Synthesis of carbocycles via intramolecular conjugate additions: Another solution to the terpenoid side chain stereochemistry problem

Article abstract of DOI:10.1021/jo951531m

Intramolecular conjugate additions of keto esters 7-11, mediated by pyrrolidine-acetic acid, provide perhydroindans or bicyclo[6.3.0]undecanes with high levels of diastereoselectivity at the acyclic stereogenic center. Levels of acyclic diastereoselection depend on starting unsaturated ester olefin geometry.

Full text of DOI:10.1021/jo951531m

J . Org. Chem. 1996, 61, 465-472
465
Syn th esis of Ca r bocycles via In tr a m olecu la r Con ju ga te Ad d ition s:
An oth er Solu tion to th e Ter p en oid Sid e Ch a in Ster eoch em istr y
P r oblem
Alyx-Caroline Guevel and David J . Hart*
Department of Chemistry, The Ohio State University, 120 W. 18th Avenue, Columbus, Ohio 43210
Received August 18, 1995X
Intramolecular conjugate additions of keto esters 7-11, mediated by pyrrolidine-acetic acid, provide
perhydroindans or bicyclo[6.3.0]undecanes with high levels of diastereoselectivity at the acyclic
stereogenic center. Levels of acyclic diastereoselection depend on starting unsaturated ester olefin
geometry.
Many terpenoids contain side chains attached to car-
bocyclic ring systems via a stereogenic carbon. Choles-
terol (1),1 ophiobolin C (2),2 and axisonitrile-1 (3)3 are only
three of numerous examples that could be cited. The
problem of establishing stereochemistry at the side chain
stereogenic center, relative to stereogenic centers in the
carbocycle, is a long-standing problem in organic syn-
thesis, and a number of creative solutions have been
developed over the years.4,5 Of course, no general solu-
tion has been developed because the stereochemical
relationships required by one natural product or another
are quite different. Nonetheless, any solution to this
problem usually has a certain set of natural products for
which it is relevant. During the course of a synthesis of
axamide-4 and related natural products, we discovered
an intramolecular conjugate addition reaction that af-
forded a carbocycle with an appended side chain in which
both the ring and side chain stereogenic centers were
established with an excellent level of relative stereo-
chemical control.6 Specifically, it was found that treat-
ment of ketone 4 with pyrrolidine and acetic acid in
tetrahydrofuran gave perhydroindans 5 (15%) and 6
(60%) (Scheme 1). The high degree of stereocontrol in
the formation of 6 was surprising. Since this observation
obviously offered another potential solution to the ter-
penoid side chain stereochemistry problem, we decided
to investigate the generality of the process. The results
of this study are reported herein.
eochemical course of the cyclization, and substrate 11
would determine whether results obtained in the perhy-
droindan-producing systems could be extrapolated to
other fused carbocyclic systems.
Cyclization substrates 7-10 were prepared as de-
scribed in Scheme 2. Peterson olefination of aldehyde
12 using the enolate derived from ethyl 2-(trimethylsilyl)-
propanoate provided a 1:1 mixture of unsaturated esters
13 and 14.6,7 On the other hand, Wittig olefination of
12 using the appropriate stabilized phosphorane gave an
8:1 mixture of 13 and 14, respectively.8 Although the
isomeric esters were inseparable by chromatography,
stereochemical assignments were easily made on the
basis of the chemical shift of the vinylic proton, which
was much further upfield for 14 (δ 5.90) than for 13 (δ
6.75) due to steric inhibition of resonance in 14. Acid-
promoted hydrolysis of the aforementioned mixtures of
13 and 14 provided a 78% yield of a mixture of keto esters
7 and 8 which could be separated by column chromatog-
raphy. In addition, isomerization of 8 to 7 was ac-
Ketones 7-11 were selected as substrates for study.
It was felt that substrates 7 and 9 would complement
one another somewhat in terms of stereochemistry at the
acyclic stereogenic center, substrates 8 and 10 would
examine the importance of olefin geometry on the ster-
X Abstract published in Advance ACS Abstracts, J anuary 1, 1996.
(1) For one synthesis that addresses the side chain stereochemistry
problem, see: Marino, J . P.; Abe, H. J . Am. Chem. Soc. 1981, 103, 2907.
(2) For syntheses that address the side chain stereochemistry
problem, see: Rowley, M.; Tsukamoto, M.; Kishi, Y. J . Am. Chem. Soc.
1989, 111, 2735 and references cited therein.
(3) For a synthesis that addresses the side chain stereochemistry
problem, see: Guevel, A.-C.; Hart, D. J . Synlett 1994, 169; J . Org. Chem.
1996, 61, 473-479.
(4) For reviews, see: Piatak, D. M.; Wicha, J . Chem. Rev. 1978, 78,
199. Redpath, B. J .; Zeelen, F. J . Chem. Soc. Rev. 1983, 12, 75.
(5) For a categorization of more recent methods, see: Hart, D. J .;
Krishnamurthy, R. Synlett 1991, 412. For some additional methods,
see: Mandai, T.; Matsumoto, T.; Kawada, M. Tsuji, J . J . Org. Chem.
1992, 57, 6090. Kametani, T.; Katoh, T.; Tsubuki, M.; Honda, T. J .
Am. Chem. Soc. 1986, 108, 7055. Evans, D. A.; Nelson, J . V. J . Am.
Chem. Soc. 1980, 102, 774. Ficini, J .; D’Angelo, J .; Noire, J . J . Am.
Chem. Soc. 1974, 96, 1213.
(7) Albaugh-Robertson, P.; Katzenellenbogen, J . A. J . Org. Chem.
1983, 48, 5288. For overviews of the Peterson olefination, see: Kelly,
S. E. In Comprehensive Organic Synthesis; Trost, B. M., Eds.; Perga-
mon Press: New York, 1991; Vol. 1, p 729. Chan, T.-H. Acc. Chem.
Res. 1977, 10, 442.
(8) House, H. O.; J ones, V. K.; Frank, G. A. J . Org. Chem. 1964, 29,
3327.
(6) Chenera, B.; Chuang, C.-P.; Hart, D. J .; Lai, C.-S. J . Org. Chem.
1992, 57, 2018. This article also describes the preparation of aldehyde
12.
0022-3263/96/1961-0465$12.00/0 © 1996 American Chemical Society

466 J . Org. Chem., Vol. 61, No. 2, 1996
Guevel and Hart
Sch em e 1
Sch em e 3
equiv of pyrrolidine and a catalytic amount of acetic acid
were used, cyclization occurred slowly, but mass balance
upon product isolation was low. In addition, it was found
that the Z-olefins isomerized to the E-olefins to some
extent under these conditions. It was eventually deter-
mined that these substrates were all converted to per-
hydroindans in a timely manner upon treatment with 1
equiv of pyrrolidine and 2.3 equiv of acetic acid in
tetrahydrofuran at reflux, followed by an aqueous acidic
workup. For example, these conditions isomerized sub-
strate 7 to a 99:1 mixture (by GC) of perhydroindans 18
and 19, respectively in 78% yield (Scheme 3). When
substrate 8 was subjected to the same reaction conditions,
a separable 3:1 mixture (by GC) of 18 and 19 was
obtained in 55% yield. The stereochemistry of 18 was
determined by X-ray crystallographic analysis of car-
boxylic acid 20, prepared in 93% by hydrolysis of 18 using
lithium hydroxide in aqueous methanol.12 The stereo-
chemistry of 19 was determined by epimerization experi-
ments. Thus, treatment of 18 with an excess of sodium
ethoxide in ethanol at reflux afforded a 1:1 mixture of
18 and 19.13 In a similar manner, substrate 9 was
converted to perhydroindan 21 in 43% yield and 10 was
isomerized to a separable 6:1 mixture of 21 and 22,
respectively, in 72% yield (Scheme 4). The stereochem-
ical assignments for the perhydroindans were based on
analogy with results obtained with substrates 7 and 8.
It is interesting to note the similarity between the
systems studied. In each case, cyclization of the E-isomer
(7 and 9) was highly diastereoselective, whereas cycliza-
tion of the Z-isomer (8 and 10) gave a mixture of epimers
at C10. In each case the major product was the same
Sch em e 2
complished in 91% yield using catalytic amounts of
thiophenol and AIBN in benzene at reflux.9 The syn-
theses of 9 and 10 were accomplished from 12 in a similar
manner. Thus, ester 17 was prepared in 53% yield by
alkylating the lithium enolate of ethyl 2-(trimethylsilyl)-
acetate with 1-iodo-4-methyl-3-pentene.10 Peterson ole-
fination of aldehyde 12 with 17 provided a 4:1 mixture
of unsaturated esters 16 and 15, respectively, in 59%
yield. Once again, stereochemical assignments were
based on the chemical shifts of the vinylic protons which
appear at δ 5.83 and 6.74 for 16 and 15, respectively.
Hydrolysis of the mixture of ketals provided a mixture
of ketones 9 and 10 in 65% yield. Once again, these
cyclization substrates were separated and purified by
chromatography over silica gel.
(11) For pioneering studies related to the stereochemical course of
intramolecular conjugate additions, see: Stork, G.; Shiner, C. S.;
Winkler, J . D. J . Am. Chem. Soc. 1982, 104, 310. For reviews of
relevant conjugate additions, see: Hickmott, P. W. Tetrahedron 1982,
38, 1975. Hickmott, P. W.; Tetrahedron 1982, 38, 3363. Oare, D. A.;
Heathcock, C. H. In Topics in Stereochemistry; Eliel, E. L., Wilen, S.
H., Ed.; Wiley: New York, 1991; Vol. 26. Seebach, D.; Imwinkelried,
R.; Weber, T. In Modern Synthetic Methods; Scheffold, R., Ed.;
Springer-Verlag: Berlin, 1986; Vol. 4. Whitesell, J . K. In Comprehen-
sive Organic Synthesis; Pergamon Press: New York, 1991; Vol. 6, p
703. For specific articles of interest, see: Massiot, G.; Mulamba, T. J .
Chem. Soc., Chem. Commun. 1984, 715. Hirai, Y.; Hagiwara, A.;
Yamazaki, T. Heterocycles 1986, 24, 571. D’Angelo, J .; Desmaele, D.;
Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459.
Kozikowski, A. P.; Greco, M. N.; Springer, J . P. J . Am. Chem. Soc.
1984, 106, 6873. Pandit, U. K.; J uisman, H. O. Tetrahedron Lett. 1967,
8, 3901. D’Angelo, J .; Guingant, A.; Riche, C.; Chiaroni, A. Tetrahedron
Lett. 1988, 29, 2667. Guingant, A. Tetrahedron: Asymmetry 1991, 2,
415. Hori, K.; Kazuno, H.; Nomura, K.; Yoshii, E. Tetrahedron Lett.
1993, 34, 2183. Yoshii, E.; Hori, K.; Nomura, K.; Yamaguchi, Synlett
1995, 568.
With cyclization substrates 7-10 in hand, their pyr-
rolidine-mediated cyclizations were examined under
several conditions.11 No cyclization occurred when sub-
strates were treated with 1 equiv of either pyrrolidine
or acetic acid in tetrahydrofuran at reflux for 6 h. If 1
(12) We thank Dr. J udith C. Gallucci for performing X-ray crystal-
lographic analyses of acids 20 and 36 at The Ohio State University
Crystallography Facility.
(13) It has previously been established that perhydroindans of type
18 are thermodynamically more stable as the cis isomers.6 Thus, the
observed epimerization is surely occurring at adjacent to the carbe-
thoxy group.
(9) Henrick, C. A.; Willy, W. E.; Baum, J . W.; Baer, T. A.; Garcia,
B. A.; Mastre, T. A.; Chang, S. M. J . Org. Chem. 1975, 40, 1. Schwarz,
M.; Graminski, G. F.; Waters, R. M. J . Org. Chem. 1986, 51, 260.
Annuziata, R.; Cinquini, M.; Cozzi, F.; Gennari, C.; Raimondi, L. J .
Org. Chem. 1987, 52, 4674.
(10) Biernacki, W.; Gdula, A. Synthesis 1979, 37.

Carbocycles via Intramolecular Conjugate Additions
J . Org. Chem., Vol. 61, No. 2, 1996 467
Sch em e 4
Sch em e 6
Sch em e 5
How might these arguments be used to rationalize the
reduced selectivity observed with 8 and 10? Cyclization
of enamines derived from these ketones in a manner that
minimizes A1,3 strain would necessarily lead to 26 or its
geometrical isomer. Although 26 is simply a C9-C10
conformer of 24, its geometrical isomer could never adopt
a conformation that enjoys electrostatic stabilization.
Thus, it is possible that the diastereofacial bias present
in 24 might not be accessible to at least a portion of the
reactive intermediates derived from cyclization of 8 and
10, the result being less stereoselectivity in the proto-
nation of C10.
Regardless of the origin of stereoselectivity, we wanted
to see if this argument could be extrapolated to the
preparation of other ring systems. With an eye on
members of the ophiobolin and ceroplastol family of
sesterterpenes, we prepared substrate 11 as described
in Scheme 6. Thus, cyclooctenone was converted to 28
in 65% yield upon treatment with the cerium reagent
derived from (4-methyl-3-pentenyl)lithium.18,19 Oxidative
rearrangement of 28 using pyridinium chlorochromate
gave 29 in 74% yield.20 Treatment of 29 with lithium
dimethylcuprate in the presence of chlorotrimethylsilane
gave 30 (92%) which was converted to ketal 31 in 73%
yield.21 Ozonolysis of 31 afforded aldehyde 32 in 83%
yield, and Wittig olefination provided R,â-unsaturated
ester 33 in 80% yield along with 3% of the corresponding
Z-isomer. Ketal hydrolysis completed the synthesis of
11.
diastereomeric perhydroindan, regardless of starting
olefin geometry. Moreover, the mixtures obtained from
these cyclizations appeared to be the result of kinetic
protonation, since no isomerization was observed when
the products were resubjected to the reaction conditions,
whereas base-promoted isomerization led to a 1:1 mixture
of epimers at C10 as described above.
Although more effort is required to determine the true
origin of the diastereoselectivity observed in these cy-
clizations, one rationalization of the results is shown in
Scheme 5. Upon treatment with pyrrolidine and acetic
acid, ketones 7 and 9 might be converted into enamines
of type 23. Subsequent conjugate addition would lead
to the formation of an axial C8-C9 bond, to avoid
developing A1,3 strain.14 Moreover, the resulting enolate
or enol might be born in conformation 24, which mini-
mizes development of charge separation.15 Subsequent
protonation would afford products of type 25 upon
workup. The relative stereochemistry at C7, C8, and C9
is consistent with results previously reported by Heath-
cock and follows from Seebach’s topological rule for
intermolecular conjugate additions.16,17 The acyclic di-
astereoselection observed at C10 might arise from kinetic
protonation of 24 from the R-face because the â-face of
the enolate or enol is blocked by the iminium ion.
Cyclization substrate 11 was much less reactive that
substrates 7-10. In fact, only traces of conversion to
(14) J ohnson, R. Chem. Rev. 1968, 68, 375. Hoffman, R. W. Chem.
Rev. 1989, 89, 1841.
(15) Although the structures depicted in Scheme 5 are enolates, the
same types of arguments could also be advanced for the corresponding
enols.
(16) Brattesani, D. N.; Heathcock, C. H. J . Org. Chem. 1975, 40,
2165.
(17) Seebach, D.; Golinski, J . Helv. Chim. Acta 1981, 64, 1413.
Blarer, S. J .; Schweizer, W. B.; Seebach, D. Helv. Chim. Acta 1982,
65, 1637.
(18) Lansbury, P. T.; Haddon, V. R.; Stewart, R. C. J . Am. Chem.
Soc. 1974, 96, 896. Hudlicky, T.; Govindan, S. V.; Frazier, J . O. J .
Org. Chem. 1985, 50, 4166.
(19) Imamoto, T.; Kusumoto, T.; Tawarayama, T.; Sugiura, Y.; Mita,
T.; Hatanaka, Y.; Yokoyama, M. J . Org. Chem. 1984, 49, 3904.
(20) Dauben, W. G.; Michno, D. M. J . Org. Chem. 1977, 42, 682.
(21) Corey, E. J .; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015.

468 J . Org. Chem., Vol. 61, No. 2, 1996
Guevel and Hart
tilled over calcium hydride. Purification of CuI was accom-
plished according to the literature procedure.24 Reactions
requiring an inert atmosphere were run under argon. Ana-
lytical thin-layer chromatography was conducted using EM
Laboratories 0.25 mm thick precoated silica gel 60F-254 plates.
Column chromatography was performed over EM Laboratory
silica gel (70-230 mesh). Medium pressure liquid chroma-
tography (MPLC) was performed using EM Laboratories Lobar
prepacked silica gel columns. All organolithium reagents were
titrated prior to use with (()-menthol using 1,10-phenanthro-
line as the indicator.25
Sch em e 7
Eth yl (()-(E)-2-Meth yl-5-(7-m eth yl-1,4-d ioxa sp ir o[4.5]-
d ec-7-yl)-2-p en ten oa te (13) a n d Eth yl (()-(Z)-2-Meth yl-
5-(7-m eth yl-1,4-dioxaspir o[4.5]dec-7-yl)-2-pen ten oate (14).
A. P eter son Olefin a tion . To a solution of 1.60 mL (11.4
mmol) of diisopropylamine in 15 mL of THF at 0 °C was added
13 mL (13.0 mmol) of n-BuLi (1.0 M in hexane). The solution
was stirred for 15 min at 0 °C and then cooled to -78 °C. A
solution of 2.00 g (11.5 mmol) of ethyl 2-(trimethylsilyl)acetate7
in 20 mL of THF was added dropwise via an addition funnel,
and the mixture was stirred for 1 h. A solution of 1.97 g (9.27
mmol) of aldehyde 126 in 12 mL of THF was added dropwise
via an addition funnel over a 35 min period, and the mixture
was stirred at -78 °C for 3 h, followed by an additional 18 h
during which the temperature was slowly raised to rt. The
reaction was quenched with 12 mL of saturated NH4Cl, and
the solution was diluted with 150 mL of Et2O. The organic
phase was washed with two 15-mL portions of brine, and the
combined washes were extracted with two 10-mL portions of
Et2O. The combined organic phases were dried (Na2SO4) and
concentrated in vacuo. The residue was chromatographed over
50 g of silica gel (eluted with EtOAc-petroleum ether, 1:9) to
afford 2.14 g (78%) of a 1:1 mixture of stereoisomers 13 and
14 by integration of selected peaks in 1H NMR spectrum: IR
(neat) 1711, 1649 cm-1; 1H NMR (CDCl3, 250 MHz) δ 0.95 and
0.97 (two s, 3H, CH3), 1.30-1.80 (m, 13H), 1.85 and 1.90 (two
s, 3H, dCCH3), 2.10 (m, 1H), 2.40 (m, 1H), 3.91 (bs, 4H,
(OCH2)2), 4.18 and 4.20 (two q, J ) 7.1 Hz, 2H, OCH2), 5.90
(t, J ) 7.5 Hz, 0.5H, dCH), 6.75 (t, J ) 7.4 Hz, 0.5H, dCH);
13C NMR (CDCl3, 75.5 MHz) δ 12.0 and 14.2 (two q), 14.1 and
20.5 (two q), 19.5 and 19.6 (two t), 23.1 and 24.0 (two t), 25.3
and 25.7 (two q), 34.4 (two s), 34.8 and 34.9 (two t), 36.9 and
37.1 (two t), 40.5 and 41.9 (two t), 44.5 and 44.7 (two t), 59.8
and 60.2 (two t), 63.8 (two t), 63.9 (two t), 109.2 and 109.3
(two s), 126.5 and 127.2 (two s), 142.7 and 143.3 (two d), 168.0
and 168.1 (two s); exact mass calcd for C17H28O4 m/e 296.1988;
found m/e 296.1989. B. Wittig Rea ction . To a solution of
302 mg (1.42 mmol) of aldehyde 12 in 26 mL of dry benzene
under argon was added 1.14 g (3.15 mmol) of (1-carbethoxy-
ethylidene)triphenylphosphorane in one portion. The resulting
solution was heated under reflux for 4.8 h, and the solvent
was removed in vacuo. The residue was chromatographed over
45 g of silica gel (eluted with petroleum ether-EtOAc, 9:1) to
afford 345 mg (82%) of an 8:1 mixture of 12 and 13 by
integration of selected peaks in 1H NMR spectrum.
cyclized materials were observed when 11 was exposed
to the optimal conditions for cyclizing 7-10. Eventually
it was found that warming 11 with 1.3 equiv of pyrroli-
dine and 2.3 equiv of acetic acid in a minimal amount of
tetrahydrofuran at 110 °C for 17 h gave a 7:1 mixture of
34 and 35 in 52% yield along with 38% of recovered 11
(Scheme 7). The structure of 34 was determined by X-ray
crystallographic analysis of carboxylic acid 36, obtained
by hydrolysis of the aforementioned mixture of 34 and
35 using lithium hydroxide in aqueous methanol.12,22
Thus, it appears that the stereoselectivity observed in
the perhydroindan synthesis will extrapolate to other
systems, although stereoselectivity may erode slightly if
more vigorous cyclization conditions are required as was
the case with 11.23
Finally, it is notable that the cyclization of substrates
7 and 11 could be catalyzed by potassium tert-butoxide
(15 mol%) in benzene at 60-78 °C for 2 h. Although keto
ester 7 gave an 85% yield of a 15:1 mixture of 18 and 19,
respectively, keto ester 11 gave only a 9% yield of a 2:1
mixture of 34 and 35. In terms of stereochemistry, these
results qualitatively parallel those obtained using pyr-
rolidine-acetic acid. It is clear, however, that the
pyrrolidine-acetic acid mediated reactions provide better
selectivity in both cases and superior yields in the case
of 11.
In summary, a diastereoselective procedure for prepar-
ing fused carbocyclic systems with appended side chains
has been developed and some of the limitations of the
process have been defined. An application of this process
to sesquiterpene synthesis is presented in the following
article in this journal.
Exp er im en ta l Section
All melting points are uncorrected as are all boiling points.
1H NMR spectra are reported on the δ scale as follows:
chemical shift [multiplicity (s ) singlet, d ) doublet, t ) triplet,
q ) quartet, p ) pentet, m ) multiplet, b ) broad), coupling
constants in hertz, integration, interpretation]. 13C NMR
spectra are recorded in parts per million from internal
chloroform or dimethyl sulfoxide on the δ scale. The 13C NMR
spectra are reported as follows: chemical shift (multiplicity
determined from DEPT spectra). Mass spectra were obtained
using EI at an ionization energy of 70 eV unless stated
otherwise. Compounds for which an exact mass is reported
exhibited no significant peaks at m/e greater than that of the
parent.
E t h yl (()-(E)-2-Met h yl-5-(1-m et h yl-3-oxocycloh exyl)-
2-p en ten oa te (7) a n d Eth yl (()-(Z)-2-Meth yl-5-(1-m eth yl-
3-oxocycloh exyl)-2-p en ten oa te (8). A. P r ep a r a tion fr om
13 a n d 14. To a solution of 2.35 g (7.93 mmol) of a 1:1 mixture
of 13 and 14 in 16.4 mL of a 1:1 mixture of Et2O and tert-
butyl alcohol was added 20.4 mL of 1 N aqueous HCl. The
reaction mixture was stirred at rt for 6.5 h, diluted with 90
mL of Et2O, and washed with 15 mL of water, followed by two
15-mL portions of saturated aqueous NaHCO3. The organic
phase was washed with two 30-mL portions of brine, dried
(Na2SO4), and concentrated in vacuo. This residue was a 1:1
mixture of E- and Z-isomers, by integration of selected peaks
in the 1H NMR spectrum of the mixture. Separation by MPLC
(eluted with EtOAc-hexanes, 1:13) afforded 0.6 g (30%) of 7,
0.6 g (30%) of 8, and 0.36 g (18%) of a mixture of 7 and 8.
Solvents and reagents were dried and purified prior to use
when deemed necessary: THF, Et2O, benzene, and pyrrolidine
were distilled from sodium metal; chlorotrimethylsilane, CH2-
Cl2, diisopropylamine, triethylamine, and toluene were dis-
(22) These conditions have been used to hydrolyze similar esters
without epimerization at an adjacent stereogenic center. For example,
see: Hart, D. J .; Huang, H.-C.; Krishnamurthy, R.; Schwartz, T. J . Am.
Chem. Soc. 1989, 111, 7507.
(23) For an approach to bicyclo[6.3.0]undecanes that affords trans-
fused structures, see: Brooker-Milburn, K. I.; Thompson, D. F. Synlett
1993, 592. Iwasawa, N.; Funahashi, M.; Hayakawa, S.; Narasaka, K.
Chem. Lett. 1993, 545.
(24) Kauffman, G. B.; Pinnell, R. P. Inorg. Synth. 1960, 6, 3.
Kauffman, G. B.; Teter, L. A. Inorg. Synth. 1963, 7, 9. Linstrumelle,
G.; Krieger, J . K.; Whitesides, G. M. Org. Synth. 1977, 55, 103.
(25) Watson, S. C.; Eastham, J . F. J . Organomet. Chem. 1967, 9,
165.

Carbocycles via Intramolecular Conjugate Additions
J . Org. Chem., Vol. 61, No. 2, 1996 469
Ester 7: IR (neat) 1713, 1650 cm-1; 1H NMR (CDCl3, 200 MHz)
δ 0.96 (s, 3H, CH3), 1.29 (t, J ) 7.1 Hz, 3H, CH3), 1.30-2.30
(m, 15H), 4.18 (q, J ) 7.1 Hz, 2H, OCH2CH3), 6.71 (t, J ) 7.4
Hz, 1H, dCH); 13C NMR (CDCl3) δ 12.2 (q), 14.2 (q), 22.1 (t),
22.9 (t), 24.8 (q), 35.8 (t), 38.6 (s), 40.29 (t), 40.9 (t), 53.5 (t),
60.4 (t), 128.0 (s), 141.6 (d), 168.1 (s), 211.6 (s); exact mass
calcd for C15H24O3 m/e 252.1725, found m/e 252.1670. Ester
(m, 4H, (OCH2)2), 4.11-4.25 (m, 2H, OCH2CH3), 5.09 (m, 1H,
CHdCMe2), 5.83 (Z-isomer) and 6.74 (E isomer) (t, J ) 7.5
Hz, 1H, CHdCCO2Et). This mixture was used in the following
reaction without further characterization.
Eth yl (()-6-Meth yl-2-[(E)-3-(1-m eth yl-3-oxocycloh exy-
l)p r op ylid en e]-5-h ep ten oa te (9) a n d Eth yl (()-6-Meth yl-
2-[(Z)-3-(1-m et h yl-3-oxocycloh exyl)p r op ylid en e]-5-h ep -
ten oa te (10). To a solution of 645 mg (1.77 mmol) of a 4:1
mixture of 16 and 15, respectively, in 4 mL of a 1:1 mixture of
Et2O and tert-butyl alcohol was added 4.6 mL of 1 N aqueous
HCl. The reaction mixture was stirred at rt for 17 h, diluted
with 30 mL of Et2O, and washed with 5 mL of water, followed
by two 7-mL portions of saturated aqueous NaHCO3. The
organic phase was washed with two 10-mL portions of brine,
dried (Na2SO4), and concentrated in vacuo to give 508 mg
(90%) of a 4:1 mixture of 10 and 9, respectively, by integration
of selected peaks in the 1H NMR spectrum. Separation by
MPLC (eluted with hexane-EtOAc, 13:1) afforded 283 mg of
10 and 64 mg of 9, along with 20 mg of a mixture of 10 and 9.
1
8: IR (CDCl3) 1702, 1645 cm-1; H NMR (CDCl3, 250 MHz) δ
0.94 (s, 3H, CH3), 1.27 (t, J ) 7.1 Hz, 3H, CH3), 1.30-2.50 (m,
15H), 4.19 (q, J ) 7.1 Hz, 2H, OCH2CH3), 5.87 (t, J ) 7.5 Hz,
1H, dCH); 13C NMR (CDCl3, 62.9 MHz) δ 14.3 (q), 20.6 (q),
22.0 (t), 23.8 (t), 24.8 (q), 35.6 (t), 38.6 (s), 40.9 (t), 41.1 (t),
53.7 (t), 60.0 (t), 127.3 (s), 142.4 (d), 167.9 (s), 211.9 (s); exact
mass calcd for C15H24O3 m/e 252.1725, found m/e 252.1674. B.
P r ep a r a tion of 7 fr om 8. To a solution of 154 mg (0.61
mmol) of 8 in 7 mL of benzene was added 16 µL (0.15 mmol)
of thiophenol. The reaction mixture was degassed and heated
under reflux, and 10 mg (0.07 mmol) of AIBN was added.
Another 10 mg of AIBN was added after 1 h, and again after
30 min. After a total of 2.8 h at reflux, the mixture was
concentrated in vacuo and chromatographed over silica gel
(eluted with hexanes-EtOAc, 9:1) to afford 140 mg (91%) of
7.
1
Ester 9: IR (CDCl3) 1703 cm-1; H NMR (CDCl3, 250 MHz) δ
0.96 (s, 3H, CH3), 1.29 (t, J ) 7.1 Hz, 3H, CH2CH3), 1.33-
1.42 (m, 3H), 1.59 (s, 3H, dCCH3), 1.68 (s, 3H, dCCH3), 1.55-
1.71 (m, 3H), 1.89 (m, 2H), 2.04-2.18 (m, 5H), 2.24-2.34 (m,
3H), 4.19 (q, J ) 7.1 Hz, 2H, OCH2CH3), 5.13 (m, 1H,
CHdCMe2), 6.69 (t, J ) 7.5 Hz, 1H, CHdCCO2Et); 13C NMR
(CDCl3, 75.5 MHz) δ 14.2 (q), 17.6 (q), 22.0 (t), 22.8 (t), 24.7
(q), 25.7 (q), 26.9 (t), 27.7 (t), 35.8 (t), 38.6 (s), 40.7 (t), 40.9 (t),
53.5 (t), 60.3 (t), 123.6 (d), 132.2 (two s), 141.9 (d), 167.8 (s),
211.5 (s); exact mass calcd for C20H32O3 m/e 320.2339, found
m/e 320.2346. Ester 10: IR (CDCl3) 1704, 1643 cm-1; 1H NMR
(CDCl3, 200 MHz) δ 0.94 (s, 3H, CH3), 1.30 (t, J ) 7.2 Hz, 3H,
OCH2CH3), 1.57 (s, 3H, dCCH3), 1.67 (s, 3H, dCCH3), 1.22-
2.46 (m, 16H), 4.20 (q, J ) 7.2 Hz, 2H, OCH2CH3), 5.08 (m,
1H, CHdCMe2), 5.81 (t, J ) 7.5 Hz, 1H, HCdCCO2Et); 13C
NMR (CDCl3, 62.9 MHz) δ 14.3 (q), 17.6 (q), 22.1 (t), 23.9 (t),
24.9 (q), 25.6 (q), 27.8 (t), 34.8 (t), 35.6 (t), 38.6 (s), 41.0 (t),
41.2 (t), 53.7 (t), 60.0 (t), 123.5 (d), 131.9 (s), 132.1 (s), 141.5
(d), 167.9 (s), 212.0 (s); exact mass calcd for C20H32O3-EtOH
m/e 274.1933, found m/e 274.1957.
Eth yl 6-Meth yl-2-(tr im eth ylsilyl)h ep t-5-en oa te (17).
To a solution of 4.2 mL (30 mmol) of diisopropylamine in 20
mL of THF at 0 °C was added 21 mL (33 mmol) of n-BuLi (1.6
M in hexanes). The solution was cooled to -78 °C and stirred
between -78 and -35 °C for 30 min. A solution of 4.03 g (25.2
mmol) of ethyl 2-(trimethylsilyl)acetate7 in 25 mL of THF was
added dropwise via an addition funnel over a 20 min period.
The mixture was stirred for 1.5 h at -30 °C, and 11.3 g (69.4
mmol) of 1-iodo-4-methyl-3-pentene10 was added neat in one
portion. The resulting mixture was stirred for 6 h at a
temperature ranging from -20 °C to rt and 2 h at rt. The
reaction was quenched with 1.8 mL of glacial acetic acid and
20 mL of water. The mixture was diluted with 70 mL of Et2O.
The organic phase was washed with two 35 mL portions of
brine. The combined aqueous washes were extracted with two
35 mL portions of Et2O. The combined organic phases were
dried (Na2SO4) and concentrated in vacuo. The low-boiling
impurities were removed by distillation. The resulting dark
brown pot material was chromatographed over 90 g of silica
gel (eluted with EtOAc-hexane, 1:49) to afford 3.22 g (53%)
E t h yl (()-(rS*,1R*,3a R*,7a S*)-H exa h yd r o-r-m et h yl-
3a -m eth yl-7-oxo-1-in d a n a ceta te (18). A. P yr r olid in e-
Med ia ted Cycliza tion of 7. To a solution of 143 mg (0.57
mmol) of keto ester 7 in 2.5 mL of THF were added 50 µL (0.59
mmol) of pyrrolidine and 80 µL (1.4 mmol) of glacial acetic
acid. The reaction mixture was heated under reflux for 6 h
and diluted with 8 mL of Et2O. The reaction was quenched
with 0.8 mL of 5% aqueous HCl, and the solution was stirred
for 15 min at rt. The aqueous phase was extracted with three
10 mL portions of Et2O. The combined organic phases were
diluted with 40 mL of Et2O, washed with 10 mL of water, 20
mL of saturated aqueous NaHCO3, and two 20 mL portions of
brine, dried (Na2SO4), and concentrated in vacuo to give 143
mg (100%) of a pale yellow oil. The residue was chromato-
graphed over silica gel (eluted with petroleum ether-EtOAc,
13:1) to give 112 mg (78%) of a 99:1 mixture of diastereoiso-
mers whose major component was 18: IR (neat) 1732, 1704
cm-1; 1H NMR (CDCl3, 250 MHz) δ 1.06 (s, 3H, CH3), 1.10 (d,
J ) 7.0 Hz, 3H, CH3), 1.25 (t, J ) 7.1 Hz, 3H, CH3), 1.30-
2.73 (m, 13H), 4.11 (q, J ) 7.1 Hz, 2H, OCH2CH3); 13C NMR
(CDCl3, 126 MHz) δ 14.2 (q), 15.4 (q), 23.0 (t), 25.8 (q), 28.3
(t), 33.4 (t), 38.0 (t), 39.9 (t), 44.8 (d), 45.3 (d), 48.7 (s), 60.1 (t),
64.8 (d), 175.6 (s), 215.1 (s); exact mass calcd for C15H24O3 m/e
252.1726, found m/e 252.1705. B. KO-t-Bu -Med ia ted Cy-
cliza tion of 7. To a solution of 6 mg (0.05 mmol) of t-BuOK
in 0.3 mL of t-BuOH was added 85 mg (0.34 mmol) of 7 in 0.2
mL of benzene. The resulting mixture was heated between
60 and 78 °C for 2 h and cooled to rt, and the reaction was
quenched with 3 µL of glacial acetic acid. The mixture was
diluted with 20 mL of water and extracted with two 25 mL
portions of ether. The combined organic layers were washed
with 20 mL of saturated aqueous NH4Cl, dried (MgSO4), and
concentrated in vacuo to afford 72 mg (85%) of a residual crude
oil. This material was a 15:1 mixture of 18 and 19, as
of the ester 17 as a clear colorless liquid: IR (neat) 1717 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 0.04 (s, 9H, (CH3)3Si), 1.23 (t, J
) 7.1 Hz, 3H, CH3), 1.28-1.51 (m, 2H), 1.57 (s, 3H, CH3), 1.67
(s, 3H, CH3), 1.72-2.10 (m, 3H), 4.09 (q, J ) 7.1 Hz, 2H,
OCH2), 5.06 (bt, J ) 6.6 Hz, 1H, CHd); 13C NMR (CDCl3, 75.5
MHz) δ -2.9 (q), 14.3 (q), 17.4 (q), 25.5 (q), 26.7 (t), 28.6 (t),
37.1 (d), 59.3 (t), 123.6 (d), 132.1 (s), 175.1 (s); exact mass calcd
for C13H26SiO2 m/e 242.1702, found m/e 242.1702.
Eth yl (()-6-Meth yl-2-[(E)-3-(7-m eth yl-1,4-d ioxa sp ir o-
[4.5]d ec-7-yl)p r op ylid en e]-5-h ep ten oa te (15) a n d Eth yl
(()-6-Meth yl-2-[(Z)-3-(7-m eth yl-1,4-d ioxa sp ir o[4.5]d ec-7-
yl)p r op ylid en e]-5-h ep ten oa te (16). To a solution of 1.7 mL
(12.1 mmol) of diisopropylamine in 18 mL of THF at 0 °C was
added 8.8 mL (14.1 mmol) of n-BuLi (1.6 M in hexanes). The
solution was cooled to -78 °C and stirred at that temperature
for 45 min. A solution of 3.22 g (13.3 mmol) of 17 in 20 mL of
THF was added dropwise via syringe pump over a 15 min
period, and the mixture was stirred for 1.5 h at -70 °C.
A
solution of 2.41 g (11.3 mmol) of 12 in 20 mL of THF was added
dropwise via syringe pump over a 15 min period, and the
mixture was stirred between -78 and 15 °C for 20 h. The
reaction was quenched with 15 mL of saturated NH4Cl, and
the solution was diluted with 100 mL of Et2O. The mixture
was washed with two 10 mL portions of brine, and the
combined washes were extracted with two 10 mL portions of
Et2O. The combined organic phases were dried (Na2SO4) and
concentrated in vacuo. The residue was chromatographed over
silica gel (eluted with EtOAc-petroleum ether, 1:9) to afford,
along with a mixed fraction containing 15, 16, and 17 (15+16:
17 ) 1:4), 2.42 g (59%) of a 4:1 mixture of 16 and 15,
1
1
estimated by H NMR spectroscopy. Traces of 7 could also be
respectively, by integration of selected peaks in the H NMR
spectrum: 1H NMR (CDCl3, 250 MHz) δ 0.97 and 0.98 (two s,
3H, CH3), 1.23-1.68 (m, 19H), 2.04-2.43 (m, 6H), 3.90-3.94
detected.
E t h yl (()-(rR*,1R*,3a R*,7a S*)-H exa h yd r o-r-m et h yl-

470 J . Org. Chem., Vol. 61, No. 2, 1996
Guevel and Hart
3a -m eth yl-7-oxo-1-in d a n a ceta te (19). To a solution of 173
mg (0.69 mmol) of 8 in 2 mL of THF were added 60 µL (0.72
mmol) of pyrrolidine and 90 µL (1.6 mmol) of glacial acetic
acid. The reaction mixture was heated under reflux for 5 h
and diluted with 10 mL of Et2O. The reaction was quenched
with 0.7 mL of 5% aqueous HCl, and the solution was stirred
for 20 min at rt. The aqueous phase was extracted with three
10 mL portions of Et2O. The combined organic phases were
diluted with 40 mL of Et2O, washed with 10 mL of water, 20
mL of saturated aqueous NaHCO3, and two 20 mL portions of
brine, dried (Na2SO4), and concentrated in vacuo to give 160
mg (92%) of a mixture of perhydroindans. Separation by
MPLC (eluted with hexane-EtOAc, 49:1) afforded 72 mg (42%)
of 18 and 22 mg (13%) of diastereoisomer 19. Ester 19: IR
was quenched with 1.5 mL of 5% aqueous HCl, and the
solution was stirred for 5 min at rt. The aqueous phase was
extracted with three 20 mL portions of Et2O. The combined
organic phases were diluted with 50 mL of Et2O, washed with
20 mL of water, 40 mL of saturated aqueous NaHCO3, and
two 40 mL portions of brine, dried (Na2SO4), and concentrated
in vacuo to give 260 mg of a mixture of perhydroindans 21
and 22. Separation of 219 mg by MPLC (eluted with hexane-
EtOAc, 49:1) afforded 168 mg (62%) of 21 and 28 mg (10%) of
diastereomer 22. Ester 22: IR (neat) 1727, 1704 cm-1; 1H NMR
(CDCl3, 200 MHz) δ 1.02 (s, 3H, CH3), 1.23 (t, J ) 7.1 Hz, 3H,
OCH2CH3), 1.29-2.25 (m, 15H), 1.56 (s, 3H, dCCH3), 1.66 (d,
J ) 0.9 Hz, 3H, dCCH3), 2.48-2.76 (m, 2H), 4.03 (q, J ) 7.1
Hz, 2H, OCH2CH3), 5.04 (bt, J ) 7.1 Hz, 1H, dCH); 13C NMR
(CDCl3, 62.9 MHz) δ 14.1 (q), 17.6 (q), 23.1 (t), 25.6 (q), 25.7
(q), 25.9 (t), 28.1 (t), 31.2 (t), 33.6 (t), 37.6 (t), 39.6 (t), 44.9 (d),
48.7 (s), 50.6 (d), 60.1 (t), 65.8 (d), 123.5 (d), 132.2 (s), 175.0
(s), 214.3 (s); exact mass calcd for C20H32O3 m/e 320.2351, found
m/e 320.2393.
1
(CDCl3) 1720, 1698 cm-1; H NMR (CDCl3, 300 MHz) δ 1.05
(s, 3H, CH3), 1.14 (d, J ) 7.0 Hz, 3H, CH3CH), 1.23 (t, J ) 7.1
Hz, 3H, CH3), 1.40-2.03 (m, 8H), 2.01 (d, J ) 9.6 Hz, 1H, CH),
2.13-2.20 (m, 1H, CH), 2.32 (m, 1H, CH), 2.51-2.60 (m, 1H,
CH), 2.68-2.71 (m, 1H, CH), 4.04 (q, J ) 7.1 Hz, 1H, OCHH),
4.05 (q, J ) 7.2 Hz, 1H, OCHH); 13C NMR (CDCl3, 62.9 MHz)
δ 14.1 (q), 15.1 (q), 22.9 (t), 26.0 (q), 27.2 (t), 33.7 (t), 37.7 (t),
39.8 (t), 43.9 (d), 45.3 (d), 48.3 (s), 60.3 (t), 65.6 (d), 175.7 (s),
214.5 (s); exact mass calcd for C15H24O3 m/e 252.1726, found
m/e 252.1747.
(()-(rS*,1R*,3a R*,7a S*)-Hexa h yd r o-r-m eth yl-3a -m eth -
yl-7-oxo-1-in d a n a cetic Acid (20). To a solution of 109 mg
(0.43 mmol) of 18 in 2.2 mL of methanol was added 1.75 mL
(3.7 mmol) of 5% aqueous lithium hydroxide in one portion.
The reaction mixture was heated at 50 °C for 1.7 h, and the
reaction was quenched with 50 mL of 1 N aqueous HCl in 50
mL of CH2Cl2. The aqueous phase was extracted with 50 mL
of CH2Cl2, and the combined extracts were washed with 25
mL of brine, dried (MgSO4), and concentrated in vacuo to give
90 mg (93%) of 20 as a pale yellow solid. Recrystallization of
a sample from petroleum ether-Et2O-CH2Cl2 gave acid 20
as a white solid: mp 81-82 °C; IR (CHCl3) 1704 cm-1; 1H NMR
(CDCl3, 200 MHz) δ 1.06 (s, 3H, CH3), 1.15 (d, J ) 6.9 Hz, 3H,
CH3), 1.20-2.70 (m, 13H), the acidic proton was not recorded;
13C NMR (CDCl3, 62.9 MHz) δ 15.4 (q), 22.8 (t), 26.0 (q), 28.3
(t), 33.7 (t), 38.1 (t), 39.9 (t), 44.2 (d), 45.3 (d), 48.3 (s), 64.5
(d), 179.9 (s), 215.6 (s); exact mass calcd for C13H20O3 m/e
224.1413, found m/e 224.1428.
(()-(Z)-1-(4-Meth yl-3-p en ten yl)-2-cycloocten -1-ol (28).
Cerium trichloride (1.31 g, 5.31 mmol) was dried at 140 °C/
0.1 mmHg for 4.5 h. The flask was cooled to rt and vented to
a dry argon atmosphere. Dry THF was added (10 mL), and
the suspension was stirred at rt under argon for 15.5 h. The
light grey slurry was then cooled to -78 °C, and a solution of
t-BuLi (1.7 M in pentane) was added until an orange color was
obtained. Meanwhile, to a solution of 642 mg (3.94 mmol) of
1-bromo-4-methyl-3-pentene10 in 10 mL of THF, stirred under
argon at -70 °C, was added dropwise 3.25 mL (3.90 mmol) of
a 1.2 M solution of t-BuLi in pentane. The resulting pale
yellow solution was stirred for another 20 min and then
transferred via cannula into the CeCl3 slurry. The resulting
mixture was stirred at -70 °C for 55 min, and 257 mg (2.07
mmol) of 2-cyclooctenone26 in 5 mL of THF was added. The
resulting mixture was stirred at -70 °C for 6 h, the reaction
was quenched with 25 mL of saturated aqueous NH4Cl, and
the solution was diluted 25 mL of Et2O. The aqueous phase
was extracted with three 25-mL portions of ether. The
combined organic phases were dried (Na2SO4) and concen-
trated to afford 398 mg of a yellow oil. Purification by column
chromatography (eluted with petroleum ether-EtOAc, 9:1 +
0.25% triethylamine) afforded 280 mg (65%) of alcohol 28 as
a clear colorless oil: IR (neat) 3416, 1651 cm-1 1H NMR
;
Anal. Calcd for C13H20O3: C, 69.64; H, 8.93. Found: C,
69.66; H, 9.00.
(CDCl3, 300 MHz) δ 1.39-1.79 (m, 8H), 1.61 (s, 3H, CH3), 1.68
(s, 3H, CH3), 1.81-1.90 (m, 2H), 2.05 (q, J ) 8.0 Hz, 2H, CH2),
2.12-2.23 (m, 2H, CH and OH), 2.41-2.52 (m, 1H, CH), 5.12
(bt, J ) 7.1 Hz, 1H, CHdCMe2), 5.46-5.56 (m, 2H, CHdCH);
13C NMR (CDCl3, 75.5 MHz) δ 17.5 (q), 22.3 (t), 22.4 (t), 24.6
(t), 24.8 (t), 25.5 (q), 26.9 (t), 39.6 (t), 44.1 (t), 75.4 (s), 124.3
Eth yl (()-(rS*,1R*,3a R*,7a S*)-Hexa h yd r o-3a -m eth yl-
r-(4-m eth yl-3-p en ten yl)-7oxo-1-in d a n a ceta te (21). To a
solution of 127 mg (0.40 mmol) of 9 in 2 mL of THF were added
40 µL (0.48 mmol) of pyrrolidine and 55 µL (0.94 mmol) of
glacial acetic acid. The reaction mixture was heated under
reflux for 6.1 h and diluted with 40 mL of Et2O, and the
reaction was quenched with 25 mL of saturated NaHCO3. The
aqueous phase (pH 7) was extracted with two 20 mL portions
of Et2O. The combined organic phases were dried (MgSO4)
and concentrated in vacuo. The residue was chromatographed
over 40 g of silica gel (eluted with petroleum ether-EtOAc,
24:1) to afford 55 mg (43%) of 21, along with traces of
unidentified byproducts, one of which (15 mg) was removed
from the silica gel by flushing the column with EtOAc. This
(d), 127.9 (d), 131.5 (s), 136.7 (d); exact mass calcd for C14H24
O
m/e 208.1827, found m/e 208.1833.
(E)-3-(4-Meth yl-3-p en ten yl)-2-cycloocten -1-on e (29). To
a bright orange slurry of 1.26 g (5.84 mmol) of pyridinium
chlorochromate in 10 mL of CH2Cl2 was added in one portion,
under argon, 599 mg (2.88 mmol) of alcohol 28 in 8 mL of CH2-
Cl2. The resulting dark brown mixture was stirred at rt for
4.5 h and diluted with 25 mL of ether. The residual black
polymer was rinsed further with three 20 mL portions of ether.
The combined organic phases were washed successively with
40 mL of 1 N aqueous sodium hydroxide, 40 mL of 1 N aqueous
HCl, and two 20 mL portions of saturated aqueous NaHCO3,
dried (MgSO4), and concentrated to afford 549 mg of a pale
orange oil. Purification by column chromatography over 40 g
silica gel (eluted with petroleum ether-EtOAc, 9:1) afforded
439 mg (74%) of enone 29 as a clear colorless oil: IR (neat)
1650, 1621 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.40-1.55 (m,
6H), 1.49 (s, 3H, CH3), 1.57 (s, 3H, CH3), 1.59-1.68 (m, 2H,
CH2), 2.07 (bs, 2H, CH2CO), 2.50 (t, J ) 6.6 Hz, 2H, dCCH2),
2.61 (t, J ) 7.1 Hz, 2H, dCCH2), 4.97 (bs, 1H, CHdCMe2),
5.92 (s, 1H, dCHCO); 13C NMR (CDCl3, 75.5 MHz) δ 17.5 (q),
22.8 (t), 23.5 (t), 23.9 (t), 25.4 (q), 26.0 (t), 31.9 (t), 41.3 (t),
1
byproduct lacked the isopropylidene moiety, as seen in the H
NMR spectrum. Ester 21: IR (neat) 1729, 1704 cm-1; 1H NMR
(CDCl3, 250 MHz) δ 1.05 (s, 3H, CH3), 1.27 (t, J ) 7.1 Hz, 3H,
OCH2CH3), 1.30-1.70 (m, 7H), 1.56 (s, 3H, dCCH3), 1.66 (d,
J ) 0.8 Hz, 3H, dCCH3), 2.05 (d, J ) 9.3 Hz, 1H, CHC(O)),
1.84-2.00 (m, 5H), 2.20-2.37 (m, 2H), 2.43-2.71 (m, 2H), 4.14
(q, J ) 7.2 Hz, 2H, OCH2CH3), 5.04 (bt, J ) 7.1 Hz, 1H, dCH);
13C NMR (CDCl3, 62.9 MHz) δ 14.3 (q), 17.6 (q), 22.9 (t), 25.7
(q), 26.0 (q), 26.1 (t), 27.8 (t), 30.7 (t), 33.6 (t), 38.2 (t), 39.8 (t),
44.5 (d), 48.7 (s), 50.8 (d), 60.1 (t), 65.2 (d), 123.5 (d), 132.1 (s),
175.1 (s), 215.0 (s); exact mass calcd for C20H32O3 m/e 320.2351,
found m/e 320.2360.
Eth yl (()-(rR*,1R*,3a R*,7a S*)-Hexa h yd r o-3a -m eth yl-
r-(4-m eth yl-3-p en ten yl)-7-oxo-1-in d a n a ceta te (22). To a
solution of 320 mg (1.0 mmol) of 10 in 7 mL of THF were added
0.1 mL (1.2 mmol) of pyrrolidine and 0.14 mL (2.4 mmol) of
glacial acetic acid. The reaction mixture was heated under
reflux for 12 h and diluted with 15 mL of Et2O. The reaction
(26) Garbisch, E. W., J r. J . Org. Chem. 1965, 30, 2109. Meier, H.;
Antony-Mayer, C.; Schulz-Popitz, C.; Zerban, G. Liebigs Ann. Chem.
1987, 1087. Mihelich, E. D.; Eickhoff, D. J . J . Org. Chem. 1983, 48,
4135.

Carbocycles via Intramolecular Conjugate Additions
J . Org. Chem., Vol. 61, No. 2, 1996 471
41.8 (t), 122.8 (d), 130.4 (d), 132.2 (s), 156.3 (s), 203.6 (s); exact
mass calcd for C14H22O m/e 206.1670, found m/e 208.1672.
39.0 (t), 40.6 (t), 63.5 (t), 64.5 (t), 112.5 (s), 203.2 (d); exact
mass calcd for C14H24O3 m/e 240.1726, found m/e 240.1716.
Eth yl (()-(E)-2-Meth yl-5-(7-m eth yl-1,4-d ioxa sp ir o[4.7]-
d od ec-7-yl)-2-p en ten oa te (33). To a solution of 130 mg
(0.542 mmol) of aldehyde 32 in 10 mL of dry benzene under
argon was added 433 mg (1.20 mmol) of (1-carbethoxyeth-
ylidene)triphenylphosphorane in one portion. The resulting
solution was heated under reflux for 4.5 h, and the solvent
was removed in vacuo. The residue was chromatographed over
35 g of silica gel (eluted with petroleum ether-EtOAc, 24:1)
to afford 6 mg (3%) of the Z-isomer of 33 and 141 mg (80%) of
ester 33 as a clear colorless oil. Ester 33: IR (neat) 1709, 1649
(()-3-Meth yl-3-(4-m eth yl-3-pen ten yl)cyclooctan on e (30).
To a suspension of 1.08 g (5.64 mmol) of CuI in 8 mL of dry
Et2O at 4 °C was added dropwise 8.50 mL (9.10 mmol) of 1.07
M ethereal methyllithium. The resulting mixture was cooled
to -70 °C and stirred for 10 min. To this mixture was added
dropwise 0.55 mL (4.4 mmol) of TMSCl, followed by 438 mg
(2.12 mmol) of enone 29 in 8 mL of ether. The resulting
mixture was stirred for 7 h between -70 and 5 °C and then
poured onto 50 mL of chilled 10% aqueous NH4Cl. The
resulting mixture was stirred for 2.5 h, and the aqueous layer
was separated and extracted with three 50-mL portions of
ether. The combined organic phases were washed with 50 mL
of brine, dried (MgSO4), and concentrated to afford 543 mg of
a mixture of silyl enol ether (mainly) and ketone (trace). This
mixture was dissolved in 11 mL of THF, and 3.5 mL (3.5 mmol)
of tetra-n-butylammonium fluoride (1M in THF) was added
under argon. The mixture was stirred at rt for 50 min, the
reaction was quenched with 40 mL of saturated aqueous NH4-
Cl, and the solution was diluted with 40 mL of ether. The
aqueous layer was extracted with two 25 mL portions of ether,
and the combined organic phases were washed with 40 mL of
brine, dried (MgSO4), and concentrated to afford 432 mg (92%)
of ketone 30 as a pale yellow oil which was used as such in
the next step: IR (neat) 1696 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.97 (s, 3H, CH3), 1.21-1.58 (m, 8H), 1.61 (s, 3H, CH3), 1.67
(d, J ) 1.0 Hz, 3H, CH3), 1.88-2.07 (m, 4H), 2.10 (d, J ) 11.0
Hz, 1H, CH(H)CO), 2.30 (m, 2H, CH2CH2CO), 2.42 (d, J ) 11.0
Hz, 1H, CH(H)CO), 5.10 (bt, J ) 6.5 Hz, 1H, CHdCMe2); 13C
NMR (CDCl3, 75.5 MHz) δ 17.4 (q), 20.0 (t), 21.7 (t), 22.3 (t),
25.5 (q), 25.9 (q), 28.8 (t), 37.1 (t), 38.6 (s), 42.0 (t), 45.2 (t),
48.8 (t), 124.5 (d), 131.1 (s), 214.7 (s); exact mass calcd for
C15H26O m/e 222.1984, found m/e 222.1985.
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.88 (s, 3H, CH3), 1.27 (t,
J ) 7.1 Hz, 3H, OCH2CH3), 1.18-1.28 (m, 1H, CH), 1.41-
1.79 (m, 13H), 1.82 (s, 3H, dCCH3), 2.04-2.20 (m, 2H), 3.82-
3.90 (m, 4H, (OCH2)2), 4.16 (q, J ) 7.1 Hz, 2H, OCH2CH3),
6.74 (t, J ) 7.5 Hz, 1H, dCH); 13C NMR (CDCl3, 75.5 MHz) δ
12.1 (q), 14.2 (q), 22.5 (t), 23.3 (t), 27.5 (q), 30.2 (t), 30.7 (t),
34.5 (s), 36.0 (t), 38.5 (t), 40.7 (t), 40.8 (t), 60.2 (t), 63.5 (t),
64.4 (t), 112.6 (s), 127.0 (s), 143.0 (d), 168.2 (s); exact mass
calcd for C19H32O4 m/e 324.2301, found m/e 324.2304. Z-Isomer
1
of 33: IR (neat) 1714, 1644 cm-1; H NMR (CDCl3, 300 MHz)
δ 0.88 (s, 3H, CH3), 1.20-1.31 (m, 1H), 1.29 (t, J ) 7.1 Hz,
3H, OCH2CH3), 1.42-1.66 (m, 11H), 1.77-1.79 (2H, CH2), 1.87
(d, J ) 1.3 Hz, 3H, dCCH3), 2.38-2.51 (m, 2H), 3.83-3.91
(m, 4H, (OCH2)2), 4.18 (q, J ) 7.1 Hz, 2H, OCH2CH3), 5.90
(dt, J ) 7.4, 1.4 Hz, 1H, dCH); 13C NMR (CDCl3, 75.5 MHz) δ
14.2 (q), 20.6 (q), 22.5 (t), 23.3 (t), 24.2 (t), 27.4 (q), 30.7 (t),
34.5 (s), 36.2 (t), 38.3 (t), 40.8 (t), 41.9 (t), 59.8 (t), 63.7 (t),
64.3 (t), 112.7 (s), 126.3 (s), 143.8 (d), 168.1 (s); exact mass
calcd for C19H32O4 m/e 324.2301, found m/e 324.2285.
Eth yl (()-(E)-2-Meth yl-5-(1-m eth yl-3-oxocyclooctyl)-2-
p en ten oa te (11). To a solution of 303 mg (0.93 mmol) of ketal
33 in 17 mL of THF was added 8 mL of 0.3 N aqueous HCl.
The reaction mixture was stirred at rt for 4.2 h, diluted with
50 mL of Et2O, and neutralized with 25 mL of saturated
aqueous NaHCO3 (until pH 7). The organic layer was sepa-
rated, and the aqueous phase was extracted with three 25 mL
portions of ether. The combined organic phases were dried
(MgSO4) and concentrated in vacuo to afford 258 mg (99%
crude) of keto ester 11 as a colorless oil which was used as
(()-7-Met h yl-7-(4-m et h yl-3-p en t en yl)-1,4-d ioxa sp ir o-
[4.7]d od eca n e (31). A solution of 432 mg (1.95 mmol) of
ketone 30, 2.5 mL (44.8 mmol) of ethylene glycol, 12 mL of
dry benzene, 1.9 mL (17.4 mmol) of trimethyl orthoformate,
and 21 mg (1.1 mmol) of p-toluenesulfonic acid monohydrate
was stirred at rt for 6 h and diluted with 50 mL of Et2O, and
the reaction was quenched by addition of 30 mL of saturated
aqueous NaHCO3. The aqueous phase was extracted with two
30 mL portions of ether. The combined organic phases were
washed with 50 mL of brine, dried (MgSO4), and concentrated
in vacuo. The residual liquid was chromatographed over 50 g
of silica gel (eluted with petroleum ether-EtOAc, 60:1) to give
such in the next step: IR (neat) 1708, 1650 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 0.98 (s, 3H, CH3), 1.27 (t, J ) 7.1 Hz, 3H,
OCH2CH3), 1.34-1.57 (m, 8H), 1.83 (bs, 3H, dCCH3), 1.87-
1.96 (m, 2H, CH2), 2.01-2.39 (m, 6H), 4.16 (q, J ) 7.1 Hz, 2H,
OCH2CH3), 6.73 (bt, J ) 7.5 Hz, 1H, dCH); 13C NMR (CDCl3,
75.5 MHz) δ 12.2 (q), 14.3 (q), 20.1 (t), 21.7 (t), 23.3 (t), 26.3
(q), 28.8 (t), 37.2 (t), 38.7 (s), 40.0 (t), 45.3 (t), 48.5 (t), 60.4 (t),
127.7 (s), 142.2 (d), 168.2 (s), 214.7 (s); exact mass calcd for
C17H28O3 m/e 280.2039, found m/e 280.2014.
1
381 mg (73%) of ketal 31 as a clear colorless liquid: H NMR
(CDCl3, 300 MHz) δ 0.88 (s, 3H, CH3), 1.13 (ddd, J ) 13.4,
11.9, 5.2 Hz, 1H, CH(H)), 1.24-1.69 (m, 11H), 1.59 (s, 3H,
dCCH3(Me)), 1.66 (bs, 3H, dCCH3(Me)), 1.76-1.79 (m, 2H),
1.83-1.98 (m, 2H), 3.86 (m, 4H, (OCH2)2), 5.08 (bt, J ) 6.5
Hz, 1H, CHdCMe2); 13C NMR (CDCl3, 75.5 MHz) δ 17.4 (q),
22.3 (t), 22.5 (t), 23.3 (t), 25.6 (q), 27.4 (q), 30.7 (t), 34.4 (s),
36.2 (t), 38.3 (t), 40.9 (t), 42.6 (t), 63.7 (t), 64.2 (t), 112.8 (s),
125.3 (d), 130.5 (s); exact mass calcd for C17H30O2 m/e 266.2246,
found m/e 266.2247.
Eth yl (()-(rR*,1R*,3a R*,7a S*)-Deca h yd r o-r,3a -d im e-
th yl-9-oxo-1H-cyclop en ta cycloocten e-1-a ceta te (34). To
a solution of 100 mg (0.36 mmol) of 11 in 0.15 mL of THF was
added 38 µL (0.45 mmol) of pyrrolidine followed by 47 µL (0.82
mmol) of glacial acetic acid. The resulting mixture was heated
in a sealed tube at 110 °C for 17 h, cooled to rt, diluted with
25 mL of ether, and washed with 15 mL of saturated aqueous
NaHCO3. The organic layer was separated, and the aqueous
phase was extracted with two 25 mL portions of Et2O. The
combined organic phases were dried (MgSO4) and concentrated
in vacuo. The residue was chromatographed over 40 g of silica
gel (eluted with petroleum ether-EtOAc, 9:1) to give, along
with 38.5 mg (38%) of recovered 11, 52 mg (52%) of cyclization
products 34 and 35. This material was a 7:1 mixture of
(()-7-Meth yl-1,4-d ioxa sp ir o[4.7]d od eca n e-7-p r op ion a l-
d eh yd e (32). Through a stirred solution of 381 mg (1.43
mmol) of alkene 31 and NaHCO3 (spatula tipfull) in 11.3 mL
of CH2Cl2 and 2.3 mL of methanol at -78 °C was passed a
stream of ozone (Welsbach ozone generator) at a flow rate of
1.0 mmol min-1. When the reaction mixture maintained a blue
color for 1 min, the stream of ozone was replaced by argon
and the solution was stirred until the color dissipated (1 h).
To the resulting clear reaction mixture was added 1.7 mL of
dimethyl sulfide. The reaction mixture was stirred for 24 h,
at a temperature ranging from -78 °C to rt. The solvent was
removed in vacuo, and the residual crude liquid was chro-
matographed over 40 g silica gel (eluted with hexane-EtOAc,
9:1) to give 286 mg (83%) of aldehyde 32 as a clear colorless
oil: IR (neat) 1725 cm-1; 1H NMR (CDCl3, 250 MHz) δ 0.85 (s,
3H, CH3), 1.42-1.84 (m, 14H), 2.40 (dddd, J ) 16.3, 10.7, 5.4,
2.0 Hz, 2H, CH2CHO), 3.82-3.94 (m, 4H, (OCH2)2), 9.76 (t, J
) 2.0 Hz, 1H, CHO); 13C NMR (CDCl3, 75.5 MHz) δ 22.5 (t),
23.2 (t), 27.5 (q), 30.6 (t), 33.8 (t), 34.1 (s), 35.9 (t), 38.5 (t),
1
isomers (34:35) by integration of the selected peaks in the H
NMR spectrum of the mixture. The 13C NMR spectrum also
showed one major isomer and one very minor isomer: IR (neat)
1731, 1698 cm-1; 1H NMR (CDCl3, 250 MHz) δ 1.03 (s, 0.36H,
CH3), 1.05 (d, J ) 7.0 Hz, 2.64H, CHCH3), 1.06 (s, 2.64H, CH3),
1.11 (d, J ) 7.0 Hz, 0.36H, CHCH3), 1.21 (t, J ) 7.1 Hz, 0.36H,
OCH2CH3), 1.22 (t, J ) 7.1 Hz, 2.64H, OCH2CH3), 1.23-1.59
(m, 8H), 1.61-1.80 (m, 4H), 2.25-2.31 (m, 2H), 2.33-2.45 (m,
1H, CH), 2.55 (bd, J ) 6.4 Hz, 1H, CHC(O)), 2.69-2.82 (m,
1H, CH), 4.05 (q, J ) 7.1 Hz, 0.24H, OCH2CH3), 4.07 (q, J )
7.1 Hz, 1.76H, OCH2CH3); 13C NMR (CDCl3, 75.5 MHz, peaks
for 34) δ 14.1 (q), 15.4 (q), 24.3 (t), 24.5 (t), 26.5 (q), 27.4 (t),

472 J . Org. Chem., Vol. 61, No. 2, 1996
Guevel and Hart
28.0 (t), 36.3 (t), 42.5 (t), 44.5 (d), 47.1 (t), 47.6 (s), 47.8 (d),
60.0 (t), 60.9 (d), 175.7 (s), 217.7 (s); exact mass calcd for
C17H28O3 m/e 280.2039, found m/e 280.2039.
recorded; 13C NMR (CDCl3, 75.5 MHz) δ 15.4 (q), 24.4 (t), 24.5
(t), 26.5 (q), 27.4 (t), 28.0 (t), 36.3 (t), 42.4 (t), 44.1 (d), 46.9 (t),
47.4 (d), 47.6 (s), 61.1 (d), 181.4 (s), 217.6 (s); exact mass calcd
for C15H24O3 m/e 252.1726, found m/e 252.1719. The relative
stereochemistry of 36 was determined by X-ray crystal-
lography.
(()-(rR *,1R*,3a R*,7a S*)-Deca h yd r o-r,3a -d im et h yl-9-
oxo-1H-cyclop en ta cycloocten e-1-a cetic Acid (36). To a
solution of 74 mg (0.26 mmol) of a mixture of esters 34 and 35
(7:1) in 1.4 mL of methanol was added 0.9 mL (1.9 mmol) of
2.07 M aqueous lithium hydroxide in one portion. The mixture
was stirred at rt for 8.5 h and poured into 15 mL of 1 N
aqueous HCl in 25 mL of CH2Cl2. The phases were separated,
and the aqueous layer (pH 1) was extracted with 25 mL of
CH2Cl2 and 15 mL of saturated brine, dried (MgSO4), and
concentrated in vacuo to afford 61 mg (93%) of a pale yellow
oil which crystallized upon standing. Recrystallization from
CH2Cl2-hexane afforded 41 mg of pure 36, and the mother
liquor contained a mixture of isomers. Acid 36: mp 108-110
°C; IR (CDCl3) 3300-2500 (broad), 1740, 1705 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.08 (s, 3H, CH3), 1.11 (d, J ) 7.0 Hz, 3H,
CHCH3), 1.26-1.48 (m, 5H), 1.51-1.66 (m, 3H), 1.68-1.93 (m,
4H), 2.24-2.50 (m, 3H, CH and CH2CdO), 2.59 (d, J ) 6.3
Hz, 1H, CHCdO), 2.79 (m, 1H, CHCO2H), acidic proton not
Anal. Calcd for C15H24O3: C, 71.39; H, 9.58. Found: C,
71.16; H, 9.54.
Ack n ow led gm en t. We thank the National Science
Foundation for generous support of this research and
Dr. Kurt Loening for help with nomenclature.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR
spectra of compounds studied (42 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O951531M