Asymmetric synthesis of (R)-[2,2-2H2]-1- aminocyclopropane-1-phosphonic acid (ACPP derivative) conformationally constrained ACC analogue using a chiral sulfinyl auxiliary

Article abstract of DOI:10.1016/j.tetasy.2013.05.024

The asymmetric cyclopropanation of vinylphosphonate using (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide was applied to obtain a dideuterated cyclopropyl sulfoxide. A three-step synthesis of enantiopure (+)-(1R)-1-amino-2,2-dideuteriocyclopropanephosphonic acid (+)-17-d₂ was developed.

Full text of DOI:10.1016/j.tetasy.2013.05.024

Tetrahedron: Asymmetry xxx (2013) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of (R)-[2,2-2H2]-1-aminocyclopropane-1-
phosphonic acid (ACPP derivative) conformationally constrained ACC
analogue using a chiral sulfinyl auxiliary
⇑
Wanda H. Midura , Aneta Rzewnicka
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry, 90-363 Lodz, Sienkiewicza 112, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric cyclopropanation of vinylphosphonate using (S)-dimethylsulfonium-(p-tolylsulfi-
nyl)methylide was applied to obtain a dideuterated cyclopropyl sulfoxide. A three-step synthesis of enan-
tiopure (+)-(1R)-1-amino-2,2-dideuteriocyclopropanephosphonic acid (+)-17-d2 was developed.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 22 May 2013
Accepted 29 May 2013
Available online xxxx
1. Introduction
acids, differentiation of the enantiotopic methylene groups was at-
tained by the presence of two deuterium atoms on one of them
1-Aminophosphonic acids, defined as analogues of amino acids
in which the carboxylic group is replaced by a phosphonic acid
moiety, are the subject of increasing interest1 due to the tetrahe-
dral structure of the phosphonic acid moiety since they act as ‘tran-
sition-state analogues’ in enzymatic hydrolysis.2 Conformationally
constrained amino acids have been the focus of both synthetic and
medicinal chemistry; in particular the cyclopropane ring has
served as a useful segment in peptidomimetic design.3 This system
affects the chemical and biological properties in peptides through
significant conformational restrictions in the amino acid residues.4
It has also been found that constrained amino acids can be highly
potent and specific agonists since they closely mimic the bioactive
conformation of natural neurotransmitters.5 Aminocyclopropane-
phosphonic acids combining both unique properties (conforma-
tional restriction and isosterism) have thus motivated several
research groups to study cyclopropanephosphonates as active ana-
logues, affording improved pharmaceutical properties in certain
cases.6 Since they have not received the same attention7,8 com-
pared to acyclic aminophosphonic acids 1 and aminocyclopropan-
ecarboxylic acids 2 (Fig. 1), a new approach to this type of
compounds requires further investigation.
(dideuterated ACPP). Although different syntheses of deuterium la-
beled 1-aminocyclopropane-1-carboxylic acid have been
reported,11 the phosphonic analogue in the deuterated version
has not been described.
2. Results and discussion
Cyclopropanation of phosphoryl acrylates 7-d2 and 8-d2 using
(S)-dimethylsulfonium-(p-tolylsulfinyl)methylide 6 afforded a sep-
arable mixture of three diastereomers 9-d2 (A–C) and 10-d2 (A–C)
in a ratio dependent on the conditions used for ylide generation
(Scheme 1). Comparison of the spectroscopic data of the resulting
diastereomers with those of the non-deuterated analogues de-
scribed earlier12 allowed us to determine their configuration.
In order to remove the chiral auxiliary, cyclopropane 10A-d2
was subjected to sulfoxide/metal exchange, a reaction that has
been widely applied for the synthesis of enantiomerically pure
sulfoxides, and also as a method to generate the corresponding car-
banions. Due to the presence of other reactive centers in cyclopro-
pyl sulfoxide 10, isopropylmagnesium chloride was used as the
reagent of choice. When the reaction was performed at ꢀ10 °C in
diethyl ether for 20 min, it gave confusing results: the formation
of two major products with the same molecular weight. Since
the desired product contains only one stereogenic center, the sec-
ond product must be its regioisomer. Initially, we assumed that
after the attack of the Grignard reagent on the sulfinyl group, the
carbanionic species formation involved a shift of one of the deute-
rium atoms to the neighboring carbon atom, resulting in the for-
mation of structure 11.12 This hypothesis was later discarded and
the correct explanation of this phenomenon was established on
the basis of our previous investigations concerning sulfinyl group
removal from mono-methylated sulfinylcyclopropanes.13 In that
We have already reported on the synthesis of conformationally
constrained analogues of bioactive amino acids based on asymmet-
ric cyclopropanation utilizing optically active sulfinyl compounds.9
Herein we turned our attention to 1-aminocyclopropanephos-
phonic acids, applying (S)-dimethylsulfonium-(p-tolylsulfi-
nyl)methylide 6, designed and described by us earlier,10 as a
chiral sulfur reagent in the cyclopropanation step. In order to intro-
duce chirality to the structure of 1-aminocyclopropanephosphonic
⇑
Corresponding author. Tel./fax: +48 42680 3216.
E-mail address: whmidura@cbmm.lodz.pl (W.H. Midura).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.024
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j.tetasy.2013.05.024

2
W. H. Midura, A. Rzewnicka / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
O
O
O
NH2
HO2C
NH2
NH2
HO2C
R
NH2
(HO)2P
(HO)2P
(HO)2P
NH2
*
*
*
*
*
D
D
D
D
R
1
R
2
4
5
3
Figure 1.
O
O
O
O
S
O
Me
Me
(R1O)2P
CO2R2
(R1O)2P
CO2R2
(R1O)2P
CO2R2
CO2R2
D
(R1O)2P
S
p-Tol
.
.
D
D
D
6
STol-p
STol-p
D
STol-p
D
D
D
O
O
O
7: R1 = Et, R2= Et
9A
9B
9C
10A
: R1 = Me, R2 = But
10B
10C
8
entry Reaction conditions
Product
Ratio of diast.
Facial
selectivity
87 : 13
A
B
C
D
1.
2.
3.
4.
5.
NaH/MeCN 0-20oC
NaH / MeCN 0oC
K2CO3 / CH2Cl2 rt.
NaH / MeCN 0oC
K2CO3 / CH2Cl2 rt.
9-d2
9d2
9-d2
10-d2
10-d2
64 : 23 : 13
68 : 27
-
:
5
-
-
-
-
95 : 5
62 : 26 : 12
62 : 28 : 10
65 : 21 : 14
88 : 12
90 : 10
86 : 14
Scheme 1. Cyclopropanation of vinylphosphonates with (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide.
case, the formation of regioisomers of the desired products was ex-
plained in terms of an unprecedented 1,2-migration of a phos-
phoryl group on the cyclopropane ring. We found that the same
rearrangement took place for cyclopropane 10, but that the reac-
tion course was temperature dependent. At a low temperature
(ꢀ50 °C), the desulfinylated cyclopropane 12 was observed as the
only product, whereas increasing the temperature and extending
the reaction time led to the formation of regioisomer 13
(Scheme 2).
Taking advantage of this observation, our further investigations
were performed at a lower temperature (ꢀ50 °C); due to slightly
better induction during cyclopropanation, (Scheme 1 entry 2) ethyl
ester 9A-d2 was used for the next set of conversions. The desired
desulfinylated product 14-d2 was obtained exclusively in high
yield.
sodium azide, converted into an acyl azide, which is subjected to
Curtius rearrangement. Thus, the hydrolysis of the ester 14-d2 with
lithium hydroxide at room temperature gave acid 15-d2, which
was used for the next step without purification. Since our prelimin-
ary experiment on undeuterated product 15 led to the formation of
some by-products, we used the alternative procedure of the Cur-
tius rearrangement using diphenylphosphoryl azide.15 The reac-
tion was carried out by boiling equimolar amounts of
cyclopropanecarboxylic acid 9A-d2, diphenylphosphoryl azide,
and triethylamine in t-BuOH and afforded the N-Boc-protected
amino ester 16-d2. The latter, upon treating with 6 N hydrochloric
acid and subsequent addition of propylene oxide and ethanol,
afforded the desired aminocyclopropane-1-phosphonic acid 17-
d2 (Scheme 3).
Examination of the 1H NMR spectra of the deuterated com-
pounds obtained for each step of the synthesis, confirmed the sub-
stitution of the methylenic protons by deuterium, since the
resonances corresponding to these protons were absent. Even
The most typical synthetic approach to aminophosphonic acids
utilizes the Curtius rearrangement,14where the carboxyl group can
be converted into the corresponding acid chlorides and then, with
O
(MeO)2P
(D)H
(D)H
CO2But
O
O
CO2But
-50 o
C
(MeO)2P
(MeO)2P
CO2But
12
i-PrMgCl
H
D
D
H
(D)H
(D)H
CO2But
STol-p
0
oC
11
O
10
(D)H
(D)H
12
+
P(OMe)2
13
O
Scheme 2. Sulfinyl exchange.
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W. H. Midura, A. Rzewnicka / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
3
O
O
O
O
NHBoc
(EtO)2P
CO2Et
(EtO)2P
CO2H
(EtO)2P
(EtO)2P
CO2Et
i-PrMgCl
-50 o
C
(PhO)2P(O)N3
Et3N, tBuOH
LiOHaq
D
D
D
D
D
D
D
D
STol-p
O
16-d2
9A-d2
15-d2
14-d2
HCl
O
O
NH2
(HO)2P
D
D
17-d2
Scheme 3.
O
(EtO)2P
CO2Et
D
D
D
D
D
H
C
C
D
H
P
13
Figure 2. C NMR of (ꢀ)-(1R)-ethyl-1-diethylphosphono-2,2-2H2-cyclopropanecarboxylate 14-d2.
more diagnostic was 13C NMR, where both methylene carbons
were different (CH2 vs CD2). However, to make it more visible in
some cases, deuterium decoupling was required (Fig. 2).
Employment of a Curtius procedure resulted in the formation of
enantiopure (+)-(1R)-1-amino-2,2-dideuteriocyclopropanephos-
phonic acid (+)-17-d2, which is the first approach to this deuterium
labeled analogue.
3. Conclusion
4. Experimental
4.1. General
In conclusion, we have reported on the asymmetric synthesis of
cyclopropyl phosphonates using the (S)-dimethylsulfonium-(p-tol-
ylsulfinyl)methylide 6 and reaction sequences that demonstrate
that these products are well-suited to the synthesis of the cyclo-
propyl analogues of aminophosphonic acids. An elaborated proce-
dure of desulfinylation allowed us to avoid 1,2-migration of a
phosphoryl group on a cyclopropane ring and obtain the cyclopro-
pyl phosphonate with the retained structure and configuration.
1H, 13C, and 31P NMR spectra were recorded on a Bruker Avance
III 600, Bruker Avance III 500, and Bruker AC 200 Spectrometer,
using deuterochloroform as solvent. Mass spectra were recorded
on Finnigan MAT95. IR spectra were recorded on Ati Mattson FTIR
Spectrometer. The optical rotations were measured on a Perkin–El-
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j.tetasy.2013.05.024

4
W. H. Midura, A. Rzewnicka / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
mer 241 MC photopolarimeter in acetone solution. The microanal-
yses were performed on Elemental Analyzer EA 1108. TLC was car-
ried out on silica gel plates (Merck F254) and silica gel 60 (70–230
ASTM) was used for chromatography. THF was freshly distilled
over potassium/benzophenone.
d: 1.52 (s, 9H, COC(CH3)3), 2.41 (s, 3H, C6H4CH3), 2.87 (d, 1H,
JPH = 15.4 Hz, CHS(O)), 3.64 and 3.77 (2 ꢂ d, 6H, POCH3, JPH = 11.1 -
Hz), 7.32 and 7.75 (AB, 4H, C6H4CH3, JHH = 8.1 Hz); 13C NMR
(125 MHz, CDCl3): 12.1 (CD2, quint. JCD = 25.5 Hz), 21.2
(C6H4CH3), 27.6 ((CH3)3C, 27.7 (d, JCP = 180.4 Hz), 44.0 (CHS, d,
JCP = 3.2 Hz), 53.3 (d, JCP = 6.0 Hz), 53.5 (d, JCP = 6.0 Hz), 83.6
((CH3)3C, 124.1, 129.9, 140.6, 141.8, 164.0 (C=O, d, JCP = 4.8 Hz);
MS(CI) m/z 391 (M+H)+. HR MS(FAB) 390.1235 calcd for C17-
1H232H2O6PS [M]+ Found 390.1239.
4.2. Cyclopropanation
To a round-bottomed flask equipped with a magnetic stirrer bar
were added 2 mmol (0.48 g) of ethyl-1-diethylphosphono-2,2-
dideuteroacrylate and 2 mmol (0.6 g) of (S)-dimethyl sulfonium-
(p-tolylsulfinyl)methyl tetrafluoroborate placed in 10 mL of CH2-
Cl2. To this suspension was added 0.3 g of K2CO3 and the mixture
was stirred vigorously overnight. Filtration and evaporation of
the solvent afforded a crude residue in 95% yield. Separation of
the diastereomers was achieved by chromatography on silica (hex-
ane/acetone 2:1).
4.2.5. (ꢀ)-(1S,2S,Ss)-t-Butyl-1-dimethylphosphono-2-p-tolyl-
sulfinyl-3,3-2H2ꢀ-cyclopropanecarboxylate 10C-d2
Yield: 21%; yellowish oil; ½a D20
ꢁ
¼ ꢀ38:7 (c 3.1 acetone); 31P NMR
(81 MHz, CDCl3) d 20.6; 1H NMR (500 MHz, CDCl3) d: 1.39 (s, 9H,
COC(CH3)3), 2.40 (s, 3H, C6H4CH3), 2.91 (d, 1H, JHH = 9.4 Hz,
CHS(O)), 3.79 and 3.82 (2 ꢂ d, 6H, POCH3, JHH = 11.1 Hz), 7.32 and
7.75 (A2B2, 4H, C6H4CH3, JHH = 8.1 Hz); 13C NMR (125 MHz, CDCl3):
17.1 (quint. JCD = 25.5 Hz), 21.2, 27.6, 28.9 (d, JCP = 196.0 Hz), 48.8
(d, JCP = 3.2 Hz), 53.0 (d, JCP = 6.1 Hz), 53.5 (d, JCP = 6.9 Hz), 83.45,
124.2, 129.8, 141.3, 141.4, 165.8 (d, JCP = 6.8 Hz); MS(CI) m/z 391
4.2.1. (+)-(1R,2S,Ss)-Ethyl-1-diethylphosphono-2-p-tolyl-
sulfinyl-3,3-2H2-cyclopropanecarboxylate 9A-d2
Yield 53%; yellowish oil; ½a D20
ꢁ
¼ þ79 (c 13.6, acetone); 31P NMR
(M+H)+; HR MS(FAB) 390.1235 calcd for C17 H232H2O6PS [M]
+
1
(81 MHz, CDCl3) d: 18.8; 1H NMR (500 MHz, CDCl3) d: 1.23 (t, 3H,
POCH2CH3, JHH = 7.0 Hz), 1.28 (t, 3H, POCH2CH3, JHH = 7.0 Hz), 1.32
(t, 3H, COCH2CH3, JHH = 7.1 Hz), 2.42 (s, 3H, C6H4CH3), 2.90 (d, 1H,
JPH = 15.2 Hz, CHS(O)), 3.89–3.94 (m, 1H, POCHHCH3), 4.0–4.03
(m, 1H, POCHHCH3), 4.07–4.14 (m, 2H, POCH2CH3), 4.26 (q, 2H,
COCH2CH3, JHH = 7.1 Hz), 7.32 and 7.58 (A2B2, 4H, C6H4CH3); 13C
NMR (125 MHz, CDCl3): 12.7 (m, CD2), 14.1 (CH3CH2OC), 16.3 (m,
CH3CH2OP), 21.5 (C6H4CH3), 27.5 (CP, d, JCP = 181.0 Hz), 44.6
(CHSO), 62.5 (CH3CH2OC), 63.1 (d, JCP = 6.0 Hz, CH3CH2OP), 63.4
(d, JCP = 6.7 Hz, CH3CH2OP), 124.3, 130.0, 140.8, 142.1, 165.7 (d,
JCP = 7.7 Hz); MS(CI) m/z 391 (M+H)+; HR MS(ES) 413.1133 calcd
found: 390.1230.
4.3. Sulfinyl exchange
At the indicated temperature under nitrogen, to a stirred solu-
tion of (+)-9A-d2 or (+)-10A-d2 (0.2 mmol) in anhydrous Et2O
(3.0 mL), i-PrMgCl (2.0 M in Et2O, 1 mmol, 0.11 mL), was added
and the mixture was stirred at ꢀ50 °C for 1 h. The reaction was
quenched by NH4Cl, and extracted with Et2O (3 x 5 mL). The com-
bined extracts were dried over anhydrous MgSO4, filtered, and con-
centrated. Purification was performed by plate chromatography
(hexane/acetone 3:1)
+
1
for C17 H232H2O6NaPS [M+Na] found: 413.1128.
4.2.2. (+)-(1S,2R,Ss)-Ethyl-1-diethylphosphono-2-p-tolyl-
sulfinyl-3,3-2H2-cyclopropanecarboxylate 9C-d2
4.3.1. (ꢀ)-(1R)-Ethyl-1-diethylphosphono-2,2-22H2-cyclopropane-
carboxylate 14-d2
Yield 8%; yellowish oil; ½a D20
ꢁ
¼ þ120 (c 10.1, acetone); 31P NMR
Yield: 83%; yellowish oil; ½a D20
ꢁ
¼ ꢀ4:5 (c 6.7, acetone); 31P
(81 MHz, CDCl3) d: 18.7; 1H NMR (500 MHz, CDCl3) d: 1.33 (t, 3H,
POCH2CH3, JHH = 7.0 Hz), 1.34 (t, 3H, POCH2CH3, JHH = 7.0 Hz), 1.37
(t, 3H, COCH2CH3, JHH = 7.1 Hz), 2.43 (s, 3H, C6H4CH3), 3.08 (d, 1H,
JPH = 13.9 Hz, CHS(O)), 4.07–4.14 (m, 4H, POCH2CH3), 4.4 (m, 2H,
COCH2CH3), 7.33 and 7.58 (A2B2, 4H, C6H4CH3); 13C NMR
(125 MHz, CDCl3): 14.0 (CH3CH2OC), 14.9 (m, CD2), 16.3 (d,
JCP = 5.8 Hz, CH3CH2OP);16.4 (d, JCP = 6.7 Hz, CH3CH2OP), 21.4
(C6H4CH3), 27.0 (d, JCP = 181.9 Hz), 48.0 (CHSO), 62.7 (CH3CH2OC),
63.4 (m, CH3CH2OP), 124.2, 130.1, 140.8, 142.0, 166.2 (d, JCP = 5.2 -
Hz); MS(CI) m/z 391 (M+H)+; HR MS(ES) 413.1133 calcd for C17-
1H232H2O6NaPS [M+Na]+ found: 413.1135.
NMR (81 MHz, CDCl3) d 23.5; 1H NMR (500 MHz, CDCl3) d:
1.25 (t, 3H, POCH2CH3, JHH = 7.1 Hz), 1.29 (t, 6H, COCH2CH3,
JHH = 7.0 Hz), 1.39–1.43 (m, 2H, CH2), 4.12–4.18 (m, 6H, OCH2-
CH3); 13C NMR (125 MHz, CDCl3): 14.0 (CH3CH2OC), 14.6 (CD2),
14.9 (CH2), 16.2 (CH3CH2OP), 16.3 (d, JCP = 6.0 Hz, CH3CH2OP),
19.1 (d, JCP = 199.4 Hz) 61.4 (CH3CH2OC), 62.5 (d, JCP = 6.0 Hz,
CH3CH2OP), 62.6 (CH3CH2OP), 170.1 (C@O); MS(CI) m/z 253
(M+H)+; MS(ES) 275.0993 calcd for C10 H172H2O5PNa [M+Na]
+
1
found: 275.0992
4.3.2. (+)-(1R)-t-Butyl-1-dimethylphosphono-2,2-2H2-cyclopro-
panecarboxylate 12-d2
4.2.3. (ꢀ)-(1S,2S,Ss)-Ethyl-1-diethylphosphono-2-p-tolyl-
sulfinyl-3,3-2H2-cyclopropanecarboxylate 9B-d2
Yield: 82%; yellowish oil; ½a D20
ꢁ
¼ þ1:7 (c 1.0, acetone); 31P NMR
(81 MHz, CDCl3) d 28.3; 1H NMR (500 MHz, CDCl3) d: 1.31–1.40 (m,
2H, CH2), 1.45 (s, 9H, (CH3)3CO), 3.78 (d, 6H, POCH3, JPH = 11.1 Hz);
13C NMR (125 MHz, CDCl3): 13.9 (quint. JCD = 25.4 Hz), 14.4, 19.2
(d, JCP = 198.8 Hz), 27.9, 53.3 (d, JCP = 6.2 Hz), 82.0, 168.8 (d,
JCP = 8.3 Hz); MS(CI) m/z 253 (M+H)+; MS(FAB) 252.1096 calcd for
Yield: 20%; yellowish oil; ½a D20
ꢁ
¼ ꢀ32 (c 7.4, acetone); 31P NMR
(81 MHz, CDCl3) d: 17.3 ppm; 1H NMR (500 MHz, CDCl3) d: 1.20 (t,
3H, POCH2CH3, JHH = 7.2 Hz), 1.31 (t, 3H, POCH2CH3, JHH = 7.0 Hz),
1.34 (t, 3H, COCH2CH3, JHH = 7.0 Hz), 2.38 (s, 3H, C6H4CH3), 3.00
(d, 1H, SCH, JPH = 9.0 Hz), 4.09–4.26 (m, 6H, OCH2CH3), 7.29 and
7.74 (A2B2 aromatic); 13C NMR (125 MHz, CDCl3): 13.8 (CH3CH2-
OC), 16.3 (m, CH3CH2OP), 18.1 (m, CD2), 21.3 (C6H4CH3), 27.6 (d,
JCP = 195.7 Hz), 49.7 (CHSO), 62.4 (CH3CH2OC), 62.9 (d, JCP = 6.2 Hz,
CH3CH2OP), 63.4 (d, JCP = 6.5 Hz, CH3CH2OP), 124.5, 129.9, 141.6,
142.1, 167.5 (d, JCP = 7.7 Hz); MS(CI) m/z 391 (M+H)+.
+
1
C10 H172H2O5P [M] found: 252.1105
4.3.3. (+)-(1S,2R)-t-Butyl-3,3-2H2-2-dimethylphosphonocyclo-
propanecarboxylate 13-d2
Yield: 48%; yellowish oil; ½a D20
ꢁ
¼ ꢀ124:2 (c 1.7, acetone); 31P
NMR (202 MHz, CDCl3) d: 30.6; 1H NMR (500 MHz, CDCl3) d: (dd,
1H, CHtrans, JHH = 4.8, 5.0 Hz), 1.43 (s, 9H, (CH3)3CO), 2.05 (dd,
1H, CHcis, JHH = 4.8, JPH = 14.8 Hz), 3.74 and 3.75 (2 ꢂ d, 6H, POCH3,
J = 10.8 Hz) 13C NMR (125 MHz, CDCl3): 10.7 (CD2, quint.
JCD = 25.5 Hz), 12.0 (CP@O, d, JCP = 195.5 Hz), 18.6, 28.0 ((CH3)3CO),
52.7 (t, JCP = 5.7 Hz), 81.4, 171.0 (d, JCP = 10.8 Hz); MS(CI) m/z 253
4.2.4. (+)-(1R,2S,Ss)-t-Butyl-1-dimethylphosphono-2-p-tolyl-
sulfinyl-3,3-2H2ꢀcyclopropanecarboxylate 10A-d
Yield: 50%; white solid; mp 92–94 °C; ½a D20
ꢁ
¼ þ286:8 (c 1.0, ace-
tone); 31P NMR (81 MHz, CDCl3) d 22.5; 1H NMR (200 MHz, CDCl3)
Please cite this article in press as: Midura, W. H. ; Rzewnicka, A. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/
j.tetasy.2013.05.024

W. H. Midura, A. Rzewnicka / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
5
+
(M+H)+; MS(FAB) 252.1096 calcd for C10 H172H2O5P [M] found:
1
Acknowledgements
252.1098.
We gratefully acknowledge financial support from the Ministry
of Science and Higher Education No N N204 257938. The authors
4.4. (ꢀ)-(1R)-1-Diethylphosphono-2,2-2H2-cyclopropane-tert-
butoxycarbonylamine
´
are indebted to Dr Sławomir Kazmierski for technical support.
At first, 76 mg of ethyl ester 14-d2 (0.3 mmol) was dissolved in
5 mL of aqueous solution of LiOH. The mixture was then stirred for
1 h at room temperature. Next to the solution was added 5% HCl.
The water phase was extracted with CHCl3 (5 ꢂ 5 mL). The com-
bined organic phases were dried over MgSO4 and the solvent was
evaporated. The crude carboxylic acid derivative (62 mg,
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0.28 mmol) and NEt3 (40
lL, 0.28 mmol) were mixed with dry t-
BuOH (5 mL) at 25 °C under N2. Diphenylphosphoryl azide
(76 mg, 0.28 mmol) was then added, and the reaction mixture
was refluxed with stirring for 12 h. The reaction solution was con-
centrated, and the crude product extracted with ether. After being
washed with 1 M HCl and saturated NaHCO3(aq) and dried, the
product was purified by chromatography on silica (hexane/acetone
4:1). Yield: 88%; colorless oil; ½a D20
ꢁ
¼ ꢀ0:3 (c 2.6, acetone); 31P NMR
(81 MHz, CDCl3) d 25.5; 1H NMR (500 MHz, CDCl3) d: 1.32 (2 ꢂ t,
6H, POCH2CH3, JHH = 7.0 Hz), 1.35–1.50 (m, 2H, CH2), 1.42 (s, 9H,
COC(CH3)3), 4.12–4.19 (m, 4H, POCH2CH3), 4.95 (s, 1H, NH); 13C
NMR (125 MHz, CDCl3): 12.9 (CH2), 14.1 (CD2), 16.3 (CH3CH2OP),
16.4 (d, JCP = 6.2 Hz, CH3CH2OP), 25.2, 27.0 (d, JCP = 221.1 Hz),
28.2 (COC(CH3)3), 61.6 (CH3CH2OC), 62.5 (CH3CH2OP), 62.6 (d,
JCP = 5.5 Hz, CH3CH2OP), 79.8 (COC(CH3)3), 155.0 (C@O) MS(CI) m/
z 297 (M+H)+; HR MS(FAB) 296.1596 calcd for C12 H232H2O5NP
1
[M]+ found: 296.1586.
4.5. (ꢀ)-(1R)-1-Amino-[2,2-2H2]-cyclopropane-1-phosphonic
_
A.; Rzewnicka, A.; Supeł, A.; Łyzwa, P. Tetrahedron 2013, 69, 730–737.
10. (a) Midura, W. H. Synlett 2006, 733–736; (b) Midura, W. H. Tetrahedron Lett.
2007, 48, 3907–3910; (c) Midura, W. H.; Cypryk, M. Tetrahedron: Asymmetry
2010, 21, 177–186.
acid 17-d2
11. (a) Hill, R. H.; Prakash, S. R.; Wiesendanger, R.; Angst, W.; Martinoni, B.;
Arigoni, D.; Liu, H. W.; Walsh, C. T. J. Am. Chem. Soc. 1984, 106, 795–796; (b)
Williams, R. M.; Fegley, G. J. J. Am. Chem. Soc. 1991, 113, 87; (c) Buñuel, E.; Bull,
S. D.; Davies, S. G.; Christopher Garner, A. C.; Savory, E. D.; Smith, A. D.; Richard,
J.; Vickers, R. J.; Watkin, D. J. Org. Biomol. Chem. 2003, 1, 2531–2542.
12. Midura, W. H. Phosphorus, Sulfur and Silicon 2011, 186, 1189–1192.
13. Midura, W. H.; Sobczak, A.; Paluch, P. Tetrahedron Lett. 2013, 54, 223–226.
14. Moore, J. D.; Sprott, K. T.; Hanson, P. R. J. Org. Chem. 2002, 67, 8123–8129.
15. Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 6203–6205.
16. Fadel, A. J. Org. Chem. 1999, 64, 4953–4955.
A solution of N-Boc-protected cyclopropylamine 16-d2 (27 mg)
in 2 mL of 6 N HC1 was heated at 100 °C for 24 h and then concen-
trated under vacuum. The residue was dissolved in absolute etha-
nol (0.5 mL) and then treated with propylene oxide (0.04 mL). After
standing overnight at room temperature, the mixture was filtered
to afford a white solid. ½a D20
ꢁ
¼ ꢀ1:3 (c 1.2, H2O); 31P NMR (81 MHz,
D2O) d 12.4 1H NMR (500 MHz, CDCl3) d: 1.02–1.11 (m, 2H, CH2),
13C NMR (125 MHz, D2O): 8.8 (CD2), 8.9 (CH2), 30.4 (d, JCP = 191.3 -
Hz) (lit.16 for undeuterated acid d 30.9, d, JCP = 193.5 Hz); MS(FAB)
m/z 139 M+.
Please cite this article in press as: Midura, W. H. ; Rzewnicka, A. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/
j.tetasy.2013.05.024