Enantioselective syntheses of bicyclo[3.1.0]hexane carboxylic acid derivatives by intramolecular cyclopropanation

Article abstract of DOI:10.1016/j.tetlet.2004.08.027

The title compounds serve as intermediates for the synthesis of mGluR agonists, which are useful for the treatment of CNS-related disorders. Enantioselective syntheses of bicyclo[3.1.0]hexane carboxylic acid derivatives are described. The syntheses were achieved by an intramolecular cyclopropanation as the key step, starting from enantiomerically pure starting materials that are commercially available.

Full text of DOI:10.1016/j.tetlet.2004.08.027

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7261–7264
Enantioselective syntheses of bicyclo[3.1.0]hexane carboxylic
acid derivatives by intramolecular cyclopropanation
Naoki Yoshikawa,* Lushi Tan, Nobuyoshi Yasuda, Ralph P. Volante and
Richard D. Tillyer
Department of Process Research, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA
Received 18June 2004; revised 27 July 2004; accepted 4 August 2004
Available online 19 August 2004
Abstract—Enantioselective syntheses of bicyclo[3.1.0]hexane carboxylic acid derivatives are described. The syntheses were achieved
by an intramolecular cyclopropanation as the key step, starting from enantiomerically pure starting materials that are commercially
available.
Ó 2004 Elsevier Ltd. All rights reserved.
L-Glutamic acid and L-aspartic acid, referred to as exci-
tatory amino acids, widely exist in the central nervous
system (CNS) and play principal roles as neurotransmit-
ters.1 The glutamate receptors are generally classified
into two types, ionotropic glutamate receptors (iGluR)
and metabotropic glutamate receptors (mGluR). The
latter class is subdivided into three groups (group I–
III) on the basis of sequence homology, pharmacologi-
Figure 1.
cal features, and signal transduction mechanisms.2–7
The group II receptors are negatively coupled to aden-
skeleton. While a limited number of examples have been
reported,11–16 a novel approach is awaited to realize an
ylate cyclase through G proteins, and the agonists of
these receptors might be useful for the treatment of
efficient synthesis.
CNS-related disorders such as anxiety8 and
schizophrenia.9,10
We report herein our strategies for the enantioselective
syntheses of 2,4-dioxybicyclo[3.1.0]hexane-6-carboxylic
acid derivatives 3 and 4, which are expected to be useful
A series of amino acids bearing a bicyclo[3.1.0]hexane
intermediates for the synthesis of 1 and 2.17 The synthe-
core (Fig. 1), such as 1 (LY354740, Eli Lilly), are potent
agonists of group II mGluR.11,12 Recently, a 6-fluori-
nated derivative (2, MGS0028, Taisho) was found to
ses were achieved by an intramolecular cyclopropana-
tion as the key step, using starting materials that are
commercially available in enantiomerically pure form.
be orally active and to be one of the most selective
and potent agonists.12 These relatively small molecules
are densely functionalized and possess many stereogenic
centers. Because 2 is 165-fold as active as ent-2,12 an
enantioselective route would be desirable for any prepa-
ration. Thus, the synthesis of this class of compounds
constitutes an interesting challenge in terms of stereo-
chemistry as well as the construction of the complex
Keywords: mGluR agonist; Cyclopropanation; Claisen rearrangement;
Fluorinated cyclopropane.
Scheme 1 summarizes the synthesis of 3. Enantiomeri-
cally pure lactone 5, either enantiomer of which is com-
mercially available, was treated with refluxing
*
Corresponding author. Tel.: +1 732 594 1903; fax: +1 732 594
5170; e-mail: naoki_yoshikawa@merck.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.027

7262
N. Yoshikawa et al. / Tetrahedron Letters 45 (2004) 7261–7264
Scheme 1. Reagents and conditions: (a) pyrrolidine, reflux; (b) TBSCl,
imidazole, DMF, rt; (c) NMO, OsO4 (cat), acetone–H2O, rt; (d)
SOCl2, Et3N, toluene, 0°C; (e) LHMDS, THF, À78°C.
Scheme 2. Reagents and conditions: (a) (PhSO2)2NF, LDA, THF,
À78°C; then chromatographic separation of diastereomers; (b) NMO,
OsO4 (cat), acetone–H2O, rt; (c) SOCl2, Et3N, toluene, 0°C.
pyrrolidine to give amide 6 in quantitative yield. The
hydroxyl group of amide 6 was protected as a TBS ether
in quantitative yield, and the resulting 7 was oxidized to
diol 8 in 96% yield by an osmium-catalyzed dihydroxyl-
ation with 4:1 diastereoselectivity. The mixture of dia-
stereomers 8 was treated with thionyl chloride in the
presence of triethylamine to afford cyclic sulfite 9 in
94% yield. Intramolecular cyclopropanation was accom-
plished using LHMDS to give bicyclic alcohol 3 in 38%
yield (based on the major diastereomer of 8).
Fluorinated cyclopropanes have received a high level of
interest, and the chemistry has recently been reviewed.18
While carbene chemistry had been dominant in the
synthesis of monofluorinated cyclopropanes, Taguchi
reported non-carbene approaches, a tandem Michael/
cyclization process in 1994,19 and an intramolecular dis-
placement of an iodide by a fluoro ester enolate in
2001.20 Scheme 2 summarizes our attempts to extend
the strategy described above to the synthesis of a 6-fluori-
nated derivative, which would lead to 2. Fluorination of
TBS-protected amide 7 using N-fluorobenzenesulfon-
imide21 and LDA afforded 10 in 95% yield with a diastereo-
meric ratio of 8:1. The major diastereomer was isolated
by silica gel column chromatography. Dihydroxylation
of 10 gave the corresponding diol 11 in quantitative
yield with a diastereomeric ratio of 7:1. Treatment of
the mixture of two diastereomers with thionyl chloride
in the presence of triethylamine gave cyclic sulfite 12.
The mixture of diastereomers was treated with various
bases (LDA, LHMDS, KHMDS, NaHMDS, KOt-Bu,
DBU, NaH, or LTMP) to induce intramolecular cyclo-
propanation; however, none of them gave the desired
bicyclic compound (13).22
Figure 2. Deprotonation of a-fluoro pyrrolidine amide 12.
perpendicular to the plain of the amide group, as in con-
former B. Conformer B is, however, expected to be less
stable than conformer A due to steric repulsion between
the fluorine and the amide moiety. The predominance of
conformer A over conformer B would prevent the
deprotonation.
To facilitate the deprotonation, we tried to convert the
amide to esters, which were expected to be less bulky
than the amide. All attempts, however, resulted in fail-
ure because the esters re-cyclized to bicyclic lactones
such as 5. We, therefore, turned our attention to a differ-
ent route to fluoroesters in order to investigate the intra-
molecular cyclopropanation. The synthesis of the
substrate was achieved by an Ireland–Claisen rearrange-
ment, as shown in Scheme 3. The hydroxyl group in 15
(commercially available) was protected as the benzyl
ether, and resulting acetate 16 was converted to the cor-
responding TBS ketene acetal 17 by treatment with
LDA, followed by TBSCl in the presence of HMPA.23
The Claisen rearrangement was achieved by heating
the TBS ketene acetal in xylene at 130°C, and the result-
ing TBS carboxylate was hydrolyzed by aqueous NaOH
To gain insight into this unsuccessful cyclization, the
reaction was quenched with CD3COOD (Fig. 2). No
deuterated compound 14 was formed, indicating that
the deprotonation was prevented for some reason. To
generate an enolate (C), the proton must be oriented

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.

7264
N. Yoshikawa et al. / Tetrahedron Letters 45 (2004) 7261–7264
9. Moghaddam, B.; Adams, B. W. Science 1998, 281,
1349–1352.
10. Chavez-Noriega, L. E.; Schaffhauser, H.; Campbell, U. C.
Curr. Drug Targets 2002, 1, 261–281.
11. Monn, J. A.; Valli, M. J.; Massey, S. M.; Hansen, M. M.;
Kress, T. J.; Wepsiec, J. P.; Harkness, A. R.; Grutsch, J.
L., Jr.; Wright, R. A.; Johnson, B. G.; Andis, S. L.;
Kingston, A.; Tomlinson, R.; Lewis, R.; Griffey, K. R.;
Tizzano, J. P.; Schoepp, D. D. J. Med. Chem. 1999, 42,
1027–1040. See also Ref. 8.
16. Wong, A.; Welch, C. J.; Kuethe, J. T.; Vazquez, E.;
Shaimi, M.; Henderson, D.; Davies, I. W.; Hughes, D. L.
Org. Biomol. Chem. 2004, 2, 168–174.
17. Manuscript submitted.
18. Dolbier, W. R., Jr.; Battiste, M. A. Chem. Rev. 2003, 103,
1071–1098.
19. Taguchi, T.; Sasaki, H.; Shibuya, A.; Morikawa, T.
Tetrahedron Lett. 1994, 35, 913–916.
20. Saito, A.; Ito, H.; Taguchi, T. Tetrahedron 2001, 57,
7487–7493.
12. Nakazato, A.; Kumagai, T.; Sakagami, K.; Yoshikawa,
R.; Suzuki, Y.; Chaki, S.; Ito, H.; Taguchi, T.; Nakanishi,
S.; Okuyama, S. J. Med. Chem. 2000, 43, 4893–4909.
´
13. Domınguez, C.; Ezquerra, J.; Prieto, L.; Espada, M.;
Pedregal, C. Tetrahedron: Asymmetry 1997, 8, 511514;
21. Differding, E.; Ofner, H. Synlett 1991, 187–189.
22. The cyclization was also examined using O-PMB or O-
trityl compound instead of O-TBS compound 12 to see the
effects of the protecting group on the conformation
depicted in Figure 2. The desired bicyclic compound,
however, was not obtained.
´
Domınguez, C.; Ezquerra, J.; Baker, S. R.; Borrelly, S.;
Prieto, L.; Espada, M.; Pedregal, C. Tetrahedron Lett.
1998, 39, 9305–9308.
23. Hodgson, D. M.; Gibbs, A. R. Synlett 1997, 657–
658.
14. Moher, E. D. Tetrahedron Lett. 1996, 37, 8637–8640.
15. Ohfune, Y.; Demura, T.; Iwama, S.; Matsuda, H.;
Namba, K.; Shimamoto, K.; Shinada, T. Tetrahedron
Lett. 2003, 44, 5431.
24. Kondo, K.; Matsumoto, M.; Mori, F. Angew. Chem., Int.
Ed. Engl. 1975, 14, 103.
25. Cyclization using the other isomer with respect to the
carbon–fluorine bond was not examined.