Scalable synthesis of (+)-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6- dicarboxylic acid as a potent and selective group II metabotropic glutamate receptor agonist

Article abstract of DOI:10.1248/cpb.55.37

We successfully synthesized the potent and selective group II mGluR agonist (+)-1 (MGS0008) via a process incorporating the key step of efficient fluorination of epoxide (±)-5c. This method would be adaptable to large-scale synthesis to produce (+)-1 in m

Full text of DOI:10.1248/cpb.55.37

January 2007
Chem. Pharm. Bull. 55(1) 37—43 (2007)
37
Scalable Synthesis of (ꢀ)-2-Amino-3-fluorobicyclo[3.1.0]hexane-2,6-
dicarboxylic Acid as a Potent and Selective Group II Metabotropic
Glutamate Receptor Agonist
a
Kazunari SAKAGAMI, ,a Toshihito KUMAGAI,a Takeo TAGUCHI,b and Atsuro NAKAZATO
*
a Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd.; 1–403 Yoshino-cho, Kita-ku, Saitama 331–9530,
b
Japan: and School of Pharmacy, Tokyo University of Pharmacy and Life Science; 1432–1 Horinouchi, Hachioji, Tokyo
192–0392, Japan. Received July 3, 2006; accepted October 31, 2006
We successfully synthesized the potent and selective group II mGluR agonist (ꢀ)-1 (MGS0008) via a process
incorporating the key step of efficient fluorination of epoxide (ꢁ)-5c. This method would be adaptable to large-
scale synthesis to produce (ꢀ)-1 in multi-gram quantities.
Key words group II mGluR agonist; large-scale synthesis; fluorination
L-Glutamate is the primary excitatory neurotransmitter in potassium hydrogen difluoride (KF·HF) gave a key interme-
the mammalian central nervous system.1,2) Glutamate recep- diate (ꢂ)-6a and an ester-exchange product (ꢂ)-7 in 18%
tors are classified as ionotropic glutamate receptors (iGluRs), and 28% yields, respectively. The requisite elaborate separa-
which have an ion channel structure, and metabotropic gluta- tion of (ꢂ)-6a and (ꢂ)-7 by silica gel column chromatogra-
mate receptors (mGluRs), which are G-protein-coupled re- phy is unsuitable for large-scale synthesis. We used com-
ceptors. mGluRs are in turn divided into three subgroups pound (ꢁ)-3a as a starting material for large-scale synthesis,
(groups I—III), a division determined by similarities in the because the reported route to optical pure compound (ꢀ)-
coupling mechanisms, molecular structure, and homology of 3a21) is unsuitable for large-scale preparation. Moreover,
sequences and the pharmacology of the receptors.3—9) Group compound (ꢂ)-7, an hydroxyethyl ester, cannot be used for
I mGluRs (mGluR 1 and 5) activate phospholipase C, while further reaction to (ꢀ)-1, due to low reactivity for selective
both group II mGluRs (mGluR 2 and 3) and group III hydrolysis at the C-6 position.
mGluRs (mGluR 4, 6, 7 and 8) inhibit adenyl cyclase.9—11)
Therefore, we initiated efforts to modify the previous syn-
Animal models and clinical trials suggest that agonists of thesis method of (ꢀ)-1 for large-scale synthesis. We tried
group II mGluRs may be effective in treating a broad range two alternative synthesis routes of (ꢁ)-6a by eliminating a
of diseases and conditions, including schizophrenia,13—15) phenylsulfinyl group and investigating other esters (ꢁ)-6 to
anxiety,16—19) and panic disorders.20)
avoid ester exchange reactions. Here we report on two ap-
We have already reported that (ꢀ)-(1S,2S,3S,5R,6S)-2- proaches to improving chemical yields and enabling use for
amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaleable synthesis of (ꢀ)-1.
(ꢀ)-1 (MGS0008) was a potent and selective group II
mGluR agonist.13) Compound (ꢁ)-1 exhibited approximately
70-fold higher agonist activity than its diastereomer (ꢁ)-2
and (ꢀ)-1 is approximately 90–fold as active as its enan-
tiomer (ꢂ)-1 (Fig. 1). Thus, stereo-controlled synthesis is re-
quired to prepare for (ꢀ)-1.
Previously, we reported the synthesis of (ꢀ)-1 (75 mg)
from a known compound (ꢀ)-3a21) in 4.1% yield (six steps),
as shown in Chart 1.13) Fluorination of epoxide (ꢀ)-5a with Fig. 1. Structures of (ꢀ)-1 MGS0008 and the Diastereomer (ꢁ)-2
Chart 1
∗ To whom correspondence should be addressed. e-mail: kazunari.sakagami@po.rd.taisho.co.jp
© 2007 Pharmaceutical Society of Japan

38
Vol. 55, No. 1
Chart 2
Results and Discussion
Table 1. Fluorination of Epoxide (ꢁ)-5a—f
First, we examined an alternative synthesis method for
(ꢁ)-6a to improve previous problems. A new synthesis
method for (ꢁ)-6a using elimination of a phenylsulfinyl
group was shown in Chart 2.
Compound (ꢁ)-11 was synthesized via the reaction of
(ꢁ)-3a19) and diphenyl disulfide with LHMDS, followed by
oxidation with sodium periodate. The hydrogen atom at C-3
position results in high acidity due to two electron withdraw-
ing groups, phenylsulfinyl and carbonyl groups, and (ꢁ)-11
can react with electrophilic fluorination reagents. Compound
(ꢁ)-12 was obtained by fluorination with N-fluoro-benzen-
sulfonimide (NFSI)22,23) and the anion of (ꢁ)-11 at the C-3
position, prepared by treatment of (ꢁ)-11 with sodium hy-
dride. Finally, eliminating the phenylsulfinyl group of (ꢁ)-12
under neutral conditions in benzene yielded vinyl fluoride
(ꢁ)-6a (34% yield). Fluorination of (ꢁ)-11 with NFSI pro-
ceeded at low temperatures in comparison to the method re-
ported with KF·HF,13) a nucleophilic fluorination reagent,
giving (ꢁ)-6a as the sole product without elaborate separa-
tion by column chromatography.
Yield (%)
Entry
(ꢁ)-5
R
(ꢁ)-6
(ꢁ)-7
113)
2
a
OEt
18
35
28
17
b
3
c
53
0
4
d
58
0
5
6
e
f
NHMe
NMe2
58
50
0
0
In spite of these improvements, we did not employ this
method, because eliminating the phenylsulfinyl group of (ꢁ)-
12 led to low yields, and phenyl sulfenylation requires hexa-
methylphosphoramide (HMPA), a highly toxic reagent.
To avoid ester-exchange reactions, we next investigated
fluorination conditions for (ꢁ)-6a. Fluorination of (ꢁ)-5a
with KH·HF in ethanol with or without 18-Crown-6 in a
sealed condition at 130 °C failed. Alternatively, we attempted
the fluorination of several alkyl esters (ꢁ)-5b—d and amides
(ꢁ)-5e and (ꢁ)-5f, as shown in Table 1. Chart 3 shows the
synthesis of (ꢁ)-5b—f from a known compound (ꢁ)-13.24)
Compound (ꢁ)-13 was esterified with the corresponding
alkyl alcohols and amines in the presence of condensing
agents. Using the reported method,13) we synthesized (ꢁ)-
5b—f from (ꢁ)-3b—f by oxidation and epoxidation.
Chart 3
Fluorination of (ꢁ)-5b (isopropyl ester), an ester of the orate separation of a key intermediate (ꢁ)-6 and an ester-ex-
secondly alcohol, resulted in a higher yield than (ꢁ)-5a change product (ꢁ)-7 by column chromatography was re-
(ethyl ester), but gave (ꢁ)-7, an ester-exchange product, in quired.
17%. The reaction of (ꢁ)-5c and (ꢁ)-5d having a bulky sec-
Next, we examined hydrogenation of (ꢁ)-6b—f. We pre-
ondly alcohol with KF·HF gave (ꢁ)-6c and (ꢁ)-6d in 53% viously reported that stereo selective hydrogenation of (ꢂ)-
and 58% yields, respectively. Moreover, no ester-exchange 6a in the presence of 5% palladium carbon gave (ꢂ)-8a in
products were detected in the reaction. Amides (ꢁ)-5e and 76% yield, due to steric hindrance with the cyclopropane
(ꢁ)-5f were also transformed into fluoride compounds (ꢁ)- ring.13) Hydrogenation of esters (ꢁ)-6b—d under the same
6e and (ꢁ)-6f as each sole product. Fluorination of bulky es- conditions proceeded selectively to give (ꢁ)-8b—d in good
ters and amides under the reported conditions13) resulted in yields, while hydrogenation of amides (ꢁ)-6e and (ꢁ)-6f
the key intermediates (ꢁ)-6c—f as the sole product. No elab- failed, as shown in Table 2.

January 2007
39
Table 2. Hydrogenation of Vinyl Fluorides (ꢁ)-6b—f
Yield (%)
(ꢁ)-8
Entry
1
(ꢁ)-6
R
b
60
86
2
c
3
d
79
Chart 5
4
5
e
f
NHMe
NMe2
0
0
Conclusions
We reported on the convenient method of synthesizing op-
tically pure (ꢀ)-1 (MGS0008) via 2,4-dimethyl-3-pentyl
ester (ꢁ)-8c. This synthetic route for (ꢀ)-1 did not require a
fine separation of a key intermediate (ꢁ)-6 and an ester-ex-
change product (ꢁ)-7 with silica gel column chromatography
and provided improved chemical yields compared to the pre-
vious method. Moreover, the 2,4-dimethyl-3-pentyl ester was
selectively removed under hydrolysis conditions using 48%
HBr, and the optical resolution of the obtained carboxylic
acid with (R)-(ꢀ)-1-phenylethylamine was successful. We
succeeded in producing (ꢀ)-1 in multi-gram quantities by
the described method. We believe this method of synthesiz-
ing (ꢀ)-1 will help advance biological and pharmacological
Chart 4
We adopted 2,4-dimethyl-3-pentyl ester for the large-scale studies of this compound.
synthesis of (ꢀ)-1, based on the yields for fluorination and
hydrogenation, given in Tables 1 and 2.
Experimental
Melting points were determined on a Yanaco MP-500D melting point ap-
paratus and are uncorrected. H-, 13C- and 19F-NMR spectra were obtained
1
Compound (ꢁ)-8c was allowed to react in Bucherer–Bergs
conditions25) to produce a hydantoin derivative (ꢁ)-14 (Chart using a Varian Gemini 2000, Varian Unity Inova 300, JEOL Alpha500 or
4). In the previous paper,13) we reported the efficient optical
JEOL Lambda500. Chemical shifts are reported in parts per million relative
to tetramethylsilane (TMS) or sodium 3-trimethylsilylpropionate-2,2,3,3-d4
(TMSP) as an internal standard. IR spectra were recorded on a Perkin-Elmer
Spectrum One FT-IR spectrometer. Mass spectra (MS) were obtained on a
resolution of carboxylic acid (ꢁ)-15 with (R)-(ꢀ)-1-
phenylethylamine in ꢃ99% ee (chemical yield 47%). In
order to apply the optical resolution, we attempted selective
hydrolysis of the 2,4-dimethyl-3-pentyl ester at the C-6 posi-
tion of (ꢁ)-14. Compound (ꢁ)-14 was selectively hy-
drolyzed with 48% HBr for 60 h to give (ꢁ)-15 in 82%, and
the optical resolution of the obtained carboxylic acid (ꢁ)-15
with (R)-(ꢀ)-1-phenylethylamine was successful (Chart 4).
On the other hand, hydrolysis of (ꢁ)-14 using NaOH aq. or
HCl aq. proceeded with 2,4-dimethyl-3-pentyl ester and hy-
dantoin moiety to render (ꢁ)-1.
Ethyl esters, (ꢁ)-3a, (ꢁ)-4a, and (ꢁ)-5a were solid, while
2,4-dimethyl-3-pentyl ester, (ꢁ)-3c, (ꢁ)-4c, and (ꢁ)-5c were
viscous oil. Therefore, we decided to change ethyl ester into
2,4-dimethyl-3-pentyl ester via carboxylic acid (ꢁ)-16 to pu-
rify (ꢁ)-3a, (ꢁ)-4a, and (ꢁ)-5a by recrystallization (Chart
5).
Micromass Platform LC (ES) or Micromass GCT (EI, CI). High resolution
spectra were recorded on a Micromass GCT instrument or Micromass Q-
TOF2 instrument. Optical rotations were determined with a JASCO DIP-360
polarimeter and are reported at the sodium D-line (589 nm). Elemental
analyses were performed on a Perkin-Elmer 2400. Silica gel (C-200, 100—
200 mesh (Wako Pure Chemical)) was used for column chromatography,
using the solvent systems (volume ratios) indicated below.
(1SR,5RS,6SR)-3-Phenylsulfanyl-2-oxobicyclo[3.1.0]hexane-6-car-
boxylic Acid Ethyl Ester ((ꢁ)-10) n-Butyl lithium (1.61 M hexane soln,
19.4 ml, 31.2 mmol) was added to the mixture of hexamethyldisilazane
(HMDS) (5.00 g, 31.0 mmol) and THF (25 ml) at ꢂ78—ꢂ75 °C, and stirred
for 1 h at this temperature under a nitrogen atmosphere. A solution of (ꢁ)-
3a19) (5.00 g, 29.7 mmol) in THF (18 ml) was added to the mixture at ꢂ78—
ꢂ73 °C. After stirring for 1 h, a solution of diphenyl disulfide (7.80 g,
35.7 mmol) in hexamethylphosphoramide (30 ml) was added, and the reac-
tion mixture was stirred for 2 h at room temperature. Saturated aqueous
NH4Cl was added and concentrated under reduced pressure. The residue was
extracted with AcOEt. The organic layer was washed with saturated aqueous
Based on the above findings, we selected the synthetic NH4Cl, saturated aqueous NaHCO3 and saturated brine, dried (Na2SO4),
concentrated under reduced pressure, and chromatographed on silica gel
route from (ꢁ)-3a to (ꢀ)-1 (MGS0008) as shown Chart 5.
We achieved the synthesis of (ꢀ)-1 (29.5 g) at a total yield of
6.7% from (ꢁ)-3a. The physical properties and spectro-
scopic data for (ꢀ)-1 described above identified with the pre-
(hexane : AcOEtꢄ10 : 1—9 : 1) to yield (ꢁ)-10 (5.51 g, 67% yield) as a col-
1
orless oil. H-NMR (200 MHz, CDCl3) d: 1.21—1.32 (3H, m), 1.98—2.93
(5H, m), 3.42—3.64 (1H, m), 4.10—4.22 (2H, m), 7.25—7.48 (5H, m). HR-
EI-MS m/z: 276.0825 [Calcd for C15H16O3S: 276.0820 (Mꢀ)].
(1SR,5RS,6SR)-3-Phenylsulfinyl-2-oxobicyclo[3.1.0]hexane-6-car-
vious date.

40
Vol. 55, No. 1
(1SR,5RS,6SR)-2-Oxobicyclo[3.1.0]hexane-6-carboxlic Acid Dimethyl-
amide ((ꢁ)-3f) In a similar manner to the preparation of (ꢁ)-3e, (ꢁ)-3f
(5.10 g, 95% yield) was obtained from (ꢁ)-13 (4.50 g, 32.1 mmol) using
50% aqueous dimethylamine (3.50 g, 38.8 mmol) as a solid. mp 49—52 °C.
1H-NMR (200 MHz, CDCl3) d: 2.01—2.28 (6H, m), 2.53—2.58 (1H, m),
2.97 (3H, s), 3.17 (3H, s). HR-CI-MS m/z: 168.1017 [Calcd for C9H14NO2:
168.1025 (Mꢀꢀ1)].
(1SR,5RS,6SR)-2-Oxobicyclo[3.1.0]hex-3-ene-6-carboxylic Acid Ethyl
Ester ((ꢁ)-4a) n-Butyl lithium (2.46 M hexane soln, 725 ml, 1.78 mol) was
added to a mixture of HMDS (288 g, 1.78 mol) and THF (750 ml) at ꢂ68—
ꢂ65 °C, and the mixture was stirred for 1 h under a nitrogen atmosphere. A
solution of (ꢁ)-3a19) (250 g, 1.49 mol) in THF (500 ml) was added to the
mixture at ꢂ68—ꢂ63 °C, and the mixture was stirred for 1 h. TMSCl
(282 ml, 2.23 mol) was added, and the reaction mixture was stirred for 1.5 h
at room temperature. The obtained inorganic salt was filtered off and the fil-
trate was concentrated under reduced pressure. Hexane was added to the
residue, the resulting inorganic salts were filtered off, and the filtrate was
concentrated under reduced pressure.
Pd(OAc)2 (367 g, 1.63 mol) was added to a solution of the residue in
MeCN (1780 ml) with ice-cooling maintained below 24 °C, and the reaction
mixture was stirred at room temperature for 16 h. The reaction mixture was
filtered through Celite® pad and the filtrate was concentrated under reduced
pressure. The Celite® pad was washed with AcOEt (1800 ml). The combined
filtrate was washed with water and saturated brine. The organic layer was
dried (Na2SO4), concentrated under reduced pressure, short-chromatog-
raphed on silica gel (750 ml, hexane : AcOEtꢄ1 : 1), and recrystallized from
isopropyl ether to yield (ꢁ)-4a (222 g, 90% yield) as a yellow solid. mp
79—82 °C. 1H-NMR (200 MHz, CDCl3) d: 1.27 (3H, t, Jꢄ7.0 Hz), 2.27
(1H, t, Jꢄ2.6 Hz), 2.60—2.65 (1H, m), 2.96 (1H, dt, Jꢄ2.6, 5.0 Hz), 4.15
(3H, q, Jꢄ7.0 Hz), 5.74 (1H, d, Jꢄ5.7 Hz), 7.61 (1H, dd, Jꢄ2.6, 5.7 Hz).
13C-NMR (126 MHz, CDCl3) d: 14.1, 28.9, 30.0, 45.8, 61.3, 129.6, 159.6,
167.9, 203.2. IR (KBr) cmꢂ1: 1718, 1697, 1566, 684. CI-MS m/z: 167
(Mꢀꢀ1). Anal. Calcd for C9H10O3: C, 65.05; H, 6.07. Found C, 65.01; H,
6.04.
(1SR,5RS,6SR)-2-Oxobicyclo[3.1.0]hex-3-ene-6-carboxylic Acid Iso-
propyl Ester ((ꢁ)-4b) Compound (ꢁ)-3b (4.60 g, 25.2 mol) was reacted
in a similar manner to preparation of (ꢁ)-4a from (ꢁ)-3a and then purified
on silica gel chromatography to yield (ꢁ)-4b (2.42 g, 79% yield) as a color-
less oil. 1H-NMR (300 MHz, CDCl3) d: 1.23 (3H, d, Jꢄ6.2 Hz), 1.24 (3H, d,
Jꢄ6.2 Hz), 2.24 (1H, t, Jꢄ2.8 Hz), 2.60—2.63 (1H, m), 2.93—2.96 (1H,
m), 4.95—5.03 (1H, m), 5.73 (1H, d, Jꢄ5.7 Hz), 7.61 (1H, dd, Jꢄ2.6,
5.7 Hz). HR-CI-MS m/z: 181.0877 [Calcd for C10H13O3: 181.0865 (Mꢀꢀ1)].
(1SR,5RS,6SR)-2-Oxobicyclo[3.1.0]hex-3-ene-6-carboxylc Acid 2,4-Di-
methyl-3-pentyl Ester ((ꢁ)-4c) Compound (ꢁ)-3c (6.53 g, 27.4 mol) was
reacted in a similar manner to preparation of (ꢁ)-4a from (ꢁ)-3a and then
purified on silica gel chromatography to yield (ꢁ)-4c (5.18 g, 80% yield) as
a colorless oil. 1H-NMR (200 MHz, CDCl3) d: 0.84—0.90 (12H, m), 1.82—
1.96 (2H, m), 2.31 (1H, d, Jꢄ2.6 Hz), 2.62—2.66 (1H, m), 2.96 (1H, dt,
Jꢄ2.6, 5.1 Hz), 4.58 (1H, t, Jꢄ6.2 Hz), 5.75 (1H, d, Jꢄ5.7 Hz), 7.64 (1H,
dd, Jꢄ2.6, 5.7 Hz). HR-CI-MS m/z: 237.1503 [Calcd for C14H21O3:
237.1491(Mꢀꢀ1)].
boxylic Acid Ethyl Ester ((ꢁ)-11) A solution of NaIO4 (0.938 g,
4.39 mmol) in water (4 ml) was added to a mixture of (ꢁ)-10 (1.01 g,
3.65 mmol) and MeOH (12 ml) with ice-cooling. The mixture was stirred for
1 d at room temperature. The obtained precipitate was filtered off, and the
filtrate was concentrated under reduced pressure. The residue was dissolved
in AcOEt, dried (Na2SO4), concentrated under reduced pressure, and chro-
matographed on silica gel (hexane : AcOEtꢄ3 : 1) to yield (ꢁ)-11 (0.830 g,
1
78% yield) as a colorless oil. H-NMR (200 MHz, CDCl3) d: 1.20—1.32
(3H, m), 1.70—3.40 (6H, m), 4.06—4.22 (2H, m), 7.49—7.56 (5H, m). HR-
ES-MS m/z: 293.0850 [Calcd for C15H17O4S: 293.0848 (Mꢀꢀ1)].
(1SR,5RS,6SR)-3-Fluoro-3-phenylsulfinyl-2-oxobicyclo[3.1.0]hexane-
6-carboxylic Acid Ethyl Ester ((ꢁ)-12) Under a nitrogen atmosphere, a
solution of (ꢁ)-11 (0.510 g, 1.74 mmol) in THF (9.3 ml) was added to a sus-
pension of 60% NaH in oil (77.0 mg, 1.92 mmol) in THF (9.3 ml) with ice-
cooling, and the mixture was stirred for 15 min. N-Fluorobenzenesulfon-
imide (NFSI) (0.660 g, 2.09 mmol) was added to the mixture, and stirred for
2 h with ice-cooling. 1 M HCl was added to the mixture and stirred for 1 h at
room temperature. The resulting mixture was concentrated under reduced
pressure, and extracted with AcOEt. The extract was dried (Na2SO4), con-
centrated under reduced pressure, and chromatographed on silica gel
(hexane : AcOEtꢄ4 : 1) to yield (ꢁ)-12 (0.340 g, 63% yield) as a colorless
1
oil. H-NMR (200 MHz, CDCl3) d: 1.23—1.35 (3H, m), 1.97—3.32 (5H,
m), 4.11—4.24 (2H, m), 7.51—7.71 (5H, m). HR-ES-MS m/z: 311.0752
[Calcd for C15H16O4FS: 311.0753 (Mꢀꢀ1)].
(1SR,5RS,6SR)-3-Fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic
Acid Ethyl Ester ((ꢁ)-6a) A solution of (ꢁ)-12 (0.310 g, 0.999 mmol) in
benzene (15.5 ml) was refluxed for 9 h, concentrated under reduced pressure,
and chromatographed on silica gel (hexane : AcOEtꢄ8 : 1) to yield (ꢁ)-6a
(61.0 mg, 34% yield) as a colorless oil. 1H-NMR (200 MHz, CDCl3) d: 1.28
(3H, t, Jꢄ7.0 Hz), 2.48 (1H, dt, Jꢄ0.66 Hz, 3.1 Hz), 2.55—2.61 (1H, m),
2.77—2.85 (1H, m), 4.17 (2H, q, Jꢄ7.0 Hz), 6.89—6.92 (1H, m). HR-CI-
MS m/z: 185.0606 [Calcd for C9H10O3F: 185.0614 (Mꢀꢀ1)].
(1SR,5RS,6SR)-2-Oxobicyclo[3.1.0]hexane-6-carboxylic Acid 2,4-Di-
methyl-3-pentyl Ester ((ꢁ)-3c) 3-Ethyl-1-[3-(dimethylamino)propyl] car-
bodiimide hydrochloride (EDC·HCl) (6.00 g, 31.1 mmol) was added to a
mixture of (ꢁ)-1324) (4.00 g, 28.5 mmol), 2,4-dimethyl-3-pentanol (3.60 g,
31.0 mmol), 4-dimethylaminopyridine (350 mg, 2.86 mmol) and CHCl3
(40 ml) with ice-cooling and the mixture was stirred for 12 h at room tem-
perature. 1 M HCl was added to the reaction mixture and the aqueous layer
was extracted twice with CHCl3. The combined organic layer was dried
(Na2SO4), concentrated under reduced pressure, and chromatographed on
silica gel (hexane : AcOEtꢄ10 : 1) to yield (ꢁ)-3c (6.69 g, 98% yield) as a
1
colorless oil. H-NMR (200 MHz, CDCl3) d: 0.84—0.94 (12H, m), 1.82—
1.99 (2H, m), 2.03—2.36 (6H, m), 2.49—2.56 (1H, m), 4.60 (1H, t,
Jꢄ6.2 Hz). HR-CI-MS m/z: 239.1645 [Calcd for C14H23O3: 239.1647
(Mꢀꢀ1)].
(1SR,5RS,6SR)-2-Oxobicyclo[3.1.0]hexane-6-carboxylic Acid Iso-
propyl Ester ((ꢁ)-3b) Compound (ꢁ)-3b (4.80 g, 92% yield) was ob-
tained, as described for (ꢁ)-3c, from (ꢁ)-13 (4.00 g, 28.5 mmol) using iso-
1
propyl alcohol (1.90 g, 31.6 mmol) as a colorless oil. H-NMR (300 MHz,
CDCl3) d: 1.24 (3H, d, Jꢄ6.2 Hz), 1.25 (3H, d, Jꢄ6.2 Hz), 1.97—2.28 (6H,
m), 2.48—2.53 (1H, m), 4.96—5.05 (1H, m). HR-CI-MS m/z: 183.1026
[Calcd for C10H15O3: 183.1021 (Mꢀꢀ1)].
(1SR,5RS,6SR)-2-Oxobicyclo[3.1.0]hex-3-ene-6-carboxylic Acid 2,4-
Dimethylcyclohexyl Ester ((ꢁ)-4d) Compound (ꢁ)-3d (5.20 g, 20.8 mol)
was reacted in a similar manner to preparation of (ꢁ)-4a from (ꢁ)-3a and
then purified on silica gel chromatography to yield (ꢁ)-4d (3.92 g, 76%
yield) as a colorless oil. 1H-NMR (300 MHz, CDCl3) d: 0.78—0.95 (6H, m),
0.98—2.59 (8H, m), 2.28—2.35 (1H, m), 2.60—2.68 (1H, m), 2.93—3.00
(1H, m), 4.25—5.05 (1H, m), 5.70—5.78 (1H, m), 7.60—7.66 (1H, m). HR-
ES-MS m/z: 271.1304 [Calcd for C15H20O3Na: 271.1310 (MꢀꢀNa)].
(1SR,5RS,6SR)-2-Oxobicyclo[3.1.0]hex-3-ene-6-carboxlic Acid Methy-
lamide ((ꢁ)-4e) Compound (ꢁ)-3e (4.51 g, 29.4 mol) was reacted in a
similar manner to preparation of (ꢁ)-4a from (ꢁ)-3a and then purified on
silica gel chromatography to yield (ꢁ)-4e (1.57 g, 37% yield) as a solid. mp
125—129 °C. 1H-NMR (200 MHz, CDCl3) d: 2.04 (1H, t, Jꢄ2.6 Hz),
2.60—2.64 (1H, m), 2.82 (3H, d, Jꢄ4.8 Hz), 2.97—3.02 (1H, m), 5.71 (1H,
d, Jꢄ5.5 Hz), 5.96 (1H, s), 7.62 (1H, dd, Jꢄ2.6, 5.5 Hz). HR-ES-MS m/z :
150.0551 [Calcd for C8H8NO2: 150.0555 (Mꢀꢂ1)].
(1SR,5RS,6SR)-2-Oxobicyclo[3.1.0]hexane-6-carboxylic Acid 2,6-Di-
methylcyclohexyl Ester ((ꢁ)-3d) Compound (ꢁ)-3d (5.22 g, 97% yield)
was obtained, as described for (ꢁ)-3c, from (ꢁ)-13 (3.00 g, 21.4 mmol)
1
using 2,6-dimethylcyclohexanol (3.00 g, 23.4 mmol) as a colorless oil. H-
NMR (200 MHz, CDCl3) d: 0.80—0.92 (6H, m), 1.09—1.82 (8H, m),
2.02—2.33 (6H, m), 2.50—2.57 (1H, m), 4.27—5.04 (1H, m). HR-ES-MS
m/z: 251.1646 [Calcd for C15H23O3: 251.1647 (Mꢀꢀ1)].
(1SR,5RS,6SR)-2-Oxobicyclo[3.1.0]hexane-6-carboxylic acid methyl-
amide ((ꢁ)-3e) EDC·HCl (7.40 g, 38.6 mmol) was added to a mixture of
(ꢁ)-13 (4.50 g, 32.1 mmol), 40% methanolic methylamine (3.00 g,
38.8 mmol), 1-hydroxybenzotriazole hydrate (6.10 g, 39.8 mmol) and N,N-
dimethylformamide (45 ml) with ice-cooling, and the mixture was stirred for
15 h at room temperature. Water and a mixture of CHCl3 and MeOH (9 : 1)
were added to the reaction mixture, and the aqueous layer was separated.
The aqueous layer was extracted with a mixture of CHCl3 and MeOH (9 : 1)
four times. The combined organic layer was dried (Na2SO4), concentrated
under reduced pressure, and chromatographed on silica gel (CHCl3 :
MeOHꢄ30 : 1) to yield (ꢁ)-3e (4.68 g, 96% yield) as a solid. mp 112—
116 °C. 1H-NMR (300 MHz, CDCl3) d: 1.79 (1H, dd, Jꢄ2.6, 3.4 Hz), 1.93—
2.29 (5H, m), 2.50—2.55 (1H, m), 2.82 (3H, d, Jꢄ4.8 Hz), 6.14 (1H, s).
HR-ES-MS m/z: 152.0704 [Calcd for C8H10NO2: 152.0712 (Mꢀꢂ1)].
(1SR,5RS,6SR)-2-Oxobicyclo[3.1.0]hex-3-ene-6-carboxlic Acid Di-
methylamide ((ꢁ)-4f) Compound (ꢁ)-3f (3.90 g, 23.3 mol) was reacted
in a similar manner to preparation of (ꢁ)-4a from (ꢁ)-3a and then purified
on silica gel chromatography to yield (ꢁ)-4f (1.57 g, 37% yield) as a color-
1
less oil. H-NMR (200 MHz, CDCl3) d: 2.40 (1H, t, Jꢄ2.9 Hz), 2.58—2.63
(1H, m), 2.95 (3H, s), 2.97—3.08 (1H, m), 3.14 (3H, s), 5.75 (1H, d,
Jꢄ5.7 Hz), 7.64 (1H, dd, Jꢄ2.6, 5.7 Hz). HR-CI-MS m/z: 166.0856 [Calcd

January 2007
41
for C9H12NO2: 166.0868 (Mꢀꢀ1)].
and chromatographed on silica gel (hexane : AcOEtꢄ6 : 1—1 : 1—1 : 2) to
(1SR,3RS,4RS,5RS,6SR)-3,4-Epoxy-2-oxobicyclo[3.1.0]hexane-6-car- yield (ꢁ)-6b (1.01 g, 35% yield) and (ꢁ)-7 (490 mg, 17% yield) as colorless
boxylic Acid Ethyl Ester ((ꢁ)-5a) Aqueous 70% tert-butyl hydroperox-
ide (TBHP) (289 g, 2.25 mol) and 40% benzyltrimethylammonium hydrox-
ide (Triton B) in water (16.8 g, 40.2 mmol) was added to a solution of (ꢁ)-
4a (220 g, 1.32 mol) in toluene (1320 ml) with ice-cooling, and the reaction
mixture was stirred for 14 h at room temperature. 2 M aqueous Na2S2O3
(125 ml) was added and the mixture was stirred for 2 h. The resulting precip-
oil.
(ꢁ)-6b: 1H-NMR (300 MHz, CDCl3) d: 1.24 (3H, d, Jꢄ6.2 Hz), 1.26 (3H,
d, Jꢄ6.2 Hz), 2.45 (1H, t, Jꢄ2.8 Hz), 2.55—2.59 (1H, m), 2.77—2.82 (1H,
m), 4.96—5.04 (1H, m), 6.89—6.91 (1H, m). HR-CI-MS m/z: 199.0785
[Calcd for C10H12O3 F: 199.0770 (Mꢀꢂ1)].
(ꢁ)-7: 1H-NMR (200 MHz, CDCl3) d: 1.72—2.00 (1H, s), 2.52—2.64
itate was filtrated and washed with toluene (80 ml) and water (650 ml) to (2H, m), 2.80—2.88 (1H, m), 3.81—3.88 (2H, m), 4.24—4.28 (2H, m),
yield (ꢁ)-5a (182 g, 75% yield) as a colorless solid.
6.90—6.93 (1H, m). HR-CI-MS m/z: 201.0588 [Calcd for C9H10O4 F:
The organic layer of filtrate was separated. The aqueous layer was ex- 201.0563 (Mꢀꢂ1)].
tracted with AcOEt. The combined organic layer was washed with saturated
brine, dried (Na2SO4), concentrated under reduced pressure to yield solid
(80 g). A suspension of the obtained solid in isopropyl ether (240 ml) was
stirred for 2 h at room temperature then was stirred for 2 h with ice-cooling.
(1SR,5RS,6SR)-3-Fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic
Acid 2,4-Dimethyl-3-pentyl Ester ((ꢁ)-6c) Compound (ꢁ)-6c (570 mg,
53% yield) was obtained, as described for (ꢁ)-6b, from (ꢁ)-5c (1.06 g,
1
4.20 mmol) as a colorless oil. H-NMR (200 MHz, CDCl3) d: 0.84—0.90
The solid was filtrated to give (ꢁ)-5a (41 g, 17% yield) as a colorless solid.
(12H, m), 1.83—1.96 (2H, m), 2.51—2.62 (2H, m), 2.77—2.85 (1H, m),
1
mp 100—105 °C. H-NMR (200 MHz, CDCl3) d: 1.28 (3H, t, Jꢄ7.0 Hz), 4.59 (1H, t, Jꢄ6.2 Hz), 6.92—6.94 (1H, m). HR-ES-MS m/z: 253.1230
2.09 (1H, t, Jꢄ3.1 Hz), 2.21 (1H, ddt, Jꢄ1.1, 2.4, 5.3 Hz), 2.93—2.98 (1H, [Calcd for C14H18O3F: 253.1240 (Mꢀꢂ1)].
m), 3.25 (1H, dt, Jꢄ1.1, 2.4 Hz), 4.00 (1H, t, Jꢄ2.4 Hz), 4.17 (2H, q,
Jꢄ7.0 Hz). 13C-NMR (126 MHz, CDCl3) d: 14.1, 28.9, 29.8, 30.4, 50.5, Acid 2,4-Dimethylcyclohexyl Ester ((ꢁ)-6d) Compound (ꢁ)-6d (453
56.3, 61.7, 168.1, 200.5. IR (KBr) cmꢂ1: 1737, 1721, 902. CI-MS m/z: 183
mg, 58% yield) was obtained, as described for (ꢁ)-6b, from (ꢁ)-5d (780
(Mꢀꢀ1). Anal. Calcd for C9H10O4: C, 59.34; H, 5.53. Found: C, 59.26; H: mg, 2.95 mmol) as a colorless oil. H-NMR (300 MHz, CDCl3) d: 0.81—
5.47. 0.92 (6H, m), 1.05—2.31 (8H, m), 2.51—2.64 (2H, m), 2.79—2.84 (1H, m),
(1SR,5RS,6SR)-3-Fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic
1
(1SR,3RS,4RS,5RS,6SR)-3,4-Epoxy-2-oxobicyclo[3.1.0]hexane-6-car- 4.02—5.03 (1H, m), 6.91—6.94 (1H, m). HR-CI-MS m/z: 267.1380 [Calcd
boxylic Acid Isopropyl Ester ((ꢁ)-5b) Compound (ꢁ)-4b (2.80 g, 15.5 for C15H20O3 F: 267.1396 (Mꢀꢀ1)].
mmol) was reacted in a similar manner to preparation of (ꢁ)-5a from (ꢁ)-
4a and then purified on silica gel chromatography to yield (ꢁ)-5b (2.42 g,
(1SR,5RS,6SR)-3-Fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic
Acid Methylamide ((ꢁ)-6e) Compound (ꢁ)-6e (573 mg, 58% yield) was
79% yield) as a colorless solid. mp 44—46 °C. 1H-NMR (300 MHz, CDCl3) obtained, as described for (ꢁ)-6b, from (ꢁ)-5e (980 mg, 5.86 mmol) as a
d: 1.24 (3H, d, Jꢄ6.2 Hz), 1.25 (3H, d, Jꢄ6.2 Hz), 2.06 (1H, t, Jꢄ3.1 Hz),
2.18—2.23 (1H, m), 2.93—2.96 (1H, m), 3.23—3.25 (1H, m), 4.00 (1H, t, 2.63 (1H, m), 2.83 (3H, d, Jꢄ5.1 Hz), 2.85—2.89 (1H, m), 5.85 (1H, s),
colorless oil. 1H-NMR (200 MHz, CDCl3) d: 2.24 (1H, t, Jꢄ2.9 Hz), 2.56—
Jꢄ2.4 Hz), 4.94—5.07 (1H, m). HR-CI-MS m/z: 197.0802 [Calcd for
6.90 (1H, dt, Jꢄ1.3, 2.9 Hz). HR-ES-MS m/z: 168.0459 [Calcd for
C10H13O4: 197.0814 (Mꢀꢀ1)].
C8H7NO2F: 168.0461 (Mꢀꢂ1)].
(1SR,3RS,4RS,5RS,6SR)-3,4-Epoxy-2-oxobicyclo[3.1.0]hexane-6-car-
boxylic Acid 2,4-Dimethyl-3-pentyl Ester ((ꢁ)-5c) Compound (ꢁ)-4c
(4.08 g, 17.3 mmol) was reacted in a similar manner to preparation of (ꢁ)-5a
from (ꢁ)-4a and then purified on silica gel chromatography to yield (ꢁ)-5c
(1SR,5RS,6SR)-3-Fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic
Acid Dimethylamide ((ꢁ)-6f) Compound (ꢁ)-6f (840 mg, 50% yield)
was obtained, as described for (ꢁ)-6b, from (ꢁ)-5f (1.68 g, 9.27 mmol) as a
1
colorless oil. H-NMR (200 MHz, CDCl3) d: 2.56—2.64 (2H, m), 2.88—
(3.46 g, 80% yield) as a colorless oil. 1H-NMR (200 MHz, CDCl3) d: 0.83— 2.94 (1H, m), 2.96 (3H, s), 3.15 (3H, s), 6.92 (1H, dt, Jꢄ1.3, 2.9 Hz). HR-
0.90 (12H, m), 1.86—1.96 (2H, m), 2.14 (1H, t, Jꢄ3.1 Hz), 2.19—2.25 (1H, ES-MS m/z: 182.0603 [Calcd for C9H9NO2F: 182.0617(Mꢀꢂ1)].
m), 2.94—2.99 (1H, m), 3.24—3.26 (1H, m), 4.03 (1H, t, Jꢄ2.3 Hz), 4.60
(1SR,3SR,5RS,6SR)-3-Fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic
(1H, t, Jꢄ6.2 Hz). 13C-NMR (126 MHz, CDCl3) d: 17.2, 19.5, 28.7, 29.3, Acid Isopropyl Ester ((ꢁ)-8b) A mixture of (ꢁ)-6b (660 mg, 3.33 mmol)
29.9, 30.3, 50.6, 56.4, 84.5, 168.1, 200.5. IR (neat) cmꢂ1: 2968, 1745, 1726, and 5% Pd–C (66.0 mg) in EtOH (6.0 ml) was stirred under a hydrogen
895. HR-CI-MS m/z: 253.1429 [Calcd for C14H21O4: 253.1440 (Mꢀꢀ1)].
atmosphere at room temperature for 12 h. Filtration through Celite® pad,
(1SR,3RS,4RS,5RS,6SR)-3,4-Epoxy-2-oxobicyclo[3.1.0]hexane-6-car- concentration under reduced pressure, and chromatographed on silica gel
boxylic Acid 2,4-Dimethylcyclohexyl Ester ((ꢁ)-5d) Compound (ꢁ)-4d
(3.80 g, 15.3 mmol) was reacted in a similar manner to preparation of (ꢁ)-5a
from (ꢁ)-4a and then purified on silica gel chromatography to yield (ꢁ)-5d
(hexane : AcOEtꢄ6 : 1) yielded (ꢁ)-8b (398 mg, 60% yield) as a colorless
oil. 1H-NMR (300 MHz, CDCl3) d: 1.25 (3H, d, Jꢄ6.2 Hz), 1.26 (3H, d,
Jꢄ6.2 Hz), 1.96—2.64 (5H, m), 4.52 (1H, dd, Jꢄ7.6, 50 Hz), 5.02 (1H, m).
(3.46 g, 80% yield) as a colorless oil. 1H-NMR (200 MHz, CDCl3) d: 0.80— HR-ES-MS m/z: 199.0743 [Calcd for C10H12O3F: 199.0770 (Mꢀꢂ1)].
0.92 (6H, m), 1.03—2.60 (8H, m), 2.10—2.27 (1H, m), 2.95—2.99 (1H, m),
3.25—3.27 (1H, m), 4.02—4.05 (1H, m), 4.27—5.04 (1H, m). HR-CI-MS Acid 2,4-Dimethyl-3-pentyl Ester ((ꢁ)-8c) Compound (ꢁ)-8c (469 mg,
m/z: 265.1447 [Calcd for C15H21O4: 265.1440 (Mꢀꢀ1)].
86% yield) was obtained, as described for (ꢁ)-8b, from (ꢁ)-6c (540 mg,
(1SR,3RS,4RS,5RS,6SR)-3,4-Epoxy-2-oxobicyclo[3.1.0]hexane-6-car- 2.12 mmol) as a colorless oil. H-NMR (200 MHz, CDCl3) d: 0.85—0.91
boxylic Acid Methylamide ((ꢁ)-5e) Compound (ꢁ)-4e (1.50 g, 9.92 (12H, m), 1.84—2.05 (2H, m), 2.19—2.60 (5H, m), 4.38—4.67 (2H, m).
(1SR,3SR,5RS,6SR)-3-Fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic
1
mmol) was reacted in a similar manner to preparation of (ꢁ)-5a from (ꢁ)-
4a and then purified on silica gel chromatography to yield (ꢁ)-5e (1.04 g,
13C-NMR (126 MHz, CDCl3) d: 17.3 (s), 19.6 (s), 26.2 (s), 27.9 (s), 29.5 (s),
30.7 (d, Jꢄ21.2 Hz), 34.0 (s), 84.3 (s), 88.7 (d, Jꢄ182.0 Hz), 169.6 (s),
63% yield) as a solid. mp 156—159 °C. 1H-NMR (200 MHz, CDCl3) d: 1.83 204.2 (d, Jꢄ12.5 Hz). 19F-NMR (470 MHz, DMSO-d6) d: ꢂ174.0. IR (neat)
(1H, t, Jꢄ3.0 Hz), 2.18 (1H, ddt, Jꢄ1.1, 2.6, 5.2 Hz), 2.84 (3H, d, cmꢂ1: 2968, 1750, 1728. HR-CI-MS m/z: 257.1556 [Calcd for C14H22O3F:
Jꢄ4.8 Hz), 2.97—3.02 (1H, m), 3.22 (1H, dt, Jꢄ1.1, 2.4 Hz), 3.98 (1H, t,
Jꢄ2.4 Hz), 5.79 (1H, s). HR-ES-MS m/z: 166.0494 [Calcd for C8H8NO3:
166.0504 (Mꢀꢂ1)].
257.1553, (Mꢀꢀ1)].
(1SR,3SR,5RS,6SR)-3-Fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic
Acid 2,4-Dimethylcyclohexyl Ester ((ꢁ)-8d) Compound (ꢁ)-8d (890
(1SR,3RS,4RS,5RS,6SR)-3,4-Epoxy-2-oxobicyclo[3.1.0]hexane-6-car- mg, 79% yield) was obtained, as described for (ꢁ)-8b, from (ꢁ)-6d (1.11 g,
1
boxylic Acid Dimethylamide ((ꢁ)-5f) Compound (ꢁ)-4f (2.71 g,
4.17 mmol) as a colorless oil. H-NMR (300 MHz, CDCl3) d: 0.80—0.94
16.4 mmol) was reacted in a similar manner to preparation of (ꢁ)-5a from (6H, m), 1.02—2.66 (13H, m), 4.00—5.05 (2H, m). HR-ES-MS m/z:
(ꢁ)-4a and then purified on silica gel chromatography to yield (ꢁ)-5f 267.1384 [Calcd for C15H20O3F: 267.1396 (Mꢀꢂ1)].
(1.88 g, 63% yield) as a solid. mp 112—118 °C. 1H-NMR (300 MHz,
(1SR,2SR,3SR,5RS,6SR)-2-Spiro-5ꢂ-hydantoin-3-fluorobicyclo[3.1.0]-
CDCl3) d: 2.13—2.16 (1H, m), 2.24 (1H, t, Jꢄ3.1 Hz), 2.97 (3H, s), 3.04— hexane-6-carboxylic Acid 2,4-Dimethyl-3-pentyl Ester ((ꢁ)-14) A mix-
3.07 (1H, m), 3.15 (3H, s), 3.24—3.26 (1H, m), 3.99 (1H, t, Jꢄ2.3 Hz). HR-
ture of (ꢁ)-8c (339 g, 1.32 mol), ammonium carbonate (318 g, 3.31 mol),
and potassium cyanide (94.6 g, 1.45 mol) in a mixture of EtOH (850 ml) and
EI-MS m/z: 181.0732 [Calcd for C9H11NO3: 181.0739 (Mꢀ)].
(1SR,5RS,6SR)-3-Fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic water (570 ml) was stirred at 36 °C for 2.5 d. Water (1130 ml) was added to
Acid Isopropyl Ester ((ꢁ)-6b) and (1SR,5RS,6SR)-3-Fluoro-2-oxobicy- the reaction mixture and the mixture was stirred for 3 h with ice-cooling.
clo[3.1.0]hex-3-ene-6-carboxylic Acid 2-Hydroxyethyl Ester ((ꢁ)-7)
mixture of (ꢁ)-5b (2.85 g, 14.5 mmol) and KF·HF (11.3 g, 145 mmol) in
ethylene glycol (42 ml) was stirred at 130 °C for 2 h under a nitrogen atmo-
A
The resulting precipitate was filtered and the precipitate was washed with a
mixture of EtOH (300 ml) and water (600 ml) and then water (1250 ml) to
yield (ꢁ)-14 (303 g, 70% yield). 2 M NaOH (200 ml) was added to the com-
sphere. The reaction mixture was poured onto ice and extracted with CHCl3. bined filtrate, and the mixture was concentrated under reduced pressure for
The organic layer was dried (MgSO4), concentrated under reduced pressure, removing EtOH. The residue was extracted with AcOEt (1000 ml, 500 ml).

42
Vol. 55, No. 1
The combined extract was washed with saturated brine (500 ml), dried
(Na2SO4), concentrated under reduced pressure, and recrystallized from iso-
propanol (240 ml) to yield (ꢁ)-14 (19.8 g, 5% yield) as a colorless solid. mp
(1SR,3SR,5RS,6SR)-3-Fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic
Acid 2,4-Dimethyl-3-pentyl Ester ((ꢁ)-8c) A suspension of (ꢁ)-6c and
5% Pd/C (13.0 g) in EtOH (700 ml) was stirred under a hydrogen atmo-
sphere for 16 h at room temperature. The mixture was filtered through
1
218—220 °C. H-NMR (200 MHz, CDCl3) d: 0.86 (6H, d, Jꢄ6.8 Hz), 0.88
(6H, d, Jꢄ6.8 Hz), 1.82—1.99 (2H, m), 2.09 (1H, t, Jꢄ2.9 Hz), 2.20—2.78 Celite® pad and filtrate was concentrated under reduced pressure. The
(4H, m), 4.60 (1H, t, Jꢄ6.2 Hz), 4.74 (1H, dd, Jꢄ5.5, 53 Hz), 5.62 (1H, s),
7.59 (1H, s). 13C-NMR (126 MHz, CDCl3) d: 17.3 (s), 19.6 (s), 23.3 (s),
25.3 (s), 29.5 (s), 31.7 (s), 34.6 (d, Jꢄ18.7 Hz), 72.5 (d, Jꢄ17.5 Hz), 83.6
residue was chromatographed (4000 ml, hexane : AcOEt ꢄ20 : 1—18 : 1) to
yield (ꢁ)-8c (106 g, 48% yield (from (ꢁ)-16)) as a yellow oil.
(1S,2S,3S,5R,6S)-2-Spiro-5ꢂ-hydantoin-3-fluorobicyclo[3.1.0]hexane-
(s), 93.4 (d, Jꢄ188.2 Hz), 155.4 (s), 171.2 (s), 172.4 (d, Jꢄ7.5 Hz). 19F- 6-carboxylic Acid ((ꢀ)-15) After (R)-(ꢀ)-1-phenylethylamine (95.6 g,
NMR (470 MHz, CDCl3) d: ꢂ176.2. IR (KBr) cmꢂ1: 3202, 2968, 1774, 0.789 mol) was added to the mixture of (ꢁ)-15 (180 g, 0.789 mol), acetone
1737, 1718. ES-MS m/z: 325 (Mꢀꢂ1). Anal. Calcd for C16H23FN2O4: C,
58.88; H, 7.10; N, 8.58; F, 5.82. Found: C, 59.19; H, 7.14; N, 8.28; F, 5.54.
(1SR,2SR,3SR,5RS,6SR)-2-Spiro-5ꢂ-hydantoin-3-fluorobicyclo[3.1.0]-
hexane-6-carboxylic Acid ((ꢁ)-15) A suspension of (ꢁ)-14 (223 g,
0.683 mol) in 48% HBr (1500 ml) was stirred for 60 h at 70 °C under a nitro-
gen atmosphere. After cooling, hexane (750 ml) was added to the mixture.
The mixture was stirred for 5 h with ice-cooling, and the resulting precipi-
(1600 ml) and water (1000 ml) at 55 °C, the mixture was left to stand at
room temperature for 16 h. The resulting crystal was filtered and washed
with acetone (500 ml) to yield (R)-(ꢀ)-1-phenylethylamine salt of (ꢀ)-15
(126 g, 46% yield).
The mixture of (R)-(ꢀ)-1-phenylethylamine salt (125 g, 0.358 mol) and
water (860 ml) was adjusted to pH 1.0 with 1 M HCl, and the mixture was
stirred at room temperature for 15 h. The resulting solid was collected by fil-
tate was filtered and washed with hexane (300 ml) and cold water (260 ml) to tration and washed with water (60 ml) to yield (ꢀ)-15 (71.3 g, 87% yield).
yield (ꢁ)-15 (128 g, 82% yield) as a yellow solid. mp 319 °C (decomposed).
mp 330 °C (decomposed). 1H-NMR (200 MHz, DMSO-d6) d: 1.85—2.44
1H-NMR (200 MHz, DMSO-d6) d: 1.85—2.44 (5H, m), 4.80 (1H, dd, (5H, m), 4.80 (1H, dd, Jꢄ5.3, 52 Hz), 8.44 (1H, m), 10.88 (1H, s), 12.30
Jꢄ5.3, 52 Hz), 8.44 (1H, m), 10.88 (1H, s), 12.30 (1H, s). 13C-NMR
(126 MHz, DMSO-d6) d: 23.3 (s), 25.3 (s), 31.9 (s), 34.7 (d, Jꢄ18.7 Hz),
72.1 (d, Jꢄ16.2 Hz), 93.7 (d, Jꢄ185.7 Hz), 156.9 (s), 173.2 (s), 174.6 (d,
(1H, s). 13C-NMR (126 MHz, DMSO-d6) d: 23.3 (s), 25.3 (s), 31.9 (s), 34.7
(d, Jꢄ18.7 Hz), 72.1 (d, Jꢄ16.2 Hz), 93.7 (d, Jꢄ185.7 Hz), 156.9 (s), 173.2
(s), 174.6 (d, Jꢄ8.7 Hz). 19F-NMR (470 MHz, DMSO-d6) d: ꢂ174.5. IR
(KBr) cmꢂ1: 3264, 3070, 1781, 1735, 1689. ES-MS m/z: 227 (Mꢀꢂ1). Anal.
Jꢄ8.7 Hz). 19F-NMR (470 MHz, DMSO-d6) d: ꢂ174.5. IR (KBr) cmꢂ1
:
3264, 3070, 1781, 1735, 1689. ES-MS m/z: 227 (Mꢀꢂ1). Anal. Calcd for Calcd for C8H9FN2O4: C, 47.37; H, 3.98; N, 12.28; F, 8.33. Found: C, 47.39;
C8H9FN2O4: C, 47.37; H, 3.98; N, 12.28; F, 8.33. Found: C, 47.51; H, 4.01; H, 3.94; N, 12.28; F, 8.37. [a]D22 ꢀ36.8° (cꢄ0.20, MeOH).
N, 12.01; F, 8.18.
(1S,2S,3S,5R,6S)-2-Amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicar-
(1SR,3RS,4RS,5RS,6SR)-3,4-Epoxy-2-oxobicyclo[3.1.0]hexane-6-car- boxylic Acid ((ꢀ)-1, MGS0008) A mixture of (ꢀ)-15 (45.0 g, 0.197 mol)
boxylic Acid ((ꢁ)-16) A mixture of (ꢁ)-5a (370 g, 2.03 mol) and 2 M
and 60% H2SO4 (495 ml) was stirred at 145 °C for 3.5 d. After cooling, the
reaction mixture was adjusted to pH 8 with 5 M NaOH. The mixture was
NaOH (1067 ml, 2.13 mol) was stirred for 15 min with ice-cooling and for
5.5 h at room temperature. A solution of KHSO4 (348 g, 2.56 mol) in water chromatographed on AG1-X8 anion exchange resin (Bio-Rad) (OHꢂ form)
(649 ml) was added to the mixture with ice-cooling. AcOEt (600 ml) was (6300 ml) [water 9000 ml, a mixture of THF and water (1 : 1) 4000 ml, water
added to the mixture, and the resulting inorganic precipitate was filtered off
and washed with AcOEt (600 ml). The aqueous layer of the filtrate was ex-
9000 ml and then 2 M aqueous AcOH 8800 ml].
The elution of 2 M aqueous AcOH was concentrated under reduced pres-
tracted with AcOEt (1000 ml, 3 times). The combined extract was dried sure to yield crude (ꢀ)-1 (38.9 g). The crude product was dissolved in hot
(Na2SO4), concentrated under reduced pressure to yield solid. A mixture of
the solid and IPE (940 ml) was refluxed for 0.5 h and stirred for 12 h at room
water (292 ml) and filtered through Celite® pad. The filtrate was concen-
trated (ca. 75 ml) and left to stand for 16 h at 10 °C. The resulting precipitate
temperature. The solid was filtered to yield (ꢁ)-16 (288 g, 92%) as a color-
was filtrated and washed with cold water (25 ml) to yield (ꢀ)-1 (29.5 g, 74%
1
1
less solid. mp 121—123 °C. H-NMR (200 MHz, DMSO-d6) d: 2.02—2.07 yield) as a colorless solid. mp 234 °C (decomposed). H-NMR (300 MHz,
(1H, m), 2.39 (1H, t, Jꢄ3.1 Hz), 2.88—2.93 (1H, m), 3.37 (1H, dt, Jꢄ1.2,
D2O) d: 2.02—2.04 (1H, m), 2.23—2.04 (3H, m), 2.56—2.78 (1H, m), 5.06
2.4 Hz), 4.18 (1H, t, Jꢄ2.4 Hz), 12.9 (1H, s). 13C-NMR (126 MHz, DMSO-
(1H, dd, Jꢄ5.8, 53 Hz). 13C-NMR (126 MHz, D2O) d: 24.2 (s), 27.6 (s), 32.8
d6) d: 28.5, 29.5, 30.6, 50.6, 56.4, 169.8, 201.8. IR (KBr) cmꢂ1: 3077, 1744, (s), 35.4 (d, Jꢄ18.7 Hz), 69.3 (d, Jꢄ13.7 Hz), 95.1 (d, Jꢄ184.5 Hz), 171.3
1702, 896. EI-MS m/z: 154 (Mꢀ). Anal. Calcd for C7H6O4: C, 54.55; H, (d, Jꢄ6.2 Hz), 175.66 (s). 19F-NMR (470 MHz, D2O) d: ꢂ174.8. IR (KBr)
3.92. Found: C, 54.30; H, 3.95.
cmꢂ1: 3017, 2698, 2081, 1699, 1651, 1620, 1603. ES-MS m/z: 202 (Mꢀꢂ1).
(1SR,3RS,4RS,5RS,6SR)-3,4-Epoxy-2-oxobicyclo[3.1.0]hexane-6-car- [a]D30 ꢀ53.1° (cꢄ0.91, H2O). Anal. Calcd for C8H10FNO4: C, 47.29; H,
boxylic Acid 2,4-Dimethyl-3-pentyl Ester ((ꢁ)-5c) A solution of dicy- 4.96; N, 6.89; F, 9.35. Found C, 47.29; H, 4.84; N, 6.94; F, 9.25.
clohexylcarbodiimide (DCC) (380 g, 1.84 mol) in CHCl3 (330 ml) was added
to a mixture of (ꢁ)-16 (258 g, 1.67 mol), 2,4-dimethyl-3-pentanol (234 g,
2.01 mol), dimethylaminopyridine (20.5 g, 167 mol) and CHCl3 (960 ml)
with ice-cooling. The reaction mixture was stirred for 2 h at room tempera-
Acknowledgments The authors wish to express their gratitude to the
Lead Generation Research Laboratory of the Taisho Pharmaceutical Medici-
nal Research Laboratories for their instrumental work in spectral data and
ture. AcOH (11.5 ml, 200 mmol) was added to the reaction mixture with ice- elemental analyses.
cooling, and the mixture was stirred for 2.5 h at room temperature. Hexane
(1500 ml) was added to the mixture, and the mixture was stirred for 15 h at
room temperature. The precipitate was filtered off and washed with
hexane : AcOEt (5 : 1, 2000 ml). The combined filtrate was concentrated
under reduced pressure. The mixture of the residue and hexane (850 ml) was
stirred for 1 h at room temperature and the resulting precipitate was filtered
off. The filtrate was concentrated under reduced pressure. Toluene (2100 ml)
and water (525 ml) were added to the residue, and the organic layer was sep-
arated. The organic layer was washed with 0.5 M HCl (500 ml), saturated
aqueous NaHCO3 (500 ml), dried (Na2SO4), and concentrated under reduced
pressure. Hexane (1200 ml) was added to the residue, and the resulting pre-
cipitate was filtered off. The filtrate was concentrated under reduced pres-
sure to yield crude (ꢁ)-5c (438 g) as a yellow oil. The residue was used for
next step without farther purification.
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