Syntheses of 2-pyrones via electrophilic substitutions at C7 of 4-hydroxy-6-methyl-2-pyrone through mono- or dianion formation

Article abstract of DOI:10.1055/s-2007-965925

Electrophilic substitution protocols useful for functionalizations at C7 of 4-hydroxy-6-methyl-2-pyrone, or triacetic acid, are described here. This method was applied to the synthesis of annularin E. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965925

PAPER
749
Syntheses of 2-Pyrones via Electrophilic Substitutions at C7 of
4
-Hydroxy-6-methyl-2-pyrone through Mono- or Dianion Formation
S
X
ynthese
s
of 2-Pyr
u
ones via Ele
e
ctrophilic
S
j
ubstitu
u
tions at C7 o
n
f
4-Hydroxy-6-met
Z
hyl-2-pyrone hang, Michael McLaughlin, R. Lizeth P. Muñoz, Richard P. Hsung,* Jiashi Wang, Jacob Swidorski
Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, Rennebohm Hall, 777 Highland Avenue,
Madison, WI 53705, USA
Fax +1(608)2625345; E-mail: rhsung@wisc.edu
Received 27 October 2006; revised 27 November 2006
yl-2-pyrone (triacetic acid, 3 ≡ 2, R = Me) via
Abstract: Electrophilic substitution protocols useful for functional-
functionalization at the C7 position. This method could
izations at C7 of 4-hydroxy-6-methyl-2-pyrone, or triacetic acid,
provide a facile entry for constructing the C9–C10 bond to
are described here. This method was applied to the synthesis of an-
connect the side chain with the AB ring of orevactaene.4
,5
nularin E.
Despite various reports for the functionalization at C7 of
4
Key words: dianion, 2-pyrones, 4-hydroxy-6-methyl-2-pyrone, tri-
acetic acid, electrophilic substitution
-hydroxy-6-methyl-2-pyrone,3 there are no general ap-
,14
proaches. We report here electrophilic substitutions at the
C7 position of 4-hydroxy-6-methyl-2-pyrones.
Pyrones are among the most important heterocyclic struc- We examined two protocols for functionalizing C7 of 4-
tures in medicinal chemistry, and specifically, 2-pyrones hydroxy-6-methyl-2-pyrone (3), the first involved tempo-
or a-pyrones can be found in a wide range of medicinally rary monoprotection of the C4-OH group as shown in 5,
1
–3
significant natural products. These natural products and the second involved dianion formation as shown in 7
range from complex natural products such as orevactaene (Scheme 1). An obvious concern would be the regioselec-
4
,5
(
anti-HIV, see Figure 1) and arisugacins (AChE inhibi- tivity of the ensuing electrophilic substitution of these an-
6
–8
tors), to simple ones such as rosellisin (antibacteri- ions (C3 vs C5 vs C7 as shown in 8). The extent of
al).9
,10
delocalization in these anions as shown in their respective
resonance structures A and B/C reveals potentially seri-
ous competing electrophilic substitutions.
HO
O
HO
HO
O
O
2
O
2
O
δ
temporary
mono-
anion
OM
O
H
O-protection
HO HO
O
6
O
6
O
δ
O
orevactaene
HO
O
7
δ
OMe
OMe
HO
4
PO
4
PO
PO
δ
3
5
6
M
A
OH
O
O
O
O
O
O
O
OMe
HO
dianion
E
O
δ
O
O
δ
O
OM
O
MeO
HO
E
3
δ
E
OH
OH
O
O
O
and
δ
O
O
δ
5
AcO
M
7
MeO
MO
MO
δ
OH
OH
MO
PO
arisugacin A
arisugacin H
3: R = Me
triacetic acid
rosellisin
O
δ
M
7: M = Li or Na
B
C
8
E
E
O
funct.
∆
H
Scheme 1 Dianion versus mono-O-protection protocol
O
O
O
2
O
6
2
O
X
R
OEt
HO
4
R
HO
6
7
O
O
1
: β,γ-diketo esters
R = aryl or alkyl
2: 6-substituted
4-hydroxy-2-pyrone
4: 7-substituted
4-hydroxy-2-pyrone
HMDS, 80 °C, 30 min, and in vacuo
O
O
4
Method A – 2 operations
4
7
HO
Me
TMSO
Me
Figure 1 C7 Functionalization of 4-hydroxy-6-methyl-2-pyrones
3
9
2
.0–2.6 equiv
THF or THF/HMPA [6:1]
–78 °C to –30 °C
n
-BuLi
1) 0.95–1.25 equiv n-BuLi,
Cyclizations of various b,d-diketo esters 1 represent a
34–53%
overall
THF, EtI, –78 °C to r.t.
2) workup
common and practical synthetic entry to 6-substituted 4-
1
1–13
hydroxy-2-pyrones 2 (Figure 1).
A subset of these 6-
substituted 4-hydroxy-2-pyrones such as 4 can also be ac-
cessed directly from readily available 4-hydroxy-6-meth-
O
O
Et-I, –78 °C to r.t., 12 h
O
O
Method B – 1 operation
Li
LiO
HO
SYNTHESIS 2007, No. 5, pp 0749–0753
x
x
.
x
x
.2
0
0
7
7
77% overall
7
1
1
10a
Advanced online publication: 08.02.2007
DOI: 10.1055/s-2007-965925; Art ID: M06606SS
Georg Thieme Verlag Stuttgart · New York
Scheme 2 Method A versus Method B
©

7
50
X. Zhang et al.
PAPER
Firstly, for the monoanion approach (Method A, The generality of this C7 functionalization protocol is il-
Scheme 2), we quickly found that we could cap the C4- lustrated in Table 1. Except in the case of benzaldehyde
OH group of 3 with a trimethylsilyl group employing (entries 8 and 9), the dianion protocol (Method B) is over-
hexamethyldisilazane. Subsequently, in a one-pot/two op- all more effective than Method A when comparisons were
eration manner, we could evaporate the excess hexameth- explicitly made (entry 1 vs 2 and 4 vs 5). A range of elec-
yldisilazane in vacuo and deprotonate at C7 using trophiles was feasible, including an epoxide (entry 7) and
butyllithium (0.95 to 1.25 equiv) at –78 °C after recharg- aldehyde (entries 8 and 9), although ketones were rather
ing the reaction flask with anhydrous tetrahydrofuran. En- sluggish (entries 10 and 11). It is noteworthy that for some
suing addition of iodoethane led to pyrone 10a1 in 34– of the lower yielding reaction, the starting pyrone was
5
5
3% overall yield with the trimethylsilyl protection being found the to be the major remaining component in the
hydrolytically cleaved during workup.
crude reaction mixture, although minor amount of prod-
ucts with substitutions at C3 and C5 were seen sometimes
in the crude mass spectrum.
On the other hand, the dianion approach (Method B) ap-
peared to be more effective. In a one-pot/one-operation
manner, pyrone 10a was obtained with an improved 77% Finally, to illustrate an application of this protocol, we
overall yield by deprotonation of 3 with 2.0–2.6 equiva- synthesized a simple 2-pyrone containing natural product
lents of butyllithium followed by addition of iodoethane. annularin E (12) (Scheme 3).1 Although related family
6,17
Table 1 Scope of Alkylations and Aldol Reactions
Entry
Electrophiles
C7 Addition products
Method
Yield (%)a
35–42%
55–87%
71
O
1
2
3
10b
A
B
B
O
I
HO
O
O
10c
10d
MeI
Me
HO
O
4
5
6
A
B
B
25
64
80
O
I
HO
O
O
Cl
O
10e
10f
10g
HO
HO
Ph
O
O
O
7
B
80
Ph
OH
O
H
O
8
9
A
B
50
54
OH
Ph
HO
O
O
O
O
1
0
O
O
10h
10i
B
B
20
27
OH
HO
HO
OH
1
1
a
Isolated yields.
Synthesis 2007, No. 5, 749–753 © Thieme Stuttgart · New York

PAPER
Syntheses of 2-Pyrones via Electrophilic Substitutions at C7 of 4-Hydroxy-6-methyl-2-pyrone
751
members have shown promising activity against Staphy- 1H NMR (300 MHz, CDCl
): d = 0.96 (t, J = 7.2 Hz, 3 H), 1.62–1.74
m, 2 H), 2.47 (t, J = 7.5 Hz, 2 H), 5.61 (d, J = 1.8 Hz, 1 H), 6.04 (d,
3
(
lococcus aureus (ATCC 29213), annularin E itself has not
1
6
J = 1.8 Hz, 1 H), 11.37 (br s, 1 H).
been tested because of its scarcity. As shown in
Schemes 3, 4-hydroxy-6-methyl-2-pyrone (3) could be
readily transformed into annularin E (12) by either
1
3
C NMR (100 MHz, CDCl ): d = 13.6, 20.3, 35.7, 90.3, 101.7,
3
1
67.3, 168.7, 172.9.
Method B-like or Method A-like (since an O-methylation MS (ESI): m/z = 177.0 (M + Na)+.
is in place of O-silylation) routes in good overall yields.
We believe that Method A is overall less consistent be-
HRMS: m/z calcd for C H NaO : 177.0528; found: 177.0523.
8
10
3
cause it depends on the extent of the silylation and the fate 6-Butyl-4-hydroxy-2-pyrone (10b); Typical Procedure for
Method B
4
and/or stability of the trimethylsilylated intermediate.
-Hydroxy-6-methyl-2-pyrone (3, 5.90 g, 46.8 mmol) was dried via
However, in the case of the annularin E synthesis, Method
A appeared to be comparably effective as Method B, as it
entailed a permanent capping of the C4-OH group.
concentrating its soln in benzene (3 ×) under reduced pressure. To
the residue solid was added anhyd THF (150 mL) and the resulting
slurry was cooled to –78 °C; 2.5 M n-BuLi in hexanes (43.0 mL,
1
07.6 mmol) was added slowly dropwise via a syringe. HMPA was
2
.6 equiv n-BuLi, THF/HMPA [6:1]
not always used, but when used, the ratio of THF to HMPA was
~ 6:1.
O
–78 °C to –30 °C
O
1
.1 equiv EtI, –78 °C to r.t., 12 h
After stirring at –78 °C for 1 h, PrI (9.20 mL, 94.2 mmol) was added
dropwise via a syringe. The resulting mixture was warmed to r.t.
and stirred for 15 h. The soln was carefully quenched with 3 M HCl
with the final pH being ~ 2. After partitioning, the aqueous layer
O
O
and then 1.5 equiv MeI, r.t., 12–18 h
MeO
Method B-like, one pot: 43% overall 12: annularin E
HO
Me
3
was extracted with Et O (3 × equal volume), washed with sat. aq
2
NaCl, and dried (Na SO ). After filtration and concentration under
2
4
1
) K2CO3, Me2SO4, acetone; then 2) 1.2 equiv n-BuLi,
reduced pressure, the crude dark oil was purified via flash column
chromatography (silica gel, gradient: 0–40% EtOAc–hexanes) to
THF/HMPA [6:1], –78 °C to –30 °C, EtI, –78 °C to r.t., 12 h
Method A-like: 38% overall
18
give the desired pyrone 10b as a yellow oil; yield: 6.85 g (87%);
Rf = 0.16 (50% EtOAc–hexanes).
Scheme 3 Application in the synthesis of annularin E
IR (film): 2961 (br s), 1693 (s), 1660 (s), 1566 (s), 1445 cm–1 (m).
We have described here a useful protocol for functional- 1H NMR (300 MHz, CDCl
): d = 0.93 (t, J = 7.4 Hz, 3 H), 1.37 (sex-
tet, J = 7.4 Hz, 2 H), 1.63 (quintet, J = 7.5 Hz, 2 H), 2.50 (t, J = 7.5
Hz, 2 H), 5.62 (d, J = 2.1 Hz, 1 H), 6.05 (d, J = 1.8 Hz, 1 H), 11.39
3
izing C7 of 4-hydroxy-6-methyl-2-pyrone en route to var-
ious substituted 2-pyrone building blocks that can be
useful for natural product synthesis.
(
1
br s, 1 H).
3
C NMR (75 MHz, CDCl ): d = 13.4, 21.8, 28.5, 33.1, 89.6, 101.3,
3
1
67.2, 168.5, 172.7.
MS (ESI): m/z = 191.1 (M + Na)+.
HRMS: m/z calcd for C : 191.0679; found: 191.0671.
Commercially available 4-hydroxy-6-methyl-2-pyrone was used.
NMR data were collected on Varian Unity-Inova 400 MHz or 500
MHz spectrometers. MS and HRMS spectra were obtained on a
Bruker BioTOF II mass spectrometer or an Agilent 1100 LC/MSD.
IR spectra were collected on a Bruker Equinox 55/5 FT-IR spectro-
photometer.
H12NaO
9 3
6-Ethyl-4-hydroxy-2-pyrone (10c)
Yellow oil; R = 0.13 (50% EtOAc–hexanes).
f
IR (film): 2979 (br s), 1696 (s), 1566 (s), 1445 (m), 1243 cm–1 (s).
4
-Hydroxy-6-propyl-2-pyrone (10a); Typical Procedure for
Method A
1
H NMR (75 MHz, CDCl ): d = 1.24 (t, J = 7.5 Hz, 3 H), 2.55 (q,
3
J = 7.5 Hz, 2 H), 5.62 (d, J = 2.1 Hz, 1 H), 6.05 (m, 1 H), 11.37 (br
s, 1 H).
A suspension of 4-hydroxy-6-methyl-2-pyrone (3, 6.31 g, 50.0
mmol) in hexamethyldisilazane (100 mL), which was used both as
the solvent and silylating agent, was heated at 80 °C and stirred un-
1
3
C NMR (300 MHz, CDCl ): d = 10.9, 26.9, 89.8, 100.7, 168.5,
3
der N for 30 min. After cooling to r.t., the solvent was removed un-
168.6, 173.0.
2
der reduced pressure. The residue was dissolved in THF and cooled
to –78 °C. To this soln was added 2.6 M n-BuLi in hexanes (24.0
mL, 62.5 mmol). After stirring for 1 h, EtI (20.0 g, 10.4 mL, 130.0
mmol) was added dropwise via syringe and the soln was warmed to
r.t. and stirred for 20 h.
MS (ESI): m/z = 163.0 (M + Na)+.
HRMS: m/z calcd for C H NaO : 163.0366; found: 163.0368.
7 8 3
6-But-3-enyl-4-hydroxy-2-pyrone (10d)
Yellow oil; R = 0.11 (50% EtOAc–hexanes).
f
The reaction was quenched with aq 6 M HCl (50 mL), and the or-
ganic layer was concentrated under reduced pressure. The crude
residue was dissolved in EtOAc (0.5 L) and washed with sat. aq
NaCl (2 × equal volume). The organic layers were combined, dried
IR (film): 3081 (br s), 1694 (s), 1665 (s), 1566 (s), 1445 cm–1 (m).
1
H NMR (500 MHz, CDCl ): d = 2.40 (q, J = 7.5 Hz, 2 H), 2.59 (t,
3
J = 7.5 Hz, 2 H), 5.01–5.10 (m, 2 H), 5.60 (d, J = 2.0 Hz, 1 H), 5.78
(dddd, J = 6.5, 6.5, 10.5, 17.0 Hz, 1 H), 6.03 (d, J = 2.0 Hz, 1 H),
(
Na SO ), and concentrated under reduced pressure. The crude res-
2 4
idue was purified by flash column chromatography (silica gel, gra-
dient: 0–40% EtOAc–hexanes) to give the desired pyrone 10a as a
1
1.30 (br s, 1 H).
1
3
C NMR (75 MHz, CDCl ): d = 30.6, 33.0, 90.0, 101.9, 116.5,
3
yellow oil; yield: 4.07 g (53%); R = 0.15 (50% EtOAc–hexanes).
f
1
35.9, 166.3, 168.6, 172.8.
IR (film): 2906 (m), 2596 (br s), 1562 (s), 1498 (s), 1421 (m), 1239
MS (ESI): m/z = 189.1 (M + Na)+.
–
1
cm (m).
HRMS: m/z calcd for C H NaO : 189.0522; found: 189.0519.
9
10
3
Synthesis 2007, No. 5, 749–753 © Thieme Stuttgart · New York

7
52
X. Zhang et al.
PAPER
1
3
4
-Hydroxy-6-(2-phenylethyl)-2-pyrone (10e)
C NMR (125 MHz, CDCl ): d = 20.2, 23.5, 26.6, 26.7, 26.8, 27.2,
3
Yellow oil; R = 0.45 (60% acetone–hexanes).
28.1, 48.6, 75.5, 90.0, 102.1, 164.4, 168.0, 172.5.
f
IR (film): 3064 (m), 3029 (m), 2929 (m), 2352 (m), 1664 (s), 1568
MS (ESI): m/z = 275.4 (M + Na)+.
–
1
(s), 1496 (m), 1448 (m), 1410 (w), 1252 (m), 1141 cm (w).
HRMS: m/z calcd for C H NaO : 275.1253; found: 275.1251.
1
4
20
4
1
H NMR (300 MHz, CDCl ): d = 2.80 (m, 2 H), 2.97 (m, 2 H), 5.64
3
(
1
d, J = 2.1 Hz, 1 H), 6.00 (d, J = 2.1 Hz, 1 H), 7.08–7.32 (m, 5 H),
1.37 (br s, 1 H).
Annularin E (12)
Yellow oil; R = 0.53 (50% EtOAc–hexanes).
f
1
3
C NMR (75 MHz, CDCl ): d = 32.9, 35.5, 90.1, 102.1, 126.6,
IR (film): 2964 (m), 2874 (w), 1703 (s), 1647 (m), 1566 (s), 1455
(m), 1409 (m), 1245 cm (m).
3
–
1
1
28.3, 128.7, 139.7, 166.1, 168.5, 172.8.
MS (ESI): m/z = 239.1 (M + Na)+.
1
H NMR (400 MHz, CDCl ): d = 0.96 (t, J = 7.2 Hz, 3 H), 1.68 (qt,
3
J = 7.4, 7.4 Hz, 2 H), 2.42 (t, J = 7.4 Hz, 2 H), 3.80 (s, 3 H), 5.41 (d,
J = 2.4 Hz, 1 H), 5.77 (d, J = 2.4 Hz, 1 H).
HRMS: m/z calcd for C H NaO : 239.0679; found: 239.0684.
1
3
12
3
1
3
4
-Hydroxy-6-(3-hydroxy-3-phenylpropyl)-2-pyrone (10f)
C NMR (100 MHz, CDCl ): d = 13.5, 20.1, 35.6, 56.0, 87.6, 100.0,
3
Yellow oil; R = 0.30 (60% acetone–hexanes).
165.2, 165.7, 171.5.
f
IR (film): 3064 (m), 3029 (m), 2926 (m), 2360 (m), 2340 (m), 1696
MS (ESI): m/z = 191.1 (M + Na)+.
–
1
(
(
1
s), 1669 (s), 1566 (s), 1505 (w), 1495 (m), 1255 (m), 1141 cm
m).
HRMS: m/z calcd for C H NaO : 191.0684; found: 191.0686.
9
12
3
H NMR (300 MHz, acetone-d ): d = 2.02 (m, 2 H), 2.61 (m, 2 H),
6
Acknowledgment
4
1
.77 (t, J = 6.4 Hz, 1 H), 4.90–5.12 (br s, 1 H), 5.32 (d, J = 2.1 Hz,
H), 5.98 (td, J = 0.9, 2.1 Hz, 1 H), 7.23–7.44 (m, 5 H), 11.39 (br
Authors thank NIH [NS38049] for funding.
s, 1 H).
1
3
C NMR (75 MHz, acetone-d ): d = 30.0, 36.5, 72.2, 89.0, 99.4,
6
1
25.8, 127.0, 128.2, 145.6, 164.2, 166.9, 170.2.
References
MS (ESI): m/z = 269.1 (M + Na)+.
(1) For a review, see: Romines, K. R.; Chrusciel, R. A. Curr.
Med. Chem. 1995, 2, 825.
HRMS: m/z calcd for C H NaO : 269.0784; found: 269.0777.
1
4
14
4
(
2) For recent reports, see: (a) Fors, K. S.; Gage, J. R.; Heier, R.
F.; Kelly, R. C.; Perrault, W. R.; Wicnienski, N. J. Org.
Chem. 1998, 63, 7348. (b) Vara Prasad, J. V. N.; Tummino,
P. J.; Ferguson, D.; Saunders, J.; Vander Roest, S.;
McQuade, T. J.; Heldsinger, A.; Reyner, E. L.; Stewart, B.
H.; Guttendorf, R. J.; Para, K. S.; Lunney, E. A.; Gracheck,
S. J.; Domagala, J. M. Biochem. Biophys. Res. Commun.
1996, 221, 815.
4
-Hydroxy-6-(2-hydroxy-2-phenylethyl)-2-pyrone (10g)
Yellow oil; R = 0.33 (50% EtOAc–hexanes).
f
IR (film): 3088 (br s), 2623 (w), 2361 (m), 2342 (w), 1678 (s), 1626
–
1
(m), 1567 (s), 1446 (w), 1254 (m), 1053 cm (w).
1
H NMR (500 MHz, acetone-d ): d = 2.81–2.86 (m, 2 H), 4.62–4.78
6
(
(
1
br, 1 H), 5.09 (t, J = 6.3 Hz, 1 H), 5.28–5.33 (m, 1 H), 5.95–6.01
m, 1 H), 7.22–7.48 (m, 5 H), 11.40 (br s, 1 H).
(3) (a) Schwartz, T. M.; Bundy, G. L.; Strohbach, J. W.;
Thaisrivongs, S.; Johnson, P. D.; Skulnick, H. I.; Tomich, P.
K.; Lynn, J. C.; Chong, K.-T.; Hinshaw, R. R.; Raub, T. J.;
Padbury, G. E.; Toth, L. N. Bioorg. Med. Chem. Lett. 1997,
7, 399. (b) Thaisrivongs, S.; Janakiraman, M. N.; Chong, K.-
T.; Tomich, P. K.; Dolak, L. A.; Turner, S. R.; Strohbach, J.
W.; Lynn, J. C.; Horng, M.-M.; Hinshaw, R. R.;
3
C NMR (75 MHz, acetone-d ): d = 44.0, 70.8, 89.3, 101.2, 125.8,
6
1
27.3, 128.3, 144.7, 163.8, 164.0, 169.9.
MS (ESI): m/z = 255.1 (M + Na)+.
HRMS: m/z calcd for C H NaO : 255.0628; found: 255.0637.
1
3
12
4
Watenpaugh, K. D. J. Med. Chem. 1996, 39, 2400.
4
-Hydroxy-6-(2-hydroxy-2-methylbutyl)-2-pyrone (10h)
(c) Thaisrivongs, S.; Watenpaugh, K. D.; Howe, W. J.;
Yellow oil; R = 0.20 (60% acetone–hexanes).
f
Tomich, P. K.; Dolak, L. A.; Chong, K.-T.; Tomich, C. S. C.;
Tomasselli, A. G.; Turner, S. R.; Strohbach, J. W.;
Mulichak, A. M.; Janakiraman, M. N.; Moon, J. B.; Lynn, J.
C.; Horng, M.-M.; Hinshaw, R. R.; Curry, K. A.; Rothrock,
D. J. J. Med. Chem. 1995, 38, 3624.
IR (film): 3362 (br s), 2974 (w), 2934 (w), 2630 (w), 1694 (s), 1567
–
1
(
s), 1448 (m), 1292 (w), 1259 (m), 1144 cm (w).
1
H NMR (500 MHz, acetone-d ): d = 0.95 (t, J = 7.0 Hz, 3 H), 1.20
6
(
(
1
q, J = 4.0 Hz, 3 H), 1.53–1.59 (m, 2 H), 2.61 (s, 2 H), 3.50–3.80
br, 1 H), 5.32–5.36 (m, 1 H), 6.02–6.06 (m, 1 H), 11.39 (br s, 1 H).
(4) For isolation, see: Shu, Y.-Z.; Ye, Q.; Li, H.; Kadow, K. F.;
Hussain, R. A.; Huang, S.; Gustavson, D. R.; Lowe, S. E.;
Chang, L. P.; Pirnik, D. M.; Kodukula, K. Bioorg. Med.
Chem. Lett. 1997, 7, 2295.
3
C NMR (125 MHz, acetone-d ): d = 44.0, 70.8, 89.3, 101.2, 125.8,
6
1
27.3, 128.3, 163.8, 164.0, 169.9.
MS (ESI): m/z = 221.1 (M + Na)+.
(
5) For recent synthetic efforts toward orevactaene, see:
a) Organ, M. G.; Bratovanov, S. Tetrahedron Lett. 2000, 41,
945. (b) Organ, M. G.; Bilokin, Y. V.; Bratovanov, S. J.
(
6
HRMS: m/z calcd for C H NaO : 221.0784; found: 221.0790.
1
0
14
4
Org. Chem. 2002, 67, 5176.
6
-(2-Cyclohexyl-2-hydroxypropyl)-4-hydroxy-2-pyrone (10i)
(
6) For isolation, see: (a) Otoguro, K.; Kuno, F.; Õmura, S.
Pharmacol. Ther. 1997, 76, 45. (b) Otoguro, K.; Shiomi,
K.; Yamaguchi, Y.; Arai, N.; Sunazuka, T.; Masuma, R.;
Iwai, Y.; Õmura, S. J. Antibiot. 2000, 53, 5.
Yellow oil; R = 0.35 (60% acetone–hexanes).
IR (film): 3082 (br s), 2961 (w), 1696 (s), 1553 (m), 1446 cm–1 (w).
f
1
H NMR (300 MHz, CDCl ): d = 0.90–1.43 (m, 10 H), 1.60–1.85
3
(
(
m, 5 H), 2.60 (d, J = 14.1 Hz, 1 H), 2.68 (d, J = 14.1 Hz, 1 H), 5.58
d, J = 2.1 Hz, 1 H), 6.08 (d, J = 2.1 Hz, 1 H), 11.40 (br s, 1 H).
(7) For a recent review on synthetic efforts toward arisugacin A,
see: Cole, K. P.; Hsung, R. P. In Strategies and Tactics in
Organic Synthesis, Vol.4; Harmata, M., Ed.; Pergamon
Press: Oxford, 2004, 41–70.
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Syntheses of 2-Pyrones via Electrophilic Substitutions at C7 of 4-Hydroxy-6-methyl-2-pyrone
753
(8) For our total synthesis efforts, see: (a) Hsung, R. P. J. Org. (14) (a) For an earlier report on generating the dianion from
Chem. 1997, 62, 7904. (b) Zehnder, L. R.; Hsung, R. P.;
Wang, J.-S.; Golding, G. M. Angew. Chem. Int. Ed. 2000,
triacetic acid, see: Wachter, M. P.; Harris, T. M.
Tetrahedron 1970, 26, 1685. For C7 alkylations, see:
3
9, 3876. (c) Cole, K. P.; Hsung, R. P. Tetrahedron Lett.
(b) Shimo, T.; Matsuzaki, S.; Somekawa, K. J. Heterocycl.
Chem. 1994, 31, 387. (c) Groutas, W. C.; Stanga, M. A.;
Brubaker, M. J.; Huang, T. L.; Moi, M. K.; Carroll, R. T. J.
Med. Chem. 1985, 28, 1106. (d) Poulton, G. A.; Cyr, T. D.
Can. J. Chem. 1982, 60, 2821. For an addition to aldehyde,
see: (e) Oikawa, H.; Kobayashi, T.; Katayama, K.; Suzuki,
Y.; Ichihara, A. J. Org. Chem. 1998, 63, 8748. For C7
oxidation, see: (f) Suzuki, E.; Hamajima, R.; Inoue, S.
Synthesis 1975, 192. (g) Bacardit, R.; Moreno-Mañas, M.;
Pleixats, R. J. Heterocycl. Chem. 1982, 19, 157. For
bromination, see: (h) Jones, R. C. F.; Patience, J. M.
Tetrahedron Lett. 1989, 30, 3217.
2002, 43, 8791. (d) Cole, K. P.; Hsung, R. P.; Yang, X.-F.
Tetrahedron Lett. 2002, 43, 3341. (e) Hsung, R. P.; Cole, K.
P.; Zehnder, L. R.; Wang, J.; Wei, L. L.; Yang, X.-F.;
Coverdale, H. A. Tetrahedron 2003, 59, 311.
(
9) For isolation, see: (a) Nair, M. S. R.; Carey, S. T.
Tetrahedron Lett. 1975, 16, 3617. (b) Nair, M. S. R.
Phytochemistry 1976, 15, 1090.
(
(
10) Shimizu, T.; Hiranuma, S.; Wantanabe, T. Heterocycles
993, 36, 2445.
1
11) For a leading reference, see: Katritzky, A. R.; Wang, Z.;
Wang, M.; Hall, C. D.; Suzuki, K. J. Org. Chem. 2005, 70,
4
854.
(15) For an application of its utility, see: McLaughlin, M. J.;
Hsung, R. P.; Cole, K. C.; Hahn, J. M.; Wang, J. Org. Lett.
2002, 4, 2017.
(16) Li, C.; Nitka, M. V.; Gloer, J. B. J. Nat. Prod. 2003, 66,
1302.
(
12) For some examples, see: (a) Organ, M. G.; Wang, J. J. Org.
Chem. 2003, 68, 5568. (b) Hagiwara, H.; Kobayashi, K.;
Hoshi, T.; Suzuki, T.; Ando, M. Tetrahedron 2001, 57,
5039. (c) Lokot, I. P.; Pashkovsky, F. S.; Lakhvich, F. A.
Tetrahedron 1999, 55, 4783.
(17) For some other recently isolated related 2-pyrone containing
natural products, see: (a) Cutignano, A.; Fontana, A.;
Renzulli, L.; Cimino, G. J. Nat. Prod. 2003, 66, 1399.
(b) Pedras, M. S. C.; Chumala, P. B. Phytochemistry 2005,
66, 81.
(
13) Douglas, C. J.; Sklenicka, H. M.; Shen, H. C.; Golding, G.
M.; Mathias, D. S.; Degen, S. J.; Morgan, C. D.; Shih, R. A.;
Mueller, K. L.; Seurer, L. M.; Johnson, E. W.; Hsung, R. P.
Tetrahedron 1999, 55, 13683.
(
18) For an application of its utility, see: Swidorski, J. J.; Wang,
J.; Hsung, R. P. Org. Lett. 2006, 8, 777.
Synthesis 2007, No. 5, 749–753 © Thieme Stuttgart · New York