Synlett 2017; 28(10): 1209-1213
DOI: 10.1055/s-0036-1588150
letter
© Georg Thieme Verlag Stuttgart · New York

Towards Waltheriones C and D: Synthesis of the Oxabicyclic Core

Mari Ella Mäkinen
University of Jyvaskyla, Department of Chemistry, P.O. Box 35, 40014 University of Jyvaskyla, Finland   Email: petri.m.pihko@jyu.fi
,
Rosy Mallik
University of Jyvaskyla, Department of Chemistry, P.O. Box 35, 40014 University of Jyvaskyla, Finland   Email: petri.m.pihko@jyu.fi
,
Juha H. Siitonen
University of Jyvaskyla, Department of Chemistry, P.O. Box 35, 40014 University of Jyvaskyla, Finland   Email: petri.m.pihko@jyu.fi
,
Katja Kärki
University of Jyvaskyla, Department of Chemistry, P.O. Box 35, 40014 University of Jyvaskyla, Finland   Email: petri.m.pihko@jyu.fi
,
Petri M. Pihko*
University of Jyvaskyla, Department of Chemistry, P.O. Box 35, 40014 University of Jyvaskyla, Finland   Email: petri.m.pihko@jyu.fi
› Author Affiliations
Further Information

Publication History

Received: 22 November 2016

Accepted after revision: 02 February 2017

Publication Date:
24 February 2017 (eFirst)

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).

Supporting Information

 
  • 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; Rf = 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; Rf = 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.