A concise synthesis of dunnianol

Article abstract of DOI:10.1055/S-0029-1219209

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

Full text of DOI:10.1055/S-0029-1219209

LETTER
633
A Concise Synthesis of Dunnianol
Synthesisof
Dunonianol ss M. Denton,* James T. Scragg
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Fax +44(115)9513564; E-mail: ross.denton@nottingham.ac.uk
Received 10 November 2009
Dedicated to Professor Gerry Pattenden on the occasion of his 70th birthday
short synthesis of dunnianol7 with a view to investigating
its potential to stimulate neurite outgrowth and protect
neurons. Our synthesis plan involved formation of the two
biaryl bonds via a double Suzuki coupling reaction.
Abstract: A short total synthesis of the neosesquilignan dunnianol
which features a double Suzuki cross-coupling as a key step is de-
scribed.
Key words: total synthesis, natural products, Suzuki cross-
coupling, neolignans
The synthesis began with the preparation of dibromide 6
and boronic acid 7 (Scheme 1). Commercially available
estragole (5)8 was demethylated (BCl3·SMe2 in refluxing
dichloroethane)9 and brominated10 with NBS to afford
coupling partner 6,11 with the remainder of the mass bal-
ance being estragole and the monobromide, respectively.
The boronic acid cross-coupling partner 712 was then ob-
tained in a single step via lithiation13 of estragole followed
by treatment with trimethylboronate and hydrolysis of the
derived intermediate boronate ester. With both coupling
partners available we investigated the key double Suzuki
coupling reaction.
A wide variety of neolignans has been isolated during the
last two decades from Illicium plants.1 For example, dun-
nianol (1, Figure 1), an ortho-linked neolignan derived
from chavicol (4),2 was isolated from the bark of Illicium
dunnianum in 1991.3
9'
8'
7'
4'
5'
6'
3'
OH
OH
1
1. BCl3⋅SMe2
DCE
OH
2'
6
5
2
1'
OMe
reflux, 18 h
63%
Br
Br
OH
OH
OH
3
4
2. NBS, t-BuNH2
CH2Cl2, 0 °C, 1 h
61%
7
8
9
dunnianol (1)
magnolol (3)
6
5
OH
s-BuLi, TMEDA, THF
–78 °C to 0 °C, 1 h
B(OMe)3, 24 h
OMe
OH
O
OMe
B(OH)2
0 °C to r.t.; aq HCl
53%
OH
7
5
isodunnianol (2)
chavicol (4)
Scheme 1
Figure 1
A range of iodophenols undergo cross-coupling reac-
tions;14 however, Suzuki reactions of para-bromophenols
are known to be difficult15 and ortho-bromophenols are
more difficult still.16 Limited literature precedent was
available for double coupling of bis-ortho-bromophe-
nols.17 In the event double coupling to produce bismethyl-
dunnianol 818 (Scheme 2) proceeded in good yield and
with no detectable alkene isomerisation.19 Lewis acid me-
diated deprotection then afforded the natural product20
along with 5% of monomethyldunnianol;21 again with no
detectable isomerisation of the allyl groups.
Whilst no biological investigations on dunnianol have
been reported to date, isodunnianol (2),3 a co-metabolite,
has been reported to promote neurite outgrowth in vitro in
primary cultured rat cortical neurons.4 Given the structur-
al similarity between these two natural products, and the
fact that the C-ortho-linked dimer magnolol (3)5 is also re-
ported to promote neurite outgrowth6 we developed a
SYNLETT 2010, No. 4, pp 0633–0635
0
1.
0
3.
2
0
1
0
Advanced online publication: 19.01.2010
DOI: 10.1055/s-0029-1219209; Art ID: D32509ST
© Georg Thieme Verlag Stuttgart · New York

634
R. M. Denton, J. T. Scragg
LETTER
Turner, A. H.; Waters, W. A. J. Chem. Soc. 1956, 2823.
Using horseradish peroxidase, see: (c) 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.
Pd(OAc)2, Ph3P
Na2CO3
i-PrOH, H2O
reflux, 48 h
OH
OMe
OH
Br
Br
+
B(OH)2
70%
(8) Commercially available estragole (98%), supplied by Acros
Organics, was used as received.
OMe
OMe
(9) 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: (a) Liu, Y.-C.;
Tzeng, S.-C.; Kong, Z.-L. Bioorg. Med. Chem. Lett. 2005,
15, 163. (b) 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. (c) Agharahimi, M. R.; LeBel, N. A. J. Org. Chem.
1995, 60, 1858.
6
7
8
BCl3⋅SMe2
DCE
relux, 48 h
OH
70%
OH
OH
(10) Pearson, D. E.; Wysong, R. D.; Breder, C. V. J. Org. Chem.
Soc. 1967, 32, 2358.
(11) Analytical Data for 6
1
Oil; Rf = 0.44 (PE–EtOAc, 9:1). IR (CHCl3): nmax = 3510
(OH), 3085 (CH), 2984 (CH), 2908 (CH), 1631 (C=C).
1H NMR (270 MHz, CDCl3): d = 3.29 (2 H, d, J = 6.7 Hz,
ArCH2CHCH2), 5.08 (1 H, dd, J = 10.3, 1.5 Hz,
ArCH2CHCHHcis), 5.12 (1 H, dd, J = 16.7, 1.5 Hz,
ArCH2CHCHHtrans), 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): d 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.
Scheme 2
In summary dunnianol has been prepared from estragole
in four steps and 17% overall yield in the longest linear se-
quence. Conditions for double Suzuki cross-couplings of
bis-ortho-bromophenols and methylether cleavage with-
out alkene isomerisation have been identified. These con-
ditions should find application in the synthesis of other
more complex oligomeric chavicol-derived natural prod-
ucts.
(12) Analytical Data for 7
Solid; mp = 77–79 °C; Rf = 0.13 (PE–EtOAc, 4:1). IR (neat)
ν
max = 3422 (OH), 3196 (CH), 2958 (CH), 1606 (C=C). 1H
Acknowledgment
NMR (400 MHz, CDCl3): δ = 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): δ = 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.
R.M.D. would like to thank Professor Gerry Pattenden for his ad-
vice and mentorship and The School of Chemistry, University of
Nottingham for funding.
References and Notes
(1) For a review, see:Fukuyama, Y.; Huang, J.-M. Studies in
Natural Products Chemistry, Vol. 32; Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 2005, 395–429.
(2) Eykman, J. F. 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.
(13) Freskos, J. N.; Morrow, G. W.; Swenton, J. S. 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, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020.
(16) Wawrzyniak, P.; Heinicke, J. Tetrahedron Lett. 2006, 47,
8921.
(17) For Suzuki couplings of 2,4,6-tribromophenol, see:
(a) Basu, B.; Das, P.; Bhuiyan, M. H.; Jha, S. Tetrahedron
Lett. 2001, 47, 8921. (b) Liu, L.; Zhang, Y.; Xin, B. J. Org.
Chem. 2006, 71, 2721.
(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.
(5) (a) 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. (b) 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. (c) Li, A. J.
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.
(7) Dunnianol has previously been prepared in low yield by
nonselective oxidative phenolic coupling of chavicol using
K3Fe(CN)6, see: (a) Sy, L.-K.; Brown, G. D. J. Chem. Res.,
Synop. 1998, 476. Using FeCl3, see: (b) Haynes, C. G.;
(18) Analytical Data for 8
Oil; Rf = 0.42 (PE–EtOAc, 9:1). IR (neat) nmax = 3360 (OH),
2930 (CH), 2837 (CH), 1639 (C=C), 1606 (CH). 1H NMR
(500 MHz, CDCl3): d = 3.40 (2 H, d, J = 6.8 Hz,
ArCH2CHCH2, H7¢), 3.42 (1 H, d, J = 6.9 Hz,
ArCH2CHCH2, H7), 3.82 (6 H, s, ArOCH3), 5.07 (2 H, dd,
J = 9.4, 2.0 Hz, ArCH2CHCHHcis, H9¢), 5.09 (1 H, dd,
J = 10.0, 1.6 Hz, ArCH2CHCHHcis, H9), 5.12 (2 H, dd,
J = 19.0, 2.0 Hz, ArCH2CHCHHtrans, H9¢), 5.14 (1 H, dd,
Synlett 2010, No. 4, 633–635 © Thieme Stuttgart · New York

LETTER
J = 18.1, 1.6 Hz, ArCH2CHCHHtrans, H9), 5.95–6.06 (3 H,
Synthesis of Dunnianol
635
H, m, ArCH2CHCH2, H8, H8¢), 6.99 (2 H, d, J = 8.1 Hz, ArH,
H3¢), 7.15 (2 H, dd, J = 8.1, 2.2 Hz, ArH, H5¢), 7.17 (2 H, d,
J = 2.2 Hz, ArH, H6¢), 7.19 (2 H, s, ArH, H3). 13C NMR (125
MHz, CDCl3): d = 39.4 (CH2, C7, C7¢), 115.9 (CH2, C9¢),
116.2 (Cq, C9), 117.2 (Cq, C6¢), 124.4 (Cq, C2¢), 125.4 (Cq,
C2), 130.0 (CH, C5¢), 131.3 (CH, C3), 131.6 (CH, C3¢), 133.2
(Cq, C4¢), 134.0 (Cq, C4), 137.2 (CH, C8), 137.5 (CH, C8¢),
147.6 (Cq, C1), 151.4 (Cq, C1¢). HRMS (ESI+): m/z calcd for
C27H26O3Na: 421.1774; found: 421.1768.
m, ArCH2CHCH2, H8, H8¢), 6.35 (1 H, s, ArOH), 6.95 (2 H,
d, J = 8.3 Hz, ArH, H3¢), 7.11 (2 H, s, ArH, H3), 7.18 (2 H,
dd, J = 8.3, 2.2 Hz, ArH, H5¢), 7.20 (2 H, d, J = 2.2 Hz, ArH,
H6¢). 13C NMR (125 MHz, CDCl3): d = 39.4 (CH2, C7¢), 39.5
(CH2, C7), 56.1 (CH3), 111.2 (CH, C6¢), 115.7 (CH2, C9, C9¢),
127.2 (Cq, C2), 127.8 (Cq, C2¢), 128.8 (CH, C3), 130.9 (CH,
C3¢), 131.9 (Cq, C4), 132.3 (CH, C5¢), 132.7 (Cq, C4¢), 137.7
(CH, C8¢), 137.8 (CH, C8), 149.5 (Cq, C1), 154.7 (Cq, C1¢).
HRMS (ESI+): m/z calcd for C29H30O3NH4: 444.2533;
found: 444.2518.
(21) Analytical Data
Oil; Rf = 0.41 (PE–EtOAc, 4:1). IR (CHCl3): nmax = 3690
(OH), 3412 (OH), 3011 (CH), 2928 (CH), 2855 (CH), 1663
(C=C), 1547 (C=C). 1H NMR (500 MHz, CDCl3): d = 3.36–
3.45 (6 H, m, ArCH2CHCH2), 3.88 (3 H, s, ArOCH3), 5.06–
5.17 (6 H, m, ArCH2CHCH2), 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): d = 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.
(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.
(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; Rf = 0.41 (PE–EtOAc, 4:1). IR
(neat): nmax = 3690 (OH), 3604 (OH), 3011 (CH), 2926
(CH), 2854 (CH), 1602 (C=C). 1H NMR (500 MHz, CDCl3):
d = 3.40 (4 H, d, J = 6.7 Hz, ArCH2CHCH2, H7¢), 3.44 (2 H,
d, J = 6.8 Hz, ArCH2CHCH2, H7), 5.09 (2 H, dd, J = 10.8,
1.5 Hz, ArCH2CHCHHcis, H9¢), 5.11 (2 H, dd, J = 17.0, 1.5
Hz, ArCH2CHCHHtrans, H9¢), 5.14 (1 H, dd, J = 18.2, 1.8 Hz,
ArCH2CHCHHtrans, H9), 5.15 (1 H, dd, J = 11.4, 1.8 Hz,
ArCH2CHCHHcis, H9), 5.72 (3 H, br s, ArOH), 5.95–6.04 (3
Synlett 2010, No. 4, 633–635 © Thieme Stuttgart · New York