The synthesis of 3-phosphonocyclobutyl amino acid analogues of glutamic acid via diethyl 3-oxycyclobutylphosphonate, a versatile synthetic intermediate

Article abstract of DOI:10.1039/a604898f

A range of novel 3-phosphonocyclobutyl amino acids have been prepared via the versatile synthetic intermediate, diethyl 3-oxocyclobutylphosphonate, which is prepared in three steps from diethyl methylphosphonate. Elaboration of the 3-oxo functionality rea

Full text of DOI:10.1039/a604898f

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The synthesis of 3-phosphonocyclobutyl amino acid analogues of
glutamic acid via diethyl 3-oxycyclobutylphosphonate, a versatile
synthetic intermediate
Jane R. Hanrahan,* Paul C. Taylor and William Errington
Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK
A range of novel 3-phosphonocyclobutyl amino acids have been prepared via the versatile synthetic
intermediate, diethyl 3-oxocyclobutylphosphonate, which is prepared in three steps from diethyl
methylphosphonate. Elaboration of the 3-oxo functionality readily facilitates the synthesis of the
3-phosphonocyclobutyl amino acids.
Phosphono amino acids have facilitated the pharmacological
Introduction
characterisation of excitatory amino acid receptors. In particu-
lar, the conformationally restrained cyclic phosphono amino
acids 2–4 have provided much structure–activity information
about the various sub-classes of receptors.4–6 Notably absent
from the cyclic phosphono amino acids that have been investi-
gated are the cyclobutane analogues 7 and 8. This is despite the
fact that the severely conformationally restrained cyclobutane
offers the promise of much important structure–activity
information.
The failure to study the cyclobutane analogues is, primarily
due to the lack of synthetic methodology for preparing 3-
substituted cyclobutylphosphonates 9, with functionality at the
3-position suitable for further elaboration. In fact, it is only
recently that syntheses of any phosphono-substituted cyclo-
butanes have been reported. We have reported the synthesis of a
range of cyclic bisphosphonate and carboxyphosphonate com-
pounds, including the cyclobutane compounds, using phase
transfer methodology7 and a recent paper has reported the
synthesis of dialkyl 1-trimethylsilylcyclobutylphosphate from
dialkyl trichloromethylphosphonate.8 We now describe the
synthesis of the versatile intermediate diethyl 3-oxocyclo-
butylphosphonate 15 from diethyl methylphosphonate, and
the elaboration of this intermediate into a range of 3-phos-
phonocyclobutyl amino acids.
There is much interest in phosphono amino acid analogues 1–4
of both natural and synthetic amino acids. These phosphono
amino acids are known to have interesting biological activity, in
particular, various phosphonic acid analogues of -aspartic
acid 5 and -glutamic acid 6 act as antagonists at excitatory
amino acid (EAA) receptors in the central nervous system
(CNS),1 at which -aspartic acid 5 and -glutamic acid 6 are
thought to be endogenous neurotransmitters. EAA receptors
are now accepted to be the main transmitter receptors mediat-
ing synaptic excitation in the mammalian CNS. They are
involved with many physiological phenomena, ranging from the
processing of sensory information through coordinated move-
ment patterns, to cognitive processes such as learning and
memory.1,2 Dysfunction of these systems leads to various
neurological disorders, including memory disorders, epilepsy
and spasticity. There is also considerable evidence to indicate
that EAA receptors play a role in neurodegenerative conditions
such as those associated with Huntington’s disease, stroke,
schizophrenia and Alzheimer’s disease.3
O
O
NH2
(HO)2P
HO2C
(CH2)n
NH2
P(OH)2
CO2H
(CH2)n
Results and discussion
2 n = 1
3 n = 2
1 n = 1–5
Reaction of 2 equiv. of diethyl methylphosphonate 10 (Scheme
1) with 2 equiv. of butyllithium and 1 equiv. of 1-chloro-2-
benzyloxy-3-bromopropane9 11 results in the formation of
diethyl 3-(benzyloxy)cyclobutylphosphonate 12 in good yields
(ca. 50%) for this type of cyclisation reaction. The reaction of 1
equiv. of diethyl methylphosphonate with 2 equiv. of butyl-
lithium results only in monoalkylated products. This cyclisation
is also successful in the diisopropyl phosphonate ester analogue
is used, although the yield is slightly lower. However, if di-
methyl methylphosphonate is used, only the monoalkylated
O
CO2H
NH2
HO2C
(CH2)n
CO2H
(HO)2P
NH2
5 n = 1
6 n = 2
4
CO2H
O
O
HO2C
H2N
intermediate,
dimethyl
3-(benzyloxy)-4-chlorobutylphos-
P(OH)2
P(OH)2
phonate 18 and some dimethyl 3-(benzyloxy)butylphosphonate
are obtained (Scheme 2).
H2N
7
Thus we suggest that the mechanism of the reaction is as
follows: the addition of butyllithium results in the formation of
the lithiophosphonate, which displaces the bromide to form a
carbon–carbon bond. The second equivalent of the lithiophos-
phonate then acts as a base, removing a proton from 17 and
completing the cyclisation. In the case of dimethyl methylphos-
phonate, the smaller ester groups allow greater aggregation of
8
X
P(OR)2
9
J. Chem. Soc., Perkin Trans. 1, 1997
493

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13C NMR spectrum of this compound corresponded to the sig-
O
O
nals that we had assigned to the minor cis-isomer of diethyl 3-
hydroxycyclobutylphosphonate produced by hydrogenolysis of
12. This can be explained by chelation of the lithium in the
intermediate by both the alkoxide and the phosphonate, hold-
ing these two groups cis to each other. A similar situation has
been described in the reaction of 4-phenyl-4-(phenylsulfonyl)-
1,2-epoxybutane with 2 equiv. of methylmagnesium bromide.
This reaction produces only one isomer of phenyl 3-phenyl-1-
hydroxycyclobutanesulfonate, which has been unambiguously
shown to be the cis-isomer by X-ray structure determination. In
this case the cis relationship is proposed to occur due to chel-
ation of the magnesium by the alkoxide ion and the sulfone, in a
system that is analogous to the alkoxide–lithium–phosphonate
system described above.10
i
MeP(OEt)2
2
BnO
P(OEt)2
Br
Cl
OBn
10
12
11
iii
O
Cl
ii
O
14
HO
P(OEt)2
13
O
O
P(OEt)2
Under standard Strecker reaction conditions compound 15
yielded a complex mixture of cyanohydrin, amino nitriles
and condensation products. Our attention therefore turned to
literature reports of high yielding modifications of the Strecker
synthesis using ultrasonic irradiation (Scheme 3).11 A procedure
15
Scheme 1 Reagents and conditions: i, BuLi (2 equiv.), THF, Ϫ78 ЊC, 30
min, then 11 (1 equiv.), 2 h, Ϫ78 ЊC to room temp.; ii, H2, 10% Pd–C,
MeOH; iii, BuLi (2 equiv.), THF, Ϫ78 ЊC, 30 min, then 14 (1 equiv.), 2
h, Ϫ78 ЊC to room temp.; iv, cat. RuCl3, CH2Cl2, NaIO4, H2O
O
O
(RO)2PCH2
O
O
PMBHN
NC
RO
NC
P(OR)2
OBn
Cl
O
P(OEt)2
P(OEt)2
H
i
MeP(OR)2
2
Br
Cl
19 R = H
20 R = BnCO
OCH2Ph
21
PMB = p-methoxybenzyl
17 R = Et
18 R = Me
ii
10 R = Et
16 R = Me
11
iii
i
O
O
P(OEt)2
O
O
15
viii
iv–vi
(RO)2P
OBn
Cl
BnO
P(OEt)2
12 R = Et
vii
O
O
O
H2N
P(OH)2
Scheme 2 Reagents and conditions: i, BuLi (2 equiv.), THF, Ϫ78 ЊC, 30
min, then 11 (1 equiv.), 2 h, Ϫ78 ЊC to room temp
P(OEt)2
H
O
22
24
HO
Me
P(OEt)2
the dimethyl lithiomethylphosphonate, making it more stable
than the diethyl lithiomethylphosphonate and thus not able to
abstract the second proton from 18.
23
Scheme 3 Reagents and conditions: i, NaCN, NH4Cl, Al2O3, MeCN,
ultrasound; ii, BnCOCl, Et3N, CH2Cl2; iii, PMB–NH2, AcOH,
MeOH, NaCN; iv, NH2OHؒHCl, H2O reflux; v, H2, Rh–Al2O3, MeOH;
vi, H+, H2O, reflux, Dowex 50W (H+) ion exchange column; vii, Me-
MgBr, THF, Ϫ78 ЊC; viii, CNCH2P(O)(OEt)2, BuLi, THF, Ϫ78 ЊC to
room temp., then 6  HCl
The cyclobutylphosphonate 12 is formed as a 2:1 mixture of
the two diastereoisomers. The stereochemistry is thought to be
directed mainly by the steric interaction of the bulky substitu-
ents, thus the major isomer is most likely to be the trans-isomer
with the phosphonate and the benzyloxy substituents on oppo-
site sides of the ring. Diethyl 3-(benzyloxy)cyclobutylphos-
phonate 12 was purified by distillation under reduced pressure.
The benzyl protecting group was removed in quantitative yield
by hydrogenolysis over palladium on carbon. The alcohol was
oxidised without further purification to give the desired diethyl
3-oxocyclobutylphosphonate 15 in high yields.
Due to the success of the reaction between the anion of
diethyl methylphosphonate 10 and 1-chloro-2-benzyloxy-3-
bromopropane 11 we decided to investigate the reaction
between the anion of diethyl methylphosphonate and epi-
chlorohydrin 14 (Scheme 1) as a simpler procedure for the prep-
aration of diethyl 3-hydroxycyclobutylphosphonate 13. Again,
2 equiv. of diethyl methylphosphonate and butyllithium were
required to react with 1 equiv. of epichlorohydrin. Diethyl 3-
hydroxycyclobutylphosphonate 13 was produced in one step in
approximately 25–30% yield. Unfortunately, we were unable to
separate 13 from monosubstituted diethyl 3-hydroxy-4-chloro-
butylphosphonate by distillation. Thus, we suggest that the use
of reagent 11 followed by deprotection is the method of choice
for the preparation of 13.
which involves the heterogeneous reaction of a ketone with
potassium cyanide, ammonium chloride and alumina in MeCN
under ultrasonic irradiation has been reported to give high
yields of amino nitriles, while suppressing the formation of
cyanohydrins and condensation products.12 Reaction of 15 with
sodium cyanide, ammonium chloride and alumina in MeCN
under ultrasonic irradiation for 12 h resulted only in the
formation of the cyanohydrins 19 in high yields.
Separation of the cis- and trans-cyclobutyl cyanohydrins 19
was achieved by chromatography of the N-phenylacetyl deriva-
tives 20 on silica gel, allowing assignment of the configurations
using 13C NMR spectroscopy and X-ray crystallography. The
major isomer from the crude reaction mixture, which eluted
first from the column, was identified as the cis-isomer cis-20
[Fig. 1(a)] and the minor component as the trans-isomer.
Comparison of the 13C NMR spectra of the two isomers
showed a singlet for the peak at δ 117.93 for cis-20, and a doub-
let (J = 3.2 Hz) at δ 117.12 for trans-20. These peaks correspond
to the signal from the nitrile carbon of the trans-isomer (in
which the nitrile and phosphonate functionalities are cis to one
In contrast to the use of 11, the reaction with epichloro-
hydrin 14 produced only one diastereoisomer. The signals in the
494
J. Chem. Soc., Perkin Trans. 1, 1997

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another) exhibiting long-range ‘w-coupling’ [NC–C(3)–C(2)–
C(1)–P] between the phosphorus and the nitrile carbon. This
long-range coupling is diagnostic of these phosphorus substi-
tuted trans isomers.
Reaction of 15 with p-methoxybenzylamine (or benzyl-
amine), sodium cyanide in MeOH and acetic acid at reflux
for 15 h was successful as a method of forming diethyl 3-
(p-methoxybenzylamino)-3-cyanocyclobutylphosphonate 21
(Scheme 3).13 Analysis of the 31P and 13C NMR spectra of the
crude reaction mixture indicated the formation of just two
products, which were identified as the two isomers (3:2 ratio).
Separation of the isomers of diethyl 3-(p-methoxybenzyl-
amino)-3-cyanocyclobutylphosphonate 21 was achieved by
careful silica gel chromatography with hexane–PriOH as eluent
(Scheme 4). p-Methoxybenzylamine was used in preference to
benzylamine as the N-benzyl group could not be removed from
N-benzyl analogues of 21 by hydrogenolysis or transfer hydro-
genolysis. In contrast, the p-methoxybenzyl (PMB) group was
easily removed under mild oxidative conditions, using ceric
ammonium nitrate,14,15 or by hydrogenolysis. The crude amino
nitriles were hydrolysed to give the amino phosphonic acids
cis-7 and trans-7 which were purified by ion exchange
chromatography.
O
NC
P(OEt)2
PMBHN
21
i
O
NC
P(OEt)2
NC
PMBHN
P(OEt)2
O
PMBHN
cis-21
trans-21
ii or iii,
iv
ii or iii,
iv
Fig. 1
O
cyanocyclobutylphosphonate trans-21 was isolated as colour-
less crystals. Slow recrystallisation from a mixture of diethyl
ether, toluene and pentane provided crystals suitable for X-ray
diffraction. The X-ray structure of trans-diethyl 3-(p-methoxy-
benzylamino)-3-cyanocyclobutylphosphonate trans-21 [Fig.
1(b)] was obtained. The dihedral angle C(1)᎐C(2)᎐C(3)᎐C(4) is
Ϫ5.7Њ, which is considerably less than that of cis-diethyl 3-
(phenhylacetoxy)-3-cyanocyclobutylphosphonate cis-20. How-
ever, it has been reported that this folding can be significantly
affected by solid-state effects, with different crystals of the same
compound showing different amounts of ring puckering.16 The
13C NMR spectra of the free amino acids 7 show similar shifts
and coupling constants for the signals due to the cyclobutane
ring to those in the spectra of the protected amino nitriles. The
signal due to the carboxylic acid functionality of the trans-
isomer at δ 176.94 is a doublet (J = 2.9 Hz) due to the long-
range coupling with the phosphorus.
Diethyl 3-oxocyclobutylphosphonate 15 can be rapidly con-
verted to 3-aminocyclobutylphosphonic acid 22 (Scheme 3) by
treatment with hydroxylamine hydrochloride in water at reflux
for 12 h, which produces the oxime in good yield with a small
amount (ca. 10%) of starting material remaining.17 The crude
oxime was converted to the amine by hydrogenolysis at 3 atmo-
spheres of hydrogen with rhodium on alumina as the catalyst.
The crude amine was hydrolysed to the phosphono amino acid
22 and purified by ion exchange chromatography (Dowex-50
H+ form).
HO2C
NH2
P(OH)2
HO2C
NH2
P(OH)2
O
cis-7
trans-7
Scheme 4 Reagents and conditions: i, flash silica chromatography
(hexane–PriOH, 85:15); ii, CAN, MeCN, H2O; iii, H2, 10% Pd–C,
MeOH; iv, H+, H2O, reflux, Dowex 50W (H+) ion exchange column
The configuration of the isomers was again assigned using
13C NMR spectroscopy and X-ray crystallography of trans-21.
The signal at δ 121.36 in the 13C NMR spectrum due to the
nitrile carbon of the cis-isomer is a singlet, whereas the signal
due to the nitrile carbon of the trans-isomer at δ 120.26 is a
doublet (J = 4.8 Hz) due to the long range ‘w-coupling’ of the
nitrile carbon to the phosphorus. It is interesting to note that
this long-range coupling between the phosphorus and the
nitrile carbon is not seen in the 13C NMR spectrum of either
diethyl 3-(acetylamino)-3-cyanocyclopentylphosphonate or 3-
(acetylamino)-3-cyanocyclohexylphosphonate.6 Presumablythis
is because the cyclobutane bond angle of approximately 90Њ
is exactly right to allow backside interaction of the C(1)᎐P and
C(3)᎐CN orbitals, whereas the bond angles of the cyclopentane
and cyclohexane compounds prevent interaction of their
equivalent orbitals.
The trans-isomer of diethyl 3-(p-methoxybenzylamino)-3-
J. Chem. Soc., Perkin Trans. 1, 1997
495

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The 13C NMR spectrum of the crude reaction mixture indi-
cated that only one of the two possible diastereoisomers is
formed. We propose this to be the cis-isomer by the following
argument. The carbonyls of cyclobutanones, e.g. 15, are known
to prefer to be distorted toward the inner endo face.18,19 Thus it
is plausible to assume that the oxime will adopt a similar con-
formation. It is also likely that the bulky phosphonate group
will prefer to be in the pseudo-axial position to minimise steric
interactions. In this conformation it is likely that hydrogenation
will occur from the substantially less hindered top side of the
cyclobutane ring rather than from the more hindered bottom
side, leading to the cis-isomer.
of condensation products occurred under these conditions.
Longer reaction times resulted in hydrolysis of the phosphonate
esters.
The amino nitriles were converted directly to the N-phenyl-
acetyl derivatives 25 and the diastereoisomers were easily separ-
ated by silica gel chromatography using hexane–PriOH as elu-
ent. The assignment of the isomers was again made using the
characteristic coupling of the phosphorus to the carbon
attached to the C-3 position of the cis-isomer, which was found
to be the second isomer that eluted from the column.
Enzymatic hydrolyses of racemic trans-25 and cis-25 (as
shown in Scheme 6 for cis-25) using penicillinacylase (EC
This proposition was supported by treatment of diethyl 3-
oxocyclobutylphosphonate 15 with methylmagnesium bromide
at Ϫ78 ЊC, resulting in the formation of only the cis-isomer of
diethyl 3-hydroxy-3-methylcyclobutylphosphonate 23. The cis-
isomer was identified by the lack of coupling between the
methyl carbon and the phosphorus in the 13C NMR spectrum.
No evidence of the other diastereoisomer was found.
Molecular modelling studies using QUANTA indicate that the
lower energy conformation of the cyclobutanone is the one in
which the ketone is distorted toward the inner endo face and the
phosphonate is in the pseudo-axial position with approximately
a 19 kJ difference between the two possible conformations (256
kJ versus 237 kJ), indicative of a ratio in the region of 99:1.
Thus the nucleophilic attack occurs at the requisite angle
(Ø = ca. 110Њ) from the exo-face to provide a trans-selective
addition. A similar selective addition has been observed in the
addition of (1-phenylvinyl)lithium to a substituted cyclo-
butanone.20 Similar selectivity has also recently been noted in
the reduction of N-[(3-chloromethyl)cyclobut-1-ylidene]amines
by lithium aluminium hydride. This reduction results in sub-
sequent nucleophilic displacement of the chloride, forming 2-
alkyl-2-azabicyclo[2.1.1]hexanes, which would only be possible
if the reduction occurred to give the cis-isomer.21
O
NHCBn
O
P(OEt)2
NC
H
(±)-cis-25
i
O
NHCBn
H
O
O
NH2
H
P(OEt)2
P(OEt)2
NC
NC
H
H
(–)-cis-25
(+)-cis-26
ii
ii
The versatile 3-oxocyclobutylphosphonate 15 also facilitates
access to the homologous diethyl 3-formylcyclobutylphos-
phonate 24 (Scheme 3), which was successfully prepared by
reaction of the anion of diethyl isocyanomethylphosphonate22
with diethyl 3-oxocyclobutylphosphonate 15 and subsequent
hydrolysis with 6  HCl. Diethyl 3-formylcyclobutylphos-
phonate 24 was isolated in good yield as a 1:1 mixture of the
two isomers as determined by 31P NMR. The two isomers were
inseparable by chromotography, so the mixture was carried
though to the next stage, when separation of the diastereoi-
somers was likely to be easier.
O
O
NH2
H
NH2
H
P(OH)2
P(OH)2
HO2C
HO2C
H
H
(–)-cis-8
(+)-cis-8
Scheme 6 Reagents and conditions: i, Penicillinacylase (immobilised
on Eupergit), phosphate buffer pH 7, MeOH, 27 ЊC; ii, H+, H2O, reflux,
Dowex 50W (H+) ion exchange column
3.5.1.11) from Escherichia coli provided a mild, highly enantio-
selective, high yielding method of resolution. The hydrolyses
were carried out using penicillinacylase immobilised on
Eupergit under the conditions described by Rossi.23 The
reactions were monitored by thin layer chromatography (TLC)
until there ceased to be an obvious increase in the amount of
phenylacetic acid produced (approximately 6 h).
Reaction of diethyl 3-formylcyclobutylphosphonate 24 with
sodium cyanide and ammonium chloride in ammonium
hydroxide for 12 h, with light excluded, produced a high yield
of the desired amino results (Scheme 5). Little or no formation
The absolute configuration of the isomers is not known.
However, it is likely that the isomer hydrolysed by the enzyme
has R stereochemistry. Penicillinacylase is known to preferen-
tially hydrolyse the -isomer of amino acids and extensive
efforts have been made to determine factors that influence the
stereoselectivity of the hydrolysis of other phenylacetylamino
compounds.23 These studies have shown that when a nitrile,
rather than a carboxylic acid functionality, is present on the
carbon α to the phenylacetylamino group and the third sub-
stituent is larger than an ethyl group, e.g. an isopropyl or phenyl
group, then the R-isomer is the one which is preferentially
hydrolysed. As the cyclobutane ring can be thought of as iso-
propyl group that has a carbon joining the two methyl groups
together, then it is plausible to expect a similar stereoselectivity
in the hydrolysis of these cyclobutane compounds.
O
O
P(OEt)2
H
24
i–iii
O
O
NHCBn
NHCBn
O
H
P(OEt)2
NC
NC
P(OEt)2
H
H
H
O
(±)-cis-25
(±)-trans-25
The amino nitriles 26 and phenylacetylamino nitriles 25 were
hydrolysed to the corresponding aminophosphine acids 8 and
purified by ion exchange chromatography (Dowex 50W, H+
Scheme 5 Reagents and conditions: i, NaCN, NH4Cl, NH4OH, room
temp.; ii, BnCoCl, Et3N, CH2Cl2; iii, flash silica chromatography
(hexane–PriOH, 7:3)
496
J. Chem. Soc., Perkin Trans. 1, 1997

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form) yielding the enantiomerically pure aminophosphonic
acids.
lect the intensity data in the ω–2θ mode. Unit cell parameters
and orientation were obtained by least-squares refinement of
the setting angles of 20 high angle reflections. The structures
were solved by direct methods (using SHELXTL-Plus) and
refined using full-matrix least-squares on F 2 (using
SHELXL93).25 All non-hydrogen atoms were refined aniso-
tropically. All hydrogen atoms were given isotropic thermal
parameters equal to 1.2 (or 1.5 for methyl groups) times the
equivalent isotropic displacement parameter of the atom to
which it is attached.
The enantiomeric purities of the compounds were deter-
mined by 19F NMR analysis of the Mosher’s amides.26
Reaction of samples of the hydrolysed isomer with α-methoxy-
α-trifluoromethylphenylacetyl chloride provided the Mosher’s
amide of the amino nitrile. On comparison of the 19F NMR
spectrum of the single enantiomer from the enzymatic
hydrolysis with the 19F NMR spectrum of a sample of the
Mosher’s amide of the racemic compound, no evidence of a
signal in the 19F NMR spectrum corresponding to the opposite
enantiomer was found in either of the two diastereoisomers.
However, given that the sample converted to the Mosher’s
amide was in the region of 3–4 mg, it would be unwise to say
that the enantiomeric purity was greater than 95%.
Conclusion
The synthesis of the key intermediate diethyl 3-oxocyclobutyl-
phosphonate 15 has facilitated the synthesis of a variety of
novel, biologically interesting 3-phosphonocyclobutyl amino
acids. Both diastereoisomers of 3-amino-3-carboxycyclobutyl-
phosphonic acid 7 have been prepared via a modified Strecker
reaction. In the synthesis of 3-aminocyclobutylphosphonic
acid 22, the cyclobutylphosphonic acid analogue of γ-amino-
butyric acid (GABA), only the cis-isomer was obtained due to a
diastereoselective hydrogenation of the intermediate hydroxyl-
amine. The synthesis of trans- and cis-diethyl 3-formylcyclo-
butylphosphonates 24 was also carried out and the products
were transformed into trans- and cis-3-[amino(carboxy)-
methyl]cyclobutylphosphonic acid 8, the homologue of 3-
amino-3-carboxycyclobutylphosphonic acid. In all cases the
diastereoisomers were separable at the N-protected amino
nitrile stage by column chromatography. The enantiomers of 3-
[amino(carboxy)methyl]cyclobutylphosphonic acids
8 were
separated by enantioselective enzymatic hydrolysis of the
intermediate diethyl 3-[(phenylacetylamino)cyanomethyl]cyclo-
butylphosphonates 25. Using this method of resolution, high
enantioselectivities were obtained. Thus, diethyl 3-oxocyclo-
butylphosphonate 15 is a versatile intermediate in the synthesis
of diastereomerically and enantiomerically pure cyclobutyl-
phosphonic acid analogues of amino acids.
Diethyl 3-(benzyloxy)cyclobutylphosphonate 12
Diethyl methylphosphonate (5 g, 32.9 mmol), as a solution in
anhydrous THF (150 cm3) at Ϫ78 ЊC under an atmosphere of
nitrogen, was treated with butyllithium (13.2 cm3, 33 mmol).
The solution was stirred at Ϫ78 ЊC for 30 min and then
1-chloro-2-benzyloxy-3-bromopropane (4.3 g, 16.45 mmol) was
added. The reaction mixture was stirred at Ϫ78 ЊC for 1 h and
then warmed to room temperature and stirred for a further 1 h.
The reaction was quenched by the addition of saturated
ammonium chloride. The THF was removed in vacuo and the
aqueous layer extracted with CH2Cl2 (4 × 40 cm3. The organic
fractions were combined, washed with water (2 × 40 cm3) and
brine (2 × 30 cm3), dried over anhydrous MgSO4 and filtered,
and the solvent removed under reduced pressure. The excess
diethyl methylphosphonate (40 ЊC, 0.1 mmHg), unreacted
1-chloro-2-benzyloxy-3-bromopropane (100 ЊC, 0.1 mmHg)
and some mono-substituted product (120–135 ЊC, 0.1 mmHg)
were removed by distillation under reduced pressure. The resi-
due was purified by Kugelrohr distillation (200–205 ЊC, 0.1
mmHg) to yield the desired products 12 as a colourless oil (2.4
g, 49% yield) as a mixture of trans- and cis-isomers in a 2:1
ratio; δH (250 MHz; CDCl3) 1.23 (6 H, t, J 7.3, OCH2CH3),
2.84–3.83 [5 H, br m, C(1)-H, C(2)-H and C(4)-H], 4.11 [4.7 H,
m, OCH2CH3 and C(3)-H of trans-isomer], 4.25 [0.3 H, m,
C(3)-H of cis-isomer], 4.35 (2 H, br s, PhCH2O), 7.33 (5 H, br s,
Experimental
Optical rotations were recorded on an Optical Activity Ltd
model AA-1000 polarimeter at 589 nm (Na D-line) with a path
length of 2 dm. Concentrations (c) are quoted in g 100 cmϪ3
.
Microanalyses were performed at the Univeristy of Warwick.
Infrared spectra were recorded neat, in solution or as Nujol
mulls on a Perkin-Elmer 1720X Fourier transform spectrometer
using sodium chloride plates. Only selected absorbances (νmax
)
1
are reported. H NMR spectra were recorded at either 250 or
400 MHz on Bruker ACF 250 or Bruker ACP 400 instruments
respectively. 13C NMR spectra were recorded at 62.9 MHz on a
Bruker ACF 250 instrument or 100.6 MHz on a Bruker ACP
400 instrument. 31P NMR spectra were recorded at 162 or 101
MHz on a Bruker ACP 400 or Bruker ACF 250 instrument,
respectively. 19F NMR spectra were recorded at 376.3 MHz on a
Bruker ACP 400 instrument. Chemical shifts (δ) are quoted in
parts per million (ppm), referenced externally to SiMe4 (1H,
13C), 85% phosphoric acid (31P) or F3CCO2H (19F); J values are
given in Hz. All mass spectra were recorded on a Kratos MS 90
spectrometer, with only molecular ions (M+) and major peaks
being reported, with intensities quoted as percentages of the
base peak. Chemicals were purchased from Aldrich, Fluka or
Sigma at the highest available grade. Penicillin G acylase,
immobilised on Eupergit (10 000 units per 100 g wet weight)
was purchased from Rohm-Pharm GMBH, Weiterstadt. All
solvents were purchased from Fisons Scientific Equipment at
SLR grade and purified, when required, by literature methods.24
Thin layer chromatography (TLC) was performed on
aluminium-backed plates pre-coated with silica (0.2 mm,
60F254) which were developed using one or more of the follow-
ing agents: UV fluorescence (254 nm), iodine vapour, potassium
permanganate solution (0.5% v/v), ammonium molybdate
(2.5% w/v), p-anisaldehyde (2.5% v/v) or ninhydrin (0.2% w/v).
Flash chromatography was performed on silica gel (Merck
Kieselgel 60F254, 230–400 mesh).
3
ArH); δC(63 MHz; CDCl3) 16.41 (d, JCP 5.9, 2 × OCH2CH3),
20.9 (d, JCP 154.5, C-1 trans-isomer), 22.6 (d, JCP 149.6, C-1 cis-
2
isomer), 30.67 (d, JCP 5.9, C-2 and C-4 cis-isomer), 31.68 (d,
2
2JCP 4.9, C-2 and C-4 trans-isomer), 61.57 (d, JCP 7.9,
2 × OCH2CH3), 69.81 (PhOCH2), 70.13 (d, 3JCP 35.4 C-3 trans-
3
isomer), 71.37 (d, JCP 4.9 C-3 cis-isomer), 127.57, 127.68,
128.27 and 137.79 (6 C, Ar); δP(162 MHz; CDCl3) 33.17 (trans-
isomer), 36.59 (cis-isomer); MS (NH3 CI) m/z 299 ([M + H]+,
40%), 209 (13), 192 (12), 163 (10), 91 (100), 79 (20) (HRMS:
calc. for C15H24O4P [M + H], 299.1412. Found, 299.1410).
Diethyl 3-hydroxycyclobutylphosphonate 13
A solution of diethyl 3-(benzyloxy)cyclobutylphosphonate 12
(20 g, 67.1 mmol) in MeOH (150 cm3) was hydrogenated (3 atm)
over palladium on carbon (200 mg) until the uptake of hydro-
gen ceased (ca. 3 h). The catalyst was removed by filtration
through Celite, which was washed with MeOH (3 × 20 cm3).
Removal of the solvent in vacuo yielded the alcohols 13 as a
colourless oil (13.9 g, 100% yield) which was used without fur-
ther purification; νmax(neat)/cmϪ1 3382, 2995, 2910, 1445, 1235,
1163; δH (250 MHz; CDCl3) 1.25 (6 H, m, OCH2CH3), 1.9–2.55
X-Ray crystallographic measurements were made with a
Siemens P3R3 four-circle diffractometer equipped with an
Oxford Cryosystems Cooler (version 2.4). Graphite mono-
chromated Mo-Kα radiation (λ = 0.710 73 Å) was used to col-
J. Chem. Soc., Perkin Trans. 1, 1997
497

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[5 H, m, C(1)-H, C(2)-H and C(4)-H], 4.05 (4 H, m,
OCH2CH3), 4.25 [0.7 H, m, C(3)-H trans-isomer], 4.45 [0.3 H,
m, C(3)-H cis-isomer]; δC(63 MHz; CDCl3) 16.31 (d, JCP
mmol) and phenylacetyl chloride (2.1 g, 13.4 mmol). The reac-
tion mixture was stirred at room temperature for 12 h, after
which time the solution as diluted to CH2Cl2 (100 cm3) and
washed with water (3 × 20 cm3), dilute hydrochloric acid
(2 × 20 cm3), saturated sodium hydrogen carbonate (3 × 20
cm3), water (2 × 20 cm3) and brine (2 × 20 cm3). The organic
solution was dried over anhydrous magnesium sulfate, filtered
and the solvent removed under reduced pressure to yield the
crude product as an orange oil. Separation of the isomers was
achieved using silica gel chromatography (CH2Cl2–MeOH,
99:1) to give each isomer as a colourless oil. The isomer with the
higher Rf value was crystallised by cooling an Et2O solution of
the compound to Ϫ100 ЊC to given an off white solid (2.4 g,
54%); Rf 0.65 (99:1 CH2Cl2–MeOH); mp 43 ЊC (Found: C,
57.76; H, 6.28; N, 3.89; C17H22NO5P requires C, 58.12; H, 6.31;
N, 3.99%); νmax(CH2Cl2)/cmϪ1 3075, 3068, 3039, 2140, 1752;
δH (250 MHz; CDCl3) 1.24 (6 H, t, J 7.7, OCH2CH3), 2.55–2.71
[3 H, m, C(1)-H, C(2)-H and C(4)-H], 2.85–2.95 [2 H, m, C(2)-
H and C(4)-H], 3.64 (2 H, s, PhCH2CO), 4.01 (4 H, m,
OCH2CH3), 7.21 and 7.32 (5 H, m, Ar-H); δC(63 MHz; CDCl3)
3
5.6, 2 × OCH2CH3), 19.14 (d, JCP 154, C-1 trans-isomer), 20.71
(d, JCP 151, C-1 cis-isomer), 33.35 (2JCP 6.2, C-2 and C-4
cis-isomer), 34.26 (2JCP 5.3, C-2 and C-4 trans-isomer), 61.61
3
3
(d, JCP 5.4, 2 × OCH2CH3), 64.28 (d, JCP 33, C-3 trans-
3
isomer), 65.00 (d, JCp 5.6, C-3 cis-isomer); δP(162 MHz;
CDCl3) 32.2 (trans-isomer), 35.0 (cis-isomer); MS (EI) m/z 208
(M+, 10%), 195 (10), 165 (25), 138 (45), 109 (60), 91 (30), 83
(100) (HRMS: calc. for C8H18O4P [M + H], 209.0943. Found,
209.0942).
Diethyl 3-oxocyclobutylphosphonate 15
To a solution of RuCl3 (150 mg) in CH2Cl2 (50 cm3) was added
a solution of NaIO4 (2 g) in water (50 cm3). The biphasic mix-
ture was stirred at room temperature for 12 h. The aqueous
layer was separated and extracted with CH2Cl2, (2 × 10 cm3).
The combined yellow organic layers were added to a solution of
diethyl 3-hydroxycyclobutylphosphonate 13 (12 g, 57.7 mmol)
in CH2Cl2 (20 cm3) and a solution of NaIO4 (24.7 g, 115.4
mmol) in water (100 cm3). The biphasic mixture was stirred
vigorously (ca. 16 h) until the yellow colour persisted on stand-
ing. Sufficient water to dissolve the NaIO3 was added to the
reaction mixture. The two layers were separated and the aque-
ous layer extracted with CH2Cl2 (3 × 30 cm3). The combined
organic layers were washed with water (2 × 50 cm3) and brine
(2 × 40 cm3), dried over anhydrous magnesium sulfate and fil-
tered, and the solvent evaporated in vacuo. The crude ketone
containing RuCl3 was purified by Kugelrohr distillation (160–
165 ЊC, 0.1 mmHg) to yield the pure ketone 15 (10.8 g, 90%);
νmax(neat)/cmϪ1 2985, 1785, 1228, 1054; δH (250 MHz; CDCl3)
1.21 (6 H, t, J 7.3, OCH2CH3), 2.55 [1 H, m, C(1)-H], 3.11–3.37
[4 H, m, C(2)-H and C(4)-H], 4.01 (4 H, q, J 7.3 OCH2CH3);
δC(63 MHz; CDCl3) 16.31 (d, 3JCP 5.6, OCH2CH3), 20.47 (d, JCP
3
16.33 (d, JCP 5.9, OCH2CH3), 21.05 (d, JCP 154.8, C-1), 35.48
2
2
(d, JCP 4.9, C-2 and C-4), 40.33 (PhCH2), 62.12 (d, JCP
6.9, OCH2CH3), 65.48 (d, 3JCP 20.95, C-3), 117.96 (CN), 127.41,
128.65, 129.06, 132.25 (6 C, Ar), 169.18 (C᎐O); δ (162 MHz;
᎐
P
CDCl3) 27.62; MS (EI) m/z 351 (M+, 27%), 205 (46), 181 (31),
169 (40), 118 (96), 91 (50), 83 (100).
X-Ray crystallography. Crystals were colourless plates of
formula C17H22NO5P grown from a saturated solution in
pentane–diethyl ether–toluene at ambient temperature; ortho-
rhombic, a = 9.991(5), b = 12.885(8), c = 28.39(2) Å, α = 90,
β = 90, γ = 90Њ, space group Pcba, U = 3655(4) Å3, Z = 8,
Dc = 1.277 mg dmϪ3, Mo-Kα radiation (λ = 0.710 69 Å), µ(Mo-
Kα) = 0.84 mmϪ1, T = 220 K, R = 0.0366 for 2405 unique reflec-
tions observed [I/σ(I) ≥ 2.0] reflections.†
2
2
trans-Diethyl 3-(phenylacetoxy)-3-cyanocyclobutylphosphonate
trans-20
157.9, C-1), 49.15 (d, JCP 4.6, C-2 and C-4), 62.13 (d, JCP 6.6,
3
OCH3CH3), 202.8 (d, JCP 18.4, C᎐O); δ (162 MHz; CDCl )
᎐
P
3
30.2; MS (NH3 CI) m/z 224 ([M + 18]+, 22%), 206 ([M + H]+,
100), 178 (32), 165 (43), 138 (25), 109 (29) (HRMS: calc. for
C8H16O4P [M + H], 207.0786. Found, 207.0789).
The lower Rf isomer from above was isolated (1.3 g, 30%),
Rf 0.55 (99:1 CH2Cl2–MeOH) (Found: C, 57.92; H, 6.38; N,
3.87; C17H22NO5P requires C, 58.12; H, 6.31; N, 3.99%);
νmax(CH2Cl2)/cmϪ1 2984, 2909, 2235, 1754; δH (250 MHz;
CDCl3) 1.30 (6 H, t, OCH2CH3), 2.62 [3 H, m, C(1)-H, C(2)-H
and C(4)-H], 2.94 [2 H, m, C(2)-H and C(4)-H], 3.63 (2 H, s,
PhCH2), 4.07 (4 H, m, OCH2CH3), 7.21–7.36 (5 H, m, Ar-H);
cis/trans-Diethyl 3-cyano-3-hydroxycyclobutylphosphonate 19
Ammonium chloride (1.09 g, 20 mmol), sodium cyanide (1 g, 20
mmol) and alumina (2.8 g, 34 mmol) were suspended in MeCN
(60 cm3). The suspension was sonicated for 10 min and then a
solution of diethyl 3-oxocyclobutylphosphonate 15 (3.5 g, 17
mmol) in MeCN (5 cm3) was added and the reaction was soni-
cated for 15 h. The reaction mixture was filtered through a pad
of Celite which was washed with MeCN (50 cm3). The com-
bined MeCN fractions were evaporated in vacuo and then taken
up in CH2Cl2 (40 cm3) and washed with water (2 × 20 cm3) and
brine (2 × 20 cm3), dried over anhydrous magnesium sulfate
and filtered, and evaporated to dryness to yield a colourless oil
which was identified as a mixture of the two isomers of diethyl
3-cyano-3-hydroxycyclobutylphosphonate 19 (3.14 g, 79%);
νmax(neat)/cmϪ1 3382, 2221, 1164, 1052, 1023; δH (250
MHz; CDCl3) 1.24 (6 H, t, J 7.2, OCH2CH3), 2.39–2.89 [5 H, br
m, C(1)-H, C(2)-H and C(4)-H], 4.08 (4 H, m, OCH2CH3);
δC(63 MHz; CDCl3) 16.23 (d, 3JCP 5.6, 2 × OCH2CH3), 21.61 (d,
JCP 158.6, C-1 minor isomer), 24.74 (d, JCP 156.1, C-1 major
isomer), 36.23 (d, 2JCP 5.7, C-2 and C-4 minor isomer), 37.56 (d,
3
δC(63 MHz; CDCl3) 16.27 (d, JCP 5.9, OCH2CH3), 23.76 (d,
2
JCP 155.5, C-1), 34.27 (d, JCP 4, C-2 and C-4), 40.53 (PhCH2),
62.20 (d, 2JCP 6.9, OCH2CH3), 66.47 (d, 3JCP 12, C-3), 117.13 (d,
4JCP 2.9, CN), 127.41, 128.48, 129.00 and 132.31 (6 C, Ar),
162.32 (C᎐O); δ (162 MHz; CDCl ) 28.25; MS (EI) m/z 351
᎐
P
3
(M+, 31%), 205 (38), 181 (32), 169 (48), 118 (93), 91 (62), 83
(100).
cis/trans-Diethyl 3-(p-methoxybenzylamino)-3-cyanocyclobutyl-
phosphonate 21
To a solution of diethyl 3-oxocyclobutylphosphonate 15 (1.5 g,
7.3 mmol) and sodium cyanide (430 mg, 8.74 mmol) in dry
MeOH was added p-methoxybenzylamine (1.2 g, 9.7 mmol).
The solution was cooled to 0 ЊC and glacial acetic acid (1 cm3)
was added in a dropwise fashion. The reaction mixture was
heated gradually with stirring to 60 ЊC for 20 h. After cooling to
room temperature the solution was neutralised with saturated
sodium hydrogen carbonate (5 cm3), the solvent was removed
under reduced pressure and the residue taken up in CH2Cl2 (30
cm3) and water (20 cm3). The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (2 × 15 cm3). The
2
2JCP 4.9, C-2 and C-4 major isomer), 62.28 (d, JCP 6.7,
3
2 × OCH2CH3), 63.26 (d, JCP 23.5, C-3 minor isomer), 64.35
3
(d, JCP 33.7, C-3 major isomer), 121.71 (CN); MS (NH3 CI)
m/z 233 ([M + H]+, 16%), 205 (83), 165 (81), 138 (100), 111 (69).
† Atomic coordinates, thermal parameters and bond lengths and angles
have been deposited at the Cambridge Crystallographic Data Centre
(CCDC). See Instructions for Authors, J. Chem. Soc., Perkin Trans. 1,
1997, Issue 1. Any request to the CCDC for this material should quote
the full literature citation and the reference number 207/75.
cis-Diethyl 3-(phenylacetoxy)-3-cyanocyclobutylphosphonate
cis-20
To a solution of the crude cyanohydrin 15 (3.0 g, 12.9 mmol) in
CH2Cl2 (40 cm3) at 0 ЊC was added triethylamine (2.73 g, 27
498
J. Chem. Soc., Perkin Trans. 1, 1997

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combined organic layers were washed with water (2 × 20 cm3)
and brine (2 × 20 cm3), dried over anhydrous magnesium sul-
fate and filtered, and the solvent removed in vacuo yielding the
crude α-(p-methoxybenzylamino) nitrile 21 as a mixture of the
two isomers in a 3:2 ratio. The crude product was purified by
silica gel chromatography (CH2Cl2–MeOH, 95:5). Separation
of the isomers was achieved by silica gel chromatography (3
times) (hexane–PriOH, 85:15) to afford pure cis-diethyl
3-(p-methoxybenzylamino)-3-cyanocyclobutylphosphonate
(1.37 g, 53%), Rf 0.52 (hexane–PriOH, 8:2) (Found: C, 57.82;
H, 7.08; N, 7.85; C17H25N2O4P requires C, 57.95; H, 7.15; N,
7.95%); νmax(CH2Cl2)/cmϪ1 3278, 2982, 2839, 2221, 1795, 1686;
δH (400 MHz; CDCl3) 1.23 (6 H, t, J 7.0, OCH2CH3), 2.06 (1 H,
br s, NH), 2.32 [2 H, m, C(2)-H and C(4)-H], 2.59 [3 H, m, C(1)-
H, C(2)-H and C(4)-H], 3.68 (2 H, s, PhCH2), 3.73 (3 H, s,
OCH3), 4.00 (4 H, m, OCH2CH3), 6.78 (2 H, d, J 8.7, Ar-H),
ladium on carbon for 4 h. The reaction mixture was filtered
through a pad of Celite, which was then washed with MeOH
(2 × 10 cm3). The combined filtrates were evaporated to dryness
under reduced pressure. The residue was dissolved in dilute
hydrochloric acid (1 , 15 cm3) and extracted with CH2Cl2
(2 × 10 cm3). The aqueous fraction was adjusted to pH 8 with
aqueous sodium hydroxide (1 ) and extracted with CH2Cl2
(3 × 15 cm3). The CH2Cl2 fractions were washed with water
(2 × 10 cm3) and brine (2 × 10 cm3), dried over anhydrous mag-
nesium sulfate and filtered, and the solvent evaporated in vacuo
to afford diethyl 3-amino-3-cyanocyclobutylphosphonate as a
crude oil which was used in the next step without further
purification.
cis-3-Amino-3-carboxycyclobutylphosphonic acid cis-7
cis-Diethyl3-(p-methoxybenzylamino)-3-cyanocyclobutylphos-
phonate 21 was deprotected by either of the methods described
above to afford cis-diethyl 3-amino-3-cyanocyclobutylphos-
phonate; δH (250 MHz; CDCl3) 1.279 (6 H, t, J 6.8, OCH2CH3),
2.16 (2 H, br s, NH2), 2.24 [2 H, m, C(2)-H and C(4)-H], 2.32 [3
H, br m, C(1)-H, C(2)-H and C(4)-H], 4.03 (4 H, m,
OCH2CH3); δC(63 MHz; CDCl3) 16.23 (d, 3JCP 6.4, OCH2CH3),
3
7.20 (2 H, d, J 8.7, Ar-H); δC(100 MHz; CDCl3) 16.31 (d, JCP
4.8, OCH2CH3), 22.20 (d, JCP 154.8, C-1), (d, 2JCP 6.4, C-2 and
3
C-4), 48.29 (PhCH2), 52.44 (d, JCP 27.1, C-3), 55.10 (OCH3),
2
61.92 (d, JCP 6.4, OCH2CH3), 113.73 (2 C, Ar), 121.35 (CN),
129.50, 130.31 and 158.85 (4 C, Ar); δP(162 MHz; CDCl3) 29.17;
MS (NH3 CI) m/z 353 ([M + H]+, 5%), 326 (71), 207 (20), 136
(12), 121 (100).
2
22.51 (d, JCP 143, C-1), 34.25 (d, JCP 6.3, C-2 and C-4), 51.78
3
2
(d, JCP 24, C-3), 61.92 (d, JCP 6.5 OCH2CH3), 121.25 (CN).
Crude cis-diethyl 3-amino-3-cyanocyclobutylphosphonate (100
mg, 0.43 mmol) was dissolved in hydrochloric acid (6 , 10 cm3)
and the solution was heated to reflux for 48 h. After cooling the
solution was evaporated to dryness under reduced pressure. The
residue was dissolved in water (2 cm3) and applied to an ion
exchange column (Dowex 50W, H+ form). The column was
washed with water (100 cm3) and then eluted with aqueous
pyridine (1 , 200 cm3). Ninhydrin active fractions were com-
bined and evaporated to dryness under reduced pressure.
Residual traces of pyridine were removed by repeatedly dissolv-
ing the compound in water (10 cm3) and re-evaporating (3
times), affording the title compound cis-7 as an off-white solid
(62 mg, 74%); δH (400 MHz; D2O) 2.28 [2 H, m, C(2)-H and
C(4)-H], 2.56 [1 H, m, C(1)-H], 2.73 [2 H, M, C(2)-H and C(4)-
trans-Diethyl 3-(p-methoxybenzylamino)-3-cyanocyclobutyl-
phosphonate trans-21
The lower Rf isomer from above was isolated as an off white
solid (801 mg, 31%), Rf 0.43 (hexane–PriOH, 85:15) mp 45 ЊC
(Found: C, 57.87; H, 7.19; N, 8.03; C17H25N2O4P requires C,
57.95; H, 7.15; N, 7.95%); νmax(CH2Cl2)/cmϪ1 3276, 2982, 2909,
2221, 1795, 1613, 1249, 1176; δH (400 MHz; CDCl3) 1.33 (6 H, t,
J 7.0, OCH2CH3), 1.63 (1 H, br, s, NH), 2.22 [2 H, m, C(2)-H
and C(4)-H], 2.68 [2 H, m, C(2)-H and C(4)-H], 2.91 [1 H, m,
C(1)-H], 3.72 (2 H, br d, J 4.9, PhCH2), 3.76 (3 H, s, OCH3),
4.07 (4 H, m, OCH2CH3), 6.83 (2 H, d, J 8.8, Ar-H), 7.23 (2 H,
3
d, J 8.8, Ar-H); δC(100 MHz; CDCl3) 16.36 (d, JCP 4.8,
OCH2CH3), 24.58 (d, JCP 154.8, C-1), 33.12 (d, 2JCP 6.4, C-2 and
3
C-4), 48.38 (PhCH2), 50.60 (d, JCP 23.9, C-3), 55.13 (OCH3),
61.89 (d, 2JCP 6.4, OCH2CH3), 113.84 (2 C, Ar), 120.21 (d, 4JCP
4.8, CN), 129.96, 130.36 and 158.92 (4 C, Ar); δP(162 MHz;
CDCl3) 29.49; MS (NH3 CI) m/z 353 ([M + H]+, 6%), 326 (28),
165 (13), 136 (22), 121 (100), 95 (11), 81 (12).
H]; δC(101 MHz; D2O) 25.10 (d, JCP 142, C-1), 31.65 (d, JCP
2
3
4.8, C-2 and C-4), 57.28 (d, JCP 14.5, C-3), 176.40 (C᎐O);
᎐
δP(162 MHz; D2O) 26.51 [HRMS (FAB): calc. for C5H10NO5P,
195.0296. Found, 195.0294].
X-Ray crystallography. Crystals were colourless plates of
formula C17H22NO5P grown from a saturated solution in
pentane–diethyl ether–toluene at ambient temperature; tri-
clinic, a = 7.630(3), b = 9.882(5), c = 13.604(6) Å, α = 94.09(4),
trans-3-Amino-3-carboxycyclobutylphosphonic acid trans-7
trans-Diethyl 3-(p-methoxybenzylamino)-3-cyanocyclobutyl-
phosphonate 21 was deprotected by either of the methods
described above to afford trans-diethyl 3-amino-3-cyanocyclo-
butylphosphonate; δH (250 MHz; CDCl3) 1.27 (6 H, t, J 6.8,
OCH2CH3), 2.18 (2 H, br s, NH2), 2.35 [3 H, m, C(1)-H,
C(2)-H and C(4)-H], 2.68 [2 H, m, C(2)-H and C(4)-H], 4.03
3
¯
β = 104.07(3), γ = 99.27(4)Њ, space group P1, U = 975.4(8) Å ,
Z = 2, Dc = 1.200 mg dmϪ3, Mo-Kα radiation (λ = 0.710 69 Å),
µ(Mo-Kα) = 0.84 mmϪ1, T = 220 K, R = 0.0548 for 3443 unique
reflections observed [I/σ(I) ≥ 2.0] reflections.†
3
(4 H, m, OCH2CH3); δC(63 MHz; CDCl3) 16.33 (d, JCP 6.4,
2
Deprotection of compound 21
OCH2CH3), 24.02 (d, JCP 144, C-1), 32.85 (d, JCP 6.3, C-2
3
2
Oxidative removal of the N-p-methoxybenzyl group. Ceric
ammonium nitrate (822 mg, 1.5 mmol) was added to a solution
of the p-methoxybenzylamino nitrile 21 (80 mg, 0.23 mmol)
in MeCN and water (6 cm3, 9:1). The reaction was monitored
by TLC(CH2Cl2–MeOH, 19:1). After 2 h no starting material
remained. The reaction mixture was diluted by the addition of
water (20 cm3) and extracted with CH2Cl2 (3 × 15 cm3). The
organic fractions were then extracted with dilute hydrochloric
acid (1 , 2 × 15 cm3) and the acidic fractions were adjusted to
pH 8 and extracted with CH2Cl2 (3 × 10 cm3). The CH2Cl2 frac-
tions were washed with water (2 × 10 cm3) and brine (2 × 10
cm3), dried over anhydrous magnesium sulfate and filtered, and
the solvent evaporated in vacuo to afford the deprotected α-
amino nitrile compound as a crude oil which was used in the
next step without further purification.
and C-4), 50.01 (d, JCP 17, C-3), 61.82 (d, JCP 6.5
4
OCH2CH3), 120.06 (d, JCP 3.9, CN). Crude trans-diethyl 3-
amino-3-cyanocyclobutylphosphonate (100 mg, 0.43 mmol)
was dissolved in hydrochloric acid (6 , 10 cm3) and the solu-
tion was heated to reflux for 48 h. After cooling the solution
was evaporated to dryness under reduced pressure. The residue
was dissolved in water (2 cm3) and applied to an ion exchange
column (Dowex 50W, H+ form). The column was washed with
water (100 cm3) and then eluated with aqueous pyridine (1 ,
200 cm3). Ninhydrin active fractions were combined and
evaporated to dryness under reduced pressure. Residual traces
of pyridine were removed by repeatedly dissolving the com-
pound in water (10 cm3) and re-evaporating (3 times) afford-
ing the title compound trans-7 as an off-white solid (67 mg,
76%); δH (400 MHz; D2O) 2.33 [3 H, m, C(1)-H, C(2)-H and
C(4)-H], 2.46 [2 H, m, C(2)-H and C(4)-H]; δC(101 MHz;
Removal of the N-p-methoxybenzyl group by hydrogenation. A
solution of the p-methoxybenzylamino nitrile 21 (100 mg, 0.29
mmol) in MeOH (15 cm3) was hydrogenated (3 atm) over pal-
2
D2O) 22.76 (d, JCP 141, C-1), 31.77 (d JCP 4.8, C-2 and
3
4
C-4), 55.18 (d, JCP 16, C-3), 175.22 (d, JCP 3.1, C᎐O). δ (162
᎐
P
J. Chem. Soc., Perkin Trans. 1, 1997
499

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MHz; D2O) 25.70 [HRMS (FAB): calc. for C5H10NO5P,
195.0296. Found 195.0293].
this temperature for 30 min and then a solution of diethyl 3-
oxocyclobutylphosphonate 15 (900 mg, 4.4 mmol) in anhydrous
THF (5 cm3) was added. The reaction mixture was stirred for a
further 2 h at Ϫ78 ЊC and then warmed to room temperature
and quenched with water (5 cm3). The THF was removed in
vacuo and the residue redissolved in diethyl ether (20 cm3) and
hydrochloric acid (6 , 10 cm3). The biphasic solution was
stirred at ambient temperature for 15 h. The diethyl ether was
removed by evaporation under reduced pressure and the aque-
ous residue was extracted with CH2Cl2 (3 × 20 cm3). The com-
bined organic extracts were washed with water (2 × 15 cm3) and
brine (2 × 15 cm3), dried over anhydrous magnesium sulfate
and filtered, and the solvent removed under reduced pressure
to afford a 1:1 mixture of the two diastereoisomers of the title
compound 24 as a colourless oil (795 mg, 83%); νmax(neat)/cmϪ1
2984, 2724, 1719, 1480, 1444, 1292, 1226; δH (250 MHz; CDCl3)
1.14 (6 H, m, OCH2CH3), 2.20–2.63 [5 H, br m, C(1)-H, C(2)-H
and C(4)-H], 3.00 [1 H, m, C(3)-H], 3.94 (4 H, m, OCH2CH3),
cis-3-Aminocyclobutylphosphonic acid 22
Hydroxylamine hydrochloride (520 mg, 8.1 mmol) was added to
a solution of diethyl 3-oxocyclobutylphosphonate (500 mg,
2.43 mmol) in water (10 cm3) and the pH of the solution was
adjusted to 4 (1  HCl). The reaction mixture was heated to
reflux for 15 h. After cooling the solution was adjusted to pH 8
(1  NaOH) and extracted with CH2Cl2 (3 × 10 cm3). The
organic extracts were washed with water (2 × 10 cm3) and brine
(2 × 10 cm3), dried over anhydrous magnesium sulfate and fil-
tered, and the solvent removed in vacuo to afford cis-diethyl 3-
hydroxyiminocyclobutylphosphonate (455 mg, 85%); νmax
-
(neat)/cmϪ1 3851, 3274, 2965, 2359, 1651; δH (250 MHz; CDCl3)
1.18 (m, 6 H, OCH2CH3), 1.75 (1 H, s, NOH), 2.25 [1 H, m,
C(1)-H], 2.97–3.30 [4 H, m, C(2)-H and C(4)-H], 3.99 (4 H, m,
OCH2CH3); δC(63 MHz; CDCl3) 16.21 (d, 3JCP 5.9, OCH2CH3),
2
21.51 (d, JCP 152.6, C-1), 31.91 (d, JCP 5.9, C-2 or C-4), 32.76
9.54 (ca. 0.5 H, t, J 1.75, HC᎐O, cis-isomer), 9.62 (ca. 0.5 H, d,
᎐
2
2
3
(d, JCP 4.9, C-2 or C-4), 62.20 (d, JCP 5.9 OCH2CH3), 152.30
(d, 3JCP 15.8, C-3); MS (NH3 CI) m/z 222 ([M + H]+, 16%), 204
(18), 191 (100), 165 (43).
J 1.2, HC᎐O, trans-isomer); δ (63 MHz; CDCl ) 16.23 (d, J
᎐
C
2
3
CP
5.9, 2 × OCH2CH3, 21.76 (d, JCP 5.9, C-2 and C-4 of one iso-
mer), 22.41 (d, 2JCP 5.9, C-2 and C-4 of other isomer), 24.59 (d,
JCP 133, C-1 of one isomer), 24.59 (JCP 151, C-1 of other iso-
mer), 42.09 (3JCP 17.7, C-3 of one isomer), 42.67 (d, 3JCP 11.8 of
other isomer), 61.79 (d, 2JCP 5.9, 2 × OCH2CH3), 200.99 (d, 4JCP
A
solution of crude diethyl 3-hydroxyiminocyclobutyl-
phosphonate (400 mg, 1.81 mmol) in MeOH (containing 4
drops of concentrated hydrochloric acid) was hydrogenated (3
atm) over rhodium on alumina (30 mg) for 15 h. The reaction
mixture was filtered through a pad of Celite, which was then
washed with MeOH (3 × 10 cm3). The combined filtrates were
evaporated to dryness under reduced pressure. The residue was
dissolved in water (3 cm3) and applied to an ion exchange col-
umn (Dowex 50W, H+ form). The column was washed with
water (100 cm3) and eluted with pyridine (200 cm3). The nin-
hydrin positive fractions were combined and evaporated to dry-
ness under reduced pressure, residual traces of pyridine were
removed by repeated addition of water (5 cm3) and re-
evaporation (3 times) to afford the title compound 22 (169 mg,
62%); δH (250 MHz; D2O) 2.26 [2 H, m, C(2)-H and C(4)-H],
2.49 [1 H, m, C(1)-H], 2.63 [2 H, m, C(2)-H and C(4)-H],
3.03 [1 H, m, C(3)-H]; δC(64 MHz; D2O) 24.32 (d, JCP 144, C-1),
28.41 (d, 2JCP 4.8, C-2 and C-4), 39.38 (d, 3JCP 4.8, C-3); δP(162
MHz; D2O) 26.32; MS (NH3 CI) m/z 169 ([M + 18]+, 24%), 152
([M + H]+, 16), 135 (12), 118 (16), 107 (100).
2.9, C᎐O cis-isomer), 201.11 (C᎐O trans-isomer); δ (162 MHz;
᎐
᎐
P
CDCl3) 29.99, 31.98; MS (NH3 CI) m/z 221 ([M + H]+, 100%),
191 (32), 165 (40), 152 (65), 138 (70), 109 (42), 55 (31) (HRMS:
calc. for C9H18O4P [M + H], 221.0943. Found, 221.0942).
(±)-cis/trans-Diethyl 2-(aminocyanomethyl)cyclobutyl-
phosphonate
To a solution of aldehyde 24 (400 mg, 1.8 mmol) in dry MeOH
(20 cm3) was added sodium cyanide (135 mg, 2.7 mmol) and
ammonium chloride (244 mg, 4.6 mmol). The reaction
was stirred at ambient temperature with light excluded for 15 h.
The MeOH was removed under reduced pressure and the resi-
due dissolved in CH2Cl2 (20 cm3) and water (20 cm3). The
organic layer was separated and the aqueous layer extracted
with CH2Cl2 (2 × 20 cm3). The combined organic layers were
washed with water (2 × 15 cm3) and brine (2 × 15 cm3), dried
over anhydrous magnesium sulfate and filtered, and the solv-
ent removed in vacuo to yield the title compound as a pale
orange oil which was used in the next step without any fur-
ther purification (385 mg, 91%); δH (250 MHz; CDCl3) 1.21 (6
H, m, OCH2CH3), 1.56 (2 H, br s, NH2), 2.11–2.74 [6 H, br
m, C(1)-H, C(2)-H, C(3)-H and C(4)-H], 3.61 [1 H, m,
HC(CN)NH2], 3.99 (4 H, m, OCH2CH3); δC(63 MHz;
cis-Diethyl 3-hydroxy-3-methylcyclobutylphosphonate cis-23
A solution of diethyl 3-oxocyclobutylphosphonate 15 (100 mg,
0.49 mmol) in anhydrous THF (15 cm3) at Ϫ78 ЊC under an
atmosphere of nitrogen, was treated with a solution of methyl-
magnesium bromide (0.17 cm3, 3  in diethyl ether). The reac-
tion mixture was stirred for 2 h at Ϫ78 ЊC then allowed to warm
to room temperature and quenched with saturated aq. ammo-
nium chloride (15 cm3). The THF was removed in vacuo and the
aqueous residue was extracted with CH2Cl2 (3 × 15 cm3). The
combined organic fractions were washed with water (2 × 15
cm3) and brine (2 × 15 cm3), dried over anhydrous magnesium
sulfate and filtered, and the solvent evaporated in vacuo to
afford the title compound cis-23 as a colourless oil (88 mg,
81%); δH (250 MHz; CDCl3) 1.24 (6 H, t, J 6.9, OCH2CH3), 1.33
(3 H, s, CH3), 2.20 [3 H, m, C(1)-H, C(2)-H and C(4)-H], 2.68 [2
H, m, C(2)-H and C(4)H], 4.01 (4 H, m, OCH2CH3); δC(63
2
CDCl3) 16.36 (3JCP 5.9, 2 × OCH2CH3), 23.79 (d, JCP 7.9, C-
2 or C-4 of one isomer), 24.01 (d, JCP 137, C-1 of one iso-
2
mer), 24.09 (d, JCP 149, C-1 of other isomer), 24.51 (d, JCP
5.9, C-2 or C-4 of one isomer and C-2 or C-4 of other iso-
2
mer), 25.36 (d, JCP 5.9, C-2 or C-4 or other isomer), 36.67
3
3
(d, JCP 21.7, C-3 of one isomer), 36.39 (d, JCP 29, C-3 of
4
other isomer), 47.55 [C(CN)NH2, trans-isomer], 47.56 [d, JCP
3.2, C(CN)NH2, cis-isomer], 61.64 (d, 2JCP 6.9,
2 × OCH2CH2), 120.62 (CN of one isomer), 120.67 (CN of
other isomer); δP(250 MHz; CDCl3) 30.52, 32.28.
3
MHz; D2O) 16.32 (d, JCP 6.9, OCH2CH3), 18.86 (d, JCP 152,
(±)-trans-Diethyl 3-[(phenylacetylamino)cyanomethyl]cyclo-
butylphosphonate (±)-trans-25
2
C-1), 26.36 (CH3), 38.30 (d, JCP 4.9, C-2 and C-4), 61.82 (d,
3
2JCP 5.9, OCH2CH3), 70.27 (d, JCP 24.6, C-3); δP(101 MHz;
Triethylamine (1.5 cm3) was added dropwise to a solution
of (±)-cis/trans-diethyl 3-(aminocyanomethyl)cyclobutylphos-
phonate (360 mg, 1.46 mmol) and phenylacetyl chloride (250
mg, 1.6 mmol) in dry CH2Cl2 (20 cm3) at room temperature.
The reaction was stirred for 15 h and then poured into water (20
cm3). The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (3 × 15 cm3). The combined organic
extracts were washed with water (2 × 15 cm3) and brine (2 × 15
cm3), dried over anhydrous magnesium sulfate and filtered, and
CDCl3) 32.15; MS (NH3 CI) m/z 223 ([M + H]+, 32%), 205 (63),
177 (24), 149 (27), 122 (100), 107 (21) (HRMS: calc. for
C9H20O4P [M + H], 223.1099. Found, 223.1094).
cis/trans-Diethyl 3-formylcyclobutylphosphonate 24
A solution of diethyl isocyanomethylphosphonate (850 mg, 4.8
mmol) in anhydrous THF (25 cm3) at Ϫ78 ЊC was treated with
butyllithium (1.92 cm3, 4.8 mmol). The solution was stirred at
500
J. Chem. Soc., Perkin Trans. 1, 1997

View Online
the solvent removed in vacuo to afford a crude product. The
diastereosiomers were separated by silica gel chromatography
to yield the title compound (±)-trans-25 (214 mg, 80.5%); Rf
0.48 (hexane–PriOH, 7:3) (Found: C, 59.29; H, 6.89; N, 7.69.
C18H25N2O4P requires C, 59.31; H, 6.92; N, 7.72%); νmax(neat)/
cmϪ1 3295, 2865, 2898, 2960, 2222, 1655, 1490, 1465, 1045;
δH (400 MHz; CDCl3) 1.26 (6 H, dt, J 7.0, 2.8, OCH2CH3), 1.96
(1 H, br s, NH), 2.04 [2 H, m, C(2)-H and C(4)-H], 2.27 [2 H, m,
C(2)-H and C(4)-H], 2.49 [1 H, m, C(1)-H], 2.79 [1 H, m, C(3)-
H], 3.57 (2 H, s, PhCH2), 4.00 (4 H, m, OCH2CH3), 4.9 [1 H, t, J
8.8, HC(CN)NHCOCH2Ph], 7.23 (3 H, m, Ar-H), 7.29 (2 H, m,
(+)-trans-26 (35 mg, 0.14 mmol) was dissolved in hydro-
chloric acid (6 , 5 cm3) and the reaction mixture heated to
reflux for 36 h. After cooling the solvent was removed by evap-
oration under reduced pressure and the residue dissolved
in water (1 cm3), applied to an ion exchange column and
washed with water (40 cm3). The column was eluted with
pyridine (1 , 90 cm3) and the ninhydrin active fractions were
combined and evaporated to dryness. Residual traces of
pyridine were removed by re-evaporation (3 times) to afford
(+)-trans-3-[amino(carboxy)methyl]cyclobutylphosphonic acid
(+)-trans-8 (19 mg, 64%); [α]2D0 +18.7 (c 0.8 in 1  HCl);
δH (400 MHz; D2O) 2.09–2.27 [2 H, br m, C(2)-H and C(4)-H],
2.30–2.62 [3 H, br m, C(1)-H, C(2)-H and C(4)-H], 2.79
[1 H, m, C(3)-H], 4.14 [1 H, m, CH(NH2)CO2H]; δC(101 MHz;
D2O) 22.45 (d, 2JCP 5.9, C-2 or C-4), 22.62 (d, 2JCP 5.2, C-2 or C-
3
Ar-H); δC(101 MHz; CDCl3) 16.33 (d, JCP 6.4, OCH2CH3),
24.02 (d, JCP 150, C-1), 24.10 (d, 2JCP 4.8, C-2 or C-4), 24.30 (d,
3
2JCP 6.4, C-2 or C-4), 34.99 (d, JCP 9.7, C-3), 42.78 (PhCH2),
2
44.17 [C(CN)NHCOCH2Ph], 61.97 (d, JCP 4.8, OCH2CH3),
2
117.35 (CN), 127.31, 128.81, 128.96 and 134.19 (6 C, Ar),
4), 23.32 (d, JCP 143, C-1), 33.28 (d, JCP 15.2, C-3), 49.29
170.94 (C᎐O); δ (162 MHz; CDCl ) 32.42; MS (NH CI) m/z
[C(NH )CO H], 176.38 (C᎐O); δ (162 MHz; D O) 25.26
᎐
2 2 P 2
[HRMS (FAB): calc. for C6H12NO5P, 209.0452. Found,
᎐
P
3
3
365 ([M + H]+, 100%), 338 (8), 273 (19), 165 (12), 136 (22), 91
(32).
209.0454].
(±)-cis-Diethyl 3-[(phenylacetylamino)cyanomethyl]cyclobutyl-
phosphonate (±)-cis-25
(Ϫ)-trans-3-[Amino(carboxy)methyl]cyclobutylphosphonic
acid (Ϫ)-trans-8
The lower Rf isomer from above was isolated (228 mg, 86%); Rf
0.40 (hexane–PriOH, 7:3) (Found: C, 59.28; H, 6.96; N, 7.77;
C18H25N2O4P requires C, 59.31; H, 6.92; N, 7.69%); νmax(neat)/
cmϪ1 3295, 2865, 2898, 2960, 2222, 1655, 1490, 1465, 1045;
δH (400 MHz; CDCl3) 1.28 (6 H, dt, J 7.0 and 2.8, OCH2CH3),
2.06 (1 H, br s, NH), 2.11–2.46 [4 H, br m, C(2)-H and C(4)-H],
2.54 [1 H, m, C(1)-H], 2.81 [1 H, m, C(3)-H], 3.62 (2 H, s,
PhCH2), 4.04 (4 H, m, OCH2C H3), 4.78 [1 H, dd, J 6.7 and 7.7,
HC(CN)NHCOCH2Ph], 7.24 (3 H, m, Ar), 7.29 (2 H, m,
(Ϫ)-trans-Diethyl 3-[(phenylacetylamino)cyanomethyl]cyclo-
butylphosphonate (Ϫ)-trans-25 (67 mg, 0.18 mmol) was
dissolved in hydrochloric acid (6 , 5 cm3) and the reaction
mixture heated to reflux for 36 h. After cooling the solvent
was removed by evaporation under reduced pressure and the
residue dissolved in water (1 cm3), applied to an ion exchange
column and washed with water (40 cm3). The column was
eluted with pyridine (1 , 90 cm3) and the ninhydrin active
fractions were combined and evaporated to dryness. Residual
traces of pyridine were removed by repeated dissolution in
water and re-evaporation (3 times) to afford (Ϫ)-trans-3-
[amino(carboxy)methyl]cyclobutylphosphonic acid (Ϫ)-trans-
8 (24 mg, 62%) [α]2D0 Ϫ17.9 (c 0.8 in 1  HCl); δH (400 MHz; D2O)
2.09–2.27 [2 H, m, C(2)-H and C(4)-H], 2.30–2.62 [3 H, br m,
C(1)-H, C(2)-H and C(4)-H], 2.79 [1 H, m, C(3)-H], 4.14 [1 H,
m, CH (NH2)CO2H]; δC(101 MHz; D2O) 22.45 (d, 2JCP 5.9, C-2
3
Ar-H); δC(101 MHz; CDCl3) 16.36 (d, JCP 6.4, OCH2CH3),
22.94 (d, 2JCP 6.5, C-2 or C-4), 23.19 (d, JCP 148, C-1), 23.63 (d,
3
2JCP 4.8, C-2 or C-4), 33.30 (d, JCP 17.7, C-3), 42.60 (PhCH2),
4
2
43.55 [d, JCP 3.2, C(CN)NHCOCH2Ph], 62.07 (d, JCP 4.8,
POCH2CH3), 117.29 (CN), 127.04, 128.61, 129.10 and 134.32
(6 C, Ar), 171.33 (C᎐O); δ (162 MHz, CDCl ) 32.24; MS (NH ,
᎐
P
3
3
CI) m/z 365([M + H]+, 100%), 338 (11), 273 (22), 165 (17),
136 (34), 91 (37).
or C-4), 22.62 (d, 2JCP 5.2, C-2 or C-4), 23.32 (d, JCP 143, C-1),
2
33.28 (d, JCP 15.2, C-3), 49.29 [C(NH )CO H], 176.38 (C᎐O);
᎐
2
2
Enantioselective enzyme hydrolysis, general procedure
δP(162 MHz; D2O) 25.26 [HRMS (FAB): calc. for C6H12NO5P,
209.0452. Found, 209.0454].
(±)-cis-Diethyl 3-[(phenylacetylamino)cyanomethyl]cyclobutyl-
phosphonate 25 (150 mg, 0.41 mmol) was dissolved in MeOH (3
cm3) and phosphate buffer (8 cm3, 0.01 M, pH 7). Penicil-
linacylase immobilised on Eupergit (ca. 20 units) was added.
The reaction mixture was incubated at 27 ЊC and monitored by
TLC (hexane–PriOH, 7:3). After conversion had ceased (ca. 6
h), the reaction mixture was filtered, adjusted to pH 4 (1  HCl)
and extracted with CH2Cl2 (3 × 10 cm3). The combined organic
fractions were washed with saturated sodium hydrogen carbon-
ate (2 × 10 cm3), water (2 × 10 cm3) and brine (2 × 10 cm3),
dried over anhydrous magnesium sulfate and filtered, and the
solvent removed in vacuo to yield crude (Ϫ)-cis-diethyl 3-
[(phenylacetylamino)cyanomethyl]cyclobutylphosphonate
(Ϫ)-cis-25 (67 mg, 45%). The acidic fraction from above was
adjusted to pH 7 (1  NaOH) and extracted with CH2Cl2
(3 × 10 cm3). The combined organic fractions were washed with
saturated aqueous sodium hydrogen carbonate (2 × 10 cm3),
water (2 × 10 cm3) and brine (2 × 10 cm3), dried over anhydrous
magnesium sulfate and filtered, and the solvent removed in
vacuo to yield crude (+)-cis-diethyl 3-(aminocyanomethyl)-
cyclobutylphosphonate (+)-cis-26 (42 mg, 41%).
(+)-cis-3-[Amino(carboxy)methyl]cyclobutylphosphonic
acid (+)-cis-8
(+)-cis-Diethyl 3-(aminocyanomethyl)cyclobutylphosphonate
(+)-cis-26 (35 mg, 0.14 mmol) was hydrolysed as described
above to afford (+)-cis-3-[amino(carboxy)methyl]cyclobutyl-
phosphonic acid (+)-cis-8 (18 mg, 61%); [α]2D0 +13.6 (c 1 in 1 
HCl), δH (400 MHz; D2O) 2.23–2.48 [4 H, br m, C(2)-H and
C(4)-H], 2.55 [1 H, m, C(1)-H], 2.87 [1 H, m, C(3)-H], 4.21 [1 H,
2
CH(NH2)CO2H]; δC(101 MHz; D2O) 22.61 (d, JCP 4.8, C-2 or
2
C-4), 22.87 (d, JCP 4.2, C-2 or C-4), 25.15 (d, JCP 142, C-1),
3
4
31.43 (d, JCP 13.8, C-3), 48.92 [d, JCP 2.8, C(NH2)CO2H],
176.21 (C᎐O); δ (162 MHz; D O) 26.48 [HRMS (FAB): calc.
᎐
P
2
for C6H12NO5P, 209.0452. Found, 209.0453].
(Ϫ)-cis-3-[Amino(carboxy)methyl]cyclobutylphosphonic
acid (Ϫ)-cis-8
(Ϫ)-cis-Diethyl3-[(phenylacetylamino)cyanomethyl]cyclobutyl-
phosphonate (Ϫ)-cis-25 (63 mg, 0.18 mmol) was treated as
described above to afford (Ϫ)-cis-3-[amino(carboxy)methyl]-
cyclobutylphosphonic acid (Ϫ)-cis-8 (24 mg, 63%); [α]2D0 Ϫ12.9
(c 9 in 1  HCl); δH (400 MHz; D2O) 2.23–2.48 [4 H, br m, C(2)-
H and C(4)-H], 2.55 [1 H, m, C(1)-H], 2.87 [1 H, m, C(3)-H],
4.21 [1 H, C(NH2)CO2H]; δC(101 MHz; D2O) 22.61 (d, 2JCP 4.8,
A similar procedure yielded (Ϫ)-trans-diethyl 3-[(phenyl-
acetylamino)cyanomethyl]cyclobutylphosphonate (Ϫ)-trans-25
(67 mg, 42%) and (+)-trans-diethyl 3-(aminocyanomethyl)cyclo-
butylphosphonate (+)-trans-26 (41 mg, 40%).
2
C-2 or C-4), 22.87 (d, JCP 4.2, C-2 or C-4), 25.15 (d, JCP 142,
(+)-trans-3-[Amino(carboxy)methyl]cyclobutylphosphonic
acid (+)-trans-8
C-1), 31.43 (d, 3JCP 13.8, C-3), 48.92 [d, 4JCP 2.8, C(NH2)CO2H],
176.21 (C᎐O); δ (162 MHz; D O) 26.48 [HRMS (FAB): calc.
᎐
P
2
(+)-trans-Diethyl3-(aminocyanomethyl)cyclobutylphosphonate
for C6H12NO56P, 209.0452. Found, 209.0454].
J. Chem. Soc., Perkin Trans. 1, 1997
501

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4 M. S. Dappen, R. Pellicciari, B. Natalini, J. B. Monham, C. Chiorri
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3767.
8 C. Grandin, N. Collignon and P. Savignac, Synthesis, 1995, 239.
9 M. Avram, C. D. Nenitzescu and M. Maxim, Chem. Ber., 1957, 90,
1424.
Preparation of 2-methoxy-2-trifluoromethyl-2-phenylacetyl-
amine derivatives
General procedure. To a sample of diethyl 3-(aminocyano-
methyl)cyclobutylphosphonate (5 mg, 20 µmol) in CH2Cl2 (1
cm3) was added triethylamine (50 mm3) and 2-methoxy-2-
trifluoromethyl-2-phenylacetyl chloride (240 mm3 of a 0.1 
solution in CH2Cl2). The reaction mixture was stirred for 12 h at
room temperature and then the solvent removed by evaporation
under reduced pressure. The residue was dissolved in CDCl3
and the sample analysed by 19F NMR spectroscopy. The spec-
tra of the enantiomerically pure samples were compared with
the spectra of the racemic samples and in all cases no evidence
of a second isomer was detected.
10 J. M. Decesare, B. Corbel, T. Durst and J. F. Blount, Can. J. Chem.,
1981, 59, 1415.
11 J. C. Menéndez, G. G. Trigo and M. M. Söllhuber, Tetrahedron
Lett., 1986, 27, 3285.
12 T. Hanafusa, J. Ichihara and T. Ashida, Chem. Lett., 1987, 687.
13 M. P. Georgiadis and S. A. Haroutounian, Synthesis, 1989, 616.
14 M. Yamamura, T. Suzuki, H. Hashimoto, J. Yoshimura, T. Oka-
moto and C.-G. Shin, Bull. Chem. Soc. Jpn., 1985, 58, 1413.
15 J. Yoshimura, M. Yamamura, T. Suzuki and H. Hashimoto,
Chem. Lett., 1983, 1001.
16 R. D. Allan, J. R. Hanrahan, T. W. Hambley, G. A. R. Johnston,
K. N. Mewett and A. D. Mitrovic, J. Med. Chem., 1990, 30, 2905.
17 H. O. House and L. F. Lee, J. Org. Chem., 1976, 41, 863.
18 K. B. Becker, M. K. Hohermuth and G. Rihs, Helv. Chim. Acta,
1982, 65, 235.
(±)-trans-Diethyl 3-[(2-methoxy-2-trifluoromethyl-2-phenyl-
acetylamino)carboxymethyl]cyclobutylphosphonate.
MHz; CDCl3) Ϫ71.89 and Ϫ7.84.
δF (376
(+)-trans-Diethyl 3-[(2-methoxy-2-trifluoromethyl-2-phenyl-
acetylamino)carboxymethyl]cyclobutylphosphonate.
MHz; CDCl3) Ϫ71.89.
δF (376
(±)-cis-Diethyl
3-[(2-methoxy-2-trifluoromethyl-2-phenyl-
acetylamino)carboxymethyl]cyclobutylphosphonate.
MHz; CDCl3) Ϫ69.85 and Ϫ71.91.
δF (376
(+)-cis-Diethyl
3-[(2-methoxy-2-trifluoromethyl-2-phenyl-
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Acknowledgements
We thank the Department of Chemistry, University of
Warwick, for financial support (J. R. H.), Professor D. H. G.
Crout for his help and suggestions and the late Dr David W.
Hutchinson for initiating this work.
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Paper 6/04898F
Received 12th July 1996
Accepted 10th October 1996
502
J. Chem. Soc., Perkin Trans. 1, 1997