Synthesis of α-aminocyclopropylphosphonic acids

Article abstract of DOI:10.1055/s-0030-1257865

A convenient, general approach to α-aminocyclopropylphosphonic acids via reduction and hydrolysis of α-nitrocyclopropylphosphonates is described. A number of the title compounds were synthesized in excellent yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1257865

PAPER
3379
Synthesis of a-Aminocyclopropylphosphonic Acids
Andrey V. Chemagin,a Nikolai V. Yashin,*a,b Yuri K. Grishin,a Tamara S. Kuznetsova,a,b Nikolai S. Zefirova,b
a
Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory 1-3, Moscow 119991, Russian Federation
Fax +7(495)9393969; E-mail: yashin-n@org.chem.msu.ru
IPhAC RAS, Severnyi Proezd 1, Chernogolovka, Moscow Region 142432, Russian Federation
b
Received 18 May 2010; revised 2 June 2010
gation of synthetic routes to the bioisosteric analogues,
aminocyclopropylphosphonic acids, is a logical continua-
tion of this work. We have already reported the synthesis
of a number of bioisosteric glycine analogues containing
small rings.5 Working further in this area, we turned our
attention to a-aminocyclopropylphosphonic acids
(Figure 2) given that only a few methods for their synthe-
sis have been described as yet.6 Moreover, a general ap-
proach to this class of compounds is lacking and needs to
be developed.
Abstract: A convenient, general approach to a-aminocyclopropyl-
phosphonic acids via reduction and hydrolysis of a-nitrocyclopro-
pylphosphonates is described. A number of the title compounds
were synthesized in excellent yields.
Key words: aminophosphonic acids, bioisosteres, cyclopropanes,
reduction, hydrolysis
Bioisosteric replacement is known to be one of the most
powerful instruments in medicinal chemistry.1 This meth-
od is used to modify lead compounds to improve pharma-
cological properties and therefore to create more effective
drugs and prodrugs. For a carboxylic group there are a
number of bioisosteres known in the literature, for exam-
ple sulfonamide, tetrazole, sulfonate or phosphonate.1c
Special interest in the phosphonic acid group2 is associat-
ed, among other issues, with its tetrahedral structure and
thereby related possible action as a ‘transition-state ana-
logue’.2d This is why bioisosteric phosphonic acid ana-
logues of such important compounds as amino acids are
finding increasing interest.
NH2
NH2
COOH
P(O)(OH)2
Figure 2 A cyclopropyl amino acid and the bioisosteric phosphonic
acid analogue
Recently, we reported a useful method for the synthesis of
structurally diverse a-nitrocyclopropylphosphonates 1 via
the rhodium(II)-catalyzed [1+2]-cycloaddition reaction of
diethyl [nitro(diazo)methyl]phosphonate (NDMP) with
various olefins (Scheme 1).7 The obtained adducts seem
to be useful synthetic precursors of the corresponding a-
aminocyclopropylphosphonic acids. Herein, we present a
convenient procedure which allows the target a-amino-
phosphonic acids bearing a cyclopropane moiety to be ob-
tained.
Restriction of conformational flexibility has also proven
effective in drug design to improve various characteristics
of biologically active substances.3 In particular, introduc-
tion of the cyclopropane ring into amino acids leads to
structures selective in binding with different subtypes of
receptors3d (Figure 1).
H2N
COOH
N2
NO2
COOH
Rh(II)
HOOC
HOOC
H2N
+
O2N
P(O)(OEt)2
P(O)(OEt)2
COOH
NDMP
1
NH2
COOH
Scheme 1 Synthesis of a-nitrocyclopropylphosphonates 1
COOH
HOOC
H2N
The first and most challenging step in the synthetic proto-
col is the reduction of the nitro group. Crucial here is to
choose appropriate reduction conditions allowing trans-
formation of the nitro group to an amine without affecting
the labile spiroconjugated cyclopropane fragment, which
can undergo ring-opening reactions.4d To the best of our
knowledge, there are no prior examples of nitro reduction
in compounds bearing a phosphonate group at the a-posi-
tion. As reported previously, for nitrocyclopropane-8 and
nitrospiropentanecarboxylates4d the best results are ob-
tained when the reduction system zinc–acetic acid–
isopropyl alcohol is applied. We investigated the behavior
Figure 1 Examples of conformationally constrained amino acids
Cyclopropyl a-amino acids have been objects of intense
interest in our laboratory for a long time.4 Previously, we
have elaborated convenient approaches to a number of
polyspirocyclic cyclopropyl amino acids, as well as con-
formationally restricted glutamate analogues.4e,f Investi-
SYNTHESIS 2010, No. 19, pp 3379–3383
x
x.
x
x
.
2
0
1
0
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1257865; Art ID: Z12910SS
© Georg Thieme Verlag Stuttgart · New York

3380
A. V. Chemagin et al.
PAPER
of a-nitrocyclopropylphosphonates7 1a–f under these
conditions and obtained the corresponding a-aminocyclo-
propylphosphonates 2a–f in high yields (Table 1). It is
essential that the spirocondensed cyclopropane fragments
remain untouched during the reaction and that the di-
ethoxyphosphoryl fragment does not affect the process.
MeOOC
HOOC
P(O)(OH)2
NH2
P(O)(OH)2
1 M HCl
H2O
NH2⋅HCl
4d, 95%
3d
Scheme 2 Hydrolysis of compound 3d
The best method for cleavage of a diethoxyphosphoryl
group is treatment of the phosphonate with trimethylsilyl
halides.6d This procedure replaces continuous boiling with
concentrated acids, unacceptable for the sensitive spiro-
condensed cyclopropane moiety. We found that heating
aminophosphonates 2a–f with excess trimethylsilyl bro-
mide in dichloromethane, followed by treatment of the re-
action mixture with propylene oxide in ethanol, leads to
the target a-aminocyclopropylphosphonic acids 3a–f in
excellent yields. In the case of [1-amino-5-(methoxycar-
ural and nonnatural amino acids. The method allows the
target compounds to be obtained under mild conditions in
excellent yields.
All reactions were performed in flame-dried glassware under a
slight positive pressure of argon using freshly distilled, anhydrous
solvents. Compounds obtained as mixtures of diastereoisomers
1
were not separated into the single isomers. H, 13C and 31P NMR
spectra were recorded at r.t. on a Bruker Avance 400 spectrometer
1
bonyl)spiro[2.3]hex-1-yl]phosphonic acid (3d), it was at 400.13, 100.61 and 161.98 MHz, respectively. The H and 13C
chemical shifts (d) were measured in ppm with respect to the sol-
vent, CDCl3 (1H: d = 7.27 ppm; 13C: d = 77.13 ppm), DMSO-d6 (1H:
d = 2.54 ppm; 13C: d = 40.45 ppm) or D2O (1H: d = 4.79 ppm; 13C:
d = 1.47 ppm for CH3CN as external standard). The 31P chemical
shifts are given relative to 85% H3PO4 (as external standard, d = 0
ppm). The NMR spectra of aminophosphonic acids 3a–c,e,f and 4d
were registered at pH 3 in D2O and those of compound 3d were reg-
also important to saponify the methyl ester group due to
its inertness towards trimethylsilyl bromide. Hydrolysis
was successfully completed after stirring for 5 minutes
with dilute aqueous hydrochloric acid, and the final ami-
nophosphonic acid was isolated in the hydrochloride form
4d in quantitative yield (Scheme 2). This compound is of
great interest as a conformationally restricted bioisosteric istered in DMSO-d6. The coupling constants in the 1H NMR spectra
were measured using selective heteronuclear 1H–{31P} decoupling.
analogue of glutamic acid.
Mass spectra were recorded on a Bruker Daltonics Ultraflex MAL-
To conclude, we have elaborated a general synthetic ap-
proach to a-aminocyclopropylphosphonic acids, a class of
DI-TOF spectrometer in positive mode, using 1,8,9-trihydroxyan-
thracene as a matrix. Melting points were determined on an
bioisosteric analogues of conformationally restricted nat- Electrothermal 9100 capillary apparatus and are uncorrected. All re-
agents, except commercial products of satisfactory quality, were
Table 1 Synthesis of a-Aminocyclopropylphosphonates and -phosphonic Acids
NO2
NH2
NH2
1. TMSBr
Zn, AcOH
i-PrOH
2. propylene oxide, EtOH
P(O)(OEt)2
P(O)(OEt)2
P(O)(OH)2
Entry Nitrophosphonate 1
Aminophosphonate 2
Yielda (%)
Aminophosphonic acid 3
Yieldb (%)
95
a
86
91
89
P(O)(OEt)2
O2N
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OH)2
H2N
H2N
b
94
92
P(O)(OH)2
H2N
P(O)(OEt)2
O2N
H2N
c
P(O)(OEt)2
P(O)(OH)2
H2N
O2N
H2N
MeOOC
MeOOC
MeOOC
P(O)(OEt)2
P(O)(OEt)2
P(O)(OH)2
d
85
82
NO2
NH2
NH2
Ph
Ph
Ph
e
f
81
91
93
87
P(O)(OEt)2
P(O)(OEt)2
P(O)(OH)2
H2N
O2N
n-Bu
H2N
n-Bu
n-Bu
P(O)(OEt)2
P(O)(OH)2
H2N
P(O)(OEt)2
O2N
H2N
a Yield of crude product.
b Yield after recrystallization.
Synthesis 2010, No. 19, 3379–3383 © Thieme Stuttgart · New York

PAPER
Synthesis of a-Aminocyclopropylphosphonic Acids
3381
purified by literature procedures prior to use. a-Nitrocyclopropyl-
phosphonates 1a–f were obtained as reported.7
2 × OCH2CH3, isomer A), 18.88 (c-Pr-CH2, isomers A and B),
22.84 (Cspiro, isomer A), 24.93 (Cspiro, isomer B), 32.55 [d,
1
1JC,P = 209 Hz, C(NH2)PO(OEt)2, isomer B], 34.20 [d, JC,P = 205
2
a-Aminocyclopropylphosphonates 2 by the Reduction of
a-Nitrocyclopropylphosphonates 1; General Procedure
Hz, C(NH2)PO(OEt)2, isomer A], 61.48 (d, JC,P = 6 Hz,
2
2 × OCH2CH3, isomer A), 61.71 (d, JC,P = 6 Hz, 2 × OCH2CH3,
To a stirred soln of a nitro compound 1 (1 mmol) and glacial AcOH
(0.6 g, 10 mmol) in i-PrOH (20 mL) was added Zn powder (1.3 g,
20 mmol) in small portions over 30 min. The resulting mixture was
stirred for 3 h, the reaction was quenched with sat. aq K2CO3 (re-
sulting in a soln at pH 10), and the mixture was stirred for 15 min
then filtered. The precipitate was washed with CH2Cl2 (2 × 5 mL).
The filtrate was extracted with CH2Cl2 (3 × 10 mL); the combined
organic fractions were dried (MgSO4) and concentrated under re-
duced pressure to yield amine 2 of satisfactory purity (>90%). The
obtained amines were used without further purification.
isomer B).
31P NMR (CDCl3): d = 26.45 (isomer A), 26.90 (isomer B).
MS (MALDI-TOF): m/z = 246 [M + 1]+.
Methyl 1-Amino-1-(diethoxyphosphoryl)spiro[2.3]hexane-5-
carboxylate (2d)
Yield: 247 mg (85%); mixture of isomers (A/B = 64:36); orange oil.
1H NMR (CDCl3): d = 0.60–0.64 (m, 1 H, c-Pr-CH2, isomer A),
0.65–0.70 (m, 1 H, c-Pr-CH2, isomer B), 1.12–1.17 (m, 1 H + 1 H,
c-Pr-CH2, isomers A and B), 1.18–1.23 (m, 6 H + 6 H,
4 × OCH2CH3, isomers A and B), 1.79 (br s, 2 H + 2 H, NH2, iso-
mers A and B), 2.19–2.31 (m, 2 H + 2 H, c-Bu-CH2, isomers A and
B), 2.44–2.58 (m, 2 H + 2 H, c-Bu-CH2, isomers A and B), 3.00–
3.05 (m, 1 H, c-Bu-CH, isomer A), 3.10–3.14 (m, 1 H, c-Bu-CH,
isomer B), 3.55 (s, 3 H, COOCH3, isomer B), 3.57 (s, 3 H,
COOCH3, isomer A), 3.95–4.03 (m, 4 H + 4 H, 4 × OCH2CH3, iso-
mers A and B).
Diethyl (1-Aminospiro[2.3]hex-1-yl)phosphonate (2a)
Yield: 200 mg (86%); orange oil.
1H NMR (CDCl3): d = 0.69–0.72 (m, 1 H, CH2), 1.17–1.22 (m, 1 H,
CH2), 1.25–1.29 (m, 6 H, 2 × OCH2CH3), 1.85–2.12 (m, 4 H,
2 × CH2), 2.25 (br s, 2 H, NH2), 2.31–2.45 (m, 2 H, CH2), 3.95–4.09
(m, 4 H, 2 × OCH2CH3).
3
13C NMR (CDCl3): d = 16.22 (c-Bu-CH2), 16.26 (d, JC,P = 7 Hz,
3
13C NMR (CDCl3): d = 16.35 (d, JC,P = 6 Hz, 4 × OCH2CH3, iso-
3
OCH2CH3), 16.32 (d, JC,P = 7 Hz, OCH2CH3), 25.20 (c-Bu-CH2),
26.87 (c-Pr-CH2), 28.37 (d, 3JC,P = 4 Hz, c-Bu-CH2), 31.39 (Cspiro),
32.69 [d, 1JC,P = 218 Hz, C(NH2)PO(OEt)2], 62.01 (d, 2JC,P = 7 Hz,
OCH2CH3), 62.11 (d, 2JC,P = 7 Hz, OCH2CH3).
mers A and B), 24.54 (c-Pr-CH2, isomer A), 24.84 (c-Pr-CH2, iso-
mer B), 27.09 (d, 2JC,P = 4 Hz, Cspiro, isomer B), 27.47 (Cspiro, isomer
A), 28.59 (c-Bu-CH2, isomer A), 29.35 (c-Bu-CH2, isomer B),
31.15 (d, 3JC,P = 5 Hz, c-Bu-CH2, isomer A), 32.00 (d, 3JC,P = 5 Hz,
c-Bu-CH2, isomer B), 32.73 (c-Bu-CH, isomer B), 33.13 (c-Bu-CH,
31P NMR (CDCl3): d = 27.01.
MS (MALDI-TOF): m/z = 234 [M + 1]+.
1
isomer A), 33.70 [d, JC,P = 205 Hz, C(NH2)PO(OEt)2, isomer B],
1
33.97 [d, JC,P = 206 Hz, C(NH2)PO(OEt)2, isomer A], 51.47
Diethyl (1-Aminospiro[2.2]pent-1-yl)phosphonate (2b)
Yield: 199 mg (91%); yellow oil.
(COOCH3, isomer B), 51.56 (COOCH3, isomer A), 61.68
2
(d, 2JC,P = 6 Hz, 2 × OCH2CH3, isomer B), 61.77 (d, JC,P = 6 Hz,
2 × OCH2CH3, isomer A), 175.29 (COOMe, isomer B), 175.60
(COOMe, isomer A).
31P NMR (CDCl3): d = 26.37 (isomer B), 26.51 (isomer A).
MS (MALDI-TOF): m/z = 292 [M + 1]+.
1H NMR (CDCl3): d = 0.82–0.91 (m, 2 H, c-Pr-CH2), 0.94–0.98 (m,
1 H, c-Pr-CH2), 1.01–1.06 (m, 1 H, c-Pr-CH2), 1.10–1.12 (m, 1 H,
c-Pr-CH2), 1.28 (dt, 3JH,H = 7.1 Hz, 4JP,H = 0.5 Hz, 3 H, OCH2CH3),
1.30 (dt, 3JH,H = 7.1 Hz, 4JP,H = 0.5 Hz, 3 H, OCH2CH3), 1.54–1.59
(m, 1 H, c-Pr-CH2), 2.61 (br s, 2 H, NH2), 4.04–4.15 (m, 4 H,
2 × OCH2CH3).
Diethyl (1-Amino-2-phenylcyclopropyl)phosphonate (2e)
Yield: 218 mg (81%); mixture of isomers (A/B = 65:35); brown oil.
13C NMR (CDCl3): d = 3.32 (c-Pr-CH2), 6.85 (d, 3JC,P = 4 Hz, c-Pr-
3
3
CH2), 16.49 (d, JC,P = 7 Hz, OCH2CH3), 16.54 (d, JC,P = 6 Hz,
1H NMR (CDCl3): d = 1.09 (t, 3JH,H = 7.1 Hz, 3 H, OCH2CH3, iso-
1
OCH2CH3), 20.09 (c-Pr-CH2), 20.14 (Cspiro), 32.85 [d, JC,P = 208
3
mer B), 1.15 (t, JH,H = 7.1 Hz, 3 H, OCH2CH3, isomer B), 1.19–
Hz, C(NH2)PO(OEt)2], 61.80 (d, 2JC,P = 7 Hz, OCH2CH3), 62.09 (d,
1.32 (m, 1 H + 1 H, c-Pr-CH2, isomers A and B), 1.33–1.41 (m, 6
H, 2 × OCH2CH3, isomer A), 1.61–1.75 (m, 1 H + 1 H, c-Pr-CH,
isomers A and B), 1.87 (br s, 2 H + 2 H, NH2, isomers A and B),
2.50–2.56 (m, 1 H, c-Pr-CH, isomer B), 2.67–2.75 (m, 1 H, c-Pr-
CH, isomer A), 3.65–3.81 (m, 4 H, 2 × OCH2CH3, isomer B), 4.13–
4.23 (m, 4 H, 2 × OCH2CH3, isomer A), 7.20–7.32 (m, 5 H + 5 H,
Ar-CH, isomers A and B).
2JC,P = 6 Hz, OCH2CH3).
31P NMR (CDCl3): d = 27.28.
MS (MALDI-TOF): m/z = 220 [M + 1]+.
Diethyl (1-Aminodispiro[2.0.2.1]hept-1-yl)phosphonate (2c)
Yield: 218 mg (89%); mixture of isomers (A/B = 67:33); yellow oil.
3
13C NMR (CDCl3): d = 16.36 (d, JC,P = 6 Hz, 2 × OCH2CH3, iso-
1H NMR (CDCl3): d = 0.69–0.75 (m, 1 H + 1 H, c-Pr-CH2, isomers
A and B), 0.78–0.88 (m, 2 H + 2 H, c-Pr-CH2, isomers A and B),
0.97–1.01 (m, 1 H, c-Pr-CH2, isomer A), 1.02–1.08 (m, 1 H + 1 H,
c-Pr-CH2, isomers A and B), 1.11–1.14 (m, 1 H, c-Pr-CH2, isomer
B), 1.19–1.25 (m, 1 H + 2 H, c-Pr-CH2, isomers A and B), 1.27–1.33
(m, 6 H + 6 H, 2 × OCH2CH3, isomers A and B), 1.38–1.39 (m, 1
H, c-Pr-CH2, isomer A), 1.42–1.46 (m, 1 H, c-Pr-CH2, isomer B),
1.57–1.61 (m, 1 H, c-Pr-CH2, isomer A), 2.45 (br s, 2 H + 2 H, NH2,
isomers A and B), 4.13–4.23 (m, 4 H + 4 H, 2 × OCH2CH3, isomers
A and B).
mer B), 16.62 (d, 3JC,P = 6 Hz, 2 × OCH2CH3, isomer A), 17.64 (c-
2
Pr-CH2, isomer A), 18.12 (d, JC,P = 3 Hz, c-Pr-CH2, isomer B),
27.42 (d, 2JC,P = 1 Hz, c-Pr-CH, isomer A), 31.93 (d, 2JC,P = 3 Hz, c-
Pr-CH, isomer B), 33.54 [d, 1JC,P = 210 Hz, C(NH2)PO(OEt)2, iso-
1
mer A], 35.78 [d, JC,P = 206 Hz, C(NH2)PO(OEt)2, isomer B],
61.60 (d, 2JC,P = 7 Hz, OCH2CH3, isomer B), 61.67 (d, 2JC,P = 7 Hz,
OCH2CH3, isomer B), 62.29 (d, 2JC,P = 7 Hz, OCH2CH3, isomer A),
62.37 (d, 2JC,P = 7 Hz, OCH2CH3, isomer A), 126.64 (Ar-CH, iso-
mer B), 126.75 (Ar-CH, isomer A), 127.79 (2 × Ar-CH, isomer B),
128.14 (2 × Ar-CH, isomer A), 129.28 (2 × Ar-CH, isomer A),
129.70 (2 × Ar-CH, isomer B), 135.30 (Ar-C, isomer A), 136.40 (d,
3JC,P = 4 Hz, Ar-C, isomer B).
13C NMR (CDCl3): d = 3.43 (c-Pr-CH2, isomer A), 4.67 (c-Pr-CH2,
isomer A), 5.22 (c-Pr-CH2, isomer B), 9.48 (c-Pr-CH2, isomer B),
12.73 (c-Pr-CH2, isomer A), 12.79 (c-Pr-CH2, isomer B), 14.96 (d,
3JC,P = 5 Hz, Cspiro, isomer B), 16.08 (Cspiro, isomer A), 16.16 (d,
31P NMR (CDCl3): d = 25.77 (isomer B), 27.63 (isomer A).
MS (MALDI-TOF): m/z = 270 [M + 1]+.
3
3JC,P = 6 Hz, 2 × OCH2CH3, isomer B), 16.21 (d, JC,P = 6 Hz,
Synthesis 2010, No. 19, 3379–3383 © Thieme Stuttgart · New York

3382
A. V. Chemagin et al.
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(1-Aminodispiro[2.0.2.1]hept-1-yl)phosphonic Acid (3c)
Diethyl (1-Amino-2-butylcyclopropyl)phosphonate (2f)
Yield: 227 mg (91%); mixture of isomers (A/B = 62:38); yellow oil.
Yield: 174 mg (92%); mixture of isomers (A/B = 78:22); mp
240 °C (dec).
1H NMR (CDCl3): d = 0.80–0.85 (m, 3 H + 3 H, 2 × CH2CH2CH3,
isomers A and B), 0.85–0.90 (m, 2 H + 2 H, CH2, isomers A and B),
1.13–1.25 (m, 4 H + 4 H, 4 × CH2, isomers A and B), 1.26–1.29 (m,
6 H + 6 H, 4 × OCH2CH3, isomers A and B), 1.32–1.35 (m, 1 H, c-
Pr-H, isomer B), 1.40–1.50 (m, 2 H + 2 H, c-Pr-H, isomers A and
B), 1.59–1.66 (m, 1 H, c-Pr-H, isomer A), 2.01 (br s, 2 H + 2 H,
NH2, isomers A and B), 4.00–4.11 (m, 4 H + 4 H, 4 × OCH2CH3,
isomers A and B).
1H NMR (D2O): d = 0.66–0.70 (m, 1 H, c-Pr-CH2, isomer B), 0.74–
0.77 (m, 1 H, c-Pr-CH2, isomer A), 0.82–1.00 (m, 3 H + 3 H, c-Pr-
2
CH2, isomers A and B), 1.26 (A of AB, JH,H = 4.4 Hz, 1 H, c-Pr-
CH2, isomer A), 1.28–1.30 (m, 1 H + 1 H, c-Pr-CH2, isomers A and
B), 1.30–1.32 (m, 1 H, c-Pr-CH2, isomer B), 1.37–1.40 (m, 1 H, c-
Pr-CH2, isomer B), 1.41–1.43 (m, 1 H, c-Pr-CH2, isomer B), 1.43 (B
of AB, 2JH,H = 4.4 Hz, 1 H, c-Pr-CH2, isomer A), 1.56–1.60 (m, 1 H,
c-Pr-CH2, isomer A).
13C NMR (CDCl3): d = 14.02 (CH2CH2CH3, isomer A), 16.41
3
(d, 3JC,P = 6 Hz, OCH2CH3, isomer B), 16.45 (d, JC,P = 6 Hz,
13C NMR (D2O): d = 4.72 (c-Pr-CH2, isomer A), 4.99 (c-Pr-CH2,
isomer B), 5.04 (c-Pr-CH2, isomer A), 5.63 (c-Pr-CH2, isomer B),
2 × OCH2CH3, isomer A), 16.51 (d, 3JC,P = 6 Hz, OCH2CH3, isomer
B), 17.96 (2 × CH2CH2CH3, isomer B), 19.83 (d, 2JC,P = 4 Hz, c-Pr-
CH2, isomer B), 22.27 (CH2, isomer B), 22.36 (CH2, isomer A),
22.55 (d, 2JC,P = 3 Hz, c-Pr-CH2, isomer A), 25.21 (CH2, isomer B),
26.11 (CH2, isomer A), 27.86 (d, 2JC,P = 4 Hz, c-Pr-CH, isomer A),
28.07 (d, 2JC,P = 3 Hz, c-Pr-CH, isomer B), 31.10 [d, 1JC,P = 207 Hz,
C(NH2)PO(OEt)2, isomer A], 31.75 (CH2, isomer A), 31.79 (CH2,
3
10.54 (c-Pr-CH2, isomer B), 12.95 (d, JC,P = 4 Hz, c-Pr-CH2, iso-
mer A), 14.12 (2 × Cspiro, isomers A and B), 15.27 (c-Pr-CH2, iso-
2
mer B), 15.36 (c-Pr-CH2, isomer A), 21.97 (d, JC,P = 3 Hz, Cspiro
,
1
isomer A), 22.68 (Cspiro, isomer B), 34.40 [d, JC,P = 198 Hz,
C(NH2)PO(OH)2, isomer B], 35.80 [d, JC,P = 195 Hz,
1
C(NH2)PO(OH)2, isomer A].
31P NMR (D2O): d = 11.41 (isomer B), 11.76 (isomer A).
1
isomer B), 32.45 [d, JC,P = 203 Hz, C(NH2)PO(OEt)2, isomer B],
61.57 (d, 2JC,P = 7 Hz, OCH2CH3, isomer B), 61.80 (d, 2JC,P = 7 Hz,
OCH2CH3, isomer B), 61.95 (d, 2JC,P = 6 Hz, 2 × OCH2CH3, isomer
Anal. Calcd for C7H12NO3P: C, 44.45; H, 6.39; N, 7.41. Found: C,
44.24; H, 6.60; N, 7.28.
A).
31P NMR (CDCl3): d = 28.87 (isomer B), 29.30 (isomer A).
MS (MALDI-TOF): m/z = 250 [M + 1]+.
[1-Amino-5-(methoxycarbonyl)spiro[2.3]hex-1-yl]phosphonic
Acid (3d)
Yield: 193 mg (82%); mixture of isomers (A/B = 70:30); mp
255 °C (dec).
a-Aminocyclopropylphosphonic Acids 3 by the Cleavage of
a-Aminocyclopropylphosphonates 2; General Procedure
To a refluxing soln of an amine 2 (1 mmol) in CH2Cl2 (3 mL), a soln
of TMSBr (0.765 g, 5 mmol) in CH2Cl2 (2 mL) was added dropwise
with stirring. The mixture was refluxed for 3 h and then concentrat-
ed under reduced pressure. The residue was dissolved in EtOH (2
mL), and propylene oxide (5 mL) was added with stirring. The pre-
cipitated aminophosphonic acid 3 was collected by filtration and re-
crystallized (boiling EtOH) to obtain pure product as a white solid.
1H NMR (DMSO-d6): d = 0.91–1.02 (m, 1 H + 1 H, c-Pr-CH2, iso-
mers A and B), 1.33–1.46 (m, 1 H + 1 H, c-Pr-CH2, isomers A and
B), 2.24–2.50 (m, 2 H + 2 H, c-Bu-CH2, isomers A and B), 2.63–
2.76 (m, 2 H + 2 H, c-Bu-CH2, isomers A and B), 2.90–2.98 (m, 1
H + 1 H, c-Bu-CH, isomers A and B), 3.70 (s, 3 H, COOCH3, iso-
mer A), 3.72 (s, 3 H, COOCH3, isomer B).
13C NMR: Not recorded, owing to insufficient solubility.
31P NMR (DMSO-d6): d = 9.00 (isomer B), 9.83 (isomer A).
(1-Aminospiro[2.3]hex-1-yl)phosphonic Acid (3a)
Yield: 168 mg (95%); mp 250–252 °C.
1H NMR (D2O): d = 1.49 (dd, 2JH,H = 6.9 Hz, 3JP,H = 6.1 Hz, 1 H, c-
Pr-CH2), 1.66 (dd, 2JH,H = 6.9 Hz, 3JP,H = 13.3 Hz, 1 H, c-Pr-CH2),
2.22–2.42 (m, 4 H, 2 × c-Bu-CH2), 2.59–2.64 (m, 1 H, c-Bu-CH2),
2.71–2.78 (m, 1 H, c-Bu-CH2).
Anal. Calcd for C8H14NO5P: C, 40.86; H, 6.00; N, 5.96. Found: C,
40.89; H, 6.09; N, 5.86.
(1-Amino-2-phenylcyclopropyl)phosphonic Acid (3e)
Yield: 198 mg (93%); mixture of isomers (A/B = 72:28); mp 248–
250 °C.
13C NMR (D2O): d = 16.68 (t, 1JC,H = 139 Hz, c-Bu-CH2), 22.19 (t,
1H NMR (D2O): d = 1.60–1.72 (m, 2 H + 1 H, c-Pr-CH2, isomers A
and B), 1.84–1.91 (m, 1 H, c-Pr-CH2, isomer B), 2.85–2.94 (m, 1 H
+ 1 H, c-Pr-CH, isomers A and B), 7.27–7.45 (m, 5 H + 5 H, Ar-CH,
isomers A and B).
1
1JC,H = 164 Hz, c-Pr-CH2), 26.46 (t, JC,H = 138 Hz, c-Bu-CH2),
1
28.28 (t, JC,H = 138 Hz, c-Bu-CH2), 29.46 (Cspiro), 35.16 [d,
1JC,P = 205 Hz, C(NH2)PO(OH)2].
31P NMR (D2O): d = 14.71.
13C NMR (D2O): d = 14.00 (c-Pr-CH2, isomer A), 14.39 (c-Pr-CH2,
isomer B), 25.94 (c-Pr-CH, isomer A), 28.10 (c-Pr-CH, isomer B),
Anal. Calcd for C6H12NO3P: C, 40.68; H, 6.83; N, 7.91. Found: C,
40.77; H, 7.06; N, 7.85.
1
34.62 [d, JC,P = 196 Hz, C(NH2)PO(OH)2, isomer A], 35.62 [d,
1JC,P = 198 Hz, C(NH2)PO(OH)2, isomer B], 127.96 (Ar-CH, iso-
mer B), 128.86 (2 × Ar-CH, isomer B), 129.00 (Ar-CH, isomer A),
129.70 (2 × Ar-CH, isomer A), 129.96 (2 × Ar-CH, isomer B),
130.57 (2 × Ar-CH, isomer A), 132.85 (Ar-C, isomer A), 134.96 (d,
3JC,P = 4 Hz, Ar-C, isomer B).
(1-Aminospiro[2.2]pent-1-yl)phosphonic Acid (3b)
Yield: 153 mg (94%); mp 235 °C (dec).
1H NMR (D2O): d = 0.95–1.01 (m, 3 H, c-Pr-CH2), 1.06–1.13 (m, 1
2
3
H, c-Pr-CH2), 1.45 (dd, JH,H = 6.1 Hz, JP,H = 4.3 Hz, 1 H, c-Pr-
31P NMR (D2O): d = 11.63 (isomer B), 12.95 (isomer A).
CH2), 1.59 (dd, 2JH,H = 6.1 Hz, 3JP,H = 10.6 Hz, 1 H, c-Pr-CH2).
13C NMR (D2O): d = 4.44 (c-Pr-CH2), 6.60 (d, 3JC,P = 3.7 Hz, c-Pr-
Anal. Calcd for C9H12NO3P: C, 50.71; H, 5.67; N, 6.57. Found: C,
50.85; H, 5.59; N, 6.33.
2
CH2), 16.10 (c-Pr-CH2), 18.05 (d, JC,P = 4.0 Hz, Cspiro), 33.99 [d,
1JC,P = 201 Hz, C(NH2)PO(OH)2].
31P NMR (D2O): d = 13.56.
(1-Amino-2-butylcyclopropyl)phosphonic Acid (3f)
Yield: 168 mg (87%); mixture of isomers (A/B = 50:50); mp 263–
264 °C.
Anal. Calcd for C5H10NO3P: C, 36.82; H, 6.18; N, 8.59. Found: C,
36.74; H, 6.25; N, 8.45.
Synthesis 2010, No. 19, 3379–3383 © Thieme Stuttgart · New York

PAPER
Synthesis of a-Aminocyclopropylphosphonic Acids
3383
1H NMR (D2O): d (isomers A and B) = 0.81–0.84 (m, 2 H), 0.84 (m,
3 H, CH2CH2CH3), 0.86 (m, 3 H, CH2CH2CH3), 1.01–1.08 (m, 2 H),
1.20–1.49 (m, 6 H + 6 H), 1.50–1.58 (m, 1 H), 1.67–1.75 (m, 1 H).
Leading Scientific School’ No. 5538.2008.3 (to N.S.Z.) for finan-
cial support of this work.
13C NMR (D2O): d (isomers A and B) = 13.74 (q, JC,H = 125 Hz,
1
References
1
CH2CH2CH3), 13.92 (q, JC,H = 125 Hz, CH2CH2CH3), 15.64 (t,
1
1JC,H = 165 Hz, c-Pr-CH2), 16.52 (t, JC,H = 165 Hz, c-Pr-CH2),
(1) (a) Sheridan, R. P. J. Chem. Inf. Comput. Sci. 2002, 42, 103.
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Marquez, V. M.; Christman, J. K.; MacKerell, A. D. J. Am.
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Lubell, W. D. Biopolymers 2000, 55, 101. (d) Pellicciari,
R.; Marinozzi, M.; Camaioni, E.; Nunez, M.; Costantino, G.;
Gasparini, F.; Giorgi, G.; Macchiarulo, A.; Subramanian, N.
J. Org. Chem. 2002, 67, 5497. (e) Brackmann, F.;
de Meijere, A. Chem. Rev. 2007, 107, 4493.
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Zefirov, N. S. Vestn. Mosk. Univ., Ser. 2, Khim. 2002, 43,
246; Chem. Abstr. 2002, 138, 254854. (b) Yashin, N. V.;
Averina, E. B.; Gerdov, S. M.; Kuznetsova, T. S.; Zefirov,
N. S. Tetrahedron Lett. 2003, 44, 8241. (c) Averina, E. B.;
Yashin, N. V.; Shvorina, E. B.; Grishin, Yu. K.; Kuznetsova,
T. S. Vestn. Mosk. Univ., Ser. 2, Khim. 2005, 46, 314; Chem.
Abstr. 2006, 145, 145989. (d) Yashin, N. V.; Averina, E. B.;
Grishin, Yu. K.; Kuznetsova, T. S.; Zefirov, N. S. Synthesis
2006, 279. (e) Yashin, N. V.; Averina, E. B.; Grishin, Yu.
K.; Kuznetsova, T. S.; Zefirov, N. S. Synthesis 2006, 880.
(f) Chemagin, A. V.; Yashin, N. V.; Averina, E. B.;
Kuznetsova, T. S.; Zefirov, N. S. Dokl. Akad. Nauk 2008,
419, 772; Chem. Abstr. 2009, 150, 121216.
1
1
21.41 (d, JC,H = 162 Hz, c-Pr-CH), 21.55 (t, JC,H = 126 Hz,
1
2 × CH2, isomers A and B), 24.85 (d, JC,H = 160 Hz, c-Pr-CH),
1
26.28 (t, JC,H = 128 Hz, 2 × CH2, isomers A and B), 31.29 (t,
1JC,H = 128 Hz, CH2), 32.31 (t, JC,H = 128 Hz, CH2), 33.84 [d,
1
1JC,P = 195 Hz, C(NH2)PO(OH)2], 33.99 [d, JC,P = 196 Hz,
1
C(NH2)PO(OH)2].
31P NMR (D2O): d (isomers A and B) = 12.85, 14.18.
Anal. Calcd for C7H16NO3P: C, 43.52; H, 8.35; N, 7.25. Found: C,
43.72; H, 8.57; N, 7.30.
1-Amino-1-phosphonospiro[2.3]hexane-5-carboxylic Acid Hy-
drochloride (4d)
Methyl ester 3d (118 mg, 0.5 mmol) was dissolved in 1 N aq HCl
(2.5 mL, 2.5 mmol) and the mixture was stirred for 5 min. Concen-
tration under reduced pressure gave 4d as a white solid; yield: 122
mg (95%).
Mixture of isomers (A/B = 73:27); mp 259–261 °C (dec).
1H NMR (D2O): d = 1.05 (dd, 2JH,H = 7.2 Hz, 3JP,H = 5.7 Hz, 1 H, c-
Pr-CH2, isomer A), 1.10 (dd, 2JH,H = 7.1 Hz, 3JP,H = 5.7 Hz, 1 H, c-
Pr-CH2, isomer B), 1.26 (dd, 2JH,H = 7.2 Hz, 3JP,H = 12.4 Hz, 1 H, c-
Pr-CH2, isomer A), 1.33 (dd, 2JH,H = 7.1 Hz, 3JP,H = 12.3 Hz, 1 H, c-
Pr-CH2, isomer B), 2.24–2.32 (m, 2 H, c-Bu-CH2, isomer A), 2.36–
2.40 (m, 2 H, c-Bu-CH2, isomer B), 2.48–2.53 (m, 1 H, c-Bu-CH2,
isomer A), 2.54–2.59 (m, 1 H, c-Bu-CH2, isomer B), 2.65–2.70 (m,
1 H, c-Bu-CH2, isomer B), 2.71–2.76 (m, 1 H, c-Bu-CH2, isomer
A), 3.20–3.27 (m, 1 H, c-Bu-CH, isomer A), 3.31–3.38 (m, 1 H, c-
Bu-CH, isomer B).
1
13C NMR (D2O): d = 21.18 (t, JC,H = 164 Hz, 2 × c-Pr-CH2, iso-
mers A and B), 25.00 (Cspiro, isomer B), 25.52 (Cspiro, isomer A),
28.65 (t, 1JC,H = 138 Hz, c-Bu-CH2, isomer A), 29.29 (t, 1JC,H = 138
Hz, c-Bu-CH2, isomer B), 31.07 (dt, 3JC,P = 4 Hz, 1JC,H = 139 Hz, c-
3
1
Bu-CH2, isomer A), 31.74 (dt, JC,P = 4 Hz, JC,H = 140 Hz, c-Bu-
(5) (a) Yashin, N. V.; Villemson, E. V.; Chemagin, A. V.;
Averina, E. B.; Kabachnik, M. M.; Kuznetsova, T. S.
Synthesis 2008, 464. (b) Matveeva, E. D.; Podrugina, T. A.;
Tishkovskaja, E. V.; Tomilova, L. G.; Zefirov, N. S. Synlett
2003, 2321.
(6) (a) Erion, M. D.; Walsh, C. T. Biochemistry 1987, 26, 3417.
(b) Groth, U.; Lehmann, L.; Richter, L.; Schöllkopf, U.
Liebigs Ann. Chem. 1993, 427. (c) Yamazaki, S.; Takada,
T.; Moriguchi, Y.; Yamabe, S. J. Org. Chem. 1998, 63,
5919. (d) Fadel, A. J. Org. Chem. 1999, 64, 4953.
(e) Tesson, N.; Dorigneux, B.; Fadel, A. Tetrahedron:
Asymmetry 2002, 13, 2267.
1
CH2, isomer B), 32.72 (d, JC,H = 142 Hz, c-Bu-CH, isomer B),
33.43 (d, 1JC,H = 141 Hz, c-Bu-CH, isomer A), 35.53 [d, 1JC,P = 194
1
Hz, C(NH2)PO(OH)2, isomer B], 35.98 [d, JC,P = 193 Hz,
C(NH2)PO(OH)2, isomer A], 179.65 (COOH, isomer B), 180.22
(COOH, isomer A).
31P NMR (D2O): d = 10.78 (isomer A), 10.87 (isomer B).
Anal. Calcd for C7H13ClNO5P: C, 32.64; H, 5.09; N, 5.44. Found:
C, 32.63; H, 5.17; N, 5.25.
Acknowledgment
(7) Chemagin, A. V.; Yashin, N. V.; Grishin, Yu. K.;
Kuznetsova, T. S.; Zefirov, N. S. Synthesis 2010, 259.
(8) Wurz, R. P.; Charette, A. B. J. Org. Chem. 2004, 69, 1262.
We thank the Russian Academy of Sciences (program ‘Biomolecu-
lar and Medicinal Chemistry’) and the President’s grant ‘Support of
Synthesis 2010, No. 19, 3379–3383 © Thieme Stuttgart · New York