Synlett 2014; 25(2): 288-292
DOI: 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
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Publikationsverlauf

Received: 19. September 2013

Accepted after revision: 22. Oktober 2013

Publikationsdatum:
03. Dezember 2013 (online)


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.

Supporting Information

 
  • References and Notes

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  • 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.
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  • 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).
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  • 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.