Stereocontrolled Synthesis of Planar Chiral Carba-Paracyclophanes via Modular Assembly

Abstract

Described herein is a flexible modular approach to planar chiral carba-paracyclophanes via the stepwise assembly of two distinct side arms and the aromatic core followed by ring-closing olefin metathesis. Planar chirality is induced by one chiral sulfinyl group by forming a hydrogen bond to the phenol in the aromatic unit.

Key words

cyclophanes - paracyclophanes - planar chirality - atropisomerism - sulfoxides - hydrogen bond - metathesis

• References and Notes

• 1a Hochmuth DH, König WA. Tetrahedron: Asymmetry 1999; 10: 1089
• 1b Gibson SE, Knight JD. Org. Biomol. Chem. 2003; 1: 1256
• 1c Rozenber V, Sergeeva E, Hopf H. Modern Cyclophane Chemistry . Gleiter R, Hopf H. Wiley-VCH; New York: 2004: 435-462
• 1d Elacqua E, MacGillivray LR. Eur. J. Org. Chem. 2010; 6883
• 1e Morisaki Y, Chujo Y. Polym. Chem. 2011; 2: 1249

For references on enantioselective synthesis of paracyclophanes, see:
• 2a Tanaka K, Hori T, Osaka T, Noguchi K, Hirano M. Org. Lett. 2007; 12: 4881
• 2b Kanda K, Koike T, Endo K, Shibata T. Chem. Commun. 2009; 1870
• 2c Kanda K, Endo K, Shibata T. Org. Lett. 2010; 9: 1980
• 2d Araki T, Hojo D, Noguchi K, Tanaka K. Synlett 2011; 539

For stereoselective synthesis of paracyclophanes, see:
• 2e Schomburg D, Thielmann M, Winterfeldt E. Tetrahedron Lett. 1985; 26: 1705
• 2f Bäurle S, Blume T, Mengel A, Parchmann C, Skuballa W, Bäsler S, Schäfer M, Sülzle D, Wrona-Metzinger H.-P. Angew. Chem. Int. Ed. 2003; 42: 3961
• 2g Krieger J.-P, Ricci G, Lesuisse D, Meyer C, Cossy J. Angew. Chem. Int. Ed. 2014; 53: 8705

For reviews associated with synthesis of planar chiral cyclophanes, see:
• 2h Gulder T, Baran PS. Nat. Prod. Rep. 2012; 29: 899
• 2i Kotha S, Shirbhate ME, Waghule GT. Beilstein J. Org. Chem. 2015; 11: 1274
• 3 An elegant work for conformational and stereocontrolled synthesis of cyclophane and its application for the total synthesis of logithorone A, see: Layton ME, Morales CA, Shair MD. J. Am. Chem. Soc. 2002; 124: 773

For syntheses of stereoselective carba-paracyclophanes, see:
• 4a Kanomata N, Ochiai Y. Tetrahedron Lett. 2001; 42: 1045
• 4b Ueda T, Kanomata N, Machida H. Org. Lett. 2005; 7: 2365
• 4c Araki T, Noguchi K, Tanaka K. Angew. Chem. Int. Ed. 2013; 52: 5617
• 5 Mori K, Ohmori K, Suzuki K. Angew. Chem. Int. Ed. 2009; 48: 5638

For references on the synthesis of paracyclophanes by ring-closing olefin metathesis, see:
• 6a El-azizi Y, Schmitzer A, Collins SK. Angew. Chem. Int. Ed. 2006; 45: 968
• 6b Bolduc P, Jacques A, Collins SK. J. Am. Chem. Soc. 2010; 132: 12790
• 6c Huang M, Song L, Liu B. Org. Lett. 2010; 12: 2504
• 6d Setaka W, Higa S, Yamaguchi K. Org. Biomol. Chem. 2014; 12: 3354 ; and references cited therein
• 7 After workup of the reaction, the crude material of 5 could also be employed for the following coupling reaction with 10, giving 12 in 88% overall yield from 4.
• 8 The five-step protocol with poor reproducibility as well as expensive reagents and materials are serious shortcomings.
• 9 Mikolajczyk M, Midura W, Grzejszczak S, Zatorski A, Chefczynska A. J. Org. Chem. 1978; 43: 473
• 10 Blanchette MA, Choy W, Davis JT, Essenfeld AP, Masamune S, Roush WR, Sakai T. Tetrahedron Lett. 1984; 25: 2183
• 11 Claus RE, Schreiber SL. Org. Synth. 1986; 64: 150
• 12 For a further scope of this one-pot HWE reaction with 6, manuscript in preparation.
• 13 The reaction with Pd(PPh₃)₄ in DMSO resulted in poor yield. In use of K₃PO₄ as a base, the reaction provided only the homocoupling product in 24% yield.
• 14 Ishiyama T, Murata M, Miyaura N. J. Org. Chem. 1995; 60: 7508
• 15 For the syntheses of 22, 27, and 28, see the Supporting Information.

For hydrogen bond effects with sulfones, see:
• 16a Patai S, Rappoport Z, Stirling C. Sulphones and Sulphoxides . John Wiley and Sons; Chichester: 1988: 561-562
• 16b Laurence C, Brameld KA, Graton J, Le Questel J.-Y, Renault E. J. Med. Chem. 2009; 52: 4073
• 17 See the Supporting Information.
• 18 Crystallographic data for compound 29·CHCl₃ have been deposited with the accession number CCDC 1415431, and can be obtained free of charge via www.ccdc.cam.ac.uk/getstructures.
• 19 Ring-closing olefin metathesis of 26 only gave undesired product when second-generation Hoveyda–Grubbs catalyst was used. See the Supporting Information for the details.
• 20 Hoye TR, Jeffrey CS, Tennakoon MA, Wang J, Zhao H. J. Am. Chem. Soc. 2004; 126: 10210
• 21 Generation of the cyclopentene was observed with the mixture of 26 and first-generation Grubbs catalyst (10 mol%) in CDCl₃, which was increased when the stoichiometric first-generation Grubbs catalyst (1.0 equiv) was used.
• 22 For the synthesis of 31, see the Supporting Information.
• 23 Stereochemistry of the major isomer was confirmed by a ¹H NMR spectroscopy, observing a large coupling constant of vinylic protons (15.2 Hz).
• 24 Typical Experimental Procedure for the Ring-Closing Olefin Metathesis To a solution of cyclization precursor 31 (0.05 mmol) in CH₂Cl₂ (0.003 M) was added Grubbs I catalyst (10 mol%) at room temperature. The reaction mixture was refluxed at 40 °C and stirred for 1 h. After cooling to room temperature, Florisil^® (10 wt% of catalyst) was added. After stirring at this temperature for 1 h, the reaction mixture was filtered through a Celite^® pad (washed with CH₂Cl₂). The filtrate was concentrated in vacuo, the residue was purified by PTLC (silica gel, hexane–EtOAc = 1:1) to afford cyclic product 32 (62%, E/Z = 21:1) as a white solid. Compound (E)-32: R_f = 0.34 (hexane–Et₂O = 1:1); mp 66–69 °C. ¹H NMR (600 MHz, CDCl₃): δ = 0.96–1.07 (m, 2 H), 1.08–1.17 (m, 2 H), 1.27–1.33 (m, 1 H), 1.43–1.51 (m, 2 H), 1.61–1.68 (m, 1 H), 1.74–1.86 (m, 4 H), 1.95–1.99 (m, 1 H), 2.01–2.08 (m, 1 H), 2.31 (ddd, 1 H, J = 14.0, 10.0, 4.3 Hz), 2.35 (s, 3 H), 2.83 (ddd, 1 H, J = 13.6, 6.6, 4.2 Hz), 4.07 (s, 1 H, OH), 4.91 (ddd, 1 H, J = 15.2, 7.2, 7.2 Hz), 5.02 (dt, 1 H, J = 15.2, 7.2 Hz), 5.72 (s, 1 H), 6.67 (s, 1 H), 6.89 (dd, 1 H, J = 9.3, 6.5 Hz), 7.20 (d, 2 H, J = 8.1 Hz), 7.35 (d, 2 H, J = 8.1 Hz), 8.99 (s, 1 H, OH). ¹³C NMR (150 MHz, CDCl₃): δ = 21.4, 25.5, 27.3, 27.7, 27.9, 28.3, 30.1, 31.3, 31.6, 117.2, 117.8, 120.1, 124.5, 129.4, 129.7, 131.4, 131.5, 137.0, 141.5, 144.8, 146.1, 146.5, 149.1. IR (neat): 3301 (br), 3017, 2925, 2855, 2360, 2342, 1629, 1595, 1507, 1493, 1455, 1381, 1249, 1194, 1083, 975, 889, 808, 756 cm^–1. [α]_D ²² +89.6 (c 0.580, CHCl₃). ESI-HRMS: m/z calcd for C₂₅H₃₁O₅S [M + H]⁺: 443.1887; found: 443.1865.