Synthesis of yangjinhualine A

Article abstract of DOI:10.1055/s-0034-1379582

Selective reduction of 3-(4-hydroxyphenyl)-2-methylmaleic anhydride provides access the corresponding γ-hydroxybutenolide natural product yangjinhualine A.

Full text of DOI:10.1055/s-0034-1379582

SYNTHESIS
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1
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 485–488
paper
485
P. S. Deore et al.
Paper
Synthesis
Synthesis of Yangjinhualine A
Prashant S. Deore
Ramesh U. Batwal
Narshinha P. Argade*
OH
OH
O
HO
O
HO
3 steps
25%
+
Division of Organic Chemistry, National Chemical Laboratory
(CSIR), Pune 411 008, India
O
np.argade@ncl.res.in
O
HO
yangjinhualine A
O
Received: 15.08.2014
Accepted after revision: 30.10.2014
Published online: 09.12.2014
HO
HO
DOI: 10.1055/s-0034-1379582; Art ID: ss-2014-n0516-op
Abstract Selective reduction of 3-(4-hydroxyphenyl)-2-methylmaleic
anhydride provides access the corresponding γ-hydroxybutenolide nat-
ural product yangjinhualine A.
HO
O
O
OH
O
O
yangjinhualine A (1a)
microperfuranone (2)
Key words anhydrides, regioselectivity, reduction, lactones, natural
products
O
HO
Maleic anhydride, γ-hydroxybutenolide, and butenolide
are common structural motifs present in many natural
products that display a broad range of biological proper-
ties.1,2 Five representative examples of lactol-bearing bioac-
tive natural products are shown in Figure 1.3 Compounds of
this type exhibit ring–chain tautomerism, so that even in
nature they exist in racemic form at the γ-position. Few
methods are known for the synthesis of γ-hydroxybuteno-
lides of this type. Most of the existing methods are based on
the condensation of glyoxylic acid with aldehydes or esters
bearing active α-hydrogen atoms,2b,4 oxyfunctionalization
of 2-(silyloxy)furans,5 oxidation of furans,6 or γ-hydroxyl-
ation reactions.7
HO
O
O
OH
O
O
chloraniolide A (4)
antrocinnamomin D (3)
H
OH
O
O
cacospongionolide C (5)
Figure 1 Naturally occurring bioactive lactols
Datura metel is one of the 50 basic herbs used in tradi-
tional Chinese medicine, in which it is called yangjinhua.8
Recently, yangjinhua has been used clinically in China for
treatment of psoriasis.9 However, ingestion of D. metel in
any form is dangerous and requires extreme caution.10 The
principal toxic elements are tropane alkaloids that can lead
to severe side effects.11 In 2008, Feng and co-workers re-
ported the isolation of very small amounts (0.000027% by
dry weight) of yangjinhualine A (1a) from the dried flowers
of D. metel.3a Recently, Ding and co-workers also isolated
this natural product from Streptomyces species YIM66017.12
A 2,2-diphenyl-1-picrylhydrazyl radical-scavenging assay
for yangjinhualine A showed activity with an IC50 value of
57.12 μg/mL. Only one synthesis of this natural product has
been reported in the literature.5b This was accomplished by
a strategy involving a Suzuki–Miyaura cross-coupling and
2-(silyloxy)furan oxyfunctionalization. Regioselective con-
trolled reduction of the corresponding nonsymmetrical
maleic anhydrides or the controlled oxidation of the corre-
sponding butenolides is a challenging task in the synthesis
of naturally occurring lactols. In this context, we report a
simple approach to yangjinhualine A.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 485–488

486
P. S. Deore et al.
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Synthesis
OAc
aq 2 M HCl–THF (1:1)
OH
O
O
O
NaOAc, AcOH–Ac2O (1:1)
OH
O
reflux, 3 h
25 °C, 6 h
HO
+
O
O
87%
63%
HO
O
O
O
6
7
8
9
Scheme 1 Preparation of essential aryl(methyl)maleic anhydrides
In a continuation of our studies on the synthesis of an-
hydride- and butenolide-based bioactive natural prod-
ucts,13 we surmised that 3-(4-hydroxyphenyl)-4-methylfu-
ran-2,5-dione (9) might be a potential precursor to yangjin-
hualine A. As shown in Scheme 1, the sodium acetate–
acetic anhydride-mediated dehydrative intermolecular con-
densation of (4-hydroxyphenyl)acetic acid (6) with pyruvic
acid (7), followed by concomitant intramolecular cycliza-
yield, respectively. The structures of regioisomers 1a and 1b
were assigned by means of H NMR spectroscopy. As a re-
1
sult of conjugation with the 4-hydroxyphenyl group, the
lactol carbon in product 1b was expected to be relatively
more electron rich than that in 1a. As expected, the
methine proton in the natural product 1a (δ = 6.39) was
more deshielded than that in the nonnatural product 1b
(δ = 5.95).
tion,
gave
4-(4-methyl-2,5-dioxo-2,5-dihydrofuran-3-
Finally, this structural assignment was confirmed by
comparison with the reported data for the natural product
1a. The hydroxy anhydride 9, on treatment with DIBAL-H,
gave a mixture of the desired natural product yangjinhual-
ine A (1a) and isoyangjinhualine A (1b) directly. Column
chromatographic separation of the resulting mixture on sil-
ica gel gave products 1a and 1b in a ~3:2 ratio and 76% total
yield. For electronic reasons, DIBAL-H preferentially forms a
complex with the unhindered carbonyl group, which is
more electron rich as a result of the electron-donating me-
someric effect of the hydroxyl group. As a result, reduction
occurs preferentially at this carbonyl group through intra-
molecular delivery of the hydride to give the lactol 1a in
46% yield. However, lowering the reaction temperature to
−78 °C did not improve the regioselectivity or yield from ei-
ther substrate. The analytical and spectral data for the syn-
thesized natural product yangjinhualine A (1a) were in
complete agreement with the reported data.3a,5b,12 Starting
from (4-hydroxyphenyl)acetic acid, natural yangjinhualine
A (1a) and nonnatural isoyangjinhualine A (1b) were ob-
tained in three steps and 25% and 33% overall yields, re-
spectively (an average of a 65% yield each step for 1a and a
70% yield for each step for 1b). Oxidation of 11 and 1b to the
corresponding anhydrides should provide an effective strat-
egy for recycling the undesired regioisomer.17
yl)phenyl acetate (8) in 63% yield.14 Deacylation of anhy-
dride 8 with 2 M hydrochloric acid in tetrahydrofuran gave
the desired 3-(4-hydroxyphenyl)-4-methylfuran-2,5-dione
(9) in 87% yield.
Regioselective reduction of anhydrides 8 and 9 by four
different reducing agents was examined.15,16 Reductions of
anhydrides 8 and 9 by sodium triacetoxyborohydride, lithi-
um tri-tert-butoxyaluminum hydride, or sodium tri(sec-bu-
tyl)borohydride showed poor selectivity and gave mixtures
of the corresponding products 10 and 11 or 1a and 1b, re-
spectively (Scheme 2); these products could be separated
by column chromatography. However, comparatively good
results were obtained by using diisobutylaluminum hy-
dride (DIBAL-H) as the reducing agent at –40 to 25 °C.
Treatment of the acetoxy anhydride 8 with DIBAL-H gave a
mixture of products 10 and 11 (Scheme 2). Separation of
this mixture by column chromatography on silica gel gave
10 and 11 in a ~1:3 ratio and 81% total yield. For steric and
electronic reasons, reduction by DIBAL-H occurs mainly at
the unhindered anhydride carbonyl group, which is more
reactive as a result of the electron-withdrawing inductive
effect of the acetate group, giving lactol 11 in 61% yield. Fur-
ther acetate deprotection in compounds 10 and 11 by using
2 M hydrochloric acid gave the desired product yangjin-
hualine A (1a) and isoyangjinhualine A (1b) in 92% and 85%
OAc
OAc
(for R = Ac)
DIBAL-H, THF
OH
+
OH
OR
(for R = H)
HO
O
O
HO
O
O
O
O
DIBAL-H, THF
– 40 °C to 25 °C, 2 h
– 40 °C to 25 °C, 2 h
+
O
O
O
10/11 = 1:3, 81%
1a/1b = 3:2, 76%
O
HO
O
HO
10
11
yangjinhualine A (1a) isoyangjinhualine A (1b)
8 R = Ac
9 R = H
Scheme 2 Regioselective reduction of anhydrides: synthesis of yangjinhualine A (1a) and isoyangjinhualine A (1b)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 485–488

487
P. S. Deore et al.
Paper
Synthesis
In summary, we have demonstrated a new route to bio-
active natural product yangjinhualine A by using regiose-
lective reduction of the corresponding aryl(methyl)maleic
anhydride as a key step. The demonstrated balance be-
tween the steric and electronic factors in the reported re-
gioselective reduction reactions of aryl(methyl)maleic an-
hydrides is noteworthy from the point of view of basic
chemistry. We foresee that the present approach might be
useful in obtaining several complex bioactive natural and non-
natural products for structure–activity relationship studies.
MS (ESI): m/z = 205 [M + H]+.
Lactols 1a, 1b, 10, and 11; General Procedure
A 1 M solution of DIBAL-H in toluene (0.18 mL, 0.18 mmol) was added
dropwise over 10 min to a stirred solution of anhydride 8 or 9 (74/60
mg, 0.15 mmol) in anhydrous THF (5 mL) at −40 °C. The mixture was
stirred at –40 °C for 1 h and then at 25 °C for 1 h. The reaction was
quenched with H2O (5 mL) and the mixture was extracted with EtOAc
(3 × 10 mL). The organic layers were combined, washed with brine
(20 mL), dried (Na2SO4), and concentrated in vacuo to give mixture of
products 10 and 11 or 1a and 1b, respectively. This residue was puri-
fied by column chromatography [silica gel, PE–EtOAc (3:1 or 3:2, re-
spectively)] to give pure products 10 and 11 in a 1:3 ratio or products
1a and 1b in a 3:2 ratio, respectively.
Melting points are uncorrected. The 1H NMR spectra were recorded
on a Bruker AV 200 MHz NMR spectrometer and a Bruker AV 400
MHz NMR spectrometer with TMS as an internal standard. The 13C
NMR spectra were recorded on a Bruker AV 200 MHz NMR spectrom-
eter (50 MHz) and a Bruker AV 400 MHz NMR spectrometer (100
MHz). Mass spectra were recorded on a Thermo Finnigan TOF mass
spectrometer. High-resolution mass spectra (ESI) were recorded on a
Thermo Scientific Q Exactive hybrid quadrupole Orbitrap spectrome-
ter with a TOF mass analyzer. IR spectra were recorded on a Bruker
ALPHA FT-IR spectrophotometer. Column chromatographic separa-
tions were carried out on silica gel (60–120 or 200–400 mesh). Com-
mercially available pyruvic acid, 4-HOC6H4CH2CO2H, NaBH(OAc)3,
Li(t-BuO)3AlH, NaB[s-Bu]3H, and DIBAL-H were used.
4-(2-Hydroxy-4-methyl-5-oxo-2,5-dihydrofuran-3-yl)phenyl Ace-
tate (10)
White solid; yield: 15 mg (20%); mp 133–135 °C.
IR (neat): 3328, 1738 cm–1
.
1H NMR (200 MHz, CD3OD): δ = 2.08 (d, J = 2 Hz, 3 H), 2.30 (s, 3 H),
6.44 (s, 1 H), 7.25 (d, J = 8 Hz, 2 H), 7.69 (d, J = 8 Hz, 2 H).
13C NMR (50 MHz, CD3OD): δ = 10.3, 20.9, 99.2, 123.3, 126.1, 130.1,
131.0, 153.3, 155.9, 170.8, 174.7.
HRMS (ESI): m/z [M + H]+ calcd for C13H13O5: 249.0757; found:
249.0760.
4-(4-Methyl-2,5-dioxo-2,5-dihydrofuran-3-yl)phenyl Acetate (8)
4-(5-Hydroxy-4-methyl-2-oxo-2,5-dihydrofuran-3-yl)phenyl Ace-
tate (11)
NaOAc (123 mg, 1.50 mmol) was added to a stirred solution of 4-
HOC6H4CH2CO2H (6, 152 mg, 1.00 mmol) and pyruvic acid (7, 0.083
mL, 1.20 mmol) in a mixture of AcOH (1.50 mL) and Ac2O (1.50 mL) at
r.t. The mixture was then refluxed for 3 h under argon. A mixture of
AcOH and Ac2O was distilled off under vacuum, H2O (5 mL) was add-
ed, and the mixture was extracted with EtOAc (3 × 10 mL). The organ-
ic layers were combined, washed with brine (20 mL), dried (Na2SO4),
and concentrated in vacuo. The residue was purified by column chro-
matography [silica gel; PE–EtOAc (4:1)] to give a white solid; yield:
155 mg (63%); mp 102–105 °C.
White solid; yield: 45 mg (61%); mp 84–86 °C.
IR (neat): 3225, 1749, 1700, 1644, 1602 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 2.19 (s, 3 H), 2.32 (s, 3 H), 4.60 (br s, 1
H), 5.98 (s, 1 H), 7.16 (d, J = 8 Hz, 2 H), 7.50 (d, J = 8 Hz, 2 H).
13C NMR (50 MHz, CDCl3): δ = 12.5, 21.1, 98.2, 121.7, 126.9, 127.6,
130.1, 150.7, 157.6, 169.7, 171.4.
MS (ESI): m/z = 271 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C13H12NaO5: 271.0577; found:
271.0571.
IR (neat): 1751, 1655, 1600 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 2.33 (s, 3 H), 2.35 (s, 3 H), 7.28 (d, J = 10
Hz, 2 H), 7.72 (d, J = 10 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 10.9, 21.1, 122.4, 125.0, 130.9, 138.6,
5-Hydroxy-4-(4-hydroxyphenyl)-3-methylfuran-2(5H)-one (1a;
Yangjinhualine A)
White solid; yield: 28 mg (46%); mp 209–211 °C (Lit.5b 210–212 °C).
139.0, 152.6, 164.8, 166.1, 168.9.
HRMS (ESI): m/z [M + H]+ calcd for C13H11O5: 247.0601; found:
247.0601.
IR (neat): 3274, 1680, 1632, 1604 cm–1
.
1H NMR (200 MHz, CD3OD): δ = 2.07 (d, J = 2 Hz, 3 H), 6.39 (s, 1 H),
6.89 (d, J = 8 Hz, 2 H), 7.54 (d, J = 8 Hz, 2 H).
13C NMR (50 MHz, CD3OD): δ = 10.5, 99.1, 116.6, 122.6, 123.7, 131.6,
3-(4-Hydroxyphenyl)-4-methylfuran-2,5-dione (9)
A solution of anhydride 8 (123 mg, 0.50 mmol) in THF (2 mL) and 2 M
aq HCl (2 mL) was stirred at 25 °C for 6 h. The solution was then dilut-
ed with H2O (5 mL) and extracted with EtOAc (3 × 10 mL). The organic
layers were combined, washed with brine (20 mL), dried (Na2SO4),
and concentrated in vacuo. The residue was purified by column chro-
matography [silica gel, PE–EtOAc (2:1)] to give a white solid; yield: 89
mg (87%); mp 166–168 °C.
156.8, 160.6, 175.4.
MS (ESI): m/z = 207 [M + H]+.
Compound 1a was also obtained in 92% yield (38 mg) from 10 (50 mg,
0.20 mmol) by using the same procedure as described for the prepa-
ration of 9.
IR (neat): 3364, 1820, 1748, 1635, 1604 cm–1
.
5-Hydroxy-3-(4-hydroxyphenyl)-4-methylfuran-2(5H)-one (1b;
Isoyangjinhualine A)
1H NMR (400 MHz, CDCl3): δ = 2.31 (s, 3 H), 5.38 (s, 1 H), 6.97 (d, J = 8
Hz, 2 H), 7.65 (d, J = 8 Hz, 2 H).
13C NMR (100 MHz, CD3OD): δ = 10.8, 116.7, 120.5, 132.6, 136.7,
White solid; yield: 18 mg (30%); mp 127–129 °C.
IR (neat): 3253, 1734, 1667, 1605 cm–1
.
140.3, 161.3, 167.0, 168.2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 485–488

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P. S. Deore et al.
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Synthesis
1H NMR (400 MHz, CD3OD): δ = 2.13 (s, 3 H), 5.95 (s, 1 H), 6.84 (d, J = 8
Hz, 2 H), 7.34 (d, J = 8 Hz, 2 H).
13C NMR (100 MHz, CD3OD): δ = 12.6, 99.8, 116.2, 122.0, 128.9, 131.5,
157.6, 159.1, 173.4.
HRMS (ESI): m/z (%) [M + H]+ calcd for C11H11O4: 207.0652; found:
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Compound 1b was also obtained in 85% yield (35 mg) from 11 (50 mg,
0.20 mmol) by using the same procedure as described for the prepa-
ration of 9.
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P.S.D. and R.U.B. thank CSIR, New Delhi, and UGC, New Delhi, respec-
tively, for the awards of research fellowships. N.P.A. thanks the De-
partment of Science and Technology, New Delhi, for financial support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379582.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 485–488