Synlett, Table of Contents Synlett 2014; 25(2): 288-292DOI: 10.1055/s-0033-1340291 letter © Georg Thieme Verlag Stuttgart · New York Asymmetric Total Synthesis of (–)-trans-Blechnic Acid via Rhodium(II)-Catalyzed C–H Insertion and Palladium(II)-Catalyzed C–H Olefination Reactions Motoki Ito Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060–0812, Japan Fax: +81(11)7064981 Email: hsmt@pharm.hokudai.ac.jp , Ryosuke Namie Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060–0812, Japan Fax: +81(11)7064981 Email: hsmt@pharm.hokudai.ac.jp , Janagiraman Krishnamurthi Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060–0812, Japan Fax: +81(11)7064981 Email: hsmt@pharm.hokudai.ac.jp , Hitomi Miyamae Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060–0812, Japan Fax: +81(11)7064981 Email: hsmt@pharm.hokudai.ac.jp , Koji Takeda Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060–0812, Japan Fax: +81(11)7064981 Email: hsmt@pharm.hokudai.ac.jp , Hisanori Nambu Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060–0812, Japan Fax: +81(11)7064981 Email: hsmt@pharm.hokudai.ac.jp , Shunichi Hashimoto* Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060–0812, Japan Fax: +81(11)7064981 Email: hsmt@pharm.hokudai.ac.jp › Author Affiliations Recommend Article Abstract Buy Article All articles of this category Abstract An asymmetric total synthesis of (–)-trans-blechnic acid, a dihydrobenzofuran neolignan, has been achieved. The key steps involve an elaboration of the cis-2,3-dihydrobenzofuran core structure by enantio- and diastereoselective intramolecular C–H insertion using dirhodium(II) tetrakis[N-phthaloyl-(R)-tert-leucinate] [Rh2(R-PTTL)4] and a direct coupling of an acrylate unit with the core structure employing Yu’s palladium(II)-catalyzed intermolecular C–H olefination. Key words Key wordschiral dirhodium(II) catalyst - C–H insertion - C–H olefination - dihydrobenzofuran neolignan - blechnic acids Full Text References References and Notes 1a Wada H, Kido T, Tanaka N, Murakami T, Saiki Y, Chen C.-M. Chem. Pharm. Bull. 1992; 40: 2099 1b Wang C.-Z, Davin LB, Lewis NG. Chem. Commun. 2001; 113 1c Davin LB, Wang C.-Z, Helms GL, Lewis NG. Phytochemistry 2003; 62: 501 2 Kelley CJ, Mahajan JR, Brooks LC, Neubert LA, Breneman WR, Carmack M. J. Org. Chem. 1975; 40: 1804 3 Hayashi T, Thomson RH. Phytochemistry 1975; 14: 1085 4 Benevides PJ. C, Sartorelli P, Kato MJ. Phytochemistry 1999; 52: 339 5a For a review, see: Apers S, Vlietinck A, Pieters L. Phytochem. Rev. 2003; 2: 201 5b Abd-Elazem IS, Chen HS, Bates RB, Huang RC. C. Antiviral Res. 2002; 55: 91 5c Coy ED, Cuca LE, Sefkow M. Bioorg. Med. Chem. 2009; 19: 6922 For reviews on stereoselective synthesis of neolignans, see: 6a Sefkow M. Synthesis 2003; 2595 6b Bertolini F, Pineschi M. Org. Prep. Proced. Int. 2009; 41: 385 For recent examples of asymmetric total synthesis of natural products containing 2-aryl-2,3-dihydrobenzofuran, see: 7a O’Malley SJ, Tan KL, Watzke A, Bergman RG, Ellman JA. J. Am. Chem. Soc. 2005; 127: 13496 7b Jiménez-González L, García-Muñoz S, Álvarez-Corral M, Muñoz-Dorado M, Rodríguez-García I. Chem. Eur. J. 2006; 12: 8762 7c Clive DL. J, Stoffman EJ. L. Org. Biomol. Chem. 2008; 6: 1831 7d Adams H, Gilmore NJ, Jones S, Muldowney MP, von Reuss SH, Vemula R. Org. Lett. 2008; 10: 1457 7e Calter MA, Li N. Org. Lett. 2011; 13: 3686 7f Ghosh AK, Cheng X, Zhou B. Org. Lett. 2012; 14: 5046 7g Ortega N, Beiring B, Urban S, Glorius F. Tetrahedron 2012; 68: 5185 7h Chen C.-Y, Weisel M. Synlett 2013; 24: 189 8a Fischer J, Savage GP, Coster MJ. Org. Lett. 2011; 13: 3376 8b Varadaraju TG, Hwu JR. Org. Biomol. Chem. 2012; 10: 5456 9 Saito H, Oishi H, Kitagaki S, Nakamura S, Anada M, Hashimoto S. Org. Lett. 2002; 4: 3887 10a Davies HM. L, Grazini MV. A, Aouad E. Org. Lett. 2001; 3: 1475 10b Davies HM. L, Morton D. Chem. Soc. Rev. 2011; 40: 1857 11a Kurosawa W, Kan T, Fukuyama T. Synlett 2003; 1028 11b Kurosawa W, Kan T, Fukuyama T. J. Am. Chem. Soc. 2003; 125: 8112 11c Koizumi Y, Kobayashi H, Wakimoto T, Furuta T, Fukuyama T, Kan T. J. Am. Chem. Soc. 2008; 130: 16854 11d Matsumoto S, Asakawa T, Hamashima Y, Kan T. Synlett 2012; 23: 1082 12 For the effective use of an immobilized catalyst based on Rh2(S-PTTL)4 in this system, see: Takeda K, Oohara T, Anada M, Nambu H, Hashimoto S. Angew. Chem. Int. Ed. 2010; 49: 6979 13 Davies and co-workers reported that Rh2(S-PTAD)4 is a highly effective catalyst for the construction of cis-2-aryl-2,3-dihydrobenzofurans. See: Reddy RP, Lee GH, Davies HM. L. Org. Lett. 2006; 8: 3437 14a García-Muñoz S, Álvarez-Corral M, Jiménez-González L, López-Sánchez C, Rosales A, Muñoz-Dorado M, Rodríguez-García I. Tetrahedron 2006; 62: 12182 14b López-Sánchez C, Álvarez-Corral M, Jiménez-González L, Muñoz-Dorado M, Rodríguez-García I. Tetrahedron 2013; 69: 5511 15 Very recently, the Yu and Davies groups reported a conceptually new asymmetric approach to highly functionalized trans-2,3-dihydrobenzofurans by a sequence involving a Rh2(R-PTTL)4-catalyzed enantioselective intermolecular C–H insertion followed by a Pd-catalyzed intramolecular C–H activation–C–O cyclization. See: Wang H, Li G, Engle KM, Yu J.-Q, Davies HM. L. J. Am. Chem. Soc. 2013; 135: 6774 16 Zheng S.-L, Yu W.-Y, Xu M.-X, Che C.-M. Tetrahedron Lett. 2003; 44: 1445 17 Natori Y, Tsutsui H, Sato N, Nakamura S, Nambu H, Shiro M, Hashimoto S. J. Org. Chem. 2009; 74: 4418 18 Kan and co-workers recently accomplished an asymmetric total synthesis of (–)-aperidine containing a cis-2,3-dihydrobenzofuran ring via a Rh2(S-PTTL)4-catalyzed C–H insertion process. See: Wakimoto T, Miyata K, Ohuchi H, Asakawa T, Nukaya H, Suwa Y, Kan T. Org. Lett. 2011; 13: 2789 19 Wang D.-H, Yu J.-Q. J. Am. Chem. Soc. 2011; 133: 5767 20a Wang D.-H, Engle KM, Shi B.-F, Yu J.-Q. Science 2010; 327: 315 20b Engle KM, Wang D.-H, Yu J.-Q. J. Am. Chem. Soc. 2010; 132: 14137 20c Engle KM, Mei T.-S, Wasa M, Yu J.-Q. Acc. Chem. Res. 2012; 45: 788 21 For further illustrations of the power of a late-stage intermolecular C–H olefination strategy, see references 7f and 15. 22 For a recent review on C–H functionalization in natural products synthesis, see: Yamaguchi J, Yamaguchi AD, Itami K. Angew. Chem. Int. Ed. 2012; 51: 8960 23 Hurd CD, Greengard H, Pilgrim FD. J. Am. Chem. Soc. 1930; 52: 1700 24 Nicolaou KC, Lister T, Denton RM, Gelin CF. Tetrahedron 2008; 64: 4736 25a Lindgren BO, Nilsson T. Acta Chem. Scand. 1973; 27: 888 25b Kraus GA, Taschner MJ. J. Org. Chem. 1980; 45: 1175 25c Bal BS, Childers WE. Jr, Pinnick HW. Tetrahedron 1981; 37: 2091 25d Hayashida J, Rawal VH. Angew. Chem. Int. Ed. 2008; 47: 4373 26 Taber DF, You K, Song Y. J. Org. Chem. 1995; 60: 1093 27 Procedure for the Rh2(R-PTTL)4-Catalyzed Intramolecular C–H Insertion of Compound 13 Rh2(R-PTTL)4 (63.9 mg, 0.045 mmol, 1 mol%) was added to a stirred solution of 4 Å MS (3.20 g) and 13 (3.20 g, 4.49 mmol) in toluene (45 mL) at –20 °C. After stirring for 1 h, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (silica gel; toluene–EtOAc, 200:1) to give 12 as a white solid (2.50 g, 81%); Rf = 0.56 (toluene–EtOAc, 100:1); mp 67.0–68.5 °C; [α]D 20 –10.5 (c 0.33, CHCl3). IR (neat): ν = 2945, 2867, 1744 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.03–1.09 (m, 36 H), 1.15–1.29 (m, 6 H), 3.51 (s, 3 H), 4.10 (ddt, J = 1.6, 6.0, 13.6 Hz, 1 H), 4.23 (ddt, J = 1.6, 6.0, 13.6 Hz, 1 H), 4.65 (d, J = 10.0 Hz, 1 H), 5.07 (d, J = 1.6 Hz, 1 H), 5.11 (dt, J = 1.6, 6.0 Hz, 1 H), 5.24 (s, 2 H), 5.52–5.62 (m, 1 H), 5.90 (d, J = 10.0 Hz, 1 H), 6.73 (s, 1 H), 6.74 (s, 1 H), 6.77 (s, 1 H), 6.88 (t, J = 7.6 Hz, 1 H), 6.96 (d, J = 7.6 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 13.1, 13.3, 18.0, 18.1, 54.0, 56.4, 65.6, 86.2, 95.6, 117.2, 118.1, 118.4, 119.4, 119.5, 119.8, 121.8, 126.3, 129.6, 131.9, 141.7, 146.7, 147.3, 149.8, 169.3. ESI-HRMS: m/z calcd for C38H60O7NaSi2 [M + Na]+: 707.3770; found: 707.3768. The ee of 12 was determined to be 80% by HPLC with a Chiralcel IF (hexane–iPrOH, 300:1, 0.5 mL/min): t R = 35.9 min for the major enantiomer, t R = 49.2 min for the minor enantiomer. 28 Boutevin B, Rigal G, Rousseau A, Bosc D. J. Fluorine Chem. 1988; 38: 47 29 Under Fujioka conditions (see ref. 30), deprotection of the MOM group did not proceed at all; instead, epimerization of 11a was observed (2,3-cis/2,3-trans = 57:43). 30a Fujioka H, Kubo O, Senami K, Minamitsuji Y, Maegawa T. Chem. Commun. 2009; 4429 30b Fujioka H, Minamitsuji Y, Kubo O, Senami K, Maegawa T. Tetrahedron 2011; 67: 2949 31 Procedure for the Pd(II)-Catalyzed C–H Olefination of Compound 19b To a solution of 19b (340 mg, 0.566 mmol), Pd(OAc)2 (25 mg, 0.113 mmol, 20 mol%), KHCO3 (199 mg, 1.98 mmol), and Ac-Ile-OH (39 mg, 0.226 mmol, 40 mol%) in tert-amyl-OH (5 mL) was added a solution of trichloroethyl acrylate (129 mg, 0.633 mmol) in tert-amyl alcohol (1 mL) under O2 (1 atm, balloon). The reaction mixture was stirred for 8 h at 50 °C. The mixture was partitioned between EtOAc and 10% aq citric acid, and the aqueous layer was separated. The organic layer was washed with brine and dried over Na2SO4. Filtration and evaporation in vacuo furnished the crude product (510 mg), which was purified by column chromatography (silica gel; toluene–MeCN, 25:1) to give 11b (226 mg, 50%) as a pale yellow amorphous; Rf = 0.41 (hexane–EtOAc, 3:1); [α]D 20 –17.3 (c 0.98, CHCl3). IR (neat): ν = 2945, 2867, 1716, 1610 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.04–1.11 (m, 36 H), 1.23–1.31 (m, 6 H), 4.65 (d, J = 9.2 Hz, 1 H), 4.82 (s, 2 H), 5.94 (d, J = 9.2 Hz, 1 H), 6.36 (d, J = 16.0 Hz, 1 H), 6.82–6.86 (m, 2 H), 6.90–6.94 (m, 2 H), 7.21 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 16.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 13.0, 13.1, 18.1, 53.3, 74.2, 87.5, 95.2, 115.7, 117.3, 118.3, 119.0, 120.0, 121.9, 123.9, 126.7, 127.7, 142.9, 143.2, 147.1, 147.6, 147.7, 165.3, 171.2. ESI-HRMS: m/z calcd for C38H55Cl3O8NaSi2 [M + Na]+: 823.2420; found: 823.2413. 32 Data for Synthetic (–)-trans-Blechnic Acid (1) A colorless needle; Rf = 0.27 (hexane–EtOAc–AcOH, 1:2:0.3); mp 196.0–197.0 °C (H2O); [α]D 26 –27.2 (c 0.78, MeOH). 1H NMR (500 MHz, CD3OD): δ = 4.59 (d, J = 9.0 Hz, 1 H), 5.93 (d, J = 9.0 Hz, 1 H), 6.26 (d, J = 16.0 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1 H), 6.80 (d, J = 8.5 Hz, 1 H), 6.84 (dd, J = 2.0, 8.5 Hz, 1 H), 6.96 (d, J = 2.0 Hz, 1 H), 7.14 (d, J = 8.5 Hz, 1 H), 7.56 (d, J = 16.0 Hz, 1 H). 13C NMR (125 MHz, acetone-d 6): δ = 54.4, 87.7, 114.9, 115.5, 117.6, 117.9, 119.4, 122.1, 124.2, 129.0, 129.1, 142.4, 144.5, 145.4, 145.9, 149.0, 167.9, 170.9. ESI-HRMS: m/z calcd for C18H14O8Na [M + Na]+: 381.0634; found: 381.0621. Supplementary Material Supplementary Material Supporting Information
