The dihydropyrone Diels-Alder reaction: Development and application to the synthesis of highly functionalized 1-oxa-4-decalones

Article abstract of DOI:10.1016/S0040-4020(00)00863-2

A facile method for the synthesis of highly functionalized 1-oxadecalone derivatives is described via the Diels-Alder reaction of 2,3-dihydro-4-pyrone dienophiles with electron rich dienes. By this process a variety of functional groups and substitution patterns can be incorporated into the oxadecalone framework. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00863-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 10185±10195
The Dihydropyrone Diels±Alder Reaction: Development
and Application to the Synthesis of Highly
Functionalized 1-Oxa-4-decalones
*
Punit P. Seth, Deqi Chen, Junquan Wang, Xiuchun Gao and Nancy I. Totah
Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA
Received 23 November 1999; accepted 25 January 2000
AbstractÐA facile method for the synthesis of highly functionalized 1-oxadecalone derivatives is described via the Diels±Alder reaction of
2,3-dihydro-4-pyrone dienophiles with electron rich dienes. By this process a variety of functional groups and substitution patterns can be
incorporated into the oxadecalone framework. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
provide useful insights for the use of this protocol in the
synthesis of more complex molecules that contain the 1-
oxadecalin ring system.4 Herein we describe such studies,
and report our ®ndings with regard to the scope of the
dihydropyrone Diels±Alder reaction in its application to the
synthesis of highly functionalized 1-oxadecalone derivatives.
The 1-oxadecalin ring system serves as the core of a variety
of structurally diverse and biologically interesting natural
products.1 As part of an effort geared toward the synthesis of
one such compound, the PAF antagonist phomactin A (1, Fig.
1),2 we recently reported a facile approach to the synthesis of
1-oxadecalones 2.3 Our goal in this endeavor was to develop
an expedient method for the synthesis of the basic 6,6-ring
system, while at the same time providing suf®cient function-
ality to allow for subsequent synthetic manipulation. Toward
this end, we anticipated that the Diels±Alder reaction of a
suitably functionalized 2,3-dihydro-4-pyrone dienophile 3
with a diene 4 would effectively meet these criteria.
Results and Discussion
Though the Diels±Alder reaction has been much utilized for
the synthesis of six membered rings, extension of this meth-
odology to the use of dienophiles that contain a b-oxygen
substituent has remained fairly limited. Indeed, though
several related examples had appeared in the literature,5 to
the best of our knowledge 2,3-dihydro-4-pyrones had not
previously been employed in this application. As such, our
®rst objective was to demonstrate the feasibility of this
method for the synthesis of 1-oxadecalones 2.
In practice, we found that dihydropyrone dieneophiles of
this type undergo cycloaddition reactions with electron
rich dienes under both thermal3a and Lewis acid catalyzed3b
conditions. This work demonstrated for the ®rst time that
dihydropyrones could be used effectively as dienophiles in
the Diels±Alder reaction, and validated this strategy as an
ef®cient entry to the basic 1-oxadecalin framework. As such,
we anticipated that further development of this method would
Toward this end, we initially chose to explore the reactivity
of 2,3-dihydro-4-pyrones of type 3 that contained an
electron withdrawing substituent at C5 (Fig. 2).6 Though a
Figure 1.
Keywords: Diels±Alder reactions; cycloaddition; pyrone.
* Corresponding author. Tel.: 11-319-335-1198; fax: 11-319-335-1270; e-mail: nancy-totah@uiowa.edu
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00863-2

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P. P. Seth et al. / Tetrahedron 56 (2000) 10185±10195
With the cycloadduct 8b in hand, reduction of the C4
ketone (NaBH4) and hydrolysis of the enol ether
provided the corresponding 1-oxadecalone 12 in 67%
overall yield without accompanying aromatization.10
Alternatively the cycloadduct 8b could be reduced with
LiAlH4 to give, upon hydrolysis, the corresponding diol
13 in 59% overall yield as a single diastereomer (Table 1,
entry 1).
Figure 2.
variety of other 2,3-dihydro-4-pyrone derivatives are
readily available,7 we anticipated that the presence of such
a functionality at C5 would enhance the reactivity of these
substrates as dienophiles relative to that of the parent
dihydropyrone (5). In addition, we anticipated that the use
of an electron rich diene would facilitate the cycloaddition
reaction with these rather unconventional dienophiles.
As shown in Table 1, a variety of activated dihydropyrones
3 undergo cycloaddition reactions with electron rich
dienes.11 In addition to the C5 ester (3a), nitrile (3b), sulfone
(3c), and ketone (3d) functionalities are also suitable acti-
vating groups for these dihydropyrones (entries 2±4). In
each of these cases, initial cycloaddition favors formation
of the endo product (e.g. 14-endo),12 with varying levels of
diastereoselectivity. As shown (entries 2, 6 and 10), highest
levels of selectivity are observed with the C5 nitrile (3b),
which reacts with 1-methoxy-3-silyloxy dienes to give a
10±16:1 ratio of isomers with the endo adduct predominat-
ing. Similar levels of selectivity (10:1) are observed with the
C5 sulfone (entries 3, 7, and 11). In these cases, secondary
orbital interactions of the diene with the C5 nitrile and sul-
fone substituents are presumably less signi®cant than those
with the ring ketone at C4.13 To a lesser extent, such differ-
ences are also apparent in the Diels±Alder reactions of the
5-carbethoxy derivative 3a, the diastereoselectivity of
which is generally 4:1 in reactions with 1-methoxy-3-
silyloxy dienes (entries 1, 5, 9, and 12). In the case of
the C5 ketone (5d), in which secondary orbital inter-
actions between the diene and substituents at C4 and C5
are expected to be similar, little diastereoselectivity is
observed (entries 4 and 8). It is interesting to note that
the use of the related 1-dimethylamino-2-silyloxy diene 20
(Rawal's diene)14 results in a signi®cant increase in
diastereoselectivity (20:1) in the Diels±Alder reaction
with dihydropyrone 3a. Though in many of these exam-
ples the stereochemistry of the cycloadduct is of little
consequence, in the current application, use of the more
highly substituted dienes 18 and 19 (entries 9±12) result
in the formation of stereocenter at C8 that is not destroyed
upon hydrolysis of the intermediate enol ether. In cases
where a signi®cant amount of the exo adduct is present,
separation of the diastereomers can be achieved by silica
gel chromatography.
The 5-carbethoxy dihydropyrone derivative 3a was thus
prepared and evaluated in the Diels±Alder reaction with
Danishefsky's diene 7a (Scheme 1). As anticipated, the
reactivity of the dihydropyrone 3a was such that high
temperatures were required to initiate the cycloaddition.
Thus, treatment of the dihydropyrone 3a with 5 equiv. of
diene 7a at 1908C under sealed tube conditions provided the
Diels±Alder adduct 8a, which was directly hydrolyzed to
give the 1-oxadecalone 9 in ca. 42% yield (impure). Inspec-
tion of the crude reaction mixture revealed the presence of
varying amounts of ethyl p-hydroxybenzoate (10) that could
not be separated from the desired product. Since formation
of this aromatic ester was believed to commence by hydra-
tion of the C4 ketone (e.g. 9),8 we anticipated that reduction
of this moiety prior to hydrolysis of the silyl enol ether
would circumvent this degradative pathway. Unfortunately,
direct synthetic manipulation of the silyl enol ether 8a
(RˆTMS) was limited by the poor hydrolytic stability of
this intermediate. However, use of the tert-butyldimethyl-
silyl derivative of Danishefsky's diene (7b)9 allowed for the
isolation of a stable cycloadduct 8b (5a:5bˆ4:1) that could
be partially puri®ed by chromatography. Use of the more
thermally stable diene 7b had the added bene®t of minimiz-
ing diene decomposition over the course of the reaction. As
such, not only were we able to reduce the amount of diene
present in the reaction mixture, but the transformation could
now be effected at lower temperature, and without the use of
a sealed tube.
Scheme 1.

P. P. Seth et al. / Tetrahedron 56 (2000) 10185±10195
Table 1. Synthesis of 1-oxadecalone derivatives using activated dienes
10187
a
3a WˆCO2Et; 3b WˆCN; 3c WˆSO2Ph; 3d WˆCOCH3.
b Ratios were obtained by analysis of H NMR spectra of the crude reaction mixtures. Relative stereochemistry was determined by NOE studies on the
individual cycloadducts.
1
c
Isolated yield.
d In addition to the compound shown, ca. 10% of the b C4 alcohol was also isolated.
As was observed in the reaction of dihydropyrone 3a with
Danishefsky's diene (cf. Scheme 1), direct hydrolysis of the
initially formed cycloadducts is often complicated by
competing aromatization of the carbocyclic ring. However,
notable differences in the stability of product oxadecalones
of type 16 were observed depending on the nature of the
electron withdrawing substituent at C4a. For example,
1-oxadecalones 16 that contained ester (WˆCO2Et) and
nitrile (WˆCN) functionalities at the ring junction are
generally subject to rapid aromatization, necessitating
reduction at C4, while those with a C4a sulfone
(WˆSO2Ph) can be readily puri®ed by silica gel chroma-
tography (entries 3, 7, and 11). In these latter cases, the
bulky phenylsulfone substituent at C4a may impede hydra-
tion of the C4 carbonyl, and thus shuts down the degradative
pathway.8 In certain cases, even those derivatives that are

10188
P. P. Seth et al. / Tetrahedron 56 (2000) 10185±10195
prone to aromatization can be isolated with the C4 ketone
intact. For example, the oxadecalone 12d that bears a keto
substitutent at the ring junction, as well as at C4, can be
isolated in 72% overall yield (entry 4). Though this deriva-
tive is subject to the degradative aromatization process,
puri®cation can be achieved by recrystallization from
hexanes:CH2Cl2. In this case, attempts to selectively reduce
the C4 carbonyl with NaBH4 result in the formation of a
complex mixture of diastereomers. Though the need to
reduce the C4 ketone prior to hydrolysis in the majority of
these cases adds length to the synthetic sequence, overall
yields for these 2±3 step processes are generally excellent.
13 in 65% overall yield from dihydropyrone 3a. Though the
dif®culties encountered with use of the 1-dimethylamino-
diene 20 for the synthesis of 1-oxadecalone derivatives of
type 15 make use of this system less practical for routine
use, the enhanced reactivity of such systems may allow for
the preparation of 1-oxadecalone derivatives that are less
stable to high reaction temperatures or are derived from
less highly activated dihydropyrone dienophiles.
In order to further assess the scope of the dihydropyrone
Diels±Alder reaction, a variety of additional dienes were
screened in this application. In particular, dienes were
chosen which allowed us to evaluate both steric and elec-
tronic factors in the success of this reaction. Toward this
end, we ®rst examined a series of electron rich dienes 30±32
that contained additional substitution at C1 (Table 2). Here,
Diels±Alder reaction of the 1-methoxy-1-methyl-3-silyl-
oxydiene 30 with dihydropyrones 3a and 3b proceeded
under standard conditions (1108C, 24 h) to give, upon
hydrolysis, the corresponding 1-oxadecalone derivatives
33 (entries 1 and 2). Though the overall yields in the
synthetic sequence suffer somewhat from the increased
steric requirements of this diene 30, useful amounts of the
1-oxadecalone products 33 can still be obtained by this
procedure. In any event, the steric restraints imposed by
the presence of a cis substituent at C1 are overcome in the
trioxygenated diene 31, reaction of which with dihydropyrones
3 occurs in excellent yields at room temperature (entries 3±6).
In these cases, the product oxadecalones (33 and 34) bear a
non-hydrogen substituent at C5 and are no longer subject to
degradative aromatization of the carbocyclic ring. Thus
reduction of the C4 ketone is not required prior to hydrolysis.
Though the cycloaddition reactions of the type described in
Table 1 generally require elevated temperatures, reaction of
the more strongly activated Rawal's diene 20 occurs quite
readily at room temperature in the absence of a solvent.
However, although clean conversion of reactants 3a and
20 to the corresponding cycloadduct 24 (EˆCO2Et) is
observed by 1H NMR analysis of the crude reaction mixture,
only ring cleavage products 25 (45%) and 26 (46%) are
obtained on attempted puri®cation (Scheme 2). Formation
of these compounds is thought to arise by fragmentation of
the initially formed cycloadduct to give a zwitterionic inter-
mediate 27 that can then undergo silyl transfer or hydrolysis
to give products 25 and 26 respectively. Presumably, the
presence of the bulky, electron rich dimethylamino group
at C5 facilitates this ring cleavage due to the proximity of
the b electron withdrawing substituents (e.g. ester and
ketone).15 As such, we anticipated that this problem could
be circumvented by reduction of the C4 ketone in analogy to
efforts described above. Unfortunately, reduction of the
cycloadduct 24 with NaBH4 was accompanied by ring clea-
vage providing the tetrahydropyran 28 as a single diastereo-
mer. In this case, ring cleavage presumably occurs prior to
reduction.16 Indeed, reduction of the tetrahydropyrone 26
under like conditions also provides alcohol 28. As the rate
of ring cleavage is enhanced in the presence of a polar
medium, we anticipated that the use of a less polar solvent
might facilitate reduction prior to cleavage of the C4a/C5
bond. In practice, treatment of the crude cycloadduct 24
with LiAlH4 in Et2O at 2788C provided the desired enone
Despite the success of dihydropyrone Diels±Alder reactions
that employ dienes 30 and 31, the related system 32 does not
participate in cycloaddition reactions with dihydropyrone
dienophiles. Indeed, this system is not reactive enough to
undergo cycloaddition at ambient conditions, while at
higher temperature, decomposition of the diene predomi-
nates.17 Though under Lewis acid catalyzed conditions reac-
tion of the diene 32 with dihydropyrones 3a and 3b is quite
facile, in these cases the unsaturated ester 36 (Fig. 3) is the
Scheme 2.

P. P. Seth et al. / Tetrahedron 56 (2000) 10185±10195
Table 2. Synthesis of 1-oxadecalone derivatives using trisubstituted dienes
10189
a
3a WˆCO2Et; 3b WˆCN; 3c WˆSO2Ph; 3d WˆCOCH3.
b Isolated yield.
Under these conditions, competing reduction of the product enone is not observed.
c
only product isolated from the reaction mixture. None of the
corresponding cycloadducts 35 are observed, even when the
reaction is quenched at low temperatures.
the nitrile derivative 3b which reacts with the hindered
diene 39 to provide oxadecalone 42b in moderate yield
(38%) after hydrolysis of the intermediate cycloadduct.18
In any event, we have since demonstrated that the low reac-
tivity of these monooxygenated dienes 38 and 39 with
dihydropyrone 3a can be overcome by the use of Lewis
acid.3b Indeed, Diels±Alder reactions of diene 38 and 39
with dihydropyrone 3a in the presence of ZnCl2 (THF,
258C, 2 h) provides the corresponding 1-oxadecalones 42a
and 42b in 73% and 76% overall yields, respectively, upon
hydrolysis of the intermediate enol ethers.3b Under these
same conditions 1-methoxybutadiene (39) shows no reac-
tion with either of these dihydropyrones.19
We next examined the ability of dihydropyrones 3 to act as
dienophiles in the Diels±Alder reactions with dienes that
contained a single oxygen functionality (Table 3). In this
context we ®rst explored the reaction of commercially avail-
able 1-methoxybutadiene (37) with the dihydropyrone ester
3a. In re¯uxing toluene, no cycloaddition products were
observed even after extended reaction times. However, the
desired Diels±Alder adduct 40a can be obtained in 54%
yield when the reaction is carried out at 2608C in toluene
for 72 h (entry 1). Examination of the crude reaction
1
mixture by H NMR indicated that the cycloadducts were
In light of our results with the monooxygenated dienes, it is
perhaps not surprising to note that to date we have been
unable to identify conditions under which unactivated
dienes 43±45 (Fig. 4) will participate in the Diels±Alder
reaction with dihydropyrone dienophiles 3. Indeed, in these
cases, none of the corresponding cycloadducts are observed,
even after 72 h at temperatures up to 3008C (sealed tube).
The use of Lewis acid catalysts has been equally unsuccess-
ful in this speci®c application. At the same time, we have
begun to explore the reactivity of the related dihydropyrones
5 and 6 (Fig. 2, XˆBr, I) as dienophiles in the Diels±Alder
reaction. As anticipated, compounds of these types are
signi®cantly less reactive than the dihydropyrones of type
3, and do not undergo cycloaddition, even with highly acti-
vated dienes such as Rawal's diene 20 and the trioxygenated
diene 31. Preliminary results also suggest that compounds of
these types are unreactive toward electron poor dienes such
as 46 and 47.
formed as a 10:1 mixture of diastereomers with the endo
isomer predominating. The nitrile 3b and sulfone 3c (entries
2 and 3) also undergo the desired cycloaddition reaction.
Here, the reactions proceed at lower temperatures (2008C),
and with higher levels of stereoselectivity. Indeed, in neither
1
case was any of the exo diastereomer apparent in the H
NMR of the crude reaction mixture.5d These results are
consistent with the higher levels of selectivity observed
for nitrile 3b and sulfone 3c derivatives versus that of the
ester 3a with more highly activated dienes (cf. Table 1).
Two additional monooxygenated dienes 38 and 39 were also
examined in this application, albeit with limited success
(entries 4±7). In general, we found that monooxygenated
dienes of these types do not undergo thermal Diels±Alder
reactions with dihydropyrones 3, perhaps due to the instabil-
ity of the dienes at temperatures required for the cyclo-
addition reaction. An exception was noted in the case of
In conclusion, the Diels±Alder reaction of 2,3-dihydro-4-
pyrone dienophiles provides a facile entry to the synthesis of
highly functionalized 1-oxadecalin derivatives. Under ther-
mal conditions, dihydropyrone dienophiles 3, that contain
an electron withdrawing substituent at C5, undergo cyclo-
addition reactions with electron rich dienes under relatively
mild conditions. Though more vigorous conditions are
Figure 3.

10190
P. P. Seth et al. / Tetrahedron 56 (2000) 10185±10195
Table 3. Synthesis of 1-oxadecalone derivatives using monooxygenated dienes
a
3a WˆCO2Et; 3b WˆCN; 3c WˆSO2Ph; 3d WˆCOCH3.
b
1
Ratios were obtained by analysis of H NMR spectra of the crude reaction mixtures. Relative stereochemistry was determined by NOE studies on the
individual cycloadducts.
Isolated yield.
c
Figure 4.
required for the use of less strongly activated dienes, in
general, the desired oxadecalone products are obtained in
high overall yields. By this process, a variety of functional
groups and substitution patterns can be incorporated into the
basic oxadecalin framework. This feature should provide for
signi®cant ¯exibility in the synthesis of more complex
substrates. Overall, the dihydropyrone Diels±Alder reaction
is a synthetically useful process that allows for the prepara-
tion of highly functionalized 1-oxadecalone derivatives in a
straightforward manner. Studies aimed at the application of
this methodology toward the synthesis of complex mole-
cules are currently ongoing. These results will be reported
in due course.
(d 77.0 ppm) was used as the internal standard. IR spectra
were obtained with a Mattson Cygnus 25 instrument.
High resolution mass spectra were obtained by the Univer-
sity of Iowa Mass Spectrometry Laboratory. Elemental
Analyses were performed by Atlantic Microlab, Inc.
(Norcross, GA).
General procedure for the reduction of cycloadducts
with NaBH4
A solution of the Diels±Alder adduct (1 mmol) in MeOH
was cooled to 08C and NaBH4 (1.5 mmol) was added. After
1 h, the reaction mixture was quenched with saturated,
aqueous NH4Cl, warmed to room temperature, and
extracted with CH2Cl2. The combined organics were dried
over anhydrous Na2SO4, ®ltered, and concentrated in vacuo
to provide the crude alcohol.
Experimental
General methods
General procedures for the acid catalyzed hydrolysis of
enol ethers
All air sensitive reactions were performed in oven dried
glassware under an atmosphere of argon. Reaction solvents
were dried over CaH2 (benzene, dichloromethane) or
sodium/benzophenone ketyl (toluene, tetrahydrofuran) and
were distilled just prior to use. All other reagents were
reagent grade and puri®ed where necessary. Melting points
are uncorrected. 1H NMR spectra were recorded on a Bruker
WM 360 spectrometer. Chemical shifts are reported in ppm,
down®eld from tetramethylsilane using residual CHCl3 (d
7.27) as the internal standard. 13C NMR spectra were
recorded on a Bruker WM-360 (90 MHz) spectrometer in
CDCl3 with complete proton decoupling. Residual CHCl3
Method A. To a solution of the enol ether (1 mmol) in wet
THF (3 mL) was added a catalytic amount of pTsOH
(25 mg). The resulting mixture was stirred at room tempera-
ture for 2 h, after which time aqueous, saturated NaHCO3
was added, and the reaction mixture diluted with CH2Cl2.
The layers were separated, and the aqueous extracted with
additional CH2Cl2. The combined organics were dried over
MgSO4, ®ltered, and the solvent removed in vacuo.
Method B. To a solution of the enol ether (1 mmol) in 4 mL

P. P. Seth et al. / Tetrahedron 56 (2000) 10185±10195
10191
CH3CN was added 0.60 mL 10% HF in CH3CN. The result-
ing mixture was stirred for 2 h at room temperature, then
saturated, aqueous NaHCO3 was added, and the reaction
mixture diluted with CH2Cl2. The layers were separated,
and the aqueous extracted with additional CH2Cl2. The
combined organics were dried over MgSO4, ®ltered, and
the solvent removed in vacuo.
68.5, 49.3, 41.3, 29.4, 27.2. IR (®lm): 1727, 1692 cm21
HRMS (FAB): Calcd for C17H18O5S ([M1H]1):
335.09532, found: 335.0944.
1-Oxadecalone 12d. A solution of diene 7b (0.260 g,
1.21 mmol) and dihydropyrone 3d (0.100 g, 0.606 mmol)
in 4 mL toluene was warmed to re¯ux and stirred for 24 h.
The reaction mixture was cooled to room temperature,
concentrated in vacuo, and the residue passed through a
short silica gel column (hexanes:EtOAc, 7:1, containing
1% Et3N) to remove lower Rf materials. The resulting
Diels±Alder adduct was concentrated in vacuo, then hydro-
lyzed directly (Method B). The product was recrystallized
from hexanes/CH2Cl2 to give the enone 12d as a white solid
(0.101 g, 72%). 1H NMR (CDCl3): d 6.88 (1H, dd, Jˆ10.2,
2.7 Hz), 6.25 (1H, d, Jˆ10.2 Hz), 5.10 (1H, m), 2.68 (1H,
dd, Jˆ17.1, 3.1 Hz), 2.58 (2H, m), 2.50 (1H, d, Jˆ13.7 Hz),
2.30 (3H, s), 1.32 (3H, s), 1.21 (3H, s). 13C NMR (CDCl3): d
204.2, 201.3, 194.4, 140.8, 130.9, 75.3, 70.9, 69.1, 49.6,
40.9, 29.8, 29.4, 25.3. IR (®lm): 1722, 1707, 1696 cm21
HRMS (EI): Calcd for C13H16O4 ([M]1): 236.1048, found:
236.1041.
1-Oxadecalone 12a. A solution of diene 7b (0.068 g,
0.32 mmol) and dihydropyrone 3a (0.021 g, 0.106 mmol)
in 0.5 mL toluene was warmed to re¯ux, and stirred for
24 h. The reaction mixture was then cooled to room
temperature, concentrated in vacuo, and the residue passed
through a short silica gel column (hexanes:EtOAc, 7:1,
containing 1% Et3N) to remove lower Rf materials. The
partially puri®ed Diels±Alder adduct was reduced with
NaBH4 according to the general procedure, then hydrolyzed
directly (Method B). The residue was puri®ed by ¯ash
chromatography (SiO2; hexanes: EtOAc, 2:1) to provide
the enone (0.019 g, 67%) as a colorless oil. 1H NMR
(CDCl3): d 6.90 (1H, dd, Jˆ10.3, 2.3 Hz), 6.23 (1H,
d, Jˆ10.3 Hz), 4.51 (1H, dd, Jˆ12.5, 4.6 Hz), 4.36 (1H,
dd, Jˆ5.6, 2.9 Hz), 4.24 (2H, q, Jˆ7.2 Hz), 2.63 (1H, dd,
Jˆ17.1, 2.7 Hz), 2.60 (1H, br s, OH), 2.52 (1H, dd, Jˆ17.1,
3.1 Hz), 1.71 (1H, dd, Jˆ13.1, 4.6 Hz), 1.44 (1H, t,
Jˆ12.8 Hz), 1.28 (3H, t, Jˆ7.2 Hz), 1.26 (3H, s), 1.16
(3H, s). 13C NMR (CDCl3): d 196.9, 171.8, 141.5, 131.5,
73.0, 70.3, 69.0, 62.2, 54.1, 41.9, 40.1, 31.1, 22.5, 14.1. IR
(®lm): 3437, 1725, 1686 cm21 HRMS (EI): Calcd for
C14H20O5 ([M]1): 268.1311, found: 268.1291.
1-Oxadecalone 13. Diene 20 (0.24 g, 1.1 mmol) and
dihydropyrone 3a (0.53 g, 0.26 mmol) were combined in
the absence of solvent and stirred at room temperature for
45 min. The crude cycloadduct was dissolved in ether
(2 mL) and the resulting solution cooled to 2788C.
LiAlH4 (0.055 g, 1.5 mmol) was added, and the reaction
mixture allowed to warm gradually to room temperature
over 3 h. After 16 h, it was diluted with wet ether (7 mL),
treated sequentially with 3 M NaOH (0.08 mL) and H2O
(0.24 mL), then stirred for 10 min. The resulting suspension
was ®ltered through celite and concentrated in vacuo. The
crude material (29) was then hydrolyzed (Method B). The
residue was puri®ed by ¯ash chromatography (SiO2;
CHCl3:MeOH, 50:1±20:1) to provide the enone (0.039 g,
1-Oxadecalone 12b. A solution of diene 7b (0.058 g,
0.27 mmol) and dihydropyrone 3b (0.015 g, 0.10 mmol)
in 0.5 mL toluene was warmed to re¯ux. After 24 h, the
reaction mixture was cooled to room temperature, concen-
trated in vacuo, and the crude Diels±Alder adduct reduced
with NaBH4, then hydrolyzed (Method B). The residue was
puri®ed by ¯ash chromatography (SiO2; hexanes:EtOAc,
7:3) to give 0.016 g (73%) of the enone as a white solid
(mp 124±1258C). 1H NMR (CDCl3): d 6.78 (1H, dd,
Jˆ10.2, 2.6 Hz), 6.28 (1H, d, Jˆ10.2 Hz), 4.35 (2H, m),
2.91 (1H, dd, Jˆ17.0, 2.7 Hz), 2.79 (1H, br d, Jˆ4.5 Hz),
2.67 (1H, ddd, Jˆ17.0, 3.2, 0.9 Hz), 1.74 (1H, dd, Jˆ13.4,
4.5 Hz), 1.38 (1H, m), 1.23 (3H, s), 1.15 (3H, s). 13C NMR
(CDCl3): d 195.1, 136.6, 133.1, 118.5, 73.7, 70.0, 68.6,
43.0, 41.7, 39.6, 30.8, 22.3. IR (®lm): 3442, 2238,
1692 cm21 HRMS (EI): Calcd for C12H15O3N ([M]1):
221.1052, found: 221.1065.
1
65%) as a white solid (mp 126±1278C). H NMR: d 7.01
(1H, dd, Jˆ10.4, 2.5 Hz), 6.22 (1H, d, Jˆ10.4 Hz), 4.33
(1H, m), 4.12 (1H, dd, Jˆ5.7, 3.0 Hz), 3.97 (1H, dd,
Jˆ10.6, 5.5 Hz), 3.79 (1H, dd, Jˆ10.6, 3.4 Hz), 2.90 (1H,
d, Jˆ3.0 Hz), 2.77 (1H, dd, Jˆ17.5, 3.2 Hz), 2.58 (1H, m),
2.50 (1H, ddd, Jˆ17.5, 3.0, 1.0 Hz), 1.72 (1H, dd, Jˆ12.7,
4.6 Hz), 1.49 (1H, t, Jˆ12.7 Hz), 1.24 (3H, s), 1.17 (3H, s).
13C NMR: d 197.7, 146.5, 131.5, 72.7, 69.5, 68.2, 66.9,
46.6, 41.9, 40.9, 31.3, 22.6. IR (®lm): 3414, 1670 cm21
.
Anal. Calcd for C12H18O5: C, 63.70%; H, 8.02%. Found:
C, 63.36%; H, 8.05%.
1-Oxadecalone 12c. A solution of diene 7b (0.084 g, 0.39
mmol) and dihydropyrone 3c (0.035 g, 0.13 mmol) in
0.5 mL toluene was warmed to re¯ux. After 24 h, the reac-
tion mixture was cooled to room temperature, the solvent
removed in vacuo, and the crude Diels±Alder adduct hydro-
lyzed (Method A). The residue was puri®ed by ¯ash chro-
matography (SiO2; hexanes:EtOAc, 7:3) to afford the enone
1-Oxadecalone 21a. A solution of diene 17 (0.082 g,
0.41 mmol) and dihydropyrone 3a (0.041 g, 0.21 mmol) in
0.5 mL toluene was warmed to re¯ux. After 24 h, the reac-
tion mixture was cooled to room temperature and concen-
trated in vacuo. The crude Diels±Alder adduct was reduced
with NaBH4, then subjected to hydrolysis (Method A). The
residue was puri®ed by ¯ash chromatography (SiO2;
hexanes: EtOAc, 3:1) to give the enone (0.033 g, 57%) as
1
as a white solid (0.038 g, 88%). H NMR (CDCl3): d 7.72
1
(3H, m), 7.58 (2H, m), 6.31 (1H, dd, Jˆ10.3, 2.4 Hz), 6.22
(1H, dd, Jˆ10.3, 0.7 Hz), 5.43 (1H, dt, Jˆ4.4, 2.2 Hz), 3.38
(1H, dd, Jˆ17.3, 4.4 Hz), 3.36 (1H, d, Jˆ13.9 Hz), 2.69
(1H, ddd, Jˆ17.3, 2.2, 0.7 Hz), 2.46 (1H, d, Jˆ13.9 Hz),
1.42 (3H, s), 1.07 (3H, s). 13C NMR (CDCl3): d 199.6,
194.0, 136.2, 135.1, 134.7, 133.0, 130.5, 129.1, 75.8, 74.8,
a pale yellow liquid. H NMR (CDCl3): d 6.61 (1H, t,
Jˆ1.2 Hz), 4.42 (1H, dt, Jˆ12.3, 3.8 Hz), 4.30 (1H, dd,
Jˆ5.2, 2.3 Hz), 4.20 (2H, q, Jˆ7.1 Hz), 2.63 (1H, dd,
Jˆ17.0, 2.2 Hz), 2.51 (1H, dd, Jˆ17.0, 2.7 Hz), 2.50 (1H,
d, Jˆ3.4 Hz; OH), 1.86 (3H, d, Jˆ1.2 Hz), 1.67 (1H, dd,
Jˆ12.7, 4.6 Hz), 1.42 (1H, t, Jˆ12.7 Hz), 1.25 (3H, t,

10192
P. P. Seth et al. / Tetrahedron 56 (2000) 10185±10195
Jˆ7.1 Hz), 1.22 (3H, s), 1.12 (3H, s). 13C NMR (CDCl3): d
197.1, 172.4, 137.7, 135.9, 72.8, 70.3, 69.2, 62.0, 54.1, 41.9,
40.0, 31.1, 22.5, 16.1, 14.1. IR (®lm): 3457, 1724,
1683 cm21 HRMS (EI): Calcd for C15H22O5 ([M]1):
282.1467, found: 282.1482.
Diels±Alder adduct was reduced with NaBH4, then hydro-
lyzed (Method B). The residue was puri®ed by ¯ash
chromatography (SiO2; hexanes:EtOAc, 2:1) to provide
the endo (0.082 g, 46%) and exo diastereomers (0.027 g,
15%) as white solids (endo mp 108±1098C). endo: 1H
NMR (CDCl3): d 6.81 (1H, dd, Jˆ10.3, 2.9), 6.20 (1H, d,
Jˆ10.3 Hz), 4.45 (1H, dt, Jˆ12.5, 4.4 Hz), 4.25 (2H, q,
Jˆ7.2 Hz), 4.17 (1H, t, Jˆ2.6 Hz), 2.55 (1H, dq, Jˆ6.9,
1.9 Hz), 2.30 (1H, d, Jˆ4.2 Hz), 1.70 (1H, dd, Jˆ13.1,
4.7 Hz), 1.42 (1H, t, Jˆ13.0 Hz), 1.28 (3H, t, Jˆ7.0 Hz),
1.23 (3H, s), 1.15 (3H, d, Jˆ6.9 Hz), 1.13 (3H, s). 13C NMR
(CDCl3): d 199.5, 172.3, 140.3, 131.4, 75.4, 72.7, 69.6,
62.1, 55.3, 44.2, 40.5, 31, 22.6, 14.1, 11.3. IR (®lm):
3417, 1684 cm21. Anal. Calcd for C151H22O5: C, 63.81;
H, 7.85. Found: C, 63.63; H, 7.74. exo: H NMR (CDCl3):
d 6.90 (1H, dd, Jˆ10.6, 2.6 Hz), 6.11 (1H, d, Jˆ10.5 Hz),
4.46 (1H, dd, Jˆ12.7, 4.5 Hz), 4.28 (1H, t, Jˆ2.4 Hz), 4.21
(2H, m), 2.56 (1H, dq, Jˆ8.0, 2.7 Hz), 2.38 (1H, s, br), 1.66
(1H, dd, Jˆ12.8, 4.6 Hz), 1.41 (1H, t, Jˆ12.6 Hz), 1.28 (3H,
t, Jˆ7.0 Hz), 1.26 (3H, s), 1.14 (3H, s), 1.03 (3H, d,
Jˆ8.1 Hz). 13C NMR (CDCl3): d 201.0, 173.2, 141.6,
129.4, 75.1, 72.9, 71.0, 61.9, 52.5, 47.1, 40.6, 31.2, 22.6,
13.9, 13.7.
1-Oxadecalone 21b. A solution of diene 17 (0.082 g,
0.44 mmol) and dihydropyrone 3b (0.083 g, 0.42 mmol) in
0.5 mL toluene was warmed to re¯ux. After 36 h, the reac-
tion mixture was cooled to room temperature and concen-
trated in vacuo. The crude Diels±Alder adduct was reduced
with NaBH4, then subjected to hydrolysis (Method A).
The residue was puri®ed by ¯ash chromatography (SiO2;
hexanes:EtOAc, 3:1) to give 0.027 g (68%) of the enone
as a pale yellow solid (mp 151±1528C). 1H NMR
(CDCl3): d 6.51 (1H, br s), 4.32 (2H, m), 2.91 (1H, dd,
Jˆ17.0, 2.7 Hz), 2.70 (2H, m), 1.87 (3H, d, Jˆ1.1 Hz),
1.72 (1H, dd, Jˆ13.3, 4.5 Hz), 1.41 (1H, t, Jˆ12.8 Hz),
1.23 (3H, s), 1.14 (3H, s). 13C NMR (CDCl3): d 195.2,
140.0, 130.8, 119.1, 73.6, 70.1, 69.0, 43.5, 41.8, 39.5,
30.9, 22.3, 16.0. IR (®lm): 3455, 2237, 1686 cm21 HRMS
(EI): Calcd for C13H17O3N ([M]1): 235.1208, found:
235.1222.
1-Oxadecalone 21c. A solution of diene 17 (0.052 g,
0.26 mmol) and dihydropyrone 3c (0.034 g, 0.13 mmol) in
0.5 mL toluene was warmed to re¯ux. After 24 h, the reac-
tion mixture was cooled to room temperature, the solvent
removed in vacuo, and the crude Diels±Alder adduct hydro-
lyzed (Method A). The residue was puri®ed by ¯ash
chromatography (SiO2; hexanes:EtOAc, 3:1) to afford the
enone as a white solid (0.035 g, 78%; mp 144±1458C).1H
NMR (CDCl3): d 7.71 (3H, m), 7.57 (2H, m), 6.07 (1H, m),
5.39 (1H, m), 3.37 (1H, dd, Jˆ17.4, 4.3 Hz), 3.31 (1H, d,
Jˆ14.0 Hz), 2.69 (1H, dd, Jˆ17.4, 2.2 Hz), 2.44 (1H, d,
Jˆ14.0 Hz), 1.83 (3H, d, Jˆ1.5 Hz), 1.40 (3H, s), 1.06
(3H, s). 13C NMR (CDCl3): d 200.1, 194.3, 140.2, 135.0,
131.0, 130.4, 129.0, 75.7, 75.2, 68.6, 49.4, 41.4, 29.5, 27.1,
16.4. IR (®lm): 1724, 1686 cm21. HRMS (EI): Calcd for
C18H20O5S ([M]1): 348.1031, found: 348.1045.
1-Oxadecalone 22b. A solution of diene 18 (0.1 g,
0.5 mmol) and dihydropyrone 3b (0.015 g, 0.1 mmol) in
toluene (0.5 mL) was re¯uxed for 24 h. The reaction mixture
was cooled to room temperature, concentrated in vacuo and
passed through a short silica gel column (hexanes:EtOAc,
15:1, containing 1% Et3N). The partially puri®ed Diels±
Alder adduct was then reduced with NaBH4, and hydrolyzed
(Method B). The residue was puri®ed by ¯ash chromato-
graphy (SiO2; hexanes:EtOAc, 2:1) to provide enone 22b
1
(0.032 g, 70%) as a white solid (mp 95±968C). H NMR
(CDCl3): d 6.73 (1H, dd, Jˆ10.3, 2.5 Hz), 6.29 (1H, d,
Jˆ10.0 Hz), 4.36 (1H, m), 4.15 (1H, t, Jˆ2.1 Hz), 3.0
(1H, m), 2.96 (1H, dq, Jˆ1.9, 6.9 Hz), 1.76 (1H, dd,
Jˆ13.5, 4.7 Hz), 1.40 (1H, d, Jˆ12.9 Hz), 1.23 (3H, s),
1.22 (3H, d, Jˆ6.5 Hz), 1.15 (3H, s). 13C NMR (CDCl3):
d 197.7, 135.2, 133.3, 118.7, 74.8, 73.4, 69.0, 44.5 (2C),
39.9, 30.8, 22.3, 11.0. IR (®lm): 3370, 2239, 1694 cm21
.
1-Oxadecalone 21d. A solution of diene 17 (0.073 g,
0.37 mmol) and dihydropyrone 3d (0.031 g, 0.18 mmol) in
0.5 mL toluene was warmed to re¯ux. After 40 h, the reac-
tion mixture was cooled to room temperature, the solvent
removed in vacuo, and the crude Diels±Alder adduct hydro-
lyzed (Method B). The product was recrystallized from
hexanes:ethyl acetate (10:1) to give the desired enone as a
white solid (0.032 g, 69%; mp 85±868C). 1H NMR (CDCl3):
d 6.59 (1H, m), 5.04 (1H, m), 2.67 (1H, dd, Jˆ17.2, 3.0 Hz),
2.56 (1H, dd, Jˆ17.2, 3.2 Hz), 2.51 (2H, s), 2.28 (3H, s),
1.90 (3H, d, Jˆ1.5 Hz), 1.29 (3H, s), 1.20 (3H, s). 13C NMR
(CDCl3): d 204.9, 202.4, 194.9, 137.8, 135.6, 75.4, 71.2,
69.3, 49.7, 41.0, 30.0, 29.5, 25.3, 16.2. IR (®lm): 1705,
Anal. Calcd for C13H17O3N: C, 66.36; H, 7.28; N, 5.95.
Found: C, 66.15; H, 7.18; N, 5.74.
1-Oxadecalone 22c. A solution of diene 18 (0.06 g,
0.28 mmol) and dihydropyrone 3c (0.015 g, 0.056 mmol)
in toluene (0.5 mL) was re¯uxed for 42 h. The reaction
mixture was cooled to room temperature, concentrated
in vacuo and passed through a short silica gel column
(hexanes:EtOAc, 15:1, containing 1% Et3N). The partially
puri®ed Diels±Alder adduct was then hydrolyzed directly
(Method A). The residue was puri®ed by recrystallization
from hexanes to provide enone 22c (0.013 g, 64%) as a
1
white solid (mp 132±1338C). H NMR (CDCl3): d 7.74
1686 cm21
.
HRMS (FAB): Calcd for C14H18O4
(3H, m), 7.62 (2H, m), 6.25 (2H, m), 5.30 (1H, dd, Jˆ3.5,
2.2 Hz), 3.51 (1H, m), 3.40 (1H, d, Jˆ14.0 Hz), 2.48 (1H, d,
Jˆ13.8 Hz), 1.42 (3H, s), 1.27 (3H, d, Jˆ6.8 Hz), 1.08 (3H,
s). 13C NMR (CDCl3): d 199.8, 196.8, 135.1, 135.0, 134.8,
133.0, 130.4, 129.1, 75.7, 75.6, 73.2, 49.2, 43.0, 29.3, 26.6,
10.6. IR (®lm): 1727, 1694 cm21. HRMS (EI): Calcd for
C18H20O5S (M1): 348.1032, found: 348.1031.
([M1Na]1): 273.1103, found: 273.1090.
1-Oxadecalone 22a. A solution of diene 18 (0.29 g,
1.27 mmol) and dihydropyrone 3a (0.13 g, 0.63 mmol)
in 2.5 mL toluene was re¯uxed for 24 h. The reaction
mixture was cooled to room temperature, concentrated in
vacuo and passed through a short silica gel column (15:1,
hexanes:EtOAc, containing 1% Et3N). The partially puri®ed
1-Oxadecalone 23a. A solution of diene 19 (2.2 g,

P. P. Seth et al. / Tetrahedron 56 (2000) 10185±10195
10193
8.9 mmol) and dihydropyrone 3a (0.59 g, 3.0 mmol) in
toluene (10 mL) was re¯uxed for 48 h. The reaction mixture
was cooled to room temperature, concentrated in vacuo and
passed through a short silica gel column (hexanes:EtOAc,
20:1, containing 2% Et3N). The individual Diels±Alder
adducts were then hydrolyzed (Method B), and the residues
puri®ed by ¯ash chromatography (SiO2; hexanes:EtOAc,
5:1) to provide endo (0.37 g, 42%) and exo (0.092 g, 10%)
adducts as yellow oils. endo: 1H NMR (CDCl3): d 6.30 (1H,
m), 4.76 (1H, t, Jˆ2.6 Hz), 4.30 (2H, m), 2.57 (1H, dq,
Jˆ2.6, 6.9 Hz), 2.50 (2H, d, Jˆ2.4 Hz), 1.89 (3H, m),
1.31 (3H, t, Jˆ7.1 Hz), 1.28 (3H, s), 1.24 (3H, s), 1.23
(3H, d, Jˆ6.8 Hz). 13C NMR (CDCl3): d 203.5, 197.8,
168.1, 137.2, 133.95, 76.6, 75.2, 63.7, 62.2, 49.7, 43.5,
30.1, 24.5, 16.2, 14.1, 11.2. IR (®lm): 1742, 1709, 1684.
HRMS (FAB): Calcd for C16H24O5Na ([M1Na]1):
317.1367, found: 317.1344. exo: 1H NMR (CDCl3): d
6.33 (1H, m), 4.82 (1H, t, Jˆ2.2, 2.9 Hz), 4.29 (2H, m),
2.75 (1H, dq, Jˆ7.7, 2.6 Hz), 2.50 (2H, s), 1.90 (3H, m),
1.32 (3H, s), 1.31 (3H, t, Jˆ7.1 Hz), 1.25 (3H, s), 1.06 (3H,
d, Jˆ7.8 Hz). 13C NMR (CDCl3): d 203.5, 199.5, 168.8,
135.2, 134.5, 76.1, 75.0, 62.2, 61.8, 49.4, 46.3, 30.1, 24.6,
16.4, 14.4, 14.0. IR (®lm): 1748, 1726, 1683. HRMS (FAB):
Calcd for C16H24O5Na ([M1Na]1): 317.1367, found:
317.1344.
(Method A). The residue was puri®ed by ¯ash chroma-
tography (SiO2; hexanes:EtOAc, 2:1) to afford the enone
as a white solid (0.220 g, 85%), mp 100±1018C. H NMR
1
(CDCl3): d 5.57 (1H, s), 4.84 (1H, t, Jˆ3.0 Hz), 4.28 (2H,
dq, Jˆ7.1, 1.3 Hz), 3.77 (3H, s), 2.65 (1H, dd, Jˆ17.4,
2.7 Hz), 2.46 (1H, dd, Jˆ17.4, 3.0 Hz), 2.43 (1H, d,
Jˆ13.6 Hz), 2.33 (1H, d, Jˆ13.6 Hz), 1.31 (3H, s), 1.23
(3H, t, Jˆ7.1 Hz), 1.21 (3H, s). 13C NMR (CDCl3): d
200.2, 194.8, 168.2, 166.5, 103.6, 76.0, 72.0, 66.3, 62.3,
56.5, 50.6, 40.2, 30.4, 23.2, 13.9. IR (®lm): 1742, 1722,
1667 cm21 HRMS (FAB): Calcd for C15H21O6 ([M1H]1):
297.1338, found: 297.1338.
1-Oxadecalone 34b. A mixture of diene 31 (0.043 g,
0.198 mmol) and dihydropyrone 3b (0.023 g, 0.152 mmol)
was dissolved in 0.5 mL benzene and stirred at room
temperature for 24 h. The solvent was removed in vacuo,
and the crude Diels±Alder adduct subjected to hydrolysis
(Method A). The residue was puri®ed by ¯ash chroma-
tography (SiO2; hexanes:EtOAc, 3:1) to afford the enone
1
as a white solid (0.028 g, 75%). H NMR (CDCl3): d 5.61
(1H, s), 4.57 (1H, dd, Jˆ2.9 Hz), 3.78 (3H, s), 2.84 (1H, dd,
Jˆ17.1, 3.0 Hz), 2.74 (1H, dd, Jˆ17.1, 2.8 Hz), 2.42 (2H,
m), 1.32 (3H, s), 1.23 (3H, s). 13C NMR (CDCl3): d 194.6,
193.2, 163.6, 113.7, 104.2, 77.1, 72.3, 57.3, 55.6, 49.6, 40.3,
30.3, 22.8. IR (®lm): 2219, 1735, 1686 cm21 HRMS (FAB):
Calcd for C13H15O4N ([M1Na]1): 272.0899, found:
272.0893.
1-Oxadecalone 33a. A solution of diene 30 (0.082 g,
0.44 mmol) and dihydropyrone 3a (0.034 g, 0.17 mmol) in
0.5 mL toluene was warmed to re¯ux. After 60 h, the reac-
tion mixture was cooled to room temperature, the solvent
removed in vacuo, and the crude Diels±Alder adduct
hydrolyzed (Method B). The residue was puri®ed by ¯ash
chromatography (SiO2; hexanes:EtOAc, 4:1) to give
1-Oxadecalone 34c. A mixture of diene 31 (0.415 g,
1.70 mmol) and dihydropyrone 3c (0.094 mg, 0.35 mmol)
was dissolved in 1.5 mL benzene and stirred at room
temperature for 24 h. The solvent was removed in vacuo,
and the crude Diels±Alder adduct redissolved in 2 mL ethyl
acetate. A catalytic amount of 10% Pd/C (0.018 g) was
added, and the resulting mixture carefully degassed, then
stirred under an atmosphere of H2 for 16 h. After that
time, the reaction mixture was ®ltered through celite and
concentrated in vacuo. The residue was puri®ed by ¯ash
chromatography (SiO2; hexanes:EtOAc, 3:2) to afford the
enone as a white solid (0.070 g, 60%). 1H NMR (CDCl3): d
8.00 (2H, m), 7.61 (1H, m), 7.51 (2H, m), 5.71 (1H, s), 5.10
(1H, dd, Jˆ4.1, 1.9 Hz), 3.54 (1H, dd, Jˆ17.9, 4.1 Hz), 3.45
(3H, s), 2.62 (1H, dd, Jˆ17.9, 1.9 Hz), 2.37 (1H, d,
Jˆ13.2 Hz), 2.29 (1H, d, Jˆ13.2 Hz), 1.25 (3H, s), 1.24
(3H, s). 13C NMR (CDCl3): d 197.3, 195.1, 163.0, 139.1,
134.2, 131.0, 128.1, 106.7, 79.3, 75.9, 70.1, 56.1, 52.6, 41.0,
30.2, 22.9. IR (®lm): 1732, 1667 cm21 HRMS (FAB): Calcd
for C18H21O6S ([M1H]1): 365.1059, found: 365.1056.
1
(0.023 g, 48%) the enone as a pale yellow oil. H NMR
(CDCl3): d 6.14 (1H, br s), 4.92 (1H, t, Jˆ3.0 Hz), 4.29
(2H, m), 2.68 (1H, dd, Jˆ17.1, 2.9 Hz), 2.46 (1H, dd,
Jˆ17.1, 3.0 Hz), 2.37 (2H, s), 1.97 (3H, d, Jˆ1.4 Hz),
1.29 (9H, m). 13C NMR (CDCl3): d 203.3, 194.8, 167.5,
150.0, 129.6, 75.8, 72.6, 66.2, 62.2, 50.9, 40.6, 30.5, 23.4,
22.0, 14.0. IR (®lm): 1737, 1717, 1687 cm21 HRMS (EI):
Calcd for C15H20O5 ([M]1): 280.1312, found: 280.1311.
1-Oxadecalone 33b. A solution of diene 30 (0.077 g,
0.39 mmol) and dihydropyrone 3b (0.020 g, 0.13 mmol) in
0.5 mL toluene was warmed to re¯ux. After 40 h, the reac-
tion mixture was cooled to room temperature, the solvent
removed in vacuo, and the crude Diels±Alder adduct was
hydrolyzed directly (Method B). The residue was puri®ed
by ¯ash chromatography (SiO2; hexanes:EtOAc, 4:1) to
give 0.012 g (40%) of the enone as a pale yellow solid
(mp 153±1548C). 1H NMR (CDCl3): d 6.18 (1H, d,
Jˆ1.5 Hz), 4.63 (1H, t, Jˆ3.0 Hz), 2.86 (1H, dd, Jˆ16.8,
2.9 Hz), 2.78 (1H, dd, Jˆ16.8, 3.1 Hz), 2.42 (2H, m), 1.90
(3H, d, Jˆ1.5 Hz), 1.31 (3H, s), 1.24 (3H, s). 13C NMR
(CDCl3): d 197.5, 193.0, 144.6, 130.6, 114.2, 76.8, 72.4,
56.0, 49.7, 40.6, 30.3, 22.9, 20.3. IR (®lm): 2243, 1726,
1689 cm21 HRMS (EI): Calcd for C13H15O3N ([M1H]1):
256.0950, found: 256.0939.
1-Oxadecalone 34d. A mixture of diene 31 (0.157 g, 0.642
mmol) and dihydropyrone 3d (0.054 mg, 0.32 mmol) was
dissolved in 0.5 mL benzene and stirred at room tempera-
ture for 36 h. The solvent was removed in vacuo, and the
crude Diels±Alder adduct subjected to hydrolysis according
to the general procedure (Method B). The residue was puri-
®ed by ¯ash chromatography (SiO2; hexanes:EtOAc, 2:1) to
1
afford the enone as a white solid (0.033 g, 56%). H NMR
(CDCl3): d 5.60 (1H, s), 4.84 (1H, t, Jˆ3.0 Hz), 3.81 (3H,
s), 2.58 (1H, dd, Jˆ17.7, 2.5 Hz), 2.46 (1H, d, Jˆ13.0 Hz),
2.45 (1H, dd, Jˆ17.7, 3.2 Hz), 2.40 (1H, d, Jˆ13.0 Hz),
2.25 (3H, s), 1.28 (3H, s), 1.21 (3H, s). 13C NMR
(CDCl3): d 203.0, 201.8, 195.2, 168.4, 104.4, 76.2, 71.8,
1-Oxadecalone 34a. A mixture of diene 31 (0.714 g,
2.92 mmol) and dihydropyrone 3a (0.193 g, 0.980 mmol)
was stirred in the absence of solvent at room temperature
for 8 h, then the crude Diels±Alder adduct hydrolyzed

10194
P. P. Seth et al. / Tetrahedron 56 (2000) 10185±10195
70.2, 56.5, 51.6, 40.2, 30.6, 29.3, 23.3. IR (®lm): 1732,
1712, 1661 cm21 HRMS (FAB): Calcd for C14H18O5
([M1H]1): 267.1232, found: 267.1207.
(3H, s), 1.29 (3H, s), 1.24 (3H, s), 1.22 (3H, s). 13C NMR
(CDCl3): d 204.5, 199.0, 117.3, 74.6, 73.6, 58.1, 53.6, 51.1,
43.6, 41.6, 30.5, 28.8, 26.4, 25.0. IR (®lm): 2244, 1722,
1712 cm21 HRMS (EI): Calcd for C14H19O3N ([M]1):
249.1365, found: 249.1340.
1-Oxadecalone 40a. A solution of diene 37 (0.17 mL,
1.7 mmol) and dihydropyrone 3a (0.056 g, 0.28 mmol) in
toluene (2 mL) was heated in a sealed tube for 72 h at
2608C. The reaction mixture was cooled to room tempera-
ture, concentrated, and the residue puri®ed by ¯ash chroma-
tography (SiO2; hexanes:EtOAc, 4:1) to provide 40a
Acknowledgements
We thank the National Science Foundation (CHE-9700141)
and the Carver Charitable Trust for support of this work.
1
(0.042 g, 54%) as a yellow oil. H NMR (CDCl3): d 6.07
(1H, m), 5.83 (1H, m), 4.68 (1H, d, Jˆ4.9 Hz), 4.37 (1H, d,
Jˆ4.0 Hz), 4.20 (2H, q, Jˆ7.2 Hz), 3.33 (3H, s), 2.70 (1H,
d, Jˆ16.1 Hz), 2.46 (1H, d, Jˆ16.1 Hz), 2.40 (1H, m), 2.23
(1H, m), 1.35 (3H, s), 1.33 (3H, s), 1.25 (3H, t, Jˆ7.2 Hz).
13C NMR (CDCl3): d 205.3, 169.1, 125.6, 123.8, 73.6, 73.5,
66.3, 62.5, 61.7, 58.3, 51.2, 30.7, 28.4, 26.4, 14.0. IR (®lm):
1735, 1712 cm21. HRMS (FAB): Calcd for C15H22O5Na
([M1Na]1): 305.1368, found: 305.1374.
References
1. (a) Bhat, J. V.; Bajwa, B. S.; Dornauer, H.; de Souza, N. J.;
Fehlhaber, H. W. Tetrahedron Lett. 1977, 33, 1669. (b) Ueno, Y.
TrichothecenesÐChemical, Biological, and Toxicological
Aspects; Elsevier: Amsterdam, 1983; Vol. 4. (c) Tazaki, H.;
Zapp, J.; Becker, H. Phytochemistry 1995, 39, 859. (d) Malakov,
P. Y.; Papanov, G. Y.; Spassov, S. L. Phytochemistry 1997, 44,
121.
1-Oxadecalone 40b. A solution of diene 37 (0.08 mL,
0.83 mmol) and dihydropyrone 3b (0.021 g, 0.14 mmol) in
toluene (1 mL) was heated in a sealed tube for 72 h at
2008C. The reaction mixture was cooled to room tempera-
ture, concentrated, and the residue puri®ed by ¯ash chroma-
tography (SiO2; hexanes:EtOAc, 4:1) to provide 40b
2. Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.;
Kuwano, H.; Hata, T.; Hanzawa, H. J. Am. Chem. Soc. 1991,
113, 5463. For a synthetic approach to the tricyclic furanochroman
core of phomactin A, see: Foote, K. M.; Hayes, C. J.; Pattenden, G.
Tetrahedron Lett. 1996, 37, 275.
1
(0.022 g, 68%) as a colorless oil. H NMR (CDCl3): d
3. (a) Chen, D.; Wang, J.; Totah, N. I. J. Org. Chem. 1999, 64,
1776. (b) Seth, P. P.; Totah, N. I. J. Org. Chem. 1999, 64, 8750.
4. For approaches to the synthesis of simple oxadecalin deriva-
tives, see: (a) Anzalone, L.; Hirsch, J. A. J. Org. Chem. 1985, 50,
2608. (b) Dolmazon, R.; Gelin, S. J. Org. Chem. 1984, 49, 4003.
5. (a) Cremins, P. J.; Saengchantara, S. T.; Wallace, T. W.
Tetrahedron 1987, 43, 3075. (b) Sain, B.; Prajapati, D.; Mahajan,
A. R.; Sandhu, J. S. Bull. Soc. Chim. Fr. 1994, 131, 313.
(c) Ohkata, K.; Kubo, T.; Miyamoto, K.; Ono, M.; Yamamoto,
J.; Akiba, K. (d) Hsung, R. P. J. Org. Chem. 1997, 62, 7904.
(e) Groundwater, P. W.; Hibbs, D. E.; Hursthouse, M. B.; Nyerges,
M. J. Chem. Soc., Perkin Trans. 1 1997, 163.
6.02 (2H, m), 4.36 (1H, d, Jˆ4.7 Hz), 4.02 (1H, m), 3.36
(3H, s), 2.80 (1H, d, Jˆ16.0 Hz), 2.64 (1H, m), 2.50 (1H, d,
Jˆ16.0 Hz), 2.49 (1H, m), 1.34 (3H, s), 1.31 (3H, s). 13C
NMR (CDCl3): d 199.5, 127.2, 121.8, 117.0, 74.4, 66.2,
58.4, 52.4, 51.6, 30.7, 28.2, 25.3. IR (®lm): 2244,
1717 cm21. Anal. Calcd for C13H17O3N: C, 66.36; H, 7.28;
N, 5.95. Found: C, 66.25; H, 7.27; N, 5.77.
1-Oxadecalone 40c. A solution of diene 37 (0.07 mL,
0.66 mmol) and dihydropyrone 3c (0.03 g, 0.11 mmol) in
toluene (1 mL) was heated in a sealed tube for 72 h at
2008C. The reaction mixture was cooled to room tempera-
ture, concentrated, and the residue puri®ed by ¯ash chroma-
tography (SiO2; hexanes:EtOAc, 4:1) to provide 14c
(0.025 g, 65%) as a white solid (mp 135±1368C). 1H
NMR (CDCl3): d 7.86 (2H, m), 7.70 (1H, m), 7.57 (2H,
m), 6.00 (2H, m), 5.00 (1H, d, Jˆ6.2 Hz), 4.03 (1H, m),
3.14 (3H, s), 3.00 (1H, m), 2.73 (1H, d, Jˆ15.4 Hz), 2.46
(1H, m), 2.45 (1H, d, Jˆ15.4 Hz), 1.27 (3H, s), 1.20 (3H, s).
13C NMR (CDCl3): d 201.3, 136.6, 134.4, 130.9, 128.9,
128.7, 121.1, 76.3, 73.8, 72.8, 64.7, 58.6, 51.3, 30.5, 29.6,
27.0. IR (®lm): 1723 cm21. Anal. Calcd for C18H22O5S: C,
61.69; H, 6.33. Found: C, 61.83; H, 6.37.
6. Totah, N. I.; Chen, D. Tetrahedron Lett. 1998, 39, 213.
7. (a) Sakai, T.; Miyata, K.; Ishikawa, M.; Takeda, A. Tetrahedron
Lett. 1985, 26, 4727. (b) Obrecht, D. Helv. Chim. Acta. 1991, 74,
27.
8. Presumably this contaminant is derived from the corresponding
1-oxadecalone 9 via hydration of the C4 ketone (48) with subse-
quent retro-Claisen reaction (49) and aromatization as indicated
below. Pure ethyl p-hydroxybenzoate (10) could be isolated by
chromatography. However, due to continued decomposition
on silica gel, this ester could not be completely separated from
oxadecalone 9.
1-Oxadecalone 42b. A solution of diene 39 (0.12 g,
0.66 mmol) and dihydropyrone 3b (0.020 g, 0.13 mmol) in
0.5 mL toluene was warmed to re¯ux. After 72 h, the reac-
tion mixture was cooled to room temperature, the solvent
removed in vacuo, and the crude Diels±Alder adduct
hydrolyzed (Method B). The residue was puri®ed by ¯ash
chromatography (SiO2; hexanes:EtOAc, 4:1) to give 0.011 g
1
(38%) of the enone as a white solid (mp 130±1328C). H
NMR (CDCl3): d 4.71 (1H, dd, Jˆ5.8, 1.8 Hz), 2.95 (1H,
ddd, Jˆ15.6, 5.8, 0.7 Hz), 2.79 (1H, d, Jˆ13.9 Hz), 2.65
(1H, dt, Jˆ15.6, 2.2 Hz), 2.60 (1H, d, Jˆ16.6 Hz), 2.49
(1H, d, Jˆ16.6 Hz), 2.23 (1H, dd, Jˆ13.9, 2.2 Hz), 1.32
9. Routinely, dienes such as 7b are prepared by deprotonation of
the corresponding ketone with KHMDS followed by treatment

P. P. Seth et al. / Tetrahedron 56 (2000) 10185±10195
10195
with TBDMSCl. (See also, Ref. [14]). Dienes obtained by this
procedure are generally .90% pure and are used without further
puri®cation.
ing reaction times, the cleavage product 26 begins to appear such
that, under anhydrous conditions, compound 26 can be isolated
cleanly in 86% yield after 8 h at room temperature. Attempts to
convert the ring opened products 25 and 26 to the corresponding
1-oxadecalin (8) under either acidic or basic conditions were
unsuccessful.
10. In addition to this product, ca. 12% of the corresponding b C4
hydroxy derivative was isolated.
11. For reviews on preparation and use of activated dienes in
Diels±Alder reactions see: (a) Barluenga, J.; Suarez-Sobrino, A.;
Lopez, L. A. Aldrichimica Acta 1999, 32, 4. (b) Petrzilka, M.;
Grayson, J. I. Synthesis 1981, 753.
16. The trans relationship between substituents at C4 and C6 in
the tetrahydropyrone 28 suggests that reduction of the C4 carbonyl
occurs after cleavage of the C4a/C5 bond of cycloadduct 24.
Reduction of the cis fused oxadecalin system (24) would be
expected to occur from the convex face to provide the a hydroxyl
function (cf. 29).
12. For our purposes, the endo isomer is de®ned as that in which
approach of the diene is directed by the 4-keto substituent of the
dihydropyrone ring. Thus, the methoxy substituent at C5 and the
W substituent at C4a will be trans in the endo-cycloadduct. See:
Seth, P. P.; Totah, N. I. Org. Lett. 1999, 1, 1401.
17. Rathke, M. W.; Sullivan, D. F. Synth. Commun. 1973, 67.
18. Yields of oxadecalone 42b do not improve when the cyclo-
addition is carried out under sealed tube conditions (2008C). In
addition to observed decomposition, there is some indication that
the cycloaddition of the C5 nitrile 3b may be reversible at these
temperatures.
13. Sauer, J.; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980, 19
779.
14. (a) Kozmin S. A.; Rawal V. H. J. Org. Chem. 1997, 62, 5252.
(b) Kozmin S. A.; Janey, J. M.; Rawal V. H. J. Org. Chem. 1999,
64, 3039.
19. In general, we have observed that monoxygenated dienes that
contain the activating substituent at C1 are signi®cantly less reac-
tive under Lewis acid catalyzed conditions than are those in which
the substituent is at C2 (Ref. 3b).
15. Formation of the cycloadduct 24 via a concerted process is
supported by the observation that the 1H NMR of the crude reaction
mixture after 45 min shows only the cycloadduct 24. With increas-