A Concise Synthesis of Dunnianol

Abstract

A short total synthesis of the neosesquilignan dunnianol which features a double Suzuki cross-coupling as a key step is described.

Key words

total synthesis - natural products - Suzuki cross-­coupling - neolignans

References and Notes

• 1 For a review, see: Fukuyama Y. Huang J.-M. Studies in Natural Products Chemistry   Vol. 32:  . Elsevier; Amsterdam: 2005.  p.395-429  
• 2 Eykman JF. Ber. Dtsch. Chem. Ges.  1890,  22:  2736 ; abstracted in J. Chem. Soc. 1890, 58, 135; chavicol has since been isolated from numerous plant sources and is found in essential oils of basil, fennel, and anise
• 3 Kuano I. Morisaki T. Hara Y. Yang S.-C. Chem. Pharm. Bull.  1991,  39:  2606 
• 4 Moriyama M. Huang J.-M. Yang C.-S. Hioki H. Kubo M. Harada K. Fukuyama Y. Tetrahedron  2007,  63:  4263 
• 5a Magnolol is one of the main constituents of the stem bark of Magnolia obovata, see: Fujita M. Itokawa H. Sashida Y. Yakushigaku Zasshi  1973,  93:  429 
• 5b Magnolol is also one of the major components of the stem bark of Magnolia officinalis, see: Ito K. Iida T. Ichino K. Masao T. Namba T. Chem. Pharm. Bull.  1982,  30:  3347 
• 5c Li AJ. Zhong Yao Ton Bao  1985,  10:  10 
• 6 Fukuyama Y. Nakade K. Minoshima Y. Yokoyama R. Zhai H. Mitsumoto Y. Bioorg. Med. Chem. Lett.  2002,  12:  1163 
• Dunnianol has previously been prepared in low yield by nonselective oxidative phenolic coupling of chavicol using K₃Fe(CN)₆, see:
• 7a Sy L.-K. Brown GD. J. Chem. Res., Synop.  1998,  476 
• Using FeCl₃, see:
• 7b Haynes CG. Turner AH. Waters WA. J. Chem. Soc.  1956,  2823 
• Using horseradish peroxidase, see:
• 7c Tzeng S.-C. Liu Y.-C. J. Mol. Catal. B: Enzymol.  2004,  32:  7 ; these studies support the hypothesis that dunnianol is derived from chavicol
• Commercially available BCl₃˙SMe₂ was found to be superior to commercially available BBr₃. For methods using BBr₃ which, in our hands, resulted in the formation of substantial amounts of 4-(2-bromopropyl)phenol, see:
• 9a Liu Y.-C. Tzeng S.-C. Kong Z.-L. Bioorg. Med. Chem. Lett.  2005,  15:  163 
• 9b Pinard E. Alanine A. Bourson A. Buttelmann B. Gill R. Heitz M.-P. Jaeschke G. Mutel V. Trube G. Wyler R. Bioorg. Med. Chem. Lett.  2001,  11:  2173 
• 9c Agharahimi MR. LeBel NA. J. Org. Chem.  1995,  60:  1858 
• 10 Pearson DE. Wysong RD. Breder CV. J. Org. Chem. Soc.  1967,  32:  2358 
• 13 Freskos JN. Morrow GW. Swenton JS. J. Org. Chem.  1985,  50:  805 ; similar reactions using n-BuLi in the absence of TMEDA resulted in alkene isomerisation
• 14 Sakurai H. Tsukuda T. Hirao T. J. Org. Chem.  2002,  67:  2721 
• 15 Littke AF. Dai C. Fu GC. J. Am. Chem. Soc.  2000,  122:  4020 
• 16 Wawrzyniak P. Heinicke J. Tetrahedron Lett.  2006,  47:  8921 
• For Suzuki couplings of 2,4,6-tribromophenol, see:
• 17a Basu B. Das P. Bhuiyan MH. Jha S. Tetrahedron Lett.  2001,  47:  8921 
• 17b Liu L. Zhang Y. Xin B. J. Org. Chem.  2006,  71:  2721 
• 19 Long reaction times for Suzuki-Miyaura couplings of 2-bromophenols have been observed by others, see: Dupuis C. Adiey K. Charruault L. Michelet V. Savignac M. Genét J.-P. Tetrahedron Lett.  2001,  37:  6523 

8

Commercially available estragole (98%), supplied by Acros Organics, was used as received.

11

Analytical Data for 6
Oil; R _f  = 0.44 (PE-EtOAc, 9:1). IR (CHCl₃): ν_max = 3510 (OH), 3085 (CH), 2984 (CH), 2908 (CH), 1631 (C=C). ^¹H NMR (270 MHz, CDCl₃): δ = 3.29 (2 H, d, J = 6.7 Hz, ArCH ₂CHCH₂), 5.08 (1 H, dd, J = 10.3, 1.5 Hz, ArCH₂CHCHH _cis ), 5.12 (1 H, dd, J = 16.7, 1.5 Hz, ArCH₂CHCHH _trans ), 5.77 (1 H, s, ArOH), 5.89 (1 H, ddt, J = 16.7, 10.3, 6.7 Hz, ArOCH₂CHCH₂), 7.28 (2 H, s, ArH). ^¹³C NMR (67.5 MHz, CDCl₃): δ 38.7 (CH₂), 100.0 (Cq), 109.7 (Cq), 114.7 (Cq), 117.0 (CH₂), 132.1 (CH), 136.3 (CH). HRMS (ESI⁺): m/z calcd for C₉H₈OBr₂Na: 312.8834; found: 312.8831.

12

Analytical Data for 7
Solid; mp = 77­­­-­­­79 ˚C; Rf = 0.13 (PE-EtOAc, 4:1). IR (neat) nmax = 3422 (OH), 3196 (CH), 2958 (CH), 1606 (C=C). 1H NMR (400 MHz, CDCl3): d = 3.37 (2 H, d, J = 6.7 Hz, ArCH2CHCH2), 3.91 (3 H, s, ArOCH3), 5.07 (1 H, dd, J = 16.8, 1.5 Hz, ArCH2CHCHHtrans), 5.09 (1 H, dd, J = 10.1, 1.5 Hz, ArCH2CHCHHcis), 5.97 (1 H, ddt, J = 16.8, 10.1, 6.7 Hz, ArCH2CHCH2), 6.05 [2 H, br s, ArB(OH)2], 6.87 (1 H, d, J = 8.5 Hz, ArH), 7.27 (1 H, dd, J = 8.5, 2.4 Hz, ArH), 7.67 (1 H, d, J = 2.4 Hz, ArH). 13C NMR (100 MHz, CDCl3): d = 39.3 (CH2), 55.6 (CH3), 110.1 (CH), 115.6 (CH2), 132.6 (Cq), 132.9 (Cq), 136.9 (CH), 137.7 (CH), 163.1 (Cq), 173.6 (Cq). HRMS (EI+): m/z calcd for C10H13O3BN: 192.0958; found: 192.0960.

18

Analytical Data for 8
Oil; R _f  = 0.42 (PE-EtOAc, 9:1). IR (neat) ν_max = 3360 (OH), 2930 (CH), 2837 (CH), 1639 (C=C), 1606 (CH). ^¹H NMR (500 MHz, CDCl₃): δ = 3.40 (2 H, d, J = 6.8 Hz, ArCH ₂CHCH₂, H_{7 ′}), 3.42 (1 H, d, J = 6.9 Hz, ArCH ₂CHCH₂, H₇), 3.82 (6 H, s, ArOCH ₃), 5.07 (2 H, dd, J = 9.4, 2.0 Hz, ArCH₂CHCHH _cis , H_{9 ′}), 5.09 (1 H, dd, J = 10.0, 1.6 Hz, ArCH₂CHCHH _cis , H₉), 5.12 (2 H, dd, J = 19.0, 2.0 Hz, ArCH₂CHCHH _trans , H_{9 ′}), 5.14 (1 H, dd, J = 18.1, 1.6 Hz, ArCH₂CHCHH _trans , H₉), 5.95-6.06 (3 H, m, ArCH₂CHCH₂, H₈, H_{8 ′}), 6.35 (1 H, s, ArOH), 6.95 (2 H, d, J = 8.3 Hz, ArH, H_{3 ′}), 7.11 (2 H, s, ArH, H₃), 7.18 (2 H, dd, J = 8.3, 2.2 Hz, ArH, H_{5 ′}), 7.20 (2 H, d, J = 2.2 Hz, ArH, H_{6 ′}). ^¹³C NMR (125 MHz, CDCl₃): δ = 39.4 (CH₂, C_{7 ′}), 39.5 (CH₂, C₇), 56.1 (CH₃), 111.2 (CH, C_{6 ′}), 115.7 (CH₂, C₉, C_{9 ′}), 127.2 (Cq, C₂), 127.8 (Cq, C_{2 ′}), 128.8 (CH, C₃), 130.9 (CH, C_{3 ′}), 131.9 (Cq, C₄), 132.3 (CH, C_{5 ′}), 132.7 (Cq, C_{4 ′}), 137.7 (CH, C_{8 ′}), 137.8 (CH, C₈), 149.5 (Cq, C₁), 154.7 (Cq, C_{1 ′}). HRMS (ESI⁺): m/z calcd for C₂₉H₃₀O₃NH₄: 444.2533; found: 444.2518.

20

TLC, IR, ^¹H NMR, ^¹³C NMR, and HRMS were all in agreement with the data reported for dunnianol in ref. 3.
Analytical Data for 1
Solid; mp 134-135 ˚C; R _f  = 0.41 (PE-EtOAc, 4:1). IR (neat): ν_max = 3690 (OH), 3604 (OH), 3011 (CH), 2926 (CH), 2854 (CH), 1602 (C=C). ^¹H NMR (500 MHz, CDCl₃): δ = 3.40 (4 H, d, J = 6.7 Hz, ArCH ₂CHCH₂, H_{7 ′}), 3.44 (2 H, d, J = 6.8 Hz, ArCH ₂CHCH₂, H₇), 5.09 (2 H, dd, J = 10.8, 1.5 Hz, ArCH₂CHCHH _cis , H_{9 ′}), 5.11 (2 H, dd, J = 17.0, 1.5 Hz, ArCH₂CHCHH _trans , H_{9 ′}), 5.14 (1 H, dd, J = 18.2, 1.8 Hz, ArCH₂CHCHH _trans , H₉), 5.15 (1 H, dd, J = 11.4, 1.8 Hz, ArCH₂CHCHH _cis , H₉), 5.72 (3 H, br s, ArOH), 5.95-6.04 (3 H, m, ArCH₂CHCH₂, H₈, H_{8 ′}), 6.99 (2 H, d, J = 8.1 Hz, ArH, H_{3 ′}), 7.15 (2 H, dd, J = 8.1, 2.2 Hz, ArH, H_{5 ′}), 7.17 (2 H, d, J = 2.2 Hz, ArH, H_{6 ′}), 7.19 (2 H, s, ArH, H₃). ^¹³C NMR (125 MHz, CDCl₃): δ = 39.4 (CH₂, C₇, C_{7 ′}), 115.9 (CH₂, C_{9 ′}), 116.2 (Cq, C₉), 117.2 (Cq, C_{6 ′}), 124.4 (Cq, C_{2 ′}), 125.4 (Cq, C₂), 130.0 (CH, C_{5 ′}), 131.3 (CH, C₃), 131.6 (CH, C_{3 ′}), 133.2 (Cq, C_{4 ′}), 134.0 (Cq, C₄), 137.2 (CH, C₈), 137.5 (CH, C_{8 ′}), 147.6 (Cq, C₁), 151.4 (Cq, C_{1 ′}). HRMS (ESI⁺): m/z calcd for C₂₇H₂₆O₃Na: 421.1774; found: 421.1768.

21

Analytical Data
Oil; R _f  = 0.41 (PE-EtOAc, 4:1). IR (CHCl₃): ν_max = 3690 (OH), 3412 (OH), 3011 (CH), 2928 (CH), 2855 (CH), 1663 (C=C), 1547 (C=C). ^¹H NMR (500 MHz, CDCl₃): δ = 3.36-3.45 (6 H, m, ArCH ₂CHCH₂), 3.88 (3 H, s, ArOCH₃), 5.06-5.17 (6 H, m, ArCH₂CHCH ₂), 5.92-6.06 (3 H, m, ArCH₂CHCH₂), 6.41 (2 H, br s, ArOH), 7.00 (1 H, dd, J = 8.5, 2.5 Hz, ArH), 7.13 (1 H, d, J = 2.5 Hz, ArH), 7.15 (1 H, d, J = 2.5 Hz, ArH), 7.16 (1 H, d, J = 2.5 Hz, ArH), 7.18 (1 H, d, J = 2.0 Hz, ArH), 7.19 (1 H, d, J = 2.0 Hz, ArH), 7.23 (1 H, d, J = 2.0 Hz, ArH), 7.25 (1 H, dd, J = 8.5, 2.0 Hz, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 39.3, 39.5, 54.6, 111.6, 115.6, 116.0, 116.1, 116.4, 116.6, 117.8, 126.6, 127.0, 129.3, 129.6, 130.0, 131.0, 131.3, 132.5, 132.8, 133.6, 134.1, 137.3, 137.4, 137.6, 137.9, 147.8, 152.1, 153.6. HRMS (ESI^-): m/z calcd for C₂₈H₂₈O₃: 412.2044; found: 412.2038.