Nickel-catalyzed cyclizations of enoate equivalents: Application to the synthesis of angular triquinanes

Article abstract of DOI:10.1021/jo9908389

Unsaturated acyloxazolidinones and α'-silyloxy enones were found to be effective substrates in nickel-catalyzed organozinc-promoted cyclizations. Both groups served as convenient enoate equivalents, whereas methyl enoates themselves were inefficient substrates. A five-step procedure for the conversion of dimethylcyclopentenone into a highly functionalized angular triquinane was developed utilizing this observation. The key step of the procedure involves a nickel-catalyzed reductive cyclization/Dieckmann condensation sequence involving a cyclic enone tethered to an unsaturated acyloxazolidinone or α'-silyloxy enone. The method was applied in a formal synthesis of pentalenene, pentalenic acid, and deoxypentalenic acid.

Full text of DOI:10.1021/jo9908389

6060
J . Org. Chem. 1999, 64, 6060-6065
Nick el-Ca ta lyzed Cycliza tion s of En oa te Equ iva len ts: Ap p lica tion
to th e Syn th esis of An gu la r Tr iqu in a n es
J eongbeob Seo, He´le`ne Fain, J ean-Baptiste Blanc, and J ohn Montgomery*
Department of Chemistry, Wayne State University, Detroit, Michigan 48202-3489
Received May 24, 1999
Unsaturated acyloxazolidinones and R′-silyloxy enones were found to be effective substrates in
nickel-catalyzed organozinc-promoted cyclizations. Both groups served as convenient enoate
equivalents, whereas methyl enoates themselves were inefficient substrates. A five-step procedure
for the conversion of dimethylcyclopentenone into a highly functionalized angular triquinane was
developed utilizing this observation. The key step of the procedure involves a nickel-catalyzed
reductive cyclization/Dieckmann condensation sequence involving a cyclic enone tethered to an
unsaturated acyloxazolidinone or R′-silyloxy enone. The method was applied in a formal synthesis
of pentalenene, pentalenic acid, and deoxypentalenic acid.
In tr od u ction
The angularly fused triquinane carbocyclic skeleton is
a common structural motif in a variety of naturally
occurring terpenes such as pentalenene, pentalenic acid,
and deoxypentalenic acid. Numerous synthetic ap-
proaches to natural products within this class have been
reported, and several excellent reviews have appeared.1
Of the numerous attractive approaches that have been
described, two strategies involved metal-catalyzed cou-
plings of enynes with carbon monoxide as a key step. The
zirconium-catalyzed approach from Negishi2 and the
cobalt-catalyzed approach from Schore3 both demon-
strated that metal-templated processes allowed efficient
assembly of the compact carbocyclic framework of the
triquinanes. An approach from Crimmins,4 in which
several members of the pentalenene family of triquinanes
were prepared from a common intermediate, is also
noteworthy in that pentalenene, pentalenic acid, and
deoxypentalenic acid were prepared from common 1,3-
dicarbonyl intermediate 1a , which was the target of the
studies reported herein (eq 1).
enone â-carbons followed by an intramolecular aldol
addition. Starting from a cyclic enone tethered to an
An efficient method for preparing [3.3.0] bicycles
involving a nickel-catalyzed reductive cyclization of bis-
enones was recently reported from our laboratories (eq
2).5-7 The process involves a reductive coupling of the
(1) For excellent reviews of approaches to these and related natural
products, see: (a) Mehta, G.; Srikrishna, A. Chem. Rev. 1997, 97, 671.
(b) Paquette, L. A. Top. Curr. Chem. 1979, 79, 41. (c) Paquette, L. A.
Top. Curr. Chem. 1984, 119, 1.
(2) Agnel, G.; Negishi, E. J . Am. Chem. Soc. 1991, 113, 7424.
(3) Rowley, E. G.; Schore, N. E. J . Org. Chem. 1992, 57, 6853.
(4) Crimmins, M. T.; DeLoach, J . A. J . Am. Chem. Soc. 1986, 108,
800.
(5) (a) Savchenko, A. V.; Montgomery, J . J . Org. Chem. 1996, 61,
1562-1563. (b) Montgomery, J .; Oblinger, E.; Savchenko, A. V. J . Am.
Chem. Soc. 1997, 119, 4911-4920.
(6) For alternative methods of effecting bis-enone reductive cycliza-
tions or enone reductive dimerizations, see: (a) Enholm, E. J .; Kinter,
K. S. J . Org. Chem. 1995, 60, 4850. (b) Enholm, E. J .; Kinter, K, S. J .
Am. Chem. Soc. 1991, 113, 7784. (c) Hays, D. S.; Fu, G. C. J . Org.
Chem. 1996, 61, 4. (d) Taniguchi, Y.; Kusudo, T.; Beppu, F.; Makioka,
Y.; Takaki, K.; Fujiwara, Y. J . Chem. Soc. J pn. 1994, 62. (e) Chavan,
S. P.; Ethiraj, K. S. Tetrahedron Lett. 1995, 36, 2281. (f) Schobert, R.;
Maaref, F.; Du¨rr, S. Synlett 1995, 83.
(7) For early references to Michael/aldol sequences, see: (a) Stork,
G.; Shiner, C. S.; Winkler, J . D. J . Am. Chem. Soc. 1982, 104, 310. (b)
Stork, G.; Winkler, J . D.; Shiner, C. S. J . Am. Chem. Soc. 1982, 104,
3767.
acyclic enoate, we envisioned that the reaction could be
applied to the synthesis of structurally complex tri-
quinanes. Relative to the simple examples reported in
our preliminary studies, additional concerns included
whether quaternary centers could be introduced during
the nickel-catalyzed cyclization, whether unsymmetrical
bis-enones could undergo efficient cyclizations, and
whether the reductive cyclization could be coupled with
a Dieckmann condensation rather than an aldol addition
to provide access to more synthetically versatile products.
Earlier studies showed that, even with simple systems,
reductive cyclizations involving methyl enoates were
significantly less effective than the corresponding alkyl
10.1021/jo9908389 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/21/1999

Nickel-Catalyzed Cyclizations of Enoate Equivalents
J . Org. Chem., Vol. 64, No. 16, 1999 6061
or aryl enones. Herein, we report that a highly direct
synthetic entry to the angular triquinane skeleton may
be achieved through the use of unsaturated acyl oxazo-
lidinones or R′-silyloxyenones as enoate equivalents.
a reductive cyclization/Dieckmann condensation sequence
appeared promising.
Resu lts a n d Discu ssion
Ch oice of En oa te Equ iva len ts. In the context of
aldol additions, Heathcock demonstrated that R-silyloxy
ketones are convenient enoate equivalents since oxidative
cleavage with periodic acid directly affords products in
the carboxylic acid oxidation state.8 Therefore, we envi-
sioned that enones possessing the R′-silyloxy functionality
would serve well as enoate synthetic equivalents in
conjugate addition processes and related reactions. To
provide convenient access to the desired R′-silyloxy
enones, we prepared a new reagent, 3-(tert-butyldimeth-
ylsilyloxy)-3-methyl-1-triphenylphosphoranylidene-2-bu-
tanone (2) (eq 3). Bis-silylation of 3-hydroxy-3-methyl-
Ap p lica tion to Tr iqu in a n e Syn th esis. Our initial
studies focused on the preparation of a triquinane that
lacked the C-ring methyl group. The requisite precursor
for a reductive cyclization/Dieckmann condensation se-
quence was prepared in direct analogy to a related
method reported by Fukumoto (eq 5).11 Accordingly, the
alkyllithium derived from 512 underwent 1,2-addition to
4,4-dimethyl-2-cyclopenten-1-one (4).13 The resulting ter-
tiary allylic alcohol 6 smoothly underwent oxidation with
allylic transposition in the presence of PCC.14 Acetal
deprotection with TsOH and Wittig olefination with
reagent 2 afforded a readily separable 4:1 E/Z mixture
of enone 7 in 45% overall yield from dimethylcyclopen-
tenone.
2-butanone with t-BuMe2SiOTf followed by bromination
of the enoxysilane with N-bromosuccinimide cleanly
afforded R-bromoketone 3 in 67% yield. Treatment of 3
with triphenylphosphine followed by a basic workup
afforded 2 in 59% yield. Aldehydes were readily trans-
formed to the desired R′-silyloxy enones upon treatment
with 2, typically as a 5:1 mixture of trans and cis isomers.
We anticipated that enones of this class would participate
cleanly in nickel-catalyzed cyclizations as well as other
conjugate addition processes that are limited by the
relative lack of reactivity of enoates (vide infra).
Cyclization of 7 with Et2Zn/ZnCl2 and 10 mol %
Ni(COD)2 in THF afforded a 44% yield of triquinane 8a
as a mixture of two diastereomers that are epimeric at
the tertiary hydroxyl center (eq 6). Spirocyclic compound
Acyloxazolidinones also typically display enhanced
reactivity relative to simple enoates in conjugate addition
processes.9 Prior to studying the performance of unsatur-
ated acyloxazolidinones in the synthesis of triquinanes,
we examined a simpler cyclization of an unsaturated acyl
oxazolidinone tethered to an alkyne since the efficiency
of this class of reactions typically parallels that of bis-
enone cyclizations.5 In contrast to the poor results
obtained with enoates tethered to alkynes, the corre-
sponding unsaturated acyloxazolidinone cyclization was
very satisfactory (eq 4).10 Therefore, participation of the
oxazolidinone unit in the preparation of triquinanes by
(8) (a) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M.
C.; Sohn, J . E.; Lampe, J . J . Org. Chem. 1980, 45, 1066. (b) Heathcock,
C. H. Science 1981, 214, 395. (c) Heathcock, C. H. Aldrichim. Acta 1990,
23, 99.
9 (of undetermined relative stereochemistry) was also
(9) (a) Lou, B.; Li, G.; Lung, F.; Hruby, V. J . J . Org. Chem. 1995,
60, 5509. (b) Wipf, P.; Takahashi, H. Chem. Commun. 1996, 2675. (c)
Ru¨ck, K.; Kunz, H. Synthesis 1993, 1018. (d) Sibi, M. P.; J asperse, C.
P.; J i, J . J . Am. Chem. Soc. 1995, 117, 10779.
(10) For a recent synthetic application of this observation, see:
Chevliakov, M. V.; Montgomery, J . Angew. Chem. 1998, 110, 3346;
Angew. Chem., Int. Ed. Engl. 1998, 37, 3144.
(11) Ihara, M.; Katogi, M.; Fukumoto, K.; Kametani, T. J . Chem.
Soc., Chem. Commun. 1987, 721.
(12) Niwa, H.; Hasegawa, T.; Ban, N.; Yamada, K. Tetrahedron Lett.
1984, 25, 2797.
(13) Magnus, P. D.; Nobbs, M. S. Synth. Commun. 1980, 10, 273.
(14) Dauben, W. G.; Michno, D. M. J . Org. Chem. 1977, 42, 682.

6062 J . Org. Chem., Vol. 64, No. 16, 1999
Seo et al.
Sch em e 1
obtained in 28% isolated yield. The diastereomeric mix-
ture of 8a was then treated with NBu4F in THF to afford
a 57% isolated yield of a single diastereomer of the
expected diol 8b and a 31% yield of a single diastereomer
of recovered 8a . Apparently, deprotection of the two
diastereomers of 8a occurs at significantly different rates,
and complete deprotection was not realized. The diol 8b
was then treated with periodic acid in ether to afford
triquinane 10 in 81% isolated yield with the desired 1,3-
dicarbonyl functionality intact. This strategy demon-
strates the utility of R′-silyloxyenones as enoate equiva-
lents; however, we realized that the postcyclization
oxidative manipulation would be avoided with the use
of an acyloxazolidinone instead.
Again starting with allylic alcohol 6, PCC oxidation,
acetal deprotection with TsOH, and Wittig olefination
with an oxazolidinone-based Wittig reagent15 afforded the
nickel-cyclization substrate 11. Treatment of 11 with a
3:1 mixture of diethylzinc/zinc chloride in the presence
of 10 mol % Ni(COD)2 in THF at 0 °C directly afforded
10 in 58% isolated yield, thus providing a convenient
preparation of a synthetically versatile triquinane inter-
mediate in five steps from dimethylcyclopentenone (eq
7).
Ta ble 1. Red u ctive Cycliza tion of 13
The oxazolidinone-based route was then selected as the
most efficient, and the procedure was applied in the
formal synthesis of pentalenene, pentalenic acid, and
deoxypentalenic acid by converging with the Crimmins
strategy. Preparation of substrate 13 proceeded as de-
scribed for 11 (Scheme 1). The nickel-catalyzed cycliza-
tion proceeded with reasonable efficiency, although high
levels of diastereoselectivity were not realized. At best,
a 1:1 ratio of diastereomers of 1a and 1b in 49% yield
was obtained, and in some instances, the undesired
epimer 1b predominated with diastereomeric ratios up
to >3:1. Numerous variables that were studied in an
attempt to improve diastereoselectivities included Lewis
acid structure, solvent composition, structure and method
of preparation of the organozinc, and variation of the
enoate equivalent (Table 1).
a
b
A 1:1 THF/toluene mixture was used as the solvent. 25 mol
% Ni(COD)2 was used.
triquinanes. While the inherent stereoselectivity within
the triquinane core is quite high, the overall control of
diastereoselectivity from preexisting chirality was poor.
Nonetheless, this procedure provides one of the most
direct entries to angular triquinanes and should be useful
in the synthesis of other structurally compact carbocyclic
ring systems.
Con clu sion s
In summary, unsaturated acyloxazolidinones and R′-
silyloxyenones were demonstrated to be efficient enoate
equivalents in nickel-catalyzed cyclizations. Utilizing
these groups, a direct and efficient method for the
preparation of angularly fused triquinanes has been
developed. The method was demonstrated in the formal
synthesis of three members of the pentalenene class of
Exp er im en ta l Section
1-Br om o-3-(ter t-bu tyld im eth ylsilyloxy)-3-m eth yl-2-bu -
ta n on e (3). A 100 mL CH2Cl2 solution of tert-butyldimethyl-
silyl trifluoromethanesulfonate (34.71 g, 131 mmol) was
treated with 2,6-lutidine (19.2 g, 180 mmol) at 0 °C, and the
resulting mixture was stirred for 10 min. 3-Hydroxy-3-methyl-
(15) Evans, D. A.; Black, W. C. J . Am. Chem. Soc. 1993, 115, 4497.

Nickel-Catalyzed Cyclizations of Enoate Equivalents
J . Org. Chem., Vol. 64, No. 16, 1999 6063
2-butanone (5.3 g, 52 mmol) was added to the mixture via
syringe at 0 °C. The mixture was stirred for 2 h, and 50 mL of
1.0 M NaOH was then added at 0 °C. The aqueous phase was
extracted with CH2Cl2 three times, and the organic layers were
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The remaining yellow oil was then taken up in THF
(100 mL). N-Bromosuccinimide (9.2 g, 52 mmol) was added to
the solution at 0 °C, and stirring was continued 4 h. The
reaction mixture was quenched with saturated aqueous NaH-
CO3, and the aqueous phase was extracted with EtOAc. The
combined organic phases were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (SiO2, 20:1
hexane/EtOAc) to afford bromoketone 3 (10.3 g, 67%) as a
colorless oil that was homogeneous by TLC analysis: 1H NMR
(500 MHz, CDCl3) δ 4.40 (s, 2H), 1.41 (s, 6H), 0.91 (s, 9H),
0.15 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 206.1, 80.6, 33.7,
27.7, 25.7, 18.0, -2.3; IR (film) 1741, 1717, 1258 cm-1; HRMS
(EI) m/z calcd for C7H14O2SiBr 236.9946, found 236.9945 ((M
- t-Bu)+).
3-(ter t-Bu t yld im et h ylsilyloxy)-3-m et h yl-2-oxob u t yl-
tr ip h en ylp h osp h on iu m Br om id e. A 50 mL THF solution
of triphenylphosphine (9.2 g, 35 mmol) was treated with neat
3 (10.3 g, 35 mmol), and the solution was stirred at 50 °C for
14 h. The reaction mixture was concentrated under reduced
pressure, and the resulting white precipitate was washed with
toluene, hexanes, and cold THF and was vacuum-dried to
afford 12.5 g (64%) of product as a white solid: mp 188-188.5
°C; 1H NMR (300 MHz, CDCl3) δ 7.4-7.7 (m, 15H), 6.13 (d, J
) 12.6 Hz, 2H), 1.40 (s, 6H), 0.78 (s, 9H), 0.10 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 205.5, 134.7 (d, J ) 3.3 Hz), 133.9 (d, J )
11.1 Hz), 130.1, (d, J ) 13.3 Hz), 118.9, (d, J ) 89.4 Hz), 80.4,
34.6 (d, J ) 58.5 Hz), 26.4, 25.6, 17.9, -2.2.
NMR (125 MHz) δ 173.5, 154.1, 145.8, 116.0, 75.2, 60.4, 41.0,
35.8, 33.1, 32.4, 24.9, 24.8, 24.0, 14.5; IR (film) 1777, 1700 cm-1
;
HRMS (EI) m/e calcd for C14H21NO3 251.1521, found 251.1525
(M+).
1-(4,4-Dim eth oxybu tyl)-4,4-d im eth ylcyclop en t-2-en -1-
ol (6). t-BuLi (2.47 mL, 3.85 mmol of a 1.56 M pentane
solution) was added dropwise to a -78 °C solution of 4-bromo-
1,1-dimethoxybutane (5)12 (0.40 g, 2.03 mmol) in THF (3 mL).
After being stirred for 20 min at -78 °C, the mixture was
warmed to 0 °C over 10 min. The solution was cooled again to
-78 °C, and a solution of 4,4-dimethylcyclopent-2-enone (4)13
(0.11 g, 1.0 mmol) in THF (3.0 mL) was added dropwise. After
being stirred for 30 min, the mixture was quenched with 30
mL of buffered NH4Cl solution (pH 8), extracted with Et2O,
washed with brine, dried over MgSO4, and concentrated. The
residue was chromatographed (SiO2, 3:1 hexanes/EtOAc),
providing 0.147 g (65%) of 6 as a colorless oil that was
homogeneous by TLC analysis: 1H NMR (500 MHz, CDCl3) δ
5.65 (d, J ) 5.5 Hz, 1H), 5.52 (d, J ) 5.5 Hz, 1H), 4.36 (t, J )
6.0 Hz, 1H), 3.31 (s, 6H), 1.84 (d, J ) 13.5 Hz, 1H), 1.72 (d, J
) 14.0 Hz, 1H), 1.57-1.66 (m, 4H), 1.55 (m, 1H), 1.40-1.47
(m, 2H), 1.15 (s, 3H), 1.06 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 144.4, 133.1, 104.5, 86.3, 52.8, 52.7, 44.6, 41.5, 32.9, 30.6,
29.2, 19.7; IR (film) 3446 cm-1; HRMS (EI) m/z calcd for
C
13H22O2 210.1620, found 210.1623 ((M - H2O)+).
(4-E)-8-(5,5-Dim eth yl-1-oxocyclop en t-2-en -3-yl)-2-(ter t-
bu tyld im eth ylsilyloxy)-2-m eth yloct-4-en -3-on e [(E)-7]. A
solution of the tertiary alcohol 6 (0.45 g, 1.97 mmol) in 8 mL
of CH2Cl2 was added dropwise to a stirred suspension of PCC
(1.7 g, 7.88 mmol) and Florisil (1.7 g) in 6 mL of CH2Cl2 at 0
°C. The reaction mixture was stirred for 80 min at 0 °C, diluted
with CH2Cl2, and filtered through a pad of Florisil. The solid
was rinsed with CH2Cl2 and then Et2O. After concentration,
the residue was treated with TsOH (0.225 g, 1.18 mmol) in
acetone/water (3:1, 40 mL) for 6 h at 25 °C. The reaction
mixture was subjected to an extractive workup (NaHCO3/
Et2O). The crude aldehyde thus obtained was dissolved in
benzene (4 mL) and was treated with compound 2 (1.4 g, 2.94
mmol) at 70 °C for 2 days. Evaporation and flash chromatog-
raphy (SiO2, 1:5 hexanes/Et2O) afforded, in order of elution,
0.102 g (14%) of (Z)-7 as a colorless oil and 0.41 g (55%) of
(E)-7 as a pale yellow oil that were both homogeneous by TLC
analysis. For (E)-7: 1H NMR (500 MHz, CDCl3) δ 6.92 (dt, J
) 15.5, 6.5 Hz, 1H), 6.80 (dt, J ) 15.8, 1.0 Hz, 1H), 5.85 (s,
1H), 2.41 (m, 2H), 2.39 (t, J ) 7.8 Hz, 2H), 2.28 (dq, J ) 1.0,
7.0 Hz, 2H), 1.76 (quintet, J ) 7.5 Hz, 2H), 1.33 (s, 6H), 1.09
(s, 6H), 0.88 (s, 9H), 0.08 (s, 6H); 13C NMR (125 MHz, CDCl3)
δ 214.2, 202.5, 178.4, 146.5, 126.9, 124.7, 79.0, 48.1, 44.0, 32.8,
32.0, 27.0, 25.8, 25.3, 25.1, 18.1, -2.4; IR (film) 1705, 1622
cm-1; HRMS (EI) m/z calcd for C18H29O3Si 321.1886, found
321.1886 ((M - C4H9)+). For (Z)-7: 1H NMR (500 MHz, CDCl3)
δ 6.71 (dt, J ) 11.5, 1.8 Hz, 1H), 6.19 (dt, J ) 11.5, 7.5 Hz,
1H), 5.85 (t, J ) 1.3 Hz, 1H), 2.65 (dq, J ) 1.5, 7.5 Hz, 2H),
2.43 (m, 2H), 2.40 (t, J ) 7.8 Hz, 2H), 1.72 (quintet, J ) 7.8
Hz, 2H), 1.32 (s, 6H), 1.09 (s, 6H), 0.88 (s, 9H), 0.08 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 214.4, 204.6, 179.0, 148.1, 126.8,
123.4, 79.3, 48.1, 44.1, 33.1, 29.0, 27.0, 26.5, 25.8, 25.1, 18.1,
-2.4; IR (film) 1703, 1617 cm-1; HRMS (EI) m/z calcd for
3-(t er t -Bu t yld im e t h ylsilyloxy)-3-m e t h yl-1-t r ip h e n -
ylp h osp h or a n ylid en e-2-bu ta n on e (2). The bromide salt
prepared above (9.3 g, 16.7 mmol) was dissolved in 60 mL of
THF and 20 mL of water at 0 °C, and aqueous NaOH (2 M, 10
mL) was added slowly via syringe. The resulting white
suspension was stirred for 1 h at 0 °C, and the reaction mixture
was concentrated to approximately 25 mL under reduced
pressure. The resulting aqueous phase was extracted with CH2-
Cl2, and then hexane was added to the combined organic
phases. The organic phases were dried over Na2SO4 and
filtered, and the solution was then concentrated to dryness
under reduced pressure to afford an off-white solid (7.3 g,
1
92%): mp 129.5-130 °C; H NMR (500 MHz, CDCl3) δ 7.7-
7.4 (m, 15H), 4.38 (d, J ) 28 Hz, 1H), 1.41 (s, 6H), 0.90 (s,
9H), 0.12 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 198.3, 133.0
(d, J ) 10.1 Hz), 131.8 (d, J ) 2.8 Hz), 128.7 (d, J ) 12 Hz),
127.7 (d, J ) 90.5 Hz), 79.1 (d, J ) 11.1 Hz), 46.9 (d, J ) 108
Hz), 28.9, 26.1, 18.3, -2.0; IR (KBr) 1716, 1708 cm-1; HRMS
(EI) m/z calcd for C25H28O2PSi 419.1597; found 419.1602 ((M
- t-Bu)+). Anal. Calcd for C29H37O2PSi: C, 73.07; H, 7.82.
Found: C, 72.87; H, 7.84.
3-(2-[(Z)-2-Eth yliden ecyclopen tyl]-acetyl)-4,4-dim eth yl-
2-oxa zolid in on e. A 2 mL THF solution of ZnCl2 (91 mg, 0.67
mmol) was stirred at 0 °C, and MeLi (0.72 mL, 1.0 mmol of a
1.4 M diethyl ether solution) was added by syringe followed
by stirring for 15 min at 0 °C. A 0.5 mL THF solution of Ni-
(COD)2 (3 mg, 0.01 mmol) was added by cannula, and the
resultant pale yellow solution was immediately transferred by
cannula to a 1.5 mL THF solution of the unsaturated N-
acyloxazolidinone (51 mg, 0.22 mmol, prepared as described
for compound 11) at 0 °C. After consumption of starting
material by TLC analysis, the reaction mixture was subjected
to an extractive workup (NH4Cl/NH4OH pH ) 8 buffer/EtOAc)
followed by flash chromatography on SiO2 (6:1 hexanes/EtOAc)
to produce 47 mg (87%) of product as a light yellow oil that
was homogeneous by TLC analysis: 1H NMR (500 MHz,
CDCl3) δ 5.03 (tq, J ) 2.0, 7.0 Hz, 1H), 3.99 (s, 2H), 3.18-
3.08 (m, 1H), 3.01 (dd, J ) 4.0, 17.0 Hz, 1H), 2.79 (dd, J )
11.0, 17.0 Hz, 1H), 2.29 (quintet of t, J ) 2.0, 6.0 Hz, 1H),
2.16 (quintet of t, J ) 1.5, 7.0 Hz, 1H), 1.86 (dq, J ) 7.5, 13.0
Hz, 1H), 1.71-1.61 (m, 1H), 1.61 (dquintet, J ) 1.5, 7.0 Hz,
3H), 1.58-1.49 (m, 1H), 1.56 (s, 6H), 1.47-1.40 (m, 1H); 13C
C
18H29O3Si 321.1886, found 321.1887 ((M - C4H9)+).
1,2,3a ,5,5a ,6,7,8-Oct a h yd r o-4-[1-(ter t-b u t yld im et h yl-
silyloxy)-1-m et h ylet h yl]-4-h yd r oxy-2,2-d im et h ylcyclo-
p en ta [c]p en ta len -3-on e (8a ). Et2Zn (41 µL, 0.397 mmol) was
added dropwise to ZnCl2 (18 mg, 0.132 mmol) in 2 mL of THF
at 0 °C followed by stirring for 30 min at 0 °C. A 2 mL THF
solution of Ni(COD)2 (4 mg, 0.0132 mmol) was added, and the
resultant mixture was immediately transferred by cannula to
a solution of enone 7 (50 mg, 0.132 mmol) in 2.5 mL of THF
at 0 °C and was allowed to warm to 25 °C. After being stirred
for 2 h at 25 °C, the reaction mixture was subjected to an
extractive workup (NH4Cl/NH4OH pH ) 8 buffer/Et2O), fol-
lowed by flash chromatography (9:1 hexanes/Et2O) to afford,
in order of elution, 22.2 mg (44%) of 8a (6:4:1 mixture of
diastereomers) as a pale yellow oil and 13.8 mg (28%) of 9 as
a pale yellow oil that were both homogeneous by TLC analysis.
Compound 8a was not fully characterized, but was directly

6064 J . Org. Chem., Vol. 64, No. 16, 1999
Seo et al.
carried through to diol 8b. For 8a : IR (film) 1740, 1720 cm-1
;
Hz, 2H), 1.08 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 214.3,
HRMS (EI) m/z calcd for C18H31O3Si 323.2042, found 323.2042
((M - C4H9)+). For 9: 1H NMR (500 MHz, CDCl3) δ 2.64 (d, J
) 2.5 Hz, 1H), 2.63 (s, 1H), 2.32 (d, J ) 17.5 Hz, 1H), 2.20 (d,
J ) 18.0 Hz, 1H), 2.18 (m, 1H), 1.88 (m, 1H), 1.81 (d, J ) 13.0
Hz, 1H), 1.62-1.71 (m, 4H), 1.53-1.59 (m, 1H), 1.33 (s, 3H),
1.29 (s, 3H), 1.16-1.20 (m, 1H) 1.10 (s, 3H), 1.05 (s, 3H), 0.91
(s, 9H), 0.13 (s, 3H), 0.12 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 223.8, 215.8, 81.0, 51.0, 47.0, 45.9, 45.8, 44.0, 39.4, 38.1, 30.9,
27.9, 27.8, 26.9, 26.5, 22.1, 18.8, -1.48, -1.52; IR (film) 1740,
1719 cm-1; HRMS (EI) m/z calcd for C18H31O3Si 323.2042,
found 323.2046 ((M - C4H9)+).
178.3, 165.0, 153.5, 149.8, 127.0, 120.9, 62.1, 48.1, 44.1, 42.7,
32.7, 32.1, 25.3, 25.1; IR (film) 1776, 1698, 1637, 1616 cm-1
;
HRMS (EI) m/z calcd for C16H21NO4 291.1470, found 291.1470
(M+).
(3a r,5a â,8a â)-1,2,3a ,5,5a ,6,7,8-Octa h yd r o-2,2-d im eth yl-
cyclop en ta [c]p en ta len e-3,4-d ion e (10). Et2Zn (32 µL, 0.309
mmol) was added dropwise to ZnCl2 (14 mg, 0.103 mmol) in 2
mL of THF at 0 °C followed by stirring for 20 min at 0 °C. A
2 mL portion of a THF solution of Ni(COD)2 (3 mg, 0.0103
mmol) was added, and the resultant mixture was immediately
transferred by cannula to a solution of enone 11 (30 mg, 0.103
mmol) in 1 mL of THF at 0 °C and then allowed to warm to
25 °C. After being stirred for 6 h at 25 °C, the reaction mixture
was subjected to an extractive workup (NH4Cl/NH4OH pH )
8 buffer/Et2O) followed by flash chromatography (5:1 hexanes/
EtOAc) on silica gel to produce 12.2 mg (58%) of 10 (spectral
data reported above).
1-(4,4-Dim eth oxy-1-m eth ylbu tyl)-4,4-dim eth ylcyclopen t-
2-en -1-ol (12). A suspension of high purity lithium foil (0.125
g, 17.8 mmol) in 7 mL of THF containing 4,4-dimethylcyclo-
pent-2-en-1-one (4)13 (0.325 g, 2.96 mmol) and 4-bromo-1,1-
dimethoxypentane12 (1.2 g, 5.69 mmol) was sonicated for 2 h
in a 10 °C bath. The mixture was filtered and was subjected
to an extractive workup (NH4Cl/NH4OH pH ) 8 buffer/Et2O).
The residue was chromatographed (SiO2, 2:1 hexanes/Et2O),
providing 0.36 g (50%) of 12 (1:1 mixture of diastereomers) as
a colorless oil: 1H NMR (500 MHz, CDCl3) δ 5.67 (d, J ) 5.5
Hz, 1Hsingle isomer), 5.66 (d, J ) 6.0 Hz, 1Hsingle isomer), 5.53 (d, J
) 5.0 Hz, 1Hsingle isomer), 5.52 (d, J ) 5.0 Hz, 1Hsingle isomer), 4.35
(m, 1H), 3.309, 3.307, 3.305, 3.302 (4 singlets, 6H), 1.82 (d, J
) 13.5 Hz, 1Hsingle isomer), 1.81 (d, J ) 14.0 Hz, 1Hsingle isomer),
1.73 (m, 2H), 1.65 (d, J ) 14.0 Hz, 1Hsingle isomer), 1.61 (d, J )
14.5 Hz, 1Hsingle isomer), 1.46-1.58 (m, 3H), 1.16 (s, 3H), 1.05
(m, 4H), 0.95 (d, J ) 7.0 Hz, 3Hsingle isomer), 0.86 (d, J ) 7.0 Hz,
3Hsingle isomer); 13C NMR (125 MHz, CDCl3) δ 145.0, 144.7, 132.7,
132.3, 104.8, 104.7, 89.6, 89.5, 52.8, 52.5, 52.4, 49.8, 49.1, 44.4,
44.3, 41.9, 41.7, 31.0, 30.9, 30.8, 29.1, 29.0, 27.1, 26.2, 15.1,
14.2; IR (film) 3471 cm-1; HRMS (EI) m/z calcd for C14H24O2
224.1776, found 224.1777 ((M - H2O)+).
1,2,3a,5,5a,6,7,8-Octah ydr o-4-(1-h ydr oxy-1-m eth yleth yl)-
4-h ydr oxy-2,2-dim eth ylcyclop en ta [c]p en ta len -3-on e (8b).
NBu4F (0.29 mL, 0.29 mmol, 1.0 M in THF) was added
dropwise to a solution of 8a (22.2 mg, 0.0584 mmol) in 0.4 mL
of THF at 0 °C. After being stirred for 6 h, the reaction mixture
was subjected to an extractive workup (NH4Cl/NH4OH pH )
8 buffer/Et2O). The residue was chromatographed (SiO2, 6:1
hexanes/Et2O) to afford, in order of elution, 6.8 mg (31%) of
recovered 8a as a colorless oil and 8.9 mg (57%) of diol 8b as
a white crystalline solid: mp 120-120.5 °C (recrystallized from
Et2O/hexane); 1H NMR (500 MHz, CDCl3) δ 3.82 (m, 1H), 3.27
(d, J ) 2.5 Hz, 1H), 2.84 (s, 1H), 2.59 (q, J ) 8.5 Hz, 1H), 2.37
(d, J ) 13.0 Hz, 1H), 2.01 (dd, J ) 13.3, 7.8 Hz, 1H), 1.89 (dd,
J ) 12.8, 1.3 Hz, 1H), 1.85-1.89 (m, 1H), 1.67-1.76 (m, 2H),
1.52-1.63 (m, 2H), 1.36 (s, 3H), 1.34-1.37 (m, 2H), 1.14 (s,
3H), 1.06 (s, 3H), 1.04 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
229.3, 89.2, 75.0, 67.7, 56.8, 54.9, 52.0, 50.4, 46.1, 44.7, 32.9,
27.7, 27.0, 26.2, 24.9, 24.4; IR (film) 3445, 3410, 1712 cm-1
;
HRMS (EI) m/z calcd for C16H26O3 266.1882, found 266.1882
(M+).
(3a r,5a â,8a â)-1,2,3a ,5,5a ,6,7,8-Octa h yd r o-2,2-d im eth yl-
cyclop en ta [c]p en ta len e-3,4-d ion e (10). A solution of H5IO6
(5.7 mg, 0.025 mmol) in 4.5 mL of Et2O was added dropwise
to a solution of diol 8b (6.0 mg, 0.0225 mmol) in 1 mL of Et2O
at 25 °C, and the mixture was stirred until the starting
material was consumed as judged by TLC analysis. After the
mixture was filtered and concentrated, the residue was chro-
matographed (SiO2, 4:1 hexanes/Et2O) to produce 3.7 mg (81%)
of 10 as a white crystalline solid: mp 65-66 °C (recrystallized
from hexane); 1H NMR (500 MHz, CDCl3) δ 2.95 (s, 1H), 2.64
(dd, J ) 19.5, 9.0 Hz, 1H), 2.45 (m, 1H), 2.25 (ddd, J ) 19.3,
3.3, 1.3 Hz, 1H), 1.84-2.06 (m, 5H), 1.64-1.80 (m, 2H), 1.34
(m, 1H), 1.11 (s, 3H), 1.05 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 213.0, 210.4, 70.8, 53.7, 51.4, 48.7, 47.0, 45.6, 42.6, 34.8, 26.3,
26.1, 25.3; IR (film) 1765, 1706 cm-1; HRMS (EI) m/z calcd for
3-[(2-E)-6-(5,5-Dim et h yl-1-oxocyclop en t -2-en -3-yl)-1-
oxoh ep t-2-en yl]-2-oxa zolid in on e (13). The procedure for
compound 11 was followed starting with 12 to afford 0.2 g of
13 as a white solid (45% for three steps) on a 1.45 mmol scale:
mp 72-73 °C; 1H NMR (500 MHz, CDCl3) δ 7.22 (dt, J ) 15.5,
1.5 Hz, 1H), 7.09 (dt, J ) 15.5, 7.0 Hz, 1H), 5.84 (s, 1H), 4.42
(t, J ) 8.0 Hz, 2H), 4.05 (t, J ) 8.3 Hz, 2H), 2.56 (m, 1H), 2.44
(dd, J ) 18.0, 1.8 Hz, 1H), 2.40 (dd, J ) 18.0, 1.8 Hz, 1H),
2.26 (m, 2H), 1.74 (m, 1H), 1.61 (m, 1H), 1.15 (d, J ) 7.0 Hz,
3H), 1.09 (s, 3H), 1.08 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
214.2, 182.7, 165.0, 153.4 149.8, 126.3, 120.6, 62.0, 45.5, 43.8,
42.6, 36.5, 32.9, 30.1, 25.1, 25.0, 18.6; IR (film) 1775, 1700,
1686, 1635, 1611 cm-1; HRMS (EI) m/z calcd for C17H23NO4
305.1627, found 305.1632 (M+).
C
13H18O2 206.1307, found 206.1310 (M+).
3-[(2-E)-6-(5,5-Dim et h yl-1-oxocyclop en t -2-en -3-yl)-1-
oxoh ex-2-en yl]-2-oxa zolid in on e (11). A solution of the
tertiary alcohol 6 (0.147 g, 0.645 mmol) in 3 mL of CH2Cl2 was
added dropwise to a mixture of PCC (0.42 g, 1.94 mmol) and
Florisil (0.42 g) in 2.5 mL of CH2Cl2 at 0 °C followed by stirring
for 80 min at 0 °C. The mixture was diluted with CH2Cl2,
filtered through a pad of Florisil, and rinsed with CH2Cl2 and
then Et2O. After concentration, the residue was treated with
TsOH (74 mg, 0.387 mmol) in acetone/water (3:1, 12 mL) at
25 °C followed by stirring for 4 h at 25 °C. The reaction mixture
was subjected to an extractive workup (NaHCO3/Et2O) to
provide the crude aldehyde that was directly used in the
following step without further purification. A solution of 3-[2-
(triphenylphosphonio)acetyl]oxazolidin-2-one bromide salt (0.395
g, 0.86 mmol) and DMAP (0.21 g, 1.72 mmol) in 4 mL of CHCl3
was added dropwise to the aldehyde in 1 mL of CHCl3 at 25
°C. After being stirred for 1 h at 60 °C, the mixture was cooled
to 25 °C and was stirred at 25 °C for 20 h. The reaction mixture
was quenched with 1.0 M NaHSO4, extracted with CH2Cl2,
washed with brine, dried over MgSO4, filtered, and concen-
trated. The residue was chromatographed (SiO2, 1:1 hexanes/
EtOAc) to produce 60.9 mg (33% for three steps) of 11 as a
colorless oil that was homogeneous by TLC analysis: 1H NMR
(500 MHz, CDCl3) δ 7.25 (dt, J ) 15.5, 1.8 Hz, 1H), 7.11 (dt,
J ) 15.5, 7.0 Hz, 1H), 5.85 (t, J ) 1.3 Hz, 1H), 4.42 (t, J ) 8.0
Hz, 2H), 4.06 (t, J ) 8.3 Hz, 2H), 2.42 (m, 2H), 2.40 (t, J ) 7.0
Hz, 2H), 2.34 (dq, J ) 1.5, 7.3 Hz, 2H), 1.78 (quintet, J ) 7.5
(3a r,5a â,8â,8a â)-1,2,3a ,5,5a ,6,7,8-Oct a h yd r o-2,2,8-t r i-
m eth ylcyclopen ta[c]pen talen e-3,4-dion e (1a). n-BuLi (0.25
mL, 0.59 mmol, 2.39 M hexane solution) was added dropwise
to a 0 °C solution of ZnCl2 (54 mg, 0.393 mmol) in 2.5 mL of
THF. After the solution was stirred for 30 min at 0 °C, a 2 mL
THF solution of Ni(COD)2 (4 mg, 0.0131 mmol) was added,
and the resultant mixture was immediately transferred by
cannula to a solution of enone 13 (40 mg, 0.131 mmol) in 2
mL of THF at 0 °C and was allowed to warm to 25 °C. After
being stirred for 20 h at 25 °C, the reaction mixture was
subjected to an extractive workup (NH4Cl/NH4OH pH ) 8
buffer/Et2O), followed by flash chromatography (4:1 hexanes/
EtOAc) on silica gel, to produce 14 mg (49%) of 1a and 1b (1:1
1
molar ratio based on H NMR integration). The key intermedi-
ate 1a was partially isolated by recrystallization from pentane
(mp 69-70 °C (lit.4 mp 71-72 °C)), and compound 1b as a
colorless oil was also partially isolated by flash chromatogra-
phy (6:1 hexanes/EtOAc). For 1a : 1H NMR (500 MHz, CDCl3)
δ 2.97 (s, 1H), 2.70 (dd, J ) 19.0, 9.0 Hz, 1H), 2.57 (m, 1H),
2.27 (ddd, J ) 18.8, 4.0, 1.3 Hz, 1H), 2.22 (dd, J ) 14.0, 1.5
Hz, 1H), 2.20 (m, 1H), 2.10 (m, 1H), 1.91 (dquintet, J ) 8.8,

Nickel-Catalyzed Cyclizations of Enoate Equivalents
J . Org. Chem., Vol. 64, No. 16, 1999 6065
6.8 Hz, 1H), 1.72 (d, J ) 14.0 Hz, 1H), 1.51 (qt, J ) 8.3, 5.5
Hz, 1H), 1.34 (qt, J ) 9.0, 5.5 Hz, 1H), 1.13 (s, 3H), 1.10 (s,
3H), 1.04 (d, J ) 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
212.6, 209.6, 69.3, 56.7, 47.6, 46.3, 44.4, 42.7, 41.8, 33.6, 30.8,
25.6, 25.3, 16.1; IR (film) 1761, 1716 cm-1; HRMS (EI) m/z
calcd for C14H20O2 220.1463, found 220.1464 (M+). The 1H
NMR spectrum of 1a matched that provided by Professor M.
T. Crimmins. For 1b: 1H NMR (500 MHz, CDCl3) δ 3.10 (s,
1H), 2.80 (dd, J ) 19.5, 10.0 Hz, 1H), 2.66 (m, 1H), 2.15 (ddd,
J ) 19.5, 4.5, 1.0 Hz, 1H), 2.07 (d, J ) 14.0 Hz, 1H), 1.95-
2.02 (m, 2H), 1.90 (m, 1H), 1.83 (m, 1H), 1.50 (m, 1H), 1.17
cm-1; HRMS (EI) m/z calcd for C14H20O2 220.1463, found
220.1464 (M+).
Ack n ow led gm en t. J .M. acknowledges receipt of a
National Science Foundation CAREER award and a
Camille Dreyfus Teacher-Scholar Award in support of
this research. Professor M. T. Crimmins is thanked for
kindly providing copies of spectra of compound 1a .
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for 1a ,b and 6-13. This material is available free of
charge via the Internet at http://pubs.acs.org.
(m, 1H), 1.14 (s, 3H), 1.06 (s, 3H), 0.92 (d, J ) 6.5 Hz, 3H); 13
C
NMR (125 MHz, CDCl3) δ 213.0, 210.2, 64.9, 55.7, 50.3, 46.9,
46.8, 46.5, 45.2, 33.0, 32.9, 26.1, 25.2, 15.0; IR (film) 1762, 1717
J O9908389