Preparation of the geranyl-α-pyrone (±)-aurantiacone via a new pyrone synthesis

Article abstract of DOI:10.1055/s-2007-967996

The structure of the leaf resin geranyl-α-pyrone auranti-acone isolated from Mimulus (= Diplacus) aurantiacus (Curtis) Jeps. (Scrophulariaceae) was confirmed through synthesis. The key step is lactonization of the sensitive 5-hydroxy-3-oxopent-4-enoic acid under mild conditions, which can be released from the corresponding bispotassium salt. The latter is accessible in a few steps from an N-acyl aziridine and an ethyl acetoacetate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-967996

LETTER
333
Preparation of the Geranyl-a-pyrone (±)-Aurantiacone via a New Pyrone
Synthesis
G
D
eranyl-
a
-pyrone
i
A
urant
ei acone tmar Schmidt, Jürgen Conrad, Iris Klaiber, Sabine Mika, Uwe Beifuss*
Bioorganische Chemie, Institut für Chemie, Universität Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
Fax +49(711)45922951; E-mail: ubeifuss@uni-hohenheim.de
Received 25 September 2006
ment was incorrect. They suggested 2 as the structure of
the natural product which was referred to as aurantiacone.
Abstract: The structure of the leaf resin geranyl-a-pyrone auranti-
acone isolated from Mimulus ( = Diplacus) aurantiacus (Curtis)
Jeps. (Scrophulariaceae) was confirmed through synthesis. The key Biogenetic considerations also support structure 2. Given
step is lactonization of the sensitive 5-hydroxy-3-oxopent-4-enoic
acid under mild conditions, which can be released from the corre-
sponding bispotassium salt. The latter is accessible in a few steps
reacts with geranyl diphosphate, nothing else but 2 can be
from an N-acyl aziridine and an ethyl acetoacetate.
that the biosynthesis of aurantiacone involves a triketo
thioester cyclizing to produce an a-pyrone which then
the correct structure, as 1 cannot be produced by this
pathway.
Key words: hydrolyses, cyclizations, lactones, heterocycles,
natural products
O
O
R1
R1
a
b
Mimulus (= Diplacus) aurantiacus (Curtis) Jeps. (Scro-
phulariaceae) is a chaparral subshrub that mainly occurs
in California. It produces striking amounts of leaf surface
N
+
CO2Et
R2
R2
CO2Et
OH
O
1
3
4
5
resins in excess of 30% of leaf dry weight. This resin is
remarkable since it reduces growth and survival of its pri-
mary herbivore, the larvae of Euphydryas chalcedona. It
2
O
O
OR
O
R1
CO2 K
R1
CO H
R1
O
consists of at least five geranyl flavonoids of known struc-
c
d, e
1
,3
ture. Additional compounds of the leaf surface resins
have been isolated, but their structures have not been
elucidated yet.3
R2
O
K
R2
2
R2
OH
a
6
7
8
9
R = COMe
R = H
OH
Scheme 1 Reagents and conditions: (a) LDA (2 equiv), THF,
78 °C → 0 °C; NH Cl (aq); (b) KOH, EtOH, r.t.; (c) tartaric acid,
–
4
OH
0 °C; (d) Ac O, py, –20 °C → 0 °C; (e) K CO , MeOH, r.t.
2
2
3
O
O
1
OH
In order to confirm the structure of aurantiacone we per-
formed a synthesis of this natural product. The procedure
we applied relies on a method for the preparation of 4-hy-
droxy-2H-pyran-2-ones 9 (Scheme 1), which has recently
been developed in our laboratory. Our protocol is based
on the assembly of 5-hydroxy-3-oxopent-4-enoic acid
OH
O
O
2
5
Figure 1 The two structural proposals for aurantiacone
esters 5 through selective g-acylation of the dianion of
In 1989, Wollenweber et al. were the first to report on the ethyl acetoacetates 4 with N-acyl-2-methyl aziridines 36
and the transformation of 5 into the corresponding stable
bispotassium salts 6. The free 5-hydroxy-3-oxopent-4-
enoic acid 7 is released from 6 by treatment with tartaric
acid and cyclized under mild conditions with acetic an-
hydride–pyridine. The primarily formed O-acetyl deriva-
isolation of a geranyl-a-pyrone from the leaf resin of
Diplacus aurantiacus with a molecular weight of 306.3
Based on the NMR spectroscopic data they proposed
structure 1 but at the same time noted that structure 2 was
also conceivable (Figure 1). Recently, this compound was
again isolated from the leaf resin of Mimulus (= Diplacus)
a
tives 8 are finally hydrolyzed with potassium carbonate to
1
b,c,4
aurantiacus by Hare et al.
Detailed NMR investiga- give the 4-hydroxy-2H-pyran-2-ones 9. In most cases 7
tions led them to conclude that the initial structure assign- can be transformed into 9 in one synthetic step using tri-
fluoroacetic acid–trifluoroacetic anhydride as a reagent.
This method is suitable for the efficient synthesis of 6-
substituted and 3,6-disubstituted 4-hydroxy-2H-pyran-2-
ones. What distinguishes this method is that it employs the
bispotassium salts 6 of 5-hydroxy-3-oxopent-4-enoic
SYNLETT 2007, No. 2, pp 0333–0335
Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-967996; Art ID: G29106ST
0
1.
0
2.
2
0
0
7
©
Georg Thieme Verlag Stuttgart · New York

3
34
D. Schmidt et al.
LETTER
acids as a stable and easy to purify storage option for 5- Though not isolated, 6a was then treated with aqueous tar-
hydroxy-3-oxopent-4-enoic acids 7. If needed, 6 can be taric acid solution to yield the free 5-hydroxy-3-oxopent-
used to generate the very sensitive free 5-hydroxy-3-oxo- 4-enoic acid 7a. The latter was then reacted with acetic
pent-4-enoic acids 7, which in turn can be lactonized to anhydride–pyridine at temperatures between –20 °C and
give the substituted 4-hydroxy-2H-pyran-2-ones 9.
0 °C to produce the O-acetyl derivative 8a. Conversion of
a with potassium carbonate in methanol delivered the
8
In order to synthesize aurantiacone 2 the 5-hydroxy-3-
oxopent-4-enoic acid ester 5a was prepared according to
substituted 4-hydroxy-2H-pyran-2-one 9a with 76% yield
9
6
(4 steps). The final cleavage of the silyl ether supplied 2
Lygo’s method by reacting the dianion of the 2-geranyl
in 90% yield. Starting from 3a and 4a the natural product
2 was synthesized in over six steps with an overall yield
of 68%.
substituted ethyl acetoacetate 4a with the N-acyl-2-
7
methyl aziridine 3a in 99% yield (Scheme 2).
As the structure of our synthetic sample is beyond doubt10
and in agreement with that proposed by Hare et al. we can
O
4
a
TBDMSO
N
+
99%
validly conclude that the structure of aurantiacone is that
shown in 2.
CO2Et
O
O
3a
4a
References and Notes
(
(
(
1) (a) Lincoln, D. E. Biochem. Syst. Ecol. 1980, 8, 397.
(b) Hare, J. D. Biochem. Syst. Ecol. 2002, 30, 281. (c)Hare,
J. D. Biochem. Syst. Ecol. 2002, 30, 709.
TBDMSO
TBDMSO
b
c
CO2Et
OH
2) (a) Lincoln, D. E. J. Chem. Ecol. 1985, 11, 1459.
5
6
7
a
a
a
(
b) Lincoln, D. E.; Newton, T. S.; Ehrlich, P. R.; Williams,
O
K. S. Oecologia 1982, 52, 216.
3) (a) Wollenweber, E.; Schober, I.; Schilling, G.; Arriaga-
Giner, F. J.; Roitman, J. N. Phytochemistry 1989, 28, 3493.
CO2
K
(
1
b) Lincoln, D. E.; Walla, M. D. Biochem. Syst. Ecol. 1986,
4, 195.
O
K
(
(
4) Hare, J. D.; Borchardt, D. B. Phytochemistry 2002, 59, 375.
5) Schmidt, D.; Conrad, J.; Klaiber, I.; Beifuss, U. Chem.
Commun. 2006, 4732.
O
(
(
6) Lygo, B. Tetrahedron 1995, 51, 12859.
TBDMSO
d, e
6%
7) Selected data for 3a (mixture of two diastereomers D1 and
D2): IR (ATR): 2957, 2929, 2856, 1696, 1471, 1405, 1374,
CO2H
OH
7
–
1
1
(
255, 1179, 1134, 1076, 1002, 832, 810, 774 cm . UV
1
MeCN): lmax (log e) = 243 (2.55) nm. H NMR (500 MHz,
*
*
CDCl ): d = 0.01 (s, 3 H, SiCH ), 0.02 (s, 3 H, SiCH ), 0.07
3
3
3
OR
*
*
(
s, 6 H, 2 × SiCH ), 0.858 [s, 9 H, SiC(CH ) ], 0.861 [s, 9
* 3 *
3
3 3
TBDMSO
H, SiC(CH ) ], 1.197 (d, J = 6.1 Hz, 3 H, 4-H ), 1.202 (d,
3
3
3
f
0%
3
*
3
J = 6.1 Hz, 3 H, 4-H ), 1.31 (d, J = 5.3 Hz, 3 H, 2¢-CH ,
3
3
9
3
3
O
O
D1), 1.32 (d, J = 5.2 Hz, 3 H, 2¢-CH , D2), 1.917 (d, J = 3.1
3
3
8
9
a
a
R = COMe
R = H
Hz, 1 H, 3¢-H , D2), 1.925 (d, J = 2.9 Hz, 1 H, 3¢-H , D1),
A
A
3
3
2.37 (d, J = 5.9 Hz, 1 H, 3¢-H , D2), 2.38 (d, J = 6.2 Hz, 1
B
2
3
*
H, 3¢-H , D1), 2.43 (dd, J = 9.7 Hz, J = 5.3 Hz, 1 H, 2-H ),
B
A
2
3
*
OH
2.45 (dd, J = 9.3 Hz, J = 5.0 Hz, 1 H, 2-H ), 2.53
A
(
(
2
overlapped, 2¢-H, D1), 2.56 (overlapped, 2-H¢, D2), 2.59
* 2 3
OH
overlapped, 2-H ), 2.61 (dd, J = 10.1 Hz, J = 7.7 Hz, 1 H,
B
*
13
-H ), 4.29–4.37 (m, 1 H, 3-H). C NMR (125 MHz,
B
O
O
*
*
CDCl ): d = –4.79 (2 × SiCH ), –4.73 (SiCH ), –4.71
(SiCH ), 17.72, 17.79 (2¢-CH ), 17.92, 17.94 [SiC(CH ) ],
2
3
4
3
3
3
*
*
*
2
3
3
3 3
*
3.92, 23.96 (C-4), 25.79 [SiC(CH ) ], 31.12 (C-3¢, D1),
3 3
Scheme 2 Reagents and conditions: (a) LDA (2 equiv), THF,
78 °C → 0 °C, 3 h; NH Cl (aq); (b) KOH, EtOH, r.t., 3 h; (c) tartaric
1.69 (C-3¢, D2), 32.18 (C-2¢, D2), 32.72 (C-2¢, D1), 47.44,
–
4
*
*
*
7.23 (C-2), 66.09, 66.17 (C-3), 183.68, 183.71 (C-1). MS
acid, 0 °C, 10 min; (d) Ac O, py, –20 °C → 0 °C, 1 h; (e) K CO ,
2
2
3
+
+
(
EI, 70 eV): m/z (%) = 257.0 (<1%) [M ], 242.0 (7) [M –
MeOH, r.t., 2 h; (f) py·HF complex, THF, r.t., 12 h
+
+
CH ], 199.9 (100) [M – C H ], 142.9 (20) [M – C H Si],
1
3
4
9
6
14
+
+
*
13.9 (35) [C H Si ], 74.9 (30) [C H OSi ]. Unambiguous
6 17 2 7
The N-acyl-2-methyl aziridine 3a was obtained through
the conversion of 2-methyl aziridine and the correspond-
ing carboxylic acid via DCC–DMAP activation in 83%
yield. The substituted acetoacetate 4a is accessible via
alkylation of ethyl acetoacetate with geranyl chloride in
assignment was not possible.
8) Selected data for 5a (mixture of four isomers; for details see
(
Figure 2): IR (ATR): 2928, 2856, 1738, 1601, 1444, 1375,
–
1
1255, 1132, 1096, 997, 834, 810, 775 cm . UV (MeOH):
1
lmax (log e) = 280 (3.92) nm. Tautomer T1: H NMR (500
*
MHz, CDCl ): d = 0.002 (s, 6 H, 2 × SiCH ), 0.04 (s, 6 H,
3
3
9
1% yield. 5-Hydroxy-3-oxopent-4-enoic acid ethyl ester
*
*
2
× SiCH ), 0.855 [s, 9 H, SiC(CH ) ], 0.858 [s, 9 H,
* 3
3
3 3
8
5
a was transformed to produce the bispotassium salt 6a.
SiC(CH ) ], 1.19 (d, J = 6.1 Hz, 3 H, 3¢¢-H ), 1.25 (t,
3
3
3
Synlett 2007, No. 2, 333–335 © Thieme Stuttgart · New York

LETTER
Geranyl-a-pyrone Aurantiacone
335
O
3
(9) Synthesis of 9a from 5a: A solution of 5a (3.46 g, 7.43
1
'
5'
3'
7'
mmol) in EtOH (15 mL) was treated with a solution of KOH
2.43 g, 41.0 mmol) in anhyd EtOH (30 mL) at r.t. and the
2
TBDMSO
''
4
(
2'
4'
6'
8'
1
CO2Et
resulting mixture was stirred for 3 h at r.t. The volatiles were
2
OH
5
3''
1''
removed in vacuo, the residue dissolved in distilled H O (ca.
2
3
0 mL) and then poured into a vigorously stirred mixture of
T1 (exists as a mixture of two diastereomers D1 and D2)
CH Cl (300 mL at –20 °C) and aq tartaric acid solution
2
2
O
(10%, 200 mL at 4 °C). The reaction mixture was stirred for
10 min and the precipitated potassium hydrogen tartrate was
1
'
5'
3'
7'
2
TBDMSO
''
4
3
filtered off. The filter cake was washed with CH Cl (100
2'
4'
6'
8'
2
2
1
CO2Et
mL at –20 °C), the filtrates were combined and the organic
phase was separated. The aqueous phase was saturated with
solid NaCl and extracted twice with cold CH Cl . The
2
O
5
3''
1''
2
2
T2 (exists as a mixture of two diastereomers D3 and D4)
organic phases were combined and dried over MgSO and
4
the volatiles were removed in vacuo (heating bath
temperature: max. 5 °C). The crude product was
Figure 2 Compound 5a exists as a mixture of
isomers in CDCl3
immediately dissolved in cold Ac O (30 mL at –20 °C).
2
Then pyridine (1 mL) was added and the resulting mixture
3
*
3
J = 7.1 Hz, 3 H, CO CH CH ), 1.27 (t, J = 7.1 Hz, 3 H,
was stirred for 2 h at 0 °C. The excess Ac O was removed in
2
2
3
2
*
CO CH CH ), 1.59 (s, 3 H, 7¢-CH ), 1.63 (s, 3 H, 3¢-CH ),
1
2
vacuo without heating and the residue was dissolved in
MeOH (50 mL). After addition of K CO (5.67 g, 41.0
2
2
3
3
3
.68 (s, 3 H, 8¢-H ), 1.94–2.00 (m, 2 H, 4¢-H ), 2.01–2.08 (m,
3 2
2 3 *
2
3
H, 5¢-H ), 2.34 (dd, J = 13.5 Hz, J = 5.0 Hz, 1 H, 1¢¢-H ),
mmol) the mixture was stirred for 2 h at r.t. The volatiles
were removed in vacuo and the residue was dissolved in
2
2
A
3
*
2
.35 (dd, J = 13.5 Hz, J = 5.0 Hz, 1 H, 1¢¢-H ), 2.40 (dd,
A
2
3
*
J = 13.7 Hz, J = 7.8 Hz, 1¢¢-H ), 2.46–2.53 (overlapped,
distilled H O (200 mL). The mixture was acidified with
B
2
m, 1 H, 1¢-H ), 2.59–2.67 (overlapped, m, 1 H, 1¢-H ), 3.26
(
Hz, 1 H, J = 6.8 Hz, 1 H, 2-H) , 4.14–4.20 (overlapped, 2 H,
glacial AcOH to pH 3, saturated with solid NaCl and
A
B
3
3
*
3
dd, J = 4.3 Hz, J = 6.8 Hz, 1 H, 2-H), 3.27 (dd, J = 4.3
extracted with CH Cl (3 ×). The combined organic phases
2
2
3
*
were washed twice with H O and dried over MgSO . The
2
4
OCH ), 4.18–4.30 (m, 1 H, 2¢¢-H), 5.02–5.09 (m, 2 H, 2¢-H,
volatiles were removed in vacuo (traces of AcOH were
removed azeotropically with toluene) and the residue was
2
*
*
6
¢-H), 5.621 (s, 1 H, 4-H), 5.623 (s, 1 H, 4-H), 15.19 (br s,
13
1
H, enolic H). C NMR (125 MHz, CDCl ): d = –5.11 (2 ×
submitted to flash chromatography (SiO ; PE–EtOAc, 8:2).
3
2
SiCH ), –4.71 (SiCH ), –4.69 (SiCH ), 14.09
Pyrone 9a (2.38 g, 76%) was obtained as a colorless oil that
3
3
3
(
[
[
4
CO CH CH ), 16.10 (3¢-CH ), 17.60 (7¢-CH ), 17.96
solidified on storage at –20 °C.
2
2
3
3
3
*
SiC(CH ) ], 24.10, 24.12 (C-3¢¢) , 25.60 (C-8¢), 25.72
(10) Selected data for 2: IR (ATR): 2965, 2913, 2726, 1667,
3
3
*
–1
SiC(CH ) ], 26.57 (C-5¢), 27.84, 28.00 (C-1¢) , 39.67 (C-
1579, 1431, 1409, 1273 cm . UV (MeOH): l (log e) =
3
3
max
*
*
1
¢), 47.79, 47.83 (C-1¢¢), 55.97, 56.03 (C-2), 61.21, 61.23
224 (4.21), 335 (4.40) nm. H NMR (500 MHz, CD OD):
3
*
*
3
(OCH ), 66.21 (C-2¢¢), 100.47, 100.54 (C-4), 119.78,
d = 1.23 (d, J = 6.2 Hz, 3 H, 3¢¢-H ), 1.58 (s, 3 H, 7¢-CH ),
2
3
3
*
*
1
7
1
19.83 (C-2¢) , 123.97, 124.01 (C-6¢), 131.44, 131.50 (C-
1.64 (s, 3 H, 8¢-H ), 1.73 (s, 3 H, 3¢-CH ), 1.94–1.99 (m, 2 H,
3
3
*
*
*
2
¢), 138.28, 138.31 (C-3¢), 169.87, 169.88 (C-1), 188.87,
4¢-H ), 2.03–2.10 (m, 2 H, 5¢-H ), 2.53 (dd, J = 14.4 Hz,
2 2
2 3
*
1
3
89.06 (C-5), 192.3 (C-3). Tautomer T2: H NMR (500
J = 7.7 Hz, 1 H, 1¢¢-H ), 2.58 (dd, J = 14.5 Hz, J = 5.3 Hz,
A
3
MHz, CDCl ): d = 2.52 (overlapped, 1¢¢-H ), 2.57
1 H, 1¢¢-H ), 3.08 (d, J = 7.2 Hz, 2 H, 1¢-H ), 4.08–4.15 (m,
B 2
3
3
A
(
overlapped, 2 H, 1¢-H ), 2.69 (overlapped, 1¢¢-H ), 3.56 (t,
1 H, 2¢¢-H), 5.07 (br t, J = 7.0 Hz, 1 H, 6¢-H), 5.17 (br t,
3 13
2
*
B
3
3
*
J = 7.5 Hz, 1 H, 2-H), 3.57 (t, J = 7.5 Hz, 1 H, 2-H), 3.61
J = 7.0 Hz, 1 H, 2¢-H), 6.06 (s, 1 H, 5-H). C NMR (125
MHz, CD OD): d = 16.27 (3¢-CH ), 17.71 (7¢-CH ), 22.79
2
(
d, J = 15.8 Hz, 1 H, 4-H , D3), 3.70 (s, 2 H, 4-H , D4), 3.77
A
2
3
3
3
2
(
d, J = 15.8 Hz, 1 H, 4-H , D3), 4.28 (overlapped, 2¢¢-H).
(C-1¢), 23.39 (C-3¢¢), 25.86 (C-8¢), 27.68 (C-5¢), 40.84 (C-
4¢), 44.01 (C-1¢¢), 66.19 (C-2¢¢), 102.92 (C-5), 103.63 (C-3),
122.44 (C-2¢), 125.38 (C-6¢), 132.08 (C-7¢), 136.54 (C-3¢),
162.29 (C-6), 167.41 (C-4), 168.62 (C-2). MS (EI, 70 eV):
B
1
3
C NMR (125 MHz, CDCl ): d = 26.82 (C-1¢), 39.64 (C-4¢),
3
*
*
5
(
1
(
7.32, 57.36 (C-4), 52.83 (C-1¢¢), 59.49, 59.47 (C-2), 65.38
*
C-2¢¢), 119.34, 119.36 (C-2¢), 138.34 (C-3¢), 169.57 (C-1),
+
+
99.03 (C-3), 202.73 (C-5). MS (EI, 70 eV): m/z (%) = 466.0
m/z (%) = 306 (41) [M ], 237 (28) [M – C H O], 183 (36)
4 5
+
+
+
+
15) [M ]. HRMS: m/z calcd for C H O Si: 466.31027;
[M – C H ], 139 (80) [M – C H O ], 123 (52) [C H ],
4 15 2 9 15
2
6
46
5
10 15
+
*
+
found: 466.30818. Unambiguous assignment was not
possible.
69 (100) [C H O ], 41 (90) [C H ].
4 3 3 6
Synlett 2007, No. 2, 333–335 © Thieme Stuttgart · New York

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