Catalytic Enantioselective Synthesis of Key Propargylic Alcohol

Jan 9, 2018 - The enantiomeric excess was determined as 95% ee by HPLC analysis on a chiral stationary phase. HPLC conditions: Chiralpak AD-H column (...
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Catalytic Enantioselective Synthesis of Key Propargylic Alcohol Intermediates of the Anti-HIV Drug Efavirenz Yu Zheng, Lilu Zhang, and Eric Meggers* Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany S Supporting Information *

ABSTRACT: The catalytic, enantioselective synthesis of key propargylic alcohol intermediates toward the synthesis of the antiHIV drug efavirenz is reported. Using a recently reported chiral-at-ruthenium catalyst (J. Am. Chem. Soc. 2017, 139, 4322), catalytic enantioselective alkynylations of 1-(2,5-dichlorophenyl)-2,2,2-trifluoroethanone (99% yield, 95% ee) and 1-(5-chloro-2nitrophenyl)-2,2,2-trifluoroethanone (97% yield, 99% ee) are achieved using catalyst loadings of merely 0.2 mol % (ca. 500 TON).

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INTRODUCTION Structural features of small molecules with respect to carbon hybridization and carbon stereochemistry are important contributors for their biological properties.1 Not surprisingly, a significant portion of small molecule drugs contain one or more stereogenic carbon centers.2,3 Since chiral drugs are typically marketed as single enanantiomers, the economical synthesis of enantiomerically pure drugs is a key aspect for the overall cost of the drug production,4 which can be of commercial and social relevance. The human immunodeficiency virus (HIV) infects cells of the human immune system and thereby induces acquired immune deficiency syndrome (AIDS). HIV is a major global health concern with millions of people living with an HIV infection.5 HIV infection can be managed successfully with antiretroviral drugs which suppress HIV replication.6 Efavirenz7 is such an important antiretroviral drug developed by Merck by potently inhibiting HIV reverse transcriptase (non-nucleoside reverse transcriptase inhibitor) (Scheme 1).8,9 Efavirenz is a chiral compound and marketed as a single enantiomer. Only the S-enantiomer displays potent inhibiton of HIV reverse transcriptase while the R-enantiomer is inactive so that efavirenz has to be produced in an enantiopure fashion. The initial synthetic route toward efavirenz developed by Merck provided a racemic mixture from which the Senantiomer was finally obtained through a resolution of (−)-camphanoyl imide diastereomers.8 Subsequently, asymmetric syntheses were reported via the enantioselective addition of lithium10−14 and zinc15 cyclopropylacetylide to trifluoromethyl ketone intermediates mediated typically by ephedrinederived chiral auxiliaries. The first catalytic, enantioselective procedure was reported by Carreira in 2011.16 Following the Merck route, trifluoromethylketone 1a was reacted with cyclopropylacetylene in the presence of n-hexyllithium, substoichiometric amounts of diethylzinc, ephedrine-derived chiral ligand, and the alkynylation product (S)-2a, to afford in this autocatalytic process the product (S)-2a in 79% yield and with 99.6% ee (Scheme 1a). Despite the impressive enantioselectivity, this method relies on a complex mixture of components including pyrophoric dimethylzinc and highly © XXXX American Chemical Society

reactive n-hexyllithium, and two chiral sources. Lonza recently developed a synthetic route through the catalytic, enantioselective alkynylation of the trifluoromethyl ketone 1b to provide the propargylic alcohol (S)-2b, although the reported enantioselectivity of 46% ee was very low (Scheme 1b).17 Finally, Shibata recently introduced an organocatalytic approach which relies on an enantioselective trifluoromethylation of an alkynylketone with the Ruppert−Prakash reagent.18−21 However, the method requires high loadings (10 mol %) of a carefully designed quaternary ammonium cinchona catalyst. Despite these important advances, the development of improved catalytic, enantioselective methods for the efficient asymmetric synthesis of efavirenz and related drugs is highly desirable. Here, we report our progress in this direction by using a previously developed novel chiral-atruthenium catalyst.22,23

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RESULTS AND DISCUSSION The previously reported reaction of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (1a) with cyclopropylacetylene in the presence of Et3N (0.2 equiv) in THF (0.5 M) at 60 °C for 48 h catalyzed by chiral-at-metal Δ-Ru1 (3 mol %) provided the Merck intermediate (S)-2a with 58% yield and 91.6% ee (Table 1, entry 1).22,24 Although this method provides a convenient catalytic, enantioselective access to the key Merck intermediate (S)-2a, the yield and the enantioselectivity are only modest and we were not able to significantly improve these results. We therefore switched our attention to a related substrate in which the electron-donating amino group (1a) is replaced with an electron-withdrawing nitro group (1c), with the expectation that this modification would accelerate the alkynylation 1c → (S)-2c and a straightforward iron-based reduction of (S)-2c to (S)-2a has been reported.20 Gratifyingly, using just 0.5 mol % Δ-Ru1, the propargylic alcohol (S)-2c was obtained in a yield of 93% with 99.6% ee after 16 h at 60 °C (entry 2). Interestingly, using a simplified catalyst devoid of the two 3,5-dimethylphenyl moieties (Δ-Ru2), an almost unReceived: December 4, 2017

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DOI: 10.1021/acs.oprd.7b00376 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Scheme 1. Established Synthesis Routes to Efavirenz Relying on Enantioselective Catalytic Alkynylations

(entry 5). Interestingly for practical reasons, at a catalyst loading of 0.5 mol % Δ-Ru2, the reaction can be executed at room temperature to afford (S)-2c with 96% yield and 99.4% ee after 16 h (entry 6). A lower catalyst loading of 0.2 mol % leads to a decreased yield (entry 7). The reaction is sensitive to air (entry 8) but not to the presence of small amounts of water (entry 9). We next investigated the catalytic, enantioselective alkynylation of the chlorinated Lonza intermediate 1b with cyclopropylacetylene. Accordingly, with Δ-Ru1 at 0.5 mol % catalyst loading, the reaction of 1b with cyclopropylacetylene at 60 °C provided the propargylic alcohol (S)-2b in 99% yield and with 90% ee (Table 2, entry 1). Interestingly, same as for the nitro substrate 1c, the simplified catalyst Δ-Ru2 provides superior results (entries 2−6). With a catalyst loading of just 0.2 mol % at room temperature, (S)-2b was provided in 95% yield and with 95% ee (entry 5). Attempts to lower the catalyst loading to 0.1 mol % led to a decreased yield, even after prolonging the reaction time to 64 h (entry 6). A reduced overall concentration also afforded a decreased yield (entry 7) whereas an increased concentration (entry 8) or CH2Cl2 as a solvent instead of THF (entry 9) provided comparable results. Control experiments reveal that the reaction is sensitive to air (entry 10) but not to water (entries 11 and 12) which means that the reaction must be performed under inert gas conditions but the solvents do not need to be dry. Finally, gram-scale reactions were carried out in order to highlight the practical utility of this protocol. As shown in Scheme 2, by employing 1b or 1c as substrate under the optimized conditions, respectively, the propargylic alcohol products were obtained in high isolated yields and with high enantioselectivity.

Table 1. Optimization of the Reaction Conditions with Substrates 1a and 1ca

entry e

1 2 3 4 5 6 7 8f 9g

catalystb Δ-Ru1 Δ-Ru1 Δ-Ru2 Δ-Ru2 Δ-Ru2 Δ-Ru2 Δ-Ru2 Δ-Ru2 Δ-Ru2

(3.0) (0.5) (0.5) (0.2) (0.1) (0.5) (0.2) (0.2) (0.2)

X

T (°C)

t (h)

yield (%)c

ee (%)d

NH2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2

60 60 60 60 60 r.t. r.t. 60 60

48 16 16 16 64 16 48 16 16

58 93 92 95 42 96 55 21 96

91.6 99.6 99.4 99.4 99.2 99.4 99.4 98.2 99.0

a

Reaction conditions: 1a or 1c (0.20 mmol), cyclopropylacetylene (0.60 mmol), catalyst, and Et3N (20 mol %) in THF (0.4 mL, 0.5 M) were stirred at the indicated temperature for the indicated time. b Catalyst loadings in mol % provided in brackets. cIsolated yields. d Determined by HPLC on a chiral stationary phase. eLarger excess of cyclopropylacetylene (2 mmol) was used instead. fPerformed under air. gPerformed in the presence of 1% H2O.

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CONCLUSION In summary, we here reported highly efficient catalytic, enantioselective syntheses of key chiral propargylic alcohol intermediates toward enantiomerically pure efavirenz. The Lonza propargylic alcohol intermediate (S)-2b can be accessed through a catalytic, enantioselective alkynylation in 99% yield and with 95% ee with a turnover number reaching almost 500 and relying only on the addition of catalytic amounts of the

changed yield and enantioselectivity were observed (entry 3). Since the synthesis of Δ-Ru2 is less time-consuming and less expensive compared to Δ-Ru1, the simplified catalyst Δ-Ru2 is apparently the catalyst of choice for the conversion 1c → (S)2c. Even at a reduced catalyst loading of 0.2 mol %, a yield of 95% with 99.4% ee was obtained (entry 4), while at a further reduced catalyst loading of 0.1 mol % the yield deteriorated B

DOI: 10.1021/acs.oprd.7b00376 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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ments over existing protocols and could contribute to lowering the cost for the production of the important anti-HIV drug efavirenz.

Table 2. Optimization of the Reaction Conditions with Substrate 1ba

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entry 1 2 3 4 5 6 7 8 9 10 11 12

catalystb Δ-Ru1 (0.5) Δ-Ru2 (0.5) Δ-Ru2 (0.2) Δ-Ru2 (0.5) Δ-Ru2 (0.2) Δ-Ru2 (0.1) Δ-Ru2 (0.2) Δ-Ru2 (0.2) Δ-Ru2 (0.2) Δ-Ru2 (0.2) Δ-Ru2 (0.2) Δ-Ru2 (0.2)

T (°C)

t (h)

yield (%)c

ee (%)d

standard

60

16

99

90.2

standard

60

16

99

93.8

standard

60

24

93

93.7

standard

r.t.

16

99

95.2

standard

r.t.

16

95

95.0

standard

r.t.

64

71

95.0

r.t.

16

76

95.2

r.t.

16

94

95.0

CH2Cl2 instead of THF under air

r.t.

16

99

94.2

r.t.

16

11g

n.d.h

1% H2O

r.t.

16

96

95.2

10% H2O

r.t.

16

93

95.2

conditions

reduced concne increased concn

f

EXPERIMENTAL SECTION General Information. All reactions were carried out under an atmosphere of nitrogen with magnetic stirring unless otherwise indicated. Catalytic reactions were performed in Schlenk tubes (10 mL). Gram-scale reactions were performed in Schlenk tubes (25 mL). The catalysts Δ-Ru1 and Δ-Ru2 were synthesized according to our published procedures.22 The substrates 1b26 and 1c27 were synthesized following reported procedures. Solvents were distilled under nitrogen from calcium hydride (CH3CN and CH2Cl2) or sodium/benzophenone (THF and Et2O). Reagents that were purchased from commercial suppliers were used without further purification. Flash column chromatography was performed with silica gel 60 M from Macherey-Nagel (irreg. shaped, 230−400 mesh, pH 6.8, pore volume: 0.81 mL × g−1, mean pore size: 66 Å, specific surface: 492 m2 × g−1, particle size distribution: 0.5% < 25 μm and 1.7% > 71 μm, water content: 1.6%). 1H NMR, proton decoupled 13C NMR spectra, and proton-coupled 19F NMR spectra were recorded on Bruker Avance 300 (300 MHz) spectrometers at ambient temperature. NMR standards were used as follows: 1H NMR spectroscopy: δ = 7.26 ppm (CDCl3), 13C NMR spectroscopy: δ = 77.0 ppm (CDCl3), All 13 C NMR signals are singlets unless noted otherwise. HPLC chromatography on chiral stationary phase was performed with an Agilent 1200 HPLC system. Optical rotations were measured on a Krüss P8000-T polarimeter with [α]D25 values reported in degrees with concentrations reported in g/100 mL. General Procedure for the Synthesis of (S)-2b. A dried 10 mL Schlenk tube was charged with 1-(2,5-dichlorophenyl)2,2,2-trifluoroethanone 1b (48.6 mg, 0.20 mmol). The tube was purged with nitrogen, and 0.4 mL of Δ-Ru2 in THF (1.0 mg/ mL) and Et3N (5.6 μL, 0.04 mmol) were added via syringe, followed by cyclopropylacetylene (50.9 μL, 0.6 mmol). The tube was sealed, and the reaction was stirred at room temperature for 16 h under a nitrogen atmosphere. The solvent was removed, and the residue was purified by flash chromatography on silica gel (EtOAc/hexane = 1:50) to afford 58.5 mg (0.189 mmol, 95% yield) of 2b as a colorless oil. The S-configuration of the product (S)-2b was assigned by comparison with published optical rotations. [α]D25 = +1.4° (c 1.0, CH2Cl2). Lit.:20 [α]D25 = +4.87° (c 1.39, CHCl3, 91% ee for S-configuration). The enantiomeric excess was determined as 95% ee by HPLC analysis on a chiral stationary phase. HPLC conditions: Chiralpak AD-H column (250 mm × 4.6 mm), UV absorption at 220 nm, mobile phase hexane/isopropanol = 98:2, flow rate 1.0 mL/min, column temperature of 25 °C, tr (major) = 11.2 min, tr (minor) = 14.0 min. 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 2.4 Hz, 1H), 7.39−7.26 (m, 2H), 3.42 (s, 1H), 1.40−1.31 (m, 1H), 0.98−0.70 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 134.0, 132.87, 132.85, 131.3, 130.4, 130.1, 123.3 (q, J = 285.0 Hz), 94.1, 71.9 (q, J = 33.5 Hz), 69.3, 8.2 (d, J = 5.3 Hz), −0.5. 19F NMR (282 MHz, CDCl3) δ −78.60. All other spectroscopic data are in agreement with the literature.20 Gram-Scale Synthesis of (S)-2b. A dried 25 mL Schlenk tube was charged with the catalyst Δ-Ru2 (8.0 mg, 0.2 mol %) and 1-(2,5-dichlorophenyl)-2,2,2-trifluoroethanone 1b (972.0 mg, 4.0 mmol). The tube was purged with nitrogen, and THF (8 mL) and Et3N (110.9 μL, 0.8 mmol) were added via syringe,

a

Standard reaction conditions: 1b (0.20 mmol), cyclopropylacetylene (0.60 mmol), catalyst, and Et3N (20 mol %) in THF (0.4 mL, 0.5 M) were stirred at indicated temperature for the indicated time. bCatalyst loadings in mol % provided in brackets. cIsolated yields. dDetermined by HPLC on a chiral stationary phase. eReaction performed in 1.0 mL of THF (0.2 M). fReaction performed in 0.2 mL of THF (1.0 M). g NMR yield with tetrachloroethane as internal standard. hNot determined.

Scheme 2. Gram-Scale Reactions under Optimized Reaction Conditions

base triethylamine.25 The Merck propargylic alcohol intermediate (S)-2a can be obtained indirectly after reduction of the nitro-derivative (S)-2c,20 which itself is formed through a catalytic, enantioselective alkynylation in 97% yield with 99% ee. These synthetic routes might constitute significant improveC

DOI: 10.1021/acs.oprd.7b00376 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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followed by cyclopropylacetylene (1.02 mL, 12.0 mmol). The tube was sealed, and the reaction was stirred at room temperature for 16 h under a nitrogen atmosphere. The solvent was removed, and the residue was purified by flash chromatography on silica gel (EtOAc/hexane = 1:50) to afford 1.22 g (3.95 mmol, 99% yield, 95.0% ee, 98.2% purity) of 2b as a colorless oil. The purity was confirmed by HPLC analysis. HPLC conditions: Purospher STAR Si column (4.6 mm × 250 mm, 5 μm, Merck), UV absorption at 220 nm, mobile phase hexane/isopropanol = 99:1, flow rate 1.0 mL/min, column temperature of 25 °C. General Procedure for the Synthesis of (S)-2c. A dried 10 mL Schlenk tube was charged with 1-(5-chloro-2-nitrophenyl)-2,2,2-trifluoroethanone 1c (50.6 mg, 0.20 mmol). The tube was purged with nitrogen, and 0.4 mL of Δ-Ru2 in THF (1.0 mg/mL) and Et3N (5.6 μL, 0.04 mmol) were added via syringe, followed by cyclopropylacetylene (50.9 μL, 0.60 mmol). The tube was sealed, and the reaction was stirred at 60 °C for 16 h under a nitrogen atmosphere. The solvent was removed, and the residue was purified by flash chromatography on silica gel (EtOAc/hexane = 1:50) to afford 60.6 mg (0.190 mmol, 95% yield) of 2c as a light-yellow oil. The Sconfiguration of the product (S)-2c was assigned by comparison with published rotation data. [α]D25 = −26.0° (c 1.0, CH2Cl2). Lit.:20 [α]D25 = −22.0° (c 0.38, CHCl3, 93% ee for S-configuration). The enantiomeric excess was determined as 99.4% ee by HPLC analysis on chiral stationary phase. HPLC conditions: Chiralpak OD-H column (250 mm × 4.6 mm), UV absorption at 220 nm, mobile phase hexane/ isopropanol = 95:5, flow rate 1.0 mL/min, column temperature 25 °C, tr (minor) = 7.9 min, tr (major) = 8.8 min. 1H NMR (300 MHz, CDCl3) δ 7.80 (s, 1H), 7.53−7.41 (m, 2H), 3.63 (s, 1H), 1.40−1.14 (m, 1H), 0.95−0.75 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 148.7, 137.1, 130.5, 130.1 (q, J = 2.2 Hz), 129.8, 125.6, 122.7 (q, J = 284.8 Hz), 94.5, 71.8 (q, J = 33.8 Hz), 68.6, 8.4, −0.8. 19F NMR (282 MHz, CDCl3) δ −78.28. All other spectroscopic data are in agreement with the literature.20 Gram-Scale Synthesis of (S)-2c. A dried 25 mL Schlenk tube was charged with the catalyst Δ-Ru2 (10 mg, 0.2 mol %) and 1-(5-chloro-2-nitrophenyl)-2,2,2-trifluoroethanone 1c (1.268 g, 5.0 mmol). The tube was purged with nitrogen, and 10 mL of THF and Et3N (138.6 μL, 1.0 mmol) were added via syringe, followed by cyclopropylacetylene (1.27 mL, 15 mmol). The tube was sealed, and the reaction was stirred at 60 °C for 16 h under a nitrogen atmosphere. The solvent was removed, and the residue was purified by flash chromatography on silica gel (EtOAc/hexane = 1:50) to afford 1.56 g (4.88 mmol, 97% yield, 99.2% ee, 97.5% purity) of 2c as a lightyellow oil. The purity was confirmed by HPLC analysis. HPLC conditions: Purospher STAR Si column (4.6 mm × 250 mm, 5 μm, Merck), UV absorption at 220 nm, mobile phase hexane/ isopropanol = 99:1, flow rate 1.0 mL/min, column temperature of 25 °C.

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Article

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Eric Meggers: 0000-0002-8851-7623 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge funding from the German Research Foundation (ME 1805/15-1). REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.7b00376. HPLC traces and NMR spectra (PDF) D

DOI: 10.1021/acs.oprd.7b00376 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Tetrahedron Lett. 2006, 47, 8083. (b) Motoki, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 2997. (c) Aikawa, K.; Hioki, Y.; Mikami, K. Org. Lett. 2010, 12, 5716. (d) Zhang, G.-W.; Meng, W.; Ma, H.; Nie, J.; Zhang, W.-Q.; Ma, J.-A. Angew. Chem., Int. Ed. 2011, 50, 3538. (e) Ohshima, T.; Kawabata, T.; Takeuchi, Y.; Kakinuma, T.; Iwasaki, T.; Yonezawa, T.; Murakami, H.; Nishiyama, H.; Mashima, K. Angew. Chem., Int. Ed. 2011, 50, 6296. (f) Wang, T.; Niu, J.-L.; Liu, S.-L.; Huang, J.-J.; Gong, J.-F.; Song, M.-P. Adv. Synth. Catal. 2013, 355, 927. (g) Dhayalan, V.; Murakami, R.; Hayashi, M. Asian J. Chem. 2013, 25, 7505. (h) Cook, A. M.; Wolf, C. Angew. Chem., Int. Ed. 2016, 55, 2929. (i) Ito, J.-i.; Ubukata, S.; Muraoka, S.; Nishiyama, H. Chem. - Eur. J. 2016, 22, 16801. (25) For the effect of the nature and amount of Brønsted base for this type of catalytic enantioselective alkynylation of trifluoromethyl ketones, see ref 22. (26) Cai, H.; Nie, J.; Zheng, Y.; Ma, J.-A. J. Org. Chem. 2014, 79, 5484. (27) Correia, C. A.; Gilmore, K.; McQuade, D. T.; Seeberger, P. H. Angew. Chem., Int. Ed. 2015, 54, 4945.

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DOI: 10.1021/acs.oprd.7b00376 Org. Process Res. Dev. XXXX, XXX, XXX−XXX