Towards the Total Synthesis of Schisandrene: Stereoselective Synthesis of the Dibenzocyclooctadiene Lignan Core

Abstract

A stereoselective synthesis of the dibenzocyclooctadiene ­lignan core of the natural product schisandrene is described. Starting from readily available gallic acid, the synthetic strategy involves Suzuki–Miyaura cross-coupling, Stille reaction, and ring-closing metathesis (RCM) in the reaction sequence. The required asymmetric center at C-7′ was established by an asymmetric reduction of a keto compound using the Corey–Bakshi–Shibata (CBS) catalyst. In our approach, the eight-membered ring was achieved by RCM for the first time.

Key words

Suzuki–Miyaura cross-coupling - Stille reaction - ring-­closing metathesis (RCM) - schisandrene - dibenzocyclooctadiene lignan

• References and Notes

• 1a Humphreys JM. Chapple C. Plant Biol. 2002; 5: 224
• 1b Anterola AM. Jeon JH. Davin LB. Lewis NG. J. Biol. Chem. 2002; 277: 1827
• 1c Dixon RA. Reddy MS. S. Phyto Chem. Rev. 2003; 2: 289
• 1d Suzuki S. Umezawa T. J. Wood Sci. 2007; 53: 273
• 2a Chen DF. Zhang SX. Kozuka M. Sun QZ. Feng J. Wang Q. Mukainaka T. Nobukuni Y. Tokuda H. Nishino H. Wang HK. Morris-Natschke SL. Lee KH. J. Nat. Prod. 2002; 65: 1242
• 2b Yasukawa K. Ikeya Y. Mitsuhashi H. Iwasaki M. Aburada M. Nakagawa S. Takeuchi M. Takido M. Oncology 1992; 49: 68
• 2c Huerta E. Grey N. Cancer J. Clin. 2007; 57: 72
• 2d Cragg GM. Grothaus PG. Newman DJ. Chem. Rev. 2009; 109: 3012
• 2e Ohtaki Y. Hida T. Hiramatsu K. Kanitani M. Ohshima T. Nomura M. Wakita H. Aburada M. Miyamoto KI. Anticancer Res. 1996; 16: 751
• 3a Panossian A. Wikman G. J. Ethnopharmacol. 2008; 118: 183
• 3b Hancke JL. Burgos RA. Ahumada F. Fitoterapia 1999; 70: 451
• 4 Chang GT. Kang SK. Kim JH. Chung KH. Chang YC. Kim CH. J. Ethnopharmacol. 2005; 102: 430
• 5a Poornima B. Anand Kumar D. Siva B. Venkanna A. Tiwari AK. Babu KS. Nat. Prod. Res. 2016; 30: 493
• 5b Venkanna A. Siva B. Poornima B. Rao VP. R. Prasad KR. Reddy AK. Reddy GB. P. Babu KS. Rao JM. Fitoterapia 2014; 95: 102
• 5c Poornima B. Siva B. Shankaraiah G. Venkanna A. Nayak CL. Rao V. Babu KS. Eur. J. Med. Chem. 2015; 92: 449
• 6 Choi YW. Takamatsu S. Khan SI. Srinivas PV. Ferreira D. Zhao J. Khan IA. J. Nat. Prod. 2006; 69: 356
• 7 Zhao Y. Hao X. Lu W. Cai J. Yu H. Sevenet T. Gueritte F. J. Nat. Prod. 2002; 65: 902
• 8 Sreedhar E. Kumar RS. C. Reddy GV. Robinson A. Babu KS. Rao JM. Srinivas PV. Tetrahedron: Asymmetry 2009; 20: 440
• 9 Song C. Zhao P. Hu Z. Shi S. Cui Y. Chang J. Bioorg. Med. Chem. Lett. 2010; 20: 2297
• 10 Alam A. Takaguchi Y. Ito H. Yoshidab T. Tsuboia S. Tetra­hedron 2005; 61: 1909
• 11 Jeon AR. Kim ME. Park JK. Shin WK. An DK. Tetra­hedron 2014; 70: 4420
• 12 Kumar S. Peruncheralathan S. Ila H. Junjappa H. Org. Lett. 2008; 10: 965
• 13 Schmidt RR. Frick W. Tetrahedron 1988; 44: 7163
• 14 Fang G. Mello JV. Finney NS. Tetrahedron 2004; 60: 11075
• 15 Barder TE. Walker SD. Martinelli JR. Buchwald SL. J. Am. Chem. Soc. 2005; 127: 4685
• 16 Morgan BJ. Dey S. Johnson SW. Kozlowski MC. J. Am. Chem. Soc. 2009; 131: 9413
• 17 Singidi RR. Babu TV. R. Org. Lett. 2008; 10: 3351
• 18 Takaoka S. Takaoka N. Minoshima Y. Huang JM. Kubo M. Harada K. Hioki K. Fukuyama Y. Tetrahedron 2009; 65: 8354
• 19 Coleman RS. Gurrala SR. Org. Lett. 2004; 6: 4025
• 20 Coleman RS. Gurrala SR. Org. Lett. 2004; 6: 3711
• 21 Boyer FD. Hanna I. Eur. J. Org. Chem. 2008; 4938
• 22 Besong G. Billen D. Dager I. Kocienski P. Sliwinski E. Tai LR. Boyle T. Tetrahedron 2008; 64: 4700
• 23 Synthetic Procedure for 18 A solution of S-(–)-2-methyl-CBS-oxazaborolidine (1 M solution in toluene, 4.9 mmol) in THF (5 mL) was treated with BH₃·DMS (2.0 M solution in THF, 0.2 mL, 04.1 mmol) at 0 °C for 15 min. A solution of enone 3 (0.150 g, 4.1 mmol) in THF (8 mL) was added slowly at –78 °C, and the reaction mixture was stirred for 1 h maintaining the temperature. After the reaction was complete, saturated NH₄Cl solution was added. The aqueous layer was extracted with EtOAc, the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 10% EtOAc/hexane to give compound 18 (0.128 g, 85%, ee 98%) as a colorless liquid: [α]_D ²⁵ –2.53 (c 4.8, CHCl₃). IR (KBr): ν_max= 3562, 2972, 2920, 2847, 1586, 1448, 1227, 1107, 720 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 6.73 (s, 1 H), 6.33 (s, 1 H), 5.93–5.84 (m, 5 H), 5.77–5.70 (m, 1 H), 4.88–4.82 (m, 1 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 2.93–2.86 (m, 1 H), 2.76–2.70 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 149.7, 149.4, 140.0, 139.6, 135.5, 135.4, 134.8, 134.7, 130.0, 129.2, 121.1, 119.9, 103.5, 101.1, 100.9, 98.8, 68.9, 59.4 (2 C), 31.9 ppm. HRMS: m/z calcd for C₂₀H₂₀O₇: 371.1052; 371.1048 [M + H]⁺.
• 24a Venkanna A. Sreedhar E. Siva B. Babu KS. Prasad KR. Rao JM. Tetrahedron: Asymmetry 2013; 24: 1010
• 24b Zhantao Y. Xiaolong X. Chun-Hua Y. Yunfeng T. Xinyi C. Lihui L. Wenwei P. Xuncheng S. Weicheng Z. Yue C. Org. Lett. 2016; 18: 5768
• 25a Adam W. Humpf H.-U. Roschmann KJ. Saha-Möller CR. J. Org. Chem. 2001; 66: 5796
• 25b Jacobsen EN. Zhang W. Muci AR. Ecker JR. Deng L. J. Am. Chem. Soc. 1991; 113: 7063
• 25c Hughes DL. Smith GB. Liu J. Dezeny GC. Senanayake CH. Larsen RD. Verhoeven TR. Reider PJ. J. Org. Chem. 1997; 62: 2222
• 25d Brandes BD. Jacobsen EN. J. Org. Chem. 1994; 59: 4378