Asymmetric Total Synthesis of (–)-trans-Blechnic Acid via Rhodium(II)-Catalyzed C–H Insertion and Palladium(II)-Catalyzed C–H Olefination Reactions

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

chiral dirhodium(II) catalyst - C–H insertion - C–H olefination - dihydrobenzofuran neolignan - blechnic acids

• 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%); R_f = 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; R_f = 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; R_f = 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.