Towards Waltheriones C and D: Synthesis of the Oxabicyclic Core

^◊ These authors contributed equally.

Abstract

A route to the oxabicyclic cores of the HIV cytoprotective quinolone alkaloids, waltheriones C and D, is described. The approach relies on a stereospecific transannular bromoetherification followed by reductive debromination. The route can also be rendered enantioselective via enzymatic reduction of a key intermediate (>99:1 er).

Key words

alkaloids - natural products - ethers - cyclization - enantioselectivity - reduction - enzymes

• References and Notes


Waltherione A:
• 1a Hoelzel SC. S. M, Vieira ER, Giacomelli SR, Dalcol II, Zanatta N, Morel AF. Phytochemistry 2005; 66: 1163-1163

Waltherione B:
• 1b Gressel V, Stüker CZ, Dias Gde O. C, Dalcol II, Burrow RA, Schmidt J, Wassjohann L, Morel AF. Phytochemistry 2008; 69: 994-994

Waltheriones C:
• 1c Jadulco DR. C, Pond CD, Van Wagoner RM, Koch M, Gideon OG, Matainaho TK, Piskaut P, Barrows LR. J. Nat. Prod. 2014; 77: 183-183

Waltherione E:
• 1d Jang JY, Dang QL, Choi YH, Choi GJ, Jang KS, Cha B, Luu NH, Kim J.-C. J. Agric. Food Chem. 2015; 63: 68-68

Waltheriones E, F:
• 1e Cretton S, Breant L, Pourrez L, Ambuehl C, Marcourt L, Ebrahimi SN, Hamburger M, Perozzo R, Karimou S, Kaiser M, Cuendet M, Christen P. J. Nat. Prod. 2014; 77: 2304-2304

Waltheriones M–Q:
• 1f Cretton S, Dorsaz S, Azzollini A, Favre-Godal Q, Marcourt L, Ebrahimi SN, Voinesco F, Michellod E, Sanglard D, Gindro K, Wolfender J.-L, Cuendet M, Christen P. J. Nat. Prod. 2016; 79: 300-300
• 2 In the original isolation paper (ref. 1c), the stereochemistry of waltherione D is drawn correctly in Figure 3 (equatorial OH, C10 R*). However, in all other figures of ref. 1c, the C10 configuration is depicted as C10 S*. Unfortunately, this error appears to have been propagated in a later paper on the biosynthesis of waltheriones: Erwin NA, Soekamto NH, van Altena I, Syah YM. Biochem. Syst. Ecol. 2014; 55: 358-358

Raltegravir:
• 3a Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M, Ferrara M, Fiore F, Gardelli C, Paz OG, Hazuda DJ, Jones P, Kinzel O, Laufer R, Monteagudo E, Muraglia E, Nizi E, Orvieto F, Pace P, Pescatore G, Scarpelli R, Stillmock K, Witmer MV, Rowley M. J. Med. Chem. 2008; 51: 5843-5843

Elvitegravir:
• 3b Sorbera LA, Serradell N. Drugs Future 2006; 31: 310-310
• 4 Systems less rigid than 14 have been shown to undergo diastereoselective transannular etherifications: Takahashi A, Aso M, Tanaka M, Suemune H. Tetrahedron 2000; 56: 1999-1999
• 5a Lizos DE, McKerchar C, Murphy J, Siigi Y, Suckling C, Yasumatsu H, Zhou S, Pratt J, Morris B. US 20060199978, 2006

An improved nitration procedure has also been described:
• 5b Lütant I, Schepmann D, Wünsch B. Eur. J. Med. Chem. 2016; 116: 136-136
• 6 Khan AM, Proctor GR, Rees L. J. Chem. Soc. C 1966; 990-990
• 7 For a similar vinylic bromide coupling, see: Piras E, Läng F, Rüegger H, Stein D, Wörle M, Grützmacher H. Chem. Eur. J. 2006; 12: 5849-5849
• 8 Reduction with NaBH₄, while chemoselective, afforded lower yields.

Representative cases for benzylic debromination of sensitive substrates with AIBN:
• 9a Miwa A, Nii Y, Sakakibara M. Agric. Biol. Chem. 1987; 12: 3459-3459
• 9b Brücher O, Bergsträßer U, Kelm H, Hartung J, Greb M, Svoboda I, Fuess H. Tetrahedron 2012; 68: 6968-6968

For enzymatic reduction of aryl alkyl ketones, see:
• 10a Itoh N, Mizuguchi M, Mizuguchi M. J. Mol. Catal. B: Enzym. 1999; 6: 41-41
• 10b Yang W, Xu JH, Xie Y, Xu Y, Zhao G, Lin GQ. Tetrahedron: Asymmetry 2006; 17: 1769-1769
• 10c Vitale P, D’Introno C, Perna FM, Perrone MG, Scilimati A. Tetrahedron: Asymmetry 2013; 24: 389-389
• 10d Liu Y, Tang TX, Pei XQ, Zhang C, Wu ZL. J. Mol. Catal. B: Enzym. 2014; 102: 1-1
• 10e Tang TX, Liu Y, Wu ZL. J. Mol. Catal. B: Enzym. 2014; 105: 82-82
• 10f Zhu D, Mukherjee C, Hua L. Tetrahedron: Asymmetry 2005; 16: 3275-3275
• 10g Zhu D, Hyatt BA, Hua L. J. Mol. Catal. B: Enzym. 2009; 56: 272-272
• 11 In a preliminary screen, N-Boc aniline derived from 10 gave poor conversion but high enantioselectivity (er 99:1). The nitro compound 10 gave very high conversions (>95% in most cases), with access to both enantiomers with different enzymes: KRED-P3-G09 gave 98:2 er, conversion 98%, and KRED-P2-H07 gave 98:2 er, conversion 98% for the corresponding enantiomeric alcohol.

The absolute configuration has been tentatively assigned as S on the basis of analogous results with one of the enzymes in our panel (KRED P1C01) with a cyclic aryl ketone, see:
• 12a Hyde AM, Liu Z, Kosjek B, Tan L, Klapars A, Ashley ER, Zhong Y.-L, Alvizo O, Agard NJ, Liu G, Gu X, Yasuda N, Limanto J, Huffman MA, Tschaen DM. Org. Lett. 2016; 18: 5888-5888

In another study with Codexis enzymes and aryl alkyl ketones, high selectivity for the S isomer was observed, see:
• 12b Liang J, Lalonde J, Borup B, Mitchell V, Mundorff E, Trinh N, Kochrekar DA, Cherat RN, Pai GG. Org. Process Res. Dev. 2010; 14: 193-193
• 13 Synthesis of 15b A solution of alcohol 14 (20 mg, 0.071 mmol, 1.0 equiv) in dioxane (0.5 mL) was cooled to 0 °C. NBS (190 mg, 0.106 mmol, 1.5 equiv) was added, and the reaction mixture was stirred under argon at r.t. for 5 h. Purification of the crude reaction mixture by flash chromatography (EtOAc–hexane, 10:90) afforded the product 15b as a white solid (20 mg, 78%); mp 130.3–132.0 °C; R_f = 0.6 (EtOAc–hexane, 2:8). IR (film): 3094, 3064, 2953, 2922, 2850, 2349, 2325, 1519, 1342, 1031 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 8.30 (dd, 1 H, J = 8.2, 2.0 Hz), 8.15 (d, 1 H, J = 2.0 Hz), 7.57–7.52 (m, 3 H), 7.45–7.41 (m, 3 H), 5.44 (d, 1 H, J = 2.2 Hz), 4.91 (dd, 1 H, J = 11.3, 5.6 Hz), 2.40–2.27 (m, 2 H); 1.77–1.65 (m, 1 H), 1.46–1.35 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 148.7, 147.6, 146.2, 137.4, 129.3, 128.7, 128.0, 125.8, 123.5, 115.6, 89.3, 78.9, 48.9, 31.3, 30.3. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for [C₁₇H₁₄BrNO₃Na]⁺: 382.0049; found: 382.0044, Δ = 0.5 mDa.
• 14 Synthesis of 17 To a solution of bromide 16 (20 mg, 0.06 mmol, 1.0 equiv) in dry toluene (1.2 mL), Bu₃SnH (33 μL, 0.12 mmol, 2.0 equiv), and AIBN (3 mg, 0.018 mmol, 0.3 equiv) were added under argon. The reaction mixture was heated at 80 °C. After completion of the reaction (6 h), the reaction mixture was loaded directly to flash column for purification (EtOAc–hexane, 15:90). Product 17 was isolated as a white solid (13 mg, 85%); mp 148.1–150.2 °C; R_f = 0.3 (EtOAc–hexane, 20:80). IR (film): 3351, 3233, 2933, 1619, 1591, 1485, 1447, 1346, 1305, 1264, 1160, 1104, 995, 757 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.53 (distorted d, 2 H, J = 7.5 Hz), 7.37 (app. t, 2 H, J = 7.6 Hz), 7.29 (app. t, 1 H, J = 7.4 Hz), 6.66 (d, 1 H, J = 7.9 Hz), 6.56 (d, 1 H, J = 1.8 Hz), 6.50 (dd, 1 H, J = 7.9, 2.0 Hz), 5.29 (br s, 1 H), 2.13–2.07 (dt, 1 H, J = 12.5, 4.5 Hz), 2.05–2.00 (m, 2 H), 1.63 (dt, 1 H, J = 11.3, 5.0 Hz), 1.50 (dd, 1 H, J = 13.1, 5.0 Hz), 1.25–1.15 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 145.7, 144.8, 143.4, 136.5, 128.3, 127.4, 125.8, 121.3, 114.0, 107.3, 86.2, 79.4, 33.2, 28.2, 17.8. HRMS (ESI⁺): m/z [M + H]⁺ calcd for [C₁₇H₁₈NO]⁺: 252.1383; found: 252.1382, Δ = 0.1 mDa.