Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Enantioselective Syntheses of (S)‑Ketamine and (S)‑Norketamine Cheng-yi Chen*,† and Xiaowei Lu‡ †
Janssen R&D, API Small Molecule Development, Discovery Product Development & Supply, Hochstrasse 201, 8205 Schaffhausen, Switzerland ‡ Porton (Shanghai) R&D Center, 1299 Ziyue Road, Zizhu Science Park, Minhang District, Shanghai 200241, China
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ABSTRACT: An efficient asymmetric synthesis of (S)-ketamine (esketamine) based on catalytic enantioselective transfer hydrogenation of cyclic enone and [3,3]-sigmatropic rearrangement of allylic cyanate to isocyanate is described. The catalytic asymmetric route afforded esketamine (99.9% ee) in 50% overall yield over four steps and forms the basis for the future development of the drug substance. Furthermore, the route was applicable to the synthesis of (S)-norketamine via simple hydrolysis of isocyanate penultimate.
K
scale production. Toste and Yang recently disclosed use of a chiral organophosphoric acid catalyst for the direct asymmetric electrophilic amination of α-substituted ketones with di-tertbutyl azodicarboxylates.10 Though the amination step proceeds in high enantioselectivity (99% ee) in 78% yield, elaboration of the advanced amino ketone intermediate to esketamine called for the three-step transformation with deprotection of the Boc group, N−N bond cleavage and methylation, affording esketamine in 30% overall yield. More recently, Gohari et al. reported two asymmetric syntheses of esketamine using Ellman’s (S)-tert-butanesulfinamide as chiral auxiliary. The imine addition step proceeded in modest diastereoselectivity (75−85%).11 The limited success in these asymmetric syntheses of esketamine may stem from the lack of efficient synthetic method for the installation of the α-tertiary amine center.12 We envisioned that esketamine (1) could be prepared from penultimate trichloroacetamide 2 via methylation and deprotection (Scheme 1). The trichloroacetamide, in turn, could be prepared via an Overman rearrangement13 of a chiral allylic alcohol 4. This synthetic design takes advantage of the methyl vinyl ethers as latent protecting group for the ketone moiety. Furthermore, the allylic alcohol can be prepared from enantioselective reduction of enone 5. As shown in Scheme 2, we started our work with the preparation of enone 5 according to the published method whereby Suzuki−Miyaura coupling of bromo enone 614 with 2-Cl-phenyl boronic acid under conventional coupling conditions afforded enone 5 in 88% yield. CeCl3-mediated 1,2-reduction of enone 5 with NaBH4 afforded racemic alcohol 7. Heating of this imidate intermediate 8 under Overman
etamine and its (S)-enantiomer (esketamine) have recently been studies for rapid-onset antidepressant effect and has been advanced as a new treatment for major depressive disorder including treatment-resistant depression.1 (S)-Ketamine (esketamine) displays approximately 3- to 4-fold greater affinity for the glutamate N-methyl D-asparate (NMDA) receptor in vitro than (R)-ketamine.2 With acceptable tolerability in short-term treatment, esketamine has drawn greater attention for the development as an antidepressant drug. With superior antidepressant efficacy in novel intranasal spray formulation, esketamine for the treatment of treatmentresistant depression was granted by the US FDA with “breakthrough therapy” designation.3 Recently, the U.S. FDA has approved Spravato (esketamine) nasal spray as a rapidly acting antidepressant for adults with treatment-resistant depression (TRD), which represents one of the most significant milestones for depression treatment in decades.4 The drug substance, however, has been produced since the discovery of ketamine5 via a racemic synthesis and classical resolution.6 Giving the importance of the drug, we herein wish to disclose an efficient asymmetric synthesis of esketamine based on catalytic enantioselective transfer hydrogenation of enone and [3,3]-sigmatropic rearrangement of allylic cyanate to set the sole stereocenter. Furthermore, hydrolysis of isocyanate penultimate led to (S)-norketamine. The structural uniqueness of esketamine and importance of the compound has prompted several asymmetric syntheses over the years.7 Kiyooka and co-workers reported the synthesis of esketamine in high enantioselectivity over 10 steps in 21% yield.8 To achieve high enantioselectivity (97% ee), this route used excess BINAL-H (3.4 equiv)9 for the reduction of an enone and relied on ozonolysis of an olefin to install the ketone functionality, both of which may not be convenient for large© XXXX American Chemical Society
Received: July 23, 2019
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DOI: 10.1021/acs.orglett.9b02575 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
Scheme 3. Racemic Ketamine via [3,3]-Rearrangement of Allylic Cyanate
Scheme 1. Retrosynthetic Analysis of Esketamine
Scheme 2. Overman Rearrangement of Racemic Allylic Alcohol the asymmetric version of esketamine and its enantiomer if the requisite chiral intermediates could be produced. We next explored the asymmetric reduction of enone 5 to its alcohol 4 as shown in Scheme 4. Among many protocols for Scheme 4. Asymmetric Transfer Hydrogenation of Enonea
rearrangement conditions13a did not render a clean reaction profile. Similar results were obtained using alternative Pdcatalyzed conditions.13c A brief literature survey revealed that Overman rearrangement of such fully substituted allylic alcohol was less precedented.13 We speculated that the steric interaction between the trichloromethyl and methoxy groups prevented the molecule from adopting a boat-transition state prior to rearrangement. The chair-transition state is also not feasible due to A1,3 interaction. The allyl cyanate/isocyanate transposition15 has been reported as an attractive alternative to the Overman rearrangement of allylic trichloroacetimidates. The success is generally believed to result from the mild reaction conditions and the high degree of stereocontrol. As illustrated in Scheme 3, we were delighted to find that rearrangement allylic alcohol 7 can be facilitated via cyanate/isocyante strategy.8 Treatment of allylic alcohol 7 with Cl3CCONCO afforded carbamate 10 in 85% yield. Dehydration of carbamate 10 afforded cyanate intermediate 11, which smoothly rearranges at 0 °C to isocyanate 12 in good yield for the two steps. We demonstrated this isocyanate can be converted to ketamine via a two-step transformation: reduction and hydrolysis to afford ketamine in 42% unoptimized yield. The enablement of this racemic synthesis of ketamine opened the possibility for
a
All reactions were run under nitrogen in HCO2H/Et3N (2/3 v/v) (10 mL/g substrate) at 80 °C for 3 h. bEnantioselectivity was assayed by chiral HPLC.
the asymmetric reduction of ketone to alcohol, we chose the asymmetric transfer hydrogenation due to its reliability, mild reaction conditions, and easy operation in the laboratory.16 We initially screened four Ru-based chiral catalysts for the enone reduction. We were delighted to find that all four catalysts reduced ketone to alcohol in >97% ee with full conversion at 1 mol % catalyst loading. At 0.1 mol % catalyst loading, however, only [(S,S)-Teth-TsDPEN]RuCl gave full conversion in 97− 98% ee; the rest three catalysts only reached 45−50% conversion at this lower catalyst load. After selecting [(S,S)Teth-TsDPEN]RuCl as the optimal catalyst for the enantioselective reduction of enone 5, we advanced the chiral product. The cyanate rearrangement worked equally well to afford isocyanate 16 in 98% ee in 88% yield.17 A complete chirality B
DOI: 10.1021/acs.orglett.9b02575 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
integrity of chirality. This asymmetric route to esketamine (99.9% ee) forms the basis for the future development of the compound and could be extended to the synthesis of (S)norketamine and esketamine-d3. The simplicity and high efficiency of this synthesis renders it attractive when compared to the others reported in the literature. We hope this work will prompt others to explore application of the milder cyanate rearrangement chemistry in the synthesis of important chiral pharmaceutical agents.
transformation without any erosion of ee was observed as shown in Scheme 5. Scheme 5. [3,3]-Sigmatropic Rearrangement of Chiral Allylic Imidate
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02575. Experimental details, characterization data, and NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Having successfully installed of α-tertiary isocyanate chiral center with a total transfer of chirality, we shifted our attention to the end game for the synthesis of esketamine. As shown in Scheme 6, reduction of isocyanate using LiAlH4 afforded
ORCID
Cheng-yi Chen: 0000-0001-7666-3087 Notes
The authors declare no competing financial interest.
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Scheme 6. Synthesis of Esketamine and S-Norketamine
ACKNOWLEDGMENTS We acknowledge Mrs. Huawei Ma and Mrs. Huan Dong at Porton (Shanghai) R&D Center for analytical support and Mr. Zhaobing Wang and Mrs. Wei Liu at the Porton (Shanghai) R&D Center for the preparation of enone 5 according to literature procedures. We also acknowledge Drs. Christopher Teleha and Qinghao Chen of Janssen R&D, Spring House, PA, for helpful discussions during the preparation of this manuscript.
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REFERENCES
(1) For selected clinical studies on esketamine, see: (a) Potter, D. E.; Choudhury, M. Drug Discovery Today 2014, 19, 1848. (b) Paul, R.; Schaaff, N.; Padberg, F.; Möller, H.-J.; Frodl, T. World J. of Bio. Psych. 2009, 10, 241. (c) Paslakis, G.; Gilles, M.; Meyer-Lindenberg, A.; Deuschle, M. Pharmacopsychiatry 2010, 43, 33. (d) Noppers, I.; Niesters, M.; Swartjes, M.; Bauer, M.; Aarts, L.; Geleijnse, N.; Mooren, R.; Dahan, A.; Sarton, E. Eur. J. of Pain. 2011, 15, 942. (e) Mathew, S. J.; Shah, A.; Lapidus, K.; Clark, C.; Jarun, N.; Ostermeyer, B.; Murrough, J. W. CNS Drugs 2012, 26, 189. (2) Himmelseher, S.; Pfenninger, E. Anasthesiol. Intensivmed. Notfallmed. Schmerzther. 1998, 33, 764. (3) For a critical review on the antidepressant efficacy and tolerability of ketamine and esketamine, see: Molero, P.; RamosQuiroga, J. A.; Calvo-Sanchez, E.; Ramos-Quiroga, J. A.; CalvoSanchez, E.; Martin-Santos, R.; Gutierrez-Rojas, L.; Meana, J. J.; Meana, J. J. CNS Drugs 2018, 32, 411. (4) (a) SPRAVATO: https://www.prnewswire.com/news-releases/ janssen-announces-us-fda-approval-of-spravato-esketamine-ciii-nasalspray-for-adults-with-treatment-resistant-depression-trd-who-havecycled-through-multiple-treatments-without-relief-300807366.html. (b) Duman, R. S. F1000Research 2018, 7:F1000, 1. (c) Dubovsky, S. L. Psychother and Psychosom 2018, 87, 129. (5) For the discovery and synthetic work of ketamine and its analogues, see: (a) Stevens, C. L.; Elliott, R. D.; Winch, B. L. J. Am. Chem. Soc. 1963, 85, 1464. (b) Stevens, C. L.; Thuillier, A.; Daniher, F. A. J. Org. Chem. 1965, 30, 2962. (c) Stevens, C. L.; Klundt, I. L.;
methylamine 17 smoothly in 80% yield. The vinyl ether moiety remained intact which was next hydrolyzed using HCl to afford esketamine in 93% yield. The isolation of esketamine as HCl salt also upgraded the ee to 99.9% and purity. Esketamine-d3 (19)19 was also readily prepared when LiAlD4 was applied to the reduction of isocyanate 16. Furthermore, hydrolysis of both vinyl ether and isocyanate functional groups of 16 led to (S)-norketamine in 84% yield. The methodology to (S)norketamine developed here is complementary to other approaches.18 In conclusion, we have developed an efficient, asymmetric synthesis of esketamine based on catalytic enantioselective transfer hydrogenation of enone and [3,3]-sigmatropic rearrangement of allylic cyanate. [(S,S)-Teth-TsDPEN]RuCl (0.1 mol %)-catalyzed transfer hydrogenation of enone affords allylic alcohol in 98% ee, and subsequent [3,3]-sigmatropic rearrangement installs the desired quaternary stereocenter with C
DOI: 10.1021/acs.orglett.9b02575 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Munk, M. E.; Pillai, M. D. J. Org. Chem. 1965, 30, 2967. (d) Stevens, C. L.; Hanson, H. T.; Taylor, K. G. J. Am. Chem. Soc. 1966, 88, 2769. (e) Stevens, C. L.; Ash, A. B.; Thuillier, A.; Amin, J. H.; Balys, A.; Dennis, W. E.; Dickerson, J. P.; Glinski, R. P.; Hanson, H. T.; Pillai, M. D.; Stoddard, J. W. J. Org. Chem. 1966, 31, 2593. (f) Stevens, C. L.; Thuillier, A.; Taylor, K. G.; Daniher, F. A.; Dickerson, J. P.; Hanson, H. T.; Nielsen, N. A.; Tikotkar, N. A.; Weier, R. M. J. Org. Chem. 1966, 31, 2601. (g) Stevens, C. L.; Glenn, F. E.; Pillai, P. M. J. Am. Chem. Soc. 1973, 95, 6301. (6) For classical resolution of ketamine using chiral acids, see: (a) Steiner, K.; Gangkofner, S.; Grunenwald, J. M. PCT Int. Appl. WO 9743244 A1, Nov 20, 1997. (b) Chen, C.-y.; Floegel, O.; Justus, M.; Maurer, A.; Reuter, K.; Strittmatter, T.; Wedel, T. PCT Int. Appl.WO 2016180984 A1, Nov 17, 2016. (7) For a minireview on the synthesis of ketamine and analogues, see: Dimitrov, I.; Jose, J.; Denny, W. A. Synthesis 2018, 50, 4201. (8) (a) Yokoyama, R.; Matsumoto, S.; Nomura, S.; Higaki, T.; Yokoyama, T.; Kiyooka, S. Tetrahedron 2009, 65, 5181. (b) Yokoyama, T.; Yokoyama, R.; Nomura, S.; Matsumoto, S.; Fujiyama, R.; Kiyooka, S. Bull. Chem. Soc. Jpn. 2009, 82, 1528. (9) The disadvantage of using excess BINAL-H in the reduction was obvious; see an example of a large-scale preparation and application of the reagent: O’Shea, P. D.; Chen, C.-y.; Chen, W.; Dagneau, P.; Frey, L. F.; Grabowski, E. J. J.; Marcantonio, K. M.; Reamer, R. A.; Tan, L.; Tillyer, R. D.; Roy, A.; Wang, X.; Zhao, D. J. Org. Chem. 2005, 70, 3021. (10) (a) Yang, X.; Toste, F. D. J. Am. Chem. Soc. 2015, 137, 3205− 3208. (11) Gohari, S. J. A.; Javidan, A.; Moghimi, A.; Taghizadeh, M. J.; Iman, M. Can. J. Chem. 2019, 97, 331. (b) Taghizadeh, M. J.; Gohari, S. J. A.; Javidan, A.; Moghimi, A.; Iman, M. J. Iran. Chem. Soc. 2018, 15, 2175−2181. (12) For general synthetic methods used to install α-tertiary amines, see: (a) Hager, A.; Vrielink, N.; Hager, D.; Lefranc, J.; Trauner, D. Nat. Prod. Rep. 2016, 33, 491. (b) Clayden, J.; Donnard, M.; Lefranc, J.; Tetlow, D. J. Chem. Commun. 2011, 47, 4624. (13) (a) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901. (b) Overman, L. E. Acc. Chem. Res. 1980, 13, 218. (c) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem. 1998, 63, 188. (d) For a chapter review, see: Overman, L. E.; Carpenter, N. E. Org. React. 2005, 66, 1. (e) For a recent review on synthesis of natural products and valuable compounds using recent advances in overman rearrangement, see: Fernandes, R. A.; Kattanguru, P.; Gholap, S. P.; Chaudhari, D. A. Org. Biomol. Chem. 2017, 15, 2672. (14) (a) Lopušanskaja, E.; Paju, A.; Järving, I.; Lopp, M. Synthesis 2018, 50, 1883. (b) Paju, A.; Kanger, T.; Müürisepp, A.-M.; Aid, T.; Pehk, T.; Lopp, M. Tetrahedron 2014, 70, 5843. (15) For cyanate rearrangement, see: (a) Christophersen, C.; Holm, A. Acta Chem. Scand. 1970, 24, 1512. (b) Ichikawa, Y. Synlett 2007, 2007, 2927. (c) Nocquet, P.-A.; Henrion, S.; Mace, A.; Carboni, B.; Villalgordo, J. M.; Carreaux, F. Eur. J. Org. Chem. 2017, 2017, 1295. (16) Transfer hydrogenation: (a) Nedden, H. G.; Zanotti-Gerosa, A.; Wills, M. Chem. Rec. 2016, 16, 2623. (b) Matsunami, A.; Ikeda, M.; Nakamura, H.; Yoshida, M.; Kuwata, S.; Kayaki, Y. Org. Lett. 2018, 20, 5213. (c) Zheng, L.-S.; Llopis, Q.; Echeverria, P.-G.; Férard, C.; Guillamot, G.; Phansavath, P.; Ratovelomanana-Vidal, V. J. Org. Chem. 2017, 82, 5607. (d) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2005, 127, 7318. (e) General review: Wang, D.; Astruc, D. Chem. Rev. 2015, 115, 6621. (17) Isocyanate 16 displays unique physical properties as it can be readily isolated, purified through SiO2 chromatography, and analyzed with routine manipulations. No hydrolysis or decomposition were observed. (18) For the asymmetric syntheses of S- or R-norketamine, see ref 10 and: (a) Biermann, M.; Zheng, G.; Hojahmat, M.; Moskalev, N. V.; Crooks, P. A. Tetrahedron Lett. 2015, 56, 2608. (b) Han, Y.; Mahender Reddy, K.; Corey, E. J. Org. Lett. 2017, 19, 5224.
(19) Only racemic synthesis of ketamine-d3 using CD3NH2 was reported. Gant, T. G.; Sarshar, S. U.S. Pat. Appl. Publ. US 20080268071 A1 Oct 30, 2008.
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DOI: 10.1021/acs.orglett.9b02575 Org. Lett. XXXX, XXX, XXX−XXX
