A Novel Synthesis of 5E-Isomer-Free Carboprost Methyl Ester

Abstract

A macrocyclic lactone strategy for the synthesis of 5E-isomer-free carboprost methyl ester was developed for the first time. The macrocyclic lactone being free of 5E-isomer can be easily prepared from modified Corey lactone. The key intermediate could be used as a building scaffold to prepare carboprost methyl ester and other prostaglandins effectively.

Key words

macrocyclic lactone - carboprost - Corey lactone - prostaglandins - Wittig reaction - Grignard reaction

• References and Notes

• 1 Collins PW, Djuric SW. Chem. Rev. 1993; 93: 1533
• 2 Das S, Chandrasekhar S, Yadav JS, Gre R. Chem. Rev. 2007; 107: 3286
• 3a Peng H, Chen FE. Org. Biomol. Chem. 2017; 15: 6281
• 3b Yan M, Rerko RM, Platzer P, Dawson D, Willis J, Tong M, Lawrence E, Lutterbaugh J, Lu S, Willson JK. V, Luo G, Hensold J, Tai H.-H, Wilson K, Markowitz SD. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 17468
• 4 Zhang F, Zeng J, Gao M, Wang L, Chen GQ, Lu Y, Zhang X. Nat. Chem. 2021; 13: 692
• 5a Schaaf TK, Corey EJ. J. Org. Chem. 1972; 37: 2921
• 5b Corey EJ, Terashima S, Ramwell PW, Jessup R, Weinshenker NM, Floyd DM, Crosby GA. J. Org. Chem. 1972; 37: 3043
• 5c Corey EJ, Moinet G. J. Am. Chem. Soc. 1973; 95: 6831
• 5d Corey EJ, Mann J. J. Am. Chem. Soc. 1973; 95: 6832
• 5e Corey EJ, Moinet G. J. Am. Chem. Soc. 1973; 95: 7185
• 5f Bindra JS, Grodski A, Schaaf TK, Corey EJ. J. Am. Chem. Soc. 1973; 95: 7522
• 5g Corey EJ, Ensley HE. J. Am. Chem. Soc. 1975; 97: 6908
• 5h Corey EJ, Imwinkelried R, Pikul S, Xiang Y. J. Am. Chem. Soc. 1989; 111: 5493
• 5i Corey EJ, Cheng X.-M. The Logic of Chemical Synthesis. John Wiley & Sons; New York: 1989: 250
• 5j Ogawa Y, Nunomoto M, Shibasaki M. J. Org. Chem. 1986; 51: 1625
• 6a Yankee EW, Axen U, Bundy GL. J. Am. Chem. Soc. 1974; 96: 5865
• 6b Cooper EL, Yankee EW. J. Am. Chem. Soc. 1974; 96: 5876
• 7a Péter BL, Zsuzsanna K, Irén HB, István L, Imre J, László F, Csaba V, Ágnes NB. WO2017093770, 2016
• 7b Shripad BK, Govindrao PA, Madhukar PN. WO2008081191, 2008
• 8 Shankar M, Mohan HR, Prasad UV, Krishna MH, Rao PM, Lakshmikumar T, Subbaraju GV. Asian J. Chem. 2013; 25: 913
• 9 González-González CA, Fuentes-Benítez A, Cuevas-Yáñez E, Corona-Becerril D, González-Romero C, González-Calderón D. Tetrahedron Lett. 2013; 21: 2726
• 10 Rey MD. L. A, Martínez-Pérez JA, Fernández-Gacio A, Halkes K, Fall Y, Granja J, Mouriño A. J. Org. Chem. 1999; 64: 3196
• 11 Bundy GL, Peterson DC, Cornette JC, Miller WL, Spilman CH, Wilks JW. J. Med. Chem. 1983; 26: 1089
• 12 Procedures and Analytical Data of Compound 19A mixture of compound 18 (120.0 g, 262.8 mmol), Ph₃P (183.5 g, 700.4 mmol), and 2,2′-dipyridyl disulfide (154.0 g, 700.0 mmol) in 4.0 L of oxygen-free toluene was stirred in an atmosphere of nitrogen for overnight at room temperature, and another 4.0 L of oxygen-free toluene was added. The mixture was heated at reflux for 15 h. (The toluene had been deoxygenated with a vigorous stream of nitrogen introduced through a gas dispersion tube for at least 30 min prior to use). The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was triturated with small volume of MTBE and filtered, thereby removing substantial amounts of triphenylphosphine oxide. The filtrate was reconcentrated and purified by chromatography on silica gel to give 90.0 g of compound 19 (78% yield) as a colorless oil; R_f = 0.7 (PE/EtOAc = 20:1).¹H NMR (400 MHz, CDCl₃): δ = 5.50 (m, 1 H), 5.12 (s, 1 H), 4.57 (m, 1 H), 4.11–3.91 (m, 1 H), 3.90–3.56 (m, 3 H), 3.42 (m, 1 H), 2.40–2.37 (m, 4 H), 2.26 (m, 1 H), 2.18–1.47 (m, 13 H), 0.84 (s, 9 H), 0.00 (s, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 173.9, 173.7, 131.0, 130.9, 128.0, 127.9,100.0, 96.7, 79.0, 75.6, 74.2, 73.6, 62.7, 62.1, 60.7, 60.5, 52. 4, 41.2, 40.4, 39.6, 36.1, 31.0, 30.9, 27.1, 26.9, 26.7, 25.9, 25.5, 25.4, 25.3, 20.0, 19.4, 18.3. HRMS (ESI): m/z calcd for C₂₄H₄₂O₅NaSi [M + Na]⁺: 461.2694; found: 461.2697.
• 13 Hayashi K, Tanimoto H, Zhang H, Morimoto T, Nishiyama Y, Kakiuchi K. Org. Lett. 2012; 14: 5728
• 14 Procedures and Analytical Data of Compound 22 To a stirred solution of compound 21 (47.0 g, 112.3 mmol) in MeOH (235 mL) at room temperature was added PPTS (3.0 g, 11.9 mmol), and the resulting mixture was allowed to stir overnight. Solvents were evaporated under reduced pressure, and the residue was dissolved in EtOAc and washed with saturated sodium hydrogen bicarbonate solution. After drying with anhydrous sodium sulfate, the solution was concentrated to give the crude residue, which was recrystallized with EtOAc and PE to give compound 22 (37.5 g, 90%) as a white solid; R_f = 0.2 (PE/EtOAc = 3:1). ¹H NMR (400 MHz, CDCl₃): δ = 6.66 (dd, J = 15.6, 8.8 Hz, 1 H), 6.30 (d, J = 15.6 Hz, 1 H), 5.38 (td, J = 11.2, 4.8 Hz, 1 H), 5.22 (m, 2 H), 4.04 (td, J = 13.2, 8.0 Hz, 1 H), 2.65–2.36 (m, 7 H), 2.26 (td, J = 13.2, 5.2 Hz, 1 H), 2.12–1.60 (m, 4 H), 1.40–1.10 (m, 10 H), 0.88 (t, J = 6.8 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 200.4, 173.4, 145.9, 132.1, 131.8, 126.9, 72.2, 45.5, 41.0, 40.8, 36.0, 31.5, 26.8, 25.3, 23.8, 22.5, 14.0. HRMS (ESI): m/z calcd for C₂₀H₃₀O₄Na [M + Na]⁺: 357.2036; found: 357.2038.
• 15 Procedures and Analytical Data of Compound 14 The key intermediate 14 was purified by column chromatography on silica gel eluting with DCM/acetone/Et₃N = 5:1:0.01) from a mixture of epimer 25 (5.0 g) to afford pure compound 14 (2.75 g, 55%) and mixture of epimers (2.5 g); R_f = 0.2 (DCM/MeOH = 15:1). ¹H NMR (400 MHz, CDCl₃): δ = 5.56 (d, J = 15.6 Hz, 1 H), 5.35 (dd, J = 15.6, 9.2 Hz, 1 H), 5.27 (m, 1 H), 3.77 (dd, J = 16.4, 8.0 Hz, 1 H), 2.55 (dd, J = 14.8, 7.6 Hz, 1 H), 2.35–1.40 (m, 15 H), 1.10 (m, 9 H), 0.81 (t, J = 6.4 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 173.5, 140.9, 127.6, 127.4, 73.0, 45.4, 42.9, 40.4, 32.2, 27.9, 26.8, 26.7, 23.8, 22.6, 14.0. HRMS (ESI): m/z calcd for C₂₁H₃₄O₄Na [M + Na]⁺: 373.2349; found: 373.2350.
• 16 Procedures and Analytical Data of Carboprost Methyl Ester To a stirred solution of compound 14 (2.5 g, 7.13 mmol) in 15 mL of MeOH was added 3 N NaOH (5 ml, 15 mmol), the reaction was continued for approximately 5 h; the starting material had disappeared (checked by TLC). The solvent was evaporated under reduced pressure to the residue, then acidified with 1 N HCl (15.0 ml) and extracted with EtOAc (3 × 30 mL), the organic layers were combined and evaporated under reduced pressure to give crude compound carboprost, which was dissolved in acetone (20 mL). To the stirred solution of compound carboprost in acetone was added DBU (2.5 g, 16.4 mmol) and MeI (2.5 g, 17.6 mmol). The resulting mixture was allowed to stir overnight, the starting material had disappeared (checked by TLC). Solvents were evaporated under reduced pressure to give the residue, which was dissolved with EtOAc and washed with water (10 mL) and brine (10 mL). Organic layer was evaporated under reduced pressure to the residue, which was purified by silica gel chromatography to afford compound carboprost methyl ester (2.2 g, 81% in two steps) as white solid; R_f = 0.2 (DCM/MeOH = 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 5.65 (d, J = 15.6 Hz, 1 H), 5.48 (dd, J = 15.6, 9.2 Hz, 1 H), 5.40 (m, 2 H), 4.19 (d, J = 3.6 Hz, 1 H), 3.90 (s, 1 H), 3.67 (s, 3 H), 2.56 (d, J = 4.8 Hz, 1 H), 2.30–2.27 (m, 5 H), 2.20–2.09 (m, 4 H), 1.80–1.60 (m, 5 H), 1.52 (m, 3 H), 1.25 (m, 8 H) , 0.88 (t, J = 6.8 Hz, 3 H). ¹³C-NMR (101 MHz, CDCl₃): δ = 174.4, 139.2, 129.5, 129.3, 128.8, 78.1, 72.8, 72.7, 55.8, 51.6, 50.6, 42.9, 42.8, 33.4, 32.3, 27.4, 26.6, 25.5, 24.8, 23.9, 22.6, 14.1. HRMS (ESI): m/z calcd for C₂₂H₃₈O₅Na [M + Na]⁺: 405.2611; found: 405.2613. [α]_D +27.9 (c = 0.81, ethanol); lit.^6a: [α]_D +24 (c = 0.81, ethanol).