5-(Trimethylstannyl)-2H-pyran-2-one and 3-(trimethylstannyl)-2H-pyran-2-one: New 2H-pyran-2-one synthons

Article abstract of DOI:10.1021/jo951394t

5-(Trimethylstannyl)-2H-pyran-2-one (11) and 3-(trimethylstannyl)-2H-pyran-2-one (30), readily prepared from the corresponding bromo-2H-pyran-2-ones, undergo Pd(0)-catalyzed coupling reactions with a variety of enol triflates to give 5- and 3- substituted 2H-pyran-2-ones, respectively. This reaction is applicable to the enol triflates of 14β-hydroxy-17-ketosteroids, and therefore may prove useful in convergent syntheses of lucibufagins and bufadienolides.

Full text of DOI:10.1021/jo951394t

J . Org. Chem. 1996, 61, 6693-6699
6693
5-(Tr im eth ylsta n n yl)-2H-p yr a n -2-on e a n d
3-(Tr im eth ylsta n n yl)-2H-p yr a n -2-on e: New 2H-P yr a n -2-on e
Syn th on s
Zhi Liu and J errold Meinwald*
Department of Chemistry, Cornell University, Ithaca, New York 14853
Received J uly 28, 1995X
5-(Trimethylstannyl)-2H-pyran-2-one (11) and 3-(trimethylstannyl)-2H-pyran-2-one (30), readily
prepared from the corresponding bromo-2H-pyran-2-ones, undergo Pd(0)-catalyzed coupling reac-
tions with a variety of enol triflates to give 5- and 3- substituted 2H-pyran-2-ones, respectively.
This reaction is applicable to the enol triflates of 14â-hydroxy-17-ketosteroids, and therefore may
prove useful in convergent syntheses of lucibufagins and bufadienolides.
Sch em e 1
In tr od u ction
Lucibufagins and bufadienolides,1 powerful cardiotonic
agents from invertebrates and vertebrates, respectively,
pose a challenging synthetic problem, in part because
both groups of compounds are characterized by the
presence of a 2H-pyran-2-one ring at the C-17 position
of a steroidal nucleus. Since the first successful bufadi-
enolide synthesis,2 many ingenious methods for the
elaboration of steroidal 2H-pyran-2-ones have been de-
scribed.3 These methods have all been based on a linear
strategy in which a suitable five-carbon chain is first built
up at C-17 and then cyclized and dehydrogenated (if
necessary) to give the desired 2H-pyran-2-one.3 We now
report a convergent strategy whereby an intact 2H-pyran-
2-one ring can be joined directly to a variety of substrates,
including steroids.
Sch em e 2
We here describe two broadly applicable, closely re-
lated approaches to the synthesis of 3- and 5-substituted
2H-pyran-2-ones: the cross-coupling of organotin re-
agents with 5-bromo-2H-pyran-2-one or 3-bromo-2H-
pyran-2-one and the coupling of stannylated 2H-pyran-
2-ones with vinyl halides or enol triflates. The Pd0-
catalyzed cross-coupling of a wide variety of organotin
reagents with vinyl halides and enol triflates has been
intensively studied by Stille.5 This type of reaction,
catalyzed by a number of palladium-containing com-
pounds, provides a versatile method for joining two sp2
carbon atoms. The reaction is especially attractive
because it is tolerant of a wide variety of functional
groups in either of the coupling partners and because it
is both stereospecific and regioselective.5
To explore the applicability of this methodology to the
problem in hand, we prepared 5-bromo-2H-pyran-2-one
from 5,6-dihydro-2H-pyran-2-one (1) as previously de-
scribed6 (Scheme 1).
The first organotin reagent we chose to couple with 2
was vinyltrimethyltin (4), prepared as previously de-
scribed.7 The coupling reaction was carried out in
refluxing toluene for 24 h, catalyzed by tetrakis(triphen-
ylphosphine)palladium(0) (Pd(PPh3)4). A 45% yield of
5-vinyl-2H-pyran-2-one (5) was obtained (Scheme 2).
As a cross-conjugated triene, 5-vinyl-2H-pyran-2-one
presents an interesting ambiguity with respect to its
Discu ssion
While the addition of phenyllithium or phenyl Grig-
nard reagents to carbonyl compounds or to other ap-
propriate substrates provides a versatile method for the
joining of a benzene ring to a desired structure, these
nucleophilic additions are not suitable for introducing a
2H-pyran-2-one moiety. The difficulty is that the 2H-
pyran-2-one ring itself is susceptible to attack by many
nucleophiles. Thus, when 5-bromo-2H-pyran-2-one is
treated with lithium reagents (n-butyllithium, sec-butyl-
lithium, tert-butyllithium, or phenyllithium) at -78 °C,
the heterocyclic ring opens instead of undergoing the
hoped for lithium-bromine exchange reaction. Posner
et al. have reported similar results in their attempts to
prepare 3-lithio-2H-pyran-2-one.4 Nevertheless, this group
did succeed in preparing an organocopper reagent from
3-bromo-2H-pyran-2-one. This novel reagent reacts with
a selected set of organic halides, although in modest
yields, giving the expected coupling products; it offers the
first successful approach to the convergent synthesis of
targets containing a 2H-pyran-2-one moiety.
X Abstract published in Advance ACS Abstracts, August 15, 1996.
(1) (a). Eisner, T.; Wiemer, D. F.; Haynes, L. W.; Meinwald, J . Proc.
Natl. Acad. Sci. U.S.A. 1978, 75, 905. (b). Meinwald, J .; Wiemer, D.;
Eisner, T. J . Am. Chem. Soc. 1979, 101, 3055. (c). Shimada, K.;
Nambara, T. Chem. Pharm. Bull. 1979, 27 (8), 1881.
(2) Sondheimer, F.; McCrae, W.; Salmond, W. G. J . Am. Chem. Soc.
1969, 91, 1228.
(3) Riffel, N., Master’s Thesis submitted to Cornell University, 1992.
(4) Posner, G.; Harrison, W.; Wettlaufer, D. J . Org. Chem. 1985,
50, 5014.
(5) Stille, J . Angew. Chem. Int. Ed. Engl. 1986, 25, 508.
(6) Posner, G.; Afarinkia, K.; Dai, H. Org. Synth. 1994, 73, 231.
(7) Seyferth, D.; Stone, F. G. A. J . Am. Chem. Soc. 1957, 79, 515.
S0022-3263(95)01394-6 CCC: $12.00 © 1996 American Chemical Society

6694 J . Org. Chem., Vol. 61, No. 19, 1996
Liu and Meinwald
Sch em e 3
Sch em e 4
F igu r e 1. MM2 calculated coupling constants.
Sch em e 6
Sch em e 5
(11) in 68% yield. In order to determine whether a tin-
substituted 2H-pyran-2-one might be a useful coupling
partner, the reaction of 11 with cyclohexenyl triflate (12)
was explored. The coupling reaction, carried out in THF
and catalyzed by Pd(PPh3)4, gave a 68% yield of the
previously characterized 10 (Scheme 6).
Comparing this result with that summarized in Scheme
3, the use of 5-(trimethylstannyl)-2H-pyran-2-one is
clearly an improvement. In fact, 5-(trimethylstannyl)-
2H-pyran-2-one provides a useful synthon for coupling a
2H-pyran-2-one ring to a variety of substrates.
Since most naturally occurring 2H-pyran-2-ones are
also steroids, it was important to determine whether this
coupling method can be applied to steroidal triflates. This
is not a trivial question, since coupling at C-17 might be
hampered by steric hindrance. Toward this end, Pd0-
catalyzed stannane coupling with the estrone-derived
enol triflate 14 was examined. Lithium diisopropylamide
was used to deprotonate the R carbon on the D-ring of
tert-butyldimethylsilated estrone 13, followed by quench-
ing of the enolate with N-phenyltrifluoromethanesul-
fonimide. A 67% yield of desired enol triflate (14) was
thus obtained. This product was then coupled with
5-(trimethylstannyl)-2H-pyran-2-one (11), using tetrakis-
(triphenylphosphine)palladium(0) as catalyst. The de-
sired steroidal 2H-pyran-2-one 15 was formed in 68%
yield; subsequent deprotection of the 3-hydroxyl group
by reaction of 15 with tetrabutylammonium fluoride gave
16 in 79% yield. Selective reduction of this steroidal
pyrone at atmospheric pressure with Pd/CaCO4 at 0 °C
for 20 min gave the desired product 17 in 80% yield
(Scheme 7).
reactivity as a diene component in Diels-Alder reac-
tions.8 For example, 5 might react with maleic anhydride
(6) to give either 7 or 8. When 5-vinyl-2H-pyran-2-one
was refluxed with maleic anhydride in benzene for 2 h,
48% of an adduct was obtained (Scheme 3). 1H NMR and
ultraviolet spectroscopy established that this product has
structure 7 rather than 8, with the stereochemistry
determined to be that shown in Scheme 3 by a NOE
experiment (31% enhancement of Hâ when HR was
irradiated).
To explore the scope of the 5-bromo-2H-pyran-2-one
plus stannane coupling technique a bit further, we set
out to prepare 5-(1-cyclohexenyl)-2H-pyran-2-one (10).
For this purpose, 1-(trimethylstannyl)cyclohexene (9) was
prepared according to a literature procedure.9 The first
trial of the coupling reaction, carried out in toluene, gave
a low conversion to the desired product. Of the number
of solvents surveyed, tetrahydrofuran gave the best
results (Scheme 4). Nevertheless, a yield of only 41%
could be obtained. This partial success encouraged us
to explore the alternative strategy of preparing and
coupling stannyl-2H-pyran-2-ones with enol triflates.
The preparation of tin-substituted benzenes was widely
studied by several investigators in the 1980s. Using
methods analogous to those used to prepare phenylstan-
nanes,10,11 we prepared 5-(trimethylstannyl)-2H-pyran-
2-one (11) (Scheme 5); 5-bromo-2H-pyran-2-one reacted
with hexamethylditin in THF, catalyzed by Pd(PPh3)4,
to give the desired 5-(trimethylstannyl)-2H-pyran-2-one
The stereochemistry at C17 in this product was con-
firmed by a consideration of the 1H NMR coupling
constants between H-17/H-16R and H-17/H-16â (Figure
1). On the basis of an MM2 calculation from PC Model,
the anticipated coupling constants for the 17-R isomer
are 9.4 and 1.5 Hz, while the corresponding expected
coupling constants for the 17-â isomer are 9.9 and 7.8
Hz. Since the observed values of 8.8 and 9.0 Hz for the
(8) Nelson, T.; Kinter, C.; Afarinkia, K.; Posner, G. Tetrahedron Lett.
1991, 32, 5295.
(9) Dueber, T. E.; Stang, R. J .; Pfeiffer, W. D.; Summerville, R. H.;
Imhoff, M. A.; Schleyer, P. v. R.; Hummel, K.; Bocher, S.; Harding, C.
E.; Hanack, M. Angew. Chem. Int. Ed. Engl. 1970, 9, 521.
(10) Azizian, H.; Eaborn, C. E.; Pidcock, A. J . Organomet. Chem.
1981, 215, 49.
(11) Kashin, A. N.; Bumagina, I. G.; Bumagin, N. A.; Bakunin, V.
N.; Beletskaya, I. P. J . Org. Chem. USSR 1981, 17, 789.

New 2H-Pyran-2-one Synthons
J . Org. Chem., Vol. 61, No. 19, 1996 6695
Sch em e 7
Sch em e 8
Sch em e 9
+
coupling constants of H-17/H-16R and H-17/H-16â agree
well with the expectations for the 17-â 2H-pyran-2-one
configuration, the stereochemistry of 17 can be consid-
ered to be established.
Since both the bufadienolides and the lucibufagins are
also characterized by a cis C/D ring fusion and a 14â-
hydroxyl group, we examined the possibility of coupling
5-(trimethylstannyl)-2H-pyran-2-one (11) with 14â-hy-
droxyestrone. The enol triflate of 14â-hydroxylestrone
was prepared as summarized in Schemes 8 and 9, based
on close literature analogies.12 TBDMS-protected estrone
13 was deprotonated by LDA, and the reaction mixture
was quenched with chlorotrimethylsilane. The crude
enol silyl ether was dissolved in benzonitrile and oxidized
with 1 equiv of palladium acetate.13 The resulting enone
(19) was treated with acetic anhydride and a catalytic
amount of p-toluenesulfonic acid to give the 14,16-dienyl
acetate 20. The (4 + 2)-cycloaddition between 20 and
benzyl nitrosoformate (21), carried out in methylene
chloride at 0 °C, gave the anticipated two stereoisomeric
Diels-Alder products.12 This mixture was hydrolzed in
methanol for 12 h. After chromatography, a 62% yield
of compound 24 was obtained. Subsequent hydrogena-
(12) Kirsch, G.; Golde, R.; Neef, G. Tetrahedron Lett. 1989, 30, 4497.
(13) Lupo, A., Ph.D thesis submitted to Cornell University, 1986.

6696 J . Org. Chem., Vol. 61, No. 19, 1996
Liu and Meinwald
Sch em e 10
Sch em e 12
nient route to this class of compounds as well. We
therefore examined the conversion of 3-bromo-2H-pyran-
2-one (3) into the corresponding trimethylstannane (30),
using the procedure described for the preparation of 11.
This conversion proceeded smoothly, and the resulting
stannane coupled readily with enol triflate 12 to give the
expected 3-(1-cyclohexenyl)-2H-pyran-2-one (31) in 72%
yield (Scheme 12). In summary, both 5- and- 3-substi-
tuted 2H-pyran-2-ones should now be readily accessible
via the stannane chemistry that was pioneered by Stille
and his co-workers.
Sch em e 11
Exp er im en ta l Section
Gen er a l. Tetrahydrofuran (THF) was distilled from Na/
benzophenone. Methylene chloride, benzene, and toluene were
distilled from CaH2. N,N-Dimethylformamide (DMF), meth-
oxyethoxymethyl chloride, and diisopropylethylamine were
distilled over anhydrous magnesium sulfate at 8 mmHg.
Tetrakis(triphenylphosphine)palladium(0), hexamethylditin,
N-phenyltrifluoromethanesulfonimide, estrone, tert-butyldi-
methylsilyl chloride, imidazole, benzyl N-hydroxycarbamate,
tetraethyl periodate (Et4IO4), N-bromosuccinimide (NBS), ben-
zoyl peroxide, methyltriphenoxyphosphonium iodide, and tet-
rabutylammonium fluoride were purchased from Aldrich
Chemical Co. Lithium chloride was dried at 120 °C overnight
and stored in a desiccator. 5-Bromo-2H-pyran-2-one and
3-bromo-2H-pyran-2-one were prepared according to the lit-
erature prcedures.6 All reactions were carried out under the
protection of Ar unless noted otherwise. TLC was performed
with precoated silica gel (Baker-flex, silica gel IB2-F, 0.25 mm).
Flash chromatography was carried out on silica 60 from EM
Science.
5-Vin yl-2H-pyr an -2-on e (5). 5-Bromo-2H-pyran-2-one (0.14
g, 0.80 mmol), vinyltrimethyltin (0.19 g, 1.00 mmol), and Pd-
(PPh3)4 (0.03 g, 0.03 mmol) were placed in a dry 10 mL round-
bottom flask together with 15 mL of toluene. The mixture was
refluxed for 24 h. Upon completion of the reaction, the toluene
was removed, the final crude material was partitioned between
acetonitrile and hexane, and the acetonitrile layer was dried
over MgSO4. After the solvent was evaporated under reduced
pressure, the product was purified by flash chromatography,
eluting with 7:3 hexane-ether. The product 5 was obtained
as a clear oil (44 mg, 45%): 1H NMR (200 MHz) δ 7.58 (dd, J
) 9.7, 2.8 Hz, 1 H), 7.45 (d, J ) 2.5 Hz, 1 H), 6.35 (m, 2 H),
5.50 (d, J ) 17.4 Hz, 1 H), 5.25 (d, J ) 12.1 Hz, 1 H); 13C NMR
(400 MHz) δ 161.7, 149.4, 140.3, 128.4, 118.0, 116.7, 114.4;
HRMS (EI) calcd for C7H6O2 122.0368, found 122.0369.
Diels-Ald er Rea ction betw een 5-Vin yl-2H-p yr a n -2-
on e a n d Ma leic An h yd r id e. 5-Vinyl-2H-pyran-2-one (40
mg, 0.33 mmol) and maleic anhydride (33 mg, 0.33 mmol) were
placed in a dry 50 mL round-bottom flask with 8 mL of benzene
and refluxed. The progress of the reaction was monitored by
TLC. After 2 h, the reaction was stopped and the crude
product was collected by filtration. The brown solid was
recrystalized from benzene, and 35 mg (48%) of pale brown
solid (7, mp 186-187 °C) was collected: 1H NMR (500 MHz,
acetone) δ 7.21 (d, J ) 9.5 Hz, 1 H), 6.41 (m, 1 H), 5.88 (dd, J
tion of this compound, using palladium on charcoal (5%),
led to the protected 14â-hydroxylestrone 25.
Treatment of 25 with 2.1 equiv of lithium diisopropyl-
amide with subsequent quenching of the reaction mixture
with 1.8 equiv of N-phenyltrifluoromethanesulfonimide
gave the desired enol triflate (26) in 65% yield. The
coupling reaction between 5-(trimethylstannyl)-2H-py-
ran-2-one and enol triflate 26 was carried out in THF
with 7.0 equiv of LiCl, catalyzed by tetrakis(triphen-
ylphosphine)palladium(0). This gave the expected prod-
uct (27) in 61% yield (Scheme 10). With this result in
hand, it appears that the stannane coupling methodology
will be useful for the synthesis of natural lucibufagins
and bufadienolides.
Having demonstrated that the coupling of 5-(trimeth-
ylstannyl)-2H-pyran-2-one with enol triflates is appli-
cable in steroid chemistry, we turned to another inter-
esting application of this synthon. In 1972, VanKerck-
hoven, Gilliams, and Stille reported a new method of
making polyphenylenes via a chain Diels-Alder reaction
between 5,5′-p-phenylenebis(2H-pyran-2-one) and 1,4-
diethynylbenzene.14 In contrast with the product ob-
tained from earlier studies, polyphenylenes from their
synthesis had number-average molecular weights of
40 000-100 000, were amorphous, and were soluble in
common organic solvents in concentrations of up to 10
wt %.
Our interest was in an improved synthesis of monomer
29, 5,5′-p-phenylenebis(2H-pyran-2-one). Toward this
end, the coupling of 5-(trimethylstannyl)-2H-pyran-2-one
with 1,4-diiodobenzene was investigated and was found
to give a 68% yield of 29 (Scheme 11).
Although 3-substituted 2H-pyran-2-ones are not com-
mon in nature, we were curious to know whether the
analogous stannane chemistry would provide a conve-
(14) VanKerckhoven, H.; Gilliams, Y.; Stille, J . Macromolecules
1972, 5, 541.

New 2H-Pyran-2-one Synthons
J . Org. Chem., Vol. 61, No. 19, 1996 6697
) 10, 1.0 Hz, 1 H), 5.50 (m, 1 H), 4.15 (dd, J ) 9.5, 6.5 Hz, 1
H), 3.81 (m, 1 H), 2.89 (ddd, J ) 16.5, 8.0, 1.5 Hz, 1 H), 2.58-
2.52 (m, 1 H); results from proton decoupling NMR experi-
ments and NOE experiments were consistent with the as-
signed structure (see the text for details); 13C NMR (400 MHz,
DMSO) δ 174.3, 170.3, 161.1, 140.8, 131.1, 129.8, 116.7, 73.2,
45.7, 38.1, 24.9; HRMS (EI) calcd for C11H8O5 220.0372, found
220.0372; UV λmax (hexane) ) 267 nm (ꢀ ) 8300).
5-(Tr im eth ylsta n n yl)-2H-p yr a n -2-on e (11). In a dry 10
mL round-bottom flask, hexamethylditin (1.19 g, 3.63 mmol),
5-bromo-2H-pyran-2-one (0.53 g, 3.02 mmol), and Pd(PPh3)4
(0.105 g, 0.09 mmol) were added to 4 mL of THF. The mixture
was refluxed under Ar for 30 h. The reaction mixture was
cooled to room temperature, the THF was evaporated under
reduced pressure, and the crude material was purified by flash
chromatography, eluting with 4:1 hexane-ether to obtain 0.53
g (68%) of a pale yellow oil (11): 1H NMR (200 MHz, acetone)
δ 7.48 (dd, J ) 9.0, 2.0 Hz, 1 H), 7.43 (dd, J ) 1.8, 1.5 Hz, 1
H), 6.24 (dd, J ) 9.0, 1.4 Hz, 1 H), 0.31 (t, tin satellite, J )
55.9, 55.1 Hz, 9 H); 13C NMR (300 MHz) δ 163.0, 154.5, 148.0,
117.3, 114.1, -7.5; MS (EI) m/ e (relative intensity) 249 (18),
247 (15), 245 (100), 244 (33), 243 (76), 242 (28), 241 (44), 215
(26), 213 (20), 211 (11), 151 (20), 149 (15), 147 (10), 135 (19),
133 (15), 120 (10), 95 (15), 39 (18); HRMS (EI) calcd for
C8H12O2118Sn 258.9853, found 258.9854.
5-(1-Cycloh exen yl)-2H-p yr a n -2-on e (10). Meth od A. In
a dry round-bottom flask, 5-bromo-2H-pyran-2-one (0.17g, 0.95
mmol), 1-(trimethylstannyl)cyclohexene (0.28 g, 1.14 mmol),
and Pd(PPh3)4 (0.02 g, 0.02 mmol) were added to 5 mL of THF
and refluxed under Ar for 36 h. The reaction mixture was
cooled to room temperature and the THF was evaporated. The
crude material was purified by flash chromatography, eluting
with 6.5:3.5 hexane-ether to give a viscous pale yellow oil
(0.069g, 41%).
Meth od B. 5-(Trimethylstannyl)-2H-pyran-2-one (0.35 g,
2.00 mmol), 1-cyclohexenyl triflate (11) (0.38 g, 1.67 mmol),
lithium chloride (0.14 g, 11.69 mmol), and Pd(PPh3)4 (39 mg,
0.04 mmol) were placed in a 5 mL round-bottom flask together
with 3 mL of THF. The mixture was refluxed under Ar for 36
h and cooled to room temperature. THF was evaporated and
the crude material was purified by flash chromatography,
eluting with 65:35 hexane-ether. A viscous oil (0.20 g, 68%)
was obtained: 1H NMR (200 MHz) δ 7.54 (dd, J ) 9.9, 2.3 Hz,
1 H), 7.41 (dd, J ) 1.9, 1.2 Hz, 1 H), 6.32 (dd, J ) 9.9, 1.4 Hz,
1 H), 6.00 (dd, J ) 3.8, 2.2 Hz, 1 H), 2.15 (m, 4 H), 1.60 (m, 4
H); 13C NMR (400 MHz) δ 161.0, 146,4, 142.2, 129.4, 125.4,
121.1, 116.1, 26.1, 25.8, 22.6, 22.0; HRMS (EI) calcd for
C11H12O2 176.0837, found 176.0837; UV λmax (hexane) ) 316
nm (ꢀ ) 5500).
layer was dried over anhydrous MgSO4, filtered, and evapo-
rated to give a pale yellow viscous oil. This crude material
was purified by flash chromatography, eluting with hexane-
ether (98.5:1.5) to yield a white solid (0.73 g, 67%): mp 69-
1
71 °C; H NMR (200 MHz) δ 7.08 (d, J ) 8.3 Hz, 1 H), 6.59
(m, 2 H), 5.61 (m, 1 H), 2.82 (m, 3 H), 2.30-1.20 (m, 10 H),
1.00 (s, 3 H), 0.97 (s, 9 H), 0.19 (s, 6 H); 13C NMR (400 MHz)
δ 159.3, 153.5, 137.5, 132.6, 125.8, 120.0, 117.3, 114.5, 94.7,
53.6, 45.1, 44.3, 36.6, 32.7, 29.3, 28.4, 26.8, 25.8, 25.7, 18.2,
15.4, -4.4; HRMS (EI) calcd for C25H35O4F3SiS 516.1977, found
516.1976.
5-(3′-(ter t-Bu tyld im eth ylsiloxy)estr a -1′,3′,5′(10′),16′-tet-
r a en -17′-yl)-2H-p yr a n -2-on e (15). To a solution of 14 (1.25
g, 2.42 mmol) in 5 mL of THF was added Pd(PPh3)4 (56 mg,
0.05 mmol), lithium chloride (0.74 g, 17.45 mmol), and 5-(tri-
methylstannyl)-2H-pyran-2-one (10) (0.63 g, 2.42 mmol). This
THF solution was stirred at 65 °C for 24 h. After the solution
was cooled to room temperature, the solvent was evaporated
and the crude material was dissolved in 40 mL of CH2Cl2. This
solution was washed with brine twice (20 mL each time) and
was dried over MgSO4. The solvent was evaporated and the
crude product was purified by flash chromatography, eluting
with hexane-ether (7:3) to give a white solid (0.71 g, 68%):
1
mp 129-131 °C; H NMR (300 MHz) δ 7.56 (d, J ) 1.3 Hz, 1
H), 7.49 (dd, J ) 7.3, 2.0 Hz, 1 H), 7.11 (d, J ) 6.4 Hz, 1 H),
6.63 (dd, J ) 8.2, 1.8 Hz, 1 H), 6.57 (d, J ) 1.9 Hz, 1 H), 6.35
(d, J ) 7.3 Hz, 1 H), 5.91 (m, 1 H), 2.95 (m, 3 H), 2.45-1.30
(m, 10 H), 0.99 (s, 9 H), 0.97 (s, 3 H), 0.20 (s, 6 H); 13C NMR
(400 MHz) δ 161.3, 153.4, 147.1, 146.7, 144.0, 137.7, 132.8,
128.3, 125.8, 120.0, 117.2, 116.3, 116.1, 56.5, 47.4, 44.0, 37.1,
35.4, 31.2, 29.4, 27.6, 26.4, 25.7, 18.2, 16.4, -4.4; HRMS (EI)
calcd for C29H38O3Si 462.2590, found 462.2583.
5-(3′-Hyd r oxyestr a -1′,3′,5′(10′),16′-tetr a en -17′-yl)-2H-p y-
r a n -2-on e (16). Compound 15 (0.11 g, 0.27 mmol) and
tetrabutylammonium fluoride (0.35 mL, 1.0 M in THF) were
added to 15 mL of THF in a round-bottom flask. The above
solution was stirred at room temperature for 2 h. After the
solvent was removed under reduced pressure, the crude
product was purified by flash chromatography, eluting with
hexane-ether-methanol (5.5:4.0:0.5) to yield 0.73 g (79%) of
1
white solid: mp 237 °C (dec); H NMR (200 MHz) δ 7.54 (dd,
J ) 2.4, 1.2 Hz, 1 H), 7.26 (dd, J ) 10.0, 2.5 Hz, 1 H), 7.12 (d,
J ) 8.3 Hz, 1 H), 6.60 (m, 2 H), 6.33 (dd, J ) 10.0, 1.2 Hz, 1
H), 5.89 (m, 1 H), 4.56 (s, 1 H), 2.86 (m, 3 H), 2.39-1.24 (m,
10 H), 0.95 (s, 3 H); 13C NMR (400 MHz) δ 161.4, 153.4, 147.0,
146.6, 144.0, 138.1, 132.4, 128.4, 126.2, 116.3, 116.2, 115.3,
112.7, 56.5, 47.4, 43.9, 37.1, 35.4, 31.2, 29.4, 27.5, 26.5, 16.4;
HRMS (EI) calcd for C23H24O3 348.1725, found 348.1727.
5-(3′-H yd r oxyest r a -1′,3′,5′(10′)-t r ien -17′-yl)-2H -p yr a n -
2-on e (17). Compound 16 (150 mg, 0.43 mmol) was dissolved
in 10 mL of THF and 10 mL of methanol which contained 15
mg of Pd catalyst (5% Pd on CaCO3). This solution was
hydrogenated under atmospheric pressure at 0 °C until 10.5
mL of hydrogen was consumed. The crude material was
filtered, concentrated, and purified by flash chromatography
eluting with 10% ethyl acetate in benzene. A crop of white
3-ter t-Bu tyld im eth ylsilyl-estr on e (13). In a dry round-
bottom flask, estrone (0.36 g, 1.34 mmol), imidazole (0.23 g,
3.36 mmol), and tert-butyldimethylsilyl chloride (0.24 g, 1.62
mmol) were added to 5 mL of DMF. This DMF solution was
stirred under Ar at room temperature for 10 h. The reaction
mixture was concentrated under reduced pressure and the
crude product was purified by flash chromatography, eluting
with CH2Cl2. A white solid (0.44g, 95%) was collected: mp
1
solid (120 mg, 80%) was collected: mp 249 °C (dec); H NMR
1
172 °C; H NMR (200 MHz) δ 7.12 (d, J ) 7.9 Hz, 1 H), 6.61
(400 MHz) δ 7.32 (dd, J ) 9.2 Hz, 2.0 Hz, 1 H), 7.30 (d, J )
1.0 Hz, 1 H), 7.14 (d, J ) 6.4 Hz, 1 H), 6.62 (dd, J ) 6.4 Hz,
1.6 Hz, 1 H), 6.57 (d, J ) 1.6 Hz, 1 H), 6.30 (d, J ) 7.2 Hz, 1
H), 4.48 (s, 1 H), 2.83 (m, 3 H), 2.39 (dd, J ) 8.0 Hz, 7.2 Hz,
1 H), 2.34-1.20 (m, 12 H), 0.60 (s, 3 H); 13C NMR (400 MHz)
δ 162.6, 153.8, 149.1, 145.9, 138.6, 132.8, 126.9, 118.9, 115.8,
115.7, 113.1, 55.1, 51.5, 44.7, 44.2, 39.4, 38.0, 30.0, 28.0, 26.6,
25.7, 24.3, 13.3; MS (EI) m/ e (relative intensity) 41 (16), 55
(11), 66 (11), 77 (14), 79 (16), 91 (17), 105 (11), 107 (16), 115
(10), 122 (10), 131 (14), 133 (37), 144 (12), 145 (23), 146 (22),
157 (23), 158 (16), 159 (39), 160 (60), 171 (10), 172 (15), 211
(17), 213 (100), 214 (18), 228 (26), 350 (70); HRMS (EI) calcd
for C23H26O3 350.1882, found 350.1883.
3-(ter t-Bu tyld im eth ylsiloxy)estr a -1,3,5(10),15(16)-tet-
r a en -17-on e (19). To a solution of diisopropylamine (0.60 mL,
4.3 mmol) in THF (5 mL) at 0 °C and under a nitrogen
atmosphere was added dropwise a solution of n-butyllithium
in hexane (2.9 mL, 4.7 mmol, 1.6 M). After the addition was
complete, the above solution was stirred for an additional 15
(m, 2 H), 2.84 (m, 3 H), 2.06-1.45 (m, 12 H), 0.97 (s, 9 H),
0.91 (s, 3 H), 0.18 (s, 6 H); HRMS (EI) calcd for C24H36O2Si
384.2485, found 384.2486.
3-(ter t-Bu tyld im eth ylsiloxy)estr a -1,3,5(10),16-tetr a en -
17-yl Tr ifla te (14). A flame-dried three-neck round-bottom
flask was supplied with a magnetic stir bar, an additional
funnel, an Ar line, diisopropylamine (0.31 mL, 2.20 mmol), and
3 mL of THF. n-Butyllithium (1.51 mL, 1.6 M in hexane) was
added dropwise after the mixture was cooled to 0 °C. This
solution was stirred for 15 min and cooled to -78 °C.
A
solution of 13 (0.84 g, 2.17 mmol) in 25 mL of THF was added
dropwise over the course of 10 min, after which the mixture
was stirred for an additional 2 h at -78 °C. N-Phenyltrifluo-
romethanesulfonimide (0.86 g, 2.42 mmol) in 10 mL of THF
was added at -78 °C and the mixture was allowed to warm to
room temperature overnight. The solvent was evaporated, the
residue was dissolved in 50 mL of CH2Cl2, and the solution
was washed twice with water (30 mL each time). The organic

6698 J . Org. Chem., Vol. 61, No. 19, 1996
Liu and Meinwald
min at 0 °C and then cooled to -78 °C. A solution of 13 (1.50
g, 3.5 mmol) in THF (10 mL) was added dropwise over 10 min,
after which the mixture was stirred for an additional 40 min.
Chlorotrimethylsilane (0.37 mL, 4.4 mmol) was injected via a
syringe and then the mixture was allowed to warm to room
temperature. The solvents were evaporated and the residue
was dissolved in diethyl ether-methylene chloride (3:2, 80
mL). The solution was washed successively with water (50
mL) and brine (50 mL). The organic layer was dried over
magnesium sulfate, decanted, and evaporated to give a yel-
lowish-white solid which was immediately added to a solution
of palladium(II) acetate (785 mg, 3.5 mmol) in 20 mL of
benzonitrile. This solution was stirred at room temperature
for 24 h, then the solvent was distilled under vacuum. The
black solid was purified by flash chromatography, eluting with
20% diethyl ether in hexane to give 963 mg (77%) of white
solid: 1H NMR (200 Hz) δ 7.63 (dd, J ) 7.0 Hz, 2.4 Hz, 1 H),
7.12 (d, J ) 6.4 Hz, 1 H), 6.64 (dd, J ) 6.4 Hz, 1.6 Hz, 1 H),
6.59 (d, J ) 1.6 Hz, 1H), 6.09 (dd, J ) 6.8 Hz, 3.0 Hz, 1 H),
2.90 (m, 3 H), 2.55-1.40 (m, 8 H), 1.10 (s, 3 H), 0.98 (s, 9 H),
0.18 (s, 6 H); HRMS (EI) calcd for C24H34O2Si 382.2328, found
382.2329.
3 H), 0.98 (s, 9 H), 0.18 (s, 6H); 13C NMR (400 MHz) δ 221.2,
153.6, 137.4, 131.7, 126.5, 120.0, 117.6, 81.9, 53.4, 44.9, 40.0,
33.2, 32.1, 30.1, 26.7, 25.7, 25.6, 22.0, 18.2, 13.0, -4.4; MS (EI)
m/ e (relative intensity) 41 (13), 73 (22), 75 (17), 163 (15), 343-
(100), 344 (31), 400 (32); HRMS (EI) calcd for C24H36O3Si
400.2434, found 400.2433.
3-(ter t-Bu t yld im et h ylsiloxy)-14â-h yd r oxyest r a -1,3,5-
(10),16-tetr a en -17-yl Tr ifla te (26). A flame-dried three-neck
round-bottom flask was equipped with a magnetic stir bar, an
additional funnel, an Ar line, diisopropylamine (0.11 mL, 0.80
mmol), and 2 mL of THF. n-Butyllithium (0.50 mL, 0.80
mmol, 1.6 M in hexane) was introduced into the flask dropwise
when the mixture was cooled to 0 °C. This solution was stirred
for 15 min and cooled to -78 °C. A solution of 25 (153 mg,
0.38 mmol) in THF (2 mL) was added dropwise over 5 min,
after which the mixture was stirred for an additional 2 h. A
solution of N-phenyltrifluoromethanesulfonimide (287 mg, 0.80
mmol) in THF (4 mL) was injected, and the mixture was
allowed to warm to room temperature in 2 h. The crude
material was poured into water (20 mL) and THF was
evaporated. Three portions of ether (10 mL each) were
employed to extract the crude product from the aqueous
3-(ter t-Bu t yld im et h ylsiloxy)est r a -1,3,5(10),14,16-p en -
ta en -17-yl a ceta te (20). Into a round-bottom flask was
placed 19 (383 mg, 1.0 mmol), 20 mL of acetic anhydride, and
p-toluenesulfonic acid (80 mg). This mixture was stirred at
room temperature for 20 h. The solution was concentrated
under the reduced pressure and then neutralized with pyri-
dine. This crude mixture was dissolved in diethyl ether (50
mL) which was washed successively with water (50 mL),
saturated sodium bicarbonate solution (two times 50 mL), and
brine (50 mL). The organic layer was dried over magnesium
sulfate, decanted, and evaporated to give a pale yellow oil.
Purification by flash chromatography (diethyl ether-hexane
5:95) gave 305 mg (72%) of the title compound as a yellow oil:
1H NMR (200 MHz) δ 7.14 (d, J ) 8.3 Hz, 1 H), 6.60 (m, 2 H),
6.16 (d, J ) 2.2 Hz), 5.85 (m, 1 H), 2.80 (m, 3 H), 2.38-1.12
(m, 10 H), 1.10 (s, 3 H), 0.96 (s, 9 H), 0.18 (s, 6 H); 13C NMR
(400 MHz) δ 168.1,162.4, 153.5, 151.1, 137.8, 132.2, 126.7,
120.1, 117.3, 116.2, 111.1, 50.4, 47.4, 38.5, 35.1, 29.5, 26.4, 25.7,
25.2, 21.3, 18.2, 17.9, -4.4; MS (EI) m/ e (relative intensity)
43 (42), 73 (46), 75 (15), 108 (12), 163 (11), 217 (14), 273 (23),
274 (18), 286 (23), 287 (29), 325 (11), 382 (100), 424 (8); HRMS
(EI) calcd for C26H36O3Si 424.2434, found 424.2435.
solution. The ether layer was dried over MgSO4
, filtered, and
concentrated. Flash chromatography (20% ether in hexane)
was applied to purify the crude product and gave 131 mg of a
thick oil (65%): 1H NMR (200 MHz) δ 7.14 (d, J ) 8.3 Hz, 1
H), 6.63 (dd, J ) 8.3 Hz, 2.4 Hz, 1 H), 6.57 (d, J ) 2.4 Hz, 1
H), 5.78 (dd, J ) 3.1 Hz, 1.8 Hz, 1 H), 2.80-2.62 (m, 5 H),
2.53-1.20 (m, 8 H), 1.14 (s, 3 H), 0.96 (s, 9 H), 0.18 (s, 6 H);
MS (EI) m/ e (relative intensity) 55 (19), 57 (11), 59 (12), 69
(14), 73 (24), 75 (11), 229 (16), 231 (10), 286 (16), 287 (100),
288 (25), 379 (18), 383 (25), 399 (53), 400 (17), 475 (51), 476
(17), 532 (81); HRMS (EI) calcd for C25H35O5SSiF3 532.1578,
found 532.1581.
5-(3′-(t er t -Bu t yld im e t h ylsiloxy)-14′â-h yd r oxye st r a -
1′,3′,5′(10′),16′-tetr a en -17′-yl)-2H-p yr a n -2-on e (27). To a
50 mL round-bottom flask provided with a magnetic stir bar
were added enol triflate 26 (74 mg, 0.14 mmol), 5-(trimethyl-
stannyl)-2H-pyran-2-one (43 mg, 0.17 mmol), LiCl (41 mg, 0.97
mmol), and Pd(PPh3)4 (5 mg) with 4 mL of THF. This solution
was purged with Ar and refluxed for 36 h. After the THF was
evaporated, the crude mixture was purified by flash chroma-
tography, eluting with 10% of acetone in benzene, and gave
40 mg of a brown solid (61%): 1H NMR (200 MHz) δ 7.48 (m,
1 H), 7.41 (dd, J ) 9.6 Hz, 2.6 Hz, 1 H), 7.15 (d, J ) 8.3 Hz, 1
H), 6.63 (dd, J ) 8.3 Hz, 2.4 Hz, 1 H), 6.58 (d, J ) 2.4 Hz, 1
H), 6.36 (dd, J ) 9.6 Hz, 0.9 Hz, 1 H), 5.82 (m, 1 H), 2.83 (m,
5 H), 2.69 (s, 1 H), 2.34-1.24 (m, 7 H), 1.18 (s, 3 H), 0.97 (s, 9
H), 0.18 (s, 6 H); 13C NMR (400 MHz) δ 161.1, 153.5, 147.6,
144.9, 144.2, 137.8, 131.6, 126.9, 125.3, 120.0, 117.5, 116.2,
116.1, 84.9, 52.5, 44.1, 40.1, 39.2, 38.8, 30.3, 25.8, 25.7, 23.5,
18.2, 16.3, -4.4; MS (EI) m/ e (relative intensity) 43 (52), 44
(16), 55 (65), 56 (21), 57 (98), 59 (16), 67 (16), 69 (34), 71 (38),
73 (64), 75 (50), 77 (12), 79 (12), 81 (16), 83 (25), 85 (26), 91
(20), 95 (13), 97 (25), 105 (11), 107 (11), 111 (13), 115 (17), 128
(13), 129 (14), 145 (12), 163 (26), 173 (13), 189 (12), 191 (20),
201 (12), 203 (16), 215 (11), 217 (17), 229 (33), 230 (13), 231
(29), 260 (13), 286 (92), 287 (100), 288 (29), 421 (25), 478 (43);
HRMS (EI) calcd for C29H38O4Si 478.2539, found 478.2539.
5,5′-p-P h en ylen ebis(2H-p yr a n -2-on e) (29). 1,4-Diiodo-
benzene (0.11g, 0.33 mmol), 5-(trimethylstannyl)-2H-pyran-
2-one (11) (0.20 g, 0.77 mmol), and Pd(PPh3)4 (31 mg, 0.03
mmol) were placed in a 5 mL round-bottom flask together with
3 mL of THF. The mixture was refluxed for 50 h. The crude
mixture was filtered to give 86 mg of a dark brown solid which
was recrystalized from 1,2,4-trichlorobenzene to give 60 mg
(68%) of a light brown solid: mp 307-309 °C (lit.7 mp 308-
Diels-Ald er Rea ction betw een 3-(ter t-Bu tyld im eth -
ylsiloxy)estr a -1,3,5(10),14,16-p en ta en -17-yl Aceta te a n d
Ben zyl Nitr osofor m a te To Yield 24. To a 50 mL round-
bottom flask provided with
a magnetic stir bar and an
additional funnel were added acetate 20 (126.7 mg, 0.30 mmol)
and benzyl N-hydroxycarbamate (54.7 mg, 0.33 mmol) dis-
solved in methylene chloride (15 mL). After this solution was
cooled to 0 °C, Et4IO4 (105 mg, 0.33 mmol) in 5 mL of
methylene chloride was added dropwise to the reaction flask
from the additional funnel. Two hours later, this crude
material was concentrated and redissolved in 15 mL of
anhydrous methanol. The above solution was refluxed under
Ar for 12 h. After the solvent was evaporated, the product
was purified by flash chromatography, eluting with 40% of
ether in hexane, and gave a thick pale yellow oil (101.7 mg,
62%): 1H NMR (200 MHz) δ 7.37-7.33 (m, 6 H), 7.00 (d, J )
8.8 Hz, 1 H), 6.80 (s, 1 H), 6.58 (dd, J ) 8.3, 2.0 Hz, 1 H), 6.54
(m, 1 H), 6.28 (d, J ) 6.0 Hz, 1 H), 5.13 (d, J ) 21.8 Hz, 1 H),
5.02 (d, J ) 21.8 Hz, 1 H), 2.79 (m, 3 H), 2.70-1.15 (m, 10 H),
1.12 (s, 3 H), 0.95 (s, 9 H), 0.15 (s, 6 H); HRMS (EI) calcd for
C32H41NO5Si 547.2754, found 547.2750.
3-(ter t-Bu tyld im eth ylsiloxy)-14â-h yd r oxyestr on e (25).
To a 50 mL round-bottom flask were placed the product from
the above Diels-Alder reaction (191 mg, 0.35 mmol) and Pd
on activated carbon (76 mg, 5%) with 15 mL of methanol. This
solution was stirred at room temperature in an atmospheric
pressure hydrogenator for 24 h and then filtered, and the
solvent was evaporated. The crude material was purified by
flash chromatography and gave 124 mg of white solid (88%):
mp 167 °C-169 °C; 1H NMR (400 MHz) δ 7.14 (d, J ) 8.3 Hz,
1 H), 6.62 (dd, J ) 8.3 Hz, 2.2 Hz, 1 H), 6.56 (d, J ) 2,2 Hz, 1
H), 2.82 (m, 3 H), 2.42 (s, 1 H), 2.36-1.12 (m, 11 H), 1.14 (s,
1
310 °C); H NMR (200 MHz, DMSO) δ 8.28 (dd, J ) 2.7, 1.6
Hz, 2 H), 8.04 (dd, J ) 9.8, 2.9 Hz, 2 H), 7.65 (s, 4 H), 6.47 (d,
J ) 9.8 Hz, 2 H); HRMS (EI) calcd for C16H10O4 266.0579,
found 266.0579.
3-(Tr im eth ylsta n n yl)-2H-p yr a n -2-on e (30). In a dry 10
mL round-bottom flask, hexamethylditin (1.19 g, 3.63 mmol),
3-bromo-2H-pyran-2-one (0.53 g, 3.02 mmol), and Pd(PPh3)4
(0.105 g, 0.09 mmol) were added to 4 mL of THF. The mixture
was refluxed for 32 h. After the reaction mixture was cooled

New 2H-Pyran-2-one Synthons
J . Org. Chem., Vol. 61, No. 19, 1996 6699
to room temperature, the THF was evaporated under reduced
pressure, and the crude material was purified by flash chro-
matography, eluting with 7:3 hexane-ether to yield 0.57 g
(73%) of yellow oil (30): 1H NMR (200 MHz) δ 7.44 (dd, J )
5.2, 2.3 Hz, 1 H), 7.38 (dd, J ) 6.0, 2.3 Hz, 1 H), 6.15 (dd, J )
6.0, 5.2 Hz, 1 H), 0.28 (t, tin satellite, J ) 59.6, 59.9 Hz, 9 H);
13C NMR (400 MHz) δ 164.7, 151.8, 150.6, 132.6, 106.7, -9.6;
MS (EI) m/ e (relative intensity) 249 (16), 247 (13), 245 (100),
244 (29), 243 (70), 242 (27), 241 (46), 215 (28), 213 (22), 211
(12), 165 (15), 163 (13), 161 (13), 159 (13), 157 (11), 151 (16),
149 (14), 135 (23), 133 (18), 131 (12), 120 (15), 118 (11), 95
(18), 39 (26); HRMS (FAB) calcd for C8H12O2119Sn 258.9870,
found 258.9929.
yellow oil (30): 1H NMR (200 MHz, acetone) δ 7.56 (dd, J )
5.1, 2.0 Hz, 1 H), 7.32 (dd, J ) 6.9, 2.0 Hz, 1 H), 6.58 (m, 1 H),
6.35 (dd, J ) 6.8, 5.0 Hz, 1 H), 2.21 (m, 4 H), 1.65 (m, 4 H);
13C NMR (300 MHz) δ 162.0, 149.0, 136.4, 132.1, 130.5, 129.4,
106.5, 26.5, 25.4, 22.6, 21.3; HRMS (EI) calcd for C11H12O2
176.0837, found 176.0837; UV λmax (hexane) ) 314 nm (ꢀ )
6900).
Ack n ow led gm en t. The partial support of this re-
search by NIH Grant No. AI 12020, by the Schering-
Plough Research Institute, and by the Research Coop-
eration is acknowledged with pleasure.
3-(1-Cycloh exen yl)-2H-p yr a n -2-on e (31). Into a dry 5
mL round-bottom flask were placed 3-(trimethylstannyl)-2H-
pyran-2-one (0.27 g, 1.04 mmol), 1-cyclohexenyl triflate (0.20
g, 0.87 mmol), lithium chloride (0.26 g, 6.09 mmol), and Pd-
(PPh3)4 (20 mg, 0.02 mmol) with 3 mL of THF. The mixture
was refluxed for 34 h. After the solution was concentrated,
the crude material was purified by flash chromatography,
eluting with 65:35 hexane-ether to obtain 0.11 g (72%) of
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
5, 7, 11, 13-17, 19, 20, 24-27, and 29-31 (18 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O951394T