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Development of the Large-Scale Synthesis of Tetrahydropyran Glycine, a Precursor to the HCV NS5A Inhibitor BMS-986097 Arvind Mathur,*,† Bei Wang,† Daniel Smith,† Jianqing Li,*,† Joseph Pawluczyk,† Jung-Hui Sun,† Michael Kwok Wong,† Subramaniam Krishnananthan,† Dauh-Rurng Wu,† Dawn Sun,† Peng Li,† Shiuhang Yip,† Bang-Chi Chen,† Phil S. Baran,‡ Qi Chen,§ Omar D. Lopez,§ Zhong Yong,§ John A. Bender,§ Van N. Nguyen,§ Jeffrey L. Romine,§ Denis R. St. Laurent,§ Gan Wang,§ John F. Kadow,§ Nicholas A. Meanwell,§ Makonen Belema,§ and Rulin Zhao*,† †

Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research and Development, PO Box 4000, Princeton, New Jersey 08543, United States ‡ Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States § Discovery Chemistry, Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States S Supporting Information *

ABSTRACT: An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of t-butyl 2-((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but-2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1. The epimerization and chiral resolution of 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran 1. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API BMS-986097 for toxicology studies. the lead candidate for further evaluation.3 Over 100 g of this compound was required to support preclinical toxicology studies.

1. INTRODUCTION The chronic hepatitis C virus (HCV) infection is a disease with a global prevalence affecting over 180 million individuals. Over the past decade, tremendous advances in HCV drug development have been made that culminated in a number of approved drugs, which demonstrated high cure rates, shorter treatment duration, and improved tolerance compared with the older standard of care, which included pegylated interferon and ribavirin.1 Inhibiting HCV NS5A, a protein with no known enzymatic function, is an approach to the suppression of virus replication that has emerged as a critical element of all currently approved therapeutic regimens that rely upon combinations of small molecule HCV inhibitors.1,2 During our efforts to identify HCV NS5A inhibitors with improved profiles, BMS-986097 was identified as a highly potent compound that was selected as © 2017 American Chemical Society

2. RESULTS AND DISCUSSION BMS-986097 was prepared by coupling core precursor 2 and cyclopropyl pyran 1 (Scheme 1). Three independent routes were devised to acid 1 during the discovery and early stage characterizations of BMS-986097, the third one proving most amenable to scale up. The first generation route to acid 1, devised as part of a broader structure−activity relation investigation that necessiReceived: July 24, 2017 Published: September 6, 2017 10376

DOI: 10.1021/acs.joc.7b01852 J. Org. Chem. 2017, 82, 10376−10387

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The Journal of Organic Chemistry Scheme 1. BMS-986097 Synthesis Disconnection

Scheme 2. First Generation Route to Cap Piece 1

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DOI: 10.1021/acs.joc.7b01852 J. Org. Chem. 2017, 82, 10376−10387

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The Journal of Organic Chemistry Scheme 3. Second Generation Route to Cyclopropyl Pyran 1

product 10, was also isolated. Asymmetric hydrogenation of E/ Z mixture 10 under Burk’s condition provided a diastereomeric mixture of 11a and 11b, which was readily separable on an AD chiral column.7 Hydrogenolysis of the individual stereoisomers in the presence of dimethyl carbonate followed by a standard ester hydrolysis afforded acids 12 and 1, whose absolute stereochemical assignment was made as described below. Although the first generation route was straightforward and provided gram quantities of acid 1, which covered the initial material demand for BMS-986097 and other associated structure−activity relation studies, the route was deemed unsuitable for scale up. Specifically, it suffered from a poor yield at a late stage (see the HWE-coupling step); it was lengthy, and most of the intermediates were purified by chromatography. To ensure material delivery within the targeted timelines, two new routes to acid 1 were devised in parallel by two subgroups, where one primarily focused on streamlining the first generation route, while the second one investigated more differentiated disconnections. A second generation route was thus devised that supplied pyranone 9 in half the number of steps compared to the first generation route (see Scheme 3). Phosphorane 14 and cyclopropanol 16, both of which were prepared in one step from commercially available materials, were condensed under the Dean−Stark conditions (in order to remove the ethanol byproduct) to afford enone 17 in a good, although variable, yield when done by different individuals (range 44−88%; average 68%). Treatment of 17 with an Amberlyst-15 resin in acetonitrile effected both desilylation and cyclization. The

tated access to all the stereoisomers of 1, is outlined in Scheme 2. It was envisioned that a Horner−Wadsworth−Emmons (HWE) coupling of pyranone 9 with a glycine phosphonate ester derivative followed by an asymmetric hydrogenation of the resultant E/Z-mixture 10 would provide an entry to the targeted stereoisomers (see Scheme 2). The preparation of pyranone 9 started from the readily available ester 3, and the elaboration of the acid- and base-sensitive β-ketoester 5 was conducted according to a literature precedent.4 A combination of standard reduction and protection steps afforded silyl ether 6, setting the stage for a key cyclopropanation step. Note that the silylation step was much slower than expected, requiring a reaction time in excess of 2 days to reach completion. The Kulinkovich cyclopropanation proved to be robust, and treatment of the resultant cyclopropanol with p-TsOH acid effected both hemiacetal exchange and desilylation, resulting in alcohol 7 of unknown stereochemical composition although inconsequential for the current purpose.5 Reductive removal of the methoxy moiety of 76 followed by a standard Swern oxidation afforded the key ketone progenitor 9 in a good overall yield. HWE condensation of 9 with N-benzyloxycarbonyl(dimethoxyphosphinyl) glycine methyl ester in the presence of tetramethyl guanidine gave a low yield of the α,βdidehydroamino ester 10 as an inseparable mixture of E/Z isomers. Alternate conditions were briefly examined (such as changing the base or the solvent) but did not provide a measurable impact on the efficiency of the reaction. It is noteworthy that a side product, not fully characterized but believed to be a close structural analogue of the targeted 10378

DOI: 10.1021/acs.joc.7b01852 J. Org. Chem. 2017, 82, 10376−10387

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The Journal of Organic Chemistry Scheme 4. Retrosynthetic Analyses of tert-Butyl Ester 21, a Precursor of Acid 1

copper-catalyzed Schollkopf condensation8 of the resultant pyranone 9 with ethyl isocyanoacetate provided a mixture of esters 18a and 18b (in a 3:2 ratio) in a combined yield (69%) that was more than twice than the yield of the corresponding HWE-coupling step in the first generation route. The E/Z isomer separation was challenging but achievable under both flash column and SFC conditions, and the latter method proved to be the relatively more efficient method due to a greater distinction in retention times. E/Z-stereochemical assignments were readily made on the basis of the NOE interactions between the formamide N−H signal and that of the differentiated allylic protons. The asymmetric hydrogenation of a clean sample of 18b under Burk’s conditions afforded 19 in 95% yield and 98.6% stereochemical excess, and 19 was elaborated through a combination of formamide deprotection and methyl carbamate formation to afford ester 20 in 88% yield. Note that since the complete removal of 18a from 18b was problematic when processing on scale, the batches that were submitted to the chiral hydrogenation step contained varying but low (99% purity.16

3. SUMMARY Three routes were developed to prepare the cap acid precursor 1 of BMS-986097. The third route, which overcame the scalability limitation of the first two, features a one-pot synthesis of the α,β-unsaturated ester 28 followed by a diastereoselective Michael addition, cyclization, and DBU-catalyzed epimerization to afford lactone 27b. The highly efficient conversion of 27b to the cyclopropyl pyran 1 was capable through acid-catalyzed deprotection, carbamate formation, lactone reduction, tosylation, cyclization, and final hydrolysis. This route generated a sufficient amount of acid 1 for coupling with amine core 2 to 10383

DOI: 10.1021/acs.joc.7b01852 J. Org. Chem. 2017, 82, 10376−10387

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The Journal of Organic Chemistry Scheme 12. Scale-Up Scheme for BMS-986097

solution was stirred for 24 h, and then potassium carbonate (461 g, 3338 mmol) and benzyl 2-(dimethoxyphosphoryl)acetate (431 g, 1669 mmol) were added. After the mixture was stirred for another 24 h, the solution was concentrated in vacuo. The residue was dissolved in EtOAc (1 L), and the resulting solution was washed with brine (500 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by flash chromatography to afford alkene 28 (334 g, 1438 mmol, 86% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.41−7.34 (m, 5H), 7.17−7.04 (m, 1H), 6.04 (dt, J = 15.7, 1.5 Hz, 1H), 5.20 (s, 2H), 2.50−2.45 (m, 2H), 2.25−2.16 (m, 1H), 0.86−0.80 (m, 2H), 0.58− 0.51 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 166.2, 145.8, 136.0, 128.6, 128.3, 128.3, 123.6, 66.3, 54.6, 41.1, 13.3. HRMS (ESI-FTMS): m/z calcd for C14H16O3 [M + H]+ 232.1099, found: 233.1170. 4.3. General Procedures for tert-Butyl 2((Diphenylmethylene)amino)-2-(5-oxo-4-oxaspiro[2.5]octan-7yl)acetates (27). To a N2 flushed 5 L three-necked round-bottom flask were added tert-butyl 2-((diphenylmethylene)amino)acetate (24) (120 g, 406 mmol) and a solution of alkene 28 (118 g, 406 mmol) in THF (1.2 L). The solution was cooled with an ice bath to 5 °C, and a solution of lithium bis(trimethylsilyl)amide (1 M in THF, 20.31 mL, 20.31 mmol) was added slowly. The reaction mixture was stirred below 10 °C for an hour and then allowed to warm to 15 °C over a period of 2 h. The reaction mixture was quenched with a saturated solution of NH4Cl (1.5 L). The organic phase was separated, and the aqueous layer was extracted with EtOAc (600 mL). The combined organic

provide over 100 g of BMS-986097 with >99% purity for toxicology studies.

4. EXPERIMENTAL SECTION 4.1. General. All reagents were obtained from Sigma-Aldrich and used without further purification unless otherwise stated. All reactions were performed under a nitrogen atmosphere. All reactions were monitored by a Shimadzu LC/MS system using the following method: Phenomenex C18 column = 10 μm 4.6 mm × 50 mm; solvent A = 10% methanol/90% water with 0.1% TFA, solvent B = 90% methanol/10% water with 0.1% TFA; gradient = 0−100% B over 4 min; flow = 4 mL/ min; wavelength = 220 nm. HPLC analyses were performed using a Shimadzu system (model SPD 10AV). Optical rotations were measured using a polarimeter in the solvent specified. All 1H NMR and 13C NMR spectra were recorded on a Bruker 400 or 500 MHz spectrometer using DMSO-d6 or CDCl3 as the solvent. HRMS were measured with electrospray ionization (ESI). All the a/b/c/d stereoisomeric designations below derive their assignments from the relative stereochemistry established in structures 27. Also note that the compound designated as acid 1 in text is the same as the compound noted as acid 1b below. 4.2. Benzyl (E)-4-(1-Hydroxycyclopropyl)but-2-enoate (28). To a solution of 1-(2,2-dimethoxyethyl) cyclopropanol (31)10 (244 g, 1669 mmol) in a mixture of THF and H2O (6:1 ratio, 3.5 L) at room temperature was added p-toluenesulfonic acid (28.7 g, 167 mmol). The 10384

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The Journal of Organic Chemistry layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product (220 g) as a yellow semisolid, which was crystallized from 10% toluene in heptane (2.2 L) (from 55 to 0 °C) to give a 1:1 mixture of 27c and 27d (146 g, 348 mmol, 86% yield) as a white solid. The above mixture was separated by SFC to give the first eluting compound 27c (62 g, 148 mmol, 85% recovery yield) as a white solid and the later eluting compound 27d (61 g, 145 mmol, 84% recovery) as a white solid. The preparative chiral SFC conditions were as follows: Lux-cellulose-4 (5 × 25 cm, 5 μm), 12% methanol in CO2, 250 mL/ min, 220 nm, 40 °C, 100 bar BPR, 100 mg/mL in acetonitrile, 2 mL/ 2.75 min stack injection. The analytical conditions were as follows: Lux-cellulose-4 (0.46 × 25 cm, 5 μm), 3 mL/min, 10% methanol in CO2, 40 °C, 210 nm, 100 bar BPR. Racemization of the α-carbon center of compound 27c afforded a mixture of 27b and 27c. A solution of 27c (46 g, 110 mmol) and 1,8diazabicyclo[5.4.0]undec-7-ene (16.40 mL, 110 mmol) in CH3CN (250 mL) was heated at reflux for 16 h. After the mixture cooled to rt, the solvent was removed under reduced pressure, and the residue partitioned between EtOAc and water (2 L, 1:1). The organic phase was separated, washed with water (2 × 1 L) and brine (1 L), dried over Na2SO4, filtered, and concentrated in vacuo to give a mixture of 27b and 27c as an oil (43 g, 102 mmol, 93% yield). The preparative chiral SFC conditions to separate the mixture of 27b and 27c were as follows: Chiralpak IC (3 × 25 cm, 5 μm), 10% methanol in CO2, 200 mL/min, 220 nm, 45 °C, 100 bar BPR, 220 mg/ mL in acetonitrile/DCM (1:1), 2 mL/3.1 min stack injection. The analytical conditions were as follows: Chiralpak IC (0.46 × 25 cm, 5 μm), 10% methanol in CO2, 3 mL/min, 40 °C, 220 nm, 100 bar BPR. The first eluting compound 27b was obtained as a white solid (15.4 g, 36.7 mmol, 72% recovery). The second eluting compound 27c was obtained as a white solid (15 g, 35.8 mmol, 70% recovery). Using a similar procedure, we can obtain pure 27a by racemization of the α-carbon center of compound 27d to a mixture of 27a and 27d, followed by chiral SFC separation. 4.3.1. tert-Butyl (R)-2-((Diphenylmethylene)amino)-2-((S)-5-oxo4-oxaspiro[2.5]octan-7-yl)acetate (27a). [α]20 D = +112.17 (c = 4.00, MeOH). 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 7.7 Hz, 2H), 7.51−7.34 (m, 6H), 7.22−7.16 (m, 2H), 3.91 (d, J = 4.5 Hz, 1H), 2.91 (ddd, J = 9.3, 6.3, 4.6 Hz, 1H), 2.59−2.52 (m, 1H), 2.43−2.35 (m, 2H), 1.82 (dd, J = 14.0, 6.5 Hz, 1H), 1.45 (s, 9H), 1.12−1.03 (m, 2H), 0.87−0.77 (m, 1H), 0.71−0.63 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 172.8, 172.3, 169.6, 139.1, 136.4, 130.7, 128.9, 128.8, 128.6, 128.1, 127.7, 81.8, 68.3, 62.2, 34.7, 33.8, 30.7, 28.1, 12.4, 11.9. Anal. Calcd for C26H29NO4: C, 74.44; H, 6.97; N, 3.34. Found: C, 74.47; H, 6.83; N, 3.39. HRMS (ESI-FTMS): m/z calcd for C26H30NO4 [M + H]+ 420.2175; found 420.2171. 4.3.2. tert-Butyl (S)-2-((Diphenylmethylene)amino)-2-((R)-5-oxo4-oxaspiro[2.5]octan-7-yl)acetate (27b). [α]20 D = −110.98 (c = 4.20, MeOH). 1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 7.6 Hz, 2H), 7.49−7.32 (m, 6H), 7.20−7.14 (m, 2H), 3.90 (d, J = 4.5 Hz, 1H), 2.95−2.85 (m, 1H), 2.58−2.50 (m, 1H), 2.42−2.33 (m, 2H), 1.80 (dd, J = 13.9, 6.5 Hz, 1H), 1.50−1.43 (m, 9H), 1.1−1.02 (m, 2H), 0.86− 0.76 (m, 1H), 0.70−0.61 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 172.8, 172.3, 169.6, 139.1, 136.4, 130.7, 128.9, 128.8, 128.6, 128.1, 127.7, 81.8, 68.3, 62.2, 34.7, 33.8, 30.7, 28.1, 12.4, 11.9. Anal. Calcd for C26H29NO4: C, 74.44; H, 6.97; N, 3.34. Found: C, 74.29; H, 6.78; N, 3.35. HRMS (ESI-FTMS): m/z calcd for C26H30NO4 [M + H]+ 420.2175; found 420.2171. 4.3.3. tert-Butyl (R)-2-((Diphenylmethylene)amino)-2-((R)-5-oxo4-oxaspiro[2.5]octan-7-yl)acetate (27c). [α]20 D = +110.28 (c = 4.00, MeOH). 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 7.6 Hz, 2H), 7.49−7.33 (m, 6H), 7.20−7.13 (m, 2H), 3.94 (d, J = 4.5 Hz, 1H), 3.00−2.86 (m, 2H), 2.80−2.69 (m, 1H), 1.89 (dd, J = 13.7, 9.5 Hz, 1H), 1.54−1.42 (m, 10H), 1.07−0.97 (m, 2H), 0.68−0.54 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 172.8, 171.7, 169.5, 139.0, 136.4, 130.7, 128.9, 128.8, 128.6, 128.1, 127.7, 81.9, 68.4, 61.9, 34.7, 32.6, 31.9, 28.1, 12.0, 12.0. Anal. Calcd for C26H29NO4: C, 74.44; H, 6.97; N, 3.34. Found: C, 74.55; H, 6.90; N, 3.22. HRMS (ESI-FTMS): m/z calcd for C26H30NO4 [M + H]+ 420.2175; found 420.2168.

4.3.4. tert-Butyl (S)-2-((Diphenylmethylene)amino)-2-((S)-5-oxo4-oxaspiro[2.5]octan-7-yl)acetate (27d). [α]20 D = −109.29 (c = 6.85, MeOH). 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 7.7 Hz, 2H), 7.49−7.33 (m, 6H), 7.19−7.13 (m, 2H), 3.94 (d, J = 4.6 Hz, 1H), 3.00−2.86 (m, 2H), 2.81−2.68 (m, 1H), 1.89 (dd, J = 13.8, 9.3 Hz, 1H), 1.54−1.48 (m, 1H), 1.45 (s, 9H), 1.08−0.97 (m, 2H), 0.68−0.54 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 172.8, 171.7, 169.5, 139.0, 136.4, 130.7, 128.9, 128.8, 128.6, 128.1, 127.7, 81.9, 68.4, 61.9, 34.7, 32.6, 31.9, 28.1, 12.0, 12.0. Anal. Calcd for C26H29NO4: C, 74.44; H, 6.97; N, 3.34. Found: C, 73.94; H, 6.88; N, 3.33. HRMS (ESI-FTMS): m/z calcd for C26H30NO4 [M + H]+ 420.2175; found 420.2168. 4.4. General Procedure for tert-Butyl 2((Diphenylmethylene)amino)-2-(5-oxo-4-oxaspiro[2.5]octan-7yl)acetates (39). To a solution of 27 (32.5 g, 72 mmol) in THF (97 mL) at 0 °C was added a solution of HCl (12 N, 12 mL) and ice (70 g). After stirring the solution at rt for 20 min, the reaction mixture was extracted with heptane (2 × 250 mL). The aqueous layer was separated and neutralized to pH 7−7.5 with NaHCO3 (15.11 g, 180 mmol) at 0 °C, and a solution of dimethyl dicarbonate (19.30 g, 144 mmol) in EtOAc (97 mL) was added. The reaction mixture was stirred at rt for 1 h. The aqueous layer was adjusted to pH = 1 and extracted with EtOAc (3 × 200 mL). The combined organic extracts were dried over Na2SO4 and evaporated to give an oil. The crude product was dissolved in THF (100 mL), and a solution of LiOH (1 M in water, 144 mL, 144 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. The aqueous layer was acidified to pH = 1 and then extracted with EtOAc (3 × 200 mL). The combined organic extracts were dried over Na2SO4 and evaporated at 50 °C under a vacuum overnight to give the cyclized product 39 (22.5 g, 71.8 mmol, 100% yield). 4.4.1. (R)-tert-Butyl 2-((Diphenylmethylene)amino)-2-((S)-5-oxo4-oxaspiro[2.5]octan-7-yl)acetate (39a). [α]20 D = −51.63 (c = 3.11, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 5.31 (br d, J = 7.9 Hz, 1H), 4.39−4.24 (m, 1H), 3.73 (s, 3H), 2.79−2.63 (m, 2H), 2.61−2.50 (m, 1H), 1.93 (dd, J = 13.9, 9.5 Hz, 1H), 1.56 (br d, J = 5.6 Hz, 1H), 1.50 (s, 9H), 1.15−1.03 (m, 2H), 0.80−0.73 (m, 1H), 0.63−0.54 (m, 1H). 13 C NMR (126 MHz, CDCl3): δ 171.6, 169.8, 157.0, 83.4, 61.7, 56.9, 52.7, 34.9, 33.1, 30.6, 28.1, 12.3, 12.0. Anal. Calcd for C15H23NO6: C, 57.50; H, 7.40; N, 4.47. Found: C, 57.59; H, 7.13; N, 4.45. HRMS (ESI-FTMS): m/z calcd for C15H23NNaO6 [M + Na]+ 336.1423; found 336.1417. 4.4.2. (S)-tert-Butyl 2-((Methoxycarbonyl)amino)-2-((R)-5-oxo-4oxaspiro[2.5]octan-7-yl)acetate (39b). [α]20 D = +50.77 (c = 6.12, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 5.31 (br d, J = 7.8 Hz, 1H), 4.37−4.25 (m, 1H), 3.71 (s, 3H), 2.77−2.62 (m, 2H), 2.60−2.48 (m, 1H), 1.91 (dd, J = 14.0, 9.4 Hz, 1H), 1.56 (dd, J = 13.7, 5.6 Hz, 1H), 1.48 (s, 9H), 1.12−1.01 (m, 2H), 0.78−0.71 (m, 1H), 0.61−0.53 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 171.6, 169.8, 157.0, 83.4, 61.7, 56.9, 52.7, 34.9, 33.1, 30.6, 28.1, 12.3, 12.0. Anal. Calcd for C15H23NO6: C, 57.50; H, 7.40; N, 4.47. Found: C, 57.79; N, 4.48; H, 7.13. HRMS (ESI-FTMS): m/z calcd for C15H23NNaO6 [M + Na]+ 336.1423; found 336.1417. 4.4.3. (R)-tert-Butyl 2-((Methoxycarbonyl)amino)-2-((R)-5-oxo-4oxaspiro[2.5]octan-7-yl)acetate (39c). [α]20 D = −25.19 (c = 4.35, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ 5.39 (br d, J = 7.5 Hz, 1H), 4.38 (br dd, J = 7.5, 3.7 Hz, 1H), 3.70 (s, 3H), 2.75−2.61 (m, 1H), 2.59−2.42 (m, 2H), 2.09−1.95 (m, 1H), 1.73 (br dd, J = 14.2, 5.5 Hz, 1H), 1.50 (s, 9H), 1.11−1.00 (m, 2H), 0.79−0.68 (m, 1H), 0.66−0.59 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 171.7, 169.5, 157.1, 83.6, 62.0, 56.9, 52.7, 34.8, 32.0, 31.2, 28.0, 12.0. HRMS (ESI-FTMS): m/z calcd for C15H23NNaO6 [M + Na]+ 336.1423; found 336.1417. 4.4.4. (S)-tert-Butyl 2-((Methoxycarbonyl)amino)-2-((S)-5-oxo-4oxaspiro[2.5]octan-7-yl)acetate (39d). [α]20 D = +23.29 (c = 4.13, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 5.41 (br d, J = 8.1 Hz, 1H), 4.44−4.34 (m, 1H), 3.72 (s, 3H), 2.72 (dt, J = 10.4, 5.2 Hz, 1H), 2.61− 2.41 (m, 2H), 2.08−1.99 (m, 1H), 1.75 (br dd, J = 14.2, 5.6 Hz, 1H), 1.51 (s, 9H), 1.15−1.00 (m, 2H), 0.81−0.71 (m, 1H), 0.67−0.59 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 171.7, 169.5, 157.1, 83.6, 62.0, 56.9, 52.7, 34.8, 32.0, 31.2, 28.1, 12.1, 12.0. HRMS (ESI-FTMS): m/z calcd for C15H23NNaO6 [M + Na]+ 336.1423; found 336.1417. 4.5. General Procedure for tert-Butyl 5-Hydroxy-3-((1hydroxycyclopropyl)methyl)-2-((methoxycarbonyl)amino)10385

DOI: 10.1021/acs.joc.7b01852 J. Org. Chem. 2017, 82, 10376−10387

Article

The Journal of Organic Chemistry pentanoates (40). To a solution of 40 (22.5 g, 71.8 mmol) in THF (225 mL) at 0 °C cooled with an ice bath was added dropwise a solution of NaBH4 (10.89 g, 288 mmol) in H2O (45.1 mL). The temperature of the reaction mixture was kept below 10 °C during the addition and then warmed to rt and stirred for 3.5 h. The solution was diluted with aqueous NaHCO3 (200 mL) and the aqueous layer extracted with EtOAc (3 × 300 mL). The combined organic layer was dried over Na2SO4 overnight and concentrated to give the diol product 40 (21.7 g, 68.4 mmol, 95% yield), which was used in the next step without further purification. 4.5.1. tert-Butyl (2R,3R)-5-Hydroxy-3-((1-hydroxycyclopropyl)methyl)-2-((methoxycarbonyl)amino)pentanoate (40a). [α]D20 = −70.58 (c = 6.25, CH2Cl2). 1H NMR (400 MHz, DMSO-d6): δ 7.22 (d, J = 8.4 Hz, 1H), 5.02 (s, 1H), 4.42 (t, J = 4.8 Hz, 1H), 4.17 (dd, J = 8.3, 3.8 Hz, 1H), 3.54 (s, 3H), 3.48−3.38 (m, 2H), 2.33 (br d, J = 3.5 Hz, 1H), 1.74−1.60 (m, 1H), 1.52−1.37 (m, 12H), 0.60−0.49 (m, 2H), 0.34 (s, 2H). 13C NMR (101 MHz, DMSO-d6): δ 171.5, 157.4, 80.9, 59.3, 56.7, 52.5, 51.9, 38.7, 34.8, 33.4, 28.2, 14.4, 13.0. HRMS (ESI-FTMS): m/z calcd for C15H27NNaO6 [M + Na]+ 340.1736; found 340.1727. 4.5.2. tert-Butyl (2S,3S)-5-Hydroxy-3-((1-hydroxycyclopropyl)methyl)-2-((methoxycarbonyl)amino)pentanoate (40b). [α]D20 = +71.39 (c = 2.42, CH2Cl2). 1H NMR (500 MHz, DMSO-d6): δ 7.22 (d, J = 8.2 Hz, 1H), 5.03 (s, 1H), 4.42 (t, J = 4.8 Hz, 1H), 4.18 (dd, J = 8.3, 3.9 Hz, 1H), 3.55 (s, 3H), 3.47−3.40 (m, 2H), 2.33 (br dd, J = 8.5, 4.7 Hz, 1H), 1.69 (br dd, J = 13.4, 6.3 Hz, 1H), 1.51−1.37 (m, 12H), 0.61−0.50 (m, 2H), 0.38−0.29 (m, 2H). 13C NMR (126 MHz, DMSO-d6): δ 171.5, 157.4, 80.9, 59.3, 56.6, 52.5, 51.9, 38.7, 34.8, 33.4, 28.2, 14.3, 13.0. HRMS (ESI-FTMS): m/z calcd for C15H27NNaO6 [M + Na]+ 340.1736; found 340.1728. 4.5.3. tert-Butyl (2R,3S)-5-Hydroxy-3-((1-hydroxycyclopropyl)methyl)-2-((methoxycarbonyl)amino)pentanoate (40c). [α]D20 = −28.04 (c = 4.35, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ 5.73 (br d, J = 8.1 Hz, 1H), 4.64 (br dd, J = 8.3, 2.1 Hz, 1H), 3.77−3.73 (m, 2H), 3.71 (s, 3H), 3.44 (br s, 1H), 2.51 (td, J = 6.7, 2.9 Hz, 1H), 2.26 (br s, 1H), 1.88 (br dd, J = 14.6, 7.3 Hz, 1H), 1.50 (s, 11H), 1.41−1.32 (m, 1H), 0.88−0.77 (m, 2H), 0.53−0.44 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 171.2, 157.5, 82.6, 60.4, 56.8, 54.4, 52.5, 39.0, 36.5, 33.1, 28.1, 14.2, 14.2, 14.1. HRMS (ESI-FTMS): m/z calcd for C15H27NNaO6 [M + Na]+ 340.1736; found 340.1728. 4.5.4. tert-Butyl (2S,3R)-5-Hydroxy-3-((1-hydroxycyclopropyl)methyl)-2-((methoxycarbonyl)amino)pentanoate (40d). [α]D20 = +23.71 (c = 6.25, CH2Cl2). 1H NMR (400 MHz, DMSO-d6): δ 7.21 (d, J = 8.4 Hz, 1H), 5.01 (s, 1H), 4.50 (t, J = 4.9 Hz, 1H), 4.25 (dd, J = 8.4, 3.8 Hz, 1H), 3.54 (s, 3H), 3.41 (qd, J = 11.0, 4.3 Hz, 2H), 2.46− 2.32 (m, 1H), 1.58−1.32 (m, 13H), 0.57−0.47 (m, 2H), 0.38−0.18 (m, 2H). 13C NMR (101 MHz, DMSO-d6): δ 171.8, 157.5, 80.8, 59.3, 57.3, 52.5, 51.8, 39.1, 34.4, 33.5, 28.2, 13.3, 13.2. HRMS (ESI-FTMS): m/z calcd for C15H27NNaO6 [M + Na]+ 340.1736; found 340.1728. 4.6. General Procedure for tert-Butyl 2-((Methoxycarbonyl)amino)-2-(4-oxaspiro[2.5]octan-7-yl)acetates (21). To a solution of diol 40 (25.4 g, 80 mmol), triethylamine (55.8 mL, 400 mmol), and DMAP (0.977 g, 8.00 mmol) in CH2Cl2 (267 mL) at 8 °C cooled with an ice bath was added 4-methylbenzene-1-sulfonyl chloride (15.25 g, 80 mmol). The ice bath was removed after completion of the addition. After 1 h, another portion of TsCl (2.29 g, 12.0 mmol) was added at 8 °C. The solution was stirred for 1 h, cooled with an ice bath, and then heated at 38 °C for 24 h. The reaction mixture was washed sequentially with H2O, saturated NaHCO3, and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (0−40% acetone/hexane) to give tetrahydropyran 22 (17.31 g, 57.8 mmol, 72.3% yield). 4.6.1. (R)-tert-Butyl 2-((Methoxycarbonyl)amino)-2-((R)-4oxaspiro[2.5]octan-7-yl)acetate (21a). [α]20 D = −63.12 (c = 5.10, CH2Cl2). 1H NMR (500 MHz, DMSO-d6): δ 7.48 (d, J = 8.2 Hz, 1H), 3.82 (t, J = 7.9 Hz, 1H), 3.78−3.73 (m, 1H), 3.54 (s, 3H), 3.39−3.33 (m, 1H), 2.04 (br d, J = 7.6 Hz, 1H), 1.79 (br t, J = 12.3 Hz, 1H), 1.52 (br d, J = 13.9 Hz, 1H), 1.41 (s, 9H), 1.39−1.33 (m, 1H), 1.01 (br d, J = 11.4 Hz, 1H), 0.73−0.65 (m, 1H), 0.53−0.44 (m, 2H), 0.32−0.25 (m, 1H). 13C NMR (126 MHz, DMSO-d6): δ 171.2, 157.3, 81.2, 65.8,

59.4, 59.2, 52.0, 36.8, 34.6, 29.0, 28.2, 12.6, 11.2. HRMS (ESI-FTMS): m/z calcd for C15H25NNaO5 [M + Na]+ 322.1630; found 322.1624. 4.6.2. (S)-tert-Butyl 2-((Methoxycarbonyl)amino)-2-((S)-4oxaspiro[2.5]octan-7-yl)acetate (21b). [α]20 D = +66.82 (c = 2.40, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 5.24 (br d, J = 7.9 Hz, 1H), 4.26 (br dd, J = 8.0, 5.0 Hz, 1H), 3.90 (ddd, J = 11.1, 4.6, 1.8 Hz, 1H), 3.71 (s, 3H), 3.53 (td, J = 11.6, 2.5 Hz, 1H), 2.27−2.11 (m, 1H), 2.04− 1.93 (m, 1H), 1.71−1.62 (m, 1H), 1.50 (s, 10H), 0.99−0.82 (m, 2H), 0.66 (dddd, J = 10.8, 6.4, 4.7, 1.9 Hz, 1H), 0.57−0.49 (m, 1H), 0.29 (ddd, J = 10.0, 6.5, 4.8 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 170.7, 156.8, 82.4, 66.3, 59.0, 58.1, 52.4, 38.5, 33.7, 28.7, 28.1, 12.6, 11.4. HRMS (ESI-FTMS): m/z calcd for C15H26NO5 [M + H]+ 300.1811; found 300.1815. 4.6.3. (R)-tert-Butyl 2-((Methoxycarbonyl)amino)-2-((S)-4oxaspiro[2.5]octan-7-yl)acetate (21c). [α]20 D = +7.86 (c = 4.35, CH2Cl2). 1H NMR (500 MHz, DMSO-d6): δ 7.50 (br d, J = 8.4 Hz, 1H), 3.86 (dd, J = 8.1, 6.9 Hz, 1H), 3.80−3.69 (m, 1H), 3.55 (s, 3H), 3.38−3.33 (m, 1H), 2.06 (br d, J = 6.7 Hz, 1H), 1.74 (t, J = 12.4 Hz, 1H), 1.55−1.41 (m, 2H), 1.40 (s, 9H), 1.02 (dd, J = 13.0, 2.2 Hz, 1H), 0.73−0.66 (m, 1H), 0.53−0.44 (m, 2H), 0.33−0.27 (m, 1H). 13C NMR (126 MHz, DMSO-d6): δ 171.0, 157.3, 81.2, 66.1, 59.1, 59.0, 52.0, 36.9, 35.0, 28.2, 12.5, 11.4. HRMS (ESI-FTMS): m/z calcd for C15H25NNaO5 [M + Na]+ 322.1630; found 322.1623. 4.6.4. (S)-tert-Butyl 2-((Methoxycarbonyl)amino)-2-((R)-4oxaspiro[2.5]octan-7-yl)acetate (21d). [α]20 D = −7.52 (c = 3.80, CH2Cl2). 1H NMR (500 MHz, DMSO-d6): δ 7.50 (br d, J = 8.4 Hz, 1H), 3.86 (dd, J = 8.1, 6.9 Hz, 1H), 3.79−3.71 (m, 1H), 3.55 (s, 3H), 3.37−3.32 (m, 1H), 2.11−1.96 (m, 1H), 1.75 (t, J = 12.4 Hz, 1H), 1.52−1.41 (m, 2H), 1.40 (s, 9H), 1.02 (dd, J = 13.0, 2.3 Hz, 1H), 0.74−0.65 (m, 1H), 0.54−0.45 (m, 2H), 0.34−0.27 (m, 1H). 13C NMR (126 MHz, DMSO-d6): δ 171.0, 157.3, 81.2, 66.1, 59.2, 59.0, 52.0, 36.9, 35.0, 28.2, 12.5, 11.4. HRMS (ESI-FTMS): m/z calcd for C15H25NNaO5 [M + Na]+ 322.1630; found 322.1624. 4.7. General Procedure for 2-((Methoxycarbonyl)amino)-2(4-oxaspiro[2.5]octan-7-yl)acetic Acids (1). A solution of tetrahydropyran 21b (41.5 g, 139 mmol) in formic acid (319 g, 6931 mmol) was stirred at rt for 46 h. The formic acid was removed by distillation in vacuo at 37 °C (external temperature). The remaining clear viscous oil was treated with toluene (50 mL), and the mixture was distilled again to remove the residual formic acid and toluene. This process was repeated three more times. The viscous oil (42.7 g) was treated with saturated NaHCO3 (250 mL) with stirring for 30 min. The basic solution was washed with ether (2 × 150 mL, 1 × 100 mL). The basic solution was treated with 1 N HCl until the pH was about 2. The acidic solution was extracted with 2-Me-THF (6 × 200 mL) until the aqueous layer indicated an absence of the desired product. (Note that after each extraction, 1 N HCl was added to the aqueous layer to adjust the pH to 2−3.) The combined organic extracts were dried over MgSO4, filtered, evaporated, and dried under a vacuum to give 35.8 g of 1. The NMR spectra indicated that the ratio of formic acid to product was 1:80. The material was treated with toluene, and the mixture was sonicated to afford a clear solution. The excess of toluene was removed by distillation. The remaining viscous oil was treated with CH2Cl2 (120 mL), and the mixture was concentrated, then treated with ether (50 mL), and dried in vacuo to give 1 (31.74 g, 130 mmol, 94% yield) as a white foam. 4.7.1. (R)-2-((Methoxycarbonyl)amino)-2-((R)-4-oxaspiro[2.5]1 octan-7-yl)acetic Acid (1a). [α]20 D = −75.55 (c = 3.75, CH2Cl2). H NMR (500 MHz, DMSO-d6): δ 12.76−12.54 (m, 1H), 7.44 (br d, J = 8.4 Hz, 1H), 3.85 (t, J = 7.9 Hz, 1H), 3.78−3.70 (m, 1H), 3.57−3.50 (m, 3H), 3.43−3.27 (m, 1H), 2.04 (dtd, J = 11.5, 7.8, 3.8 Hz, 1H), 1.78 (t, J = 12.2 Hz, 1H), 1.53 (br d, J = 12.1 Hz, 1H), 1.35 (qd, J = 12.5, 4.6 Hz, 1H), 1.05 (br d, J = 11.6 Hz, 1H), 0.73−0.65 (m, 1H), 0.52−0.43 (m, 2H), 0.35−0.26 (m, 1H). 13C NMR (126 MHz, DMSO-d6): δ 173.5, 157.3, 65.9, 59.2, 59.0, 51.9, 36.5, 34.7, 29.2, 12.6, 11.2. HRMS (ESI-FTMS): m/z calcd for C11H18NO5 [M + H]+ 244.1185; found 244.1178. 4.7.2. (S)-2-((Methoxycarbonyl)amino)-2-((S)-4-oxaspiro[2.5]octan-7-yl)acetic Acid (1b) (Same as Acid 1 in Text). [α]20 D = +78.31 (c = 5.04, CH2Cl2). 1H NMR (400 MHz, DMSO-d6): δ 12.64 10386

DOI: 10.1021/acs.joc.7b01852 J. Org. Chem. 2017, 82, 10376−10387

The Journal of Organic Chemistry

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(br s, 1H), 7.46 (br d, J = 8.3 Hz, 1H), 3.85 (br t, J = 7.9 Hz, 1H), 3.75 (br dd, J = 11.1, 2.8 Hz, 1H), 3.54 (s, 3H), 3.36 (br t, J = 10.8 Hz, 1H), 2.03 (ddd, J = 11.4, 7.6, 3.7 Hz, 1H), 1.78 (br t, J = 12.2 Hz, 1H), 1.53 (br d, J = 12.7 Hz, 1H), 1.43−1.28 (m, 1H), 1.05 (br d, J = 11.9 Hz, 1H), 0.74−0.64 (m, 1H), 0.53−0.42 (m, 2H), 0.30 (br dd, J = 9.5, 2.9 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ 173.5, 157.3, 65.9, 59.2, 58.9, 51.9, 36.5, 34.7, 29.2, 12.6, 11.2. HRMS (ESI-FTMS): m/z calcd for C11H18NO5 [M + H]+ 244.1185; found 244.1178. 4.7.3. (R)-2-((Methoxycarbonyl)amino)-2-((S)-4-oxaspiro[2.5]1 octan-7-yl)acetic Acid (1c). [α]20 D = +13.40 (c = 3.75, CH2Cl2). H NMR (500 MHz, DMSO-d6): δ 12.64 (s, 1H), 7.47 (d, J = 8.5 Hz, 1H), 3.92 (dd, J = 8.2, 6.9 Hz, 1H), 3.79−3.69 (m, 1H), 3.55 (s, 3H), 3.36−3.30 (m, 1H), 2.14−2.00 (m, 1H), 1.77 (t, J = 12.4 Hz, 1H), 1.57−1.39 (m, 2H), 1.02 (dd, J = 13.0, 2.1 Hz, 1H), 0.73−0.65 (m, 1H), 0.53−0.44 (m, 2H), 0.34−0.26 (m, 1H). 13C NMR (126 MHz, DMSO-d6): δ 173.3, 157.4, 66.1, 59.0, 58.6, 51.9, 36.6, 35.2, 28.2, 12.5, 11.3. HRMS (ESI-FTMS): m/z calcd for C11H18NO5 [M + H]+ 244.1185; found 244.1179. 4.7.4. (S)-2-((Methoxycarbonyl)amino)-2-((R)-4-oxaspiro[2.5]1 octan-7-yl)acetic Acid (1d). [α]20 D = −15.70 (c = 2.19, CH2Cl2). H NMR (400 MHz, DMSO-d6): δ 12.64 (br s, 1H), 7.47 (d, J = 8.6 Hz, 1H), 3.92 (dd, J = 8.3, 6.8 Hz, 1H), 3.79−3.71 (m, 1H), 3.55 (s, 3H), 3.38−3.29 (m, 1H), 2.15−2.00 (m, 1H), 1.77 (t, J = 12.0 Hz, 1H), 1.57−1.38 (m, 2H), 1.02 (dd, J = 13.0, 2.3 Hz, 1H), 0.72−0.65 (m, 1H), 0.53−0.44 (m, 2H), 0.35−0.26 (m, 1H). 13C NMR (101 MHz, DMSO-d6): δ 173.3, 157.4, 66.1, 59.0, 58.7, 52.0, 36.7, 35.2, 28.2, 12.5, 11.3. HRMS (ESI-FTMS): m/z calcd for C11H18NO5 [M + H]+ 244.1185; found 244.1178. 4.8. General Procedure for Dimethyl ((1S,1′S)((2S,2′S,5S,5′S)-([1,1′-Biphenyl]-4,4′-diylbis(1H-imidazole-5,2diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(2-oxo-1-((S)-4oxaspiro[2.5]octan-7-yl)ethane-2,1-diyl))dicarbamate (BMS986097). To a solution of chiral acid 1 (28.3 g, 107 mmol) in DMSO (486 mL) were added 2-hydroxypyridine 1-oxide (HOPO) (11.87 g, 107 mmol) and EDC (22.34 g, 117 mmol). The light yellow solution was stirred at rt for 100 min before adding 4,4′-bis(2-((2S,5S)5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,1′-biphenyl, 4 N salt, 5.65 mL water (2) (34.0 g, 48.6 mmol), and DIPEA (40.8 g, 316 mmol). The yellow solution was maintained at 25 °C and stirred for 16 h before pouring into 2.5 kg of ice water with mechanical stirring. The resulting white suspension was stirred for 4 h. The white solid was filtered off, washed with H2O (500 mL), and dried under a house vacuum overnight to give a wet white solid (265 g). This was dissolved in CH2Cl2 (750 mL), and the layers were separated. The organic layer was washed with H2O (6 × 200 mL), dried over MgSO4, and evaporated to give 47.7 g of a light brown solid. The crude material was purified by flash chromatography (0−15% MeOH/DCM) to give BMS-986097 (41.1 g, 45.5 mmol, 93.7% yield, 99.1% HPLC purity). 1 [α]20 D = −73.61 (c = 3.62, MeOH). H NMR (500 MHz, DMSO-d6): δ 11.84 (br s, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.77 (d, J = 6.3 Hz, 2H), 7.67 (br s, 3H), 7.57 (d, J = 7.9 Hz, 1H), 7.49 (br s, 1H), 5.01 (t, J = 8.2 Hz, 1H), 4.75 (br s, 1H), 4.16−3.96 (m, 2H), 3.67 (d, J = 7.6 Hz, 1H), 3.54 (s, 4H), 3.18 (t, J = 11.2 Hz, 1H), 2.55 (s, 1H), 2.26 (br s, 2H), 2.10−1.95 (m, 3H), 1.80 (d, J = 5.4 Hz, 1H), 1.65 (t, J = 12.1 Hz, 1H), 1.57 (d, J = 11.0 Hz, 2H), 1.46 (d, J = 6.3 Hz, 4H), 1.30 (d, J = 10.1 Hz, 1H), 1.24−1.10 (m, 2H), 0.78−0.59 (m, 2H), 0.52−0.36 (m, 4H), 0.35−0.25 (m, 1H). 13C NMR (126 MHz, DMSO-d6): δ 170.2, 156.8, 149.4, 138.8, 137.1, 134.0, 126.2, 124.5, 112.4, 65.6, 58.9, 56.4, 54.6, 53.7, 51.5, 36.9, 34.7, 32.4, 29.2, 29.0, 22.0, 12.2, 10.7. Anal. Calcd for C50H62N8O8: 1.57, H2O; 0.074, EtOH; 0.026, DMSO; C, 64.42; H, 7.08; N, 12.00; H2O 3.01. Found: C, 64.33; H, 7.59; N, 11.96; H2O, 3.01. Pd, Cu, and Rh < 10 ppm.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (A. Mathur). *E-mail: Jianqing·[email protected] (J. Li). *E-mail: [email protected] (R. Zhao). ORCID

Jianqing Li: 0000-0002-8445-9796 Phil S. Baran: 0000-0001-9193-9053 Notes

The authors declare no competing financial interest.

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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.joc.7b01852. 1 H and 13C NMR spectra of compounds 28, 27a−d, 39a−d, 40a−d, 21a−d, 1a−d and BMS-986097 (PDF) 10387

DOI: 10.1021/acs.joc.7b01852 J. Org. Chem. 2017, 82, 10376−10387