N. Yoshikawa et al. / Tetrahedron Letters 45 (2004) 7261–7264
7263
Scheme 3. Reagents and conditions: (a) BnBr, NaH, DMF, 0°C to rt;
(b) LDA, HMPA, TBSCl, THF, À78°C to rt; (c) xylene, 130°C; then
NaOH, THF–H2O, rt; (d) t-BuOH, DCC, DMAP, CH2Cl2, 0°C to rt.
in THF to afford carboxylic acid 18 in 71% yield (three
steps from 16).23 Esterification of 18 to give tert-butyl
ester 19 was effected by treatment with t-BuOH and
DCC in the presence of DMAP.
Scheme 5. Reagents and conditions: (a) LDA, (PhSO2)2NF, THF,
À78°C; (b) mCPBA, Na2HPO4, CH2Cl2, rt; then chromatographic
separation of diastereomers; (c) LDA, Et2AlCl, THF, À78°C.
The synthesis of a similar ester was also achieved by a
Johnson–Claisen rearrangement (Scheme 4). Alcohol
21 was prepared from 15 in two steps and treated with
triethyl orthoacetate in the presence of hydroquinone
as an acid catalyst.24 The rearrangement proceeded at
140°C to afford desired ethyl ester 22 in 46% overall
yield (three steps).
expected to be useful intermediates for the synthesis of
mGluR group II agonists. Each synthetic route starts
from enantiomerically pure materials that are commer-
cially available. The non-fluorinated derivative was syn-
thesized through an intramolecular displacement of a
cyclic sulfite by an ester enolate. Whereas this process
was not applicable to the construction of a monofluori-
nated cyclopropane ring, a Lewis acid–lithium amide
base system was effective for the intramolecular cyclo-
propanation of an epoxy fluoro ester. Further studies
on the cyclopropanation and its application to the syn-
thesis of group II mGluR agonists will be reported sep-
arately in a full account.17
Treatment of tert-butyl ester (19) with LDA and N-
fluorobenzenesulfonimide afforded fluoro ester 23 in
80% yield as a mixture of diastereomers (4:1) (Scheme
5). Epoxidation of the mixture of diastereomers 23 with
mCPBA proceeded with a diastereoselectivity of 2:1 to
afford 24 in 96% combined yield as a mixture of four
diastereomers (8:4:2:1). The diastereomers were sepa-
rated by column chromatography, and the major isomer
was subjected to the cyclization reaction. Treatment of
(S,R)-24 with LDA did not give bicyclic alcohol 4.
The starting material was recovered, however, as the
other epimer with respect to the carbon–fluorine bond.
This indicated that the deprotonation had occurred on
this epoxy ester ((SR)-24) whereas amide 12 did not un-
dergo deprotonation. This observation supports the
stereoelectronic rationale discussed above (Fig. 2).
When the resulting enolate was treated with Et2AlCl,
cyclization proceeded instantaneously to afford desired
bicyclic alcohol 4 in 57% yield.25
Acknowledgements
The authors thank Professor David A. Evans (Harvard
University) for helpful discussions. We would also like
to thank Robert A. Reamer (Merck Research Laborato-
ries) for his support with structural determinations by
NMR.
References and notes
1. Monaghan, D. T.; Bridges, R. J.; Cotman, C. W. Annu.
Rev. Pharmacol. Toxicol. 1989, 29, 365–402.
2. Nakanishi, S. Science 1992, 258, 597–603.
3. Nakanishi, S.; Masu, M. Annu. Rev. Biophys. Biomol.
Struct. 1994, 23, 319–348.
In conclusion, we have achieved an enantioselective syn-
thesis of a 2,4-dioxybicyclo[3.1.0]hexane-6-carboxylic
acid ester and its 6-fluorinated derivative, which are
4. Hollmann, M.; Heinemann, S. Annu. Rev. Neurosci. 1994,
17, 31–108.
5. Schoepp, A. A.; Jane, D. A.; Monn, J. A. Neuropharma-
cology 1999, 38, 1431–1476.
6. Chavez-Noriega, L. E.; Schaffhauser, H.; Campbell, U. C.
Curr. Drug Targets 2002, 1, 261–281.
7. Pin, J.-P.; Acher, F. Curr. Drug Targets 2002, 1, 297–317.
8. Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright, R. A.;
Salhoff, C. R.; Johnson, B. G.; Howe, T.; Alt, C. A.;
Rhodes, G. A.; Robey, R. L.; Griffey, K. R.; Tizzano, J.
P.; Kallman, M. J.; Helton, D. R.; Schoepp, D. D. J. Med.
Chem. 1997, 40, 528–537.
Scheme 4. Reagents and conditions: (a) TBSCl, imidazole, DMF, rt;
(b) aq NaOH, MeOH, rt; (c) CH3C(OEt)3, hydroquinone (cat), 140°C.