Preparation of enantiomerically pure (1S,2S)-1-aminocyclopropanephosphonic acid from methylcyclopropanone acetal via spirophosphonate intermediates

Article abstract of DOI:10.1016/S0957-4166(00)00134-8

An easy and efficient one-pot reaction from readily available methylcyclopropanone acetal (2S)-4b gave the spirophosphonates 8a-b with excellent diastereoselectivity. These phosphonates, after catalytic hydrogenolysis and hydrolysis, furnished the enantio

Full text of DOI:10.1016/S0957-4166(00)00134-8

Tetrahedron: Asymmetry 11 (2000) 2023±2031
Preparation of enantiomerically pure (1S,2S)-1-
aminocyclopropanephosphonic acid from
methylcyclopropanone acetal via spirophosphonate
intermediates
Antoine Fadel* and Nicolas Tesson
 Â
Ã
Laboratoire des Carbocycles (Associe au CNRS), Institut de Chimie Moleculaire d'Orsay Bat. 420,
Â
Universite de Paris-Sud, 91405 Orsay, France
Received 27 March 2000; accepted 4 April 2000
Abstract
An easy and ecient one-pot reaction from readily available methylcyclopropanone acetal (2S)-4b gave
the spirophosphonates 8a±b with excellent diastereoselectivity. These phosphonates, after catalytic hydro-
genolysis and hydrolysis, furnished the enantiomerically pure (1S,2S)-1-amino-2-methylcyclopropane-
phosphonic acid 3b (analogue of (1R,2S)-allo-norcoronamic acid). # 2000 Elsevier Science Ltd. All rights
reserved.
1. Introduction
The biologically active phosphonic acids 1 analogues of a-amino acids are ®nding increasing
interest,1 4 due to the tetrahedral structure of phosphonic acid moiety, since they act as `transi-
tion-state analogues'.5,6 In recent years, 1-aminocyclopropanecarboxylic acids 2 (ACCs) have
attracted special attention owing to their use as enzyme inhibitors as well as their incorporation in
strained peptides.7,8 However, the aminocyclopropanephosphonic acids 3 did not receive the
same attention compared to the acyclic aminophosphonic acids 1 and aminocyclopropane-
carboxylic acids 2 (Scheme 1).
Scheme 1.
* Corresponding author. Fax: +33(1)69156278; e-mail: antfadel@icmo.u-psud.fr
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00134-8

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A. Fadel, N. Tesson / Tetrahedron: Asymmetry 11 (2000) 2023±2031
To our knowledge only a few methods for the synthesis of this class of compounds 3 have been
described in either racemic9 or optically active form.10
We have previously reported a simple and convenient synthesis of 1-aminocyclopropane-
phosphonic acid (ACC analogue) 3a (R=H), in three steps, from cyclopropanone acetal 4a.11
Similarly, for the preparation of optically active amino acids 2,12 we have recently used the same
methodology to synthesize (1S,2S)-1-aminocyclopropanephosphonic acid 3b [analogue of
(1R,2S)-allo-norcoronamic acid 2b (R=CH3)]. This sequence occurred in three steps from the
acetal (2S)-4b, via the iminium 5b and aminophosphonates 7 in good overall yield (Scheme 2).13
Scheme 2.
In order to obtain alkylaminophosphonic acid (1S,2S)-3b, via the cyclic phosphonates 8a±b, we
decided in connection with our ongoing program to study the asymmetric addition of triethyl
phosphite to the acetal (2S)-4b. These reactions should occur in the presence of 2-hydroxyamines
9a±b via the iminium intermediate 5 (Scheme 3).
Scheme 3.
2. Results and discussion
The synthesis of (1S,2S)-1-amino-2-methylcyclopropanephosphonic acid 3b was carried out
starting from the cyclopropanone acetal (2S)-4b. This latter was easily obtained in two steps from
commercially available (S)-3-hydroxy-2-methylpropionate.14 Thus, in a one-pot procedure, the
hemiacetal 10 formed in situ from acetal (2S)-4b by acidic ethanolysis (EtOH, cat. TMSCl)
reacted under acidic conditions with amines 9a±b to give, via aminols 11a±b,y the iminium
intermediate 5.{ The latter underwent phosphite addition to directly furnish a diastereoisomeric
mixture of cyclic aminophosphonates 8 and 12 (Scheme 4). Our results are summarized in Table
1.
y
{
A spiroamino acetal cannot be obtained by heating 11a: A. Fadel, unpublished results.
The formation of a linked phosphite with the hydroxyl group of the amine moiety in 5, then an intramolecular
addition of the resulting phosphite on the iminium function, cannot be excluded.

A. Fadel, N. Tesson / Tetrahedron: Asymmetry 11 (2000) 2023±2031
2025
Scheme 4.
Table 1
Preparation of spiroaminophosphonates 8 and 12 from acetal (2S)-4b
The use of triethyl phosphite and amine 9a gave a mixture of spirophosphates 8a and 12a in
good yields with the trans isomers as the major products (ratio, 89:11) (Table 1, entries 1 and 2).
With (^)-norephedrine 9b under the same conditions, the yield and mixture ratios were lower
(entry 3). These compounds 8a, 8b, 12a and 12b, obtained as a mixture of epimers at the phosphorus
atom in an 80:20 (P*major:P*minor) ratio, were easily separated by ¯ash chromatography. We
observed that the protected hydroxyl amine 9c gave, under the same conditions, the expected
phosphonates 7c and 13c (85:15 ratio) in 39% yield, and the cyclic phosphonate 8a (3% yield).
The latter was probably formed by cyclization of 7c under reaction conditions (Scheme 5).
Scheme 5.
3
Assignment of the stereochemistry of these di€erent compounds was based on JP H coupling
constants between the cyclopropane proton H-C1 and the phosphorus atom. The observed values
(3JPH=12.8 Hz) were in agreement with reported values for the cis con®guration,9 and with our
previously reported results.13 These conclusions were supported by 13C NMR spectra of the cis
12a by the coupling constants between P and CH3-C1 (3JPC cis=5.2 Hz). Thus, we assigned the S
con®guration on C3 for the major 8a±b and R for the minor 12a±b. The phosphorus atom

2026
A. Fadel, N. Tesson / Tetrahedron: Asymmetry 11 (2000) 2023±2031
con®guration was arbitrarily assigned from the optimized energy determined by molecular
mechanics (MM2) calculations of 8 and 12 with R con®guration for the major epimers.
After separation the major 8a.PM and the minor epimer 8a.Pm, which were assigned the same
con®guration S at C3, were hydrogenolyzed separately to give the same compound 14
(‰ꢀŠ2D0=+26.3 (c 1, MeOH)) in 79% yield. Such epimerization on the phosphorus atom has
already been reported by Royer et al. upon hydrogenolysis of cyclic aminophosphonate.15 This
monoester was treated by trimethylsilyl iodide then with propylene oxide in ethanol to lead to
enantiomerically pure (1S,2S)-(+)-1-amino-2-methylcyclopropanephosphonic acid 3b (87% yield,
mp=220±222ꢀC, ‰ꢀŠD20=+34 (c 1, H2O), ‰ꢀŠ2D0=+45 (c 0.2, H2O)). These values are in agreement
with our previously reported results,13 and with the literature10b for the enantiomer (1R,2R)-3b:
mp=245ꢀC (decomp.), ‰ꢀŠD20=^46.4 (c 0.2, H2O). Its enantiomeric excess, determined from 19F
NMR analysis of the corresponding Mosher amide,13,16 was found to be 98% (Scheme 6).
Scheme 6.
Probably the minor 12a.PM, isolated by chromatography, was hydrogenolyzed into the
monoester 15, which was treated by ISiMe3 followed by propylene oxide to furnish the cis-amino-
phosphonic acid ((1R,2S)-16, ‰ꢀŠ2D0=+23 (c 0.5, H2O)) (Scheme 7).
Scheme 7.
In the same way, the major 8b.PM and 8b.Pm, when hydrogenolyzed separately, gave the same
monoester 17 in 86% yield (Scheme 8).
Scheme 8.

A. Fadel, N. Tesson / Tetrahedron: Asymmetry 11 (2000) 2023±2031
2027
3. Conclusion
From the readily available methylcyclopropanone acetal (2S)-4b, we have developed an easy
and ecient three-step synthesis of enantiomerically pure (1S,2S)-1-amino-2-methylcyclo-
propanephosphonic acid 3b. This latter was obtained from the interesting cyclic phosphonate 8a±b
in high overall yield. This approach should constitute an ecient way for the synthesis of a wide
variety of aminocyclopropanephosphonic acids.
4. Experimental
For general experimental information, see Fadel11 or Fadel and Tesson.13
4.1. General procedure
To a solution of cyclopropanone acetal (2S)-4b (520 mg, 3 mmol) in EtOH (6 mL) was added
one drop of TMSCl. After 5 min of stirring, chiral amine (R)-9a (550 mg, 4.5 mmol), AcOH (360
mg, 6 mmol), and P(OEt)3 (750 mg, 4.5 mmol) were added successively. The mixture was stirred
and heated at 55ꢀC for 42 h. The reaction mixture was concentrated under vacuum, concentrated
ammonia (2 mL) was added, and then the mixture was ®ltered through a 5 cm pad of silica gel and
eluted with ether (60 mL). The ®ltrate was concentrated under vacuum to give crude phosphonates
8a and 12a obtained as two diastereoisomers in an 89:11 ratio. Puri®cation by ¯ash chromatography
(FC) twice (eluent, EtOAc:CH2Cl2, 1:9!1:1, or ether) a€orded 410 mg (49%) of (1S,2S)-8a.PM
as the major trans.major phosphorus atom, 80 mg (9.6%) of (1S,2S)-8a.Pm as the major trans.minor
phosphorus atom, 39 mg (4.6%) of (1R,2S)-12a.PM as the minor cis.major phosphorus atom, and
70 mg (8%) as a mixture.
4.1.1. (1S,3S,4S*,7R)-4-Ethoxy-1-methyl-7-phenyl-5-oxa-8-aza-4-phospha-spiro[2.5]octane 4-oxide
8a.PM
‰ꢀŠ2D0=+55.4 (c 1, CHCl3); Rf=0.22 (ether); RT=43.40 min [Cydex B, 170ꢀC (5 min) +1ꢀC/
min!180ꢀC (1 h), 1 bar]; IR (neat): 3440, 3265, 1260 (PˆO), 1046 (P±O); 1H NMR (CDCl3, 250
MHz): ꢁ=7.54±7.16 (m, 5H), 4.60±4.28 (m, 2H), 4.21 (dq, 3JPH=1 Hz, J=7.3 Hz, 2H), 4.30±4.00
(m, 1H, CH-N), 2.05 (br s, NH), 1.80±1.50 (m, 1Hcycle), 1.39 (t, J=7.3 Hz, 3H), 1.50±1.00 (m,
1Hcycle), 1.25 (d, J=5.9 Hz, 3H, CH3-C1), 0.46 (ddd, J=5.4 Hz, JPH trans=6.8 Hz, J=8.3 Hz,
1Hcycle); 13C NMR (CDCl3, 62.86 MHz): ꢁ=[6 arom. C: 137.2, 128.7 (2C), 128.1, 126.4 (2C)],
2
2
3
70.0 (d, JPC=9.0 Hz, O-CH2-CH), 61.5 (d, JPC=6.7 Hz, 1C), 58.8 (d, JPC=5.3 Hz, CH-N),
1
3
34.8 (d, JPC=193.5 Hz, C3), 17.5 (C1), 17.4 (C2), 16.5 (d, JPC=5.3 Hz, CH3-CH2-O), 10.6
(CH3-C1); 31P NMR (CDCl3, 101.25 MHz): ꢁ=18.61; MS (70 eV); m/z (%): 282 (M++1, 6), 281
(M+, 31), 252 (19), 171 (12), 104 (100), 103 (48); HRMS m/z: 281.1183 (calcd for C14H20NO3P:
281.1180).
4.1.2. (1S,3S,4R*,7R)-4-Ethoxy-1-methyl-7-phenyl-5-oxa-8-aza-4-phospha-spiro[2.5]octane 4-oxide
8a.Pm
‰ꢀŠ2D0=+32.6 (c 0.75, CHCl3); Rf=0.18 (ether); RT=38.42 min [Cydex B, 170ꢀC (5 min) +1ꢀC/
min!180ꢀC (1 h), 1 bar]; IR (neat): 3435, 3265, 1260 (PˆO), 1046 (P±O); 1H NMR (CDCl3, 250
MHz): ꢁ=7.40±7.20 (m, 5H), 4.70 (ddd, J=4.4 Hz, J=9.7 Hz, Jab=14.4 Hz, 1H), 4.47 (ddd,

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A. Fadel, N. Tesson / Tetrahedron: Asymmetry 11 (2000) 2023±2031
J=3.7 Hz, J=11.4 Hz, Jab=14.4 Hz, 1H), 4.30±4.10 (m, 2H and CH-N), 2.32 (br s, NH), 1.55±
1.00 (m, 2Hcycle), 1.31 (t, J=7.2 Hz, 3H), 1.23 (d, J=5.8 Hz, 3H, CH3-C1), 0.39 (ddd, J=5.9 Hz,
J=6.7 Hz, J=8.4 Hz, 1Hcycle); 13C NMR (CDCl3, 62.86 MHz): ꢁ=[6 arom. C: 137.8, 128.7 (2C),
2
2
128.0, 126.9 (2C)], 75.3 (d, JPC=6.7 Hz, O-CH2-CH), 62.6 (d, JPC=6.7 Hz, O-CH2), 58.6 (d,
3JPC=5.2 Hz, CH-N), 35.0 (d, JPC=193.5 Hz, C3), 18.2 (C1), 17.5 (C2), 16.6 (d, JPC=5.2 Hz,
O-CH2-CH3), 10.9 (CH3-C1); 31P NMR (CDCl3, 101.25 MHz): ꢁ=19.86; MS (70 eV); m/z (%):
282 (M++1, 3), 281 (M+, 15), 252 (12), 156 (11), 105 (13), 104 (100), 103 (31).
1
3
4.1.3. (1S,3R,4R*,7R)-4-Ethoxy-1-methyl-7-phenyl-5-oxa-8-aza-4-phospha-spiro[2.5]octane 4-oxide
12a.PM
‰ꢀŠ2D0=+57 (c 1.45, CHCl3); Rf=0.28 (ether); RT=41.27 min [Cydex B, 170ꢀC (5 min) +1ꢀC/
min!180ꢀC (1h), 1 bar]; 1H NMR (CDCl3, 250 MHz): ꢁ=7.44±7.15 (m, 5H), 4.54±4.10 (m, 5H,
CH2-O, CH2-O and N-CH), 2.15 (br s, NH), 1.41 (t, J=7.2 Hz, CH3-CH2-O), 1.34 (d, J=5.8 Hz,
CH3-C1), 1.40±1.10 (m, 2Hcycle), 1.10±0.96 (m, 1Hcycle); 13C NMR (CDCl3, 62.86 MHz):
2
ꢁ=[6 arom. C: 137.0, 128.8 (2C), 128.2, 126.5 (2C)], 76.8 (C6), 61.3 (d, JPC=6.2 Hz, O-CH2-
3
1
2
CH3), 58.1 (d, JPC=4.8 Hz, CH-N), 37.1 (d, JPC=192.5 Hz, C3), 21.9 (C1), 20.2 (d, JPC=3.8
3
Hz, C2), 16.6 (d, 3JPC=5.4 Hz, O-CH2-CH3), 13.8 (d, JPC cis=5.2 Hz, CH3-C1);
31P NMR (CDCl3, 101.25 MHz): ꢁ=17.43.
4.1.4. (1S,3S,4S*,6R,7S)-4-Ethoxy-1,7-dimethyl-6-phenyl-5-oxa-8-aza-4-phospha-spiro[2.5]octane
4-oxide 8b.PM
Following the procedure: Chiral acetal (2S)-4b (350 mg, 2 mmol), TMSCl (cat.), norephedrine
(1R,2S)-9b (450 mg, 3 mmol), EtOH (7 mL) and P(OEt)3 (500 mg, 3 mmol) gave, after heating at
55ꢀC for 90 h and the usual work up, 500 mg of crude cyclic phosphonates as a mixture of 8b and
12b in a 78:22 ratio. Puri®cation by FC (twice) a€orded 115 mg (19.5%) of (1S,3S)-8b.PM as the
major trans.major phosphorous atom, 32 mg (5.5%) of (1S,3S)-8b.Pm as major trans.minor
phosphorus atom, 32 mg (5.5%) of (1S,3R)-12b.PM as minor cis.major phosphorus atom, and 25
mg (4%) as a mixture.
4.1.4.1. Data for (1S,3S)-8b.PM. ‰ꢀŠ2D0=+40.4 (c 1, CHCl3); mp=142.0±146.0ꢀC; Rf=0.24
(EtOAc:CH2Cl2, 15:85); IR (neat): 3296 (NH), 1248 (PˆO), 1195, 1053 (P±O); 1H NMR (CDCl3,
3
250 MHz): ꢁ=7.42±7.18 (m, 5H), 5.55 (dd, J=2.0 Hz, JPH=2.5 Hz, H-C6), 4.24±3.95 (m, 2H,
CH2-O), 3.01 (dq, J=2.0 Hz, J=7.4 Hz, 1H-C7), 2.35 (br s, NH), 1.78±1.53 (m, H-C1), 1.29 (t,
J=7.4 Hz, 3H), 1.40±1.15 (m, 1H-C2), 1.12 (d, J=6.3 Hz, 3H, CH3-C1), 0.90 (d, J=7.4 Hz, 3H,
CH3-C7), 0.31 (ddd, J=5.2 Hz, J=6.8 Hz, J=8.8 Hz, 1H-C2); 13C NMR (CDCl3, 62.86 MHz):
ꢁ=[6 arom. C: 137.8 (d, 3JPC=5.2 Hz, 1C), 128.3 (2C), 127.6 (1C), 124.9 (2C)], 87.5 (d, 2JPC=8.6
Hz, C6), 61.3 (d, 2JPC=6.7 Hz, 1C), 53.3 (d, 3JPC=4.7 Hz, C7), 31.4 (d, 1JPC=188.2 Hz, C3), 19.9
3
2
(d, JPC=5.8 Hz, 1C), 16.5 (C2), 16.45 (d, JPC=5.2 Hz, C1), 12.2 (CH3-C7), 10.8 (CH3-C1); 31P
NMR (CDCl3, 101.25 MHz): ꢁ=21.36; MS (EI), m/z (%): 296 (M++1, 5), 295 (M+, 5), 178 (100),
118 (82), 117 (71), 97 (52), 91 (56); HRMS, m/z: 295.1344 (calcd for C15H22NO3P: 295.1337);
anal. calcd for C15H22NO3P: C, 61.01; H, 7.51; N, 4.74. Found: C, 60.73; H, 7.68; N, 4.52.
4.1.5. (1S,3S,4R*,6R,7S)-4-Ethoxy-1,7-dimethyl-6-phenyl-5-oxa-8-aza-4-phospha-spiro[2.5]octane
4-oxide 8b.Pm
20
D
20
365
‰ꢀŠ =^12.1; [ꢀ] =^30 (c 0.35, CHCl3); Rf=0.07 (EtOAc:CH2Cl2, 15:85); IR (neat): 3300
1
(NH), 1245 (PˆO), 1195, 1053 (P±O); H NMR (CDCl3, 250 MHz): ꢁ=7.45±7.15 (m, 5H), 5.83

A. Fadel, N. Tesson / Tetrahedron: Asymmetry 11 (2000) 2023±2031
2029
3
3
(dd, J=3.4 Hz, JPH=3.9 Hz, 1H-C6), 4.17 (dq, JPH=8.3 Hz, J=7.3 Hz, 2H), 3.25 (dq, J=3.4
Hz, J=6.8 Hz, 1H-C7), 2.24 (br s, NH), 1.55±1.00 (m, 2H c-propyl), 1.33 (t, J=7.3 Hz, 3H), 1.17
(d, J=6.0 Hz, 3H, CH3-C1), 0.85 (d, J=6.8 Hz, 3H, CH3-C7), 0.45 (ddd, J=4.9 Hz, J=6.8 Hz,
3
J=8.3 Hz, 1H-C2); 13C NMR (CDCl3, 62.86 MHz): ꢁ=[6 arom. C: 137.6 (d, JPC=5.5 Hz, 1C),
128.3 (2C), 127.6 (1C), 125.4 (2C)], 84.5 (d, JPC=6.9 Hz, C6), 62.5 (d, 2JPC=6.6 Hz, 1C), 53.4 (d,
1
3
3JPC=4.1 Hz, C7), 33.0 (d, JPC=188.6 Hz, C3), 19.0 (d, JPC=2.6 Hz, 1C), 18.0 (C2), 16.6 (d,
2JPC=5.3 Hz, C1), 13.0 (CH3-C7), 12.1 (CH3-C1); 31P NMR (CDCl3, 101.25 MHz): ꢁ=22.99; MS
(70 eV); m/z (%): 296 (M++1, 2), 295 (M+, 4), 178 (93), 177 (21), 118 (100), 117 (69), 97 (44), 91
(27); HRMS m/z: 295.1340 (calcd for C15H22NO3P: 295.1337).
4.1.6. (1S,3R,4R*,6R,7S)-4-Ethoxy-1,7-dimethyl-6-phenyl-5-oxa-8-aza-4-phospha-spiro[2.5]octane
4-oxide 12b.PM
1
From a mixture we can read: Rf=0.15 (EtOAc:CH2Cl2, 15:85); H NMR (CDCl3, 250 MHz):
ꢁ=7.45±7.15 (m, 5H), 5.58 (dd, J=2.4 Hz, J=2.3 Hz, 1H-C6), 4.30±4.03 (m, 2H), 3.15 (dq,
J=2.3 Hz, J=7.3 Hz, 1H-C7), 1.56 (br s, NH), 1.40±1.30 (m, 1Hc-propyl), 1.33 (t, J=6.8 Hz, 3H),
1.32 (d, J=6.3 Hz, 3H, CH3-C1), 1.30±0.90 (m, 2Hc-propyl), 0.98 (d, J=7.3 Hz, 3H, CH3-C7); 13
NMR (CDCl3, 50.29 MHz): ꢁ=[6 arom. C: 137.8 (d, JPC=5.0 Hz, 1C), 128.4 (2C), 127.7 (1C),
C
3
2
2
3
125.0 (1C)], 87.2 (d, JPC=9.0 Hz, C6), 61.0 (d, JPC=7.1 Hz, 1C), 54.6 (d, JPC=3.9 Hz, C7),
1
2
2
32.3 (d, JPC=196.9 Hz, C3), 22.8 (d, JPC=4.0 Hz, C2), 19.1 (1C), 16.6 (d, JPC=5.9 Hz, C1),
13.8 (d, 3JPC cis=5.9 Hz, CH3-C1), 11.2 (CH3-C7).
4.2. Diethyl (1S,2S,10R)-1-(2-methoxy-1-phenylethylamino)-2-methylcyclopropanephosphonate 7c
Following the procedure: acetal 4b (2 mmol) and amine 9c (616 mg, 3 mmol) gave, after FC
(twice), 185 mg (27%) of 7c, 18 mg (3%) of spirophosphonate 8a.PM and 37 mg (5.2%) as a
mixture of 7c, 8a.PM and minor 13c. ‰ꢀŠ2D0=^38.7 (c 1, CHCl3); Rf=0.23 (EtOAc:CH2Cl2, 1:1);
RT=24.37 min [Cydex B, 170ꢀC (5 min) +1ꢀC/min!180ꢀC (1 h), 1 bar]; IR (neat): 3430 (NH),
1
1240 (PˆO), 1030 (P±O); H NMR (CDCl3, 250 MHz): ꢁ=7.45±7.15 (m, 5H), 4.20 (m, 1H),
4.13±3.77 (m, 4H), 3.60±3.25 (m, 2H), 3.29 (s, 3H), 2.10 (br s, NH), 1.53±1.05 (m, 2Hcycle), 1.23 (t,
J=7.3 Hz, 3H), 1.21 (t, J=7.3 Hz, 3H), 0.98 (d, J=6.6 Hz, CH3-C2), 0.60 (m, 1Hc-propyl); 13C
NMR (CDCl3, 62.86 MHz): ꢁ=[6 arom. C: 142.5 (1C), 127.9 (2C), 127.8 (2C), 127.0 (1C)], 77.0
3
3
(CH2-CH-N), 61.65 (d, JPH=6.2 Hz, 1C), 61.6 (d, JPH=6.2 Hz, 1C), 60.3 (CH-N), 58.8
(CH3-O), 35.8 (d, 1JPC=207.8 Hz, C1), 18.8 (C3), 18.4 (d, 2JPC=4.3 Hz, C2), 16.4 (1C), 16.3 (1C),
11.9 (CH3-C2); 31P NMR (CDCl3, 101.25 MHz): ꢁ=28.93; MS (70 eV); m/z (%): 341 (M+, 1), 296
(27), 295 (29), 172 (87), 171 (41), 103 (100), 102 (38), 91 (36); HRMS m/z: 341.1753 (calcd for
C17H28NO4P: 341.1756); anal. calcd for C17H28NO4P: C, 59.81; H, 8.27; N, 4.01. Found: C,
59.62; H, 7.48; N, 4.23.
4.3. Ethyl (1S,2S)-1-amino-2-methylcyclopropanephosphonate 14
Following a reported procedure:11 cyclic phosphonate 8a.PM (197 mg, 0.7 mmol), EtOH (4
mL) and 20% Pd(OH)2/C (Pearlman's catalyst, 90 mg) under H2 (1 atm) gave, after 6 h and FC
(eluent 50:50, MeOH:EtOAc), 99 mg (79%) of (1S,2S)-14 as a white solid. ‰ꢀŠ2D0=+26.3 (c 1,
ꢀ
1
MeOH); mp=169.7 C (decomp.); Rf=0.21 (MeOH:CH2Cl2, 1:1); IR (neat): H NMR (D2O,
HOD, 4.6 ppm, 250 MHz): ꢁ=3.74 (dq, 3JPH=6.7 Hz, J=7.1 Hz, 2H), 1.30±1.03 (m, 1H), 1.03 (t,
J=7.1 Hz, 3H), 1.03±0.80 (m, 1Hcycle), 0.95 (d, J=6.3 Hz, 3H), 0.39 (ddd, Jtrans=6.6 Hz,

2030
A. Fadel, N. Tesson / Tetrahedron: Asymmetry 11 (2000) 2023±2031
3
2
Jgem=6.4 Hz, JPH trans=6.8 Hz, 1H); 13C NMR (D2O, 82.86 MHz): ꢁ=61.5 (d, JPC=5.7 Hz,
1C), 32.1 (d, 1JPC=195.4 Hz, C1), 16.7 (C3), 16.1 (d, 2JPC=5.2 Hz, C2), 14.9 (1C), 10.9 (1C); 31
NMR (D2O, 101.25 MHz): ꢁ=19.29.
P
4.4. Ethyl (1S,2S,10S)-2-methyl-1-(10-methyl-2-phenylethylamino)cyclopropanephosphonate 17
Following a reported procedure:11 cyclic phosphonate 8b.PM (60 mg, 0.2 mmol), AcOH (2 mL)
and 20% Pd(OH)2/C (25 mg), under H2 (1 atm) gave, after 4 h and FC (eluent 20:80,
MeOH:CH2Cl2), 51 mg (86%) of (1S,2S)-17. ‰ꢀŠ2D0=+13.7 (c 0.9, MeOH); IR (neat): 3600±3200
+
1
(NH3, OH), 2750 (P±OH), 1602, 1216 (PˆO), 1052 (P±O); H NMR (d4-MeOH, 4.78 ppm, 200
3
MHz): ꢁ=7.30±7.00 (m, 5H), 4.28±4.02 (m, 1H), 3.85 (dq, JPH=7.2 Hz, J=7.3 Hz, 2H), 3.21
(dd, J=3.8 Hz, J=12.6 Hz, 1Hbenzyl), 2.43 (dd, J=10.5 Hz, J=12.6 Hz, 1Hbenzyl), 1.67 (m,
1H-C2), 1.44±1.20 (m, 1Hc-propyl), 1.20 (d, J=6.4 Hz, 3H, CH3-C2), 1.10 (t, J=7.3 Hz, 3H, CH3-
CH2-O), 1.07 (d, J=7.0 Hz, 3H), 0.58 (ddd, J=6.2 Hz, J=6.4 Hz, J=6.6 Hz, 1Hcycle); 13C NMR
(d4-MeOH, 49 ppm, 62.86 MHz): ꢁ=[6 arom. C: 138.1 (1C), 130.4 (2C), 129.8 (2C), 128.1 (1C)],
61.9 (d, 2JPC=6 Hz, 1C), 57.5 (CH-N), 40.9 (1C, benzyl), 39.0 (d, 1JPC=190.0 Hz, C1), 17.8 (1C),
2
17.3 (d, JPC=6.1 Hz, C2), 17.0 (1C), 16.4 (C3), 12.1 (CH3-C2); 31P NMR (d4-MeOH, 101.25
MHz): ꢁ=12.53.
4.5. (1S,2S)-1-Amino-2-methylcyclopropanephosphonic acid 3b
Trimethylsilyl iodide (300 mg, 1.5 mmol) was added dropwise to a stirred solution of the
monoethyl phosphonate 14 (90 mg, 0.50 mmol) in CH2Cl2 (5 mL), and stirring was continued at
room temperature for 30 min. Organic solvents were removed under vacuum, and a mixture of EtOH
(3 mL) was added with stirring. After complete precipitation, the pure aminophosphonic acid 3b
was ®ltered o€, giving after crystallization from (e.H2O, MeOH/Et2O) 65 mg (86%) as a white
solid (dried under high vacuum). ‰ꢀŠ2D0=+34 (c 1, H2O), ‰ꢀŠD20=+45 (c 0.2, H2O) [lit.10b for an
enantiomer (1R,2R)-3b ‰ꢀŠ2D0=^46.4 (c 0.2, H2O); mp=220±222ꢀC (decomp.), lit.9 mp=224±
225ꢀC (decomp.)]; Rf=0.41 (H2O:MeOH, 1:9); IR (KBr): 3600±3100 (OH and NH+3), 1190
1
(PˆO), 1050 (P±O); H NMR (D2O, 250 MHz): ꢁ=1.28 (dddd, Jcis=9.4 Hz, Jtrans=6.8 Hz,
3
3
J=6.4 Hz, JPH cis=12.7 Hz, 1H-C2), 1.06 (ddd, Jcis=9.4 Hz, Jgem=6.4 Hz, JPH cis=12.7 Hz,
1H), 1.00 (d, J=6.4 Hz, 3H, CH3-C2), 0.58 (ddd, Jtrans=6.8 Hz, Jgem=6.4 Hz, 3JPH trans=6.9 Hz,
1H); 13C NMR (D2O, 62.86 MHz): ꢁ=33.6 (d, JPC=192.5 Hz, C1), 16.0 (C3), 14.8 (C2), 10.9
(CH3-C2); 31P NMR (D2O, 101.25 MHz): ꢁ=13.36; anal. calcd for C4H10NO3P (151.1029): C,
31.80; H, 6.67; N, 9.27. Found: C, 31.88; H, 6.32; N, 8.88.
1
4.6. (1R,2S)-1-Amino-2-methylcyclopropanephosphonic acid 16
From minor 12a following the procedure used for (1S,2S)-3b, we obtained 10 mg (78% overall
yield) of (1S,2S)-16. ‰ꢀŠ2D0=+23 (c 0.5, H2O); mp=234±236ꢀC (decomp.); Rf=0.41 (H2O:MeOH,
1
1:9); H NMR (D2O, 250 MHz): ꢁ=1.23 (dddd, Jcis=11.8 Hz, Jtrans=5.1 Hz, J=6.4 Hz,
3JPH trans=6.8 Hz, 1H-C2), 1.04 (d, J=6.4 Hz, 3H, CH3-C2), 0.98 (ddd, Jtrans=5.1 Hz, Jgem=6.2
3
3
Hz, JPH cis=10.8 Hz, 1H), 0.79 (ddd, Jcis=11.8 Hz, Jgem=6.2 Hz, JPH trans=6.2 Hz, 1H); 13C
1
NMR (D2O, 62.86 MHz): ꢁ=34.0 (d, JPC=191.6 Hz, C1), 17.9 (C3), 16.7 (C2), 12.6 (d,
3JPC cis=3.4 Hz, CH3-C2); 31P NMR (D2O, 101.25 MHz): ꢁ=11.48; in agreement with our
previously reported data.13

A. Fadel, N. Tesson / Tetrahedron: Asymmetry 11 (2000) 2023±2031
2031
References
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