Gram-Scale Total Synthesis of Cordiachrome B

Abstract

Cordiachromes A–C are terpenoid benzoquinones that exhibit significant antimalarial, antimycobacterial, antifungal, antileishmanial, and cytotoxic activities. Herein, we report a gram-scale total synthesis of cordiachrome B from inexpensive, commercially available 3-methoxybenzaldehyde in six linear steps. Highlights of the synthesis include a Ti(O-i-Pr)₄-promoted photoenolization/Diels–Alder (PEDA) reaction to construct the desired cis configuration at the B–C ring junction, matching that of the natural product; an N,N,N′-trimethylethylenediamine-directed regioselective methylation; a Pd-catalyzed ortho-C–H methoxylation enabled by a monodentate transient directing group to give 3,6-dimethoxy-2-methylbenzaldehyde on a large scale for the PEDA reaction; and a Tebbe olefination to convert the carbonyl group into the methylene group required for the natural product. The concise and scalable synthesis provides a novel strategy for producing these natural products and related congeners for further medicinal-chemistry studies. Cordiachrome B was shown, for the first time, to exhibit a moderate antibacterial activity against Staphylococcus aureus and its methicillin-resistant strain.

Key words

cordiachrome B - total synthesis - gram-scale synthesis - photoenolization - Diels–alder reaction

• References and Notes

• 1 Moir M, Thomson RH. J. Chem. Soc., Perkin Trans. 1 1973; 1352
• 2 Kuroyanagi M, Seki T, Hayashi T, Nagashima Y, Kawahara N, Sekita S, Satake M. Chem. Pharm. Bull. 2001; 49: 954
• 3 Kahn HP, Cossy J. Tetrahedron Lett. 1999; 8113
• 4 Ioset J.-R, Marston A, Gupta MP, Hostettmann K. J. Nat. Prod. 2000; 63: 424
• 5 Ioset J.-R, Marston A, Gupta MP, Hostettmann K. Phytochemistry 2000; 53: 613
• 6 Moir M, Thomson RH, Hauson BM, Simatupang MH. J. Chem. Soc., Chem. Commun. 1972; 363
• 7 Mori K, Kawano M, Fuchino H, Ooi T, Satake M, Agatsuma Y, Kusumi T, Sekita S. J. Nat. Prod. 2008; 71: 18
• 8 Dettrakul S, Surerum S, Rajviroongit S, Kittakoop P. J. Nat. Prod. 2009; 72: 861
• 9 Watabe T, Hosoda Y, Okada K, Oda M. Bull. Chem. Soc. Jpn. 1987; 60: 3801
• 10 Yang NC, Rivas C. J. Am. Chem. Soc. 1961; 83: 2213
• 11 Nicolaou KC, Gray D, Tae J. Angew. Chem. Int. Ed. 2001; 40: 3675
• 12 Nicolaou KC, Gray D. Angew. Chem. Int. Ed. 2001; 40: 761
• 13 Yang B, Lin K, Shi Y, Gao S. Nat. Commun. 2017; 8: 622
• 14 Hou M, Xu M, Yang B, He H, Gao S. Chem. Sci. 2021; 12: 7575
• 15 Yang B, Wen G, Zhang Q, Hou M, He H, Gao S. J. Am. Chem. Soc. 2021; 143: 6370
• 16 Xu M, Hou M, He H, Gao S. Angew. Chem. Int. Ed. 2021; 60: 16655
• 17 Comins DL, Brown JD. J. Org. Chem. 1984; 49: 1078
• 18 Comins DL, Brown JD. J. Org. Chem. 1989; 54: 3730
• 19 Li F, Zhou Y, Yang H, Wang Z, Yu Q, Zhang F.-L. Org. Lett. 2019; 21: 3692
• 20 Hoskin JF, Sorensen EJ. J. Am. Chem. Soc. 2022; 144: 14042
• 21 Tebbe FN, Parshall GW, Reddy GS. J. Am. Chem. Soc. 1978; 100: 3611
• 22 Chordiachrome B A solution of ceric ammonium nitrate (7.5 g, 13.8 mmol, 2.5 equiv) in H₂O (45 mL) was added over 3-min to a solution of 15 (1.5 g, 5.4 mmol, 1.0 equiv) in MeCN (180 mL) and Et₂O (180 mL) cooled to 0 °C in an ice–brine bath under N₂. The resulting yellow solution was stirred in the ice–brine bath for 30 min then diluted with H₂O (150 mL) and extracted with CH₂Cl₂ (3 × 400 mL). The combined extracts were washed with brine, dried (MgSO₄), and concentrated in vacuo. The solid residue was purified by flash column chromatography [silica gel, EtOAc–hexane (10:1)] to give a pale-yellow solid; yield: 1.2 g (95%). ¹H NMR (400 MHz, CDCl₃): δ = 6.70 (q, J = 10.0 Hz, 2 H), 4.71 (s, 1 H), 4.36 (s, 1 H), 2.82–2.77 (m, 1 H), 2.55–2.47 (m, 1 H), 2.39–2.20 (m, 2 H), 2.17–2.16 (m, 1 H), 2.11–2.06 (m, 1 H), 2.03–1.98 (m, 1 H), 1.72–1.62 (m, 3 H), 1.46–1.38 (m, 1 H), 0.96 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.4, 187.2, 148.4, 140.7, 139.9, 136.5, 136.3, 107.3, 44.6, 37.1, 34.8, 34.0, 30.4, 27.5, 23.8, 23.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₉O₂: 243.1385; found: 243.1385.