Total syntheses of daldiniapyrone, annularin B, and (±)-annularin F

Article abstract of DOI:10.1055/s-2006-942355

The first concise total syntheses of daldiniapyrone, annuarin B, and (±)-annularin F are described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942355

PAPER
1787
Total Syntheses of Daldiniapyrone, Annularin B, and (±)-Annularin F
a
a
b
T
A
otal
S
yntheses of
l
D
aldin
e
iapyrone,
A
k
nnularin B,
s
and
(
±
)-A
e
nnularinFy V. Kurdyumov, R. Lizeth P. Muñoz, Richard P. Hsung*
a
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, Madison, WI 53705, USA
Fax +1(608)2625345; E-mail: rphsung@pharmacy.wisc.edu
b
Received 19 December 2005; revised 18 January 2006
by using higher temperatures produced mainly the self-
condensation product of 5a–c. Use of Lewis acid, such as
Abstract: The first concise total syntheses of daldiniapyrone, annu-
larin B, and (±)-annularin F are described.
ZnBr , did not notably improve the yield. Other attempts
2
Key words: pyrones, malonic chloride condensation, selenium ox-
idation, daldiniapyrone, annularins
9
such as deprotonation-alkylation at the C-7 position of 6a
or 7a also failed to give 6b,6c or 7b and 1. The synthesis
of daldiniapyrone (1) was ultimately completed through
treating 2-pyrone 6c with methyl sulfate and K CO in re-
2
3
Pyrones are among the most important heterocyclic struc-
tures in medicinal and natural product chemistry, and spe-
cifically, 4-hydroxy-2-pyrones (or a-pyrones) can be
found in a wide range of medicinally significant natural
fluxing acetone. The spectroscopic data of synthetic dal-
diniapyrone are identical to the reported values.4
The ester group in 4-hydroxy-2-pyrone 6b was subse-
1
–3
4
quently reduced by using BH ⋅Me S at room temperature
products. Daldiniapyrone (1) was isolated from organ-
3
2
8
for two hours and the resulting alcohol 8 was selectively
O-methylated to afford annularin B (2) (Scheme 2). Syn-
thetic annularin B also gave spectroscopic data that are
identical to the reported data.5
ic extracts of fruit bodies of Daldinia concentria collected
5
in Europe. Annularins B (2), C (3) and F (4) were isolated
from a fresh water fungus Annulatascus triseptatus, and
were reported to possess antibacterial properties. Herein,
we report the first total syntheses of daldiniapyrone, annu- We then investigated the application of this methodology
larin B, and (±)-annularin F.
to the synthesis of annularins (i.e., C and F). Allylic
oxidation at C-7 of 7a was best accomplished using 5.0
10
Despite numerous known pathways,6,7 condensation of
8
equivalents of SeO in dioxane at 150 °C in a sealed tube
malonyl dichloride with b-keto esters 5a–c still remains
2
for two days. Under these conditions, 4-methoxy-2-py-
rone 7a was completely consumed at the end of the reac-
tion and the only isolatable product was aldehyde 9.
to be the more straightforward and economical method for
the preparation of 4-hydroxy-2-pyrones 6a–c (Scheme 1).
Our own attempts to modify the outcome of this reaction
O
O
O
O
2
2
2
O
O
O
O
7
7
MeO
n-pentyl
OMe
: daldiniapyrone
MeO
n-Pr
MeO
MeO
10
10
OH
O
O
HO
HO
O
1
2: annularin B
3: annularin C
4: annularin F
Figure 1 Daldiniapyrone and annularins B, C and F
O
O
O
O
O
O
O
K CO , Me SO
4
O
Cl
Cl
2
3
2
CH2Cl2, r.t., 7 d
acetone, reflux
R
OMe
HO
R
MeO
R
O
OMe
O
OMe
5
5
5
a: R = Me
b: R = n-Pr
c: R = n-pentyl
6a: 40%
6b: 51%
6c: 47%
7a: 93%
7b: 95%
1: 95%
daldiniapyrone
Scheme 1
SYNTHESIS 2006, No. 11, pp 1787–1790
x
x.
x
x
.
2
0
0
6
Advanced online publication: 05.05.2006
DOI: 10.1055/s-2006-942355; Art ID: M08505SS
Georg Thieme Verlag Stuttgart · New York
©

1
788
A. V. Kurdyumov et al.
PAPER
O
O
O
BH3⋅Me2S
K2CO3, Me2SO4
acetone, reflux
O
O
O
HO
n-Pr
OMe
CH2Cl2–THF
r.t., 2 h
HO
n-Pr
MeO
n-Pr
9
0%
O
HO
8: 89%
HO
6b
2
: annularin B
Scheme 2
Higher temperatures than 150 °C or longer reaction times was stirred at r.t. for 7 d. After which, the mixture was then washed
with aq sat. NaHCO . The aqueous layer was acidified with 1% aq
than two days did not improve the yield of the reaction.
Addition of EtMgBr Grignard reagent to aldehyde 9 for-
tuitously led to a spontaneous formation of the lactone
ring, thereby completing the total synthesis of (±)-annu-
larin F (4) (Scheme 3). Synthetic annularin F also gave
spectroscopic data that are identical to the reported data.5
3
HCl and the crude product extracted with equal volume of CH Cl .
The combined organic extracts were washed with brine and dried
Na SO ). Solvent was evaporated under reduced pressure and the
resulting crude residue was subjected to silica gel column flash
chromatography (50% EtOAc in hexanes) to give 2-pyrone 6a;
2
2
(
2
4
yield: 12.9 g (40%); R = 0.11 (50% EtOAc in hexanes); mp 105–
f
1
08 °C.
To explore the possible biosynthetic connection, we at-
tempted to convert (±)-annularin F to (±)-annularin C. To
our big disappointment, reduction of annularin F proved
to be very challenging. Our attempts to finish the total
synthesis of (±)-annularin C via allylic oxidation of C-7
position of 2-pyrone 6b, annularin B, or TBS-protected 169.1, 169.3, 173.8.
annularin B all failed resulting in either no reaction or de-
composition of the starting material.
–
1
IR (film): 2988m, 1745s, 1693s cm .
1
H NMR (300 MHz, CDCl ): d = 2.60 (s, 3 H), 3.95 (s, 3 H), 5.47
s, 1 H), 11.52 (s, 1 H).
3
(
1
3
C NMR (75 MHz, CDCl ): d = 22.4, 53.3, 88.8, 101.8, 161.7,
3
+
MS (APCI): m/z (%) = 185 (100, [M + H]), 101 (5).
HRMS: m/z calcd for C H O : 184.0372; found: 184.0452.
8
8
5
In conclusion, we have described here the first concise to-
tal syntheses of new pyrone-based natural products dal-
diniapyrone, annularin B, and (±)-annularin F. However,
the synthesis of annularin C remains to be further studied.
4
-Hydroxy-5-methoxycarbonyl-6-propyl-2-pyrone (6b)
Rf = 0.20 (50% EtOAc in hexanes); mp 98–101 °C.
–
1
IR (film): 2964m, 1700s, 1652s cm .
1
H NMR (300 MHz, CDCl ): d = 1.02 (t, J = 7.5 Hz, 3 H), 1.77 (tq,
3
J = 7.5, 7.5 Hz, 2 H), 2.95 (t, J = 7.5 Hz, 2 H), 4.00 (s, 3 H), 5.55 (s,
Column chromatography was performed on Bodman silica gel (60
Å, 230–400 mesh). Solvents were dried before use. Flasks were
1
H), 11.50 (s, 1 H).
13C NMR (75 MHz, CDCl
162.0, 169.0, 169.3, 176.9.
flame dried under vacuum and purged with N before use. TLC
3
): d = 13.8, 21.3, 36.6, 53.3, 90.1, 101.5,
2
plates (Whatman, polyester backed) were visualized with UV (254
nm) and either anisaldehyde or permanganate stains. IR spectra
were recorded on NaCl plates using a Midac M2000 FTIR spec-
+
MS (APCI): m/z (%) = 211 (50, [M – H]), 167 (5), 111 (100).
HRMS: m/z calcd for C H O : 212.0685; found: 212.0732.
1
trometer. 500 MHz H NMR spectra were recorded on a Varian In-
10 12
5
ova spectrometer; 300 MHz spectra were recorded on a Varian
Unity or Varian Inova instruments and are referenced to TMS at
d = 0.00. C NMR spectra were recorded on a Varian Inova spec-
trometers at 125 MHz and 75 MHz and are referenced to the center
4
-Hydroxy-5-methoxycarbonyl-6-pentyl-2-pyrone (6c)
1
3
Rf = 0.50 (50% EtOAc in hexanes); mp 86–89 °C.
–
1
IR (film): 2958m, 2872m, 1739s, 1652m cm .
of CHCl peak at d = 77.23. Electrospray mass spectra were record-
3
1
H NMR (300 MHz, CDCl ): d = 0.92 (t, J = 6.3 Hz, 3 H), 1.26–
3
ed on a Bruker Biotof II ESI-TOF/MS using PEG standards as high
resolution calibrants. Unless noted, all reagents (Acros, TCI, Ald-
rich) were used as received.
1
3
.41 (m, 4 H), 1.65–1.79 (m, 2 H), 2.95 (t, J = 7.8 Hz, 2 H), 3.99 (s,
H), 5.55 (s, 1 H), 11.51 (s, 1 H).
1
3
C NMR (75 MHz, CDCl ): d = 14.1, 22.3, 27.9, 32.1, 35.6, 53.1,
3
4
-Hydroxy-5-methoxycarbonyl-6-methyl-2-pyrone (6a); Typi-
90.7, 101.3, 161.9, 169.2, 169.4, 177.5.
cal Procedure
+
MS (APCI): m/z (%) = 241 (80, [M + H]), 209 (100), 123 (5).
A solution of methyl acetoacetate (5a; 18.9 mL, 0.175 mol) and ma-
lonyl dichloride (17.0 mL, 0.175 mol) in anhyd CH Cl (750 mL)
HRMS: m/z calcd for C H O : 240.0998; found: 240.1016.
1
2
16
5
2
2
O
O
O
5
.0 equiv SeO2
EtMgBr, THF
–78 °C
150 °C, dioxane
O
O
O
7
46%
20%
MeO
7
MeO
MeO
CHO
7
O
O
OMe
O
OMe
O
7a
9
4
: (± ±-annularin F
Scheme 3
Synthesis 2006, No. 11, 1787–1790 © Thieme Stuttgart · New York

PAPER
Total Syntheses of Daldiniapyrone, Annularin B, and (±)-Annularin F
1789
4
-Methoxy-5-methoxycarbonyl-6-methyl-2-pyrone (7a); Typi- HRMS: m/z calcd for C H O : 184.0736; found: 184.0812.
9
12
4
cal Procedure
To a solution of 2-pyrone 6a (8.50 g, 46.2 mmol) in acetone (300
mL) were added anhyd K CO (19.0 g, 0.14 mol) and dimethyl sul-
Annularin B (2)
Diol 8 was converted to the methoxy derivative 2 following the typ-
2
3
fate (8.90 mL, 94.1 mmol). The mixture was refluxed for 5 h and
then allowed to stir at r.t. for an additional 16 h. The mixture was
filtered through Celite and concentrated under reduced pressure.
Recrystallization of the crude product from acetone–hexane gave
ical procedure given above for the preparation of 7a; R = 0.42
(EtOAc); mp 88–92 °C (Lit. mp 92–95 °C).
f
5
IR (film): 3412br, 1751w, 1655m cm–1.
1
H NMR (300 MHz, CDCl /DMSO-d ): d = 0.96 (t, J = 7.5 Hz, 3
7
a; 8.50 g (93%); R = 0.20 (50% EtOAc in hexanes); mp 91–94 °C.
3
6
f
H), 1.70 (tq, J = 7.5, 7.5 Hz, 2 H), 2.37 (br s, 1 H), 2.55 (t, J = 7.5
–
1
IR (film): 2996w, 2957w, 1748s, 1713s cm .
Hz, 2 H), 3.85 (s, 3 H), 4.45 (s, 2 H), 5.46 (s, 1 H).
1
H NMR (300 MHz, CDCl ): d = 2.32 (s, 3 H), 3.84 (s, 3 H), 3.86
13
3
C NMR (75 MHz, CDCl /DMSO-d ): d = 13.8, 21.3, 32.8, 55.5,
3
6
(
s, 3 H), 5.46 (s, 1 H).
5
6.4, 88.4, 110.9, 164.1, 164.6, 170.2.
1
3
C NMR (75 MHz, CDCl ): d = 19.0, 52.8, 56.6, 87.7, 108.9,
+
3
MS (APCI): m/z (%) = 199 (100) [M + H].
1
62.7, 164.0, 164.3, 168.3.
HRMS: m/z calcd for C H O : 198.0892; found: 198.0904.
+
10 14
4
MS (APCI): m/z (%) = 199 (100, [M + H]), 141 (5), 115 (5).
HRMS: m/z calcd for C H O : 198.0528; found: 198.0548.
4-Methoxy-5-methoxycarbonyl-6-carbaldehyde-2-pyrone (9)
9
10
5
A solution of 4-methoxy-2-pyrone (7a; 2.20 g, 11.1 mmol) and
4
-Methoxy-5-methoxycarbonyl-6-propyl-2-pyrone (7b)
SeO (6.60 g, 59.5 mmol) in anhyd dioxane (30 mL) was heated for
2
Rf = 0.25 (40% EtOAc in hexanes); mp 67–70 °C.
2 d at 150 °C in a sealed reaction flask. After cooling, the precipitate
was filtered through Celite and the filtrate was evaporated under re-
duced pressure. The crude residue was subjected to silica gel col-
umn flash chromatography (20% EtOAc in hexanes) to afford
–
1
IR (film): 2964m, 1739s, 1559s cm .
1
H NMR (300 MHz, CDCl ): d = 0.96 (t, J = 7.5 Hz, 3 H), 1.73 (tq,
3
J = 7.5, 7.5 Hz, 2 H), 2.53 (t, J = 7.5 Hz, 2 H), 3.87 (s, 3 H), 3.88 (s,
aldehyde 9; yield: 1.08 g (46%); R = 0.18 (50% EtOAc in hexanes);
f
3
H), 5.50 (s, 1 H).
mp 96–99 °C.
IR (film): 2955w, 1751brs, 1640m cm–1.
1
3
C NMR (75 MHz, CDCl ): d = 13.4, 20.6, 34.0, 52.6, 56.5, 87.6,
3
1
08.7, 162.7, 164.2, 166.3, 168.0.
1
H NMR (300 MHz, CDCl ): d = 3.92 (s, 3 H), 3.95 (s, 3 H), 5.81
3
+
MS (APCI): m/z (%) = 227 (60, [M + H]), 209 (40), 195 (50), 177
(
s, 1 H), 9.64 (s, 1 H).
(100), 149 (80).
1
3
C NMR (75 MHz, CDCl ): d = 53.7, 57.3, 94.4, 114.2, 150.6,
3
HRMS: m/z calcd for C H O : 226.0841; found: 226.0892.
1
1
14
5
160.1, 162.0, 166.2, 182.7.
+
MS (APCI): m/z (%) = 213 (100) [M + H], 185 (10), 137 (5).
HRMS: m/z calcd for C H O : 212.0321; found: 212.0506.
Daldiniapyrone (1)
R = 0.29 (40% EtOAc in hexanes); mp 54–56 °C (Lit. mp 56–58
4
f
9
8
6
°
C).
–
1
(±)-Annularin F (4)
IR (film): 1733s, 1652m, 1558m cm .
Aldehyde 9 (75.0 mg, 0.36 mmol) was taken up in anhyd THF (5
1
H NMR (300 MHz, CDCl ): d = 0.89 (t, J = 6.9 Hz, 3 H), 1.26–
.36 (m, 4 H), 1.60–1.75 (m, 2 H), 2.54 (t, J = 7.8 Hz, 2 H), 3.84 (s,
3
mL) and cooled to –78 °C. To this solution was added dropwise
EtMgBr (3.0 M solution in Et O, 0.13 mL, 0.39 mmol). After stir-
ring for 2 h at –78 °C, the mixture was allowed to warm up to r.t.
and stirred for an additional 14 h. The reaction was quenched with
ice-cold 3% aq HCl. The crude mixture was then extracted several
times with equal volume of CH Cl , and the combined organic ex-
1
2
3
H), 3.87 (s, 3 H), 5.47 (s, 1 H).
1
3
C NMR (75 MHz, CDCl ): d = 14.5, 23.4, 28.1, 32.3, 33.1, 53.4,
7.7, 88.6, 110.5, 165.2, 165.7, 167.7, 170.3.
3
5
+
2
2
MS (APCI): m/z (%) = 255 (100, [M + H]), 197 (10), 171 (5).
HRMS: m/z calcd for C H O : 254.1154; found: 254.1168.
tracts were washed with brine, dried (Na SO ), and concentrated
under reduced pressure. Silica gel column flash chromatography
2
4
1
3
18
5
(
20% EtOAc in hexanes) of crude residues afforded (±)-annularin F
4
-Hydroxy-5-hydroxymethyl-6-propyl-2-pyrone (8)
(4); yield: 14.9 mg (20%); R = 0.47 (90% EtOAc in hexanes); mp
140–144 °C (Lit. mp 143–145 °C).
f
5
To a solution of 6b (4.53 g, 21.3 mmol) in anhyd THF was added a
solution of BH ·Me S (1.0 M in CH Cl , 32.0 mL, 32.0 mmol) care-
IR (film): 2963w, 1740brs, 1662m, 1575m, 1486m, 1457m cm–1.
1
3
2
2
2
fully dropwise at 0 °C. The mixture was allowed to warm up to r.t.
and stirred for an additional 2 h. Anhyd MeOH was added and the
resulting mixture was stirred for 1 h before being concentrated un-
der reduced pressure. The crude residue was subjected to silica gel
column flash chromatography (EtOAc) to afford diol 8; yield: 3.46
H NMR (300 MHz, CDCl ): d = 1.05 (t, J = 7.2 Hz, 3 H), 1.84–
3
1
.96 (m, 1 H), 2.09–2.19 (m, 1 H), 3.99 (s, 3 H), 5.11 (dd, J = 4.5,
6
.9 Hz, 1 H), 5.49 (s, 1 H).
13
C NMR (75 MHz, CDCl ): d = 8.4, 25.0, 57.0, 78.5, 87.6, 101.1,
3
g (89%); R = 0.37 (EtOAc); mp 135–137 °C.
f
161.8, 164.1, 166.3, 179.5.
–
1
IR (film): 3436br, 1700m, 1683w, 1652m cm .
+
MS (GC): m/z (%) = 210 (50, [M ]), 185 (100), 153 (20), 124 (100).
HRMS: m/z calcd for C H O : 210.0528; found: 210.0534.
1
H NMR (300 MHz, CDCl /DMSO-d ): d = 0.96 (t, J = 7.5 Hz, 3
3
6
1
0
10
5
H), 1.70 (tq, J = 7.5, 7.5 Hz, 2 H), 2.57 (t, J = 7.5 Hz, 2 H), 3.81 (br
s, 1 H), 4.47 (s, 2 H), 5.52 (s, 1 H), 11.23 (br s, 1H).
1
3
Acknowledgment
C NMR (75 MHz, CDCl /DMSO-d ): d = 12.5, 19.8, 31.2, 52.4,
3
6
8
8.1, 110.5, 163.4, 164.0, 169.3.
The authors thank the National Institutes of Health (NIH, grant
number NS38049) for funding.
+
MS (APCI): m/z (%) = 183 (100) [M – H], 139 (30), 121 (20), 113
10).
(
Synthesis 2006, No. 11, 1787–1790 © Thieme Stuttgart · New York

1
790
A. V. Kurdyumov et al.
PAPER
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Synthesis 2006, No. 11, 1787–1790 © Thieme Stuttgart · New York