the University of North Carolina at Chapel Hill (UNC-CH), where he studied under the direction of Prof. Jeffrey S. Johnson. Upon graduating from UNC-CH in 2011, he completed a postdoctoral appointment at Emory University under the guidance of Prof. Huw M. L. Davies.
Jason S. Tedrow is currently Scientific Director and lead of the Synthetic Technologies (ST) function within Amgen’s Pre-Pivotal Drug Substance Technologies organization, which is responsible for advancing all of Amgen’s early-stage synthetic portfolio to proof of concept clinical studies. In addition to these responsibilities ST houses Amgen’s catalysis and hydrogenation laboratory, supporting all of the synthetic pipeline to advance novel catalytic solutions. Jason obtained a B.Sc. in chemistry from Trinity University and a Ph.D. in organic chemistry from Harvard University. He has over 17 years of industrial experience including 15 years at Amgen at both the Thousand Oaks and Cambridge sites. Over his career Jason has authored over 60 papers in the field of chemical synthesis with a focus on selective catalysis to build novel molecular architectures, with a cumulative >3000 citations and h-index score of 27.
Oliver R. Thiel is currently the Executive Director for Drug Substance Technologies, Pivotal and Commercial Synthetics. His team supports commercial process development and commercialization of the Amgen small-molecule portfolio. Oliver has an undergraduate degree in chemistry from the Technical University Munich, and he completed a Ph.D. at the Max-Planck-Institut für Kohlenforsching, Mülheim an der Ruhr under the guidance of Prof. Alois Fürstner. After postdoctoral studies with Prof. Barry M. Trost at Stanford University, he joined the Amgen Process Development organization in 2003. His teams have supported multiple commercial products (Blincyto®, Carfilzomib®, Corlanor®, Imlygic®, Kanjinti®, Neulasta®, Parsabiv®, Sensipar®) and >40 clinical development candidates. Oliver has over 50 peer-reviewed publications and has presented over 20 invited lectures.
Introduction
The past decade and recent ‘Fridays for Future’ movement has highlighted the rising importance of sustainability, resource sparing and environmental protection. While aspects of the approach and message of this movement can be debated, there is significant scientific consensus regarding the contribution of mankind to climate change, and therefore it is the duty of all scientists to consider sustainability as a critical component of any research program. In this context it is testament of the visionary outlook from Prof. Barry M. Trost that nearly three decades have passed since his seminal publication on atom economy.[1] This work defined the enduring metric of atom economy, but it also emphasized the importance of ‘synthetic efficiency’ to the buildup of ‘molecular complexity’ and offered transition-metal catalysis as a method for improving atom economy.
This Account shares our perspectives on the evolution of ‘molecular complexity’ in our two decades in the pharmaceutical industry and highlights the impact of catalysis through recent case studies from the Process Development laboratories of Amgen. While many of the selected examples demonstrate the value of transition-metal catalysis for the assembly of molecular complexity, we have purposefully included two examples employing biocatalysis, which serves as a complementary capability and critical enabling technology.
# 2
The Evolution of Molecular Complexity
The key deliverable for every process chemist working at a pharmaceutical company is the design of processes that enable manufacturing of active pharmaceutical ingredients (APIs) for clinical studies or commercial distribution. The main drivers for route design can be summarized under the framework of safety, reliability or reproducibility, and efficiency. While efficiency may be measured in economic terms by the cost of goods manufactured, the concepts of atom efficiency and process mass intensity are compelling alternatives.
Individually at Amgen,[2] and as an industry,[3] we have made significant strides at improving the efficiency of our processes by employing green chemistry concepts. These positive developments have been achieved despite an increasing level of molecular complexity within our portfolio (Figure [1]).[4] We derive molecular complexity scores for Amgen molecules based on number of stereocenters, number of rings, number of synthetic steps, and molecular weight.[5] The attributes of the compounds discussed in this Account article are summarized in Table [1].
a MW: Molecular weight.
b MCS: Molecular complexity score.
# 3
Catalysis as a Lever to Build Complexity
As drug discovery shifts its focus toward the investigation of more and more complex biological processes and targets, the complexity of the molecules used to interdict these processes also tends to increase. This ramp up in molecular complexity improves not only binding efficiency, but also selectivity over other enzymes, balancing metabolic liabilities and achieving the appropriate pharmacodynamic and pharmacokinetic properties.[6] Harmonizing these characteristics requires atomic level precision and the ability to design and synthesize architectures not typical of drug candidates in the past. Multiple strategies may be deployed to access these targets, often containing multiple stereocenters, ranging from reliance on chiral-pool-based syntheses to leveraging chemo and enzymatic transformations. Amgen’s approach is to intercept these stereochemical opportunities early in therapeutic discovery to alleviate synthetic bottlenecks, build sustainable and flexible strategies to support the advance of multiple candidates, and deliver robust processes to ensure large-scale supply and enable early-phase clinical development. As the molecule then progresses through development, these strategies are re-evaluated in the context of commercialization where the catalytic approaches to the late-phase candidates can be wholly replaced or further developed as needed.
Early in discovery chemistry, it can be advantageous to prepare racemates and mixtures of stereoisomers followed by separation and individualized testing for biological activity. A single synthesis can access multiple isomers of the chemical matter being interrogated. A process utilizing chromatographic separation may still be considered once the optimum stereochemical array has been identified; however, syntheses of more complex targets with multiple stereocenters challenge the efficiency of this approach.
The chiral sulfonamide of AMG 986 (see Section 8) serves as a prime example where early synthetic efforts were focused on delivering stereochemical diversity but proved inefficient for scale-up of the desired stereoisomer upon candidate selection (Scheme [1]). Proactive collaboration with discovery chemistry anticipated this bottleneck and engendered the stereo-controlled synthesis of a single cis-stereoisomer via enantioselective hydrogenation. The change in strategy was utilized for early-phase clinical development where several 10’s of kilograms of sulfonamide were produced using the new hydrogenation chemistry (Scheme [2]).
Chemocatalysis can be preferred early in a molecule’s lifecycle over alternate strategies (enzymatic or chiral pool), as this approach tends to be more tolerant to structure changes as structure–activity relationships (SAR) emerge. As molecular complexity increases, all synthetic methods and strategies must be considered to deliver the target molecule. A multi-pronged approach was exemplified in the synthetic effort to produce AMG 176, a selective MCL-1 inhibitor (see Section 5). Early discovery routes to the target molecules were lengthy (>60 steps), challenging the preparation of even milligram to gram quantities of material. Engagement between the catalysis group and discovery team during the SAR development enabled selection of the appropriate strategy to set the required stereocenters and alleviated key bottlenecks by identifying and developing robust and scalable chemistry from the start (Scheme [3]).
In an ideal case, leveraging a single catalytic transformation to set multiple stereocenters is highly preferred, as exemplified by the chiral sulfonamide hydrogenation (Scheme [2]). For AMG 232 (see Section 4), all but one stereocenter could be set early in the sequence, with the remainder of the synthesis relying on diastereoselective and diastereospecific processes. In other cases, chiral catalysis may be required even on a highly dense stereochemical array to override or enhance the natural selectivity bias of the molecule, as highlighted by our approach to fucostatin 1 (see Section 6).
# 4
Ru(II)-Catalyzed Dynamic Kinetic Resolution Enabling the Manufacture of AMG 232
AMG 232 (1), a small-molecule inhibitor designed to disrupt the MDM2–p53 protein–protein interaction in human cells, was evaluated in the clinic as a potential treatment for several different types of cancer.[7] AMG 232 (1) possesses a stereochemically dense trans-5,6-piperidinone core. Our strategic assembly of the stereodefined skeleton of 1 centered on a highly diastereo- and enantioselective dynamic kinetic resolution (DKR) to rapidly build molecular complexity from a racemic starting material (Scheme [4]). Noyori hydrogenation converted readily accessible, racemic ketone 2 into enantioenriched secondary alcohol 3, with concomitant installation of two vicinal benzylic stereocenters. The cis relationship forged in the DKR directed, via lactone 4, a highly diastereoselective alkylation to install the challenging α-quaternary stereocenter found in the final molecule.[8] Downstream ring opening of 5 and stereospecific ring closure at the benzylic stereocenter C6 established the trans-vicinal relationship seen in 1 (Scheme [4]).[9] By identifying the highly active and selective ruthenabicyclic complex (S)-6a (Figure [2]), we successfully scaled the ketone hydrogenation to >200 kg through multiple manufacturing campaigns, affording 1, after a series of downstream operations, in high yield and high optical purity.[10]
Our initial efforts on the transformation of 2 into 3 began with Noyori precatalyst (S)-6b (Ar = Ph) (Figure [2]), which was used to deliver 1 on kilo scale as part of the first-in-human manufacturing process. Dissolving 2 in 2-propanol (2-PrOH) and treatment with KO t Bu under 70 psi H2 gave product 3 in 77% yield as a mixture of carboxyl functionality and in 91:9 er (~60:40 mixture of epimers at the C3 position). The moderate enantioselectivity in the DKR proved challenging downstream; lactone 5 was obtained in only 93:7 er. Several downstream intermediate recrystallizations were required to upgrade the enantiopurity of 1 but to the detriment of yield. Additionally, several additions of (S)-6b were required to overcome catalyst stalling in the DKR and to drive the reaction of 2 into 3 to full conversion. While suitable for early-phase development, the synthesis demanded a reliable and cost-effective route to access >100 kg quantities of 1 that were not hampered by the yield bottlenecks of the first-in-human process. Key to this approach was a robust and highly selective DKR that performed reproducibly on scale and gave the product in high diastereo- and enantioenrichment to obviate the need for downstream chiral purity upgrades.
Initial optimization of the DKR rapidly identified commercially available ruthenabicyclic precatalyst (S)-6a (Ar = mesityl, Figure [2]) as an improved catalyst for the transformation of 2 into 3. Under otherwise identical conditions, the reaction was complete in under 2 hours, with product measured in 97:3 er (~1:1 dr at C3) (Scheme [5]). Catalyst (S)-6a has been previously reported in the literature to lead to enhanced efficiency and selectivity in hydrogenation studies with a variety of ketone substrates.[11] The authors hypothesized that the bicyclic framework of the precatalyst, upon activation with base, generates a Ru–H bond trans to the arene carbon which accounts for the enhanced reactivity.
Hydrogenation of 2 with (S)-6a led to unexpected reduction of the pendent carboxyl group after extended reaction times. Under the conditions described in Scheme [5, a] diol by-product 7 was measured in 48% assay yield and 74% assay yield at the 6 hour and 18 hour time points, respectively.[12] These data correspond well with H2 update data measured over the course of the reaction; at 6 hours, 1.9 equivalents of H2 had been consumed and at 18 hours, 2.6 equivalents of H2 had been consumed. Hypothesizing that the rate of reduction of the carboxyl group may be dependent on steric hindrance, compound 2 was transesterified to the bulkier isopropyl ester by allowing the substrate to stir in the presence of KO t Bu and 2-PrOH overnight, prior to treatment under hydrogenation conditions. The result in the hydrogenation was a slower H2 uptake, with conversion complete in 6 hours. Diol 7 was measured in 2% yield at 6 hours and in 9% yield at 18 hours; correspondingly, the H2 uptake curve showed 1.01 equivalents of H2 consumed at 6 hours, and 1.17 equivalents of H2 at 18 h. Importantly, the isopropyl ester had no detrimental impact on the enantioselectivity and 3 was measured in 97.5:2.5 er (Scheme [6]). As a scalable solution to this problem, we employed a Fischer esterification of 2, using H2SO4 in 2-propanol, to convert the methyl ester into the isopropyl ester prior to hydrogenation. This process was scaled to 215 kg, with the isopropyl ester obtained in 92% yield.
Optimization of the Noyori reductive DKR identified a 0.05 mol% catalyst loading of (S)-6a and 70 psi H2 to be suitable conditions for large-scale production and the chemistry was scaled to >200 kg (Scheme [7]). After 6 hours, 3 was measured in 98.7:1.3 er with complete conversion and an assumed quantitative yield. After through-processing the mixture via hydrolysis and ring-closure steps, intermediate 4 was alkylated to provide lactone 5 in 80% yield and 99.9:0.1 er as a single diastereomer. The process improvements led to the isolation of 5 in 56% overall yield over 7 steps, an improvement from the 28% yield in the first-in-human process. Thus, through advancements in stereoselective catalysis, we were able to realize marked improvements to the yield and throughput of a challenging API on process scale.
# 5
Application of Enzymatic Desymmetrization toward Scale-Up of the MCL-1 Inhibitor AMG 176
As pharmaceutical innovators invest to discover and develop new therapeutics to treat grievous disease, molecular complexity has proven an effective weapon to enable the identification of novel potent inhibitors of targets once largely viewed as undruggable. Such is the case with Amgen’s first in class MCL-1 inhibitor AMG 176 (Figure [3]).[13] Totaling 42 synthetic steps after route selection and optimization, this exceedingly complex drug target required a synthetic strategy leveraging principles of sustainability to generate complexity from simple building blocks via catalysis to in turn enable commercial-scale manufacture.
The catalytic desymmetrization of meso feedstocks is an attractive approach to introduce chirality, as one can capitalize on favorable raw material availability and cost. It is also of little surprise that biocatalysis has seen a resurgence of interest today in process development applications when considering modern green chemistry initiatives. Aside from the E-factor improvements, the utilization of enzymatic strategies often proves to be the most attractive option for the classical process development goals of lowering manufacturing costs while improving robustness and quality. An example highlighted herein is the synthetic approach to the cyclobutane fragment 8 of AMG 176 (Scheme [8]). Application of an enzymatic route provided an inexpensive, fast, and reliable solution to enable multi-kilogram scale-up of an advanced intermediate (INTERM-A) under compressed timelines.
The original route to cyclobutane fragment 8, a small yet complex substrate, presented a synthetic bottleneck to early development efforts. The nine-step ring-expansion route from cyclopropane acetal was not suited for scale-up due to low yields and difficult isolations owing to the water solubility and non-crystallinity of intermediates. Further, chromatographic purification was complicated by the lack of chromophores. These molecular attributes that challenged a conventional synthetic approach would become an asset for an aqueous biocatalytic route in which the substrate would be readily solubilized along with the enzyme. A suitable achiral precursor was required that could be readily synthesized or purchased. Cyclobutane anhydride (Scheme [9]) was sought as the starting material, however, its limited commercial availability on gram scale[14] stifled initial development potential. The immediate challenge of scaling up a photochemical [2+2] approach under short timelines led to alternative ideas to utilize 1,2-trans cyclobutane dicarboxylic acid as the starting material. Unfortunately, the material was available only as the racemate and classical resolution was not straightforward or efficient. It was therefore gratifying to discover that racemic trans-1,2-cyclobutane dicarboxylic acid could be epimerized in situ and effectively ‘trapped’ in the desired cis confirmation as the anhydride upon treatment with catalytic Et3N in Ac2O/toluene at 110 °C. This solution provided the ultimate pathway for development of an enzymatic route, as the racemic diacid could be purchased or synthesized readily from adipic acid in a four-step process.[15] With a means of preparing an ample supply of the meso cyclobutane anhydride substrate, development efforts on an enzymatic route to target fragment 8 began in earnest (Scheme [9]). Beginning with exhaustive LAH reduction to the cis-meso diol, literature conditions for the enzymatic desymmetrization of this substrate were leveraged, work which dated back to the mid-1980s.[16] Porcine pancreas lipase (PPL)[16] and later Pseudomonas sp. [17] were both reported as effective enzymes, yielding moderate to high enantioselectivity. Both the lipase-catalyzed enantioselective acyl transfer of the diol and alternative hydrolysis of the corresponding diacetate are described. Although formation of the diacetate required an added step, this approach was found favorable as the acylation approach was sluggish and often stalled, while the hydrolysis of the diacetate was complete within 14 hours affording enantioselectivities >99% using Pseudomonas fluorescens from Amano lipase. This bacterial-derived enzyme was also viewed as a preferable alternative to the porcine-derived PPL. Controlling background hydrolysis for the diacylation step required careful monitoring and control of pH, so a buffer system with capacity to maintain a productive pH throughout the entire reaction was explored. It was found that through addition of 1.1 equivalents of trisodium citrate to a 0.1 M phosphate buffer, the pH remained stable and resulted in high selectivity (>99% ee by chiral GC) and yield (89%). As such, the enzymatic step could be readily scaled in conventional reactors with a charge and stir approach obviating the requirement of a pH feedback dosing control system. Given the lack of crystallinity of the synthetic intermediates and a desire to avoid chromatography, a highly telescoped route was implemented to deliver the final target aldehyde 8 (Scheme [9]).
Downstream steps to the trans-aldehyde began with oxidation of the chiral monoacetate by employing iodobenzene diacetate with catalytic TEMPO to generate the cis-cyclobutane aldehyde. Upon direct treatment of the reaction mixture with i Pr2NEt, epimerization to the desired trans-aldehyde 8 was achieved in 92:8 dr in 24 hours at room temperature. Having carried forward impurities from the anhydride stage without purifications, isolation as a stable adduct was deemed critical. Attempts to isolate the crude aldehyde (oil) as a bisulfite adduct gave only amorphous material that filtered poorly without an upgrade in purity. Evaluation of the unpurified aldehyde (31 wt%) in the next step (reductive amination with amine fragment 9, see Scheme [8]) using sodium triacetoxyborohydride surprisingly gave INTERM-A in 98:2 dr (as measured on the crude reaction mixture). This significant and fortuitous upgrade in chiral purity is likely driven by a highly disfavored steric compression of the cis iminium intermediate (Figure [4]).
Thus, a direct reductive amination approach with crude aldehyde 8 and amine 9 enabled initial scale-up efforts of this late-stage intermediate toward AMG 176. Coordinating supply of intermediates to work within the confines of the limited stability of 8 was required and therefore promoted the re-investigation of an aldehyde adduct. Treatment of the parent aldehyde with semicarbazide indeed gave a filterable, crystalline semicarbazone derivative of 8, albeit requiring an added deprotection step before reductive amination. A stable yet otherwise equally reactive adduct of the parent aldehyde was ultimately realized using a well published but less popularized strategy via benzotriazole adduct formation.[18] Treatment of crude 8 with benzotriazole in a mixture of MTBE and heptane afforded a bench-stable crystalline solid of 8 in high purity and yield (98 wt%, 99% dr; 91% yield) that was capable of reacting directly with amines without deprotection. Direct addition of ‘CBTA’ with intermediate 9 in the presence of sodium triacetoxyborohydride, followed by acetate hydrolysis, gave INTERM-A in 89% yield (Scheme [10]).
In summary, the generation of small, complex molecular substructures from relatively simple starting materials is often best achieved through biocatalysis. While these approaches are far from new, their industrial application to date has lagged, perhaps due in part to the perception that the reaction conditions themselves are inherently complex. As shown in this example, a simple add and stir approach is adequate. The enzymatic route to cyclobutane aldehyde 8 well exemplifies how biocatalysis enables the synthesis of complex targets such as AMG 176 at reduced cost, improved process robustness and quality, while reaching towards our aspirational goals of sustainability in the pharma industry.
# 6
Synthesis of Fucostatin 1: Catalytic Asymmetric Transfer Hydrogenation
IgG1 monoclonal antibodies with reduced glycan fucosylation have been shown to improve antibody-dependent cellular cytotoxicity (ADCC) by allowing effective binding of the Fc region of these proteins to T-cell receptors. Increased in vivo efficacy in animal models and oncology clinical trials has been associated with the enhanced ADCC offered by these engineered mAbs.[19] [20] Fucostatin 1[21] is a new inhibitor of fucosylation that has been shown to allow the preparation of IgG1 monoclonal antibodies with lower fucosylation levels and thus improve the ADCC of these proteins. A new manufacturing process was developed to support the preparation of Fucostatin 1 on large scale for wide mAb applications, featuring a catalytic asymmetric transfer hydrogenation. The heavily telescoped process includes seven steps, two crystallizations, and presents creative solutions to the solubility and extraction challenges inherent to the manufacture of carbohydrates (Scheme [11]).[22]
The initial reaction sequence of the process involves the synthesis of ester 12a from the inexpensive commodity d-arabinose.[23] The preparation is low-yielding overall (16%) but highly efficient, including three telescoped steps along with one aqueous work-up and one crystallization to afford 12a (Scheme [12]). The synthesis of carboxylic acid 11 has been previously reported.[24] Acid-catalyzed formation of kinetic[25] furanoside products 10a and 10b is followed, after a basic quench, by selective Heyns[26] oxidation of the primary alcohol in water using platinum black and air at controlled pH[27] and elevated temperature (65 °C). Crude 11 is used for conversion into the corresponding benzyl ester 12 and the major diastereomer 12a is isolated by crystallization in methyl tert-butyl ether (MTBE) in >98:2 dr and >95 wt% potency (Scheme [12]). Though both 12a and 12b may be competent to prepare Fucostatin 1, the isolation of 12a in high diastereomeric purity simplifies the study of the subsequent diastereoselective transformation.
Due to the propensity of trifluoromethyl ketones[28] to form hydrates and the associated purification challenges, ketal 14 was prepared with the goal of unmasking the ketone group under conditions also affecting its reduction. A two-step telescoped process was designed to manufacture 14, starting with per-silylation of 12a affording a solution of ester 13. The ester 13 was treated with TMSCF3 and catalytic TBAF to afford 14 in 95% yield after removal of excess reagents via agitation with silica gel and filtration to afford a toluene solution (Scheme [13]).
The ketal hydrolysis and transfer hydrogenation affording secondary alcohol 15 is performed in high yield and stereoselectivity using potassium hydroxide (0.3 equiv) and R,R-TsDPEN RuCl (mes)[29] (2 mol%) in isopropanol. A proposed mechanism for the desilylation cascade observed upon treatment of 14 with potassium hydroxide is shown in Scheme [14]. Ketal hydrolysis of 14 to afford 17 would lead to proximal transfer of trimethylsilyl from the silyl ether group at C2 to the hydrate function and further hydrolysis to generate 19. This ketone would undergo diastereoselective reduction. We have observed that in the absence of a catalyst, at low catalyst loading (<2 mol%), or using catalysts with lower transfer hydrogenation rates, decomposition of 19 is a competing pathway and the yield of 15 is diminished. R,R-TsDPEN RuCl (mes) is observed to offer the matched stereoselective case for this catalyst[30] and erosion of stereoselectivity was not observed upon prolonged exposure to the reaction conditions. Following reaction completion, 15 was treated with aqueous hydrochloric acid to cleave the trimethylsilyl ether group at C3; insoluble trimethylsilanol was removed via filtration of the mixture over Celite®, and the aqueous filtrate was washed with dichloromethane to eliminate the benzyl alcohol by-product. After reduction of ruthenium levels to <1.5 ppm via agitation with resin Quadrapure BZA, the resin is removed by filtration to afford a solution of 20 (85% assay yield) and its diastereomer (7% assay yield).
Furanoside hydrolysis is conducted to afford Fucostatin 1 in water using 2 equivalents of hydrochloric acid at 50 °C and a subsurface nitrogen sparge to remove methanol from the reaction mixture. Upon complete conversion, the mixture is cooled to 20 °C and neutralized using aqueous sodium hydroxide. The solvent is exchanged to isopropyl acetate (IPAc), the resultant solution azeotropically dried, and by-product sodium chloride removed by polish filtration in preparation for the crystallization of Fucostatin 1 (Scheme [15]). The fluorinated carbohydrate is crystallized by seeding at 40 °C, cooling to 20 °C, addition of anti-solvent heptane, and filtration. The C5 anomer of Fucostatin 1 is largely rejected in the crystallization and is present at <0.5% in the isolated solids. Fucostatin 1 is isolated as a single pyranoside form (B) in 74% yield from 20 with 96 LC area%, 97 wt%, >99.5:0.5 dr (573 g scale). The NMR signals corresponding to the two pyranoside and two furanoside forms of Fucostatin 1 in solution were identified using detailed studies (1H, 13C, 19F, 2D 1H-1H TOCSY, 2D 1H-13C HSQC, and 2D 1H-13C HMBC). Dissolution of crystalline Fucostatin 1 in DMSO-d 6 and rapid collection (<30 min) of the 1H and 19F NMR spectra of the solution showed almost exclusively form B, providing evidence that the material crystallizes in the latter form. This evidence is corroborated by the results of density functional theory calculations at the M06-2X/6-31+G(d,p) level[31] on species B–E in the absence of solvent. Based on the computed free energy differences, it was predicted that form B should represent >80% of the isomeric mixture.[32] After dissolution of the material in DMSO-d 6 and standing for multiple hours, a mixture of isomers B–E was observed by NMR.
In summary, a process to prepare kilogram quantities of Fucostatin 1 has been developed including a catalytic asymmetric transfer hydrogenation. The key transformation of the sequence involves the diastereoselective formation of the desired trifluoromethyl-bearing alcohol in >9:1 dr from a trimethylsilylketal intermediate via a ruthenium-catalyzed tandem ketal hydrolysis–transfer hydrogenation step. The new technology enables the preparation of mAbs displaying improved ADCC and in vivo efficacy.
# 7
Manganese-Catalyzed Asymmetric Epoxidation To Prepare a Carfilzomib Intermediate
Carfilzomib is the active pharmaceutical ingredient (API) of Kyprolis®, a marketed proteasome inhibitor indicated for the treatment of patients with relapsed or refractory multiple myeloma.[33] Critical to the manufacture of Carfilzomib is the efficient synthesis of epoxyketone 22, a drug substance intermediate (Scheme [16]).[34] The existing route to prepare epoxyketone 22 proceeds through a bleach-mediated epoxidation of the corresponding enone 21, resulting in a mixture of epoxide stereoisomers (ca. 2:1). The low diastereoselectivity of the process, together with the low melting point of the target compound (mp 41 °C), necessitates the use of a tedious column chromatography operation prior to isolating the target compound by crystallization. In the theme of improving process efficiency and environmental impact, development efforts focused on the identification of an asymmetric epoxidation method to deliver the requisite stereocenter with high selectivity and eliminating the inefficient column chromatography operation.
A focused development effort was catalyzed by the emergence of asymmetric epoxidation methods utilizing bioinspired non-heme manganese catalysts bearing tetradentate N-donor ligands.[35] Of immediate relevance was an application of catalyst F to prepare epoxyketone 23, a diastereomer of the target compound, using hydrogen peroxide as the stoichiometric oxidant (Scheme [17]).[36] Attempts to overcome the substrate-biased selectivity through modification of the ligand architecture, catalyst stereochemistry, or reaction conditions (e.g., chelating solvents, additives, etc.) were not successful in delivering the desired diastereomer 22. Nevertheless, an improved catalyst was identified that allowed for a significant reduction in catalyst loading while maintaining high yield and selectivity for epoxyketone 23. To evaluate scalability of the exothermic process, the procedure described in Scheme [17] was demonstrated with catalyst G leveraging slow addition of H2O2 to deliver 0.91 kg of epoxyketone 23 in 77% yield and >99.5% chiral purity after crystallization.
Numerous aspects of the epoxidation reaction warranted further consideration of equipment design and prompted the development of a small-footprint continuous platform, specifically: (1) the fast reaction rate, (2) the low-temperature operation required to maximize selectivity and minimize H2O2 disproportionation (O2 off-gassing), (3) the heat of reaction (–375 kJ/mol), and (4) the handling of 50 wt% H2O2. In this context, both plug-flow reactor (PFR) and continuous stirred-tank reactor (CSTR) platforms were evaluated. Ultimately, CSTRs were advanced based on the ability to minimize localized hot-spots using multiple H2O2 addition ports and to efficiently handle O2 off-gassing through a head-space nitrogen sweep. A process flow diagram for the optimized reactor design is detailed in Figure [5]. Feed tanks containing solutions of enone 21, catalyst G, and H2O2 are fed continuously into CSTR1 through pre-cooling loops to minimize the heat duty requirements of the chiller. The H2O2 is segregated into two equivalent portions feeding CSTR1 and then CSTR2 to minimize the detrimental impact of localized hot spots and O2 off-gassing. Regression of the kinetic data and in silico predictive design supported the inclusion of a third CSTR to ensure the conversion target (>99%) was met prior to quench. Finally, the reaction stream was combined in CSTR4 with a 15 wt% solution of NaHSO3 to quench residual H2O2, which can be safely discarded as aqueous waste.
These epoxidation studies highlighted the improved solid-state phase behavior of the undesired diastereomer relative to that of the target compound. Therefore, a new synthetic route was proposed that would leverage the epoxyketone diastereomer as a purity control point, followed by epimerization and isolation of (S,R)-epoxyketone 22 in the absence of column chromatography (Scheme [18]). The improved route, detailed in Scheme [18], requires the use of unnatural Boc-d-leucine·monohydrate such that the Mn-catalyzed epoxidation may deliver the correct epoxide stereochemistry. Isolation by crystallization of the higher melting (R,R)-epoxyketone 24 (mp 78 °C) provides a crystalline solid with high stereochemical purity. Finally, epimerization of the leucine side chain to prepare (S,R)-epoxyketone 22 with high stereoselectivity (target ≥95:5 dr) and purity could facilitate a final isolation by crystallization of the low-melting compound.
Efforts to identify conditions for epimerization revealed a thermodynamic preference for the desired diastereomer under base-promoted conditions (95:5 dr at 20 °C). A range of organic bases was investigated, demonstrating the requirement for a small, strong, and non-nucleophilic base. Of note, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was productive in effecting the desired epimerization event and providing near quantitative assay yields for the process. Importantly, the diastereoselectivity for epimerization met the required target purity to enable a final isolation by crystallization (Scheme [19]). Despite the inclusion of an additional epimerization step, the development and implementation of an asymmetric epoxidation protocol resulted in an overall improved process, as compared through an 88% reduction in E-factor.
# 8
Asymmetric Reduction Strategies: Novel Apelin Receptor Agonists and AMG 986
Heart failure represents a major unmet medical need across modern society. Globally, the disease affects more than 20 million people, with 1 million new cases diagnosed every year. In the US alone there are over 300,000 reported deaths associated with this degenerative and terminal condition annually.[37] Furthermore, the current primary standard of care employing angiotensin-converting enzyme inhibitors, beta-blockers, and diuretics merely serves to alleviate clinical symptoms instead of treating the disease directly by improving the performance of the heart as a pump.[38] As such the apelin receptor (APJ), a widely expressed G protein-coupled receptor found in the heart and thought to be important for cardiovascular function and heart development, presents an intriguing and promising novel target for the direct treatment of this grievous illness.[39] During the course of the discovery and development of the novel APJ agonist AMG 986, we identified a series of biologically active compounds derived from sulfonamide moieties bearing well-defined patterns of vicinal stereocenters.[40] In addition to the syn-1,2-dimethyl motif ultimately found in AMG 986, the team discovered clinically relevant analogs that contained syn- and anti-stereopatterns with ether substitution replacing one of the methyl groups (Figure [6]). It turned out that both the relative as well as the absolute configuration of the two stereocenters were absolutely critical for protein selectivity, which presented a substantial synthetic challenge for chemical development.
To support discovery research and enable clinical development of these specific targets, we decided to explore a variety of asymmetric reduction strategies to gain access to such complex chiral building blocks. First, we envisioned a catalytic asymmetric hydrogenation of the tetrasubstituted vinylsulfonamide 30 to install the syn-1,2-dimethyl groups present in AMG 986 (Scheme [20, a]). Enantioselective hydrogenation reactions of tetrasubstituted olefins are particularly difficult due to the challenges associated with catalyst-controlled asymmetric induction.[41] At the outset of our studies, some examples of asymmetric hydrogenations of vinyl sulfones with Rh catalysts were known, but the substrates required a secondary coordinating group.[42] Another relevant example from the literature used a Ru-BINAP catalyst for the hydrogenation of a trisubstituted vinyl sulfone with a free carboxylic acid to obtain products in moderate enantioselectivity.[43]
Initial reaction screening efforts with different transition-metal catalysts, including Rh-, Ru- and Ir-based systems, revealed that Rh(COD)(S-Phanephos)BF4 in the presence of molecular hydrogen was able to deliver the desired product in high conversion and encouraging levels of enantioselectivity (55% ee).[44] Ru- and Ir-based catalysts did not exhibit the desired reactivity to justify further exploration. However, the initial result with the rhodium-based catalyst system required relatively high reaction pressures (435 psi) and elevated temperatures (50 °C). Following reaction development and optimization efforts it was uncovered that a combination of Rh(COD)2BF4 and Josiphos ligand 34 in the presence of sub-stoichiometric amounts of zinc triflate was reactive at just 40 psi of hydrogen at ambient temperature (Scheme [21]). The optimized conditions gave 29 in high yield and high enantioselectivity.[45] [46]
Concurrent to our asymmetric hydrogenation efforts, we envisioned a reductive dynamic kinetic resolution scenario to synthesize the syn- and anti-alkoxysulfonamides 32 and 33 (Scheme [20, b]). With this approach, β-keto sulfonamide 31 would serve as the common precursor that could, in principle, give rise to all four stereoisomers previously discussed. To guarantee the success of such ambitions, we would first need to develop reaction conditions that enable fast racemization between ketone S-(31) and R-(31) (Scheme [22]), and second, find catalysts that discriminate between the two chiral substrates while performing highly enantioselective, catalyst-controlled ketone reductions.
Based on Noyori’s seminal work on the enantioconvergent hydrogenation of α-methyl β-ketoesters using ruthenium and additional examples of syn-selective reductions using asymmetric transfer hydrogenations (ATH), we anticipated that 33 could be obtained using similar conditions.[47] [48] Indeed, we discovered that Noyori-type Ru-catalyst 35 under ATH conditions yielded the desired alcohol product in high enantioselectivity, albeit with 2:1 dr favoring the undesired anti-diastereomer (Scheme [23]). Examination of other RuCl-based catalysts revealed that tethered catalyst analogues, such as 36, popularized by Wills and co-workers,[49] [50] reversed the diastereoselectivity to the desired syn-diastereomer 33. Finally, a strong steric effect of the sulfonamide group on the diamine ligand allowed us to further optimize the reaction outcome and obtain the desired syn-diastereomer in >20:1 dr and >99% ee.
Lastly, we decided to investigate the anti-selective reduction of ketone 31 using a biocatalytic strategy. While an enzymatic dynamic kinetic resolution of α-substituted β-ketosulfonamides had not been disclosed previously, reports of stereo-controlled reductions of α-substituted β-ketoesters using alcohol dehydrogenase (ADH) enzymes and whole cell reduction of substituted β-ketosulfones served as promising examples to justify an enzymatic approach.[51] Indeed, after screening and optimizing a panel of ADH enzymes, we identified that when exposing ketone 31 to NAD+, glucose dehydrogenase, glucose and ADH-150, the anti-product could be obtained in high yield and selectivity (Scheme [24]). To complete our studies, we undertook another round of enzyme screening to enable access to the enantiomeric alcohol product 32, something that could be achieved easily with the enantiomeric catalyst under chemocatalysis but that is much more challenging with enzymes. Using IPA/water at 30 °C instead of CyH/water at 40 °C, we were pleased to find that KRED-P2-H07 (Codexis) delivered the anti-enantiomer (ent-32) in equally high yield and selectivity.
In summary, we have developed an efficient strategy for the enantioselective synthesis of α,β-substituted chiral sulfonamides through various asymmetric hydrogenation reactions. Not only were we able to develop two challenging chemical methodologies using chiral transition-metal catalysts but we were also able to highlight the growing power of biocatalysis to synthesize stereochemical complexity more difficult to access using traditional chemistry. Finally, we harnessed a stereo-divergent dynamic kinetic resolution strategy combining both chemo- and biocatalytic methods to access the possible stereoisomers of a valuable α-substituted β-alkoxysulfonamide.
# 9
Conclusions
The selected examples in this Account showcase the diversity of chemo-catalysis and biocatalysis for the synthesis and manufacture of complex molecular entities. While industrial applications of catalysis are still dominated by hydrogenations, it is noteworthy that catalytic approaches to oxidations and ester hydrolysis are equally useful in the buildup of complexity. A variety of metals, ranging from ruthenium and rhodium to manganese, were highlighted. The application of catalytic processes must be considered early in the route design phase, such that the following criteria are met: (1) ready availability and sustainability of the substrate and catalyst to ensure long-term supply, and (2) integration early in the synthetic sequence to serve as a foundation for subsequent complexity-building operations. A strong continued evolution of fundamental science in academic laboratories coupled with practical applications in industrial laboratories is required to advance to further heights of efficiency and molecular complexity.
#
#
Acknowledgment
We would like to acknowledge the contributions of our co-workers at Amgen, as the work presented in this Account article relied upon the outstanding scientific and technical contributions of members of the Amgen Process Development organization.
-
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For syn selectivity, see:
For anti selectivity, see:
For a review, see:
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For syn selectivity, see:
For anti selectivity, see:
For a review, see: