Intramolecular 4 + 3 cycloadditions. Cycloaddition reactions of cyclic alkoxyallylic and oxyallylic cations

Article abstract of DOI:10.1021/ja952740r

The intramolecular 4 + 3 cycloaddition of oxyallylic and alkoxyallylic cations has been studied. Cyclopentenyl oxyallylic cations tethered to a furan by a three or four carbon chain react with high stereoselectivity via a compact (endo) transition state a

Full text of DOI:10.1021/ja952740r

2860
J. Am. Chem. Soc. 1996, 118, 2860-2871
Intramolecular 4 + 3 Cycloadditions. Cycloaddition Reactions
of Cyclic Alkoxyallylic and Oxyallylic Cations
Michael Harmata,* Saleh Elomari, and Charles L. Barnes
Contribution from the Department of Chemistry, UniVersity of MissourisColumbia,
Columbia, Missouri 65211
ReceiVed August 11, 1995X
Abstract: The intramolecular 4 + 3 cycloaddition of oxyallylic and alkoxyallylic cations has been studied.
Cyclopentenyl oxyallylic cations tethered to a furan by a three or four carbon chain react with high stereoselectivity
via a compact (endo) transition state analogous to that seen in intermolecular cycloadditions. Six- through eight-
membered oxyallylic cations react differently and give increasingly larger amounts of cycloadduct derived from
extended (exo) transition states. This has been rationalized on the basis of ring strain in the endo transition states
in this series. Cyclodecenyl oxyallylic cations are sickle-shaped and stereoselectively undergo cycloaddition via
extended transition states to a furan diene tethered by three carbons. Cyclododecenyl oxyallylic cations behave
similarly, although the evidence suggests that a small amount of W-shaped cation also is formed. Cyclic alkoxyallylic
sulfones give rise to the corresponding cations upon treatment with TiCl4, and the latter give rise to cycloadducts via
apparent intramolecular 4 + 3 cycloadditions in variable yields. Side product formation in certain cases provides
evidence for the intermediacy of cationic species which may also be important in the formation of the cycloadducts
themselves.
Introduction
the presence of furan gave adduct 2.5 Similar irradiation of
The 4 + 3 cycloaddition reaction of allylic cations and dienes
is a powerful method for the construction of seven-membered
rings.1 In its intramolecular form, it has not received the amount
of attention of its counterpart, the intramolecular Diels-Alder
reaction.2,3 We are engaged in a program of study of the
intramolecular 4 + 3 cycloaddition reaction.4 This report details
our studies of the intramolecular cycloaddition reactions of
cyclic cations.
cyclohexadienones and pyrones also led to cycloadduct forma-
tion.6 More recently, Schultz and West have developed
intramolecular reactions based on a photochemical approach.7
The use of cyclic cations as dienophiles has been the subject
of only a few studies. Among the earliest and most interesting
routes to such cations are those involving photochemical
electrocyclic reactions of dienones. For example, Crandall and
co-workers reported that irradiation of 2,7-cyclooctadienone in
Thermal approaches to cyclic allylic cations for 4 + 3
cycloaddition have also been developed. Reductive debromi-
nation of R,R′-dibromoketones has been reported in this regard.8
For example, Noyori reported that treatment of 3 with Fe2(CO)9
in the presence of excess furan resulted in the formation of 4
with complete stereocontrol in 61% yield.8a Hoffmann made
X Abstract published in AdVance ACS Abstracts, March 15, 1996.
(1) For reviews of 4 + 3 cycloadditions, see: (a) Hosomi, A.; Tominaga,
Y. [4 + 3] cycloadditions. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 5, Chapter 5.1,
pp 593-615. (b) Hoffman, H. M. R. Angew. Chem., Int. Ed. Engl. 1984,
23, 1. (c) Mann, J. Tetrahedron 1986, 42, 4611. (d) Noyori, R.; Hayakawa,
Y. Org. React. 1983, 29, 163-344. (e) Hoffman, H. M. R. Angew. Chem.,
Int. Ed. Engl. 1973, 12, 819.
(2) For a review of intramolecular 4 + 3 cycloadditions, see: Harmata,
M. In AdVances in Cycloaddition; Lautens, M., Ed.; JAI: Greenwich, CT,
1996; Vol. 4 (in press).
(3) For reviews of intramolecular Diels-Alder reactions, see: (a) Roush,
W. R. In AdVances in Cycloaddition; Curran, D. P., Ed.; JAI: Greenwich,
CT, 1990; Vol. 2, pp 91-146. (b) Roush, W. R. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991;
Vol. 5, Chapter 4.4.
(4) (a) Harmata, M.; Gamlath, C. B.; Barnes, C. L.; Jones, D. E. J. Org.
Chem. 1995, 60, 5077. (b) Harmata, M.; Elahmad, S.; Barnes, C. L.
Tetrahedron Lett. 1995, 36, 1397. (c) Harmata, M.; Elahmad, S.; Barnes,
C. L. J. Org. Chem. 1994, 59, 1241. (d) Harmata, M.; Herron B. F. J. Org.
Chem. 1993, 58, 7393. (e) Harmata, M.; Herron, B. F. Tetrahedron Lett.
1993, 34, 5381. (f) Harmata, M.; Herron, B. F. Synthesis 1993, 202. (g)
Harmata, M.; Elahmad, S. Tetrahedron Lett. 1993, 34, 789. (h) Harmata,
M.; Gamlath, C. B.; Barnes, C. L. Tetrahedron Lett. 1993, 34, 265. (i)
Harmata, M.; Fletcher, V. R.; Claassen, R. J., II J. Am. Chem. Soc. 1991,
113, 9861. (j) Harmata, M.; Gamlath, C. B.; Barnes, C. L. Tetrahedron
Lett. 1990, 31, 5981. (k) Harmata, M.; Gamlath, C. B. J. Org. Chem. 1988,
53, 6154.
use of a different reductive dehalogenation protocol in a study
of cyclic oxyallylic cations of varying ring size.8c Base-
mediated dehydrohalogenation as a means of oxyallyl generation
(5) Crandall, J. K.; Haseltine, R. P. J. Am. Chem. Soc. 1968, 90, 6251.
(6) (a) Barber, L. L.; Chapman, O. L.; Lassila, J. D. J. Am. Chem. Soc.
1969, 91, 3664. (b) Chapman, O. L.; Clardy, J. C.; McDowell, T. L.; Wright,
H. E. J. Am. Chem. Soc. 1973, 95, 5086. (c) Barltrop, J. A.; Day, A. C.;
Samuel, C. J. J. Am. Chem. Soc. 1979, 101, 7521.
(7) (a) Schultz, A. G.; Reilly, J. J. Am. Chem. Soc. 1992, 114, 5068. (b)
Schultz, A. G.; Macielag, M.; Plummer, M. J. Org. Chem. 1988, 53, 391.
(c) West, F. G.; Hartker-Karger, C.; Koch, D. J.; Kuehn, C. E.; Arif, A. M.
J. Org. Chem. 1993, 58, 6795.
(8) (a) Noyori, R.; Taba, Y.; Makino, S.; Takaya, H. Tetrahedron Lett.
1973, 14, 1741. (b) Ito, S.; Ohtani, H.; Amiya, S. Tetrahedron Lett. 1973,
14, 1737. (c) Vinter, J. G.; Hoffmann, H. M. R. J. Am. Chem. Soc. 1974,
96, 5466.
0002-7863/96/1518-2860$12.00/0 © 1996 American Chemical Society

Intramolecular 4 + 3 Cycloadditions
J. Am. Chem. Soc., Vol. 118, No. 12, 1996 2861
Scheme 1
was used by Fo¨hlisch.9 For example, treatment of R-chloro-
cyclopentanone with sodium trifluoroethoxide in trifluoroethanol
gave 6 in 44% yield.9a More recently, certain limitations to
Reaction of keto ester 8 with sodium hydride and alkylation
of the resulting enolate with 2-(3-iodopropyl)furan gave 10a in
91% yield. Krapcho decarboalkoxylation afforded ketone 11a
in 74% yield.15 Treatment of ketone 11a with LDA and triflyl
chloride produced the corresponding R-chloroketone.16 This
was immediately dissolved without purification in a 3 M ethereal
solution of LiClO4 containing 3 equiv of triethylamine. Stirring
for several hours and workup resulted in the isolation of
cycloadducts 12a and 13a as a 15:1 mixture of diastereomers
in 55% yield. The ratio of diastereomers for this and all other
this type of approach have been reported.9c Levisalles reported
that a steroidal cyclic sulfite gave a 4 + 3 cycloadduct with
furan.10 Schmid demonstrated that chloroenamines react with
silver salts in the presence of dienes to give 4 + 3 cycload-
ducts.11 This methodology has been used by Cha in an approach
to natural products.12
Our work began as a general approach to the synthesis of
complex polycyclic systems using the intramolecular 4 + 3
cycloaddition reaction. In particular, we had the goal of using
the methodology to prepare cyclooctanoids and ingenanes.4b,c
1
reactions was determined by H NMR of the crude reaction
mixture. Also isolated were the chlorinated cycloadduct 14a,
enone 15a, and the starting ketone in 6%, 17%, and 6% yields,
respectively. The major isomer of the cycloadduct mixture, 12a,
was characterized by spectral data analysis (1H, 13C NMR; IR;
MS). The structure of 12a was confirmed and its stereochem-
istry defined by X-ray analysis of the corresponding dihydro
derivative 16a.4b The structure of 14a was also assigned on
Results and Discussion
We initially planned to adapt our alkoxyallylic sulfone
methodology to cyclic systems.4j However, treatment of 7 with
TiCl4 under typical reaction conditions resulted in the formation
of a small amount of a carbonyl-containing product which was
clearly not a cycloadduct by NMR. We therefore sought to
use a methodology which would give rise to the intermediates
suitable for cycloaddition but under much milder conditions.13
We chose to use the methodology introduced by Fo¨hlisch.14
the basis of spectroscopic data and its stereochemistry assigned
on the basis of that seen in 12a. The formation of 14a is
doubtless due to some dichlorination of ketone 11a. Such a
compound would be expected to lead to 14a and accounts for
the recovered ketone.
Avoiding the competitive formation of enone 15a has not
been experimentally addressed. In the presence of base, oxyallyl
17a, a plausible intermediate in this reaction, may undergo either
cycloaddition or a bimolecular elimination reaction. The
hydrogens flanking the oxyallylic cation are approximately
parallel to the π system of the cation and stereoelectronically
poised to undergo elimination.17 The formation of R,â-
(9) (a) Fo¨hlisch, B.; Joachimi, R. Chem. Ber. 1987, 96, 5466. (b) Fo¨hlisch,
B.; Gottsein, W.; Kaiser, R.; Wanner, I. Tetrahedron Lett. 1980, 21, 1951.
(c) Fo¨hlisch, B.; Joachimi, R.; Reiner, S. J. Chem. Soc. (S) 1993, 253. (d)
Matzinger, P.; Eugster, C. M. HelV. Chim. Acta 1979, 62, 2325.
(10) Levisalles, J.; Rose, E.; Tkatchenko, I. Chem. Commun. 1969, 445.
(11) (a) Schmid, R.; Schmid, H. HelV. Chim. Acta 1974, 57, 1883. (b)
Ernst, B.; Ganter, C. HelV. Chem. Acta 1978, 61, 1775.
(12) (a) Jin, S.-j.; Choi, J.-R.; Oh, J.; Lee, D.; Cha, J. K. J. Am. Chem.
Soc. 1995, 117, 10914. (b) Kim, H.; Ziani-Cherif, C.; Oh, J.; Cha, J. K. J.
Org. Chem. 1995, 60, 792. (c) Oh, J.; Cha, J. K. Synlett 1994, 967. (d)
Lee, J.; Oh, J.; Jin, S.-j.; Choi, J.-R.; Atwood, J. L.; Cha, J. K. J. Org.
Chem. 1994, 59, 6955. (e) Oh, J.; Lee, J.; Jin, S.-j.; Cha, J. K. Tetrahedron
Lett. 1994, 35, 3449. (f) Oh, J.; Choi, J.-R.; Cha, J. K. J. Org. Chem. 1992,
57, 6664.
(13) We have treated 12a with TiCl4 and found that it does not give the
same product as that from the reaction of 7. Studies of the reactions of the
cycloadducts with Lewis acids continue and will be reported elsewhere.
(14) (a) Kaiser, R.; Fo¨hlisch, B. HelV. Chim. Acta 1990, 73, 1504. (b)
Fo¨hlisch, B.; Hetter, R. Chem. Ber. 1984, 117, 2580. (c) Fo¨hlisch, B.;
Flogaus, R.; Oexle, J.; Scha¨del, A. Tetrahedron Lett. 1984, 25, 1773. (d)
Fo¨hlisch, B.; Gehrlach, E.; Herter, R. Angew. Chem., Int. Ed. Engl. 1982,
21, 137.
(15) Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G.
E., Jr.; Lovey, A. J.; Stephens, W. P. J. Org. Chem. 1978, 48, 138.
(16) Wender P. A.; Holt, D. A. J. Am. Chem. Soc. 1985, 107, 7771.
(17) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: Oxford, U.K., 1983; p 190.

2862 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Harmata et al.
Figure 2. Plausible transition state structures for the formation of 12c
and 13c.
Figure 1. Plausible transition state structures for the formation of 12a
and 13a.
conformation.20 We set out to establish some generality with
respect to ring size of the oxyallylic species. The precursors
for this study were prepared by simple alkylation of the
appropriate ketone enolates (eq 6). Dialkylation was a signifi-
unsaturated ketones from R-halo precursors may proceed by a
similar mechanism.18b Further, analogues of 17 are putative
intermediates in the Nazarov cyclization which leads to
cyclopentenones.18a
The stereochemistry of 12a is that expected on the basis of
precedent.9a Assuming a concerted reaction, two approaches
of diene to dienophile are possible: an endo or compact
approach leading to the observed major product 12a or an
extended or exo approach leading to 13a (Figure 1). In the
exo approach, there are steric (eclipsing) interactions between
the furan ring and the methylene groups on the cyclopentenyl
ring. Further, dipole-dipole repulsion is evident, though in a
very polar medium it may not be a severe problem. In the endo
approach, a repulsive interaction between a hydrogen on the
tether and one on the cyclopentenyl ring should exist. Overall,
it appears that the unfavorable electronic and steric effects
associated with the exo approach are sufficient to make the endo
approach favored to a considerable extent.
The stereoselection observed in intermolecular cycloadditions
of cyclopentenyl and larger oxyallylic cations with furans has
been rationalized as arising from secondary orbital interactions
and steric effects.1 Interestingly, West observed poor endo/
exo selectivity in related intramolecular cycloadditions and
rationalized this result on the basis of unfavorable steric
interactions between the oxyallylic cation and the tether.7c
The cyclization of ketone 11b proceeded in a manner
analogous to that of 11a. However, no chlorinated cycloadduct
was found. Only one stereoisomer of cycloadduct 12b was
detected, and its structural and stereochemical assignment was
based on analogy to 12a. Enone 15b and recovered ketone were
obtained in 15% and 13% yields, respectively.
cant problem, but no attempt was made to optimize the
alkylation and the dialkylation products were not rigorously
characterized.
Chlorination of 20a and cycloaddition under standard condi-
tions resulted in the formation of a 54% yield (61% based on
recovered starting material) of cycloadducts 21a,b in a ratio of
1:2.5. The dramatic change in diastereomer distribution relative
to cycloadducts 12a/13a is noteworthy. The exo diastereomer
21b is now favored. Control experiments suggest that this
reaction is taking place under kinetic control. Treatment of a
1:1.6 mixture of 21a,b under cycloaddition conditions resulted
in no change in their relative ratio. The basis of this stereo-
chemical change is not clear. This observation differs from
results of intermolecular 4 + 3 cycloaddition reactions of
cyclohexenyl cations. For example, Schmid found that the
cyclohexenyl allylic cation 24 underwent 4 + 3 cycloaddition
with furan to give 4 + 3 adducts which were obtained as a
97:3 mixture of diastereomers favoring the endo isomer 25.11
Adding an additional methylene group to the tether joining
cation and diene places entropic demands on the cycloaddition
which have deleterious effects. The cycloadduct from ketone
11c was obtained in only 40% yield along with a 9% yield of
the chlorinated cycloadduct 14c. The elimination product was
obtained in 36% yield. As expected, as the entropic demands
on the cycloaddition grow, elimination becomes increasingly
competitive.
Similar findings were reported by Fo¨hlisch.9 It seems clear that
the change in stereoselectivity in the intramolecular 4 + 3
cycloaddition is due to the tether joining the cyclohexenyl
oxyallylic cation and the furan. However, transition states
leading to 21a,b should not differ substantially from those
leading to 12a and 13a. We believe that a major source of the
disparity arises due to an increase in torsional strain in the
transition state leading to 21a.
Molecular mechanics (PCMODEL, version 5) calculations
on the cations 26a-d show that as ring size increases the angle
“a” decreases. This will have the effect of inducing strain in
endo transition states in intramolecular 4 + 3 cycloaddition
reactions by forcing the methylene groups adjacent to the diene
The structure of 12c was confirmed and its stereochemistry
established by X-ray crystallographic analysis.19 As in the case
of 12a, two transition states can be envisaged on the basis of
the assumption of a concerted reaction (Figure 2). The endo
transition state is once again favored. Untoward steric interac-
tions and dipole-dipole repulsion are at a minimum, and the
incipient six-membered ring takes on a chair conformation. In
19b, the steric and electronic problems found in 18b are present.
The incipient six-membered ring is also forced into a boat
(18) (a) Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994,
45, 1. (b) Warnhoff, E. W.; Martin, D. G.; Johnson, W. S. In Organic
Syntheses CollectiVe Volume 4; Rabjohn, N., Ed.; Wiley: New York, 1963;
pp 162-66.
(19) Data on 12c: MW ) 204.27; space group p21/c; a ) 7.0682(7) Å,
b ) 19.641(4) Å, c ) 8.0446(9) Å, â ) 110.980(4)°; V ) 1042.8(3) Å3;
Z ) 4; Dcalcd ) 1.301; radiation ) Mo KR (λ ) 0.709 30) Å; m ) 0.08
mm-1; F(000) ) 440; temperature ) 23/-1°; final R ) 0.050 for 1056
reflections with I > 2σ(I).
(20) As a cautionary note, it must be pointed out that we have not
rigorously established that the cycloaddition reactions involving cyclopen-
tenyl cations are under kinetic control or that the mechanism of the reaction
is indeed concerted.

Intramolecular 4 + 3 Cycloadditions
Table 1. Cycloaddition Results for 20a-c
J. Am. Chem. Soc., Vol. 118, No. 12, 1996 2863
Figure 3.
entry
n
educt reagent product yield (%)a ratio (a:b)
2-alkylcyclooctanones, it is likely that the stereochemistry of
28 is as shown in Figure 3.25 In this conformation, both
hydrogens R to the carbonyl group are parallel to the carbon-
oxygen bond, not perpendicular to it, as would be required for
a facile deprotonation. Thus, 28 would have to undergo a
conformational change in order to form the enolate precursor
to the oxyallylic cation. We concluded that the use of a stronger
base might prove more effective in siphoning off any reactive
conformer present in solution and improve conversion rates and
cycloadduct yield. Stirring chloroketone 28 in the presence of
a trifluoroethanol solution of sodium trifluoroethoxide gave
cycloadducts 23a,b in 61% yield (69% based on recovered
starting material) in a ratio of 1:10.1.
1
2
3
4
1
2
3
3
20a
20b
20c
20c
A
A
A
B
21
22
23
23
54 (61)
56 (66)
17
1:2.5
1:7.3
1:9.5
1:10.1
61 (69)
a Yield in parentheses based on recovered starting material.
and dienophile to move away from each other as shown in 27.
Exo transition states do not suffer from such strain.21
The structure and stereochemistry of the major cycloadduct
were determined by spectroscopic analysis. The stereochemical
assignments of both 23a and 23b were established by compari-
The structure of 21b was determined by spectral data analysis
(1H, 13C NMR; IR; MS). The stereochemistry of 21b was
assigned on the basis of an X-ray crystal structure.22 Cycload-
duct 21a could not be isolated in pure form, and its structure is
based on our conclusion that it is in fact a 4 + 3 cycloadduct
1
son of certain resonances in their H NMR spectra with other
4 + 3 cycloadducts whose structures were firmly established
1
by X-ray crystallography. It was observed in the H NMR
1
by H NMR and it must be isomeric to 21b.
spectra of all of the cycloadducts that the olefinic protons Ha
and Hb in the exo isomers resonated at lower field than the
corresponding protons in the endo isomers (Table 2). This same
pattern was also observed for the chemical shift of the proton
on the methine of the oxygen bridge (Hc). This trend in the
chemical shift was also observed by Hoffmann in his study of
intermolecular cycloaddition of cyclic oxyallylic cations with
furan.8c
The cycloaddition of 20b led to two cycloadducts in a ratio
of 1:7.3 in 56% yield (66%, corrected). The increased torsional
strain in the endo approach was expected to bias the cycload-
dition toward an exo transition state. Indeed, the major product
was the 22b. The structure was determined by spectral and
X-ray analysis.23 This result differs from the results of similar
intermolecular reactions and underscores the considerable effect
that intramolecularity can have on simple diastereoselection. As
shown in eq 2, Noyori and Ito showed that a cycloheptenyl
oxyallylic cation reacts with furan to give a 4 + 3 cycloadduct
possessing the endo stereochemistry exclusively.8a,b Hoffmann
reported that a similar reaction proceeded to produce a 36:1
ratio of diastereomers.8c
Cycloadducts 29a,b were obtained in 59% yield (67% based
on recovered starting material) as a 19:1 mixture of isomers by
1H NMR deom 20d. The major isomer in the mixture was
The cyclization of substrate 20c was not as straightforward.
Chlorination proceeded uneventfully, but cyclization using 3
M ethereal LiClO4 even up to reflux temperature was not
effective in affording yields of cycloadducts in excess of 17%.
Both 20c and the corresponding chloroketone 28 were obtained
in 16% and 41% yields, respectively. Changing the nature of
the base had no effect on the outcome of the cycloaddition.24
The recovery of chloroketone was telling, and we believe the
reluctance of this species to undergo cyclization can be traced
to its conformation.
characterized spectroscopically and crystallographically.26 This
demonstrated that 29a possessed a Bae conformation.27
The minor isomer 29b could not be isolated in pure form.
1
However, inspection of an H NMR of a mixture of 29a,b
Although the stereochemistry of 28 was not confirmed, from
what is known about the alkylation of kinetic enolates of
showed a signal for the methine proton at 4.71 ppm as a doublet
of doublets (J ) 1.8, 2.9 Hz). If it is assumed that the smaller
coupling constant involves the adjacent olefinic proton, coupling
to the R-ketone proton amounts to about 3 Hz. This is the value
that Hoffmann found for coupling between the axial proton Ha
and the methine proton Hb in adducts such as 30, which possess
(21) Other factors could certainly be involved. Further studies are needed
to paint a complete picture of the basis of simple diastereoselection in these
reactions.
(22) Data on 21b: MW ) 218.29; space group p21/n; a ) 11.9350(20)
Å, b ) 11.9910(20) Å, c ) 7.8920(20) Å, b ) 99.512(5)°; V ) 1113.9(4)
Å3; Z ) 4; Dcalcd ) 1.302 g‚cm-3; m ) 0.64 mm-1; F(000) ) 471.95;
radiation ) Cu KR (λ ) 1.540 56) Å; temperature ) 23/-1°; final R )
0.041 for 2095 reflections with I > 2.5σ(I).
(25) Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981.
(26) Harmata, M.; Elomari, S.; Barnes, C. L. Acta Crystallogr., C
(submitted).
(23) Data on 22b: MW ) 204.27; space group p21/n; a ) 8.6163(10)
Å, b ) 11.4938(6) Å, c ) 22.0340(20) Å, â ) 100.800(4)°; V ) 2143.5(3)
Å3; Z ) 8; F(000) ) 871.90; Dcalcd ) 1.26 g‚cm-3; radiation ) Cu Ka (λ
) 1.540 56) Å; temperature ) 23/-1°; final R ) 0.049 for 2831 reflections
with I > 2.0σ(I).
(27) This nomenclature was introducted by Hoffmann and Vinter.8c The
first letter denotes the conformation of the tetrahydropyranone portion of
the molecule, boat (B) or chair (C). The subscripts describe the orientation
of the polymethylene chain joining the positions R to the carbonyl group
of the tetrahydropyranone, axial (a) and/or equatorial (e).
(24) Base (yield, 23a:23b): pyridine (12%, 1:9.3); diisopropylethylamine
(11%, 1:9.8); 2,6-lutidine (9%, 1:9.8); 2,6-di-tert-butylpyridine (11%, 1:9.6).

2864 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Table 2. Chemical Shift Data for Selected Cycloadducts
Harmata et al.
Table 3. Coupling Constants (Ha/Hb) for Selected Cycloadducts
cycloadduct
n
typea
conformation
JH /Hb (Hz)
a
cycloadduct
n
typea δHa (ppm)b δHb (ppm)b δHc (ppm)b
12a
13a
21a
21b
22a
22b
23a
23b
29a
29b
31a
31b
31c
1
1
2
2
3
3
4
4
6
6
8
8
8
endo
exo
endo
exo
endo
exo
endo
exo
exo
endo
exo
endo
exo
Caa
Baa
Caa
Baa
Caa
Baa
Caa
Baa
Bae
Cae
Bae
Cae
Baa
3.7
7.8
0.0
8.7
0.0
8.6
1.2
8.0
2.2
2.9
2.0
3.6
7.9
12a
13a
21a
21b
22a
22b
23a
23b
1
1
2
2
3
3
4
4
endo
exo
6.09
6.41
6.23
6.46
6.02
6.40
6.05
6.37
6.28
6.48
6.38
6.64
6.33
6.54
6.29
6.49
4.69
5.04
4.94
5.02
4.72
4.95
4.67
4.94
endo
exo
endo
exo
endo
exo
a Refers to the relationship between the oxygen and carbonyl bridges
of the cycloadducts. b In CHCl3, downfield from TMS.
the Cae conformation. Hence, we tentatively assigned the
structure of the minor isomer as 29b.
a Refers to the relationship between the oxygen and carbonyl bridges
of the cycloadducts.
isomer in this mixture was 33b. The olefinic protons of the
major component of this mixture appeared at 6.23 ppm (dd, J
) 1.8, 5.8 Hz) and 6.07 ppm (d, J ) 5.8 Hz). The methine of
the ether bridge appeared as a doublet of doublets at 4.68 ppm
(J ) 1.8, 3.6 Hz). The olefinic protons of the minor component
appeared at 6.40 ppm (dd, J ) 2.1, 5.9 Hz) and 6.26 ppm (d,
J ) 5.9 Hz). The corresponding bridge methine proton
resonated at 4.89 ppm (dd, J ) 2.1, 7.9 Hz). These data suggest
that the major component of the mixture is indeed 33b and that
the minor component possesses structure 33c (Baa conformation).
This conclusion is based on good literature precedent. In
their study of the intermolecular 4 + 3 cycloaddition of cyclic
oxyallyls and furans, Hoffmann and Vinter observed coupling
constants of 7.5-8.5 Hz between protons Ha and Hb in
cycloadducts such as 34, possessing the Baa conformation.8c The
The inside-outside stereochemistry of 29a/b suggests strongly
that the products are derived from a sickle-shaped cation 31
through an exo transition state. An isomeric cation 32 is
probably considerably higher in energy for steric reasons. In
an earlier report, we raised the question of whether a U-shaped
cation might be preferred over the sickle-shaped species on the
basis of MNDO calculations.4b Recently, theoretical studies by
Hoffmann and Vinter have provided strong support for the idea
that the products in the cyclodecanone series arise from a sickle-
shaped cation as those same authors concluded in their seminal
paper.8c,28
Three products were obtained in 69% yield (72% based on
recovered ketone) in a ratio of 7.3:1:1 from 20e. The structure
and stereochemistry of 33a were secured by X-ray analysis.29
As in 29a, the tetrahydropyranone ring possesses the Bae
conformation.
The two minor cycloadducts were obtained as an inseparable
mixture (1:1). Recrystallization from hexanes and X-ray
analysis of a randomly chosen single crystal gave a structure
for 33b (Cae).30 It is to be noted that such a recrystallization
observed coupling constants between the same two protons in
all other conformations ranged between 0.4 and 3.5 Hz. We
also observed this same trend (Table 3). Thus, the large
coupling constant (7.9 Hz) observed between the appropriate
protons in 33c implies that the structure is as shown and the
compound possesses a Baa conformation. Subjecting the 3:1
mixture of 33b,c to the cyclization conditions for 86 h or
treatment with sodium methoxide in methanol at room temper-
ature for 2 days resulted in no change in composition. Refluxing
a 1:2 mixture of 33b,c in methanolic sodium methoxide resulted
in no change in the composition of the mixture as evidenced
by 1H NMR. Further, 33a was recovered unchanged after being
stirred under the cyclization conditions for 23 days or refluxed
with methanolic sodium methoxide. These data suggest that
cycloadduct formation is under kinetic control.
gave crystals as well as an oily material. An 1H NMR spectrum
of the crystals contaminated with some of this oily material
showed an isomer ratio of 3:1. It was assumed that the major
It would therefore appear that both 33a and 33b are formed
via a sickle-shaped oxyallylic species, with the major cycload-
duct 33a being derived from an exo approach. While one might
predict that 33c is derived from an exo approach of a U-shaped
cation, the absence of cycloadduct 33d suggests that this is not
the case. At least a small amount of this cycloadduct should
have been formed if a U-shaped cation were an intermediate in
the cycloaddition. On the other hand, molecular models suggest
(28) Goodman, J. M.; Hoffmann, H. M. R.; Vinter, J. G. Tetrahedron
Lett. 1995, 36, 7757.
(29) Data on 33a: MW ) 288.43; space group P21/c; a ) 18.497(6) Å,
b ) 8.770(4) Å, c ) 10.650(3) Å, â ) 106.320(20)°; V ) 1658.0(10) Å3;
Z ) 4; F(000) ) 632.22; m ) 0.07 mm-1; Dcalcd ) 1.155 g‚cm-3; radiation
) Mo KR (0.709 30) Å; temperature ) 23/-1°; final R ) 0.043 for 1886
reflections with I > 2.0σ(I).
(30) Harmata, M.; Barnes, C. L.; Elomari, S. J. Chem. Crystallogr.
(manuscript in preparation).

Intramolecular 4 + 3 Cycloadditions
J. Am. Chem. Soc., Vol. 118, No. 12, 1996 2865
Scheme 2
The mechanism of formation of the cycloadducts is open to
some question. The high electrophilicity of the alkoxyallylic
cation may predispose the system toward a stepwise cycload-
dition process. Evidence for the intervention of stepwise
processes in other systems has been obtained (Vide infra). In
any case, transition states leading to the epimeric cycloadducts
41a,b are not sufficiently different in energy to lead to high
simple diastereoselection. Circumventing this problem is a
subject for future study.
In order to begin to explore the scope of this reaction,
substrate 44 was prepared and subjected to Lewis acid treat-
ment.34 Cycloadducts 45a,b were obtained in 57% yield in a
ratio of 2.3:1. The structures of these compounds were assigned
in accord with 41a,b. Interestingly, 46 occurred as a major
side product in this reaction.
Scheme 3
(11)
that a W-shaped cation can only cyclize via a transition state
such as 35 (assuming a concerted mechanism). This could give
rise to a cycloadduct with a Cee conformation. A ring flip would
then lead to 33c with the Baa conformation. Such a process
was proposed by Hoffmann and Vinter for the formation of 34.
The structure of 46 could be deduced spectroscopically. The
1H NMR spectrum showed an olefinic signal which appeared
as a triplet at 5.47 ppm (J ) 8.0 Hz). The two protons of the
methylene group bearing the chlorine atom appeared as a
multiplet between 4.15 and 4.70 ppm. The 13C NMR spectrum
showed 14 carbons including a carbonyl at 223.7 ppm and
olefinic carbons at 148.1 and 121.6 ppm. Low-resolution mass
spectrometry gave a parent ion peak (m/e 240) consistent with
the formula C14H21OCl. Treatment of 46 with potassium
p-bromobenzoate in DMF/HMPA resulted in the formation of
47, whose structure and stereochemistry were established by
X-ray analysis.35
All of the cycloadditions discussed thus far involved furans
as the diene component. In an effort to broaden the scope of
the cycloaddition, we examined a few cycloadditions in which
the diene component was a substituted butadiene. Our initial
attempt to apply Fo¨hlisch’s methodology to this part of the study
failed. Treatment of 36 according to our standard procedure
resulted in the formation of enone 37 in 42% yield. Apparently
(10)
(12)
the tethered diene was not sufficiently nucleophilic to compete
with elimination, at least under these reaction conditions, or
the s-cis/s-trans conformational equilibrium of the diene was
not conducive to cyclization.
The formation of 46 suggests that a stepwise process may
be involved in the formation of the cycloadducts. This is
particularly true in the case of highly electrophilic dienophiles
and nucleophilic dienes such as alkyl-substituted butadienes.
However, while the postulation of an intermediate carbocation
is tenable, the intervention of such an intermediate in the
formation of 41 or 45 is by no means certain.
That cycloadduct formation is decreased when electrophilic
addition becomes easier was further demonstrated by the
attempted cycloaddition of 48.36 Treatment of this substrate
with TiCl4 resulted in the formation of cycloadducts 49a,b in
11-20% yield in a ratio of 1.2:1. The major product of the
reaction was hemiacetal 50, formed in 27-31% yield.
We anticipated that the generation of a more reactive allylic
cation in the absence of base would render the desired
cycloaddition process tenable. The application of our alkoxy-
allylic sulfone methodology seemed appropriate despite the fact
that it failed with substrate 7 (cf. eq 4). Thus, substrate 40 was
prepared by the alkylation of 38.31,32 Treatment of 40 with TiCl4
resulted in the formation of a 2.4:1 mixture of cycloadducts
41a,b in 78-81% yield. The structures of both cycloadducts
were determined from spectroscopic data. The stereochemistry
of 41a was determined by X-ray analysis of benzoate 43.
Hydrogenation of 41a followed by treatment with mCPBA gave
lactone 42 in 70% yield.33 Lithium aluminum hydride reduction
and selective benzoylation gave 43 in 79% yield. X-ray analysis
of 43 proved its stereochemistry, and the stereochemistry of
41a was assigned accordingly.4b On the basis of the assumption
that 41a was epimeric to 41b, the latter’s relative configuration
was also established.
The structure of 49a was determined by standard spectral
means. The 1H NMR spectrum contained a signal for an olefinic
proton at 5.23 ppm (J ) 1.9 Hz). The 13C NMR spectrum
(34) For the experimental details of the preparation of the dienyl iodide
used to make 44, see the supporting information.
(35) Data on 47: MW ) 405.33; space group P21/n; a ) 7.3050(20)
Å, b ) 10.5060(10) Å, c ) 25.198(5) Å, â ) 19024.8(20)°; V ) 1924.8(7)
Å3; Z ) 4; F(000) ) 840; m ) 3.04 mm-1; Dcalcd ) 1.399 g‚cm-3; radiation
) Mo KR (0.709 30) Å; temperature ) 23/-1°; final R ) 0.047 for 2537
reflections with I > 2.0σ(I).
(31) Funk, R. L.; Bolton, G. L.; Brummond, K. M.; Ellstead, K. E.;
Stallman, J. B. J. Am. Chem. Soc. 1993, 115, 7024.
(32) Wulff, W. D.; Powers, T. S. J. Org. Chem. 1993, 58, 2381.
(33) Koch, S. S. C.; Chamberlin, R. Synth. Commun. 1989, 289.
(36) For the experimental details of the preparation of the dienyl iodide
used to make 48, see the supporting information.

2866 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Harmata et al.
Scheme 4
(13)
showed a signal for the carbonyl carbon at 217.2 ppm and two
olefinic carbons at 143.7 and 124.0 ppm. The IR had a band
at 1735 cm-1, suggesting the presence of a cyclopentanone.
Similar data were obtained for 49b. In this case, however, the
olefinic proton appeared at 5.57 ppm in the 1H NMR spectrum.
Indeed, it appears that endo isomers such as 41a, 45a, and 49a
all have their olefinic proton resonances at higher field than
their corresponding exo isomers. This is presumably due to
the fact that, in the “endo” series, the olefinic protons lie within
the shielding cone of the carbonyl group. This difference
appears to be a useful and consistent means of assigning
stereochemistry for this class of cycloadducts.
mixture of 49a,b in 61% yield. The scope of this process, which
leads rapidly to a 5-8-5 fused ring system, remains to be
determined.
Conclusion
In summary, we have shown that the intramolecular 4 + 3
cycloaddition of cyclic oxyallylic cations gives rise to cycload-
ducts stereoselectively and in fair to good yields. On the basis
of the assumption of a concerted cycloaddition, the following
conclusions can be drawn. Five-, six-, seven-, and eight-
membered ring oxyallylic cations are U-shaped and react
preferentially via exo transtion states, except for the cyclopen-
tenyl case, in which the endo mode is preferred. The cyclo-
decenyl oxyallylic cation is apparently exclusively sickle-shaped
in accord with Hoffmann’s analysis.8c The cyclododecenyl
cation derived from 20e is also mostly sickle-shaped, with a
small amount of W-shaped cation contributing to product
formation. Some progress has been made in the study of
cycloadditions to substituted butadienes, and both alkoxyallylic
and oxyallylic cations show promise in this area. Side products
formed with alkoxyallylic cations suggest that a stepwise
reaction involving cationic intermediates may be involved in
the formation of certain cycloadducts.
The structure elucidation of 50 was less straightforward. The
1H NMR contained a total of 26 protons including an olefinic
proton at 5.50 ppm as a singlet. A one-proton singlet at 4.11
ppm suggested an oxygenated carbon, and a broad, one-proton
signal at 2.38 ppm was indicative of a hydroxy group. The
13C NMR spectrum had signals for two olefinic carbons at 141.9
and 124.9 ppm and a signal at 115.1 ppm, suggestive of a ketal-
like carbon. No carbonyl group was evident. The IR spectrum
had strong bands at 3374 and 1068 cm-1, indicative of the
alcohol and ether functionalities assumed present in the structure.
The structure and stereochemistry were confirmed by X-ray
analysis.37
It is clear that much mechanistic and methodological work
remains to be done. These studies and the application of these
results to total synthesis are in progress and will be reported in
due course.
The formation of 50 clearly indicates a stepwise reaction with
the intermediacy of an allylic carbocation as shown in Scheme
4. The precise mechanism of the carbon-oxygen bond-forming
and dealkylation steps is not known, and other pathways to the
product are certainly viable.
Experimental Section
Concerned about the apparent lack of generality involving
cycloadditions based on alkoxyallylic sulfones, we decided to
prepare a substrate which would possess a less reactive
dienophile. To that end ketone 54 was prepared and chlorinated.
General Information. All air- or moisture-sensitive reactions were
carried out in oven-dried (at 120 °C) or flame-dried glassware under a
nitrogen atmosphere. Moisture-sensitive and hydroscopic solid materi-
als were added to the reaction vessels in a glovebag in a nitrogen
atmosphere. HMPA was distilled from CaH2 and was stored over
activated molecular sieves. DMF was used as received from the
supplier unless indicated otherwise. 2,2,2-Trifluoroethanol was dried
over CaSO4 and distilled. Sulfone 38 was prepared according to a
procedure (unpublished at the time) that was provided to us by Professor
Funk of Pennsylvania State University.30 Cyclodecanone was prepared
according to a literature procedure.38 Flash chromatography was
performed as described by Still and co-workers on 230-400 mesh silica
gel with technical grade solvents that were distilled prior to use.39 Gas
chromatographic analyses were done with a SPB-5 fused silica capillary
column (length 15 m, 0.25 mm i.d.) and a flame ionization detector.
Melting points are uncorrected. Boiling points are the distilling
temperatures for vacuum distillation at the indicated reduced pressures
using Kugelrohr distillation apparatus. Infrared spectra were obtained
(14)
The resulting R-chloroketone was dissolved in a solution of
sodium trifluoroethoxide in trifluoroethanol. This led to a 1:1
(37) Data on 50: space group P21/n; a ) 10.1970(20) Å, b ) 15.2430-
(20) Å, c ) 10.1480(20) Å, b ) 95.196(9)°; V ) 1570.9(5) Å3; Z ) 4;
F(000) ) 576; Dcalcd ) 1.109 g‚cm-3; m ) 0.23 mm-1; radiation ) Mo
KR (λ ) 0.709 30) Å; temperature ) 23/-1°; final R ) 0.059 for 1686
reflections with I > 2σ(I).
(38) Burpitt, R. D.; Thweatt, J. G. In Organic Syntheses CollectiVe
Volume 5; Baumgarten, H. E., Ed.; Wiley: New York, 1973; pp 277-80.
(39) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

Intramolecular 4 + 3 Cycloadditions
J. Am. Chem. Soc., Vol. 118, No. 12, 1996 2867
as a neat liquid or as a KBr pellet. 1H NMR spectra were recorded on
a 250 or 500 MHz spectrometer with tetramethylsilane as the internal
standard as CDCl3 solutions unless otherwise stated. 13C spectra were
obtained using the same instruments at 62.9 or at 125.8 MHz,
respectively. Low-resolution mass spectra were obtained with a
capillary GC interfaced with a mass selective detector at an ionization
voltage of 70 eV. Elemental analyses were performed by MHW
Laboratories, Phoenix, AZ.
cm-1; MS (70 eV) 192 (M+, 24), 108 (33), 95 (59), 81 (100). Anal.
Calcd for C12H16O2: C, 74.97; H, 8.39. Found: C, 75.16; H, 8.31.
General 4 + 3 Cycloaddition Procedures for Cyclic r-Chloroke-
tones. Preparation of (()-(3ar,6r,7â,9aâ)-2,3,6,7,8,9-Hexahydro-
3a,6-epoxy-7,9a-methano-1H-cyclopentacycloocten-10-one (12a). To
a solution of diisopropylamine (290 mg, 2.85 mmol; 1.1 mmol/1.0 mmol
of ketone) in freshly distilled THF (6.55 mL; 2.5 mL/1.0 mmol of
ketone) was added n-BuLi (1.04 mL of 2.5 M solution; 1.0 equiv) at
-78 °C. After the mixture was stirred for 15 min at -78 °C, the ketone
11a (500 mg, 2.6 mmol) in dry THF (6.5 mL; 2.5 mL/1.0 mmol of
ketone) was added dropwise via a syringe with stirring over 10 min
period. The reaction mixture was then stirred for an additional 30 min,
and trifluoromethanesulfonyl chloride (526 mg, 3.1 mmol; 1.2 mmol/
mmol of ketone) was added. The reaction mixture was stirred for 5-10
min and then removed from the cold bath and quenched with water.
The reaction mixture was diluted with ether (5 mL/1 mmol of ketone)
and worked up. The resulting crude R-chloroketone was cyclized
without purification by one of two methods.
General Alkylation Procedure for Methyl 2-Oxocyclopentan-
ecarboxylate: Preparation of (()-Methyl 2-Oxo-1-[3-(2-furanyl)-
propyl]cyclopentanecarboxylate (10a). In an oven-dried two-necked
flask equipped with a stirring bar and a reflux condenser under an inert
nitrogen atmosphere, sodium hydride (390 mg, 16.2 mmol; 1.15 mmol
of NaH/1.0 mmol of keto ester) was suspended in freshly distilled THF
(42 mL; 3 mL/1.0 mmol of keto ester). Sodium hydride was used as
supplied (60% suspension in mineral oil). The suspension was cooled
to 0 °C. Methyl 2-oxocyclopentanecarboxylate (2.9 g, 14.1 mmol)
dissolved in dry THF (28 mL; 2 mL/mmol of ester) was added to the
suspension dropwise via a syringe. When the addition of the keto ester
was completed, the mixture was allowed to continue stirring at 0 °C
until the grayish color of the suspension disappeared. The cold bath
was then removed and the alkylating halide (4.4 g, 18.3 mmol, 1.3
equiv) was added via a syringe. The reaction mixture was then refluxed
for 48-72 h while the progress of the reaction was monitored by TLC.
Analytical thin layer chromatography was performed on silica gel plates
(0.25 mm thickness) with F254 indicator. Detection was accomplished
by visualization under UV (254 nm) lamp and or by developing in
iodine, vanillin solution (prepared by dissolving 6 g of vanillin in a
solution of 1.5 mL of concentrated H2SO4 and 100 mL of absolute
ethanol), or phosphomolybdic acid (PMA) solution (prepared by
dissolving 32 g of PMA in 320 mL of absolute ethanol) followed by
heating on a hot plate. Upon completion of the reaction, the reaction
mixture was allowed to cool to room temperature followed by
quenching with water and extraction in ether. The organic extracts
were dried over anhydrous MgSO4 or Na2SO4. Filtration and removal
of the solvent under reduced pressure on a rotary evaporator gave the
products as yellow residues that were purified by column chromatog-
raphy on silica gel. The crude product was purified by flash column
chromatography and eluted with 10% ethyl acetate in hexanes (Rf 0.28).
The pure product was obtained as a colorless oil (bp 134-136 °C/0.2
mmHg by Kugelrohr distillation) in 86-92% yield: 1H NMR (CDCl3,
500 MHz) δ 7.28 (d, 1H, J ) 1.0 Hz), 6.26 (dd, 1H, J ) 1.0, 3.0 Hz),
5.98 (d, 1H, J ) 3.0 Hz), 3.70 (s, 3H), 2.67-2.60 (m, 2H), 2.58-2.51
(m, 1H), 2.43-2.37 (m, 1H), 2.28-2.21 (m, 1H), 2.04-1.95 (m, 2H),
1.94-1.85 (m, 2H), 1.73-1.52 (m, 3H); 13C NMR (CDCl3, 125 MHz)
δ 214.54, 171.27, 155.23, 140.75, 109.96, 104.93, 60.26, 52.41, 37.78,
33.25, 32.63, 27.98, 23.34, 19.48; IR (neat) 2955 (s), 1746 (s), 1726
(s), 1147 (s) cm-1; MS (70 eV) 232 (M+ - 18, 16), 173 (73), 162
(52), 108 (32), 94 (97), 81 (100). Anal. Calcd for C14H18O4: C, 67.18;
H, 7.25. Found: C, 66.93; H, 7.09.
Method A: The crude chloroketone was dissolved in freshly distilled
ether (26 mL; 10 mL/1 mmol of ketone). Anhydrous LiClO4 (8.3 g,
78 mmol; to make 3.0 M solution in LiClO4) and freshly distilled (from
CaH2) triethylamine (790 mg, 7.8 mmol; 3 equiv) were added. The
mixture was allowed to stir at room temperature for 12-48 h while
the progress of the reaction was monitored by TLC.
Method B: In a flame-dried reaction flask equipped with a stir bar
and rubber septum, thin shavings of sodium metal (5 mmol/mmol of
ketone) were dissolved in dry 2,2,2-trifluroethanol (8 mL/mmol of
ketone) at 0 °C. A TFE solution (2 mL/mmol of ketone) of the crude
chloroketone was then added to the sodium trifluoroethoxide solution
dropwise. The solution was stirred at room temperature, and the
reaction progress was monitored by TLC. Although refluxing was not
necessary, the reaction proceeded much faster when refluxed. In either
method, when the reaction was completed the mixture was diluted with
ether (10 mL/1 mmol of ketone) in a separatory funnel and standard
aqueous workup was performed. The crude products were purified by
flash column chromatography or by MPLC. Cycloadduct 12a was
prepared via method A. Silica gel flash column chromatography of
the crude reaction mixture (12% ethyl acetate in hexanes, Rf 0.11) gave
the cycloadduct as a mixture of two isomers in the ratio of 14.5-16:1
in favor of the endo product in a combined yield of 53-56%. Attempts
to obtain the minor product in its pure form were unsuccessful. The
major isomer was obtained as a white solid substance (from hexanes,
mp 83 °C): 1H NMR (CDCl3, 500 MHz) δ 6.28 (br d, 1H, J ) 5.7
Hz), 6.09 (d, 1H, J ) 5.8 Hz), 4.69 (dd, 1H, J ) 1.5, 3.4 Hz), 2.41
(dd, 1H, J ) 4.0, 5.6 Hz), 2.17-2.12 (m, 1H), 2.08-1.99 (m, 3H),
1.94-1.69 (m, 4H), 1.5-1.41 (m, 2H); 13C NMR (CDCl3, 125 MHz)
δ 210.42, 135.05, 133.42, 97.10, 83.95, 64.21, 50.26, 29.40, 28. 21,
23.22, 21.03, 20.31; IR (KBr pellet) 1743 (s), 1099 (m), 981 (s) cm-1
;
MS (70 eV) 190 (M+, 69), 162 (61), 135 (50), 134 (62), 91 (54), 81
(100), 55 (68). Anal. Calcd for C12H14O2: C, 75.63; H, 7.42.
Found: C, 75.57; H, 7.31.
Krapcho Decarboalkoxylation of â-Keto Esters: Preparation of
(()-2-[3-(2-Furanyl)propyl]cyclopentanone (11a).15 Substrate 10a
(2.5 g, 10 mmol) was dissolved in DMF (20 mL; 2.0 mL/1 mmol of
keto ester) in a reaction flask equipped with a stirring bar and refluxing
condenser. To the solution were added H2O (360 mg, 20 mmol; 2
mmol/1 mmol of keto ester) and LiCl (850 mg, 20 mmol; 2.0 mmol/1
mmol of keto ester). The reaction solution was then refluxed for 12-
36 h while the progress of the reaction was monitored by TLC. Upon
reaction completion, the mixture was allowed to cool down to room
temperature and then diluted with pentane (100 mL; 10.0 mL/1.0 mmol
of keto ester) in a separatory funnel and worked up (standard aqueous
workup). The resulting crude brown oils were purified by column
chromatography. Purification of the crude residue by flash column
chromatography (eluting with 10% ethyl acetate in hexanes, Rf 0.26)
gave the product as a colorless oil (bp 99-101 °C/0.5 mmHg) in 69-
73% yield: 1H NMR (CDCl3, 500 MHz) δ 7.27 (d, 1H, J ) 1.6 Hz),
6.25 (dd, 1H, J ) 1.6, 2.6 Hz), 5.9 (d, 1H, J ) 2.6 Hz), 2.75-2.57 (m,
2H), 2.30-2.19 (m, 2H), 2.12-1.91 (m, 3H), 1.84-1.65 (m, 4H), 1.60-
1.47 (m, 1H), 1.34-1.26 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ
220.55, 155.68, 140.57, 109.90, 104.69, 48.69, 37.86, 29.41, 29.10,
27.81, 25.93, 20.55; IR (neat) 2959 (s), 2870 (s), 1737 (s), 1148 (s)
(()-(3ar,6r,7â,9aâ)-2,3,6,7,8,9-Hexahydro-7-chloro-3a,6-epoxy-
7,9a-methano-1H-cyclopentacycloocten-10-one (14a). This chlori-
nated adduct was produced in 4-7% yield from the cyclization of 11a
via method A. It was isolated as a white solid (from hexanes, mp
91-93 °C): 1H NMR (CDCl3, 250 MHz) δ 6.39 (br d, 1H, J ) 5.8
Hz), 6.23 (br d, 1H, J ) 5.8 Hz), 4.70 (d, 1H, J ) 1.5 Hz), 2.53-2.42
(m, 1H), 2.33-1.80 (m, 7H), 1.71-1.51 (m, 2H); 13C NMR (CDCl3,
62 MHz) δ 202.00, 137.00, 132.55, 97.84, 88.63, 74.71, 63.85, 31.50,
30.46, 27.80, 24.10, 20.94; IR (KBr) 1763 (s) cm-1; MS (70 eV) 226
(M+ + 2, 7), 224 (M+, 26), 196 (100), 91 (51), 81 (88). Anal. Calcd
for C12H13O2Cl: C, 64.15; H, 5.83. Found: C, 64.25; H, 6.03.
2-[3-(2-Furanyl)propyl]cyclopent-2-en-1-one (15a). This product
was obtained in 14-17% yield as a byproduct from the cyclization
process of precursor 11a via method A. It was separated from the
cycloadduct by MPLC chromatography (12% ethyl acetate in hexanes).
It was obtained as a colorless oil: 1H NMR (CDCl3, 500 MHz) δ 7.31-
7.29 (m, 1H), 7.27 (dd, 1H, J ) 0.7, 1.9 Hz), 6.25 (dd, 1H, J ) 1.9,
3.0 Hz), 5.97 (dd, 1H, J ) 0.7, 3.0 Hz), 2.62 (t, 2H, J ) 7.5 Hz),
2.60-2.53 (m, 2H), 2.38-2.36(m, 2H), 2.23-2.20 (m, 2H), 1.8 (pentet,
2H, J ) 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 209.75, 157.57,
155.55, 145.67, 140.70, 109.99, 104.91, 34.45, 27.52, 26.38, 25.95,

2868 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Harmata et al.
24.20; IR (neat) 2927 (s), 2884 (m), 1699 (s), 1004 (s) cm-1. Anal.
Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.68; H, 7.18.
(()-(3ar,6r,7â,9aâ)-2,3,6,7,8,9-Hexahydro-6-methyl-3a,6-epoxy-
7,9a-methano-1H-cyclopentacycloocten-10-one (12b). Prepared from
the cyclization of the cyclopentanone derivative 11b (1 g, 4.85 mmol)
via cycloaddition method A. Purification of the reaction mixture by
MPLC chromatography (10% ethyl acetate in hexanes) afforded the
cycloadduct as a single stereoisomer in 56% (65% based on recovered
11b). The product was isolated as a white solid (from hexanes, mp
91-92 °C): 1H NMR (CDCl3, 500 MHz) δ 6.11 (d, 1H, J ) 5.7 Hz),
6.04 (d, 1H, J ) 5.7 Hz), 2.22 (d, 1H, J ) 6.0 Hz), 2.08-2.00 (m,
4H), 1.97-1.73 (m, 4H), 1.50-1.37 (m, 8H; including singlet at 1.43
for 3H); 13C NMR (CDCl3, 125 MHz) δ 211.02, 136.94, 135.08, 96.84,
89.21, 61.91, 54.74, 28.25, 28.21, 22.93, 20.34, 19.77, 19.26; IR (KBr)
2972 (s), 1734 (s), 1135 (m) cm-1; MS (70 eV) 204 (M+, 75), 133
(53), 95 (100). Anal. Calcd for C13H16O2: C, 76.44; H, 7.89.
Found: C, 76.61; H, 7.79.
flask. The reaction flask was affixed to a hydrogenation apparatus at
40 psi of hydrogen gas for 4 h. TLC indicated completion of the
hydrogenation, and the reaction solution was filtered through Celite.
The filtrate was concentrated under reduced pressure, and the resulting
solid residue was further purified by recrystallization from hexanes to
afford the desired product as white crystals (mp 68-69 °C) in 98%
yield: 1H NMR (CDCl3, 500 MHz) δ 4.35 (dd, 1H, J ) 4.2, 5.8 Hz),
2.30-2.21 (m, 3H), 2.14-2.08 (m, 1H), 1.99-1.83 (m, 4H), 1.77-
1.42 (m, 5H), 1.40-1.23 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ
212.93, 95.77, 83.63, 61.07, 52.68, 33.16, 31.51, 29.12, 28.60, 22.70,
20.03, 19.13; IR (KBr) 1743 (s), 1065 (s) cm-1
. Anal. Calcd for
C12H16O2: C, 74.97; H, 8.93. Found: C, 75.04; H, 8.33.
General Procedure for the Alkylation of Cyclic Ketones: Prepa-
ration of (()-2-[3-(2-Furanyl)propyl]cyclohexanone (20a). To a
freshly distilled diisopropylamine (1.18 g, 11.7 mmol; 1.15 mmol/1.0
mmol of ketone) dissolved in freshly distilled THF (35 mL; 2.5 mL/
1.0 mmol of ketone) was added n-BuLi (4.5 mL of 2.5 M solution; 1.1
equiv) at -78 °C under an inert nitrogen atmosphere. After the mixture
was allowed to stir for 20-30 min at -78 °C, the ketone (cyclohex-
anone, 1 g, 10.2 mmol) dissolved in dry THF (10 mL; 1 mL/1.0 mmol
of ketone) was added dropwise via a syringe over 10 min period. The
reaction mixture was then stirred at -78 °C for 60 min, and 2-(3-
iodopropyl)furan (3.1 g, 13.3 mmol, 1.3 equiv) was added. The reaction
was allowed to warm up slowly to room temperature while stirring,
and stirring continued for 6-12 h. Upon completion, the mixture was
transferred to a separatory funnel and worked up. The ether extracts
were dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification of the crude reaction mixture by flash column
chromatography using ethyl acetate-benzene-hexane (1:9:10) as an
eluent gave the monoalkylation product along with the dialkylation
product in 49-53% and 14-17% yields, respectively. The desired
monoalkylation product was obtained as a colorless oil (bp 96-98 °C,
0.35 mmHg): 1H NMR (CDCl3, 500 MHz) δ 7.27 (d, 1H, J ) 2.0
Hz), 6.25 (dd, 1H, J ) 2.0, 3.0 Hz), 5.98 (d, 1H, J ) 3.0 Hz), 2.65-
2.56 (m, 2H), 2.38-2.34 (m, 1H), 2.30-2.24 (m, 2H), 2.11-1.97 (m,
2H), 1.88-1.79 (m, 2H), 1.75-1.59 (m, 4H), 1.49-1.33 (m, 1H), 1.28-
1.21 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 212.91, 155.96, 140.53,
109.92, 104.61, 50.37, 41.88, 33.80, 28.87, 27.97, 27.89, 25.53, 24.79;
IR (neat) 2936 (s), 1709 (s) cm-1. Anal. Calcd for C13H18O2: C, 75.69;
H, 8.80. Found: C, 75.60; H, 9.01.
(()-(3ar,6r,7r,10ar)-2,3,6,7,8,9-Hexahydro-3a,6-epoxy-7,10a-
methano-1H,10H-cyclopentacyclononen-11-one (21b). Produced by
subjecting the cyclization precursor 20a (500 mg, 2.4 mmol) to the 4
+ 3 cycloaddition process via method A. The crude reaction residue
was purified by flash chromatography (12% ethyl acetate in hexanes)
to give an inseparable mixture of two 4 + 3 cycloadducts in combined
yield of 56% (61% based on recovered ketone 20a) in a ratio of 2.6:1
as was determined by 1H NMR of the isolated mixture. Separation of
the mixture was accomplished by MPLC (12% ethyl acetate in hexanes,
Rf 0.15 for the major isomer 21b). The minor isomer was never isolated
in its pure form. The major adduct 21b was further recrystallized from
hexanes to give a crystalline solid (from hexanes, mp 47-48 °C) whose
X-ray structure revealed the syn relationship between the oxygen and
carbonyl bridges: 1H NMR (CDCl3, 500 MHz) δ 6.64 (dd, 1H, J )
2.1, 5.8 Hz), 6.46 (d, 1H, J ) 5.8 Hz), 5.02 (dd, 1H, J ) 2.1, 8.7 Hz),
3.02-2.99 (m, 1H), 2.69-2.58 (m, 1H), 2.19-2.08 (M, 1H), 1.99-
1.91 (m, 3H), 1.9-1.84 (m, 1H), 1.82-1.72 (m, 2H), 1.69-1.61 (m,
2H), 1.37-1.26 (m, 1H), 1.10-1.04 (m, 1H); 13C NMR (CDCl3, 125
MHz) δ 211.83, 137.95, 136.47, 96.52, 80.32, 63.92, 49.05, 36.60,
36.11, 33.21, 28.75, 24.28, 17.78; IR (KBr) 2953 (s), 1716 (s), 989 (s)
cm-1; MS (70 eV) 204 (M+, 6), 147 (73), 117 (100), 94 (64). Anal.
Calcd for C13H16O2: C, 76.44; H, 7.89. Found: C, 76.66; H, 7.75.
2-[3-(5-Methyl-2-furanyl)propyl]cyclopent-2-en-1-one (15b). This
elimination product was produced in 13-16% as a side product in the
cycloaddition process of ketone 11b discussed above: 1H NMR (CDCl3,
500 MHz) δ 7.33-7.30 (m, 1H), 5.85-5.82 (m, 2H), 2.61-2.53 (m,
4H), 2.41-2.37 (m, 2H), 2.24-2.20 (m, 5H), 1.87-1.75 (m, 2H); 13
C
NMR (CDCl3, 125 MHz) δ 209.74, 157.46, 153.73, 150.13, 145.82,
105.72, 105.15, 34.48, 27.64, 26.40, 26.11, 24.24, 13.40; IR (neat) 1701
(s) cm-1. Anal. Calcd for C13H16O2: C, 75.76; H, 7.42. Found: C,
75.50; H, 7.60.
(()-(4ar,7r,8r,10ar)-1,2,3,4,7,8,9,10-Octahydro-4a,7-epoxy-8,
10a-methanobenzocycloocten-11-one (12c). Cyclization of the cy-
clopentanone derivative 11c (1.25 g, 6.1 mmol) via cycloaddition
method A followed by silica gel column chromatography (15% ethyl
acetate in hexanes) gave 12c mixed with elimination product. Separa-
tion of this mixture was accomplished by flash column chromatography
using a 9:10:1 solution mixture of benzene-hexanes-ethyl acetate as
an eluting solvent. The cycloadduct was obtained as a white solid (from
hexane, mp 65-66 °C) in 38-42% yield: 1H NMR (CDCl3, 500 MHz)
δ 6.29 (d, 1H, J ) 5.9 Hz), 6.26 (dd, 1H, J ) 1.5, 5.9 Hz), 4.67 (dd,
1H, J ) 1.5, 4.1 Hz), 2.48 (dd, 1H, J ) 4.1, 6.0 Hz), 2.29 (ddd, 1H,
J ) 4.2, 1.5, 9.5 Hz), 1.93-1.75 (m, 5H), 1.72-1.69 (m, 1H), 1.60
1
(dt, 1H, J ) 4.0, 14.0 Hz), H NMR (CDCl3, 500 MHz) δ 7.28 (dd,
1H, J ) 0.7, 1.9 Hz), 6.26 (dd, 1H, J ) 1.9, 3.0 Hz), 1.47 (dq, 1H, J
) 3.3, 14.4 Hz), 1.42-1.24 (m, 3H); 13C NMR (CDCl3, 125 MHz) δ
212.22, 134.54, 133.18, 89.79, 81.82, 56.88, 50.89, 28.98, 27.55, 27.08,
23.98, 22.33, 21.10; IR (KBr) 2963 (s), 1745 (s), 945 (s) cm-1; MS
(70 eV) 204 (M+, 100), 176 (62), 135 (55), 81 (73). Anal. Calcd for
C13H16O2: C, 76.44; H, 7.89. Found: C, 76.63; H, 7.81.
(()-(4ar,7r,8r,10ar)-1,2,3,4,7,8,9,10-Octahydro-8-chloro-4a,7-
epoxy-8,10a-methanobenzocycloocten-11-one (14c). This chlorinated
cycloadduct was obtained in 7% yield as a side product from the
cycloaddition of 11c above. It was isolated as a crystalline solid (from
hexane, mp 77 °C): 1H NMR (CDCl3, 500 MHz) δ 6.78 (d, 1H, J )
5.9 Hz), 6.32 (dd, 1H, J ) 5.9, 1.6 Hz), 4.67 (d, 1H, J ) 1.6 Hz), 2.46
(ddd, 1H, J ) 4.0, 11.0, 11.7 Hz), 2.35 (ddd, 1H, J ) 4.0, 11.7, 12
Hz), 1.96-1.80 (m, 4H), 1.75-1.66 (m, 2H), 1.60-1.56 (m, 1H), 1.50
(ddd, 1H, J ) 4.0, 11.4, 12 Hz), 1.40-1.24 (m, 2H); 13C NMR (CDCl3,
125 MHz) δ 204.27, 136.57, 132.03, 90.15, 86.70, 74.14, 56.52, 31.64,
28.80, 28.47, 27.66, 23.68, 21.48; IR (KBr) 2941 (s), 1762 (s), 967 (s)
cm-1; MS (70 eV) 238 (M+, 22), 95 (55), 81 (100). Anal. Calcd for
C13H15OCl: C, 65.41; H, 6.33. Found: C, 65.64; H, 6.24.
2-[4-(2-Furanyl)butyl]cyclopent-2-en-1-one (15c). This compound
was produced in a competing elimination process during the cycload-
dition of ketone 11c. It was obtained as a colorless oil in 36% yield:
1H NMR (CDCl3, 500 MHz) δ 7.49-7.23 (m, 2H), 6.27 (dd, 1H, J )
2.0, 3.0 Hz), 5.98 (d, 1H, J ) 3.0 Hz), 2.64 (t, 2H, J ) 7.4 Hz), 2.57-
2.55 (m, 2H), 2.41-2.39 (m, 2H), 2.23-2.20 (m, 2H), 1.70-1.64 (m,
2H), 1.56-1.52 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 209.87,
157.41, 156.00, 146.03, 140.63, 109.96, 104.67, 34.50, 27.69, 27.61,
(()-(3ar,6r,7r,11ar)-2,3,6,7,8,9,10,11-Octahydro-3a,6-epoxy-
7,11a-methano-1H-cyclopentacyclodecen-12-one (22b). Cyclization
of precursor 20b (550 mg, 2.5 mmol) via method A followed by
purification on silica gel (15% ethyl acetate in hexane, Rf 0.22 for the
major isomer) gave a 7.3:1 isomeric mixture (1H NMR ratio) of two 4
+ 3 cycloaddition products in combined yield of 56% (64% based on
recovered ketone 20b). The stereochemical relationships for the major
adduct were established by X-ray analysis (from hexane, mp 97-98
°C): 1H NMR (CDCl3, 500 MHz) δ 6.54 (dd, 1H, J ) 1.9, 5.8 Hz),
6.40 (d, 1H, J ) 5.8 Hz), 4.95 (dd, 1H, 1.9, 8.6 Hz), 3.2 (t, 1H, J )
27.10, 26.36, 24.41; IR (neat) 1700 (s) cm-1
. Anal. Calcd for
C13H16O2: C, 76.44; H, 7.90. Found: C, 76.40; H, 7.96.
(()-(3ar,6r,7â,9aâ)-2,3,4,5,6,7,8,9-Octahydro-3a,6-epoxy-7,9a-
methano-1H-cyclopentacycloocten-10-one (16a). Two hundred mg
(1.05 mmol) of 12a and 30 mg of 10% palladium on carbon (2.5 mol
% Pd) were dissolved in 20 mL of ethyl acetate in a hydrogenation

Intramolecular 4 + 3 Cycloadditions
J. Am. Chem. Soc., Vol. 118, No. 12, 1996 2869
8.6 Hz), 2.77-2.72 (m, 1H), 2.00-1.59 (m, 8H), 1.43-1.26 (m, 5H);
13C NMR (CDCl3, 125 MHz) δ 210.10, 137.83, 136.10, 95.38, 80.06,
66.01, 49.72, 37.54, 36.30, 35.82, 26.16, 25.33, 24.25, 23.50; IR (KBr)
2957 (s), 1708 (s) cm-1; MS (70 eV) 218 (M+, 3), 131 (100). Anal.
Calcd for C14H18O2: C, 77.07; H, 8.29. Found: C, 77.18; H, 8.20.
General Procedure for Alkylation of 2-Ethoxy-3-(phenylsulfo-
nyl)cyclopentene 38. Preparation of (()-[[2-Ethoxy-1-[3-(2-fura-
nyl)propyl]-2-cyclopentenyl]sulfonyl]benzene (7). To a solution of
38 (1.19 g, 4.36 mmol) in freshly distilled THF (22 mL; 5 mL/1 mmol
of sulfone) was added dry HMPA (1.6 g, 8.9 mmol; 2 mmol/1 mmol
of sulfone), and the solution was cooled to -78 °C. After the mixture
was stirred for several min at -78 °C, n-BuLi (1.92 mL of a 2.5 M
solution, 1.1 equiv) was added dropwise via a gas-tight syringe. After
the addition of n-BuLi was complete, the mixture was allowed to stir
at -78 °C for an additional 30 min followed by quenching of the
resulting anion with 2-(3-iodopropyl)furan (1.34 g, 5.7 mmol; 1.3
equiv). The reaction mixture was then allowed to warm gradually to
room temperature and continued to stir for 30-60 min. The mixture
was diluted with ether in a separatory funnel, and standard aqueous
workup was performed. The crude products were purified by column
chromatography in the presence of 0.5% Et3N in the eluting solvent to
prevent the hydrolysis of the enol ether functionality. Purification of
the crude product by flash column chromatography on silica gel (30%
ethyl acetate in hexanes, Rf 0.32) afforded the product as a white solid
(from tert-butyl methyl ether, mp 78 °C) in 92% yield: 1H NMR
(CDCl3, 500 MHz) δ 7.84 (dd, 2H, J ) 1.1, 7.3 Hz), 7.6 (br t, 1H, J
) 7.4 Hz), 7. 47 (br t, 2H, J ) 8.0 Hz), 2.27 (br d, 1H, J ) 1.0 Hz),
6.25 (dd, 1H, J ) 1.0, 3.0 Hz), 5.96 (d, 1H, J ) 3.0 Hz), 4.66 (t, 1H,
J ) 2.0 Hz), 3.69-3.64 (m, 2H), 2.69-2.62 (m, 3H), 2.16-2.02 (m,
4H), 1.93 (dt, 1H, J ) 4.5, 10.0 Hz), 1.74-1.65 (m, 1H), 1.57-1.44
(m, 1H), 1.14 (t, 3H, J ) 7.0 Hz); 13C NMR (CDCl3, 125 MHz) δ
155.45, 153.36, 140.84, 137.51, 133.25, 130.13, 128.14, 110.04, 105.00,
102.40, 78.58, 65.20, 29.69, 28.17, 28.02, 26.06, 22.62, 14.22; IR (KBr)
1645 (s), 1445 (s), 1341 (s), 1285 (s), 1245 (s), 1097 (s) cm-1. Anal.
Calcd for C20H24O4S: C, 66.64; H, 6.71. Found: C, 66.50; H, 6.61.
(()-(3ar,6r,7r,12ar)-2,3,6,7,8,9,10,11,12-Octahydro-3a,6-epoxy-
7,12a-methano-1H,6H-cyclopentacycloundecen-13-one (23b). Cy-
cloadditon of 20c (400 mg, 1.7 mmol) via method A followed by
purification (15% ethyl acetate in hexanes) gave the product as a mixture
of two stereoisomers in 14-17% yield in a ratio of 9.5:1 as determined
by 1H NMR. The syn isomer 23b was the major adduct. Chlorination
of 240 mg (1 mmol) of 20c and cycloaddition via method B proceeded
smoothly to give the cycloaddition products. Purification by column
chromatography on silica gel (15% ethyl acetate in hexanes) afforded
the same mixture of the two adducts obtained in method A in 61%
yield (69% corrected) in 10:1 ratio (by 1H NMR) favoring the syn
adduct. The minor adduct was produced in small amounts and was
never obtained in its pure form. The major isomer was obtained as a
white solid (from pentane, mp 40-41 °C): 1H NMR (CDCl3, 500 MHz)
δ 6.49 (dd, 1H, J ) 2.1, 5.9 Hz), 6.37 (d, 1H, J ) 5.9 Hz), 4.94 (dd,
1H, J ) 2.1, 8.0 Hz), 2.89 (q, 1H, J ) 8.2 Hz), 2.48-2.38 (m, 1H),
2.09-1.99 (m, 2H), 1.92-1.87 (m, 1H), 1.72-1.68 (m, 6H), 1.64-
1.32 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 215.05, 137.54, 134.29,
95.86, 80.54, 65.83, 50.88, 37.59, 36.35, 35.44, 29.98, 28.97, 24.85,
24.30, 23.02; IR (KBr) 1700 (s) cm-1. Anal. Calcd for C15H20O2: C,
77.55; H, 8.68. Found: C, 77.47; H, 8.49.
(()-(3aR*,6S*,7S*,14aR*)-2,3,7,8,9,10,11,12,13,14-Decahydro-
1H,6H-3a,6-epoxy-7,14a-methanocyclopentacyclotridecen-15-one
(29a). Chlorination and cyclization of ketone 20d (580 mg, 2.2 mmol)
via method A gave a 19:1 (1H NMR) mixture of two adducts in 59%
yield (67% yield based on the recovered ketone 20d). Column
chromatography (10% ethyl acetate in hexanes) gave the major isomer
as a white solid (from hexanes, mp 53-54 °C) whose stereochemistry
was established by crystallographic analysis (the minor adduct was not
produced in enough quantity to be isolated in its pure form): 1H NMR
(CDCl3, 500 MHz) δ 6.69 (dd, 1H, J ) 1.8, 5.8 Hz), 6.16 (d, 1H, J )
5.8 Hz), 4.43 (br t, 1H, J ) 2.2 Hz), 3.38 (dt, 1H, J ) 2.7, 12.6 Hz),
2.82 (ddd, 1H, J ) 3.5, 6.4, 12.6 Hz), 2.29-2.22 (m, 1H), 2.10 (ddd,
1H, J ) 2.7, 9.3, 16.6 Hz), 1.92-1.84 (m, 3H), 1.79-1.68 (m, 2H),
1.52-1.20 (m, 12H); 13C NMR (CDCl3, 125 MHz) δ 207.57, 138.36,
133.45, 98.65, 83.67, 69.94, 46.76, 35.18, 33.60, 30.02, 26.41, 26.10,
General 4 + 3 Cycloaddition Procedure from Cyclic Alkoxyal-
lylic Sulfones: Preparation of (()-(3ar,6r,9aâ)-1,2,3,4,5,6,7,9a-
Octahydro-3a,6-methano-3aH-cyclopentacycloocten-10-one (41a).
To a stirring solution of the cyclic alkoxyallylic sulfone derivative 40
(350 mg, 1 mmol) in freshly distilled methylene chloride (10 mL; 10
mL/1 mmol of substrate) at -78 °C was added neat TiCl4 (210 mg,
1.1 mmol, 1.1 equiv) dropwise via a gas-tight syringe. When the
addition of TiCl4 was complete, the reaction mixture was allowed to
stir for additional 2-3 min. Then, the flask was removed from the
cold bath and the reaction was quenched with water. The mixture was
diluted with methylene chloride (10 mL/1 mmol of starting substrate)
and washed three times with water and once with saturated sodium
chloride. All aqueous washes were back extracted with methylene
chloride, and the organic layers were combined and dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude products
were purified by chromatography (4% ethyl acetate in hexanes) to afford
an inseparable mixture of two cycloaddition products in 78-81% yield
in a ratio of 2.4:1 by GC analysis. The major adduct (Rf 0.23) was
obtained as a sweet smelling colorless oil: 1H NMR (CDCl3, 500 MHz)
δ 5.65 (d finely split, 1H, J ) 12.9 Hz), 5.34 (d finely split, 1H, J )
12.8 Hz), 2.56 (dddd, 1H, J ) 3 × 4.8, 9.6 Hz), 2.41 (ddq, 1H, J )
2.7, 4.8 18 Hz), 2.30-2.22 (m, 2H), 2.15-2.03 (m, 2H), 1.95-1.72
(m, 5H), 1.63-1.48 (m, 2H), 1.28-1.20 (m, 1H); 13C NMR (CDCl3,
125 MHz) δ 220.82, 130.64, 122.48, 58.68, 50.65, 43.67, 35.65, 35.12,
32.77, 31.75, 23.89, 23.31; IR (neat) 1733 (s) cm-1; MS (70 eV) 176
(m+, 75), 108 (100), 91 (84). Anal. Calcd for C12H16O: C, 81.77; H,
9.15. Found: C, 81.60; H, 8.91.
24.90, 24.62, 23.34, 23.15, 21.66; IR (KBr) 2957 (s), 1714 (s) cm-1
.
Anal. Calcd for C17H24O2: C, 78.42; H, 9.29. Found: C, 78.66; H,
9.27.
(()-(3aR*,6S*,7S*,16aR*)-2,3,7,8,9,10,11,12,13,14,15,16-Dodecahy-
dro-3a,6-epoxy-7,14a-methano-1H,6H-cyclopentacyclopentadecen-
17-one (33a). Reaction of ketone 20e (500 mg, 1.7 mmol) via
cycloaddition method A followed by chromatography (12% ethyl acetate
in hexanes) gave a 7.3:1:1 mixture of three 4 + 3 adducts (33a:33b:
33c) in combined yield of 68% (71% corrected yield). The major
adduct (white solid, mp 99-100 °C) was recrystallized from hexanes
and a single X-ray structure indicated the shown stereochemical
relationship: 1H NMR (CDCl3, 500 MHz) δ 6.64 (dd, 1H, J ) 1.95,
5.8 Hz), 6.16 (d, 1H, J ) 5.8 Hz), 4.42 (t, 1H, J ) 2.0 Hz), 2.84 (dt,
1H, J ) 2.4, 12.0 Hz), 2.66-2.60 (m, 1H), 2.21-2.14(m, 1H), 1.95-
1.85 (m, 2H), 1.75-1.60 (m, 3H), 1.56-1.48 (m, 1H), 1.46-1.32 (m,
5H), 1.30-1.16 (m, 6H), 1.15-0.96 (m, 5H); 13C NMR (CDCl3, 125
MHz) δ 208.23, 137.07, 133.75, 97.42, 83.98, 68.86, 44.40, 35.28,
33.33, 30.12, 27.36, 26.42, 26.28, 24.16, 22.64, 22.31, 22.12, 21.48,
19.93; IR (KBr) 2951 (s), 1712 (s), 1469 (s), 997 (s) cm-1. Anal. Calcd
for C19H28O2: C, 79.12; H, 9.80. Found: C, 78.83; H, 9.69. Adducts
33b and 33c: 1H NMR (1:1 mixture, CDCl3, 250 MHz) δ 6.42 (dd,
1H (33c), J ) 2.1, 5.9 Hz), 6.28 (d, 1H (33c), J ) 5.9 Hz), 6.23 (dd,
1H (33b), J ) 1.8, 5.8 hz), 6.07 (d, 1H (33b), J ) 5.8 Hz), 4.90 (dd,
1H (33c), J ) 2.1, 7.9 Hz), 4.68 (dd, 1H (33b), J ) 1.8, 3.6 Hz), 3.33
(dt, 1H (33b), J ) 2.8, 11.0 Hz), 2.72-2.62 (m, 1H (33c)), 2.30-2.24
(m, 2H), 2.13-1.95 (m, 2H), 1.88-1.80 (m, 2H), 1.78-0.94 (m, 43H);
13C NMR (1:1 mixture of 33b:33c, CDCl3, 62 MHz) δ 212.40, 210.8,
137.31, 136.53, 133.5, 95.73, 94.51, 85.20, 80.34, 71.10, 66.67, 65.65,
51.76, 48.02, 34.52, 33.52, 32.86, 28.23, 27.44, 26.82, 26.25, 26.10,
25.36, 24.87, 23.90, 23.71, 23.37, 23.10, 22.84, 22.22, 22.11, 22.00,
21.22, 20.70, 20.11, 18.60, 17.77.
(()-(3ar,6r,9aâ)-Decahydro-3a,6-methano-3aH-cyclopentacy-
cloocten-1-one. One hundred ten mg (0.62 mmol) of cycloadduct 41a
and 25 mg of 10% palladium on activated carbon (4.6 mol % of
palladium) were dissolved in 25 mL of ethyl acetate in a hydrogenating
flask. The flask was affixed to a hydrogenation apparatus at 48 psi of
H2 for 5 h. TLC indicated completion of the hydrogenation, and the
mixture was filtered through Celite. Concentration of the filtrate under
reduced pressure and purification of the resulting residue by column
chromatography (5% ethyl acetate in hexanes; Rf 0.24) gave the
hydrogenated product as a colorless oil in 99% yield: 1H NMR (CDCl3,
500 MHz) δ 2.47 (dddd, 1H, J ) 3 × 4.3, 8.9 Hz), 2.18 (ddd, 1H, J
) 6.6, 11.1, 12.7 Hz), 2.04-1.85 (m, 1H), 1.30-1.67 (m, 2H), 1.65-
1.48 (m, 10H), 1.42-1.34 (m, 1H), 1.16-1.10 (m, 1H), 0.98-0.91
(m, 1H); 13C NMR (CDCl3, 125 MHz) δ 221.67, 58.28, 50.25, 45.51,
37.38, 36.51, 34.22, 32.95, 30.70, 26.49, 23.37, 19.07; IR (neat) 1734

2870 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Harmata et al.
(s) cm-1; MS (70 eV) 178 (M+, 49), 79 (100). Anal. Calcd for
C12H18O: C, 80.85; H, 10.18. Found: C, 80.73; H, 10.33.
27.33, 24.33, 24.06, 20.48; IR (KBr) 3523 (s), 1699 (s), 1317 (s), 1123
(s) cm-1. Anal. Calcd for C19H26O3: C, 75.46; H, 8.67. Found: C,
75.23; H, 8.54.
(()-(3ar,6r,9ar)-Heptahydro-2H,7H-3,9a-ethanocyclopent[b]-
oxocin-2-one (42). The above ketone (75 mg, 0.4 mmol) and technical
(80-85%) 3-chloroperoxybenzoic acid (145 mg, 0.8 mmol; 2 mmol/1
mmol of ketone) were dissolved in freshly distilled methylene chloride
(2 mL/1 mmol of ketone). The solution was then cooled to 0 °C and
kept under inert atmosphere of nitrogen. Then, trifluoroacetic acid (48
mg, 0.4 mmol; 1 mmol/1 mmol of ketone) was added dropwise at 0
°C over 5 min period while stirring.32 The reaction was protected from
light by wrapping the flask with aluminum foil. The mixture was
allowed to warm slowly to room temperature while stirring, and then
stirring continued until completion. Reaction progress was monitored
by TLC. Once the reaction was complete, the reaction mixture was
diluted with methylene chloride (2 mL; 5 mL/1 mmol of starting ketone)
and transferred to a separatory funnel. The mixture was then washed
once with 10% aqueous Na2SO3 (1 mL; 2 mL/1 mmol), once with
saturated aqueous K2CO3 (2 mL/1 mmol), and twice with water (2 mL;
5 mL/1 mmol). The organic layer was dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure on a rotary evaporator.
Purification on silica gel (10% ethyl acetate in hexanes; Rf 0.18) gave
a colorless soft solid substance in 77% yield: 1H NMR (CDCl3, 500
MHz) δ 2.88-2.84 (m, 1H), 2.13-2.03 (m, 2H), 2.00-1.93 (m, 2H),
1.92-1.71 (m, 9H), 1.65-1.42 (m, 3H), 1.25-1.14 (m, 1H); 13C NMR
(CDCl3, 125 MHz) δ 178.22, 90.44, 52.61, 44.03, 35.77, 34.68, 33.85,
30.92, 28.10, 13.62, 21.80, 19.10; IR (thin film) 2931 (s), 1724 (s)
cm-1; MS (70 eV) 194 (M+, 15), 122 (100), 79 (66), 55 (82). Anal.
Calcd for C12H18O2: C, 74.19; H, 9.34. Found: C, 73.97; H, 9.23.
(()-(3ar,6r,9aâ)-Decahydro-3a-hydroxy-1H-cyclopentacyclooctene-
6-methanol: A suspension of LiAlH4 (11 mg, 0.28 mmol; 1.1 mmol/1
mmol of lactone) in freshly distilled THF (0.5 mL; 2.5 mL of THF/1
mmol of lactone) was cooled to 0 °C. To the suspension was added
dropwise the lactone 42 (50 mg, 0.26 mmol) dissolved in dry THF
(2.5 mL/1 mmol of lactone) under an inert environment of nitrogen.
After the addition of the lactone was completed, the cold bath was
removed and the reaction mixture was allowed to stir at room
temperature until the reaction was complete. The progress of the
reaction was followed by TLC. When completed, the reaction was
worked up by slow addition of crystalline sodium sulfate decahydrate
(Na2SO4‚10H2O) to the reaction mixture while stirring until the grayish
color of the solution disappeared. The mixture was then allowed to
stand for 15-20 min to give a colorless liquid layer and a white
precipitate. The liquid layer was separated from the precipitate by
filtration. The filtrate was dried over MgSO4, filtered, and concentrated.
The crude solid residue was purified by recrystallization from 5% ethyl
acetate in hexanes. The pure diol (mp 86 °C) was obtained in 87%
yield: 1H NMR (CDCl3, 500 MHz) δ 3.48-3.39 (m, 2H), 2.09-2.04
(m, 1H), 1.89-1.84 (m, 1H), 1.74-1.63 (m, 4H), 1.58-1.53 (m, 5H),
1.51-1.31 (m, 7H), 1.24-1.19 (m, 2H); 13C NMR (CDCl3, 125 MHz)
δ 83.48, 68.98, 48.28, 43.99, 41.55, 36.18, 35.90, 30.58, 28.20, 27.29,
26.56, 22.19; IR (KBr) 3347s (br), 2951 (s), 1458 (s) cm-1; MS (70
eV) 180 ((M - H2O)+, 28), 134 (45), 91 (63), 79 (100). Anal. Calcd
for C12H22O2: C, 72.68; H, 11.18. Found: C, 72.80; H, 10.98.
(()-(3ar,6r,9aâ)-1,2,3,4,5,6,7,9a-Octahydro-9-ethyl-3a,6-methano-
3aH-cyclopentacycloocten-10-one (45a). This compound was pre-
pared by cyclization of 44 (250 mg, 0.67 mmol) according to the
procedure for 41a. Purification of resulting reaction residue by flash
chromatography (8% ethyl acetate in hexanes) gave a mixture of two
4 + 3 adducts in 56-59% yield in a ratio of 2.35:1. The major isomer
(Rf 0.32) was obtained in 41% yield as a colorless oil with a sweet
odor: 1H NMR (CDCl3, 500 MHz) δ 5.20 (d finely split, 1H, J ) 6.3
Hz), 2.53 (app. sextet, 1H, J ) 4.4 Hz), 2.35 (ddddd, 1H, J ) 17.6, 2
× 4.0, 2 × 2.0 Hz), 2.20-2.14 (m, 2H), 2.11-2.04 (m, 3H), 2.03-
1.90 (m, 3H), 1.88-1.80 (m, 2H), 1.76-1.68 (m, 1H), 1.66-1.50 (m,
2H), 1.22 (m, 1H, J ) 2 × 9.3, 2 × 12.6 Hz), 1.03 (t, 3H, J ) 4.1);
13C NMR (CDCl3, 125 MHz) δ 222.67, 142.70, 117.39, 57.95, 53.56,
44.75, 33.40, 33.26, 33.22, 32.20, 31.88, 22.60, 22.14, 14.05; IR (neat)
2999 (s), 1735 (s) cm-1; MS (70 eV) 204 (m+, 10), 124 (91), 95 (100),
79 (89). Anal. Calcd for C14H20O: C, 82.30; H, 9.87. Found: C,
82.50; H, 10.00.
(()-(3ar,6r,9ar)-1,2,3,4,5,6,7,9a-Octahydro-9-ethyl-3a,6-methano-
3aH-cyclopentacycloocten-10-one (45b). The compound was pro-
duced as the minor isomer (Rf 0.29) from the cycloaddition of sulfone
44 (discussed above). It was obtained in 17% yield as a colorless oil
with a sweet odor: 1H NMR (CDCl3, 500 MHz) δ 5.56-5.54 (m, 1H),
2.54-2.51 (m, 1H), 2.40-2.35 (m, 1H), 2.32-2.26 (m, 1H), 2.14-
2.00 (m, 5H), 1.94-1.80 (m, 2H), 1.75-1.59 (m, 3H), 1.56-1.40 (m,
3H), 1.01 (t, 3H, J ) 7.3 Hz); 13C NMR (CDCl3, 125 MHz) δ 224.33,
143.18, 120.75, 58.05, 52.71, 47.04, 33.58, 32.26, 32.02, 30.96, 29.35,
23.34, 22.65, 13.94; IR (neat) 2959 (s), 1734 (s) cm-1. Anal. Calcd
for C14H20O: C, 82.30; H, 9.87. Found: C, 82.21; H, 9.87.
(5R*,6S*)-6-(3-Chloro-1-ethyl-1-propenyl)spiro[4.4]nonan-1-
one (46). This compound was produced as a side product during the
cyclization of sulfone 44. It was obtained as a colorless oil in 19-
21% yield: 1H NMR (CDCl3, 500 MHz) δ 5.47 (t, 1H, J ) 8.0 Hz),
4.15-4.07 (m, 2H), 2.98 (dd, 1H, J ) 10.3, 6.8 Hz), 2.36-2.31 (m,
1H), 2.25-2.17 (m, 1H), 2.15-2.04 (m, 1H), 1.91-1.80 (m, 3H), 1.78-
1.69 (m, 4H), 1.67-1.51 (m, 4H), 0.97 (t, 3H, J ) 7.5 Hz); 13C NMR
(CDCl3, 500 MHz) δ 223.72, 148.07, 121.64, 59.16, 50.47, 40.51, 38.92,
37.71, 33.16, 30.63, 24.10, 23.36, 19.16, 13.75; IR (neat) 2979 (s),
1731 (s) cm-1; MS (79 eV) 240 (M+, 14), 204 (100), 175 (55), 97
(58). Anal. Calcd for C14H21OCl: C, 69.84; H, 8.79. Found: C, 70.00;
H, 8.80.
(5R*,6S*)-6-[3-(4-Bromobenzoxy)-1-ethyl-1-propenyl]spiro[4.4]-
nonan-1-one (47). An oven-dried 25 mL flask equipped with a stir
bar and septum was charged with 38 mg of NaH (64 mg of 60% NaH
in oil, 1.6 mmol). The oil was removed by rinsing several times with
dry THF under nitrogen. The NaH was suspended in 2 mL of dry
THF. 4-Bromobenzoic acid (318 mg, 1.6 mmol) dissolved in 2 mL of
dry THF was added dropwise under nitrogen. The resulting milky
solution was allowed to stir at room temperature for 30 min. The
solvent was removed under reduced pressure on a rotary evaporator to
yield a white solid which was dried under vacuum. The salt was
suspended in 2 mL of dry DMF, and 46 (38 mg, 0.16 mmol) in 1 mL
of dry DMF was added. The reaction mixture was heated to reflux for
several min, but the salt did not dissolve. Dry HMPA (2 mL) was
added and reflux resumed. After 1.5 h, TLC indicated reaction
completion. The greenish solution was cooled and standard aqueous
workup gave a residue which was purified by flash chromatography
and recrystallized from ethanol (mp 76-78 °C) to give 53 mg of 47
(83%). This compound was characterized by X-ray analysis.34
(()-(3aâ,4r,6ar,9aâ)-1,2,3,3a,4,5,6,6a,7,8,9,9a-Dodecahydro-2,2-
dimethyl-4a,6-methanodicyclopenta[a,d]cycloocten-11-one (49a). This
compound was prepared from 48 (350 mg, 0.85 mmol) by the method
described for the synthesis of 41a or from 54 (500 mg, 2 mmol) by
the method described for the synthesis of 12a (method B). The crude
mixture was purified by column chromatography to give a 1:1 mixture
of adducts in 61% yield (67% yield based on recovered ketone 48).
The two isomers were separated by flash column chromatography
(gradient: 0%, 0.65%, 1.25%, 1.75%, 2.5%, and 3.25% ethyl acetate
in hexanes). The stereochemistry of the adducts was established on
(()-(3ar,6r,9aâ)-Decahydro-3a-hydroxy-r-benzoxy-1H-cyclo-
pentacyclooctene-6-methanol (43): Thirty mg (0.15 mmol) of the
above diol, 37 mg (0.30 mmol) of DMAP, and 50 mg (0.23 mmol) of
benzoic anhydride were all dissolved at the same time in freshly distilled
methylene chloride (1.5 mL). The reaction mixture was allowed to
stir at room temperature for 28 h (without monitoring). TLC indicated
reaction completion, and the mixture was diluted with 5 mL of ether
in a separatory funnel. The mixture was washed once with saturated
aqueous potassium carbonate (5 mL), twice with water (5 mL each),
and once with brine. All aqueous rinses were back-extracted in 5 mL
of ether, and the two ether extracts were combined and dried over
MgSO4. Filtration and removal of the solvent on a rotary evaporator
followed by chromatography (15% ethyl acetate in hexanes (Rf 0.23)
gave the benzoate ester as a white solid (from hexanes, mp 88 °C) in
91% yield: 1H NMR (CDCl3, 500 MHz) δ 8.03 (dd, 2H, J ) 7.75, 1.2
Hz), 7.55 (t, 1H, J ) 7.44 Hz), 7.44 (t, 2H, J ) 7.75 Hz), 4.19-4.13
(m, 2H), 2.07-2.00 (m, 2H), 1.99-1.52 (m, 10H), 1.50-1.41 (m, 6H),
1.15 (br s, 1H); 13C NMR (CDCl3, 125 MHz) δ 166.65, 132.82, 130.47,
129.51, 128.33, 80.45, 69.60, 46.00, 43.95, 38.31, 38.24, 33.99, 28.11,
1
the basis of H NMR comparison with other cycloaddition products.

Intramolecular 4 + 3 Cycloadditions
J. Am. Chem. Soc., Vol. 118, No. 12, 1996 2871
Adduct 49a was obtained as a colorless soft solid which melts at room
temperature: 1H NMR (CDCl3, 500 MHz) δ 5.23 (t, 1H, J ) 1.9 Hz),
2.58 -2.54 (m, 1H), 2.25-2.44 (m, 1H), 2.40-2.34 (m, 1H), 2.26-
2.18 (m, 2H), 2.16-2.15 (m, 1H), 2.11-1.92 (m, 3H), 1.87-1.66 (m,
4H), 1.62-1.47 (m, 2H), 1.41-1.33 (m, 2H), 1.01 (s, 3H), 0.97 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 217.64, 143.71, 124.05, 60.51,
51.12, 49.60, 48.18, 47.60, 47.30, 36.98, 36.84, 34.99, 32.83, 30.04,
29.63, 26.95, 25.55; IR (neat) 2950 (s), 1735 (s) cm-1. Anal. Calcd
for C17H24O: C, 83.55; H, 9.90. Found: C, 83.36; H, 9.91.
) 5.6 Hz), 1.78-1.48 (m, 8H), 1.23-1.14 (m, 2H), 1.08 (s, 3H), 1.01
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 141.94, 124.90, 115.06, 81.75,
62.19, 58.38, 47.25, 45.77, 41.40, 38.29, 36.05, 29.76, 29.74, 29.24,
26.34, 22.81; IR (KBr) 3374 (s), 2956 (s), 1013 (s) cm-1. Anal. Calcd
for C17H26O2C, 77.82; H, 9.99. Found: C, 77.84; H, 10.01.
Acknowledgment. This work was supported by a grant from
the National Science Foundation (CHE-8912190 and CHE-
9220679) to whom we are grateful. We thank the National
Science Foundation for partial support of the NMR (PCM-
8115599) facility at the University of MissourisColumbia and
for partial funding for the purchase of a 500 MHz spectrometer
(CHE-89-08304) and an X-ray diffractometer (CHE-90-11804).
(()-(3ar,4r,6ar,9ar)-1,2,3,3a,4,5,6,6a,7,8,9,9a-Dodecahydro-2,2-
dimethyl-4a,6-methanodicyclopenta[a,d]cycloocten-11-one (49b). This
compound was produced by the cyclization procedures described for
the preparation of 49a above. This stereoisomer was obtained as white
crystals (from hexanes, mp 94-95 °C): 1H NMR (CDCl3, 500 MHz)
δ 5.57 (br s, 1H), 2.56-2.53 (m, 1H), 2.40-2.32 (m, 2H), 2.26-2.24
(m, 1H), 2.15-2.00 (m, 2H), 1.99-1.97 (m, 1H), 1.92 (ddd, 1H, J )
4.7, 12.3, 14.5 Hz), 1.78-1.63 (m, 4H), 1.60-1.45 (m, 2H), 1.42-
1.27 (m, 3H), 1.08 (s, 3H), 0.90 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 224.20, 146.40, 123.52, 59.26, 51.42, 51.08, 50.05, 46.83, 45.29,
37.37, 33.03, 32.44, 31.08, 28.66, 26.64, 22.59, 19.63; IR (KBr) 2957
Supporting Information Available: Crystallographic data
for 12c, 21b, 22b, 33a, 47, and 50, spectral and analytical data
for 10b,c, 11b,c, 20b-e, 40, 44, 48, and 54 (and its precursor),
and procedures for the synthesis of the dienyl iodides involved
in the synthesis of 44 and 48 (61 pages). This material is
contained in many libraries on microfiche, immediately follows
this article in the microfilm version of the journal, can be ordered
from the ACS, and can be downloaded from the Internet; see
any current masthead page for ordering information and Internet
access instructions.
(s), 1724 (s) cm-1
. Anal. Calcd for C17H24O: C, 83.55; H, 9.90.
Found: C, 83.69; H, 10.14.
(1R*,3R*,4R*,8R*)-1-Hydroxy-3-(4,4-dimethylcyclopent-1-enyl)-
2-oxatricyclo[6.3.0.04,8]undecane (50). This compound was produced
as the major product (27-32% yield) during the cyclization reaction
of sulfone 48. It was obtained as a white solid (from hexanes, mp
96-99 °C): 1H NMR (CDCl3, 500 MHz) δ 5.50 (br s, 1H), 4.11 (d,
1H, J ) 9.2 Hz), 2.38 (br s, 1H), 2.19-2.03 (m, 6H), 2.02 (d, 1H, J
JA952740R