FIELD OF THE INVENTION
The present invention provides a compound of formula (I)

and the process for the preparing the same thereof.
BACKGROUND AND PRIOR ART
in the mammalian central nervous system (CNS), the transmission of
nerve impulses is controlled by the interaction between a
neurotransmitter that is released by a sending neuron, and a surface
receptor on a receiving neuron, which causes excitation of this
receiving neuron. L-Glutamate, which is the most abundant
neurotransmitter in the CNS, mediates the major excitatory pathway
in mammals, and is referred to as an excitatory amino acid (EAA) .
The receptors that respond to glutamate are called excitatory amino
acid receptors (EAA receptors). See Watkins & Evans, Ann. Rev.
Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman,
Ann. Rev. Pharmacol, Toxicol., 29, 365 (1989); Watkins, Krogsgaard-
Larsen, and Honore, Trans. Pham. Sci., 11, 25 (1990). The excitatory
amino acids are of great physiological importance, playing a role in
a variety of physiological processes, such as long-term potentiation
(learning and memory), the development of synaptic plasticity, motor
control, respiration, cardiovascular regulation, and sensory
perception.
Excitatory amino acid receptors are classified into two general, types.
Receptors that are directly couOled to the opening of cation channels
in the cell membrane of the neurons are termed "ionotropic". This type
or receptor has been subdivided into at least three subtypes, which arc
defined by the depolarizing actions of the selective agonists N-
rr.ethyl-D-aspartate (NDMA) , ti~amino-3-hyudroxy-5-methylisoxaz.o! e-4-
propionic acid (AMPA) , and kainic acid (KA) . The second genera.i ;.ype
of receptor is the G-protein or second messenger-1inkoa
"metabotropic" excitatory amino acid receptor. This second type is
coupled to multiple second messenger systems that 2ead to enhanced
or second messenger-linked "metabotropic" excitatory amino
acid receptor. This second type is coupled to multiple
second messenger systems that lead to enhanced
phosphoinositide hydrolysis, activation of phospholipase D
or C, increases or decreases in c-AMP formation, and changes
in ion channel function. Schoepp and Conn, Trends in
Pharmacol. Sci., 14, 13 (1993). Both types of receptors
appear not only to mediate normal synaptic transmission
along excitatory pathways, but also participate in the
modification of synaptic connections during development and
throughout life. Schoepp, Bockaert, and Sladeczek, Trends
in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson,
Brain Research Reviews, 15, 41 (1990).
The excessive or inappropriate stimulation of
excitatory amino acid receptors leads to neuronal cell
damage or loss by way of a mechanism known as
excitotoxicity. This process has been suggested to mediate
neuronal degeneration in a variety of conditions. The
medical consequences of such neuronal degeneration makes the
abatement of these degenerative neurological processes an
important therapeutic goal.
The metabotropic glutamate receptors are a highly
heterogeneous family of glutamate receptors that are linked
to multiple second-messenger pathways. These receptors
function to modulate the presynaptic release of glutamate,
and the postsynaptic sensitivity of the neuronal cell to
glutamate excitation. Compounds which modulate the function
of these receptors, in particular agonists and antagonists
of glutamate, are useful for the treatment of acute and
chronic neurodegenerative conditions, and as antipsychotic,
anticonvulsant, analgesic, anxiolytic, antidepressant, and
anti-emetic agents.
International Patent Application Publication No. WO
96/0517_5^ discloses the compound 2-aminobicyclo [3 .1. 0] hexane-
2,6-dicarboxylic acid and its salts and esters as
metabotropic glutamate receptor agonists.
DETAILED DESCRIPTION
The present invention provides a compound of formula I

in which:
(a) R' represents fluoro, XOR!, XNR4R5, SOjH, tetrazol-5-yl, CN or
P03R^6 and R' represents hydrogen; or
(b> R: and R: each represents fluoro, or
(c) R and R" together represent =O, =N0R or =CR"R'; or
(d) One of R1 and R2 represents amino and the other represents
carboxyl; or
(e) R" and R'' represents N>, 275°C. FDMS: M+ + 1 = 202. Anal, calcd. for
C8HuNO5«0.25 H20: C, 46.72; H, 5.64; N, 6.81. Found: C,
46.68; H, 5.72; N, 6.59.
Example 2
(IS*,25*,5R*,6R*)-2-Amino-4-oxobicyclo[3.1.0]hexane-2,6-
dicarboxylic Acid

(a) (1S*,2S*,4S*,5R*,6R*) -Ethyl 2-(3'-benzyl-5'-spiro-
hydantoin)-4-hydroxybicyclo[3.1.0]hexane-6-carboxylate. To
a stirred solution of the product of Example 1, step (c)
(14.5 g, 78.7 mmol) in EtOH/H20 (2:1) (150 mL total volume)
was added NH2C02NH4 (18.42 g, 23 6 mmol) then KCN (7.68 g, 118
mmol). Upon complete addition, the reaction mixture was
warmed at 40°C for 2 days. The reaction mixture was
concentrated in vacuo, partitioned with EtOAc/lN HC1, and
brine. The mixture of hydantoins was extracted with EtOAc,
dried over MgS04, and concentrated. The crude hydantoins
were reconstituted in DMF (50 mL) and stirred at room
temperature as NaHCO., (16.85 g, 200 mmol) and then benzyl
bromide (12.6 g, 73.5 mmol) were consecutively added. The
reaction mixture was warmed at 100°C overnight. The
reaction mixture was diluted with EtOAc and partitioned with
0.5 N HC1. The hydantoins were extracted with EtOAC, washed
with H20 then brine, dried over MgS04, and purified via HPLC
(hexanes/EtOAc) to afford 5.14 g (19%, 14.9 mmol) of the
title compound. FDMS: M+ = 344. Anal, calcd. for C18H20N2O5:
C, 62.78; H, 5.85; N, 8.13. Found: C, 62.97; H, 5.97; N,
8.06.
(b) (IS*, 2S*, 5fl*,6i?*)-Ethyl 2- (3 ' -benzyl-5 ' -spirohydantoin) -
4-oxo-bicyclo-[3.1.0]hexane-6-carboxylate. A 0°C solution
of the product of step (a) (1.03 g, 3.0 mmol) in acetone (20
mL) was treated in one portion with Jones Reagent (~2M, 7.5
mL-Cr03, H2S04, H20) and stirred at room temperature for 2
hours. 2-Propanol (2 mL) was added to quench the oxidant.
The reaction mixture was then diluted with Et20, flashed
through a pad of celite and Si02, and concentrated to yield
0.9 0 g (88%, 2.6 mmol) of the title compound. FDMS: M+ =
342. Anal, calcd. for C1BH18N205: C, 63.15; H, 5.30; N, 8.18.
Found: C, 62.87; H, 5.56; N, 8.26.
(c) Following the method of Example 1(e), the product of
step (b) is hydrolyzed to afford the title compound.
Example 3
(IS*,2R*,4R*,55*,6S*)-2-Aminobicyclo[3.1.0]hexane-2,6-
dicarboxylic-4-phosphonic acid monohydrochloride monohydrate
(a) (IS*,4R*,5S*,6S*)-Ethyl 2-oxo-4-(diethyl)phosphono-
bicyclo[3.1.0]hexane-6-carboxylate. A mixture of the
product of Example 1(a) (1.6 g, 9.6 mmol), triethylphosphite
(2.0 g, 12.0 mmol) in 4.2 g of phenol was heated at 100°C
overnight. The resulting reaction mixture was purified
using HPLC (hexanes/EtOAc) to afford 2.7 g (92%, 8.9 mmol)
of the title compound. mp = 67 - 70°C. FDMS: M* + 1 = 305.
Anal, calcd. for CJ;]H2106P: C, 51.32; H, 6.96. Found: C,
51.11; H, 6.89.
(b) (IS*,2R*,4R*,5S*,6S*)-Ethyl 2-aminoacetyl-2-cyano-4-
(diethyl) phosphonobicyclo[3.1.0]-hexane-6-carboxylate. A
mixture of KCN (3.2 g, 49 mmol), NH.Cl (2.6 g, 49 mmol) and
Al203 (25 g) in CH3CN were sonicated under N, in a Branson
3200 ultrasonic bath for 1 hr. Then the product of step (a)
(1.5 g, 4.9 mmol) was added and sonicated for 72 hrs at
45°C. The reaction mixture was filtered through Celite* and
the filtrate was concentrated to dryness. The intermediate
amino nitrile so obtained was dissolved in CH2C12, cooled to
0°C, and treated with acetyl chloride (0.5 g, 6.4 mmol) and
N,N-diisopropylethylamine (0.8 g, 6.4 mmol). The reaction
was allowed to proceed at ambient temperature for 1 h, then
the mixture was partitioned between CH2C12 and H20. The
organic phase was separated, dried (MgSOj , filtered and
concentrated under reduced pressure. The crude products
were purified by chromatography (hexane/EtOAc). From this
was obtained 1.0 g (55%) ethyl-2-aminoacetyl-2-cyano-4-
diethylphosphonate bicyclo[3.1.0]hexane-6-carboxylate,
(isomer A) and 0.10 g (5%) of ethyl-2-aminoacetyl-2-cyano-4-
diethylphosphonatebicyclo[3.1.0]hexane-6-carboxylate (isomer
B). (isomer A): mp = 135 - 138°C. FDMS: M+ + 1 = 373.
Anal, calcd. for C16H25N206P: C, 51.61; H, 6.77; N, 7.52.
Found: C, 51.89; H, 6.78; N, 7.75.
(c) (15*,2i?*,4i?*,5S*, 6S*)-2-Aminobicyclo[3.1.0]hexane-2,6-
dicarboxylic-4-phosphonic acid monohydrochloride
monohydrate. The title compound was prepared by refluxing
the product of step (b) (isomer A) (0.08 g, 0.2 mmol) in 30
mL of 6N HC1 for 48 hours. The crude product was
concentrated and purified using an anion exchange column
eluted with IN HC1. Collected 0.06 g (99%, 0.2 mmol) of
the title compound. FDMS: M4 + 1 = 2 66. Anal, calcd. for
CeH12N07P • HC1» H20: C, 30.06; H, 4.73; N, 4.38. Found: C,
2 9.87; H, 4.36; N, 4.13.
Example 4
(IS*,25*,45*,5R*,6R*) 2-Amino-4-methoxybicyclo[3.1.0]hexane-
2,6-dicarboxylic acid

(a) (15*, 25*, 45*, 5R*, 6R*) -Diethyl 2-N-t-butyloxycarbonyl-
amino-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate. To a
stirred solution of the product from Example 1(c) (23.9 g,
130 mmol) in EtOH/H20 (1:1) (500 mL total volume) was added
(NHJ2C03 (30.4 g, 390 mmol) then KCM (12.7 g, 195 mmol).
Upon complete addition, the reaction mixture was warmed at
40°C until complete. The reaction mixture was cooled to
0°C, acidified to pH = 1 with concentrated HC1 and the
mixture of diastereomeric 5'-spirohydantoins extracted with
EtOAc. All organics were combined, washed with brine,
dried over MgS04 and concentrated under reduced pressure to
afford a 1:1 mixture of crude hydantoins. The mixture of
crude 5'-spirohydantoins (27.9 g, 110 mmol) was warmed under
reflux in 2N NaOH (275 mL) for 5 days until the reaction was
judged complete by TLC. The reaction mixture was cooled to
0°C/ acidified to pH = 1 with cone. HC1, and concentrated to
dryness in vacuo. The resulting solids were reconstituted
in 100% EtOH (500 mL), and chilled to 0°C. SOCl2 (120 g, 1
mol) was then added dropwise to the reaction mixture at a
rate to maintain reaction temperature at 10°C. Upon
complete addition the reaction was warmed at reflux
overnight. The reaction mixture was then concentrated in
vacuo and reconstituted in a 1:1 mixture of saturated
aqueous NaHC03:THF (500 mL) total volume. Boc20 (118 g, 550
mmol) was then added to the reaction mixture in one portion
and stirred at room temperature overnight. The reaction
mixture was then reduced in vacuo and the crude N-Boc
diethylesters extracted with EtOAc. All the organic extracts
were combined, washed with H20 then brine, dried over K2CO^,
and concentrated to yield 120 g of crude product. The two
diastereomers are isolated and purified via prep-HPLC (100%
hexanes to 50% EtOAc/hexanes) to yield 10.12 g (26%, 28
mmol) of the desired product as a foam. FDMS: M+ + 1 = 3 58.
Anal, calcd. for C]7H27N07: C, 57.13; H, 7.61; N, 3.92.
Found: C, 56.84; H, 7.64; N, 3.96.
(b) (15*,2S*,4S*,5R*,6R*)-Diethyl 2-N-t-butyloxycarbonyl-
amino-4-methoxybicyclo[3.1.0]hexane-2,6-dicarboxylate. To a
0°C solution of the product of step (a) (0.50 g, 1.4 mmol)
in THF (30 mL) was added NaH (0.07 g, 1.7 mmol) in one
portion followed by dropwise addition of methyl iodide (0.21
g, 1.5 mmol). The resulting reaction mixture was allowed to
warm to room temperature as it stirred overnight. The
reaction was diluted with H20 and the product extracted with
EtOAc. All organics were combined, washed with brine, dried
over K2C03, concentrated under reduced pressure and purified
by PC-TLC (10% EtOAc/hexanes to 90% EtOAc/hexanes) to
afford 0.12 g (0.32 mmol, 23 %) of the desired product.
FDMS: M+ + 1 = 372. Anal, calcd. for C19H29N07: C, 58.21; H,
7.87; N, 3.77. Found: C, 58.69; H, 7.52; N, 4.85.
(c) {IS*, 2S*AS*, 5R*, 6R*) -Diethyl 2-Amino-4-methoxy-
bicyclo[3.1.0]-hexane-2,6-dicarboxylate. A 0°C solution of
the product from step (b) in EtOAc (25 mL) was purged with
anhydrous HCl gas until the solution reached saturation.
The resulting reaction mixture was stirred at 0°C for 1 hour
and then concentrated to dryness under reduced pressure.
The solids were dissolved in saturated NaHC03 (aq) and the
product extracted with EtOAc. All organics were combined,
washed with brine, dried over K2C03, concentrated under
reduced pressure and purified by PC-TLC (10% EtOAc/hexanes
to 100% EtOAc) to afford 0.05 g (0.18 mmol, 61%) of the
desired product. FDMS: M+ + 1 = 271. :H NMR (CDC13) : S 1.25
(t, J = 7 Hz, 3H) , 1.29 (t, J = 7 Hz, 3H), 1.61 (t, J = 3
Hz, 1H), 1.80-1.95 (br m 3H), 2.17-2.20 (m, 1H), 2.46-2.50
(m, 2H), 3.27 (s, 3H), 3.85-3.87 (m, 1H), 4.15 (q, J= 7 Hz,
2H) , 4.24 (q, J = 7 Hz, 2H) . nC NMR (CDC13) : 5 13.96,
14.11, 20.82, 31.90, 33.96, 40.17, 56.00, 60.69, 61.26,
64.63, 82.14, 172.14, 174.85. Anal, calcd. for CJ3H2]N05: C,
57.55; H, 7.80; N, 5.16. Found: C, 56.04; H, 7.70; N, 5.81.
(d) {1S*,2S*,4S*,5R*, 6R*) -2-Amino-4-methoxybicyclo [3 .1.0]-
hexane-2,6-dicarboxylate. The product from step (c) (0.04
g, 0.11 mmol) was stirred in a 1:1 solution of IN NaOH/THF
(10 mL total volume) at room temperature overnight. The
reaction mixture was acidified to pH = 1 with 6N HCl and
concentrated to dryness. The resulting solids were
reconstituted in water at pH = 2, applied to Dowex®50X8-100
cation exchange resin, eluted with 10 % pyridine/H20 to
afford 0.012 g (37 %, 0.06 mmol) of the desired product, mp
= >275°C. FDMS: M+ + 1 = 216. 2H NMR (D20/KOD) : 5 1.08-
1.14 (m, 2H), 1.74-2.07 (m 3H), 3.05 (s, 3H), 3.65-3.75 (m,
1H) . Anal, calcd. for C,H13NO5-0.2 NaCl: C, 47.64; H, 5.78;
N, 6.17. Found: C, 47.75; H, 5.74; N, 7.49.
Example 5
(IS*,2S*,5R*,6R*) 2-Amino-4-oxobicyclo[3.1.0]hexane-2,6-
dicarboxylic acid

(a) (IS*,2S*,5R*,6R*)-Diethyl 2-N-fc-butyloxycarbonylamino-4-
oxobicyclo-[3.1.0]hexane-2,6-dicarboxylate. A solution of
the product from Example 4(a) (0.50 g, 1.4 mmol) in CH2C12
(15 mL) was stirred at room temperature as pyridinium
dichromate (1.60 g, 4.2 mmol) was added in one portion. The
resulting reaction mixture was stirred at room temperature
overnight. The reaction was diluted with EtOAc and filtered
through celite to remove chromium by-products. The filtrate
was concentrated in vacuo and purified via PC-TLC (10%
EtOAc/hexanes to 20% EtOAc/hexanes) to yield 0.49 g (1.38
mmol, 98%) of a white foam. FDMS: M+ + 1 = 356. Anal,
calcd. f or C,7H25N07: C, 57.46; H, 7.09; N, 3.94. Found: C,
57.60; H, 7.14; N, 4.03.
(b) {1S*,2S* ,5R*, 6R*) -2-Amino-4-oxobicyclo [3 .1. 0] hexane-2 , 6-
dicarboxylic acid. A 0°C solution of the product from step
(a) (0.37 g, 1.04 mmol) in EtOAc (30 mL) was purged with
anhydrous HCl gas until saturation occurred. The resulting
reaction mixture was stirred at 0°C for 1 hour then
concentrated to dryness in vacuo. The resulting solids were
reconstituted in 10 mL IN NaOH and stirred overnight. The
reaction mixture was adjusted to pH = 2 with 6N HC1,
applied to Dowex® 50X8-100 cation exchange resin, and the
product eluted with 10 % Pyridine/H20. The product was
obtained from a recrystallization from H20 to afford 0.06 g
(31%, 0.30 mmol) of the desired product, mp = dec > 210°C.
FDMS: M+ + 1 = 200. Anal, calcd. for C8H9N05: C, 48.25; H,
4.55; N, 7.03. Found: C, 48.19; H, 4.46; N, 7.16.
Example 6
(1S*,2S*,5R*,6R*) 2 -Amino-4-[anti]-
hydroximinobicyclo[3.1.0]hexane-2,6-dicarboxylic acid and
(IS*,2S*,5R*,6R*) 2-Amino-4-[syn] -
hydroximinobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

(a) (1S*,2S*,5R*,6R*)-Diethyl 2-Amino-4-oxobicyclo[3.1.0]-
hexane-2,6-dicarboxylate. A 0°C solution of the product
from Example 5(a) (0.37 g, 1.04 mmol) in EtOAc (30 mL) was
purged with anhydrous HC1 gas until saturation occurred.
The resulting reaction mixture was stirred at 0°C for 1
hour. The reaction mixture was diluted with saturated
aqueous NaHC03 and the product extracted with EtOAc. All
organics were combined, washed with brine, dried over K2COj
and concentrated in vacuo to yield the desired intermediate
(0.36 g, 1.4 mmol, 100%). FDMS: M+ + 1 = 256. Anal, calcd.
for C12H17NO5-0.2 H20: C, 55.68; H, 6.78; N, 5.41. Found: C,
55.47; H, 5.91; N, 5.24.
(b) (IS*,2S*,4R*; 6R*)-Diethyl 2-Amino-4-hydroximino-
bicyclo[3.1.0]hexane-2,6-dicarboxylate. Hydroxylamine
hydrochloride (0.15 g, 2.1 mmol) was added to a room
temperature solution of the product from step (a) (0.36 g,
1.4 mmol) and NaOAc (0.23 g, 2.8 mmol) in a 3:1 mixture of
EtOH/H20 (20 mL total volume) and heated at 80°C for 1 hour.
Aqueous NaHCO-, was added to the reaction mixture, the
product extracted with EtOAc, washed with brine, dried over
K2C03 and concentrated in vacuo to afford a 2:1 mixture of
the E and Z isomers. Purification by PC-TLC (10%
EtOAc/hexanes to 67% EtOAc/hexanes) afforded clean products.
anti-isomer: 0.18 g (0.67 mmol, 56%). FDMS: M+ + 1 = 271.
Anal, calcd. for C,2H18N205-0 .35 CH2C12: C, 49.44; H, 6.28; N,
9.34. Found: C, 49.62; H, 5.89; N, 9.39. syn-isomer: 0.09
g (0.33 mmol, 28 %). mp = 135 - 137°C. FDMS: M+ + 1 = 271.
Anal, calcd. For C12HieN205 • 0 .1 hexanes: C, 54.26; H, 7.01; N,
10.04. Found: C, 54.03; H, 6.71; N, 10.14.
(c) (IS*,2S*,5R*,6R*)-2-Amino-4-[anti]-hydroximinobicyclo-
[3.1.0]hexane-2,6-dicarboxylic acid. A solution of the
anti-oxime from step (b) (0.13 g, 0.48 mmol) was stirred at
room temperature in a 1:1 mixture of IN NaOH:THF (20 mL
total volume) for 4 days. The reaction mixture was then
diluted with H20 and the product washed with EtOAc (3X) to
remove organic impurities. The aqueous layer was adjusted
to pH - 10 with IN HC1 and concentrated in vacuo. The
solids were reconstituted in H20 and purified by anion-
exchange chromatography (Bio-Rad® AG1-X8: elution with 3N
AcOH). Recrystallization from H20/2-propanol (1:1) afforded
0.07 g (0.33 mmol, 68%) of the product, mp = dec > 2 60°C.
FDMS: M+ + 1 = 215. Anal, calcd. for CBH10N2O5-0 .15 H20: C,
44.30; H, 4.79; N, 12.91. Found: 'C, 44.53; H, 4.48; N,
12.51.
(d) (IS* ,2S* , 5R*, 6R*)-2-Amino-4-[syn]-hydroximinobicyclo-
[3.1.0]-hexane-2,6-dicarboxylic acid. Utilizing 0.085 g
(0.31 mmol) of the syn-oxime product from step (b), the
reaction conditions, work-up and isolation were identical
to those in step (c). Yield 0.04 g (0.19 mmol, 60%). mp =
dec > 250°C. FDMS: M+ + 1 = 215. Anal, calcd. for
C8H]0N2O,-0.15 NaCl: C, 43.10; H, 4.52; N, 12.57. Found: C,
43.46; H, 4.74; N, 11.75.
Example 7
(lS*,2i?*/4S*/ 5S* , 6S*) -2-Amino-4-fluorobicyclo[3 . l.Ojhexane-
2,6-dicarboxylic acid

(a) [1S*,2R*,45*,55*,65*)-Diethyl 2-N-fc-butyloxycarbonyl-
amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylate. To a
0°C solution of the product from Example 4(a) (0.50 g, 1.40
mmol) in CH2C12 (25 mL) was added diethylaminosulfur
trifluoride (DAST) in one portion. The resulting reaction
mixture was allowed to warm to room temperature as it
stirred overnight. The reaction was diluted with 10%
aqueous NaHCO^ and the product extracted with EtOAc. All
organics were combined, washed with brine, dried over K2C03
and purified via PC-TLC (10% EtOAc/hexanes to 20% EtOAc) to
afford 0.38 g (1.06 mmol, 74%) of the desired product as a
clear colorless oil. FDMS: M+ + 1 = 3 60. Anal, calcd.
for C17H26N06: C, 56.81; H, 7.29; N, 3.90. Found: C, 56.79;
H, 7.42; N, 4.11.
(b) (IS*,2R*,AS*,5S*,6S*)-Diethyl 2-Amino-4-fluorobicyclo-
[3.1.0]hexane-2,6-dicarboxylate. A 0°C solution of the
product from step (a) (0.33 g, 0.92 mmol) in EtOAc (30 mL)
was purged with anhydrous HC1 gas until saturation occurred.
The resulting reaction mixture was stirred at 0°C for 1
hour. The reaction mixture was diluted with saturated
aqueous NaHC03 and the product extracted with EtOAc. All
organics were combined, washed with brine, dried over K2C03
and concentrated in vacuo to afford 0.23 g (0.89 mmol, 96%)
of the desired product. FDMS: M+ + 1 = 260. Anal, calcd.
for C)2H17FN04: C, 55.59; H, 7.00; N, 5.40. Found: C,
55.56; H, 6.79; N, 5.21.
(c) (IS*,2R*, iS*, 5S*,6S*)-2-Amino-4-fluorobicyclo[3.1.0]-
hexane-2,6-dicarboxylic acid. A solution of the product
from step (b) (0.12 g, 0.46 mmol) in a 1:1 mixture of IN
NaOH:THF (20 mL total volume) was stirred at room
temperature overnight. The reaction mixture was then
adjusted to pH = 12 with 6N HC1 and purified via anion
exchange chromatography (Bio-Rad® AG1-X8 ion exchange resin.
3N acetic acid as eluent. Recrystallization from H20/2-
propanol (1:1) afforded 0.04 g (0.20 mmol, 49%) of the
desired product. mp = dec > 260°C. FDMS: M+ + 1 = 204.
Anal, calcd. for C8H10FNCVO. 45 NaCl: C, 41.87; H, 4.39; N,
6.10. Found: C, 41.91; H, 4.00; N, 5.76.
Example 8
(15*,2S*,4R*,5R*,65*) 2 , 4-Diaminobicyclo[3.1.0]hexane-2,6-
dicarboxylic acid

(a) (15*,25*,45*, 5R*,6R*)-Diethyl 2-N-t-butyloxycarbonyl-
amino-4-(p-toluenesulfonyloxy)bicyclo[3.1.0]hexane-2,6-
dicarboxylate. p-Toluenesulfonyl chloride (5.3 g, 28 mmol)
was added to a solution of the product of Example 4(a) (5.0
g, 14 mmol) in pyridine (25 mL) and the resulting reaction
mixture stirred at room temperature overnight. The reaction
mixture was diluted with EtOAc (lOOmL) and washed with
saturated aqueous CuS04 to remove the pyridine. The
organics were washed with brine, dried over MgS04 and
concentrated under reduced pressure to afford the crude
product which was purified by Si02 chromatography (HPLC: 10%
EtOAc/hexanes to 50% EtOAc/hexanes) to obtain 6.55 g (91%,
12.8 mmol) of the desired product as a white foam. FDMS: M+
+ 1 = 512. Anal, calcd. for C24H33N09S: C, 56.35; H, 6.50;
N, 2.74. Found: C, 56.48; H, 6.44; N, 2.60.
(b) {IS*,2S*,AR*,5K*,65*)-Diethyl 2-N-t-butyloxy-
carbonylamino-4-azidobicyclo[3.1.0]hexane-2,6-dicarboxylate.
A solution of the product from step (a) (6.35 g, 12.4 mmol)
and NaNj (2.42g, 37.2 mmol) in DMSO (15 mL) was warmed at
35°C for 3 days. The reaction mixture was diluted with H20
and the product extracted with EtOAc. All organics were
combined, washed with brine, dried over MgSO,, and
concentrated under reduced pressure to yield the crude azide
which was purified by vacuum filtration through Si02 (2 0%
EtOAc/hexanes to 50% EtOAc/hexanes) to afford 4.68 g (98%,
12.2 mmol) of the desired product as a waxy solid. FDMS: M+
+ 1 = 512. Anal, calcd. for C17H26N4O6-0 .1 hexanes: C, 54.06;
H, 7.06; N, 14.33. Found: C, 53.94; H, 6.88; N, 14.30.
(c) (IS*, 25*, 4i?*,5i?*,6S*) -Diethyl 2-N-fc-butyloxycarbonyl-4-
aminobicyclo[3.1.0]hexane-2,6-dicarboxylate. Triphenyl-
phosphine (2.90 g, 11 mmol) was added in one portion to a
solution of the product of step (b) (3.5 g, 9.2 mmol) in
THF/H20 (5:1) and stirred at room temperature overnight.
The reaction mixture was diluted with EtOAc and washed with
0.5N NaOH (3X). The organics were combined, washed with H20
then brine, dried over K2C03, concentrated under reduced
pressure and purified by Si02 chromatography (HPLC: Si02
(10% EtOAc/hexanes to 50% EtOAc/hexanes) to afford 2.03 g
(62 %, 5.7 mmol) of the desired product as a foam. FDMS: M+
+ 1 = 357. Anal, calcd. for C17H2eN206: C, 57.30; H, 7.92; N,
7.86. Found: C, 57.02; H, 7.73; N, 7.72.
(d) {IS* ,2S* ,4,R*,5R* ,6S*) 2,4-Diaminobicyclo[3.l.OJhexane-
2,6-dicarboxylic acid. The product from step (c) was warmed
under reflux in IN HC1 overnight. The reaction mixture was
adjusted to pH = 2 with IN NaOH and purified by cation
exchange chromatography (Dowex 50X8-100: 10%
Pyridine/H20) . The resulting product was recrystallized
from 2-propanol/H20 (1:1) to yield 0.09 g (45%, 0.45 mmol)
of the desired product as a white solid, mp = > 275 °C.
FDMS: M+ + 1 = 201. Anal, calcd. for C8H12N2O4-0 .5 H20: C,
45.93; H, 6.26; N, 13.39. Found: C, 45.66; H, 7.45; N,
13.32.
Example 9
(1S*,2S*,4R*,5R* , 65*) 2-Amino-4-azidobicyclo[3.1.OJhexane-
2 , 6-tricarboxylic acid

A solution of the product from Example 8{b) (0.25 g, 0.65
mmol), in EtOAc (30 mL) was chilled to 0°C and purged with
anhydrous HC1 gas until the solution reached saturation. The
reaction mixture was stirred at 0°C for two hours,
concentrated to dryness, and the resulting solid stirred in
a 1:1 mixture of IN NaOH:THF (20 mL total volume) at room
temperature overnight. The THF was removed under reduced
pressure, the aqueous mixture adjusted to pH = 12 with IN
HC1, and purified by anion exchange chromatography (Bio-
Rad® AG1-X8: acetate form converted to hydroxide form,
elute with 3N acetic acid) to yield 0.10 g (0.44 mmol, 68%)
of the desired product, mp = dec > 270°C. FDMS: M+ + 1 =
227. Anal, calcd. for C8H]0N,O4-0.2 AcOH: C, 42.3 6; H, 4.57;
N, 23.52. Found: C, 41.96; H, 4.54; N, 23.55.
Example 10
(IS* ,2S* ,4R* ,5R*.6S*) 2-Amino-4-acetamidobicyclo[3.1.0]-
hexane-2,6-dicarboxylic acid

2
(a) (IS*,2S*,4R*,5R*,6S*)-Diethyl 2-N-fc-butyloxy-
carbonylamino-4-acetamidobicyclo[3.1.0]hexane-2,6-
dicarboxylate. Acetyl chloride (0.09 g, 1.1 mmol) was added
by dropwise addition to a 0°C solution of the product from
Example 8(c) (0.35 g, 1.0 mmol) and triethylamine (0.20 g,
2.0 mmol) in CH2C12 (20 mL), and the resulting reaction
mixture allowed to warm to room temperature as it stirred
overnight. The reaction mixture was diluted with Et20,
washed with aqueous NaHSO, then brine, dried over MgS04 and
concentrated in vacuo to yield the crude acetamide which was
purified by PC-TLC (10% EtOAc/hexanes to 67% EtOAc/hexanes)
to afford 0.35 g (88%, 0.88 mmol) of the desired product as
a white solid. mp = dec 85 - 95°C. FDMS: M+ + 1 = 399.
Anal, calcd. for C19HJ0N2O7: C, 57.27; H, 7.58; N, 7.03.
Found: C, 57.41; H, 7.28; N, 6.94.
(b) (IS*,2S*,4R*,5R*,65*)-2-Amino-4-acetamidobicyclo[3.1.0]-
hexane-2,6-dicarboxylic acid. A solution of the product from
step (a) (0.30 g, 0.75 mmol), in EtOAc (30 mL) was chilled
to 0°C and purged with anhydrous HC1 gas until the solution
reached saturation. The reaction mixture was stirred at 0°C
for two hours, concentrated to dryness, and the resulting
solid stirred in a 1:1 mixture of IN NaOH-.THF (20 mL total
volume) at room temperature overnight. The THF was removed
under reduced pressure, the aqueous mixture adjusted to pH =
2 with IN HC1, and purified by cation exchange
chromatography (Dowex® 50X8-100, elute with 10%
pyridine/H20) . Recrystallization from H20/2-propanol (1:1)
afforded 0.09 g (0.37 mmol, 50 %) of the desired product.
mp = > 275°C. FDMS: M+ + 1 = 243. Anal, calcd. for
C10H]4N2O5-0 .3 NaCl: C, 46.24; H, 5.43; N, 10.78. Found: C,
45.93; H, 5.50; N, 10.88.
Example 11
(IS*,2S*,4R*,5R*,6S*) 2-Amino-4-
benzoylaminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

(a) {IS*,2S*,AR*,5R*,6S*)-Diethyl 2-N-t-butyloxycarbonyl-
amino-4-benzoylaminobicyclo[3.1.0]hexane-2,6-dicarboxylate.
Benzoyl chloride (0.16 g, 1.1 mmol) was added by dropwise
addition to a 0°C solution of the product from Example 8(c)
(0.35 g, 1.0 mmol) and triethylamine (0.20 g, 2.0 mmol) in
CH2C12 (20 mL), and the resulting reaction mixture allowed to
warm to room temperature as it stirred overnight. The
reaction mixture was diluted with Et20, washed with aqueous
NaHS04 then brine, dried over MgS04 and concentrated in vacuo
to yield the crude amide which was purified by PC-TLC (10%
EtOAc/hexanes to 67% EtOAc/hexanes) to afford 0.31 g (67%,
0.67 mmol) of the desired product as a white foam. FDMS: M+
+ 1 = 461. Anal, calcd. for C24H32N207: C, 62.59; H, 7.00; N,
6.08. Found: C, 62.75; H, 6.70; N, 5.99.
(b) {IS*,2S*,4R*,5R*, 6S*) -2-Amino-4-benzoylaminobicyclo-
[3.1.0]hexane-2,6-dicarboxylic acid. A solution of the
product from step (a) (0.30 g, 0.75 mmol), in EtOAc (30 mL)
was chilled to 0°C and purged with anhydrous HC1 gas until
the solution reached saturation. The reaction mixture was
stirred at 0°C for two hours, concentrated to dryness, and
the resulting solid stirred in a 1:1 mixture of IN NaOH:THF
(20 mL total volume) at room temperature overnight. The THF
was removed under reduced pressure, the aqueous mixture
adjusted to pH = 2 with IN HC1, and purified by cation
exchange chromatography (Dowex 50X8-100, elute with 10%
pyridine/H20) . Recrystallization from H20/2-propanol (1:1)
afforded 0.095 g (0.31 mmol, 58 %) of the desired product.
mp = dec > 275°C. FDMS: M+ + 1 = 305. Anal, calcd. for
C15H16N2O5-0.3 2-propanol: C, 59.25? H, 5.75; N, 8.69. Found:
C, 59.50; H, 5.65; N, 8.32.
Example 12
(IS* ,2S* ,4R*, 5R*, 6S*) 2-Amino-4-(methanesulfonylamino)-
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid

(a) (IS*,2S*,4R*,5R*,6S*)-Diethyl 2-N-t-butyloxycarbonyl-
amino-4-(methanesulfonylamino)bicyclo[3.1.0]hexane-2,6-
dicarboxylate. Methanesulfonyl chloride (0.13 g, 1.1 mmol)
was added by dropwise addition to a 0°C solution of the
product from Example 8(c) (0.35 g, 1.0 mmol) and
triethylamine (0.21 g, 2.0 mmol) in CH2C12 (25 mL), and the
resulting reaction mixture stirred at 0°C for 1 hour. The
reaction mixture was diluted with EtOAc, washed with aqueous
NaHS04 then brine, dried over MgS04 and concentrated in vacuo
to yield the crude methylsulfonamide which was purified by
PC-TLC (10% EtOAc/hexanes to 67% EtOAc/hexanes) to afford
0.44 g (99%, 1.0 mmol) of the desired product as a white
foam. FDMS: M+ + 1 = 435. Anal, calcd. for C18H30N2O8S: C,
49.76; H, 6.96; N, 6.45; S, 7.38. Found: C, 50.04; H, 6.68;
N, 6.21; S, 7.38.
(b) (IS*,2S*,AR*,5R*,65*)-2-Amino-4-(methanesulfonylamino)-
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid. A solution of
the product from step (a) (0.40 g, 0.92 mmol), in EtOAc (3 0
mL) was chilled to 0°C and purged with anhydrous HC1 gas
until the solution reached saturation. The reaction mixture
was stirred at 0°C for two hours, concentrated to dryness,
and the resulting solid stirred in a 1:1 mixture of IN
NaOH:THF (20 mL total volume) at room temperature overnight.
The THF was removed under reduced pressure, the aqueous
mixture adjusted to pH = 2 with IN HC1, and purified by
cation exchange chromatography (Dowex® 50X8-100, elute with
10% pyridine/H20) . Recrystallization from H20/2-propanol
(1:1) afforded 0.13 g (0.46 mmol, 50%) of the desired
product. mp = > 27 5°C. FDMS: M+ + 1 = 27 9. Anal, calcd.
for C9H14N-,0„S: C, 38.84; H, 5.07; N, 10.07. Found: C,
39.01; H, 5.21; N, 10.07.
Example 13
(IS*,2S*,AR*, 5R*,65*) 2-Amino-4-(methylaminocarbonylamino)-
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid

(a) (IS*,2S*,4R*,5R*,6S*)-Diethyl 2-N-t-butyloxycarbonyl-
amino-4-(methylaminocarbonylamino)bicyclo[3.1.0]hexane-2,6-
dicarboxylate. Methyl isocyanate (0.07 g, 1.2 mmol) was
added by dropwise addition to a 0°C solution of the product
from Example 8(c) (0.35 g, 1.0 mmol) in CH2C12 (25 mL), and
the resulting reaction mixture allowed to warm to room
temperature as it stirred overnight. The reaction mixture
was diluted with EtOAc, washed with aqueous NaHS04 then
brine, dried over MgS04 and concentrated in vacuo to yield
the crude methyl urea which was purified by PC-TLC (10%
EtOAc/hexanes to 50% EtOAc/hexanes) to afford 0.35 g (85%,
0.85 mmol) of the desired product as a white foam. FDMS: M+
+ 1 = 414. Anal, calcd. for C^H^N-P, • 0.5 H20: C, 54.01; H,
7.63; N, 9.95;. Found: C, 53.81; H, 7.52; N, 10.64.
(b) (IS*,2S*,4R*,5R*.6S*)-2-Amino-4-(methylaminocarbonyl-
amino) bicyclo [3 . 1 . 0] hexane-2 , 6-dicarboxylic acid. A
solution of the product from step (a) (0.30 g, 0.72 mmol),
in EtOAc (30 mL) was chilled to 0°C and purged with
anhydrous HC1 gas until the solution reached saturation. The
reaction mixture was stirred at 0°C for one hour,
concentrated to dryness, and the resulting solid stirred in
a 1:1 mixture of IN NaOH:THF (2 0 mL total volume) at room
temperature overnight. The THF was removed under reduced
pressure, the aqueous mixture adjusted to pH = 2 with IN
HC1, and purified by cation exchange chromatography (Dowex
50X8-100, elute with 10% pyridine/H20) . Recrystallization
from H20/2-propanol (1:1) afforded 0.12 g (0.46 mmo1, 64%)
of the desired product. mp = > 275°C. FDMS: M+ + 1 =
258. Anal, calcd. for C10H15N3O5-0.1 H20: C, 46.37; H, 5.91;
N, 16.22. Found: C, 46.03; H, 6.01; N, 16.12.
Example 14
(IS*,2S*,4R*,5R*,65*) 2-Amino-4-(N,N-
dicyclopropylmethylamino)bicyclo[3.1.0]hexane-2,6-
dicarboxylic acid

(a) (IS*,25*,AR* , 5R*,65*)-Diethyl 2-N-t-butyloxycarbonyl-
amino-4-(N,N-dicyclopropylmethylamino)bicyclo[3.1.0]hexane-
2,6-dicarboxylate. Cyclopropylmethyl bromide (0.27 g, 2.0
mmol) was added by dropwise addition to a room temperature
solution of the product from Example 8(c) (0.32 g, 0.90
mmol) and triethylamine (0.30 g, 3.0 mmol) in CH3CN (25 inL) ,
and the resulting reaction mixture stirred overnight. The
reaction mixture was concentrated in vacuo and purified by
PC-TLC (10% EtOAc/hexanes to 67% EtOAc/hexanes) to afford
0.33 g (78%, 0.70 mmol) of the desired product as a light
yellow oil. FDMS: M+ + 1 = 465. Anal, calcd. for C25H40N2O6:
C, 64.63; H, 8.68; N, 6.03. Found: C, 64.38; H, 8.60; N,
5.93.
(b) (IS*,2S*,4R*,5R*,6S*)-2-Amino-4-(N,N-dicyclopropyl-
methylamino)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid. A
solution of the product from step (a) (0.28 g, 0.61 mmol),
in EtOAc (30 mL) was chilled to 0°C and purged with
anhydrous HCl gas until the solution reached saturation. The
reaction mixture was stirred at 0°C for four hours,
concentrated to dryness, and the resulting solid stirred in
a 1:1 mixture of IN NaOH:THF (20 mL total volume) at room
temperature overnight. The THF was removed under reduced
pressure, the aqueous mixture adjusted to pH = 2 with IN
HCl, and purified by cation exchange chromatography (Dowex®
50X8-100, elute with 10% pyridine/H20) . Recrystallization
from H20/2-propanol (1:1) afforded 0.15 g (0.49 mmol, 80%)
of the desired product. mp = dec > 27 0°C. FDMS: M+ + 1 =
309. Anal, calcd. for C16H24N2O4-0.6 H20: C, 60.21; H, 7.96;
N, 8.78. Found: C, 59.92; H, 7.99; N, 8.93.
Example 15
(IS* ,2S*,5R*,6S*)-2-Amino-4-Z-
carboxymethylenebicyclo[3.1.0]hexane-2,6-dicarboxylic acid
(15*,2S*,5R*,6S*)-2-Amino-4-£-
carboxymethylenebicyclo[3.1.0]hexane-2,6-dicarboxylic acid
]
(a) (15*,25*, 4i?*, 65*) -Diethyl-2- (N-tert-butyloxycarbonyl) -
amino-4-(benzyloxycarbonyl)methylene bicyclo[3.1.0]hexane-
2,6-dicarboxylate, Isomers A and B. The sodium salt of
benzyl diethylphosphonoacetate was prepared by the addition
of sodium bis(trimethylsilyl)-amide (4.2 mmol) to an
anhydrous toluene solution of benzyl diethylphosphonoacetate
(1.2 g, 4.2 mmol) at 0°C. The sodium salt was rapidly added
to a anhydrous toluene solution of the product of Example
5(a) (1.0 g, 2.8 mmol) at 0C and stirred for 15 minutes.
The reaction was allowed to warm to room temperature and
stir until it was determined to be complete by TLC. IN HC1
was added and the reaction mixture was extracted using ethyl
acetate. The combined organic layers were washed with
aqueous NaCl and dried with MgS04. The organics were
concentrated and the crude product purified using HPLC
(EtOAc/hexanes) to afford 1.3 g (94%) of a mixture of two
isomers. FDMS: M+ - 1 = 486. Anal, calcd. for C H NO :
26 33 1 8
C, 64.05; H, 6.82; N, 2.87. Found: C, 64.04; H, 6.87; N,
2.96.
(b) (IS*,25*, SR*, 65*)-Diethyl-2-amino-4-£-
(benzyloxycarbonyl)methylenebicyclo[3.1.0]hexane-2,6-
dicarboxylate, Isomer A and (15*,25*,4R*,65*)-Diethyl-2-
amino-4-Z-(benzyloxycarbonyl)methylenebicyclo[3.1.OJhexane-
2,6-dicarboxylate, Isomer B. Anhydrous HC1 (g) was bubbled
into a EtOAc solution of the product of step (a) (0.4 g,
0.82 mmol) at 0C. The reaction was allowed to warm to room
temperature and stir until judged complete by TLC. The
organics were partitioned over aqueous NaHCO-,, dried with
K2C03, and concentrated under vacuum. Purification by HPLC
(EtOAc/hexanes) afforded 0.154 g (48%) isomer A and 0.13 g
(41%) isomer B.
Isomer A: FDMS: M+ + 1 = 388. Anal, calcd. for C H NO :
2] 25 1 6
C, 65.10; H, 6.50; N,3.62. Found: C, 64.91; H, 6.40; N,
3.83.
Isomer B: FDMS: M+ + 1 = 388. Anal, calcd. for C H NO +
21 25 1 6
0.5 eq. CH2C12: C, 60.07; H, 6.10; N, 3.26. Found: C,
60.33; H, 6.05; N, 3.43.
(c) (IS*, 25*, 5R* , 65*) -2-Amino-4-£,-carboxymethylenebicyclo-
[3.1.0]hexane-2,6-dicarboxylic acid. The product of step
(b), Isomer A (0.134 g, 0.35 mmol), was stirred in 5 mL of
2N NaOH and 2 mL of THF for 5 hours. The reaction was
adjusted to a pH = 7 with IN HC1 and concentrated to
dryness. The resulting solid was reconstituted in water at
a pH = 10 and applied to an anion exchange resin (Bio-Rad®
AG1-X8, eluted with 2N acetic acid) to afford 0.038 g (45%)
of the desired product. FDMS: M+ + 1 = 242. Anal, calcd.
for C H NO + 0.14 eq. NaCl: C, 48.16; H, 4.44; N, 5.62.
10 11 6
Found: C, 48.15; H, 4.29; N, 5.36.
(d) (15*,25*,5R*,65*)-2-Amino-4-Z-carboxymethylenebicyclo-
[3.1.0]hexane-2,6-dicarboxylic acid. The product of step
(b), Isomer B (0.107 g, 0.28 mmol), was stirred in 5 mL of
2N NaOH and 2 mL of THF for 5 hours. The reaction was
adjusted to a pH = 7 with IN HC1 and concentrated to
dryness. The resulting solid was reconstituted in water at
a pH = 10 and applied to an anion exchange resin (Bio-Rad®
AG1-X8, eluted with 2N acetic acid) to afford 0.050 g (75%)
of the desired product. FDMS: M+ + 1 = 242. Anal, calcd.
for C H NO + 1.0 eq. H,0: C, 46.34; H, 5.06; N, 5.40.
10 11 6 ^2
Found: C, 46.43; H, 5.04; N, 5.45.
Example 16
(IS* ,2S* ,5R*,6S*)-2-Amino-4-methylenebicyclo[3. 1.0]hexane-
2,6-dicarboxylic acid

(a) {1S*,2S* ,5R*,65*)-Diethyl-2-(N-fcerfc-butyloxycarbonyl)-
amino-4-methylenebicyclo[3.1.OJhexane-2,6-dicarboxate.
Sodium bis(trimethylsilyl)amide (4.2 mmol) was added to a
slurry of methyltriphenylphosphonium bromide (1.5 g, 4.2
mmol) in anhydrous THF at OC. A solution of the product of
Example 5(a) (0.75 g, 2.1 mmol) in anhydrous THF was added
to the reaction vessel and stirred for overnight at 0°C. IN
HC1 was added and the reaction mixture was extracted using
ethyl acetate. The combined organic layers were washed with
aqueous NaCl and dried with MgS04. The organics were
concentrated and the crude product was purified using HPLC
(EtOAc/Hexanes) to afford 0.52 g (70%) of the desired
product. FDMS: M+ + 1 = 354.
(b) [IS*,2S*,5R*,6S*)-2-Amino-4-methylenebicyclo[3.1.0]-
hexane-2,6-dicarboxylic acid. The product of step (a) (0.36
g, 1.0 mmol) was stirred in 1 ml of TFA for 1 hour,
concentrated and dissolved in 5 mL of THF. The reaction was
adjusted to pH = 13-14 with IN NaOH and stirred for 2
hours. The reaction mixture was concentrated and adjusted
to pH = 10 with IN HC1. The resulting material was applied
to an anion exchange resin (Bio-Rad® AG1-X8, eluted with IN
acetic acid) to afford 0.061 g (31%) of the desired product.
FDMS: M+ + 1 = 198. Anal, calcd. for C H NO + 0.25 eq. of
9 11 i ^
H20: C, 53.60; H, 5.75; N, 6.94. Found: C, 53.65; H,
5.64? N, 6.85.
Example 17
(15*,25*, 5R*,6S*)-2-Amino-4-(Z)-(diethylphosphonomethylene)-
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid
(IS*,2S*,5R*,65*)-2-Amino-4-(E)-diethylphosphonomethylene)-
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid

(a) (15*, 25*, 5i?*,65*)-Diethyl-2-(N-tert-butyloxycarbonyl)-
amino-4-((E and Z)-diethylphoshonomethylene)bicyclo-
[3.1.0]hexane-2,6-dicarboxylate, Isomers A and B. The
sodium salt of tetraethyl methylenediphosphonate was
prepared by the addition of sodium bis(trimethylsilyl)amide
(2.1 mmol) to an anhydrous toluene solution of tetraethyl
methylene-diphosphonate (0.6 g, 2.1 mmol) at 0C. The
sodium salt was rapidly added to a anhydrous toluene
solution of the product of Example 5(a) (0.5 g, 1.4 mmol) at
0C and stirred for 15 minutes. The reaction was allowed to
warm to room temperature and stir until it was determined to
be complete by TLC. IN HCl was added and the reaction
mixture was extracted using ethyl acetate. The combined
organic layers were washed with aqueous NaCl and dried with
MgSO„. The organics were concentrated and the crude product
purified using HPLC (EtOAc/hexanes) to afford 0.190 g (28%)
isomer A and 0.119 (17%) isomer B.
Isomer A (E isomer): FDMS: M+ + 1 = 490. Exact mass calcd.
for C H NOP: 490.2206. Found: 490.2202
22 36 9
Isomer B (Z isomer): FDMS: M+ + 1 = 490.
(b) {IS*,2S*,5R*,65*)-2-Amino-4-(Z)-diethylphosphono-
methylenebicyclo[3.1.0]-hexane-2,6-dicarboxylic acid. The
product of step (a). Isomer A (0.15 g, 0.31 mmol), was
stirred in 2 mL of TFA for 1 hour, concentrated and
dissolved in 5 mL of THF. The reaction was then treated
with 2 mL of IN NaOH for 5 hours. The reaction mixture was
concentrated and adjusted to pH = 10 with IN HC1. The
resulting material was applied to an anion exchange resin
(Bio-Rad® AG1-X8), eluted with IN HC1 and recrystallized in
H20 to afford 0.03 g (27 %) of the desired product. FDMS:
M+ + 1= 334. Anal, calcd. for C H NO P + 2.6 eq. HC1: C,
13 20 7 ^
36.48; H, 5.32; N, 3.27. Found: C, 36.33; H, 5.50; N, 3.72.
The other two title compounds are prepared in a similar
manner, starting respectively from Isomer B or Isomer C.

(a) (IS*,25*,5R*,6S*)-2-Amino-4-phosphonomethylenebicyclo-
[3.1.0]hexane-2,6-dicarboxylic acid. The product of Example
17(a); Isomer A (0.15 g, 0.31 mmol), was stirred in 2 mL of
TFA for 1 hour and concentrated. The resulting reaction
material was treated with 6N HC1 at reflux overnight,
concentrated and resulting the product was triturated in H20
and IPA to afford 0.005 g (5%) of the desired product.
FDMS: M+ + 1 = 278.
Example 19
(15*, 25*, 5R*,65*)-2-amino-4-Z-cyanomethylenebicyclo-
[3.1.0.]hexane-2,6-dicarboxylic acid
(15*, 25*,5R*,65*)-2-amino-4-E-cyanomethylenebicyclo-
[3.1.0]hexane-2,6-dicarboxylic acid

(a) (15*,25*,5R*,65*)-Diethyl-2-(N-tert-butyloxycarbonyl)-
amino-4-cyano-methylenebicyclo[3.1.0]hexane-2,6-
dicarboxyate, Isomers A and B. The sodium salt of diethyl
cyanomethylphosphonate was prepared by the addition of
potassium bis(trimethyl-silyl)amide (2.6 mmol) to an
anhydrous toluene solution of diethyl cyanomethylphosphonate
(0.45 g, 2.6 mmol) at 0°C. The salt was rapidly added to
the product of Example 5(a) (0.6 g, 1.7 mmol) at 0°C and
stirred for 15 minutes. The reaction was allowed to warm to
room temperature and stir until it was determined to be
complete by TLC. IN HC1 was added and the reaction mixture
was extracted using ethyl acetate. The combined organic
layers were washed with aqueous NaCl and dried with MgS04.
The organics were concentrated and the crude product
purified using HPLC (EtOAc/hexanes) to afford 0.525 g (82%)
of a mixture of two isomers. Isomer A and Isomer B were
separated using HPLC (EtOAc/Hexanes).
Isomer A: M* + 1 = 379. Exact mass calcd. for C H NO (+H)
19 26 2 6
= 379.1869. Found: 379.1875
Isomer B: M* = 378
(b) (IS*,2S*,5R*, 6S*)-2-amino-4-cyanomethylenebicyclo-
[3.1.0.]hexane-2,6-dicarboxylic acid. The product of step
(a), Isomer A (0.15 g, 0.39 mmol), was stirred in 5 mL of
TFA for 1 hour, concentrated and dissolved in 5 mL of THF.
The reaction was then treated with 5 mL of IN NaOH for 5
hours. The reaction was adjusted to a pH = 7 with IN HC1
and concentrated to dryness. The resulting solid was
reconstituted in water and the was adjusted to pH = 10,
applied to anion exchange resin (Bio-Rad8 AG1-X8), eluted
with 2N acetic acid, to afford 0.032 g (36%) of the desired
product. FDMS: M+ + 1= 223. Anal, calcd. for C H NO +
r 10 10 2 t
0.3eq. H20: C, 52.77; H, 4.69; N, 12.31. Found: C, 52.53;
H, 4.76; N, 12.17.

(b) (15*,25*,4R*,5S*,6S*)-2-amino-4-cyanobicyclo[3.1.0]-
hexane-2,6-dicarboxylic acid. The product of step (a)
(12 0mg, 0.38mmol) was dissolved in trifluoroacetic acid
(5ml) and stirred at room temperature for 2 hours.
The reaction mixture was evaporated in vacuo, the
residue redissolved in water and azeotroped in vacuo to give
a white solid (62mg). The crude solid was redissolved in the
minimum of water and purified by cation-exchange
chromatography (Dowex 50X8-100; column eluted sequentially
with H20, H20:THF 1:1 and H20 again. The amino acid was
finally eluted with H20-.pyridine 9:1) . The pyridine was
removed in vacuo and the residual solid redissolved in water
and freeze-dried to give the amino acid as a fluffy white
solid (35mg). Mpt. 240-242°C.
'H MR (300MHz, D20, 8 ppm) : 1.85 (1H, dd, C3-H), 2.21 (1H,
t, C6-H) , 2.42 (1H, dd, C,-H), 2.60 (2H, m, C,-H + Cs-H) , 3.83
(1H, m, C4-H) .
Example 22
(IS* ,2S*,4R*,5S* , 6S*) -2-Arnino-4-
carboxamidobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

(a) (1S*,25*, AR*,5S*,65*)-2-(N-tert-butyloxycarbonyl)amino-
4-carboxamidobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. To •
a solution of the product of Example 20(a) (145mg, 0.40mmol)
in absolute ethanol (1ml) at 0-5°C was added (1) 30%
hydrogen peroxide (0.157ml) (2) 6M sodium hydroxide
(0.20ml). The reaction mixture was allowed to warm to room
temperature and stirred for a further 4 hours, when it was
diluted with more water(4ml).
After 72 hours the reaction mixture was acidified with
2M hydrochloric acid and extracted three times with ethyl
acetate. The combined organic extracts were washed with
saturated sodium chloride solution, dried over magnesium
sulfate, filtered and evaporated in vacuo to give a white
solid (84mg). The crude product was purified by
chromatography on silica gel (eluant ethyl acetate 5%
glacial acetic acid) to give the desired acid as a white
solid (34mg).
lH NMR (300MHz, DMSO-d6, 5 ppm) : 1.42 !9H, s, t-butyl), 1.65
(1H, dd, C3-H) , 1.75 (1H, broad s, C$-H) , 2.08 (2H, m, C,-H +
C3-H), 2.14 (1H, m, C5-H), 3.10 (1H, m, C,-H), 6.90 (1H, s,
NH), 7.44 (1H, s, NH), 7.64 (1H, s, NH>, 12.35 (2H, broad
hump, 2 X C02H) .
(b) (IS* ,2S* ,4R* ,5S* ,6S*) -2-Amino-4-carboxamidobicyclo-
[3.1.0]hexane-2,6-dicarboxylic acid. A solution of the
product of step (a) (34mg, O.lmmol) in trifluoroacetic acid
(5ml) was stirred at room temperature for 2 hours.
The reaction mixture was then evaporated in vacuo to
dryness, redissolved in water and then azeotroped in vacuo
at 7 0°C. The crude solid was dissolved in the minimum volume
of water and purified by cation-exchange chromatography
(Dowex 50X8-100; column eluted sequentially with H20,
H20:THF 1:1 and H20 again. The amino acid was finally eluted
with H20:pyridine 9:1), The pyridine was removed in vacuo
and the residual solid redissolved in water and freeze-dried
to give the desired amino acid as a fluffy white solid
(12mg). Mpt. 260-262°C (dec).
"H NMR (300MHz, D20, 5 ppm) : 1.95 (1H, dd, C3-H) , 2.30 (1H,
d, C6-H) , 2.42-2.64 (3H, m, CrH + C3-H + C5-H) , 3.78 (1H, m,
C<-H) .
WE CLAIM:
1. A compound of formula (I)

in which:
(a) R1 represents fluoro, XOR3, XNR4R5 SO3H tetrazol-5- yl. CN or PO3R26 and R2
represents hydrogen; or
(b) R1 and R2 each represents fluoro; or
(c) R1 and R2 together represent =O, =NOR7 or =CRV: or
(d) one of R and R" represents amino and the other represents carboxyl: or
(e) R' represents Ni.(CH2)mCOOR3\(CH2)mP03Rh\NHCONHR3\>r N!ISO:RA and
R" represents hydrogen; or
(f) R1 and R2 together represent =CHCOOR31'. =(CH)mP03R;Aaor =CHCN: and
R' represents a hydrogen atom; a (1-6C) alky 1 group; a (3-6C) alkenyl group: a (3-6i ;
alkynyl group; an optionally substituted aromatic group: an optionally substituted
heteroaromatic group: a non-aromatic carbocyclic group: a non-aromatic heterocyclic
group: a non-aromatic monocyclic carbocyclic group fused with one or mo
monocyclic aromatic or heteroaromatic groups; a non-aromatic monoc\ciie
heterocyclic group fused with one or two monocyclic aromatic or heteroaromatie
groups: or a (I-6C) alkyl, (3-6C) alkenyl or (3-6C) alkynyl group which is substituted
by one. two or three groups selected independently from an optionalh substituted
aromatic group, an optionally substituted heteroaromatic group, a non-aromatic
carbocyclic group, a non-aromatic heterocyclic group, a non-aromatic monocyclic
carbocyclic group fused with one or two monocyclic aromatic or heteroaromatic
groups and a non-aromatic monocyclic heterocyclic group fused with one or two
monocyclic aromatic or heteroaromatic groups;
R''1. R3h and R3° are as defined for R3;
X represents a bond, CH: or CO:
m represents an integer of from 1 to 3;
R4 represents COR10 or is as defined for R"R\ R7. R8. R" and R1" arc as defined for R3;
R° represents hydrogen or a (1-6C) aikyl group; and
R(1il is defined for R6: or a non-toxic metabolically labile ester or amide thereof: or a
pharmaceutical^ aeceptable salt thereof.
2. A compound as claimed in Claim 1. in which:
(a) R' represents fluoro, XOR3. XNR4R5. SO,H. tetrazol-5-yl. CN or PO,R; and R
represents hydrogen: or
(b) R1 and R each represents fluoro: or
(c) R 1 and R2 together represent =O, =NOR7 or =CRV: or
(d) one of R1 and R" represents amino and the other represents carboxyl.
3. A compound as claimed in Claim 1. in which
(a) R1 represents fluoro; XOR3: XNR4R5: S03H: tetrazol-5- yl; CN or P():dl:: X
represents a bond. CO or CHv RJ represents a hydrogen atom or a (1-6C) aikyl group:
a phenyl group which is unsubstituted or substituted by one or two substitucnt-
selected independently from halogen. (I-4C) aikyl and (1- 4C) alkoxy: a phenyl (1-
4C) aikyl or diphenyl (I-4C) aikyl group which is unsubstituted or substituted o,i
phenyl by one or two substituents selected from halogen, (I-4C) alky 1 and (I-4C)
alkoxy; R4 represents hydrogen, (1-6C) alkanoyl. benzoyl. (3-6C) cycloalkyl (I-4C)
aikyl or (1-6C) aikyl; and R"" represents hydrogen. (3-6C) cycloalkyl (l-4(.'i aikyl tr
(l-6C)alkyl: and R" represents hydrogen; or
(b) R and R" each represents fluoro: or
(c| R1 and R2 together and represent =O,=NOH. or =CR>VR<; which each of Rs am.1 K
independently represents a hydrogen atom, a (1-6C) aikyl group or a phenyl group
which is unsubstituted or substituted by one or two substituents selected from
halogen. (1-4C) aikyl and (1-4C) alkoxy; or
(d) one of R and R" represents amino and the other represents carboxyl: or
(e) Rl represents N.3.CH2CO()Ri^CH;PO,R26',. NHCONHRib or represents
NHS02R-k: R"5a represents hydrogen or (l-6C)alkyi: R3b represents (I-6C) aikyl: R"
represents (I-6C) aikyl; R~ represents hydrogen; and each of Rha independently
represents hydrogen or (I-6C) aikyl: or
(0 R1 and R2 together represent =CHCOOH, =C!IPChfb -CHPChfOH^ <>,-
---CHCN.
4. A compound as claimed in Claim 2, in which (a) R1 represents fluoro-. XOR -.
XNR'R?i SChH ; tetrazol-5- yl; CN or P03H:; X represents a bond. CO or Oh: l<~
represents a hydrogen atom or a (I-6C) alkyl group: a phenyl group which is
unsubstituted or substituted by one or two substitucnts selected independently from
halogen, 0-4C) alkyl and (1- 4C) alkoxy; a phenyl (1-4C1 alkyl or diphenvl (l-4(")
alkyl group which is unsubstituted or substituted on phenyl by one or two substitiienls
selected from halogen. (1-4C) alkyl and (I-4C) alkoxy; R represents hydrogen. (1-
6C) alkanovl or (I-6C) alkyl; and R" represents hydrogen or (I-6C) alky); and R~
represents hydrogen; or
(b) R1 and R" each represents fluoro: or
(c) R' and R: together represent K), =NOH, or =CR8Ry in which each of R's and R
independently represents a hydrogen atom, a (1-6C) alkyl group or a phenyl group
which is unsuhsfiluted or substituted by one or two subsmuenrs selected from
halogen. < I-4C) alkyl and (1-4C) alkoxy;
or (d) one oir R' and R~ represents amino and the other represents earboxv I.
5. A compound as claimed in Claim 1, in which R represents fluoro, hydroxy!, PO;lf.
methoxy, amino, azido, acetylamino. benzoylamino, methanesulfonylamino. methyl-
aminocarbonylamino. N. N-dicyclopropylmelhyl, carboxy. cyano or carboxamido air.1
R represents hydrogen, or R1 and R; together representee). =NO)I. =CHC04i.
=Cl-b: <:HP05(C:llc): =CHP()3H2 or=CHCN.
6. A compound as claimed in Claim I. which is selected from (IS*. 2S*. 5R*. 6R*)-2-
amino-4-oxobicyclo [3.1.0] hexane- 2.6-dicarboxylic acid: (IS*. 2S*. 5R*. 6R*')-2-
amino-4- |anti]- hydroximinobicyclo [3.1.0] hexane-2.6-dicarboxylic acid: (IS*.
2S*.5R*.6R*)-2-amino-4-|syn]-hydTOxiininobicyclo-j3.l .0]hexa»ic-2.6-dtcarlx>x\ik
acid; (IS*. 2R*. 4S*. 5S*. 6S*)-2-amino-4-fluorobicyclo[3.1 .()|hexane-16-
dicarboxylic acid; (IS*, 2S*. 5R*, 6S*)-2-amino-4-Z-carboxymethylenebicyelo-[3.
1.0]hexane-2.6-dicarboxylic acid and (IS*. 2S*. 5R*. 6S*)-2-amino-1-
methylenebicyclo [3.1.0] hcxane-2,6-dicarboxylic acid.
7. A process for the preparation of a compound as defined in any one of Claims I to 6.
which comprises:

in which ll" represents a hydrogen atom or an acyl group and R'~ represents a
carboxyl group or an esterified carboxyl group, or a salt thereof;

in which R ' represents a carboxyl group or an esterified carboxyl group, and R'" a'id
R 'each and independently represent a hydrogen atom, a (2-6C) alkanoyl group, a (1-
4C) alky] group, a (3-4C) alkenyl group or a phenyl (1-4C) alkyl group in which the
phenyl is unsubstituted or substituted by halogen. (1-4C) alkyl or (l-4C> alkow. or a
salt thereof; or

iii which Rlh represents a hydrogen atom or a nitrogen protecting group atul each ¦-¦>!'
R!6 and R17 independently represents a hydrogen atom or a carboxyl protecting group,
or a salt thereof;
where after, if necessary and/or desired
(i) resolving the compound of formula I:
(ii) converting the compound of formula 1 into a non- toxic metabolicalK
labile ester or amide thereof; and/or;
(iii) converting the compound of formula 1 or a non- toxic melaboficaih
labile ester or amide thereof into a pharmaceutical!} acceptable sal;
thereof.
S. A compound as claimed in Claim 1. which is (IS*.2R*.4S*.5S*.6S*)-2-amino-4-
lluorobicyclo[3.l.0'Jhexane-2,6-dicarboxylic acid; or a non-toxic meiaholically labile
ester or amide thereof; or a pharmaceutically acceptable salt thereof.

A compound of the formula (I), useful as modulators of metabotropic glutamate receptor

in which R1 and R2 are as defined in the specification, non-toxic metabolically labile ester
and amides or a pharmaceutical acceptable salt thereof and a process for preparing the
same.