Liebeskind-srogl cross coupling mediated synthesis of verbenachalcone

Article abstract of DOI:10.1016/j.tetlet.2010.08.073

A flexible and scalable total synthesis of verbenachalcone is achieved in eight linear steps from cheap commercially available starting material, 3-(4-hydroxyphenyl)propanoic acid.

Full text of DOI:10.1016/j.tetlet.2010.08.073

Tetrahedron Letters 51 (2010) 5753–5756
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Liebeskind–Srogl cross coupling mediated synthesis of verbenachalcone q
Srinivasa Reddy Dandepally a, Alfred L. Williams a,b,
⇑
a Biomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University, Durham, NC 27707, USA
b Department of Pharmaceutical Sciences, College of Science Technology (CST), North Carolina Central University, Durham, NC 27707, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A flexible and scalable total synthesis of verbenachalcone is achieved in eight linear steps from cheap
commercially available starting material, 3-(4-hydroxyphenyl)propanoic acid.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 1 August 2010
Accepted 23 August 2010
Available online 27 August 2010
Keywords:
Natural product synthesis
Verbenachalcone
Liebeskind–Srogl cross coupling
Ullmann ether synthesis
The biaryl ether subunits are prevalent in a variety of medici-
nally important natural products such as verbenachalcone (1),2 lit-
torachalcone (2),3 combretastatin (3, antifungal),4 and ricccardin C
(4, cytotoxin),5 as well as in purely synthetic bioactive compounds,
such as triclosan (5, antibacterial and antifungal),6 RH6201 (6,
herbicidal)7, and LY293111 (7, LTB4 receptor antagonist).8 The 2-
hydroxydiphenyl ether functionality is the core unit in the major-
ity of these bioactive compounds.
The two novel dimeric dihydrochalcones, 1 and 2 were isolated
from the aerial parts of Verbena littoralis (Verbenaceae) by Li et al.,
and are known to act as enhancers of nerve growth factor (NGF)-
mediated neurite outgrowth and axonal branching in PC12D
cells.2,3 Recently, both natural products and a few verbenachalcone
analogs have been synthesized.9,10 The first total synthesis of 1 was
reported by Cuny and co-workers9a using an Ullmann ether
coupling reaction as a key step for constructing the biaryl ether
core. Subsequently, Tanabe et al. have achieved the syntheses of
1 by employing anodic oxidation of the mixed-halogenated phenol
derivative.9c Kraus et al. have reported a synthetic route to 2 by the
desymmetrization of the commercially available para-tolyl ether.10
As part of our research interests in developing novel therapies
for treating neurological diseases, we have actively been involved
in identifying and preparing small molecules, such as verbenachal-
cone that can enhance the activity of NGF, assist in elucidating the
patho-physiological role of neurotrophins, and provide lead com-
pounds for therapeutic development.11 Currently, we have focused
on developing a more flexible and scalable synthetic strategy for 1,
which could easily be amenable for making numerous derivatives
for expanding the SAR studies of verbenachalcone NGF-potentiat-
ing efficacies. For this endeavor, we have chosen the classical
Ullmann ether synthesis12 and Liebeskind–Srogl cross coupling
reactions13 as two key transformations. Herein, we describe a facile
and scalable total synthesis of verbenachalcone (1).
Our retrosynthetic strategy of 1 depicted in Scheme 1 relied on
a copper-mediated palladium-catalyzed Liebeskind–Srogl cross
coupling reaction of dithioester derivative 8 and 2,4-bis(methoxy-
methoxy)phenylboronic acid (9) under neutral conditions. In our
attempts to synthesize a series of verbenachalcone derivatives,1,11
initial use of Cuny and co-workers’ approach toward removing
the benzyl-protecting group in the final step proved to be prob-
lematic due to inconsistent yields that were caused by the com-
plete reduction of the vital ketone functionality. In order to
overcome this hurdle, we chose an acid labile MOM group for
protecting the phenol.
Accordingly, our synthesis commenced from commercially
available 3-(4-hydroxyphenyl)propanoic acid (10) by first convert-
ing to the corresponding ethyl ester after esterification with EtOH
in the presence of a catalytic amount of H2SO4 and ortho-bromin-
ation of the phenol with bromine in acetic acid to give 11.9a,b,14
Treatment of 11 with MOMCl and DIPEA produced MOM-protected
compound 12. The other coupling partner, ethyl 3-(4-hydroxy-3-
methoxyphenyl)propanoate (14) was prepared from ferulic acid
(13) in two steps. Palladium-catalyzed hydrogenation of 13,15
and the subsequent transformation of carboxylic acid to ethyl ester
furnished 14 in excellent yield (Scheme 2).
With the appropriate precursors in hand, we next carried out
the Ullmann ether coupling reaction of 12 and 14 with different
copper catalysts, such as (CuOTf)2PhMe, CuOAc, and CuI using a
mild base Cs2CO3 in boiling pyridine. Anticipating better yields,
q
See Ref. 1.
⇑
Corresponding author. Tel.: +1 919 530 6706; fax: +1 919 530 6600.
E-mail address: awilliams@nccu.edu (A.L. Williams).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.073

5754
S. R. Dandepally, A. L. Williams / Tetrahedron Letters 51 (2010) 5753–5756
O
OH
OH
HO
O
OH
HO
OH
OH
O
O
OMe
O
OH
O
OH
O
O
OH
MeO
O
Littorachalcone (2)
Combretastatin D-2 (3)
Verbenachalcone (1)
Cl
NO
OH
2
CO Na
F
2
HO
HO
OH
HO
O
O
O
O
O
O
CO H
2
Cl
F C
3
Cl
Cl
LY293111 (7)
Riccardin (4)
RH6201 (6)
Triclosan (5)
we also used 2-picolinic acid as an additive with the above-men-
tioned copper catalysts.16 2-Picolinic acid assisted in reducing the
reaction times but failed to improve the yields of biaryl ether 15.
Eventually, we found that the (CuOTf)2PhMe was the better cata-
lyst system for the synthesis of biaryl ether 15.9a
the introduction of the terminal resorcinol units. Thus, 15 was sub-
jected to saponification using 2 M aqueous NaOH solution in a sol-
vent mixture of THF and MeOH to obtain the diacid derivative,17
which was further reacted with p-toluenethiol in the presence of
a coupling reagent, O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyl-
uroniumhexafluorophosphate (HBTU) and DIPEA in CH2Cl2 to fur-
nish dithioester derivative 8.18
Having synthesized biaryl ether 15, we next focused our atten-
tion on exploring the Liebeskind–Srogl cross coupling reaction for
Me
O
O
OH
S
HO
OH
OH
MOMO
O
OH
O
S
MeO
MeO
O
O
8
+
1
Me
OMOM
(HO)2B
OMOM
9
Scheme 1. Retrosynthetic strategy.
a, b
CO2Et
CO2H
CO2Et
c
MOMO
HO
HO
Br
Br
10
11
12
f
d, e
CO2Et
CO2H
HO
O
HO
OMe
OMe
OEt
13
14
MOMO
O
OEt
MeO
O
15
Scheme 2. Reagents and conditions: (a) EtOH, H2SO4 (cat.), rt, 4 h, 99%; (b) Br2, AcOH, rt, 1 h, 86%; (c) MOMCl, DIPEA, CH2Cl2, 0 °C–rt, 4 h, 99%; (d) 10% Pd/C, H2, MeOH, rt,
24 h, 99%; (e) EtOH, H2SO4 (cat.), 0 °C–rt, 12 h, 96%; (f) (CuOTf)2PhMe (10 mol %), Cs2CO3, py, 110 °C, 48 h, 62% (BRSM).

S. R. Dandepally, A. L. Williams / Tetrahedron Letters 51 (2010) 5753–5756
5755
Me
O
O
OEt
a, b
S
MOMO
MOMO
O
O
OEt
S
MeO
MeO
O
O
Me
15
8
O
OMOM
c
MOMO
OMOM
OMOM
d
1
O
MeO
O
OMOM
16
Scheme 3. Reagents and conditions: (a) 2 N NaOH, THF/MeOH (2:1), 6 h, rt; (b) p-toluenethiol, HBTU, DIPEA, CH2Cl2, rt, 48 h, 77% (2 steps); (c) 9 (3 equiv), CuTC (3 equiv),
Pd(PPh3)4 (2 mol %), THF, 60 °C, 1 h, 73%; (d) p-TSA, MeOH, 50 °C, 3 h, 96%.
5. Gottesegen, A.; Vermes, B.; Kajtarperedy, M.; Bihatsikarasai, E.; Nogradi, M.
Then, 8 was subjected to Liebeskind–Srogl cross coupling reac-
Tetrahedron Lett. 1988, 29, 5039–5040.
tion using boronic acid 9,19 copper(I)thiophene-2-carboxylate
6. Levy, C. W.; Roujeinikova, A.; Sedelnikova, S.; Baker, P. J.; Stuitje, A. R.; Slabas, A.
(CuTC),20 and Pd(PPh3)4 in anhydrous THF to obtain 16,9c in 73%
R.; Rice, D. W.; Rafferty, J. B. Nature 1999, 398, 383–384.
7. Johnson, W. O.; Kollman, G. E.; Swithenbank, C.; Yih, R. Y. J. Agric. Food. Chem.
yield. Other attempted catalyst/ligand systems, Pd2dba3ꢀCHCl3/
1978, 26, 285–287.
PPh3 and Pd(OAc)2/dppf gave 16 in 67% and 61% yields, respec-
8. (a) Sawyer, J. S. Drugs Future 1996, 21, 610–614; (b) Sawyer, J. S. Exp. Opin.
tively. Finally, the acidic hydrolysis of 16 with p-TSA in MeOH at
50 °C afforded the natural product 1 in excellent yield (Scheme
3). The spectral data of the synthetic product was identical in all
respects to the reported data of natural product.
Invest. Drugs 1996, 5, 73–77.
9. (a) Xing, X.; Padmanaban, D.; Yeh, L.-A.; Cuny, G. D. Tetrahedron 2002, 58,
7903–7910; (b) Yeh, L.-A.; Padmanaban, D.; Ho, P.; Xing, X.; Rowley, P.; Morse,
L. J.; Jensen, R. V.; Cuny, G. D. Biorg. Med. Chem. Lett. 2005, 15, 1193–1196; (c)
Tanabe, T.; Doi, F.; Ogamino, T.; Nishiyama, S. Tetrahedron Lett. 2004, 45, 3477–
3480; (d) Tanabe, T.; Ogamino, T.; Shimizu, Y.; Imoto, M.; Nishiyama, S. Biorg.
Med. Chem. 2006, 14, 2753–2762.
10. (a) Kraus, G. A.; Kumar, G.; Phillips, G.; Michalson, K.; Mangano, M. Biorg. Med.
Chem. Lett. 2008, 18, 2329–2332; (b) Although Tanabe et al. claimed to have
achieved the synthesis of littorachalcone (Ref. 9d), their final compound
differed from the natural product as reported by Li et al. (see Ref. 3).
11. (a) Clement, C. M.; Dandepally, S. R.; Williams, A. L.; Ibeanu, G. Neurosci. Lett.
2009, 459, 157–161; (b) Yeyeodu, S.; Gilyazova, N.; Huh, E. Y.; Dandepally, S. R.;
Oldham, C.; Williams, A. L.; Ibeanu, G. Cell. Mol. Neurobiol. 2010, in press.
12. (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1904, 37, 853–854; (b) Ullmann, F.;
Sponagel, P. Ber. Dtsch. Chem. Ges. 1905, 38, 2211–2212.
In conclusion,
a flexible and scalable synthetic route to
verbenachalcone has been developed in eight linear steps from
3-(4-hydroxyphenyl)propanoic acid in 28% overall yield.21 The cop-
per-mediated palladium-catalyzed Liebeskind–Srogl cross coupling
reaction was successfully applied for introducing the aryl ketone
moieties. Our method is practically more suitable for incorporating
diverse terminal aryl groups with numerous readily available boro-
nic acids and can be carried on a gram scale. Its application for gen-
erating various verbenachalcone derivatives together with their
biological activities will be reported in due course.
13. (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260–11261; For a
review article, see: (b) Kappe, C. V.; Prokopcová, H. Angew. Chem., Int. Ed. 2009,
48, 2276–2286.
14. Kita, Y.; Egi, M.; Takada, T.; Tohma, H. Synthesis 1999, 885–897.
Acknowledgments
´
ˇ
15. Junek, R.; Kverka, M.; Jandera, A.; Panajotová, V.; Šatinsky, D.; Machácek, M.;
ˇ
Kuchar, M. Eur. J. Med. Chem. 2009, 44, 332–344.
16. (a) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423–17429; (b)
Maiti, D.; Buchwald, S. L. J. Org. Chem. 2010, 75, 1791–1794.
17. Ralph, J.; Quideau, S.; Grabber, G. H.; Hatfield, R. D. J. Chem. Soc., Perkin Trans. 1
1994, 23, 3485–3498.
18. We have modified the procedure originally reported by Movassagh et al., who
used O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium tetrafluoroborate
(TBTU) as the coupling reagent. see: Movassagh, B.; Balaleie, S.; Shaygan, P.
Arkivoc 2007, xiii, 47–52. and references cited therein.
The authors gratefully acknowledge the Golden LEAF Founda-
tion, Rocky Mount, NC, for the financial support in setting-up the
BRITE institute. The authors thank Dr. Li-An Yeh, Director, BRITE,
for the encouragement and support.
Supplementary data
19. 2,4-Bis(methoxymethoxy)phenylboronic acid (9) was prepared from 2-
Supplementary data (copies of 1H and 13C NMR spectra) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.08.073.
bromoresorcinol in an improved yield by
a slight modification of the
reported procedure: J. Med. Chem. 2006, 49, 6950–6953 (S2 and S3 of
Supplementary data).
20. Copper(I)thiophene-2-carboxylate (CuTC) was prepared according to the
procedure reported in Supplementary data: Allred, G. D.; Liebeskind, L. S. J.
Am. Chem. Soc. 1996, 118, 2748–2749.
References and notes
Br
Br
1) n-BuLi, (MeO)3B, B(OH)2
1.
A portion of this work has been presented at the following conference:
º
THF, -78 C, 6 h
MOMCl, DIPEA
OH
OMOM
OMOM
Dandepally, S. R.; Williams, A. L.; Clement, C. M.; Ibeanu, G. Abstracts of Papers,
August 16–20, 2009; 238th National Meeting of the American Chemical
Society, Washington, DC, ORGN-077.
º
CH2Cl2, 0 C-rt,
º
2) 1N HCl, 0 C- rt,
2. Li, Y.-S.; Matsunaga, K.; Kato, R.; Ohizumi, Y. J. Nat. Prod. 2001, 64, 806–808.
3. Li, Y.; Ishibashi, M.; Chen, X.; Ohizumi, Y. Chem. Pharm. Bull. 2003, 51, 872–874.
4. (a) Deshpande, V. E.; Gohkhale, N. J. Tetrahedron Lett. 1992, 33, 4213–4216; (b)
Boger, D. L.; Sakaya, S. M.; Yohannes, D. J. Org. Chem. 1991, 56, 4204–4207.
3 h, 95%
15 min, 69%
OH
OMOM
OMOM
17
9
18

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S. R. Dandepally, A. L. Williams / Tetrahedron Letters 51 (2010) 5753–5756
21. Spectroscopic data of the selected compounds: ethyl 3-(4-(5-(3-ethoxy-3-
oxopropyl)-2-(methoxymethoxy)phenoxy)-3-methoxyphenyl) propanoate (15):
Colorless syrup. 1H NMR (500 MHz, CDCl3) d (ppm) 1.21 (t, 3H, J = 7.5 Hz),
1.25 (t, 3H, J = 7.5 Hz), 2.51 (t, 2H, J = 7.5 Hz), 2.63 (t, 2H, J = 7.5 Hz), 2.81 (t, 2H,
J = 7.5 Hz), 2.93 (t, 2H, J = 7.5 Hz), 3.45 (s, 3H), 3.83 (s, 3H), 4.08 (q, 2H, J = 7.5 Hz),
4.14 (q, 2H, J = 7.5 Hz), 5.17 (s, 2H), 6.65 (d, 1H, J = 2.0 Hz), 6.69 (dd, 1H, J = 2.0,
8.0 Hz), 6.74 (d, 1H, J = 8.0 Hz), 6.82 (d, 1H, J = 2.0 Hz), 6.85 (dd, 1H, J = 2.0,
8.5 Hz), 7.11 (d, 1H, J = 8.5 Hz). 13C NMR (125 MHz, CDCl3) d (ppm) 14.1, 14.2,
30.3, 30.7, 36.0 (2C), 55.9, 56.1, 60.3, 60.4, 95.6, 112.8, 117.8, 118.8, 119.0, 120.3,
123.3, 135.2, 136.5, 144.2, 146.2, 147.1, 150.4, 172.7, 172.8. HRMS (ESI) m/z
1H NMR (500 MHz, CDCl3) d (ppm) 2.88 (t, 2H, J = 7.5 Hz), 3.00 (t, 2H, J = 7.5 Hz),
3.18 (t, 2H, J = 7.5 Hz), 3.30 (t, 2H, J = 7.5 Hz), 3.43 (s, 3H), 3.46 (s, 3H), 3.47 (s,
3H), 3.48 (s, 6H), 3.82 (s, 3H), 5.17 (s, 2H), 5.18 (s, 2H), 5.19 (s, 2H), 5.20 (s, 2H),
5.24 (s, 2H), 6.69–6.75 (m, 6H), 6.80 (d, 1H, J = 2.0 Hz), 6.82 (d, 1H, J = 2.0 Hz),
6.85 (d, 1H, J = 2.0 Hz), 6.88 (dd, 1H, J = 1.5, 3.0 Hz), 7.10 (d, 1H, J = 3.0 Hz), 7.69
(d, 1H, J = 3.5 Hz), 7.74 (d, 1H, J = 3.5 Hz). 13C NMR (125 MHz, CDCl3) d (ppm)
29.9, 30.3, 45.2 (2C), 55.9, 56.1, 56.3, 56.4, 56.5, 94.2, 94.4, 94.6, 95.7, 102.8,
102.9, 108.9, 109.0, 113.0, 117.8, 118.9, 119.0, 120.3, 122.5, 122.6, 123.4, 132.2
(2C), 136.5, 137.7, 144.0, 145.9, 147.1, 150.3, 158.0, 161.6 (2C), 199.6, 199.7.
HRMS (ESI) m/z calcd for C41H48NaO14 [M+Na]+ 787.2936, obsd: 787.2922.
Verbenachalcone (1): White pluffy solid. 1H NMR (500 MHz, CDCl3) d (ppm) 2.89
(t, 2H, J = 7.5 Hz), 3.06 (t, 2H, J = 7.5 Hz), 3.12 (t, 2H, J = 7.5 Hz), 3.22 (t, 2H,
J = 7.5 Hz), 3.80 (s, 3H), 5.39 (s, 1H, OH), 5.84 (s, 1H, OH), 5.94 (s, 1H, OH), 6.34
(dd, 1H, J = 3.5, 8.5 Hz), 6.35 (dd, 1H, J = 3.0, 8.5 Hz), 6.37 (d, 1H, J = 2.5 Hz), 6.38
(d, 1H, J = 2.5 Hz), 6.57 (d, 1H, J = 2.0 Hz), 6.75 (dd, 1H, J = 2.0, 8.0 Hz), 6.81 (d, 1H,
J = 1.5 Hz), 6.83 (dd, 1H, J = 2.0, 8.5 Hz), 6.91 (t, 2H, J = 8.0 Hz), 7.56 (d, 1H,
J = 9.0 Hz), 7.59 (d, 1H, J = 9.0 Hz), 12.60 (s, 1H, OH), 12.76 (s, 1H, OH). 13C NMR
(125 MHz, CDCl3 + CD3OD) d (ppm) 29.7, 30.1, 39.3, 39.4, 55.7, 102.8 (2C), 108.2,
108.3, 112.5, 112.9, 116.4, 118.0, 119.1, 120.7, 123.6, 132.0, 132.6, 137.1, 143.7,
144.2, 145.5, 149.9, 164.7, 203.3, 203.5. HRMS (ESI) m/z calcd for C31H28O9
[M+H]+ 545.1806, obsd: 545.1807.
calcd for
C
25H32NaO8 [M+Na]+ 483.1995, obsd: 483.1970. S-p-Tolyl 3-(3-
methoxy-4-(2-(methoxymethoxy)-5-(3-oxo-3-(p-tolylthio)propyl)phenoxy)phen-
yl) propanethioate (8): Colorless syrup. 1H NMR (500 MHz, CDCl3) d (ppm) 2.36
(2s, 6H), 2.82–2.88 (m, 4H), 2.93–3.01 (m, 4H), 3.45 (s, 3H), 3.83 (s, 3H), 5.18 (s,
2H), 6.66 (d, 1H, J = 2.0 Hz), 6.69 (dd, 1H, J = 2.0, 8.0 Hz), 6.76 (d, 1H, J = 8.0 Hz),
6.81 (d, 1H, J = 1.5 Hz), 6.85 (dd, 1H, J = 2.0, 8.5 Hz), 7.12 (d, 1H, J = 8.5 Hz), 7.18–
7.27 (m, 8H). 13C NMR (125 MHz, CDCl3) d (ppm) 21.3, 30.6, 31.2, 44.9, 45.1, 55.9,
56.1, 95.5, 112.9, 117.7, 118.8, 119.0, 120.5, 123.4, 124.1, 129.9, 130.0, 134.3,
134.4, 134.5, 135.9, 139.6, 139.7, 144.3, 146.3, 147.1, 150.4, 196.9, 197.1. HRMS
(ESI) m/z calcd for C35H36NaO6S2 [M+Na]+ 639.1851, obsd: 639.1841. 1-(2,4-
Bis(methoxymethoxy)phenyl)-3-(4-(5-(3-(2,4-bis(methoxyme-thoxy)phenyl)-3-
oxopropyl)-2-(methoxymethoxy) phenoxy)-3-methoxyphenyl)propan-1-one (16):