Stereoselective syntheses of highly functionalized bicyclo[3.1.0]hexanes: A general methodology for the synthesis of potent and selective mGluR2/3 agonists

Article abstract of DOI:10.1021/jo0511187

A Et₃Al mediated intramolecular epoxide opening, cyclopropanation reaction is described. The transformation provided highly functionalized bicyclo[3.1.0]hexane systems in high efficiency and with perfect H or F endo selectivity. Application of

Full text of DOI:10.1021/jo0511187

Stereoselective Syntheses of Highly Functionalized
Bicyclo[3.1.0]hexanes: A General Methodology for the Synthesis of
Potent and Selective mGluR2/3 Agonists
Lushi Tan,* Nobuyoshi Yasuda,* Naoki Yoshikawa, Frederick W. Hartner, Kan Kaung Eng,
William R. Leonard, Fuh-Rong Tsay, Ralph P. Volante, and Richard D. Tillyer
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
lushi_tan@merck.com
Received June 2, 2005
A Et3Al mediated intramolecular epoxide opening, cyclopropanation reaction is described. The
transformation provided highly functionalized bicyclo[3.1.0]hexane systems in high efficiency and
with perfect H or F endo selectivity. Application of this reaction to the synthesis of mGluR2/3 agonist
1 (43% overall yield) and a few intermediates suitable for the synthesis of other bicyclo[3.1.0]hexane
mGluR2/3 agonists is discussed.
Introduction
biochemical processes within cells, and are capable of
subtle modulatory actions.
L-Glutamate is a major excitatory neurotransmitter in
the mammalian central nervous system.1 Drugs that
modulate glutamate activity hold promise for treating an
exceptionally wide range of disorders, including schizo-
phrenia, depression, anxiety, addiction, pain, epilepsy,
and neurodegenerative diseases such as Parkinson’s and
Alzheimer’s. Currently, glutamate receptors are classified
into two broad types: the ionotropic glutamate receptors
(iGluRs) and the metabotropic glutamate receptors
(mGluRs).2,3 The latter mGluRs are further classified into
eight subtypes and three groups (I-III). The discovery
of mGluRs represents one of the most noteworthy ad-
vances in glutamate research.4 The mGluRs activate
In recent years, highly selective, orally active, and
potent Type II/III mGluR (mGluR2/3) agonists have been
reported.5 Some of them possess a densely functionalized
bicyclo[3.1.0]hexane skeleton and are shown in Figure
1. These compounds are designed as constrained glutamic
acid analogues that closely mimic the proposed bioactive
conformation of the neurotransmitter when acting at the
specific receptor. They also offer a unique synthetic
challenge because they incorporate many functional
groups and four or five contiguous chiral centers in a
relatively small molecule. Although syntheses of these
(5) (a) 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. A.; Schoepp,
D. D. J. Med. Chem. 1997, 40, 528. (b) Helton, D. R.; Tizzano, J. P.;
Monn, J. A.; Schoepp, D. D.; Kallman, M. J. Neuropharmacology 1997,
36, 1511. (c) Moghaddam, B.; Adams, B. W. Science 1998, 281, 1349.
(d) 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.; Kinston, A.; Tomlinson, R.; Lewis, R.;
Griffey, K. R.; Tizzano, J. P.; Schoepp, D. D. J. Med. Chem. 1999, 42,
1027. (e) 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. (f) Pedregal, C.; Prowse, W. Bioorg. Med.
Chem. 2002, 10, 433.
(1) Collingridge, G. L.; Lester, R. A. Pharmacol. Rev. 1989, 40, 143.
(2) Sommer, B.; Seeburg, P. H. Trends Pharmacol. Sci. 1992, 13,
291.
(3) (a) Nakanishi, S. Science 1992, 258, 597. (b) Schoepp, D. D.;
Conn, P. J. Trends Pharmacol. Sci. 1993, 14, 13. (c) Nakanishi, S.;
Masu, M. Annu. Rev. Biophys. Biomol. Struct. 1994, 23, 319. (d)
Hollmann, M.; Heinemann, S. Annu. Rev. Neurosci. 1994, 17, 31. (e)
Pin, J. P.; Duvoisin, R. Neuropharmacology 1995, 34, 1. (f) Schoepp,
D. D.; Jane, D. E.; Monn, J. A. Neuropharmacology 1999, 38, 1431. (g)
Pin, J. P.; Acher, F. Curr. Drug Targets 2002, 1, 297.
(4) Holden, C. Science 2003, 300, 1866.
10.1021/jo0511187 CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/31/2005
J. Org. Chem. 2005, 70, 8027-8034
8027

Tan et al.
SCHEME 2. Stereoselective Preparation of 10
(IV: X ) F)a
FIGURE 1. Highly selective and potent mGluR2/3 agonists.
SCHEME 1. Synthetic Plan for MGluR2/3 Agonists
1-5
a Reagents and conditions: (a) (i) LDA, THF, -70 °C, (ii) NFSI
(13), -82 °C, 84%; (b) TBHP, VO(acac)2 (2-4 mol %), toluene, 0-40
°C, 91%; (c) TBSCl, imidazole, DMF, 0-25 °C, 95%; (d) Et3Al,
LHMDS, -60 °C, 96%.
SCHEME 3. Diastereoselective Fluorination of 6
addition of a THF solution of NFSI to the corresponding
dianion of 6, prepared with LDA. However, the conver-
sion was low even though an excess of NFSI was used.
We reasoned that protonation of the dianion by the more
acidic fluorinated product was the cause of the low
conversion. This problem was resolved by addition of the
dianion solution to a THF solution of NFSI at low
temperature, which afforded the fluorinated product 7
in 84% yield. The reaction gave ∼29:1 diastereoselectivity
at the R carbon of the fluoroester. The absolute config-
uration of the newly generated chiral center is not clear,
but the S-configuration is consistent with the proposed
chelated structure of the dianion 11 (Scheme 3), where
fluorinating reagent 13 approaches from the less hin-
dered side. The major impurity of the reaction was the
corresponding O-benzenesulfonate 12, which was sup-
pressed at low temperatures (<-78 °C).
A trans relationship between the methyl fluoroacetate
group and the epoxide is required for cyclopropanation.
To take advantage of the free hydroxyl group, which is
trans to the methyl fluoroacetate group, vanadium-
mediated epoxidation of homo-allylic alcohol was ap-
plied.9 Epoxide 8 was isolated in 91% yield as the sole
diastereomer. The desired trans relationship in 8 was
supported by nOe analysis (Figure 2). The hydroxyl group
was protected with a TBS group, leading to crystalline
TBS ether 9 in 95% yield.
compounds have been reported, most of them were
racemic syntheses and required chiral HPLC column
separations.5,6 Herein we report a highly efficient and
general approach toward these molecules and a large-
scale preparation of 1, one of the most selective and
potent agonists.
Results and Discussion
Synthetic Plan. The synthetic plan called for the
initial construction of the selectively protected bicyclic
diol IV in Scheme 1. Hydroxy ketone III resulting from
oxidation of IV was expected to be suitable for the
installation of the amino acid functional groups in 1 and
2. Compound III, through enone II or its saturated
analogue, was also set for the preparation of I, an
intermediate designed for the introduction of the amino
acid functionality in 3-5. An intramolecular cyclopro-
panation reaction between the epoxide and the ester
enolate of V, prepared from the known compound 6,7
would provide IV with the highly functionalized bicyclo-
[3.1.0]hexane skeleton. Thus, this intramolecular cyclo-
propanation reaction became the cornerstone of our
synthesis.
Stereoselective Synthesis of Monoprotected Flu-
orinated Diol 10 (IV, X ) F). The key intermediate,
monoprotected fluorinated diol 10, was synthesized as
depicted in Scheme 2. Fluorination of chiral methyl ester
6 was accomplished with N-fluorobenzenesulfonimide
(NFSI, 13).8 Initially, the reaction was carried out by
With the requisite trans epoxide 9 in hand, we then
addressed the key intramolecular epoxide opening to
construct the functionalized bicyclo[3.1.0]hexane skel-
eton.10 No desired bicyclic compound 10 was observed
when 9 was treated with excess LHMDS at -78 °C,
followed by warming to 0 °C and aging for 5 h.11 After
aqueous workup, a portion of the starting material was
(6) (a) Dom´ınguez, C.; Ezquerra, J.; Prieto, L.; Espada, M.; Pedregal,
C. Tetrahedron: Asymmetry 1997, 8, 511. (b) Ohfune, Y.; Demura, T.;
Iwama, S.; Matsuda, H.; Namba, K.; Shimamoto, K.; Shinada, T.
Tetrahedron Lett. 2003, 44, 5431.
(7) (a) Partridge, J. J.; Chadha, N. K.; Uskokovic, M. R. J. Am. Chem.
Soc. 1973, 95, 7171. (b) Partridge, J. J.; Chadha, N. K.; Uskokovic, M.
R. Org. Synth. 1985, 83, 44.
(8) Differding, E.; Ofner, H. Synlett 1991, 3, 187.
(9) For directed epoxidation, see: Hoveyda, A. H.; Evans, D. A.; Fu,
G. C. Chem. Rev. 1993, 93, 1307.
8028 J. Org. Chem., Vol. 70, No. 20, 2005

Syntheses of Functionalized Bicyclo[3.1.0]hexanes
TABLE 1. Epoxide Opening Cyclopropanation of 9
entry
Lewis acid
time (h)
temp (°C)
10 (%)
1
2
3
4
5
6
7
8
Al(OiPr)3
Ti(OiPr)4
BF3‚Et2O
Et2Zn
Et2AlCl
Et3Al
5
-78
trace
trace
trace
67
5
-78
4.5
4.5
4.5
6
1
0.5
-78 to 0
-78 to 0
-78
74
-78
96
FIGURE 2. Partial nOe analysis of epoxide 8.
Et3Al
Et3Al
-60
96
-20
70
SCHEME 4. Preparation of Agonist 1 from
Monoprotected Diol 10a
FIGURE 3. Major byproducts from lithium enolate of 9.
recovered together with unidentified impurities. Based
on its 1H NMR, the recovered epoxide was the epimer at
the R-position of the fluoroester. The result suggested
that the enolate of 9 was indeed generated and that
activation of the epoxide may be required for this
cyclization. Lewis acids were examined,12 and we found
that addition at -78 °C of a stoichiometric amount of
Et2AlCl to a THF solution of the anion, generated from
the reaction of 9 with LDA or LHMDS, gave product 10
in ∼60% yield. With 10 mol % of Sc(OTf)3, the cyclization
of the anion (with LHMDS) went slowly, and 10 was
obtained in ∼60% yield after 37 h at -50 °C. Addition of
a stoichiometric amount of Sc(OTf)3 accelerated the
reaction, but the outcome was similar to the catalytic
reaction. The BF3‚Et2O mediated reaction proceeded
rapidly, and though the reaction was complete in 45 min
at -78 °C, it afforded 10 in only 30% yield. Inverse
addition of the enolate solution to a solution of Lewis acid,
such as Et2AlCl, Et3Al, Ti(OiPr)4, and Zn(OTf)2, did not
improve the results. The major byproducts of these
reactions were identified as dimers 14 and 15 by NMR
analyses (Figure 3). It was speculated that formation of
dimers had come from the Claisen condensation of the
enolate as fluoroester enolates are prone to self-conden-
sation.13 To avoid this problem, epoxide 9 was premixed
with Lewis acid prior to enolate generation.
a Reagents and conditions: (a) NaClO, RuCl3 (1 mol %), MeCN,
0 °C; (b) 1 M HCl, 25 °C, 95% from 10; (c) (S,S)-PhCH(OTMS)-
CH(OTMS)Ph, TfOH (10 mol %), CH2Cl2, 0 °C, 100%; (d) NaClO,
RuCl3 (0.5 mol %), MeCN, AcOH, 0 °C, 93%; (e) NH3/MeOH,
Ti(OiPr)4, TMSCN, -10 to 0 °C, 80%; (f) HCl (8 M), AcOH, 75 °C;
(g) H2O, 94% from 20.
followed by addition of 1.4 equiv of LHMDS at -60 °C
for 1 h. When run at -20 °C, the reaction was not as
clean, and the yield of 10 suffered (70%). Lower temper-
ature (-78 °C) increased the reaction time to 6 h in the
same yield (96%). The stereochemistry at C-6 was
perfectly controlled, and only the F-endo product was
obtained, as confirmed by a single-crystal X-ray analysis
of subseqent intermediate 19. Thus, an unprecedented,
highly efficient, enantioselective cyclopropanation reac-
tion was realized for the construction of these densely
substituted bicyclo[3.1.0]hexane systems. To the best of
our knowledge, the reaction described here represents
the first example of an epoxide opening with a fluoroester
enolate (intramolecularly or intermolecularly). The eno-
late stability issue was addressed by the precomplexation
of epoxy ester 9 and a Lewis acid.
Preparation of Agonist 1 from Monoprotected
Diol 10. The conversion of 10 to agonist 1 is summarized
in Scheme 4. Monoprotected diol 10 was first converted
to hydroxy ketone 17. Of the many choices for oxidation
of 10, we used a RuCl3-mediated oxidation with bleach.14
Crystalline TBS ketone 16 was isolable, but instead, the
crude solution of 16 was subjected to hydrolysis with 1
M HCl, and hydroxy ketone 17 was isolated as a crystal-
line compound in 95% overall yield from 10.
LHMDS was slowly added to a mixture of epoxide 9
and Et2AlCl at -78 °C. After 4.5 h, product 10 was
isolated in 74% yield together with 12% of 9. Further
studies improved the results as summarized in Table 1.
The best Lewis acid was Et3Al, and 10 was isolated in
96% yield when 9 was treated with 1.2 equiv of Et3Al
(10) (a) An intramolecular cyclopropanation reaction of ester enolate
to an iodide has been reported and complete F-endo products were
observed. See: Saito, A.; Ito, H.; Taguchi, T. Tetrahedron 2001, 57,
7487. (b) Yoshikawa, N.; Tan, L.; Yasuda, N.; Volante, R. P.; Tillyer,
R. D. Tetrahedron Lett. 2004, 45, 7261. (c) Zhang, F.; Song, Z. J.;
Tschaen, D.; Volante, R. P. Org. Lett. 2004, 6 (21), 3775.
(11) Agami, C.; Couty, F.; Evano, G. Tetrahedron Lett. 2000, 41,
8301.
(12) For Lewis acid assisted epoxide opening with enolates, see: (a)
Taylor, S. K.; Fried, J. A.; Grassl, Y. N.; Marolewski, A. E.; Pelton, E.
A.; Poel, T.-J.; Rezanka, D. S.; Whittaker, M. R. J. Org. Chem. 1993,
58, 7304. (b) Crotti, P.; Bussolo, V. D.; Favero, L.; Pineschi, M.; Pasero,
M. J. Org. Chem. 1996, 61, 9548. (c) Crotti, P.; Bussolo, V. D.; Favero,
L.; Macchia, F.; Pineschi, M.; Napolitano, E. Tetrahedron 1999, 55,
5853. (d) Hojo, M.; Sakata, K.; Maimaiti, X.; Ueno, J.; Nishikori, H.;
Hosomi, A. Chem. Lett. 2002, 142.
(13) (a) Brandange, S.; Dahlman, O.; Morch, L. J. Am. Chem. Soc.
1981, 103, 4452. (b) Welch, J. R.; Seper, K.; Eswarakrishnan, S.;
Samartino, J. J. Org. Chem. 1984, 49, 4720.
(14) Cai, D.; Hughes, D. L.; Verhoeven, T. R. Tetrahedron Lett. 1996,
37, 2537.
J. Org. Chem, Vol. 70, No. 20, 2005 8029

Tan et al.
SCHEME 5. Reaction of 17 with Alcoholsa
a Reagents: (a) alcohol, BF3OEt2.
FIGURE 4. Stable ketal ketones evaluated.
Next, we turned our attention to the installation of the
amino acid functionality. Reported methods for this
transformation had many drawbacks,5 including a slow
reaction (5 days) for hydantoin synthesis and harsh
global hydrolysis conditions (60% H2SO4, 145 °C, 5 days).
Furthermore, the instability of 1 in aqueous and/or
organic solvents made this preparation more challenging,
especially because 1 had previously been isolated by resin
chromatography.15 It would be ideal to avoid protection
of the ketone and directly install the amino acid moiety
onto hydroxy ketone 17 or TBS protected 16. However,
complex mixtures were obtained in all the attempted
amino acid installation reactions including the Bucherer-
Bergs hydantoin formation reaction and the titanium-
mediated Strecker reaction.16,17 Therefore, we protected
ketone 17.
Although the ethylene dithioketal of 17 was readily
prepared and performed well in the Strecker reaction,
the final hydrolysis was difficult under a variety of
conditions, resulting in the formation of a complex
mixture. Protection of ketone 17 as a simple ketal was
deemed ideal for global hydrolysis at a later stage, but
formation of acyclic ketals with methanol, ethanol, and
2-propanol all gave ethers at the â-position of the ketone
(22, Scheme 5) via enone 23. Although we prepared a
cyclic ketal from ethylene glycol, it was not stable to
Strecker conditions. Sterically bulky diols, such as pina-
col, gave only enone 23. 2,3-Butanediols and hydroben-
zoins were considered hindered enough to avoid conjugate
addition yet small enough to permit ketalization. The
ketals were prepared by reaction of the bis-O-TMS ethers
of the diols with 17 in the presence of 10 mol % of TfOH
in CH2Cl2.18 For example, reaction of the bis-O-TMS ether
of (S,S)-hydrobenzoin with 17 gave the hydroxy ketal 18
in quantitative yield. Oxidation of 18 with NaOCl in
MeCN in the presence of RuCl3 (0.5 mol %) and AcOH
yielded crystalline ketal-ketone 19 in 93% isolated yield.
Other ketal-ketones 24-26 were prepared similarly
(Figure 4), and all successfully extended into the Strecker
reaction.
TABLE 2. Strecker Reaction of Ketal Ketones
ketal
ketone
diastereo
ratioa
HPLC assay
entry
yield [%]b
1
2
3
4
19
24
25
26
13.1:1
6.9:1
7.1:1
6.3:1
83.2
71.9
76.9
80.4
a Ratios were determined by 19F NMR and were designated as
the ratio of desired diastereomer to unwanted diastereomer.
b Yield of major diastereomer.
hydrobenzoin proved the best based on the diastereose-
lectivity of the Strecker reaction and the crystallinity of
related intermediates. Treatment of 19 with ammonia
and titanium isopropoxide in methanol at room temper-
ature, followed by the addition of TMSCN at -10 to 0 °C
gave the aminonitrile 20 in a 13.1:1 diastereomeric ratio.
The reaction was complete in 20 h, and the highly
crystalline compound 20 was isolated as a single isomer
in 80-85% yield by filtration of the crude reaction.
Global hydrolysis of aminonitrile 20 was accomplished
in 5 h using a 1:3 (v/v) mixture of AcOH and 8 M HCl at
75 °C. During the hydrolysis, hydrobenzoin from the ketal
moiety was converted into benzyl phenyl ketone, which
was removed by extraction with CH2Cl2. The aqueous
layer was concentrated to yield the crystalline hydro-
chloride salt of 1, which was converted to 1 by simply
dissolving the salt in water and adjusting the pH to 1.25.
Agonist 1 was isolated as the monohydrate in 94% yield,
and the physical properties and spectroscopic and bio-
logical data were all consistent with that reported and
an authentic sample.
Application to the Synthesis of Other mGluR
Agonists. The successful preparation of 1 encouraged us
to investigate the application of our methodology to the
synthesis of mGluR2/3 agonists 2-5. As previously
discussed, the selectively protected bicyclic diol 29 (IV,
X ) H in Scheme 1) would serve as a key intermediate
for all these compounds. The synthesis of 29 is sum-
marized in Scheme 6. Hydroxyl group directed epoxida-
tion of 6 mediated by VO(acac)2 followed by protection of
the hydroxyl group as a TBS ether gave 28 in 65% overall
yield. The Lewis acid-mediated cyclopropanation reaction
of epoxide 28 provided 29 in 99% yield. The reaction
proceeded more rapidly (1.5 h) than the fluorinated
analogue 9 at -78 °C, presumably a result of the higher
nucleophilicity of the enolate lacking a fluorine atom.
Again, the stereochemistry was perfectly controlled based
on nOe experiments (Figure 5).
Strecker reactions of ketal-ketones 19 and 24-26 were
evaluated. The diastereoselectivity and yields are sum-
marized in Table 2. Ketal-ketone 19 derived from (S,S)-
(15) Compound 1 is not stable in DMSO-d6 at room temperature
and was decomposed completely to a mixture of several aromatic
compounds in 3-5 days.
(16) In ref 5e, the desired hydantoin was obtained in 16% yield from
the ethyl ester of the enantiomer of hydroxy ketone 17 under
Bucherer-Bergs conditions.
(17) Postel, D.; Nguyen Van Nhien, A.; Pillon, M.; Villa, P.; Ronco,
G. Tetrahedron Lett. 2000, 41, 6403.
8030 J. Org. Chem., Vol. 70, No. 20, 2005

Syntheses of Functionalized Bicyclo[3.1.0]hexanes
of 6 are readily accessible from sodium cyclopentadienide
makes this method flexible and general.
Conclusion
In summary, we have developed a general and highly
efficient asymmetric synthesis of potent and selective
bicyclo[3.1.0]hexane mGluR2/3 agonists. Densely func-
tionalized, enantiomerically pure, monoprotected diols 10
and 29 were prepared via a Et3Al-mediated intramolecu-
lar cyclopropanation with perfect H or F endo selectivity
in excellent yields. This key transformation sets all
functional groups within the targeted bicyclo[3.1.0]-
hexane systems with high efficiency. The instability of
the corresponding fluoro enolate was avoided by precom-
plexation of the epoxide with Lewis acids, and the
conditions were found applicable to the formation of
analogue 29, which was converted into both enantiomers
of enone 32 efficiently. Both enones are precursors to
agonists 2-5. Fluorinated monoprotected diol 10 was
converted to 1, one of the most potent and selective
agonists. Ketal protection with (S,S)-hydrobenzoin, fol-
lowed by a titanium-mediated Strecker reaction served
as a mild method for the introduction of the amino acid
moiety in high stereoselectivity and efficiency. A mild
global hydrolysis was developed, addressing the previ-
ously troublesome ketone protecting group strategy. The
overall yield of 1 by this route from enantiomerically pure
hydroxy methyl ester 6 was 43% in 10 steps, and this
highly robust synthesis of 1 was applicable to other
bicyclo[3.1.0]hexane mGluR2/3 agonists.
FIGURE 5. nOe analysis of bicylo[3.1.0]hexane derivative 29.
SCHEME 6. Preparation of 29 as a Key
Intermediate for mGluR2 Agonists 2-5a
a Reagents and conditions: (a) TBHP, VO(acac)2 (4 mol %),
toluene, 25 °C; (b) TBSCl, imidazole, DMF, 25 °C, 65% from 6; (c)
Et3Al, LHMDS, -78 °C, 99%.
SCHEME 7. Preparation of Enone (-)-32a
a Reagents and conditions: (a) p-TsCl, pyridine, CH2Cl2, 0-25
°C, 96%; (b) 1 M HCl, MeCN, 25 °C, 96%; (c) TFAA, DMSO, TEA,
CH2Cl2, -78 °C, 74%.
SCHEME 8. Preparation of Enone (+)-32 and
Hydroxy Ketone 34a
Experimental Section
Methyl (2S)-Fluoro[(1R,5R)-5-hydroxycyclopent-2-en-
1-yl]acetate (7). To a solution of diisopropylamine (10.8 mL,
76.8 mmol) in THF (28 mL) was added a solution of butyl-
lithium (28.2 mL, 70.4 mmol, 2.5 M in hexanes) over 40 min
while the inside temperature was maintained between 0 and
5 °C. The resulting solution was stirred at 0 °C for 3 min before
being cooled to -78 °C by a dry ice-acetone bath. A solution
of ester 6 (5.00 g, 32.0 mmol) in THF (41.3 mL) was added
dropwise to the LDA solution over 45 min while the inside
temperature was maintained below -73 °C, and the resulting
solution was stirred at -78 °C for 20 min to form an orange
(or dark orange) solution of dianion. A separate flask was
charged with N-fluorobenzenesulfonimide (14.1 g, 44.8 mmol)
and THF (62 mL), and the resulting solution was cooled to
-96 °C by a liquid nitrogen-acetone bath. The solution of the
dianion was added via an addition funnel to the suspension
of the fluorinating reagent over 1 h while the internal
temperature was maintained around -95 °C. The funnel and
the flask were flushed with 2.5 mL of THF into the reaction
mixture. The resulting mixture was stirred at -96 °C for 1 h
before being warmed to -80 °C over 30 min. Acetic acid (11
mL) in THF (5 mL) was added slowly over 7 min. The mixture
was allowed to warm to ambient temperature after the
addition of MTBE (100 mL). The resulting solid was removed
by filtration and was washed thoroughly with MTBE (6 × 70
mL). The combined filtrate and wash were filtered again and
analyzed by HPLC. The chemical yield was 86%. The filtrate
was passed through a short plug of silica gel (30 g), and the
plug was washed with MTBE (200 mL). The combined MTBE
solutions were concentrated under reduced pressure. The
a Reagents and conditions: (a) TFAA, DMSO, TEA, CH2Cl2, -78
°C, 94%; (b) DBU, CH2Cl2, 82%; (c) 1 M HCl, CH3CN, 79%.
Monoprotected diol 29 is a versatile intermediate that
permits ready conversion to either enantiomer of enone
32, the ethyl ester of which had been reported as the key
intermediate for 2-5.5,6
Enone (-)-32 was obtained as shown in Scheme 7.
Activation of the hydroxyl group of 29 as the tosylate
followed by removal of the TBS group provided free
alcohol 31 in high yield. Swern oxidation of 31 using
TFAA and DMSO gave the ketone. Simultaneously,
elimination of the tosyl group occurred during the reac-
tion to give enone (-)-32 in an unoptimized yield of 74%.
Enone (+)-32 was prepared as shown in Scheme 8.
Swern oxidation of 29 provided ketone 33, and elimina-
tion of the TBSO group with DBU provided enone (+)-
32. Thus, both enantiomers were efficiently accessed. The
corresponding ethyl esters of 32 have been used for the
preparation of 2-4.5,6 Furthermore, hydroxy ketone 34,
which would be a key intermediate for 2, was prepared
by mild acidic hydrolysis of 33.19 That both enantiomers
(18) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357.
(19) Nakazato, A.; Kumagai, T.; Sakagami, K.; Tomisawa, K.
worldwide patent number WO00/58258, 2000.
J. Org. Chem, Vol. 70, No. 20, 2005 8031

Tan et al.
residue was dissolved in EtOAc (250 mL) and washed with
saturated aqueous NaHCO3 (170 mL). The aqueous layer was
back-extracted with EtOAc (2 × 60 mL). The combined organic
solutions were washed with brine (60 mL) and dried over
Na2SO4. Evaporation of solvent gave 5.76 g of crude ester,
which was subjected to bulb-to-bulb distillation (1.6 Torr) to
afford 4.87 g of ester 7 as a yellow oil.
An analytically pure sample was obtained by flash silica gel
column chromatography (hexanes/MTBE) to give 9 as a
1
colorless solid: mp 28-30 °C; H NMR (400 MHz, CDCl3) δ
5.00 (dd, J ) 48.2, 3.5 Hz, 1 H), 4.45 (m, 1 H), 3.85 (s, 3 H),
3.51 (m, 1 H), 3.42 (m, 1 H), 2.64-2.52 (dm, J ) 34.5 Hz, 1
H), 2.14 (m, 1 H), 1.91 (m, 1 H), 0.88 (s, 9 H), 0.054 (s, 3 H),
and 0.051 (s, 3 H); 13C NMR (101 MHz, CDCl3) δ 168.8 (d, J )
24.1 Hz), 88.3 (d, J ) 186.1 Hz), 75.4 (d, J ) 1.6 Hz), 58.3,
57.2 (d, J ) 7.2 Hz), 52.8 (d, J ) 19.3 Hz), 52.7, 38.3, 25.9,
18.0, -4.5, and -4.7; 19F NMR (377 MHz, CDCl3) δ -199.9
(dd, J ) 48.2, 34.5 Hz); LRMS m/z 305 (M + 1), 121 (base
peak); [R]2D5 -27 (c 1.0, CHCl3). Anal. Calcd for C14H25FO4Si:
C, 55.23; H, 8.28; F, 6.24. Found: C, 55.27; H, 8.63; F, 6.31.
An analytically pure sample was obtained by further flash
silica gel column chromatography to give 7 as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 5.84 (m, 1 H), 5.55 (m, 1 H),
4.95 (dd, J ) 48.8, 5.5 Hz, 1 H), 4.49 (dt, J ) 7.2, 4.6 Hz, 1 H),
3.82 (s, 3 H), 3.11 (dm, J ) 24.4 Hz, 1 H), 2.75 (m, 1 H), 2.51
(s, 1 H), and 2.33 (m, 1 H); 13C NMR (101 MHz, CDCl3) δ 170.0
(d, J ) 24.1 Hz), 132.3, 126.1 (d, J ) 5.0 Hz), 89.5 (d, J )
188.0 Hz), 73.9 (d, J ) 4.0 Hz), 57.1 (d, J ) 20.1 Hz), 52.6,
and 41.8; 19F NMR (377 MHz, CDCl3) δ -196.5; IR (film) 3409,
Methyl (1R,2R,4S,5S,6R)-2-{[tert-Butyl(dimethyl)silyl]-
oxy}-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-6-carboxyl-
ate (10). To a solution of epoxide TBS-ether 9 (assay wt 1.60
kg, 5.24 mol) in THF (16.1 L) was added a solution of Et3Al
(1.0 M in hexanes, 6.81 L, 6.81 mol), while maintaining the
batch temperature at -60 °C over 1 h, and the resulting
solution was stirred at -60 °C for 20 min. A solution of
LHMDS (1.0 M solution in hexanes, 7.86 L, 7.86 mol) was
added to the reaction mixture over 1 h while maintaining the
batch temperature below -60 °C, and the reaction was aged
at -60 °C. The progress of the reaction was monitored by GC.
After complete consumption of the epoxide (6 h), an aqueous
solution of citric acid (3 M, 10.5 L) was added over 1 h while
maintaining the batch temperature below -50 °C. After MTBE
(12.4 L) was added, the resulting suspension was allowed to
gradually warm to 15 °C with stirring. Two liquid phases were
produced after addition of H2O (4.93 L). The organic layer was
separated and washed twice with saturated aqueous NaHCO3
(11.1 L then 5.6 L). GC assay of the organic solution indicated
1.54 kg (96%) of 10. Concentration of the organic layer afforded
crude alcohol as a yellow oil, which was used for the next
reaction without further purification.
An analytically pure sample was obtained by flash silica gel
column chromatography to give 10 as a colorless glass: 1H
NMR (400 MHz, CDCl3) δ 4.47 (d, J ) 4.4 Hz, 1 H), 4.34 (m,
1 H), 3.83 (s, 3 H), 2.44 (d, J ) 6.8 Hz, 1 H), 2.37 (d, J ) 11.2
Hz, 1 H), 2.25 (d, J ) 6.8 Hz, 1 H), 2.07 (m, 1 H), 1.84 (m, 1
H), 0.91 (s, 9 H), 0.131 (s, 3 H), and 0.128 (s, 3 H); 13C NMR
(101 MHz, CDCl3) δ 169.2 (d, J ) 26.5 Hz), 79.7 (d, J ) 244.3
Hz), 74.1, 74.0, 52.9, 44.6 (d, J ) 10.4 Hz), 37.9 (d, J ) 12.0
Hz), 37.6 (d, J ) 11.2 Hz), 25.8, 18.0, -4.8, and -4.9; 19F NMR
(377 MHz, CDCl3) δ -217.1 (m); LRMS m/z 305 (M + 1), 304
(M), 303 (M - 1), 75 (base peak); [R]2D5 +8.6 (c 1.9, CHCl3).
Anal. Calcd for C14H25FO4Si: C, 55.23; H, 8.28, F, 6.24.
Found: C, 55.44; H, 8.46; F, 6.39.
Methyl (1R,2R,5S,6S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-
6-fluoro-4-oxobicyclo[3.1.0]hexane-6-carboxylate (16). To
a solution of bicyclic mono-TBS-diol 10 (2.08 kg, 6.83 mol) in
acetonitrile (8.0 L) at -5 °C was added acetic acid (0.70 L)
and water (2.5 L), followed by RuCl3 hydrate (14.20 g). To the
mixture was added aqueous sodium hypochlorite solution
(∼13%; 7.0 L) over 2 h, keeping the temperature around 0 °C.
The resulting mixture was stirred at 0 °C for another 1 h until
all bicyclic mono-TBS-diol 10 disappeared, monitoring by TLC
and NMR. The excess aqueous sodium hypochlorite was
decomposed by the addition of 2-propanol (0.70 L) and aging
at 0 °C for 15 min. The two layers were separated, and the
organic solution was used for the next reaction without further
treatment.
An analytically pure sample was obtained by flash silica gel
column chromatography (MTBE/hexane) to give 16 as a
colorless crystalline solid: mp 70-71 °C; 1H NMR (400 MHz,
CDCl3) δ 4.66 (d, J ) 5.4 Hz, 1 H), 3.86 (s, 3 H), 2.73 (m, 2 H),
2.54 (dt, J ) 19.1, 5.7 Hz, 1 H), 2.22 (dd, J ) 19.1, 3.8 Hz, 1
H), 0.91 (s, 9 H), 0.13 (s, 3 H), and 0.11 (s, 3 H); 13C NMR (101
MHz, CDCl3) δ 206.2, 167.1 (d, J ) 26.1 Hz), 78.9 (d, J ) 246.4
Hz), 67.6 (d, J ) 2.8 Hz), 53.4, 47.5 (d, J ) 3.9 Hz), 42.0 (d,
J ) 11.4 Hz), 39.6 (d, J ) 13.3 Hz), 25.7, 18.0, -4.76, and
3059, 1744, 1439, 1288, 1209, 1153, 1099, 1048, 951, 733 cm-1
;
[R]2D5 -123.5 (c 1.02, CHCl3). HRMS calcd for C8H11FO3 (M +
H+) 175.0770, found 175.0773.
Methyl (2S)-Fluoro[(1R,2S,3R,5S)-3-hydroxy-6-oxabi-
cyclo[3.1.0]hex-2-yl]acetate (8). To a solution of olefin 7
(1.92 kg, 11.0 mol) in toluene (4.83 L) was added vanadyl
acetylacetonate (VO(acac)2, 58.3 g, 0.22 mol) at 0 °C. After a
solution of TBHP (5.7 M in decane, 38.6 mL) was added to
the solution at 0 °C, the resulting suspension was allowed to
warm to 14 °C. An additional solution of TBHP (5.7 M in
decane, 4.36 L) was slowly added to the reaction mixture over
50 min while maintaining the batch temperature between 14
and 28 °C. The resulting suspension was stirred for another 2
h, and then heated at 40 °C for 8 h. Excess TBHP was
quenched with aqueous Na2S2O3 solution (2.95 kg of Na2S2O3
and 4.71 kg of H2O), which was slowly added at 0 °C. The
resulting mixture was stirred at 20 °C for 1.5 h. The disap-
pearance of peroxides was confirmed by test paper. The
aqueous layer was separated and extracted with EtOAc (2 ×
9.42 L). The combined organic solutions were washed with
brine (6.33 L). The brine layer was back-extracted with EtOAc
(4 × 3.42 L). GC assay of the combined organic solutions
indicated 1.90 kg (91%) of product 8. The combined organic
solutions were concentrated, and the resulting residue was
purified by silica gel chromatography in a filter pot (first eluted
with hexanes/EtOAc (4/1) then pure EtOAc).
Analytically pure sample was prepared by flash silica gel
column chromatography (hexanes/MTBE) followed by recrys-
tallization (EtOAc) to give 8 as a pale yellow solid: mp 31-33
°C; 1H NMR (400 MHz, CDCl3) δ 5.01 (dd, J ) 48.3, 3.9 Hz, 1
H), 4.13 (br s, 1 H), 3.86 (s, 3 H), 3.71 (m, 1 H), 3.59 (m, 1 H),
2.77 (dd, J ) 32.8, 3.9 Hz, 1 H), 2.30 (br s, 1 H), and 2.11 (m,
2 H); 13C NMR (101 MHz, CDCl3) δ 168.4 (d, J ) 24.1 Hz),
88.1 (d, J ) 186.1 Hz), 73.2 (d, J ) 1.6 Hz), 58.4, 57.1 (d, J )
5.6 Hz), 52.8, 51.6 (d, J ) 19.3 Hz), and 37.7 (d, J ) 1.6 Hz);
19F NMR (377 MHz, CDCl3) δ -200.8 (dd, J ) 48.3, 32.8 Hz);
LRMS m/z 191 (M + 1), 189 (M - 1), 172 ([M - H2O]+), 59
([COOCH3]+, base peak); [R]25 -56 (c 1.0, CHCl3). Anal. Calcd
D
for C8H11FO4: C, 50.53; H, 5.83; F, 9.99. Found: C, 50.36; H,
5.92; F, 10.05.
Methyl (2S)-((1R,2R,3R,5S)-3-{[tert-Butyl(dimethyl)si-
lyl]oxy}-6-oxabicyclo[3.1.0]hex-2-yl)(fluoro)acetate (9).
To a solution of epoxy alcohol 8 (1.60 kg, 8.40 mol) and DMF
(3.40 L) was added imidazole (1.26 kg, 18.5 mol) at 10 °C.
TBSCl (1.52 kg, 10.1 mol) was added to the reaction mixture
while maintaining the batch temperature below 8 °C. The
resulting solution was stirred at 5 °C for 10 min, then allowed
to warm to 20 °C over 30 min and stirred for 2 h at the same
temperature. The consumption of the starting alcohol was
monitored by GC, and the reaction mixture was diluted with
cold toluene (17.0 L, 5 °C). The resulting mixture was washed
with H2O (5.67 L), saturated aqueous NaHCO3 (5.67 L), H2O
(2 × 5.67 L), and brine (5.67 L). HPLC assay of the organic
solution indicated 2.38 kg (93%) of 9. Concentration of the
solution gave 9 as a yellow liquid, which was used for the next
step without further purification.
8032 J. Org. Chem., Vol. 70, No. 20, 2005

Syntheses of Functionalized Bicyclo[3.1.0]hexanes
-4.78; 19F NMR (377 MHz, CDCl3) δ -210.7; [R]25 + 58.2
(c 0.50, CH3OH). Anal. Calcd for C14H23FO4Si: C, D55.60; H,
7.67, F, 6.28. Found: C, 55.60; H, 7.56; F, 6.33.
at the same temperature, aqueous cold NaHCO3 (5 wt %,
10.7 L) was added to the mixture over 12 min between 0.4
and 3.3 °C. The resulting slurry was stirred for 30 min at
3 °C, and the product 19 was filtered. The wet cake was
washed with cold water (2 × 2 L) and dried to give the first
crop (1.40 kg) of the ketal ketone 19. The filtrate and washes
were combined and the layers were separated. The organic
layer was concentrated in vacuo. The resulting slurry was
filtered. The cake was washed with water (2 × 0.48 L) and
was recrystallized from acetonitrile (1.8 L) and water (1.08 L)
to give the second crop (0.46 kg) of 19. A total of 1.86 kg (91.6%)
of ketal ketone 19 was obtained.
Methyl (1R,2R,5S,6S)-6-Fluoro-2-hydroxy-4-oxobicyclo-
[3.1.0]hexane-6-carboxylate (17). The above organic layer,
containing TBS-ketone 16 (6.83 mol), was warmed to 22 °C
and 1 M HCl (1.37 L) was added. The mixture was stirred at
22-24 °C for 3.5 h until cleavage of the TBS group was
complete. To the mixture was added saturated sodium bicar-
bonate solution (4.8 L). The mixture was stirred for 15 min
and diluted with isopropyl acetate (20 L), and the organic layer
was separated. The aqueous layer was back extracted with
isopropyl acetate (6 L). The combined organic solutions were
concentrated to dryness, and the compound was purified by
silica gel chromatography in a filter pot (first eluted with 30%
MTBE in hexane then MTBE alone) to give 1.28 kg (95% from
10) of 17 as off-white crystals.
An analytically pure sample was obtained by flash silica gel
column chromatography to give 19 as a colorless crystalline
1
solid: mp 58.5-59.5 °C; H NMR (400 MHz, CDCl3) δ 7.40-
7.34 (m, 6 H), 7.28-7.25 (m, 4 H), 4.97 (d, J ) 8.4 Hz, 1 H),
4.88 (d, J ) 8.4 Hz, 1 H), 3.93 (s, 3 H), 3.10 (dd, J ) 6.4, 2.0
Hz, 1 H), 2.94 (d, J ) 4.0 Hz, 2 H), and 2.87 (d, J ) 6.4 Hz, 1
H); 13C NMR (101 MHz, CDCl3) δ 201.5, 166.9 (d, J ) 25.7
Hz), 136.1, 135.3, 129.0, 128.8, 128.72, 128.69, 126.8, 126.5,
110.8, 86.3, 85.8, 78.9 (d, J ) 251.6 Hz), 53.6, 48.3 (d, J ) 3.3
Hz), 42.2 (d, J ) 13.2 Hz), and 41.7 (d, J ) 12.0 Hz); 19F NMR
An analytically pure sample was obtained by further flash
silica gel column chromatography to give 17 as a colorless
crystalline solid: mp 61-62 °C; 1H NMR (400 MHz, CDCl3) δ
4.92 (br s, 1 H), 3.85 (s, 3 H), 2.86 (dd, J ) 6.2, 2.1 Hz, 1 H),
2.71 (d, J ) 6.2 Hz, 1 H), 2.61 (dt, J ) 19.4, 5.7 Hz, 1 H), 2.59
(br s, 1 H), and 2.30 (dd, J ) 19.4, 3.7 Hz, 1 H); 13C NMR (101
MHz, CDCl3) δ 206.9, 167.0 (d, J ) 26.2 Hz), 79.0 (d, J ) 246.6
Hz), 67.0 (d, J ) 3.1 Hz), 53.5, 46.8 (d, J ) 4.2 Hz), 41.6 (d,
J ) 11.8 Hz), and 39.4 (d, J ) 13.1 Hz); 19F NMR (377 MHz,
(377 MHz, CDCl3) δ -208.5. [R]25 -61.6 (c 1.0, CHCl3). Anal.
D
Calcd for C22H19FO5: C, 69.10; H, 5.01. Found: C, 69.09; H,
4.86.
(1S,4′S,5R,5′S,6S)-4-Amino-4-cyano-6-fluoro-4′,5′-diphen-
ylspiro[bicyclo[3.1.0]hexane-2,2′-[1.3]dioxolane]-6-car-
boxamide (20). To a solution of 7 M ammonia in methanol
(7.4 L, 47.8 mol) and Ti(OiPr)4 (1.77 L, 5.93 mol) at 23 °C was
added ketal ketone 19 (2.11 kg, 1.89 kg as pure 19, 4.94 mol)
and the mixture was stirred for 4 h at 20-23 °C. The mixture
was cooled to -12 °C, and TMSCN (505 g, 5.09 mol) was added.
The mixture was warmed to -4.5 °C and stirred at that
temperature for 16 h. The mixture was filtered, and the
crystals were washed with cold MeOH (7.0 L) and dried at
20-25 °C at reduced pressure to afford 1.64 kg of aminonitrile
20 as a colorless solid.
CDCl3) δ -210.6; [R]25 + 77 (c 0.50, CH3OH). Anal. Calcd for
D
C8H9FO4: C, 51.07; H, 4.82, F, 10.10. Found: C, 51.06; H, 4.83;
F, 10.05.
Methyl (1S,4R,4′S,5R,5′S,6S)-6-Fluoro-4-hydroxy-4′,5′-
diphenylspiro[bicyclo[3.1.0]hexane-2,2′-[1.3]dioxolane]-
6-carboxylate (18). To a solution of hydroxy ketone 17 (1.09
kg, 5.76 mol) and CH2Cl2 (7.7 L) was added a solution of (S,S)-
bis-O-TMS-hydrobenzoin (assay 2.01 kg, 5.60 mol) and CH2-
Cl2 (2.55 L). The solution was cooled to -20 °C. TfOH (50.9
mL; 0.576 mol) was charged through an addition funnel over
4 min at -15 to ca. -20 °C. The solution was warmed to -10
°C and aged at -10 °C for 1.5 h. An additional solution of (S,S)-
bis-O-TMS-hydrobenzoin (assay 107 g; 0.298 mol) in CH2Cl2
(188 g) was charged to the reaction mixture at -10 °C. The
reaction was completed after 30 min age at -10 °C. The
reaction was quenched by addition of pyridine (46.9 mL, 0.576
mol) at <-15 °C. The solution was warmed to -10 °C, washed
with 5 wt % of a cold aqueous solution of NaHCO3 (3.75 L), 1
M cold aqueous HCl (8.6 L), 5 wt % of a cold aqueous NaHCO3
(3.75 L), and 10 wt % of a cold aqueous solution NaCl (5.0 L)
in turn and dried over Na2SO4 (1.5 kg). The solvent was
switched into acetonitrile and the solution was used for the
next reaction without further purification. HPLC assay of the
solution indicated 2.06 kg (93%) of ketal alcohol 18.
An analytically pure sample was prepared by silica gel
column chromatography to give 20 as a colorless crystalline
1
solid: mp 196.9-197.4 °C. H NMR (400 MHz, DMSO-d6) δ
8.04 (s, 1 H), 7.78 (s, 1 H), 7.38-7.25 (m, 10 H), 5.15 (d, J )
8.8 Hz, 1 H), 4.81 (d, J ) 8.8 Hz, 1 H), 2.86, (s, 2 H), 2.78 (dd,
J ) 14.5, 3.2 Hz, 1 H), 2.63 (d, J ) 6.8 Hz, 1 H), 2.46 (d, J )
6.8 Hz, 1 H), and 2.23 (dd, J ) 14.5, 4.4 Hz, 1 H); 13C NMR
(101 MHz, DMSO-d6) δ 168.7 (d, J ) 23.3 Hz), 136.5, 135.9,
128.6, 128.5, 128.5, 127.1, 126.9, 123.4, 115.1, 84.7, 84.3, 81.1
(d, J ) 255.4 Hz), 54.6, 48.3 (d, J ) 7.2 Hz), 36.6 (d, J ) 11.2
Hz), and 35.9 (d, J ) 10.4 Hz). 19F NMR (377 MHz, DMSO-d6)
δ -211.6. [R]2D5 + 59.4 (c 1.0, DMF). Anal. Calcd for C22H20-
FN3O3: C, 67.17; H, 5.12; N, 10.68. Found: C, 67.16; H, 5.06;
N, 10.60.
An analytically pure sample was obtained by flash silica gel
column chromatography to give 18 as a colorless crystalline
(1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1.0]hex-
ane-2,6-dicarboxylic Acid (1). A mixture of aminonitrile 20
(1.63 kg crude, 1.55 kg pure basis), HOAc (3.25 L), H2O (3.25
L), and concentrated HCl (6.50 L) was heated to 75 ( 2 °C for
4 h. 19F NMR showed that the reaction was complete. The
solution was cooled to 18 °C and extracted with CH2Cl2 (1 ×
9 L and 2 × 5 L). The aqueous layer was concentrated to ∼2
L at 10-25 Torr and 50 °C internal temperature. The resulting
slurry was cooled to 0 °C and stirred for 1 h. The cooled slurry
was filtered, and the cake containing the HCl salt of product
1 was maintained under vacuum filtration for 5-10 min to
remove as much of the filtrate as possible. The cake of HCl
salt was added to water (5.0 L) at 65 °C, and rinsed in with
hot H2O (300 mL). The solution was allowed to cool to 17 °C
over 45 min. The pH was adjusted to 1.25 with 50% NaOH
(230 mL). The slurry was cooled to 0 °C and stirred for 45 min.
The slurry was filtered, and the cake was washed with H2O
(2 × 1 L) and dried under nitrogen to afford 872 g of off-white
crystalline product 1 in 94% yield as monohydrate:5e mp
174.5-175.5 °C. 1H NMR (400 MHz, TFA-d) δ 3.67 (d, J ) 8.8
Hz, 1 H), 3.46 (d, J ) 8.8 Hz, 1 H), 3.45 (dd, J ) 6.1, 26 Hz, 1
1
solid: mp 118-120 °C; H NMR (400 MHz, CDCl3) δ 7.38-
7.21 (m, 10 H), 4.89 (d, J ) 8.3 Hz, 1 H), 4.83 (d, J ) 8.3 Hz,
1 H), 4.51 (br s, 1 H), 3.89 (s, 3 H), 2.54-2.51 (m, 2 H), 2.43-
2.37 (m, 2 H), and 2.18 (br s, 1 H); 13C NMR (101 MHz, CDCl3)
δ 168.7 (d, J ) 25.7 Hz), 136.6, 135.8, 128.7, 128.6, 128.5,
128.4, 126.9, 126.3, 117.7, 86.2, 86.1, 77.6 (d, J ) 247.1 Hz),
71.1, 53.0, 45.7 (d, J ) 7.8 Hz), 37.5 (d, J ) 12.1 Hz), and
36.7 (d, J ) 11.9 Hz); 19F NMR (377 MHz, CDCl3) δ -216.3.
[R]2D5 + 37.5 (c 0.80, CHCl3). Anal. Calcd for C22H21FO5: C,
68.74; H, 5.51. Found: C, 68.72; H, 5.43.
Methyl (1S,4′S,5R,5′S,6S)-6-Fluoro-4-oxo-4′,5′-diphen-
ylspiro[bicyclo[3.1.0]hexane-2,2′-[1.3]dioxolane]-6-car-
boxylate (19). To a solution of ketal alcohol 18 (assay 2.04
kg, 5.31 mol) in acetonitrile (36.7 L) was added RuCl3 hydrate
(8.25 g) followed by water (2.0 L) and acetic acid (0.41 L) at 0
°C. Aqueous sodium hypochloride solution (∼13%, 5.37 L) was
added to the reaction solution slowly over 19 min, while
maintaining the reaction temperature below 4 °C. The solution
was aged at 0-3.5 °C for 2 h. The reaction was quenched by
addition of 2-propanol (2.2 L) at 3.5 °C. After 30 min of aging
J. Org. Chem, Vol. 70, No. 20, 2005 8033

Tan et al.
H), and 3.16 (dd, J ) 6.1, 26 Hz, 1 H). [R]2D5 + 73.2 (c 0.14, 1
M HCl). Other characterization data and biological data all
matched with that reported and with that of an authentic
sample provided by Dr. Atsuro Nakazato of Taisho Phama-
ceutical Co.; Ltd.
Taisho Pharmaceutical Co., Ltd. for providing us an
authentic sample of 1 and an early stage intermediate.
Supporting Information Available: Procedures and
characterization data for compounds 24A/24, 25A/25, 26A/26,
28, 29, 30, 31, (-)-32/(+)-32, 33, and 34, single X-ray structure
of ketal ketone 19 (Figure 6), and 13C NMR of 7 and 31. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Mr. Robert A. Reamer
for his support on structure identification by NMR, Dr.
David J. Mathre and Ms. Jennifer Chilenski for X-ray
structure determination, and Dr. Atsuro Nakazato of
JO0511187
8034 J. Org. Chem., Vol. 70, No. 20, 2005