Concise, regiocontrolled synthesis of yangjinhualine A

Article abstract of DOI:10.1016/j.tetlet.2011.01.036

The first synthesis of yangjinhualine A, a recently isolated α,β-disubstituted γ-hydroxybutenolide from the Chinese medicinal herb Datura metel L., has been accomplished in concise, entirely regiocontrolled fashion through the combined use of Suzuki-Miyaura cross-coupling and 2-silyloxyfuran oxyfunctionalization.

Full text of DOI:10.1016/j.tetlet.2011.01.036

Tetrahedron Letters 52 (2011) 1202–1204
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Concise, regiocontrolled synthesis of yangjinhualine A
⇑
John Boukouvalas , Lucas C. McCann
Département de Chimie, Université Laval, Quebec City, Que., Canada G1V 0A6
a r t i c l e i n f o
a b s t r a c t
Article history:
The first synthesis of yangjinhualine A, a recently isolated
a,b-disubstituted c-hydroxybutenolide from
Received 26 November 2010
Revised 29 December 2010
Accepted 7 January 2011
Available online 14 January 2011
the Chinese medicinal herb Datura metel L., has been accomplished in concise, entirely regiocont-
rolled fashion through the combined use of Suzuki–Miyaura cross-coupling and 2-silyloxyfuran
oxyfunctionalization.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Dimethyldioxirane
Furan
Lactone
Oxidation
Natural product synthesis
HO
O
Datura metel L. (Solanaceae) is a shrubby perennial herb praised
throughout Southern Asia for its therapeutic benefits.1 In tradi-
tional Chinese medicine, its dried flowers, known as ‘yangjinhua’,
have been prescribed since antiquity as a remedy for asthma,
cough, convulsions, pain, and insanity.1a At present, yangjinhua is
clinically used in China for the treatment of psoriasis.2 Its antipso-
riatic properties were recently shown to reside in the non-alkaloid
fraction which displays strong anti-inflammatory and anti-ana-
phylactic activities.2b,3
O
O
HO
HO
O
O
1
2
R
HO
In 2008, Feng and co-workers reported the isolation of a novel
component of this fraction, named yangjinhualine A (1), along with
some previously known terpenoids.3 Structurally, 1 belongs to a
O
HO
O
O
HO
O
3 R = H
4 R = OH
5
growing family of naturally occurring a,b-disubstituted c-hydroxy-
butenolides4,5 that also includes antrocinnamomin D (2),6 the
microperfuranones (3 and 4)7, and chloraniolide A (5)8 (Fig. 1).
Only minute amounts of 1 could be obtained from the natural
source (0.000027% of dry weight) after multiple chromatography
steps.3 Although its biological effects have yet to be investigated,
Figure 1. Yangjinhualine A (1) and related natural products.
1
2
1
2
2
R
R
R
R
X
R
many
c
-hydroxybutenolides, including antrocinnamomin D (2),6
O
O
O
are known to possess potent anti-inflammatory properties.9 In fact,
a founding member of this class, the marine natural product
manoalide, has been evaluated in phase II clinical trials for the
HO
O
O
O
A
B
C
oxyfunctionalization
cross-coupling
treatment of psoriasis.10 Moreover, several
c-hydroxybutenolides
Scheme 1. Plan for regiocontrolled assembly of A.
are endowed with other significant biological properties,4b includ-
ing antitumor,9b antidiabetic11, and antifungal activities.4c,g
It comes as no surprise, then, that these molecules have at-
tracted considerable attention by the synthetic community.12,13
tuted
c
-hydroxybutenolides is still a challenge,14 as illustrated by
Clive’s synthesis of microperfuranone (3) from phenylsuccinic acid
(6 steps, ca. 1% overall yield), which provides 3 together with its
regiomer 7 (1:1 mixture) via oxidation of furan 6 (Eq. 1).15 As
yet, there have been no other reports on the synthesis of 3 or
any of its relatives depicted in Figure 1.
Even so, regiocontrolled access to unsymmetrically
a,b-disubsti-
⇑
Corresponding author. Tel.: +1 418 656 5473; fax: +1 418 656 7916.
E-mail address: john.boukouvalas@chm.ulaval.ca (J. Boukouvalas).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.036

J. Boukouvalas, L. C. McCann / Tetrahedron Letters 52 (2011) 1202–1204
1203
TBSO
TBSO
d
O
RO
b
a
c
O
O
O
OTIPS
B(OH)
O
O
O
EtO
2
9 R = H
10 R = Tf
12
13
8
11
OTBS
O O
(DMDO)
e
TBSO
HO
HCl
H
OTIPS
O
HO
O
O O
1
14
Scheme 2. Reagents and conditions: (a) (i) Br2, H2O/ice, 0 °C ? rt; (ii) cat. HBr, 100 °C (80%, 2 steps, Ref. 19); (b) Tf2O/Et3N (1.2 equiv each), CH2Cl2, 0 °C ? rt, 2 h (81%); (c) 11
(1.2 equiv), Pd(OAc)2/P(Cy)3 (0.05 equiv each), Na2CO3 (3.0 equiv), THF/H2O (20:1), rt, 3 h (77%); (d) TIPSOTf/Et3N (1.3 equiv each), CH2Cl2, ꢀ78 °C ? rt, 1 h (74%); (e) (i)
DMDO in acetone (ca. 0.07 M, 1.5–2 equiv), CH2Cl2, ꢀ78 °C ? rt; 1 h; (ii) THF/aq 10% HCl (2:1), rt, 18 h (92%, one-pot procedure).
Ph
Ph
Ph
unsymmetrically a,b-disubstituted c-hydroxybutenolides. Further
work in this area is underway and will be reported in due course.
Ph
Ph
Ph
O
HO
O
O
OH
ref. 15
O
6
O
O
ð1Þ
1 : 1
3
7
Acknowledgments
1
O = O /i-Pr NEt or NaClO /NaH PO
2
2
2
4
2
We thank the Natural Sciences and Engineering Research Coun-
cil of Canada (NSERC), the Department of Education of Québec
(FQRNT program), and the FQRNT Centre in Green Chemistry and
Catalysis (CGCC) for financial support.
Clearly, the development of a more utilitarian, potentially
general pathway to these natural products would be worthwhile.
We envisaged that such targets (A) should be accessible with com-
plete regiocontrol from butenolides B by application of our oxy-
functionalization protocol.13a Practical access to B was in turn
envisioned from C (X = Br or OTf)16,17 using cross-coupling tactics18
(Scheme 1).
Described herein is the successful implementation of this strat-
egy to the first synthesis yangjinhualine A (1). As shown in Scheme
2, our endeavor began with the conversion of inexpensive ethyl 2-
methylacetoacetate (8) to methyltetronic acid 9 using the two-step
procedure of Stoltz.19 Treatment of 9 with triflic anhydride and tri-
ethylamine afforded the known triflate 1017a,b in 81% yield after
purification by flash chromatography.20
In keeping with our previous findings on the arylation of 3-chlo-
rotetronic acid triflate,18g the Suzuki–Miyaura coupling of 10 with
commercially available 4-(tert-butyldimethylsilyloxy)phenylbo-
ronic acid (11, Aldrich) proceeded smoothly in the presence of
Pd(OAc)2/P(Cy)3 at room temperature, albeit under slightly modi-
fied conditions (THF–water), to deliver butenolide 12 in a yield of
77%.21
References and notes
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(74%),22 thereby setting the stage for one-pot oxyfunctionalization
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(DMDO)13,23 gave the silyl ester 14, which was not purified but
subjected to the action of aq HCl in THF, to afford after flash chro-
matography racemic yangjinhualine A (1, 92%) whose 1H and 13C
NMR properties24 were in full agreement with those reported for
the natural product.3
In conclusion, the first synthesis of yangjinhualine A has been
accomplished in concise, entirely regiocontrolled fashion from
commercially available starting materials (6 steps, 34% overall
yield). Our synthesis makes this scarce natural product easily
accessible for biological studies and demonstrates the serviceabil-
ity of the general plan outlined in Scheme 1 for constructing
5. Although yangjinhualine A possessed a specific rotation value of [
a]D +5.2 (Ref.
3), -hydroxybutenolides lacking additional asymmetric centers are usually
c
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1204
J. Boukouvalas, L. C. McCann / Tetrahedron Letters 52 (2011) 1202–1204
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20. Data for 10: colorless oil; 1H NMR (400 MHz, CDCl3) d 4.91 (s, 2H), 1.95 (s, 3H);
13C NMR (100 MHz, CDCl3) d 170.4, 160.5, 120.2, 117.1 (q, JCF = 321 Hz), 66.8,
7.7; 19F NMR (376 MHz, CDCl3) d ꢀ73.4; HRMS: Calcd for C6H5F3O5S (m/z):
245.9810, Found: 245.9809. Although this is a known compound, its 13C NMR
data have not been reported (Refs. 17a,b).
13. For our own work on the synthesis of
c-hydroxybutenolides, see: (a)
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6.93 (d, J = 8.8 Hz, 2H), 5.03 (s, 2H), 2.13 (s, 3H), 0.99 (s, 12H), 0.24 (s, 6H); 13
C
NMR (100 MHz, CDCl3) d 176.1, 157.9, 154.6, 129.0, 124.8, 121.0, 70.6, 25.8,
18.5, 10.7, ꢀ4.1; HRMS: Calcd for
C17H24O3Si (m/z): 304.1495, Found:
304.1486.
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6.92 (s, 1H), 6.87 (d, J = 8.8 Hz, 2H), 2.00 (s, 3H), 1.30 (m, 3H), 1.15 (d, J = 7.2 Hz,
18H), 1.03 (s, 9H), 0.25 (s, 6H); 13C NMR (100 MHz, CDCl3) d 154.8, 153.9, 128.6,
128.3, 127.3, 126.9, 120.4, 91.4, 26.0, 18.5, 17.9, 12.6, 8.4, ꢀ4.1; HRMS: Calcd
for C26H44O3Si2 (m/z): 460.2829, Found: 460.2837.
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Morris, K. A.; Vallakati, R.; Zhang, W.; Romo, D. J. Org. Chem. 2009, 74, 4772–
4781.
23. For some related synthetic applications of DMDO, see: (a) Boukouvalas, J.;
Cheng, Y.-X. Tetrahedron Lett. 1998, 39, 7025–7026; (b) Snider, B. B.; Neubert, B.
J. J. Org. Chem. 2004, 69, 8952–8955; (c) Boukouvalas, J.; Xiao, Y.; Cheng, Y.-X.;
Loach, R. P. Synlett 2007, 3198–3200.
24. Data for 1: amorphous solid (mp 210–212 °C); 1H NMR (400 MHz, CD3OD) d
7.52 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.38 (d, J = 1.0 Hz, 1H), 2.06 (d,
J = 1.0 Hz, 3H); 13C NMR (100 MHz, CD3OD) d 175.5, 160.7, 156.8, 131.7, 123.7,
122.6, 116.7, 99.1, 10.6; HRMS: Calcd for C11H10O4 (m/z): 206.0579, Found:
206.0579.