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Catalytic Kinetic Resolution of Saturated N‑Heterocycles by Enantioselective Amidation with Chiral Hydroxamic Acids Imants Kreituss and Jeffrey W. Bode* Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich, 8093 Zürich, Switzerland CONSPECTUS: The preparation of enantioenriched chiral compounds by kinetic resolution dates back to the laboratories of Louis Pasteur in the middle of the 19th century. Unlike asymmetric synthesis, this process can always deliver enantiopure material (ee > 99%) if the reactions are allowed to proceed to sufficient conversion and the selectivity of the process is not unity (s > 1). One of the most appealing and practical variants is acylative kinetic resolution, which affords easily separable reaction products, and several highly efficient enzymatic and small molecule catalysts are available. Unfortunately, this method is applicable to limited substrate classes such as alcohols and primary benzylamines. This Account focuses on our work in catalytic acylative kinetic resolution of saturated N-heterocycles, a class of molecules that has been notoriously difficult to access via asymmetric synthesis. We document the development of hydroxamic acids as suitable catalysts for enantioselective acylation of amines through relay catalysis. Alongside catalyst optimization and reaction development, we present mechanistic studies and theoretical calculation accounting for the origins of selectivity and revealing the concerted nature of many amide-bond forming reactions. Immobilization of the hydroxamic acid to form a polymer supported reagent allows simplification of the experimental setup, improvement in product purification, and extension of the substrate scope. The kinetic resolutions are operationally straight forward: reactions proceed at room temperature and open to air conditions, without generation of difficult-to-remove side products. This was utilized to achieve decagram scale resolution of antimalarial drug mefloquine to prepare more than 50 g of (+)-erythro-meflqouine (er > 99:1) from the racemate. The immobilized quasienantiomeric acyl hydroxamic acid reagents were also exploited for a rare practical implementation of parallel kinetic resolution that affords both enantiomers of the amine products in high enantiopurity. The success of this process relied on identification of two cleavable acyl groups alongside implementation of flow-chemistry techniques to ensure reusability of the resolving agents. The work discussed in this Account has laid foundations for new catalyst design as well as development of desymmetrization and dynamic kinetic resolution processes. In the meantime, as all the requisite reagents are commercially available, we hope that hydroxamic acid promoted acylative kinetic resolution will become a method of choice for preparation of saturated N-heterocycles in enantiopure form. are improving but have not yet reached practical levels.4 Recent work by the groups of Fu,5 Seidel,6 Birman,7 and others8 demonstrated that small molecule catalysts can be applied in the KR of various primary amines; however their widespread use has been precluded by the restricted substrate scope along with lengthy reagent synthesis or inconvenient experimental setups. The major challenge in developing catalytic kinetic resolution of amines is overcoming the inherent background rate of amine acylation. Primary or secondary amines are sufficiently nucleophilic to undergo acylation with any conventional acylating agent present in the reaction mixture, leading to unwanted background reactions and decrease of the process selectivity. In this Account, we document our decade-long development of new catalytic amide-forming reactions, their expansion into catalytic kinetic resolutions of cyclic secondary amines (chiral N-heterocycles),
1. INTRODUCTION Kinetic resolution (KR) is a chemical transformation mediated by a chiral reagent, catalyst, or other chiral material in which one enantiomer of the racemic starting material is converted to a product faster than the other enantiomer.1 It is a widely used strategy to separate one enantiomer of a chiral compound from a racemic mixture. One of the best-known and widely used approaches is acylative resolution by enzymes or small molecule catalysts, as this process typically allows facile separation of the reaction products from the resolved starting materials.2 For the resolution of chiral substrates with primary or secondary alcohols, both enzymatic and chemical approaches are highly developed and have been employed on scale to procure enantioenriched materials.3 In contrast, the kinetic resolution of chiral amines has proven much more challenging. For many years, enzymatic approaches were limited to the resolution of primary amines. Recent advances with non-acylative enzymatic redox processes © XXXX American Chemical Society
Received: September 10, 2016
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DOI: 10.1021/acs.accounts.6b00461 Acc. Chem. Res. XXXX, XXX, XXX−XXX
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Accounts of Chemical Research Scheme 1. Catalytic Generation of Acylazoliums by Redox Neutral Reactions of α,β-Epoxyaldehydes Enables Catalytic Esterification Reactionsa
a
The attempted amidation reactions, however, afforded almost none of the desired product.
Scheme 2. (a) Rovis HOAt Catalyzed Redox Amidation and (b) Bode’s Imidazole Promoted Amidation of α-Reducible Aldehydes
nucleophiles, a property that we have discussed in another Account of our research program on NHC catalysis.10 Contemporaneously in 2007, our group and that of Prof. Tom Rovis (then at Colorado State University) recognized that amide-formation could be restored by an additive that intercepted the acylazolium and returned a classical acylating agent such as HOAt-ester or acyl imidazolium. The Rovis group found that 1-hydroxy-7-azabenzotriazole (HOAt) could be used for relay catalysis in amidation of various α-halo or α,β-epoxy and aziridino aldehydes (Scheme 2a).11 Our group identified imidazole as an agent fulfilling the same role for amidations of α,β-cyclopropyl aldehydes, enals, and other α-reducible aldehydes and various primary and secondary amines. Depending on the substrate, either catalytic or stoichiometric amounts of imidazole promoted the formation of the amide products; in its absence almost no amide formation occurred (Scheme 2b).12
mechanistic studies into acylative amide formation, and the development of practical variants for decagram-scale resolutions of pharmaceutical substrates.
2. NHC CATALYZED REDOX NEUTRAL AMIDATION Among the very first reactions run in our newly established lab at the University of California, Santa Barbara, in 2003, were the attempted catalytic amidation and esterification of α,β-unsaturated aldehydes using a thiazolium precatalyst. Ester formation worked brilliantly, but only a trace ( 15) toward the reagent, and sufficient conversion and high enantiopurity of the amine could be reached without using excess of the polymer. However, acyclic and 3-, 4-, and 5-membered cyclic amines proved to be more difficult substrates, and so far we have not been able to successfully resolve these compounds with our chiral hydroxamic acids (Scheme 21).
10. FLOW-CHEMISTRY ENABLED PARALLEL KINETIC RESOLUTION OF CHIRAL N-HETEROCYCLES In a typical kinetic resolution with selectivity s = 20, the enantioenriched starting material is recovered at the expense of the enantiopurity of the product by running the reaction to higher conversion; the scalemic product is often discarded. To increase the efficiency of the resolution, maximize the product enantiopurity, and gain access to both enantiomers from the racemate, Vedejs introduced the concept of parallel kinetic resolution (PKR).25 In PKR, two kinetic resolution reactions proceed simultaneously to yield two distinct non-enantiomeric products. If both enantiomers of the racemate react with comparable rates, the optimal 1:1 enantiomer concentration is maintained throughout the course of the resolution and both products are L
DOI: 10.1021/acs.accounts.6b00461 Acc. Chem. Res. XXXX, XXX, XXX−XXX
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Accounts of Chemical Research formed in improved enantiopurity as compared to a classical kinetic resolution. (A simulation of a KR and PKR reaction progress is depicted in Scheme 22.) For a successful PKR, the implemented resolution reactions should (a) have comparable (preferably identical) rates, (b) occur without mutual interference, (c) have opposite selectivity with respect to the substrate, and (d) yield separable products.26 Due to these requirements, the reaction design of PKR is difficult and only a few practical implementations of this methodology have emerged.27 In most of the cases with our catalytic, stoichiometric, or immobilized variants, kinetic resolution afforded selectivities in the range of 10−20. With optimized conversion, the unreacted starting material often could be obtained in an enantiopure form, albeit in diminished yields at the expense of the product, which was discarded. As both enantiomers of the polymerized hydroxamic acid are readily available on scale, we sought to address the resolution of saturated N-heterocycles via parallel kinetic resolution. To fulfill the requirements, we had to prepare the quasienantiomeric resolving agents necessary for the parallel kinetic resolution, we first set out to identify two orthogonal acyl groups that would meet strict requirements. They should be inexpensive and easy to come by, react with similar rates (i.e., provide similar selectivity in classical kinetic resolution), and exhibit good selectivity and afford separable products. We prepared numerous acylating agents and applied them in classical kinetic resolution (Scheme 23). The Cbz group 3 and the acetyl group 4, which can be cleaved under hydrogenolysis conditions or using strong bases
(e.g., LiOH), did not afford any selectivity. The hydrocinnamoyl group 5, which we had used before, afforded good selectivity; however the products turned out to be exceptionally stable and hydrolysis conditions involving strong acids (HCl, H2SO4) or strong bases (LiOH, NaOH) did not afford the amine product. Eventually, we identified the pent-4-enoyl 6 and 3-(2-nitrophenyl)propanoyl 7 groups, which afforded acceptable selectivities in the classical kinetic resolution and, more importantly, could be cleaved from the resulting amide product under mild conditions. The pent-4-enoyl amide could be hydrolyzed by treatment with molecular iodine in a 1:1 mixture of water and THF, and the corresponding amines were obtained in excellent yields.29 For the 3-(2-nitrophenyl)propanoyl derived amides, the nitro group was reduced to the corresponding aniline followed by an intramolecular lactamization and concomitant deprotection in AcOH at 90 °C. To test if the polymeric reagents could be applied for parallel kinetic resolution, the quasienantiomeric acylating agents were combined in an equimolar ratio and treated with the racemic amines. After the reaction, amide products were isolated in good yields and high enantiopurity. The enantiomeric ratio of the amides was independent of the amount of the polymer used in the process, suggesting that the resolution proceeds without mutual interference between the acylating reagents. A broad range of saturated N-heterocycles were tested, and all products were obtained with useful enantiomeric ratios (Scheme 24). To achieve comparable results in classical kinetic resolution of cyclic secondary amines, very high s-factors would be required
Scheme 25. Flow Enabled Parallel Kinetic Resolution
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DOI: 10.1021/acs.accounts.6b00461 Acc. Chem. Res. XXXX, XXX, XXX−XXX
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Accounts of Chemical Research Scheme 26. Sequential Amide Hydrolysis Protocol
We hope that methods discussed herein will find a broader application in both academic and industrial laboratories for access of otherwise difficult to prepare enantiopure amines.
(s up to 90), which so far have been unprecedented in amine resolution with small molecule resolving agents. Our initial results demonstrated the feasibility of the polymers in a PKR process; however the experimental setup did not allow us to separate and recover the polymers after each cycle. To address this problem and render the process more practical we turned to advances of flow chemistry. We constructed a suitable system for parallel kinetic resolution in flow from two glass columns, a column heater and a HPLC pump. The columns were charged separately with the acylating agents and sealed with a membrane to ensure that the polymer could not elute. A solution of the amine in THF was cycled through the columns at a flow rate 2−3 mL/min for 24 h at 45 °C. The enantiopurities and the yields of the obtained products were in a similar range as the scenario when both resins were mixed together (Scheme 25). However, the flow chemistry approach allowed us to recover and recycle the resins multiple times. The conditions we used for amide hydrolysis could be applied also in a sequential manner in cases when the amide separation after the PKR proved difficult. The mixture of both amides 21 and 22 was treated with molecular I2 in aqueous THF to selectively hydrolyze the pentenoyl amide 21. The amine 23 and the unreacted amide 22 separation was straightforward using either acid/base wash or column chromatography. Finally, the amide 22 was hydrogenated and the intramolecular cyclization was induced by heating the aniline intermediate in AcOH to release the amine 24. Both amines could be isolated in good yields without detectable epimerization (Scheme 26).30
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Funding
This work was supported by the European Research Council (ERC Starting Grant No. 306793-CASAA) and the Swiss Federal Commission for Technology and Innovation (CTI 15523.1). Notes
The authors declare no competing financial interest. Biographies Imants Kreituss received his bachelor degree in chemical engineering in 2010 from Riga Technical University (Latvia). He then moved to ETH Zürich to pursue his master’s studies in chemistry and obtained his master’s degree in 2012. In the same year, he joined the group of Prof. Jeffrey W. Bode to continue his doctoral studies. After obtaining the Dr. Sc. degree he moved to the Australian National University (Canberra) as the Swiss National Science Foundation postdoctoral fellow to join the group of Prof. Michael Sherburn. Jeffrey W. Bode is Professor of Synthetic Organic Chemistry at ETH Zürich. In addition, he serves as an Executive Editor for the Encyclopedia of Reagents for Organic Synthesis, co-Editor in Chief of Helvetica Chimica Acta, and a Principal Investigator at the Institute of Transformative bioMolecules (ITbM) at Nagoya University in Japan. His research group focuses on the development of new reactions, including methods for Nheterocycles, chemical protein synthesis, bioconjugation, and chemical biology.
11. CONCLUSION What initially started as project toward catalytic, redox neutral chemoselective amide bond formation evolved into the first general method for the catalytic kinetic resolution of chiral N-heterocycles. The chiral aminoindanol derived hydroxamic acid proved to be the key to obtaining high selectivity in the asymmetric acylation. The acyl hydroxamates can be used in combination with NHCs in relay catalysis or in stoichiometric amounts, both in solution and as immobilized reagents. Experimental results alongside theoretical work have given us great insight into the reaction mechanism and the origins of stereoselectivity. The reactions can be carried out on an analytical and preparative scale using a polymer supported reagent as exemplified by resolution of antimalarial drug mefloquine. Finally, immobilized acyl hydroxamates have been successfully applied to parallel kinetic resolution of saturated N-heterocycles to afford both enantiomers of the amine in excellent enantiopurity in a single operation. The flow-based system offers a user-friendly, recyclable system that brings the underappreciated advantages of parallel kinetic resolution into practical implementation.
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ACKNOWLEDGMENTS The authors thank the past and present Bode group members whose work contributed to the knowledge and the results described in this Account, especially, Kenneth Chow, Stephanie Sohn, Pei-Chen Chiang, Jessada Mahatthananchai, Yoonjoo Kim, Michael Binanzer, Sheng-Ying Hsieh, Kuang Yen Chen, and Benedikt Wanner. We are very grateful to Paula L. Nichols for critical proofreading of this manuscript. We thank collaborators from Hoffmann-La Roche (Basel) for fruitful discussions and for the kind gift of racemic mefloquine.
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REFERENCES
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