Synthesis of (1S,2S)- and (1R,2R)-1-amino-2-methylcyclopropane-phosphonic acids from racemic methylcyclopropanone acetal

Article abstract of DOI:10.1016/S0957-4166(02)00609-2

An efficient and easy one-pot reaction from readily available racemic alkylcyclopropanone acetals gave the corresponding aminophosphonates with excellent diastereoselectivity. After catalytic hydrogenolysis, and hydrolysis, these trans-phosphonates led to

Full text of DOI:10.1016/S0957-4166(02)00609-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2267–2276
Synthesis of (1S,2S)- and (1R,2R)-1-amino-2-
methylcyclopropane-phosphonic acids from racemic
methylcyclopropanone acetal†
Nicolas Tesson, Benoist Dorigneux and Antoine Fadel*
Laboratoire des Carbocycles (Associe´ au CNRS), Institut de Chimie Mole´culaire d’Orsay Baˆt. 420, Universite´ de Paris-Sud,
91405 Orsay, France
Received 29 August 2002; accepted 27 September 2002
Abstract—An efficient and easy one-pot reaction from readily available racemic alkylcyclopropanone acetals gave the correspond-
ing aminophosphonates with excellent diastereoselectivity. After catalytic hydrogenolysis, and hydrolysis, these trans-phospho-
nates led to enantiopure (+)-1-amino-2-methylcyclopropanephosphonic acid and its antipode (analogues of allo-norcoronamic
acid). © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
synthesis of 1-aminocyclopropanephosphonic acid
(ACC analogue) 3a (R=H), in three steps, starting
from cyclopropanone acetal 4a and proceeding via the
aminophosphonates 6A.a.11 We have recently applied
the same methodology for the preparation of (1S,2S)-1-
aminocyclopropanephosphonic acid 3b [an analogue of
(1R,2S)-allo-norcoronamic acid 1b (R=CH3)].12 This
sequence occurred in three steps from acetal (2S)-
4b, proceeding by asymmetric addition of phosphite to
the intermediate iminium species 5A via aminophos-
phonates 6A.b13 or spirophosphonates 7a–b.14 The
products were obtained in good overall yields (Scheme
2).
In recent years, 1-aminocyclopropanecarboxylic acids 1
(ACCs) have attracted special attention owing to their
use as enzyme inhibitors as well as their incorporation
in strained peptides.1,2 The biologically active phospho-
nic acids 2, which are analogues of a-a-amino acids, are
the subject of increasing interest,3–6 due to the tetra-
hedral structure of the phosphonic acid moiety and
since they act as ‘transition-state analogues’.7,8 How-
ever, the aminocyclopropanephosphonic acids 3 did not
receive the same attention compared to the acyclic
aminophosphonic acids 2 and aminocyclopropanecar-
boxylic acids 1 (Scheme 1).
This strategy appeared to be a promising approach for
the asymmetric synthesis of various aminophosphonic
acids 3. In order to obtain such acids through the
corresponding aminophosphonates 6A.b–f and 6C.b–f,
we decided in connection with our ongoing program,13
As far as we are aware, only a few methods for the
synthesis of compounds of this class have been
described in either racemic9 or optically active form.10
We have previously reported a simple and convenient
Scheme 1.
* Corresponding author. Fax: +33(1)69156278; e-mail: antfadel@icmo.u-psud.fr
† Dedicated to Professor Dr. Dieter Seebach in honour of the occasion of his 65th birthday.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00609-2

2268
N. Tesson et al. / Tetrahedron: Asymmetry 13 (2002) 2267–2276
Scheme 2.
to study the asymmetric addition of triethyl phosphite
to the inexpensive and readily available racemic acetal
( )-4.12b We anticipated that this reaction, involving the
iminium species 5A and 5C as intermediates, should
occur in the presence of a chiral amine (Scheme 3).
furnish the amino phosphonates 6A–D in good yields
(62–80%) as mixtures of diastereoisomers in which the
major trans products 6A and 6C were obtained with
high selectivity (trans:cis ratio of up to 88:12, Table 1,
entries 1–4). The selectivity of this one-pot reaction
increase to 100:0 for sterically hindered acetal 4f (R=t-
Bu) (entry 7). Nevertheless, the low yields from the
reactions of bulky acetals were improved by forming
the iminium intermediate prior to adding the phosphite,
thus preventing the competitive formation of the
hydroxy phosphonates 11e,f (X=PO3Et2), giving 56
and 60% yields, respectively, of the major trans 6A and
6C (entries 6, 8 and 9).
2. Results and discussion
The reactions were carried out using a one-pot proce-
dure. Thus, the hemiacetal ( )-8b–f, generated in situ
from the acetal ( )-4b–f by alcoholysis in the presence
of a catalytic amount of an acid (TMSCl or AcOH),14
reacted with chiral amine (S)-9, and 3 equiv. of AcOH
to give the aminals 10. Under acidic conditions, the
latter were converted into the iminium intermediates
(S,S)-5A and (R,S)-5C (Scheme 4), which then under-
went triethylphosphite addition in EtOH at 60°C, to
We anticipated that the nucleophilic attack of phos-
phite on the iminium intermediates (S,S)-5A and (R,S)-
5C, would afford one predominant diastereoisomer
(path a or c with a like approach in Scheme 4) of the
Scheme 3.
Scheme 4.

N. Tesson et al. / Tetrahedron: Asymmetry 13 (2002) 2267–2276
Table 1. Preparation of aminophosphonates 6A–D from racemic acetals 4*
2269
Run
4b–f
Amine 9
Time (h)
Yield (%)
6 Diastereomeric ratioa
A:B–C:D
trans/cis
6A+6B/6C+6D
R
1
2
3
4
5
6
7
8
9
b
b
c
d
e
e
f
Me
Me
Et
Bn
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
(S)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
23
40
30
60
80
78
78
62
30c
56
14d
42
60
b
b%
c
d
e
e
f
41.8:5.7–46.4:6.1
46.5:6.1–41.5:5.9
41:9–41:9
88.2/11.8
88/12
82/18
86/14
76/24
76/24
100/0
100/0
100/0
47.5/52.5
52.6/47.4
50/50
50/50
50/50
50/50
50/50
50/50
50/50
43:7–43:7
49
38:12–38:12
38:12–38:12
50:0–50:0
50:0–50:0
50:0–50:0
16b+20
89
f
f
15b+48
16b+63
f
f
4 equiv. (S)
* All reactions of racemic acetal 4 were carried out in the presence of 1.5 equiv. of amine and P(OEt)3 and 3 equiv. of AcOH in EtOH at 55°C.
a Diastereoisomeric ratios were measured by GC analysis on a chiral column.
b Time allowed for iminium formation before adding phosphite.
c In plus 10% of hydroxy phosphonate 11e.
d In plus 55% of 11f.
four possible isomers.12b,15 However, only a slight dif-
ference in the 6A:6C ratio was observed using (S)-9 and
(R)-9. Thus, the ratio changed from 41.8/46.4 to 46.5/
41.5, respectively (Table 1, entries 1 and 2).
isomers 6B.b–f and 6D.b–f by chromatography on silica
gel. Unfortunately, we were unable to isolate 6A.b–f
from 6C.b–f even after exhaustive chromatography, and
only in the case of 6C.c/6A.c the mixture was enriched
to 28% d.e.
We have previously reported13 that no reaction occurs
when bulky phosphites such as (iPrO)3P or (PhO)3P are
used in i-PrOH or phenol, respectively (see also Table
2, entries 2 and 5 compared to entry 1). In contrast, in
DMSO solvent the triisopropylphosphite gave a mix-
ture of major trans isomers 12A and 12C in 20% yield
(entry 3). Furthermore, by forming the iminium inter-
mediate before adding the bulky phosphite the yield of
12A/12C and 13A/13C could be improved to 40 and
35%, respectively (Table 2, entries 4 and 6).
To overcome this problem of separation we selected
some mixtures of major trans 6A.b/6C.b, 6A.c/6C.c and
12A.b/12C.b. However, it was possible to protect these
mixtures, as its formamide derivatives 14A–16A and
14C–16C using in situ generated acetic formic
anhydride16 under solvent free conditions (Scheme 5).
Since our goal was to find a practical protocol for
preparation of 2-alkyl-1-aminocyclopropanephosphonic
acids, it was critical to demonstrate that the N-benzyl
group could be removed along with the N-formamide
group under the same conditions. Indeed, the major
The major amino phosphonates 6A.b–f and 6C.b–f
obtained above were readily isolated from the minor cis
Table 2. Preparation of aminophosphonates X(A–D).b from racemic acetals 4b
Run P(OR%)3
(R%)
Solvent* (equiv.)
Time (h)
Yield (%)
Products (X(A–D).b)
Major/minor (A+C/B+D)
1
2
3
4
5
6
Et
EtOH
30
46
160
78
0
20
40
0
6(A–D).b
12(A–D).b
12(A–D).b
12(A–D).b
13(A–D).b
13(A–D).b
88/12
–/–
100/0
100/0
–/–
i-Pr
i-Pr
i-Pr
Bn
i-PrOH
DMSOb
DMSOb
BnOH
18a+48
53
Bn
DMSOc
17a+140
35
\95/5
* All reactions of acetal ( )-4b were carried out in the presence of amine (S)-9 (1.5 equiv.), P(OR%)3, (1.5 equiv.) and AcOH (3 equiv.) at 55°C.
a Time of iminium formation before adding phosphite.
b With 2 equiv. of i-PrOH.
c With 2 equiv. of BnOH.

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N. Tesson et al. / Tetrahedron: Asymmetry 13 (2002) 2267–2276
Scheme 5.
trans phosphonates 14A and 15A, could be reacted
under mild conditions (20% Pd(OH)2/C, and 1 atm H2,
in 2N HCl17 to effect double deprotection affording
2-methylphosphonates 17A ([h]D=+23.7 (c 1, CHCl3),
and 18A ([h]D=+19.5 (c 1.1, CHCl3), in good yield.
with the literature data,10b is 1S,2S for (+)-3b, 1R,2R
for (−)-3b, and consequently the major trans isomers 6A
and 6C have 1S,2S and 1R,2R configuration, respec-
tively. These conclusions were corroborated by the 13C
NMR spectra of the cis-6B.b–c, by the coupling con-
stants between P and CH3–C1 or P and CH3–CH2–C1
(3JPC cis=3.8 Hz), were measured.19
Under the same conditions, the isolated 14C, gave the
antipodal ethyl phosphonate (−)-17C ([h]D=−23.5 (c
1.2, CHCl3)) in 95% yield. Subsequent treatment of the
phosphonates (+)-17A and (+)-18A with trimethylsilyl-
iodide in dichloromethane, followed by the addition of
propylene oxide in ethanol, furnished the same enan-
3. Conclusion
We have developed an easy and efficient three-step
synthesis of enantiopure (+)-trans-(1S,2S)-1-amino-2-
methylcyclopropanephosphonic acid (+)-3b and its
antipode (−)-(1R,2R)-3b starting from the readily avail-
able racemic alkylcyclopropanone acetals 4b–f. These
acids were obtained from separable formamide deriva-
tives (14 and 15) of the major trans aminophosphonates
6A and 6C. This approach should constitute an efficient
method for the synthesis of a wide variety of aminocy-
clopropanephosphonic acids. Efforts to improve the
diastereoselective phosphite approach are currently in
progress in our laboratory.
tiopure
(1S,2S)-1-amino-2-methylcyclopropanephos-
phonic acid (+)-3b ([h]D=+33.6 (c 1, H2O)) in yields of
90 and 100%, respectively. To demonstrate the
efficiency of this method, we applied the same treat-
ment to (−)-17C, which furnished the enantiopure
antipodal aminophosphonic acid (−)-3b in 91% yield,
([h]D=−43.5 (c 0.2, H2O)) (Scheme 6). These values are
in agreement with our previously reported results,13,14
([h]D=+34 (c 1, H2O)) and ([h]D=+45 (c 0.2, H2O)) for
(+)-3b, and with the literature value10b for (−)-3b
([h]D=−46.4 (c 0.2, H2O)). Its enantiomeric excess,
determined from 19F NMR analysis of the correspond-
ing Mosher amide,18 was found to be >98%.
4. Experimental
For general experimental information, see Fadel,11 or
Tesson and Fadel.13
The absolute configuration of these acids, assigned in
agreement with our previously reported results13,14 and
Scheme 6.

N. Tesson et al. / Tetrahedron: Asymmetry 13 (2002) 2267–2276
2271
4.1. General procedure A: Preparation of aminophospho-
nates according to our reported method13,14
(2C), 147.4]; 31P NMR (CDCl3, 101 MHz) l: 29.88
ppm.
To a solution of cyclopropanone acetal 4 (5 mmol) in
EtOH (10 mL), was added one drop of TMSCl, after 5
min of stirring, a-methylbenzylamine (S)-9 (910 mg,
7.50 mmol), AcOH (1.2 mL, 3 equiv.), and P(OEt)3,
(1.25 g, 1.31 mL, 7.50 mmol) were added successively.
The mixture was stirred and heated at 55°C for 3–6
days. It was then concentrated under vacuum, concen-
trated ammonia (2 mL) was added, and then the mix-
ture was filtered through a 5 cm pad of silica gel and
eluting with ether (100 mL). The filtrate was concen-
trated under vacuum to give the crude phosphonates as
a mixture of four diastereomers. Purification was done
by flash chromatography (FC) on silica gel, (eluent,
EtOAc/CH2Cl2: 10/90 to 40/60).
The spectral data are identical with those already
reported by us for (1S,2S,1%S) and the (1S,2S,1%R)
antipode, respectively.13
4.1.2. Diethyl (1S*,2S*,1%S)-2-ethyl-1-(1%-methylphenyl-
amino)-cyclopropane-phosphonates: (1S,2S,1%S)-6A.c and
(1R,2R,1%S)-6C.c. Following procedure A: reaction of
acetal 4c (5 mmol), EtOH (10 mL), TMSCl (cat.),
amine (S)-9 (7.50 mmol), AcOH (15 mmol), and
P(OEt)3 (1.31 mL, 7.5 mmol), for 30 h at 55°C gave,
after standard work-up 2.80
g of a (41:41:9:9)
diastereomeric mixture of the crude trans/cis-phospho-
nates. Purification by FC (twice) furnished 817 mg
(50%) of a non separable mixture of trans diastereomers
(1S,2S,1%S)-6A.c and (1R,2R,1%S)-6C.c, along with 407
mg (28%) as a mixture and 48 mg (3%) of a cis-
(1R,2S,1%S)-6B.c/trans mixture (in 90:10 ratio).
4.1.1. Diethyl (1S*,2S*,1%S)-2-methyl-1-(1%-methyl-
phenylamino)-cyclopropane-phosphonates: (1S,2S,1%S)-
6A.b and (1R,2R,1%S)-6C.b. Following procedure A:
reaction of acetal 4b (5 mmol), EtOH (10 mL), TMSCl
(cat.), amine (S)-9 (7.50 mmol), AcOH (15 mmol), and
P(OEt)3 (1.31 mL, 7.5 mmol), for 40 h at 55°C gave,
after standard work-up 2.50 g of a (41.8:46.4:6.1:5.7)
diastereomeric mixture of the crude trans/cis phospho-
nates. Purification by FC (twice) afforded 771 mg (60%)
of a non separable mixture of trans diastereomers
(1S,2S,1%S)-6A.b and (1R,2R,1%S)-6C.b, along with 224
mg (18%) as a mixture.
4.1.2.1. Data for (1S,2S,1%S)-6A.c major trans isomer.
1
(Data obtained from a trans/trans mixture) H NMR
(CDCl3, 250 MHz) l: 0.70–0.85 (m, 1Hcycle), 0.94 (t,
J=6.5 Hz, 3H), 1.05–1.45 (m, 2Hcycle), 1.31 (t, J=6.7
Hz, 3H), 1.33 (d, J=6.4 Hz, 3H), 1.34 (t, J=6.7 Hz,
3H), 1.54 (dq, J=6.3 Hz, J=6.5 Hz, 2H), 1.80 (br s,
NH), 4.00–4.25 (m, 4H), 4.43 (dq, JPH=3.5 Hz, J=6.4
Hz, 1H), 7.15–7.40 (m, 5H); MS (70 eV) m/z (%): 325
[M+] (2.6), 187 (100), 186 (53), 105 (88).
4.1.1.1. Data for (1S,2S,1%S)-6A.b major trans isomer.
4.1.2.2. Data for (1R,2R,1%S)-6C.c major trans isomer.
1
1
(Data obtained from a trans/trans mixture) H NMR
(Data obtained from a trans/trans mixture) H NMR
(CDCl3, 250 MHz) l: 0.67 (ddd, JPH=5.9 Hz, J=3.9
Hz, J=7.8 Hz, 1Hcycle), 1.08 (d, J=5.8 Hz, 3H), 1.28 (t,
J=7.0 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H), 1.31 (d, J=6.8
Hz, 3H), 1.20–1.46 (m, 2Hcycle), 1.76 (br. s, 1H, NH),
(CDCl3, 250 MHz) l: 0.13 (ddd, J=5.5 Hz, J=7.2 Hz,
J=8.2 Hz, 1Hcycle), 0.84 (ddd, J=8.9 Hz, J=3.9 Hz,
J=14.4 Hz, 1Hcycle), 0.95 (t, J=6.5 Hz, 3H), 1.05–1.28
(m, 1Hcycle), 1.33 (d, J=6.4 Hz, 3H), 1.36 (t, J=6.7 Hz,
3H), 1.39 (t, J=6.7 Hz, 3H), 1.52 (dq, J=6.1 Hz,
J=6.5 Hz, 2H), 1.60–2.10 (m, NH), 4.12 (dq, JPH=2.1
Hz, J=6.7 Hz, 2H), 4.15 (dq, JPH=2.1 Hz, J=6.7 Hz,
3
4.04 (dq, J=7.0 Hz, JPH=1 Hz, 2H), 4.12 (dq, J=7.0
3
4
Hz, JPH=1 Hz, 2H), 4.35 (dq, J=6.8 Hz, JPH=3.4
Hz, 1H), 7.10–7.40 (m, 5H); 13C NMR (CDCl3, 63
MHz) l: 11.8 (C4), 16.35 (d, 3JPC=5.7 Hz, 1C), 16.5 (d,
4
2H), 4.30 (dq, JPH=2.6 Hz, J=6.8 Hz, 1H), 7.15–7.40
3JPC=5.7 Hz, 1C), 17.1 (d, JPC=3.8 Hz, C2), 19.7 (d,
(m, 5H); MS (70 eV) m/z (%): 325 [M+] (2), 187 (100),
2
2JPC=2.9 Hz, C3), 23.3, 34.6 (d, 1JPC=200 Hz, C1),
186 (54), 105 (95).
2
2
56.1, 61.4 (d, JPC=6.7 Hz, 1C), 61.7 (d, JPC=6.7 Hz,
1C), [6 arom. C: 126.7, 126.8 (2C), 128.1 (2C), 147.0];
31P NMR (CDCl3, 101 MHz) l: 29.51 ppm.
4.1.2.3. Data for (1R,2S,1%S)-6B.c isolated minor cis
1
isomer. [h]D=−17.6 (c 1, CHCl3) e.e. >98%; H NMR
(CDCl3, 250 MHz) l: 1.00–1.26 (m, 2Hcycle), 1.05 (t,
J=7.4 Hz, 3H), 1.20–1.30 (m, 1Hcycle), 1.34 (t, J=7.3
Hz, 3H), 1.35 (d, J=6.1 Hz, 3H), 1.36 (t, J=7.3 Hz,
3H), 1.45–1.68 (m, 1H), 1.68–1.90 (m, 1H), 1.90–2.20
(m, NH), 4.14 (dq, JPH=2.1 Hz, J=7.3 Hz, 2H), 4.16
4.1.1.2. Data for (1R,2R,1%S)-6C.b major trans iso-
mer. (Data obtained from a trans/trans mixture) 1H
NMR (CDCl3, 250 MHz) l: 0.08 (ddd, J=7.7 Hz,
J=5.2 Hz, JPH=6.4 Hz, 1Hcycle), 0.85 (ddd, J=14.0
Hz, J=9.3 Hz, J=5.2 Hz, 1Hcycle), 1.10 (d, J=6.0 Hz,
CH3-C2), 1.29 (d, J=6.7 Hz, 3H), 1.28 (dddd, Jcis=9.3
Hz, Jtrans=7.7 Hz, J=6.0 Hz, JPH cis=14 Hz, 1Hcycle),
1.31 (t, J=6.7 Hz, 3H), 1.33 (t, J=6.7 Hz, 3H), 1.76
4
(dq, JPH=2.1 Hz, J=7.3 Hz, 2H), 4.34 (dq, JPH=2.9
Hz, J=6.1 Hz, 1H), 7.17–7.40 (m, 5H); 13C NMR
3
(CDCl3, 63 MHz) l: 13.8 (C5), 16.5 (d, JPC=6.2 Hz,
3
2
2C), 18.5 (d, JPC=3.8 Hz, C4), 21.6 (d, JPC=2.9 Hz,
3
2
(br. s, 1H, NH), 4.10 (dq, JPH=4.0 Hz, J=6.7 Hz,
C3), 22.2, 30.9 (d, JPC=5.7 Hz, C2), 36.9 (d, J=195.9
3
2
2H), 4.14 (dq, JPH=4.0 Hz, J=6.7 Hz, 2H), 4.29 (dq,
Hz, C1), 56.2, 61.6 (d, JPC=5.2 Hz, 2C), [6 arom. C:
4JPH=2.8 Hz, J=6.7 Hz, 1H), 7.10–7.34 (m, 5H); 13C
126.7 (2C), 127.0, 128.3 (2C), 146.1]; 31P NMR (CDCl3,
2
NMR (CDCl3, 63 MHz) l: 11.9, 16.5 (d, JPC=5.1 Hz,
101 MHz) l: 28.80 ppm.
2
2
1C), 16.6 (d, JPC=1.5 Hz, C3), 16.7 (d, JPC=5.1 Hz,
2
1
1C), 17.7 (d, JPC=4.8 Hz, C2), 25.4, 35.8 (d, JPC
=
4.1.3. Diethyl (1S*,2S*,1%S)-2-benzyl-1-(1%-methylphenyl-
2
200.6 Hz, C1), 56.1, 61.6 (d, JPC=7.2 Hz, 1C), 61.9 (d,
amino)-cyclopropane-phosphonates:
(1S,2S,1%S)-6A.d
2JPC=7.2 Hz, 1C), [6 arom. C: 126.6, 127.0 (2C), 128.1
and (1R,2R,1%S)-6C.d. Following procedure A: reaction

2272
N. Tesson et al. / Tetrahedron: Asymmetry 13 (2002) 2267–2276
of acetal 4d (550 mg, 0.88 mmol), EtOH (2 mL), TMSCl
(cat.), amine (S)-9 (160 mg, 1.32 mmol), AcOH (150 mL),
and P(OEt)3 (230 mL, 1.32 mmol), for 60 h at 55°C gave,
after standard work-up 1.030 g of a (43:43:7:7)
diastereomeric mixture of the crude trans phosphonates.
Purification by FC (twice) furnished 171 mg (50%) of a
non separable mixture of trans diastereomers
(1S,2S,1%S)-6A.d and (1R,2R,1%S)-6C.d, 4 mg (1%) as oil
of cis-(1R,2S,1%S)-6B.d, 10 mg (3%) of cis-(1S,2R,1%S)-
6D.d, and 20 mg (6%) as a mixture.
6.78–6.90 (m, 1H), 7.05–7.40 (m, 9H); 31P NMR (CDCl3,
101 MHz) l (ppm): 30.34; MS (70 eV) m/z (%): 387 [M+]
(1.7), 249 (24), 192 (33), 144 (21), 105 (100), 91 (33);
HRMS m/z: 387.1957 (calcd for C22H30NO3P: 387.1963).
4.1.4. Diethyl (1S*,2R*,1%S)-2-iso-propyl-1-(1%-methyl-
phenylamino)-cyclopropane-phosphonates: (1S,2R,1%S)-
6A.e and (1R,2S,1%S)-6C.e. Following procedure A: reac-
tion of acetal 4e (1 mmol), EtOH (2 mL), TMSCl (cat.),
amine (S)-9 (170 mg, 1.5 mmol), AcOH (170 mL, 3
mmol), and P(OEt)3 (260 mL, 1.5 mmol), for 49 h at 55°C
gave, after standard work-up 850 mg of a (38:38:12:12)
diastereomeric mixture of the crude trans phosphonates.
Purification by FC (three times) furnished 70 mg (20%)
of a non separable mixture of trans diastereomers
(1S,2R,1%S)-6A.e and (1R,2S,1%S)-6C.e, 8 mg (2%) of
minor cis-(1R,2R,1%S)-6B.e (or (1S,2S,1%S)-6D.e), 4 mg
(1%) of minor cis-(1S,2S,1%S)-6D.e (or (1R,2R,1%S)-
6B.e), 24 mg (7%) as a mixture, and 33 mg (14%) of
hydroxyphosphonate 11e.
4.1.3.1. Data for (1S,2S,1%S)-6A.d (a) and (1R,2R,1%S)-
6C.d (b), major trans isomer. Rf=0.38 (Et2O); RT=35.79
min (a) and 36.18 min (b) [CPSIL-5CB, 200–240°C, 1.3
1
bar)]; H NMR (CDCl3, 250 MHz) l (ppm) (a/b): 0.28
(ddd, J=5.9 Hz, J=6.8 Hz, J=8.3 Hz, 1Hcycle b),
0.83–1.00 (m, 1Hcycle a+1Hcycle b), 1.17 (t, J=7.3 Hz,
3Ha, CH3), 1.23 (t, J=7.3 Hz, 3Hb, CH3), 1.29 (t, J=7.3
Hz, 3Ha, CH3), 1.32 (d, J=6.8 Hz, 3Hb, CH3-C1%), 1.35
(d, J=6.8 Hz, 3Ha, CH3-C1%), 1.36 (t, J=7.3 Hz, 3Hb,
CH3), 1.40–1.48 (m, 1Hcycle b), 1.48–1.62 (m, 1Hcycle a),
1.62–1.81 (m, 1Hcycle a), 2.72–2.95 (m, 2Hbenzyl b+2Hbenzyl
a), 3.75–4.10 (m, 8H, 4CH2-O), 4.31 (dq, J=2.9 Hz,
J=6.8 Hz, H-C1%b), 4.40 (dq, J=3.4 Hz, J=6.4 Hz,
H-C1%a), 7.09–7.40 (m, 10Ha+10Hb); 13C NMR (CDCl3,
63 MHz) l (ppm) (a/b): 15.1 (C3b), 16.3–16.7 (m,
2CH3a+2CH3b), 18.8 (C3a), 23.4 (CH3-C1%a), 23.5 (d,
4.1.4.1. Data for (1S,2R,1%S)-6A.e and (1R,2S,1%S)-
6C.e major trans isomer. (Data obtained from a trans/
trans mixture) Rf=0.43 (Et2O); RT=23.73 min and 25.92
min [CPSIL-5CB, 165°C (5 min)+1°C/min to 180°C (20
min)+3°C/min to 240°C (20 min), 1 bar]; 1H NMR
(CDCl3, 250 MHz) l (ppm): 0.05–0.17 (m, 1Hcycle),
0.70–0.85 (m, 2Hcycle), 0.91 (d, J=6.8 Hz, 6H, 2CH3),
0.99 (d, J=6.4 Hz, 3H, CH3), 0.88–1.01 (m, 1H), 1.04
(d, J=6.8 Hz, 3H, CH3), 1.08–1.37 (m, 2H), 1.24–1.44
(m, 18H, 4CH3+2CH3-C1%), 1.50–1.83 (m, 2Hcycle), 1.87
(br s, 2H, NH), 4.00–4.21 (m, 8H, 4CH2-O), 4.30 (dq,
J=2.4 Hz, J=6.8 HZ, H-C1%), 4.42 (dq, J=3.4 Hz,
J=6.4 Hz, H-C1%), 7.12–7.41 (m, 10H); 13C NMR
(CDCl3, 62.86 MHz) l (ppm): 14.5(C3), 16.6 (4C, CH3),
18.0 (d, J=3.2 Hz, C3), 22.2 (1C, CH3-C1%), 22.4 (1C,
CH3-C-O), 22.6 (1C, CH3-C-O), 22.65 (1C, CH3-C-O),
23.3 (CH3-C1%), 25.9 (CH3-C1%), 26.7 (C4), 26.8 (C4), 30.9
2
2JPC=3.8 Hz, C2a), 24.2 (d, JPC=4.6 Hz, C2b), 25.8
1
(CH3-C1%b), 32.8 (C4b), 32.9 (C4a), 35.0 (d, JPC=198.7
Hz, C1a), 36.6 (d, 1JPC=199.6 Hz, C1b), 56.3 (C1%a), 56.4
(C1%b), 61.6–62.2 (m, 4C, 2CH2-Oa/b), [24 arom.C: 125.8
(Ca/b), 126.2 (2Ca/b), 126.7 (Ca/b), 127.0 (2Ca/b), 128.1
(2Ca/b), 128.3 (3Ca/b), 141.3 (Ca), 141.5 (Cb), 147.0
(Cb), 147.4 (Ca)]; 31P NMR (CDCl3, 101 MHz) l (ppm):
29.24 (a) and 29.75 (b); MS (70 eV) m/z (%): 387 [M+]
(4.2), 250 (35), 249 (87), 192 (51), 131 (41), 105 (100);
HRMS m/z (a): 387.1953, (b): 387.1958 (calcd for
C22H30NO3P: 387.1963).
1
(br s, C2), 31.5 (d, J=3.3 Hz, C2), 32.2 (d, JPC=198.3
1
Hz, C1), 36.7 (d, JPC=199.7 Hz, C1), 56.3 (2C, C1%),
4.1.3.2. Data for (1R,2S,1%S)-6B.d, minor cis isomer.
Rf=0.48 (Et2O); RT=37.67 min [CPSIL-5CB, 200–
61.5–61.8 (m, 4C, 4CH2-O), [12 arom. C: 126.4, 126.5,
126.8 (2C), 126.9 (2C), 128.0 (2C), 128.2 (2C), 147.2,
147.5]; 31P NMR (CDCl3, 101 MHz) l (ppm): 29.99 and
29.41.
1
240°C, 1.3 bar)]; H NMR (CDCl3, 250 MHz) l (ppm):
0.81–0.94 (m, 1Hcycle), 1.09 (ddd, J=4.9 Hz, J=7.3 Hz,
J=12.7 Hz, 1Hcycle), 1.28 (d, J=6.8 Hz, 3H, CH3-C1%),
1.34 (t, J=7.3 Hz, 6H, CH3), 1.32–1.48 (m, 1Hcycle), 2.84
(dd, J=10.9 Hz, J=14.7 Hz, 1Hbenzyl), 3.14 (dd, J=4.4
Hz, J=14.7 Hz, 1Hbenzyl), 4.14 (dq, J=2.9 Hz, J=7.3 Hz,
CH2-O), 4.15 (dq, J=7.3 Hz, J=7.3 Hz, CH2-O), 4.31
(dq, J=2.9 Hz, J=6.8 Hz, H-C1%), 7.14–7.32 (m, 10H);
31P NMR (CDCl3, 101 MHz) l (ppm): 29.44; MS (70 eV)
m/z (%): 387 [M+] (2.1), 250 (27), 249 (51), 192 (35), 131
(26), 105 (100); HRMS m/z: 387.1971 (calcd for
C22H30NO3P: 387.1963).
4.1.4.2. Data for (1R,2R,1%S)-6B.e (or cis-(1S,2S,1%S)-
6D.e) minor cis isomer. Rf=0.48 (Et2O); RT=26.62 min
1
[CPSIL-5CB, 165–240°C, 1 bar]; H NMR (CDCl3, 250
MHz) l (ppm): 0.77 (ddd, J=4.4 Hz, J=8.8 Hz, J=13.7
Hz, 1Hcycle), 0.82–0.94 (m, 1Hcycle), 0.93 (d, J=6.4 Hz,
3H, CH3), 1.12 (d, J=6.8 Hz, 3H, CH3), 1.30 (t, J=7.3
Hz, 3H, CH3-C-O), 1.33 (t, J=7.3 Hz, 3H, CH3-C-O),
1.34 (d, J=6.8 Hz, 3H, CH3-C1%), 1.25–1.50 (m, H4),
1.60–1.85 (m, 1Hcycle), 4.01–4.22 (m, 4H, 2CH2-O), 4.30
(dq, J=2.9 Hz, J=6.8 HZ, H-C1%), 7.10–7.45 (m, 5H);
13C NMR (CDCl3, 63 MHz) l (ppm):, 16.5 (br s, 2CH3),
18.3(C3), 22.5 (CH-C2), 22.8 (CH3), 22.9 (CH3), 27.8
4.1.3.3. Data for (1S,2R,1%S)-6D.d, minor cis. Rf=0.31
(EtOAc/CH2Cl2 15:85); RT=33.84 min [CPSIL-5CB,
200°C+3°C/min, 1.3 bar)]; 1H NMR (CDCl3, 250 MHz)
l (ppm): 0.78–0.89 (m, 1Hcycle), 1.03–1.14 (m, 1Hcycle),
1.30 (d, J=6.8 Hz, 3H, CH3-C1%), 1.38 (t, J=7.3 Hz, 3H,
CH3), 1.40 (t, J=7.3 Hz, 3H, CH3), 1.40–1.60 (m,
1Hcycle), 2.50 (dd, J=9.3 Hz, J=14.6 Hz, 1Hbenzyl), 2.67
(dd, J=4.9 Hz, J=14.6 Hz, 1Hbenzyl), 4.06–4.29 (m, 4H,
1
(CH3-C1%), 37.5 (d, JPC=195.9 Hz, C1), 37.6 (d, J=7.4
2
Hz, C2), 56.0 (C1%), 61.4 (d, JPC=6.5 Hz, CH2-O), 61.7
(d, 2JPC=6.5 Hz, CH2-O), [6 arom. C: 126.6 (2C), 126.9,
128.3 (2C), 147.0]; 31P NMR (CDCl3, 101 MHz) l (ppm):
29.74; MS (70 eV), m/z (%): 340 [M++1] (0.6), 339 [M+]
(0.6), 201 (32), 105 (100), 103 (20); HRMS m/z: 339.1964
(calcd for C18H30NO3P: 339.1963).
4
2CH2-O), 4.29 (dq, JPH=2.5 Hz, J=6.8 Hz, H-C1%),

N. Tesson et al. / Tetrahedron: Asymmetry 13 (2002) 2267–2276
2273
4.1.4.3. Data for (1S,2S,1%S)-6D.e (or cis-
(1R,2R,1%S)-6B.e) minor cis isomer. Rf=0.40 (Et2O);
RT=24.19 min [CPSIL-5CB, 165–240°C, 1 bar]; 1H
NMR (CDCl3, 250 MHz) l (ppm): 0.52 (d, J=6.4 Hz,
3H, CH3), 0.70 (d, J=6.8 Hz, 3H, CH3), 0.57–0.96 (m,
3H), 1.16–1.29 (m, 1H), 1.24 (d, J=6.8 Hz, 3H, CH3-
C1%), 1.36 (t, J=7.3 Hz, 3H), 1.37 (t, J=7.3 Hz, 3H),
1.25–1.50 (m, H4), 1.60–1.85 (m, 1Hcycle), 4.03–4.22 (m,
4H, 2CH2-O), 4.26 (dq, J=2.4 Hz, J=6.8 Hz, H-C1%),
7.10–7.38 (m, 5H); 31P NMR (CDCl3, 101 MHz) l
(ppm): 31.19.
(dq, J=3.9 Hz, J=6.4 Hz, H-C1%), 7.13–7.36 (m, 10H);
13C NMR (CDCl3, 50.3 MHz) l (ppm): 12.3 (C3), 14.5
(C3), 16.5 (4CH3), 22.6 (CH3-C1%), 25.1 (CH3-C1%), 29.9
(6C, CH3t-butyl), 30.5 (2C4), 32.1 (C2), 33.0 (C2), 35.7 (d,
1
1JPC=192.4 Hz, C1), 36.9 (d, JPC=193.4 Hz, C1), 56.4
2
(C1%), 56.8 (C1%), 61.4 (d, JPC=6.5 Hz, 2 CH2-O), 61.7
2
(d, JPC=6.5 Hz, 2 CH2-O), [12 arom.C: 126.5 (3C),
126.8, 127.4 (2C), 127.7 (2C), 128.2 (2C), 146.2, 147.1];
31P NMR (CDCl3, 101 MHz) l (ppm): 30.06 and 29.30;
MS (70 eV) m/z (%) (a): 353 [M+] (0.9), 215 (76), 192
(31), 105 (100), m/z (b): 353 [M+] (0.1), 215 (71), 192
(26), 105 (100).
4.1.4.4. Data for diethyl rac-trans-1-hydroxy-2-iso-
propyl-cyclopropylphosphonate, 11e. Rf=0.08 (EtOAc/
CH2Cl2: 15/85); RT=4.51 min [CPSIL-5CB, 165°C, 1
4.2.1.2.
Diethyl
(1S*,2R*,1%S)-2-tert-butyl-1-(1%-
phenylethylamino)-cyclopropane-phosphonates: (1S,2R,
1%S)-6A.f and (1R,2S,1%S)-6C.f. Method II. Following
procedure A: 148 mg (14%) of a mixture of trans-
(1S,2R,1%S)-6A.f and (1R,2S,1%S)-6C.f were obtained
along with 412 mg (55%) of hydroxyphosphonate 11f.
1
bar]; H NMR (CDCl3, 250 MHz) l (ppm): 0.61 (m,
with J=5.9 Hz, 1Hcycle), 1.02 (d, J=6.8 Hz, 3H, CH3),
1.07 (d, J=6.8 Hz, 3H, CH3), 0.90–1.28 (m, 2Hcycle),
1.33 (t, J=6.8 Hz, 3H), 1.34 (t, J=6.8 Hz, 3H), 1.44–
1.60 (m, CHiPr), 2.35 (br s, OH), 4.15 (dq, J=6.8H,
J=6.8H, 2H, CH2-O), 4.16 (dq, J=6.8 Hz, J=6.8 Hz,
2H, CH2-O); 13C NMR (CDCl3, 50.3 MHz) l (ppm):
16.4 (CH3-C4), 16.5 (CH3-C4), 17.1 (C3), 22.3 (CH3),
4.2.1.2.1. Data for diethyl rac-trans-2-tert-butyl-1-
hydroxy-cyclopropylphosphonate, 11f. Rf=0.20 (EtOAc/
CH2Cl2: 15/85); RT=30.54 min and 31.65 min (two
enantiomers) [chiral Cydex B, 120°C, 1 bar]; IR (neat):
1
22.7 (CH3), 26.7 (C4), 30.3 (C2), 52.5 (d, JPC=224.4
Hz, C1), 62.4 (br s, CH2-O), 62.5 (br s, CH2-O); 31P
NMR (CDCl3, 101 MHz) l (ppm): 24.84; MS (70 eV),
m/z (%): 236 (M+, 2.5), 139 (29), 138 (100), 111 (64);
HRMS m/z: 236.1179 (calcd for C10H21NO4P:
236.1177).
3256 (OH), 1215 (PꢀO), 1033 (P-O); H NMR (CDCl3,
1
250 MHz) l (ppm): 0.88–0.98 (m, 1Hcycle), 1.13 (s, 9H),
1.10–1.39 (m, 2Hcycle), 1.32 (t, J=7.3 Hz, 6H), 1.83 (br
s, OH), 4.18 (dq, J=6.3H, J=6.3H, 4H, 2CH2-O); 13C
NMR (CDCl3, 50.3 MHz) l (ppm):, 13.7 (C3), 16.3
(CH3), 16.4 (CH3), 29.6 (3CH3 tBu), 30.4 (C(CH3)3),
1
2
4.2. General procedure B
32.2 (C2), 53.05 (d, JPC=222.4 Hz, C1), 62.3 (d, JPC=
2
5.0 Hz, CH2-O), 62.4 (d, JPC=5.0 Hz, CH2-O); 31P
NMR (CDCl3, 101 MHz) l (ppm): 24.46; MS (70 eV),
m/z (%): 250 (M+] (1.2), 193 (42), 181 (89), 138 (100),
125 (58), 111 (65); HRMS m/z: 250.1332 (calcd for
C11H23O4P: 250.1333).
To a solution of cyclopropanone acetal 4 (1 mmol) in
alcohol (2 mL), was added one drop of TMSCl, after
stirring for 5 min, amine (S)-9 (1.50 mmol), AcOH (3
mmol) and MgSO4 (100 mg) were added. The mixture
was stirred and heated at 55°C for 15–18 h before
adding trialkylphosphites (1.5 mmol), then the mixture
was heated at 55°C for 3–6 days. After standard work-
up as in the procedure A, the residue was purified by
FC on silica gel.
4.3. Procedure C
As for procedure B, but DMSO solvent was used
instead of alcohol. After heating at 55°C for 3–6 days,
the mixture was concentrated under vacuum, concen-
trated ammonia (2 mL) was added, then the mixture
was extracted with EtOAc (2×50 mL). The organic
layer was washed with water (2×4 mL) and concen-
trated, to give after FC the aminophosphonates.
4.2.1. Diethyl (1S*,2R*,1%S)-2-tert-butyl-1-(1%-phenyl-
ethylamino)-cyclopropane-phosphonates:
(1S,2R,1%S)-
6A.f and (1R,2S,1%S)-6C.f. Following procedure B: reac-
tion of acetal 4f (3 mmol), TMSCl (cat.), EtOH (6 mL),
amine (S)-9 (510 mL, 4.5 mmol), AcOH (6 mmol),
MgSO4 (300 mg), then P(OEt)3 (780 mL, 1.5 mmol), for
48 h at 55°C gave, after standard work-up 2.62 g of a
(50:50) diastereomeric mixture of the crude trans phos-
phonates. Purification by FC furnished 444 mg (42%)
of a non separable mixture of trans diastereomers
(1S,2R,1%S)-6A.f and (1R,2S,1%S)-6C.f.
4.3.1. Diisopropyl (1S*,2S*,1%S)-2-methyl-1-(1%-phenyl-
ethylamino)-cyclopropane-phosphonates:
(1S,2S,1%S)-
12A.b and (1R,2R,1%S)-12C.b. Following procedure C:
reaction of acetal 4b (3 mmol), DMSO (6 mL), TMSCl
(cat.), i-PrOH (600 mL), amine (S)-9 (545 mg, 4.5
mmol), AcOH (510 mL, 4.5 mmol), MgSO4 (300 mg),
then P(O-iPr)3 (1.11 mL, 4.5 mmol), for 48 h at 55°C
gave, after standard work-up 1.82 g of a (50:50)
diastereomeric mixture of the crude trans phospho-
nates. Purification by FC furnished 405 mg (60%) of a
non separable mixture of trans diastereomers
(1S,2S,1%S)-12A.b and (1R,2R,1%S)-12C.b.
4.2.1.1. Data for (1S,2R,1%S)-6A.f and (1R,2S,1%S)-
6C.f major trans isomer. RT=28.10 min (a) and 30.25
min (b) [CPSIL-5CB, 150–175°C, 1 bar)]; 1H NMR
(CDCl3, 250 MHz) l (ppm): 0.30 (ddd, J=5.4 Hz,
J=8.3 Hz, J=8.3 Hz, 1Hcycle), 0.68 (ddd, J=5.9 Hz,
J=10.3 Hz, J=15.4 Hz, 1Hcycle), 0.95 (s, 9H, 3CH3),
1.05 (s, 9H, 3CH3), 1.21–1.42 (m, 18H, 4CH3 and
2CH3-C1%), 0.86–1.43 (m, 4Hcycle), 3.97–4.21 (m, 8H,
4CH2-O), 4.29 (dq, J=2.9 Hz, J=6.4 Hz, H-C1%), 4.40
4.3.1.1. Data for (1S,2S,1%S)-12A.b and (1R,2R,1%S)-
12C.b major trans isomer. Rf=0.30 (EtOAc/CH2Cl2
15:85); RT=33.62 min (a) and 34.82 min (b) [CPSIL-

2274
N. Tesson et al. / Tetrahedron: Asymmetry 13 (2002) 2267–2276
5CB, 120°C, 1 bar)]; IR (neat): 3468 (NH), 1244 (PꢀO),
each)]. The mixture was stirred at 0°C for 3–5 h. Then
water (40 mL) was added, the resulting mixture was
extracted with CH2Cl2 (80 mL). The organic layer was
washed with a 10% solution of NaHCO3 (70 mL), dried
(MgSO4) then concentrated. The residue was purified
by FC on silica gel to give the desired formylated
aminophosphonates.
1
1107 (P-O); H NMR (CDCl3, 250 MHz) l (ppm): 0.03
(ddd, J=4.9 Hz, J=6.4 Hz, J=7.8 Hz, 1Hcycle), 0.61
(ddd, J=4.4 Hz, J=5.4 Hz, J=6.8 Hz, 1Hcycle), 0.80
(ddd, J=5.4 Hz, J=9.0 Hz, J=14.6 Hz, 1Hcycle), 1.20–
1.36 (m, 33H, 8CH3, 2CH3-C1% and 3H cycle), 4.31 (dq,
J=2.4 Hz, J=7.3 Hz, H-C1%), 4.39 (dq, J=2.9 Hz,
J=6.0 Hz, H-C1%), 4.52–4.78 (m, 4H, 4CH-O), 7.05–
7.43 (m, 10H); 13C NMR (CDCl3, 50.3 MHz) l (ppm):
11.9 (2C4), 16.2 (C3) 17.1 (d, J=3.7 Hz, C2), 17.7 (d,
J=5.5 Hz, C2), 19.9 (C3), 23.2 (CH3-C1%), 24.1 (4 CH3),
4.4.1. Diethyl 1-[formyl-(1%-phenylethylamino)-2-methyl-
cyclopropane-phosphonates:
(1R,2R,1%S)-14C
and
(1S,2S,1%S)-14A. Following procedure D: reaction of 200
mg (0.64 mmol) of a non separable mixture of major
trans (1R,2R,1%S)-6C.b and (1S,2S,1%S)-6A.b Ac2O
(1.58 mL, 16.6 mmol) and 0.630 mL of HCOOH, for
3 h at 0°C gave, after work-up, 377 mg of residue.
Purification by FC (three times) (eluent, MeOH/Et2O:
3/97 to 10/90) furnished 72 mg (33%) of (1R,2R,1%S)-
14C as oil, 65 mg (30%) of (1S,2S,1%S)-14A as oil and
55 mg (27%) as a mixture.
1
25.4 (CH3-C1%), 35.4 (d, JPC=200.5 Hz, C1), 36.7 (d,
1JPC=201.5 Hz, C1), 55.9 (C1%), 56.0 (C1%), 69.6–70.2 (m,
4C, CH-O), [12 arom.C: 126.4 (2C), 126.6 (2C), 126.9
(2C), 127.9 (2C), 128.1 (2C), 147.3, 147.6]; 31P NMR
(CDCl3, 101 MHz) l (ppm): 31.44 and 31.17; MS (70
eV) m/z (%): 339 [M+] (0.3), 174 (29), 173 (74), 150 (27),
144 (30), 105 (100); HRMS m/z: (a) 339.1959, (b):
339.1967 (calcd for C18H30NO3P: 339.1963).
4.4.1.1. Data for (1R,2R,1%S)-14C. rotamers (a/b: 85/
4.3.2. Dibenzyl (1S*,2S*,1%S)-2-methyl-1-(1%-phenylethyl-
1
15): [h]D=+104.7 (c 1, CHCl3); H NMR (CDCl3, 250
amino)-cyclopropane-phosphonates:
(1S,2S,1%S)-13A.b
MHz) l: 0.41 (ddd, J=7.3 Hz, J=7.3 Hz, J=7.4 Hz,
1Hcycle b), 0.62 (ddd, J=7.3 Hz, J=7.3 Hz, J=7.4 Hz,
1Hcycle a), 0.85–1.01 (m, 1Hcycle b), 0.93 (d, J=5.9 Hz
CH3-C2 a), 0.97 (d, J=5.9 Hz, CH3-C2 b), 1.11–1.25
(m, 1Hcycle a), 1.27 (t, J=6.8 Hz, 3H b), 1.29 (t, J=6.8
Hz, 3H b), 1.31 (t, J=6.8 Hz, 3H a), 1.35 (t, J=6.8 Hz,
3H a), 1.58–1.72 (m, 1Hcycle a/b), 1.72 (d, J=7.3 Hz,
CH3-C1% b), 1.87 (d, J=7.3 Hz, CH3-C1% a), 4.00–4.25
(m, 4H a and 4H b), 4.42 (q, J=7.3 Hz, H–C1% a), 4.66
(q, J=7.3 Hz, H–C1% b), 7.08–7.42 (m, 5H a and 5H b),
8.15 (s, CHO a), 8.58 (s, CHO b); 13C NMR (CDCl3,
63 MHz) l: 13.2 (C4 a), 13.5 (C4 b), 15.2 (C3 b), 15.9
and (1R,2R,1%S)-13C.b. Following procedure C: reaction
of acetal 4b (1 mmol), DMSO (2 mL), TMSCl (cat.),
n-butanol (210 mL), amine (S)-9 (180 mg, 1.5 mmol),
AcOH (170 mL, 4.5 mmol), MgSO4 (100 mg), then
P(OBn)3 (528 mg, 1.5 mmol), for 5.8 days at 55°C gave,
after standard work-up 771 mg of
a
(50:50)
diastereomeric mixture of the crude trans phospho-
nates. Purification by FC furnished 180 mg (45%) of a
non separable mixture of trans diastereomers
(1S,2S,1%S)-13A.b and (1R,2R,1%S)-13C.b with 40 mg
(10%) of a non identified compound.
2
(C3 a), 16.5–23.6 (m, 2C a/b), 20.4 (d, JPC=2.9 Hz, C2
4.3.2.1. Data for (1S,2S,1%S)-13A.b and (1R,2R,1%S)-
13C.b major trans isomer. Rf=0.32 (Et2O/pentane
60:40); RT=49.63 min (a) and 52.59 min (b) [CPSIL
5CB, 200–240°C, 1.3 bar)]; 1H NMR (CDCl3, 250
MHz) l (ppm): 0.11 (m, with J=7.8 Hz, 1Hcycle), 0.68
(ddd, J=4.4 Hz, J=5.9 Hz, J=7.3 Hz, 1Hcycle), 0.92
(ddd, J=4.9 Hz, J=8.8 Hz, J=14.2 Hz, 1Hcycle), 1.02
(d, J=5.9 Hz, 3H, CH3), 1.22 (d, J=6.4 Hz, 3H, CH3),
2
a), 20.9 (CH3-C1% a), 21.4 (d, JPC=2.9 Hz, C2 b), 24.6
1
(CH3-C1% b), 39.2 (d, JPC=212.1 Hz, C1 b), 40.8 (d,
2
1JPC=217.8 Hz, C1 a), 61.1 (C1% b), 61.8 (d, JPC=7.1
2
Hz, O-CH2 b), 62.6 (d, JPC=5.7 Hz, 2C a), 62.8 (d,
2JPC=7.1 Hz, O-CH2 b), 63.3 (C1% a), [6 arom. C: 125.8
(a), 127.1 (2C a/b), 127.5 (b), 128.4 (2C a), 128.8 (2C b),
142.9 (b), 143.1 (a)], 163.2 (CHO b), 166.5 (CHO a);
31P NMR (CDCl3, 101 MHz) l: a/b: 24.78/25.76 ppm.
1.28 (d, J=6.4 Hz, 3H, CH3), 1.16–1.51 (m, 3Hcycle
)
1.80 (br s, 2NH), 4.29 (dq, J=2.9 Hz, J=6.4 Hz,
H-C1%), 4.37 (dq, J=3.4 Hz, J=6.4 Hz, H-C1%), 4.97–
5.13 (m, 8H, 4CH2-O), 7.02–7.47 (m, 30H); 13C NMR
(CDCl3, 50.3 MHz) l (ppm) a/b: 11.8 (2C4), 16.8 (C3)
17.4 (d, J=3.8 Hz, C2), 17.9 (d, J=4.8 Hz, C2), 20.0 (d,
J=2.9 Hz, C3), 23.3 (CH3-C1%), 25.1 (CH3-C1%), 35.0 (d,
J=198.8 Hz, C1), 36.0 (d, J=200.0 Hz, C1), 55.9 (C1%),
56.1 (C1%), 66.9–67.1 (m, 4C, CH-O), [36 arom.C: 126.1–
136.9 (34C), 146.8, 147.1]; 31P NMR (CDCl3, 101 MHz)
l (ppm): 31.44 and 31.17; MS (70 eV) m/z (%): 435
[M+] (0.1), 210 (8), 105 (26), 103 (11), 91 (100); HRMS
m/z: 435.1966 (calcd for C26H30NO3P: 435.1963).
4.4.1.2. Data for (1S,2S,1%S)-14A: rotamers (a/b: 85/
1
15). [h]D=−14.3 (c 0.8, CHCl3); H NMR (CDCl3, 250
MHz) l: 0.62 (m, 1Hcycle a), 0.75 (m, 1Hcycle b), 0.88 (d,
J=5.9 Hz, CH3-C2 a), 0.85–1.05 (m, 1Hcycle b), 0.99 (t,
J=7.3 Hz, 3H b), 1.08 (d, J=6.4 Hz, CH3-C2 b), 1.16
(t, J=7.3, Hz, 3H a), 1.26 (t, J=7.3 Hz, 3H a), 1.42 (t,
J=7.3 Hz, 3H b), 1.21–1.44 (m, 1Hcycle a), 1.69 (d,
J=7.3 Hz, CH3-C1% b), 1.72 (d, J=7.3 Hz, CH3-C1% a),
1.60–2.10 (m, 1Hcycle a/b), 3.90–4.25 (m, 4H a and 4H
b), 4.68 (q, J=6.8 Hz, H–C1% b), 5.27 (q, J=7.3 Hz,
H–C1% a), 7.09–7.47 (m, 5H a and 5H b), 8.18 (s, CHO
a), 8.29 (s, CHO b); 13C NMR (CDCl3, 63 MHz) l:
13.0 (C4 a), 13.8 (C4 b), 15.2 (C3 b), 16.0 (C3 a),
15.8–16.2 (m, 2C b), 16.2 (d, 3JPC=8.1 Hz, CH3 a), 16.3
(d, 3JPC=6.2 Hz, CH3 a) 17.5 (CH3-C1% a), 20.2 (d,
4.4. Procedure D: Formylation of aminophosphonates
completed according to Ref. 16
2
2JPC=3.3 Hz, C2 a), 21.7 (d, JPC=3.8 Hz, C2 b), 37.9
To
a mixture of the major trans aminocyclo-
1
1
propanephosphonates 6A/6C, cooled at 0°C, was added
a solution of acetic formic anhydride (26 mmol, 26
equiv.), [generated in situ by heating an equimolar
amount of acetic anhydride and formic acid (26 mmol,
(d, JPC=219.2 Hz, C1 a), 38.4 (d, JPC=214.0 Hz, C1
b), 54.2 (C1% a), 58.8 (C1% b), 61.4 (d, 2JPC=7.0 Hz,
2
O-CH2 b), 62.5 (d, JPC=3.0 Hz, O-CH2 a), 62.6 (d,
2JPC=3.0 Hz, O-CH2 a), 62.9 (d, JPC=5.2 Hz, O-CH2
2

N. Tesson et al. / Tetrahedron: Asymmetry 13 (2002) 2267–2276
2275
b), [6 arom. C: 126.7 (2C b), 127.1 (a), 127.2 (b), 127.6
(2C a), 127.9 (a), 128.3 (2C b), 141.3 (a), 141.8 (b),],
164.1 (CHO b), 166.8 (CHO a); 31P NMR (CDCl3, 101
MHz) l: a/b: 24.30/25.33 ppm.
NMR (CDCl3, 250 MHz) l (ppm) a/b rotamers: 0.40
(m, with J=7.8 Hz, 1Hcycle b), 0.63 (m, with J=5.4 Hz,
J=7.3 Hz, 1Hcycle a), 0.91 (d, J=5.6 Hz, 3H, CH3-C-C2
a), 0.70–0.96 (m, CH2-C2 a), 1.33 (t, J=7.3 Hz, 3H,
O-C-CH3 a), 1.38 (t, J=7.3 Hz, 3H, O-C-CH3 a),
1.48–1.71 (m, 2Hcycle a), 1.74 (d, J=7.3 Hz, CH3-C1% b),
1.87 (d, J=7.3 Hz, CH3-C1% a), 3.98–4.26 (m, 4Ha+
4Hb, 2CH2-O), 4.43 (q, J=7.3 Hz, H-C1% a), 5.67 (q,
J=7.3 Hz, H-C1% b), 7.07–7.43 (m, 5Ha+5Hb), 8.18 (s,
N-CHO a), 8.56 (s, N-CHO b); 31P NMR (CDCl3, 101
MHz) l (ppm): 24.68 (a) and 25.50 (b).
4.4.2. Diisopropyl 1-[formyl-(1%-phenylethylamino)-2-
methyl-cyclopropane-phosphonates: (1R,2R,1%S)-15C and
(1S,2S,1%S)-15A. Following procedure D: reaction of a
non separable mixture of major trans (1R,2R,1%S)-
12C.b and (1S,2S,1%S)-12A.b (283 mg, 0.83 mmol) with
Ac2O (2.5 mL) and HCOOH (1 mL), for 10 h at 0°C
gave, after work-up, 394 mg of residue. Purification by
FC (two times) (eluent, MeOH/Et2O: 15/85 to 50/50)
furnished 116 mg (38%) of pure (1R,2R,1%S)-15C as oil,
115 mg (38%) of pure (1S,2S,1%S)-15A as oil.
4.5. Procedure E: Hydrogenolysis of formylated
aminophosphonates
To a solution of formylated aminophosphonates (0.25
mmol) in EtOH (2 mL), was added 2N HCl (2 mL) and
20% Pd(OH)2/C (Pearlman’s catalyst, 80% w/w). The
flask was connected to a hydrogenation apparatus
equipped with a graduated burette containing water
that allowed the uptake of hydrogen to be monitored.
TLC control showed that under 1 atm. H2 at 50°C for
40–72 h, the reaction was then degassed under a stream
of argon, filtered through paper, and the collected solid
was washed with EtOH (3×10 mL). The combined
filtrate and washings were concentrated and the result-
ing residue was neutralised with concentrated ammonia
(0.2 mL). Purification by FC on silica gel gave the
desired aminophosphonate.
4.4.2.1. Data for (1R,2R,1%S)-15C. [h]D=+118.7 (c 1,
CHCl3); 1H NMR (CDCl3, 250 MHz) l: 0.61 (ddd,
J=5.9 Hz, J=7.7 Hz, J=7.9 Hz, 1Hcycle), 0.95 (d,
J=6.3 Hz CH3), 1.15–1.29 (m, 1Hcycle), 1.34 (d, J=6.3
Hz, 6H), 1.40 (dd, J=6.3 Hz, J=6.3 Hz, 6H), 1.62–
1.80 (m, 1Hcycle), 1.80 (d, J=7.3 Hz CH3), 4.47 (d,
J=7.3 Hz, 1H), 4.69 (sept, J=6.3 Hz, CHiPr), 4.75
(sept, J=6.3 Hz, CHiPr), 7.12–7.48 (m, 5H), 8.20 (s,
CHO); 13C NMR (CDCl3, 63 MHz) l: 13.4 (CH3-C2),
15.9 (C3), 20.6 (d, J=3.3 Hz, C2), 21.0 (CH3-C1%), 24.0
1
(2C), 24.1 (2C), 41.7 (d, JPC=219.4 Hz, C1), 63.4 (C1%),
71.4 (O-CH-), 71.5 (O-CH-), [6 arom. C: 127.0, 127.2
(2C), 128.5 (2C), 143.4], 166.9 (CHO); 31P NMR
(CDCl3, 101 MHz) l: 22.50 ppm.
4.5.1. Diethyl (1S,2S)-1-amino-2-methyl-cyclopropane-
phosphonate, 17A. Following procedure E: reaction of
formylated aminophosphonate (1S,2S,1%S)-14A (70 mg
0.21 mmol), EtOH (2 mL), 2N HCl (2 mL), Pd(OH)2/C
(60 mg), for 50 h at 50°C under H2 (1 atm) gave, after
work-up, and FC (eluent, MeOH/CH2Cl2: 4/96) 30 mg
(80%) of (1S,2S)-17A as a yellow oil.
4.4.2.2. Data for (1S,2S,1%S)-15A. [h]D=−14.5 (c 1,
CHCl3); 1H NMR (CDCl3, 250 MHz) l: 0.65 (ddd,
J=6.9 Hz, J=7.0 Hz, J=7.2 Hz, 1Hcycle), 0.92 (d,
J=6.4 Hz CH3), 1.18 (d, J=6.3 Hz, CH3), 1.19 (d,
J=6.3 Hz, CH3), 1.29 (d, J=6.3 Hz, CH3), 1.30 (d,
J=6.3 Hz, CH3), 1.23–1.43 (m, 1Hcycle), 1.74 (d, J=7.3
Hz, CH3), 1.67–1.92 (m, 1Hcycle), 4.61 (sept, J=6.3 Hz,
CHiPr), 4.67 (sept, J=6.3 Hz, CHiPr), 5.24 (q, J=7.3
Hz, 1H), 7.12–7.34 (m, 3H), 7.34–7.52 (m, 2H), 8.20 (s,
CHO); 13C NMR (CDCl3, 63 MHz) l: 13.2 (CH3-C2),
4.5.1.1. Data for (1S,2S)-17A. [h]D=+24.0 (c 1,
CHCl3); 1H NMR (CDCl3, 250 MHz) l: 0.41 (ddd,
J=6.4 Hz, J=4.4 Hz, J=7.3 Hz, 1Hcycle), 1.17 (t,
J=6.4 Hz, 3H), 1.30 (t, J=6.9 Hz, 3H), 1.31 (t, J=6.9
Hz, 3H), 1.14–1.42 (m, 2Hcycle), 1.52 (br s, NH2), 4.07
(dq,, 2JPH=3.4 Hz, J=6.9 Hz, 2H), 4.10 (dq,, 2JPH=3.4
Hz, J=6.9 Hz, 2H); 13C NMR (CDCl3, 63 MHz) l:
2
16.1 (C3), 17.7 (CH3-C1%), 20.5 (C2), 23.8 (d, JP1C=4.0
2
Hz, 2C), 23.9 (d, JPC=4.0 Hz, 2C), 38.9 (d, JPC
=
221.1 Hz, C1), 54.6 (C1%), 71.3 (d, 2JPC=6.3 Hz, O-CH-),
2
71.4 (d, JPC=6.3 Hz, O-CH-), [6 arom. C: 127.0, 127.7
2
(2C), 127.9 (2C), 141.3], 167.0 (CHO); 31P NMR
(CDCl3, 101 MHz) l: 21.98 ppm.
11.1 (CH3-C2), 16.41 (d, JPC=5.0 Hz, 1C), 16.42 (d,
3JPC=5.0 Hz, 1C), 16.7 (d, 2JPC=3.3 Hz, C2), 19.0 (C3),
30.9 (d, 1JPC=205.9 Hz, C1), 61.8 (d, 2JPC=6.2 Hz,
2
4.4.3. Diethyl 1-[formyl-(1%-phenylethylamino)-2-ethyl-
1C), 61.9 (d, JPC=6.2 Hz, 1C); 31P NMR (CDCl3, 101
cyclopropane-phosphonates:
(1R,2R,1%S)-16C
and
MHz) l: 29.28 ppm; in agreement with those of the
(1S,2S,1%S)-16A. Following procedure D: reaction of 130
mg (0.4 mmol) of a non separable mixture of major
trans (1R,2R,1%S)-6C.c and (1S,2S,1%S)-6A.c, Ac2O (980
mL, 10.4 mmol) and HCOOH (390 mL), for 19 h at 0°C
gave, after work-up, 187 mg of residue. Purification by
FC (three times) (eluent, EtOAc/CH2Cl2: 20/80–70/30)
afforded only 11 mg (8%) of one diastereomer
(1R,2R,1%S)-16C (or (1S,2S,1%S)-16A), 102 mg (72%) as
a mixture of (1R,2R,1%S)-16C and (1S,2S,1%S)-16A.
enantiopure (1S,2S) isomer.13,14
4.5.2.
Diisopropyl
(1S,2S)-1-amino-2-methyl-cyclo-
propane-phosphonate 18A. Following procedure E: reac-
tion of formylated aminophosphonate (1S,2S,1%S)-15A
(80 mg 0.22 mmol), EtOH (2 mL), 2N HCl (2 mL),
Pd(OH)2/C (64 mg), for 72 h at 50°C under H2 (1 atm)
gave, after work-up, and FC (eluent, MeOH/CH2Cl2:
4/96) 40 mg (79%) of (1S,2S)-18A as a yellow oil.
4.4.3.1. Data for (1R,2R,1%S)-16C or (1S,2S,1%S)-16A.
(a/b rotamers: 85/15): Rf=0.38 (EtOAc/CH2Cl2 30:70);
RT=40.50 min [CPSIL-5CB, 180–200°C, 1 bar)]; 1H
4.5.2.1. Data for (1S,2S)-18A. [h]D=+19.5 (c 1.1,
CHCl3); 1H NMR (CDCl3, 250 MHz) l: 0.37 (ddd,
J=4.4 Hz, J=6.4 Hz, J=6.4 Hz, 1Hcycle), 1.15 (t,

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N. Tesson et al. / Tetrahedron: Asymmetry 13 (2002) 2267–2276
J=5.9 Hz, CH3-C2, 3H), 1.27 (t, J=6.4 Hz, 12H),
1.10–1.45 (m, 2Hcycle), 1.59 (br s, NH2), 4.61 (sept,
J=6.4 Hz, CHiPro), 4.64 (sept, J=6.4 Hz, CHiPro); 13C
NMR (CDCl3, 63 MHz) l: 11.3 (CH3-C2), 16.7 (C2),
EtOH (2 mL) and propylene oxide (0.6 mL), for 10 h at
20°C gave, after usual work-up, 14 mg (91%) of
(1R,2R)-(−)-3b as an amorphous white solid.
1
19.0 (C3), 24.0 (4C), 31.7 (d, JPC=206.1 Hz, C1), 70.1
4.6.3.1. Data for (−)-(1R,2R)-3b. [h]D=−43.5 (c 0.2,
H2O), [lit.10b [h]D=−45.6 (c 0.2, H2O)], the spectral
data are in agreement with those of the antipode
(1S,2S)-(+)-3a and with the literature.10b
(O-CH-), 70.2 (O-CH-); 31P NMR (CDCl3, 101 MHz)
l: 27.72 ppm;
4.5.3. Diethyl (1R,2R)-1-amino-2-methyl-cyclopropane-
phosphonate, 17C. Following procedure E: reaction of
formylated aminophosphonate (1R,2R,1%S)-14C (60 mg
0.18 mmol), EtOH (2 mL), 2N HCl (2 mL), Pd(OH)2/C
(48 mg), for 39 h at 50°C under H2 (1 atm) gave, after
work-up, and FC (eluent, MeOH/CH2Cl2: 4/96 to 6/94)
32 mg (86%) of (1R,2R)-17C as a yellow oil.
References
1. For some recent reviews, see: (a) Stammer, C. Tetra-
hedron 1990, 46, 2231–2254; (b) Alami, A.; Calmes, M.;
Jacquier, R. Bull. Soc. Chim. Fr. 1993, 130, 5–24.
2. (a) Burgess, K.; Kwok-Kan, H.; Destradi, M. S. Synlett
1994, 575–583; (b) Jimenez, J. M.; Rife, J.; Ortun˜o, R. M.
Tetrahedron: Asymmetry 1996, 7, 537–558.
4.5.3.1. Data for (1R,2R)-17C. [h]D=−23.5 (c 1.2,
CHCl3), all spectral data are identical with those of
antipode (+)-17A.
3. For a comprehensive review, see: Dhawan, B.; Redmore,
D. Phosphorus Sulfur Relat. Elem. 1987, 32, 119–144.
4. Kafarski, B.; Lejczak, B. Phosphorus Sulfur Silicon 1991,
63, 193–215.
4.6. Procedure F: Hydrolysis of aminophosphonates
according to our reported method13
5. De Lombaert, S.; Blanchard, L.; Tan, J.; Sakane, Y.;
Berry, C.; Ghai, R. D. Bioorg. Med. Chem. Lett. 1995, 5,
145–150.
6. Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med.
Chem. 1986, 29, 29–40 and references cited therein.
7. Wolfenden, R. Annu. Rev. Biophys. Bioeng. 1976, 5,
271–306; Chem. Abstr. 1976, 85, 73952b.
8. Jacobsen, N. E.; Bartlett, P. A. J. Am. Chem. Soc. 1981,
103, 654–657.
9. For a synthesis of racemic substituted a-aminocyclo-
propanephosphonic acid, see: Groth, U.; Lehmann, L.;
Richter, L.; Scho¨llkopf, U. Liebigs Ann. Chem. 1993,
427–431.
10. For an optically active synthesis, see: (a) Yamazaki, S.;
Takoda, T.; Moriguchi, Y.; Yamabe, S. J. Org. Chem.
1998, 63, 5919–5928; (b) Hercouet, A.; Le Corre, M.;
Carboni, B. Tetrahedron Lett. 2000, 41, 197–199.
11. Fadel, A. J. Org. Chem. 1999, 64, 4953–4955.
12. (a) Fadel, A. Synlett 1993, 503–505; (b) Fadel, A.; Khes-
rani, A. Tetrahedron: Asymmetry 1998, 9, 305–320 and
references cited therein.
13. Fadel, A.; Tesson, N. Eur. J. Org. Chem. 2000, 2153–
2159.
14. Fadel, A.; Tesson, N. Tetrahedron: Asymmetry 2000, 11,
2023–2031.
4.6.1. (1S,2S)-1-Amino-2-methyl-cyclopropane-phospho-
nic acid, (+)-3b. Following procedure F: reaction of
diethyl aminophosphonate (1S,2S)-17A (103 mg, 0.5
mmol), CH2Cl2 (5 mL), TMSI (300 mg, 1.5 mmol),
then EtOH (2.5 mL) and propylene oxide (1 mL), for
10 h at rt gave, after usual work-up and crystallisation
130 mg (86%) of (1S,2S)-(+)-3b as a white solid.
4.6.1.1. Data for (+)-(1S,2S)-3b. [h]D=+33.6 (c 1,
H2O), [h]D=+45.0 (c 0.2, H2O); 1H NMR (D2O,
lHOD=4.60 ppm, 250 MHz) l: 0.58 (ddd, Jtrans=6.8
Hz, J=6.4 Hz, JPH trans=6.9 Hz, 1Hcycle), 1.00 (d,
J=6.4 Hz, 3H, CH3-C2), 1.06 (ddd, Jcis=9.4 Hz, Jgem
=
3
6.4 Hz, JPH cis=12.7 Hz, 1H), 1.28 (dddd, Jcis=9.4 Hz,
J
trans=6.8 Hz, J=6.4 Hz, 3JPH cis=12.7 Hz, 1H-C2); 13
C
NMR (D2O, 63 MHz) l: 10.9 (C4), 14.8 (C2), 16.0 (C3),
1
33.6 (d, JPC=192.5 Hz, C1); 31P NMR (CDCl3, 101
MHz) l: 13.36.
4.6.2. (1S,2S)-1-Amino-2-methyl-cyclopropane-phospho-
nic acid, (+)-3b. Following procedure F: reaction of
diisopropyl amino-phosphonate (1S,2S)-18A (35 mg,
0.15 mmol), CH2Cl2 (1.5 mL), TMSI (90 mg, 0.45
mmol), then EtOH (1 mL) and propylene oxide (0.5
mL), for 10 h at rt gave, after usual work-up and
crystallisation 22 mg (98%) of (1S,2S)-(+)-3b as an
amorphous solid. [h]D=+33.3 (c 1, H2O), all spectral
data are identical to those noted above.
15. Volk, F.-J.; Frahm, A. W. Liebigs Ann. 1996, 1893.
16. (a) Edwards, R. J. Am. Chem. Soc. 1942, 64, 1583; (b)
Vachal, P.; Jacobsen, E. N. Org Lett. 2000, 2, 867.
17. Losse, D.; Nadolski, D. J. Prakt. Chem. 1964, 24, 118.
18. Mosher, H. S.; Dale, J. A.; Dull, D. L. J. Org. Chem.
1969, 34, 2543–2549.
4.6.3. (1R,2R)-1-Amino-2-methyl-cyclopropane-phospho-
nic acid, (−)-3b. Following procedure F: reaction of
diethyl amino-phosphonate (1R,2R)-17C (20 mg, 0.116
mmol), CH2Cl2 (2 mL), TMSI (60 mL, 0.30 mmol), then
19. Part of Tesson, N., Ph.D. Thesis, Universite´ Paris-Sud,
Orsay, France, 16 November 2001.