(3, R ) Me), prepared from the R,R-dibromo ester (1.0
mmol) and a solution of t-BuLi (4.0 mmol, 1.4 M in pentane)
at -78 °C for 3 h and 0 °C for 0.5 h in THF was added a
solution of 5 (0.8 mmol) in THF. The mixture was stirred
for 30 min at -78 °C. After the addition of saturated aqueous
NH4Cl and the usual workup, acid-catalyzed decarboxylation
(refluxing in benzene in the presence of a catalytic amount
of silica gel) was carried out without purification of the
â-lactone (8). After filtration, concentration, and purification
by silica gel column chromatography, the desired ethyl
2-methyl-3-phenyl-2-cyclopentenylacetate (9) was isolated
in 84% yield (Scheme 2).
single isomer.7 It is noteworthy that a seven-membered
carbocycle was successfully obtained by this tandem reaction
(entry 11), although this type of cyclization could not be
achieved by the tandem [2 + 2] cycloaddition-Dieckmann
condensation.8
The synthesis of bicyclic carbocycles was more challeng-
ing. As shown in Scheme 3, the ynolate anion (3a) reacted
Scheme 3. Synthesis of Octahydronaphthalene 11
Scheme 2. Synthesis of Cycloalkenylacetates via Ynolates
smoothly with the keto ester 10 to provide the desired
octahydronaphthalene in excellent yield as a single stereo-
isomer. The stereochemistry was determined by a single-
crystal X-ray analysis of the corresponding carboxylic acid
(11′), which was produced by hydrolysis of compound 11.
The stereoselectivity of this tandem reaction can be
explained by the assumption that the cycloaddition proceeded
by equatorial attack, followed by Michael addition, through
the proposed transition state model (Figure 1). As the
To establish the generality of this process, we examined
reactions using several kinds of keto-R,â-unsaturated esters
(5). As shown in Table 1, the 2,3-disubstituted 2-cyclopen-
Table 1. Synthesis of Ethyl
2,3-Disubstituted-2-cycloalkenylacetates via a Tandem Reaction
Figure 1. Proposed transition state model of Michael addition.
entry
R
R′
n
yield (%)
1
2
3
4
5
6
7
8
9
Me
Bu
cyclohexyl
Me
Bu
cyclohexyl
Me
Bu
cyclohexyl
Me
Me
Me
Ph
Ph
Ph
Me
Me
Me
Ph
1
1
1
1
1
1
2
2
2
2
3
64
74
75
84
94
97
75
79
93
78
63
stereochemistry of the intermediate â-lactone has not been
determined, the detailed mechanism is unclear.
This tandem reaction was applied to the synthesis of
polysubstituted naphthalenes. The ynolates anion 3b reacted
with (E)-4-(2-acetylphenyl)-2-butenoic acid ethyl ester (12)
at -78 °C (Scheme 4), and the resulting â-lactone was
decarboxylated by acid to give the dihydronaphthalene (13),
which was oxidized with DDQ to furnish the desired ethyl
3,4-dimethyl-2-naphthalenylacetate (14).
10
11a
Bu
Bu
Me
In conclusion, we have developed an efficient synthesis
of highly substituted carbocycles via a tandem [2 + 2]
cycloaddition-Michael reaction using ynolates, taking ad-
vantage of the high nucleophilicity of â-lactone enolates
a
-40 °C, 1 h.
tenylacetates were obtained in good yields (entries 1-6). In
these reactions, the intermediate â-lactones (8) were mixtures
of diastereomers with ratios from 1:1 to 4:1, determined from
1H NMR spectra. 2,3-Disubstituted 2-cyclohexenylacetates
were also synthesized in good yields (entries 7-10). In these
(6) For recent reviews on tandem reactions, see: Chapdelaine, M. J.;
Hulce, M. In Organic Reactions; Paquette, L. A., Ed.; Wiley: New York,
1990; pp 225-653. Ho, T.-L. Tandem Organic Reactions; Wiley: New
York; 1992. Bunce, R. A. Tetrahedron, 1995, 51, 13103-13159. Tietze,
L. F. Chem. ReV. 1996, 96, 115-136. Denmark, S. E.; Thrarensen, A. Chem
ReV. 1996, 96, 137-165. Winkler, J. D. Chem ReV. 1996, 96, 167-176.
Ryu, I.; Sonoda, N.; Curran, D. Chem. ReV. 1996, 96, 177-194. Parsons,
P. J.; Penkett, C. S.; Shell, A. J. Chem ReV. 1996, 96, 195-206.
(7) The relative configurations have not been determined.
1
cases, the H NMR spectra of the â-lactones (8) showed a
(5) Shindo, M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc. 1999, 121,
6507-6508.
(8) Shindo, M.; Sato, Y.; Shishido, K. Manuscript in preparation.
2030
Org. Lett., Vol. 3, No. 13, 2001
Shindo, Mitsuru
