Asymmetric synthesis of conformationally constrained L-AP4 analogues using chiral sulfinyl auxiliary

Article abstract of DOI:10.1016/j.tet.2012.10.085

Constrained L-AP4 analogues, (2S,1′R,2′S)- and (2S,1′S,2′R)-2-(2′-phosphonocyclopropyl) glycines as well as their phenyl analogues (2S,1′S,2′R,3′S)-2-(2′-phosphono- 3′-phenylcyclopropyl) glycine (PPCG-1) and (2S,1′R,2′S, 3′R)-2-(2′-phosphono-3′-phenylcyclopropyl) glycine (PPCG-2) were synthesized. The stereogenic centers in cyclopropane ring were formed under sulfinyl group control, in asymmetric cyclopropanation of enantiomerically pure a-phosphoryl vinyl sulfoxides. The sulfinimine-mediated asymmetric Strecker reaction allowed to introduce amino acid moiety.

Full text of DOI:10.1016/j.tet.2012.10.085

Accepted Manuscript
Asymmetric synthesis of conformationally constrained L-AP4 analogues using chiral
sulfinyl auxiliary
Wanda H. Midura, Jerzy Krysiak, Aneta Rzewnicka, Anna Supeł, Piotr Łyżwa, Ashraf
M. Ewas
PII:
S0040-4020(12)01681-X
10.1016/j.tet.2012.10.085
TET 23703
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 April 2012
Revised Date: 8 October 2012
Accepted Date: 29 October 2012
Please cite this article as: Midura WH, Krysiak J, Rzewnicka A, Supeł A, Łyżwa P, Ewas AM,
Asymmetric synthesis of conformationally constrained L-AP4 analogues using chiral sulfinyl auxiliary,
Tetrahedron (2012), doi: 10.1016/j.tet.2012.10.085.
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ACCEPTED MANUSCRIPT
Asymmetric synthesis of conformationally constrained L-
AP4 analogues using chiral sulfinyl auxiliary
Wanda H. Midura*, Jerzy Krysiak, Aneta Rzewnicka, Anna Supeł, Piotr Łyżwa, Ashraf M.
Ewas
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of
Heteroorganic Chemistry, 90-363 Lodz, Sienkiewicza 112, Poland
whmidura@cbmm.lodz.pl
Abstract: Constrained L-AP4 analogues, (2S,1’R,2’S)- and (2S,1’S,2’R)-2-(2’-phosphonocyclopropyl) glycines as well
as their phenyl analogues (2S,1'S,2'R,3'S)-2-(2'-phosphono-3'-phenylcyclopropyl) glycine (PPCG-1) and
(2S,1'R,2'S,3'R)-2-(2'-phosphono-3'-phenylcyclopropyl) glycine (PPCG-2) were synthesized. The stereogenic centers in
cyclopropane ring were formed under sulfinyl group control, in asymmetric cyclopropanation of enantiomerically pure
α-phosphoryl vinyl sulfoxides. The sulfinimine-mediated asymmetric Strecker reaction allowed to introduce aminoacid
moiety.
Keywords: glycine analogues; asymmetric cyclopropanation; sulfinyl auxiliary; sulfonium ylides; Strecker reaction;
sulfinimines.
1.
Introduction
(S)-Glutamic acid (Glu) (1) is the major excitatory neurotransmitter in the central nervous system
(CNS), and activates both ionotropic and metabotropic excitatory amino acid (EAA) receptors. Glu
is involved in most brain functions such as learning, memory, motor control, vision and pain
sensitivity. It is generally agreed that all classes of EAA receptors play important roles in the CNS,
and that ligands affecting ionotropic as well as metabotropic1 receptors would serve as useful
therapeutic targets in relation to various neurological disorders. Therefore, the development of
selective ligands for glutamate receptors allows a fine modulation of the glutamatergic pathways
and may provide an appropriate therapeutic approach for the treatment of neurodegenerative
pathologies such as Alzheimer’s or Huntington’s disease, or neuropsychiatric disorders as
Parkinson’s desease or neuronal damage resulting from cerebral ischemia and epilepsy.2
More potent analogues can be designed by manipulation of a functional group, stereochemistry or a
conformational constrain, since flexible molecules suffer from a significant loss in entropy upon
binding to receptors. Many strategies have been devised to reduce or eliminate the conformational
flexibility of the natural ligand. However, the most widely used technique is ring insertion, since
constrained amino acids closely mimic the bioactive conformation of natural neurotransmitters. For
this reason, intensive studies have been performed on the synthesis of three to six-membered
carbocyclic analogues.3,4 Among all these analogues, the carboxycyclopropylglycines (CCG)
represent the most important source of active analogues for the Glu receptors. For instance, trans-

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(2S,1'S,2'S)-2-(2'-carboxycyclopropyl)gly (L-CCG-I 2) has been shown to be a potent agonist of
group II mGluRs, while the cis-isomer (3) is a potent and selective NMDA agonist.5
Bioisosteric replacement of substituents is another way to improve pharmacological properties, and
thus create more effective drugs and prodrugs. Special interest in the phosphonic acid group is
associated, among other issues, with its tetrahedral structure, where the planar and less bulky
carboxylic acid (CO2H) is replaced by a tetrahedral phosphonic acid functionality (PO3H2). α-
Aminophosphonic acids, structurally analogous to α-amino acids, are important compounds which
exhibit interesting biological activities by themselves or as components of peptidomimetics,
particularly in research involving the modification of physiological processes in living organisms.
Fig. 1. Selected L-Glu analogues
(2S)-2-Amino-4-phosphonobutanoic acid L-AP4 (4) acts as an agonist for the group III
metabotropic glutamate receptors, although with a lack of selectivity between the different mGluR
group III subtypes.6
Combining both techniques: conformational restriction and isosterism became a reasonable way of
searching for effective potential selective mGluRs agonists. According to this concept, the synthesis
of enantiomerically pure (2S,3R,4R)-ethoxycarbonylcyclopropyl phosphonoglycine7 and 4-
phosphonophenylglycine 4-PPG, were elaborated; the latter turned out to be a potent and selective
group III mGluRs agonist.8 Recently we described the synthesis of optically active bicyclic
aminophosphonic acid 6, which is an analogue of one of the most potent and selective group II
agonist, LY354740 (5).9
Continuing our studies on asymmetric cyclopropanation mediated by a chiral sulfinyl group and its
application to the synthesis of biologically active compounds, we decided to apply our methodology
as a key step in the preparation of phosphonate analogues of carboxycyclopropylglycines.10 In 2006

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Pellicciari and coworkers11 evaluated the synthesized phosphonocyclopropylaminoacids (PCG) as
mGluR ligands and proved their activity as group III mGluRs agonists. One year later, the same
group published12 their results on the stereocontrolled synthesis of 3'-phenyl substituted analogues
(PPCG) and evaluation as mGluRs ligands. The (2S,1'R,2'S,3'R)-isomer (PPCG-2) showed to be a
group III mGluRs selective ligand endowed with a moderate potency as mGluR4/mGluR6 agonist.
These publications prompted us to disclose our own results concerning the synthesis of those
ligands. This approach is based on our previous work and applies a different methodology, which
allowed to use less expensive materials and gave the desired products in higher overall yield.
2. Results and discussion
In the approach to the synthesis of PCG we utilized our methodology for the synthesis of
enantiomericaly pure cyclopropylphosphonates, based on the reaction of (S)-(+)-(1-
diethoxyphosphoryl)vinyl p-tolyl sulfoxide with sulfonium ylides.13 We have found14 that
cyclopropanation using ethyl (dimethylsulfuranylidene)acetate (EDSA) occurs in a highly
diastereoselective manner with facial stereoselectivity up to 12:1.15 The major diastereomer
obtained in this reaction, (1S,2S)-(1-diethoxyphosphoryl-2-ethoxycarbonyl)cyclopropyl p-tolyl
sulfoxide, was converted in two steps into enantiopure 12a (Scheme 1). Desulfurization performed
on the second diastereomer 10b, where carboethoxy and phosphoryl groups are in cis relationship,16
gave, under the same conditions, a mixture of ent-11a and 11b, which were separated by column
chromatography. The formation of ent-11a in this reaction is due to inversion of the configuration at
C(1) and thermodynamic control, affording a more stable trans-isomer as the major product
(Scheme 1).

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Scheme 1.
Alcohol 12a, obtained by ester 11a reduction was then oxidized by CrO3 in pyridine to the aldehyde
13a in 80% yield. Analogous conversions were performed on its enantiomer, leading to ent-13a
(Scheme 2).
To introduce the amino acid moiety at this stage, we decided to apply the asymmetric Strecker
synthesis involving the highly diastereoselective addition of ethylaluminum cyano alkoxide
[“EtAl(OR)CN”] to non-racemic sulfinimines developed by Davis.17 It was established that the
configuration of the sulfinyl group controls cyanide addition: Re-face addition to sulfinimines of
(S)-configuration gives (S,SS)-amino nitriles as the major diastereoisomers.
For this purpose, the sulfinimine 15a was prepared by condensing commercially available (S)-(+)-p-
toluenesulfinamide (14) with the cyclopropyl aldehyde 13a in the presence of Ti(OEt)4 running the
reaction overnight (Scheme 2). After purification and removal of the unreacted aldehyde, the
isolated yield of 15a was 75%. Next, Strecker reaction was performed by addition of
ethylaluminum cyanoisopropoxide [EtAl(O-i-Pr)CN], prepared by treatment of 2 equiv of
diethylaluminum cyanide with 1.0 equiv of i-PrOH, to a solution of the sulfinimine 15a at −78 °C.
Quenching at low temperature afforded the mixture of (2S,1’S,2’R)- and (2R,1’S,2’R)-aminonitriles
16a and 16b in 5 to 2 ratio (43% de). We assume that the major diastereomer 16a, isolated after
chromatography, has S configuration on a newly created center, which is consistent with Davis’
hypothesis17b about the coordination of EtAl(O-i-Pr)CN to the sulfinyl oxygen and intramolecular
delivery of CN moiety.

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Hydrolysis of the aminonitrile 16a occurs efficiently, without epimerization, on heating in 6.0 N
HCl to afford the corresponding amino acid 7 (Scheme 2).
To obtain the more potent diastereomer 8, the same sequence of transformations was performed
using cyclopropyl aldehyde ent-12a as a starting material. Sulfinamide ent-13a was subjected to
diastereoselective Strecker reaction affording corresponding (2S,1’R,2’S)- and (2R,1’R,2’S)-
aminonitriles 16c and 16d. To our delight, the asymmetric induction was much higher in this case
and the ratio of diastereomers attained 6 : 1 (71.4% de). Separation of the major diastereomer 16c
and final hydrolysis of the amino nitriles, when a cleavage of the chiral auxiliary takes place,
afforded desired (2S,1'R,2'S)-2-(2'-phosphonocyclopropyl)glycine 8 (PCG-1).
Scheme 2.
The absolute configuration of the substituted cyclopropane ring was tentatively assigned by us
earlier, based on the model of transition state for the cyclopropanation reaction of chiral 1-
phosphorylvinyl sulfoxides.13b,18 During the transformations which lead to cyclopropylglycines 7
and 8, this configuration is retained. Formation of a new chiral center during Strecker reaction is
evidently controlled by the stereogenic sulfinyl group, with a moderate “match” effect for
sulfinimine 15b. Configuration of this center was assigned by analogy to other reactions of this

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type, where (S,SS)-amino nitriles are formed as the major diastereoisomers from sulfinimines of (S)-
configuration.
For further modifications of cyclopropane ring in order to obtain phenyl substituted -(2’-
phosphonocyclopropyl) glycines we used E-(S)-(1-dimethoxyphosphoryl-2-phenyl)vinyl p-tolyl
sulfoxide as a starting material for cyclopropanation. The presence of an additional substituent on
carbon 2 in this sulfoxide caused an increase of diastereoselectivity during cyclopropanation with
ethyl (dimethylsulfuranylidene)acetate. Though three new stereogenic centres of chirality were
formed under the control of the chiral p-toluenesulfinyl group, the cyclopropane 17E was formed as
a mixture of only two diastereomers in an 8:1 ratio.19 Our former investigations evidenced that the
major diastereomer of cyclopropylphosphonate 17E obtained in this reaction was easily separated
by column chromatography and converted into the corresponding methyl ester 17 in quantitative
yield by transesterification with methanol under basic conditions. Desulfurization of the latter was
performed by treatment with sodium amalgam. Under the reaction conditions applied, the
cyclopropanephosphonate 18 was obtained as a 3:1 mixture of two diastereomers 18a and 18b,
which were easily separated by column chromatography. Based on the homo- and heteronuclear
two-dimensional NMR and a three-bond carbon–phosphorus coupling constants, as well as on NOE
measurements,13 the diastereomers were found to have an opposite configuration at the α-
phosphonate carbon atom.14 The major diastereomer (+)-18a was formed with retention of
configuration (Fig. 2).
7.5%
O
O
O
O
3JCP= 3.6 Hz
H1
H1
CO2R
3JCP= 8.5 Hz
(MeO)2P
STol-p
(MeO)2P
(MeO)2P
5.0%
CO2R
H2
H3
Ph
H3
Ph
CO2R
Ph
H2
17E : R = Et
17 : R = Me
18b
18a
Fig. 2.
Cyclopropyl phosphonate 18a, with trans relationship of the ester group to both remaining
substituents was effectively reduced to appropriate alcohol 19. Oxidation of 19 by CrO3 in pyridine
in dichloromethane at room temperature led in 95% yield to the aldehyde 20.

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Scheme 3.
In order to obtain the appropriate cyclopropylaminoacid, we again used sulfinimine-mediated
asymmetric Strecker synthesis to introduce the aminoacid moiety. Condensation of 20 with (S)-(+)-
p-toluenesulfinamide (14) formed sulfimine 21a, which was reacted with ethylaluminum
cyanoisopropoxide [EtAl(O-i-Pr)CN], affording a mixture of aminonitriles 22a and 22b in 3:1 ratio.
The major diastereomer (2S,1'S,2'R,3'S)-22a, which was separated by column chromatography, was
subjected to hydrolysis leading to PPCG-1 23 in reasonable 56% yield (Scheme 3).
To obtain diastereomer (2S,1'R,2'S,3'R) PPCG-2 24 showing agonistic activity12, the sequence of
transformations presented above should be performed using the opposite enantiomer of 20 (ent-20).
Fig. 3.
Therefore, cyclopropanation reaction was performed on vinyl sulfoxide with R configuration on the
sulfinyl group. The opposite configuration on sulfur caused that the approach of EDSA to the
carbon-carbon double bond, which takes place preferentially from the less hindered diastereotopic
face occupied by the lone electron pair of sulfur, in E-(R)-(1-dimethoxyphosphoryl-2-phenyl)vinyl
p-tolyl sulfoxide, occurs from the opposite side (bottom-face attack) (Figure 3). In this way the
(1R,2R,3S,RS) cyclopropyl sulfoxide ent-17 was formed as the major product and after
desulfurization afforded ent-18a, used for further transformations.

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Scheme 4.
Diastereoselective Strecker reaction and final hydrolysis of the α-amino nitrile 22c provided
(2S,1'R,2'S,3'R)-2-(2'-phosphono-3'-phenylcyclopropyl)glycine (PPCG-2, 24) in 18.2% overall
yield, starting from the easily available (1R,2S,3R)-methyl 2-(dimethoxyphosphoryl)-3-
phenylcyclopropanecarboxylate ent-18a (Scheme 4).
Although configuration of stereogenic center during the synthesis was assigned by analogy to other
Strecker reactions, the spectral data of (2’-phosphonocyclopropyl) glycines, as well as their phenyl
analogues, which were obtained by us, are consistent with those described in the literature.11,12 In
this way the presented transformations, leading to known products, provide another confirmation of
the former configurational assignment.
3.
Summary
The
stereocontrolled synthesis
of the trans-(2S,1'R,2'S)- and
(2S,1'S,2'R)-2-(2'-
phosphonocyclopropyl) glycines (PCG-2, 7) and (PCG-1, 8) and appropriate phenyl analogues
(2S,1'S,2'R,3'S)-2-(2'-phosphono-3'-phenylcyclopropyl) glycine (PPCG-1, 23) and (2S,1'R,2'S,3'R)-
2-(2'-phosphono-3'-phenylcyclopropyl) glycine (PPCG-2, 24) was elaborated. The stereogenic
centers in cyclopropane ring were formed under sulfinyl group control, utilizing asymmetric
synthesis of cyclopropylphosphonates using enantiomerically pure α-phosphoryl vinyl sulfoxides.
The sulfinimine-mediated asymmetric Strecker reaction allowed to introduce aminoacid moiety.
Hydrolysis of appropriate aminonitriles was easily accomplished, simply by heating in acidic
medium, avoiding toxic reagents. Although sulfinyl auxiliary was used twice during transformations

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to cyclopropyl glycines, it improved efficiency of the synthesis, since separation of diastereomers
was easier to perform.
4.
Experimental section
4.1. General
13
31
1H, C and P NMR spectra were recorded on a Bruker DRX 500, Bruker MSL 300 and Bruker
AC 200 Spectrometers using deuterochloroform as a solvent. Mass spectra were recorded on
Finnigan MAT95. The optical rotations were measured on a Perkin–Elmer 241 MC
photopolarimeter at 20 oC. The microanalyses were performed on an Elemental Analyzer EA 1108.
TLC was carried 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
4.2. Preparation of 1-(diethoxyphosphoryl)-2-(formyl)cyclopropane
In a single-neck round-bottom flask was placed a solution of alcohol (0.322 g, 1.55 mmol, 1 eq) in
CH2Cl2 (10 mL), then CrO3 in pyridine (1.549 g, 0.0155 mol, 10 eq) was added and stirred
overnight. At this time CH2Cl2 was evaporated and the resulting precipitate dissolved in Et2O (5
mL). The suspension was filtered through Celite, and concentrated to give pure aldehyde.
4.2.1. (1R, 2S)-1-(Diethoxyphosphoryl)-2-(formyl)cyclopropane 13a
A colorless oil. Yield: 0.254 g (80%), [α]D20 = −61 (c 3.0, acetone); IR (KBr) 2985, 1725, 1230 cm-
1; 31P NMR (81 MHz, CDCl3): δ 25.2; 1H NMR (200 MHz, CDCl3): δ 0.80−0.98 (m, 2H, 3’-CH2),
1.30 (t, J = 7.1 Hz, 3H, CH3CH2O), 1.32 (t, J = 7.1 Hz, 3H, CH3CH2O), 1.40−1.55 (m, 1H, 2’-CH),
1.56−1.66 (m, 1H, 1’-CH), 4.06–4.23 (m, 4H, CH3CH2O), 9.25 (d, J = 4.3 Hz, 1H, CHO); 13C
NMR (50 MHz, CDCl3): δ 13.4 (d, J = 196.5 Hz), 16.3 (d, J = 5.9 Hz), 26.1, 26.2, 62.4 (d, J = 6.1),
198.2 (d, J = 4.3 Hz); MS (CI) m/z = 207 (M + H)+; HR MS(EI) 206. 0711. calcd for C8H15O4P.
Found: 206. 0708.
4.3. Preparation of N-(2-diethoxyphosphoryl)cyclopropylmethylidene-p-toluenesulfinamide
In a dried single-neck round-bottom flask equipped with magnetic stirring bar, rubber septum, and
an argon baloon was dissolved (S)-(+)-p-toluensulfinamide (0.377 g, 22.1 mmol, 1.8 eq) in dry
CH2Cl2, then was added aldehyde (0.254 g, 12.3 mmol, 1 eq) and Ti(OEt)4 (2.805 g, 0.015 mol,

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3.61 mL, 12.5 eq), and the mixture was stirred overnight. At this time to the reaction mixture water
was added. The suspension was filtered through Celite, and washed with CH2Cl2 (5 mL). The
organic and aqueous phases was separated, and the aqueous phase was extracted with CH2Cl2 (5 x 5
mL). The combined organic phases was dried over MgSO4, and concentrated to give crude
sulfinimine, which was washed with petroleum ether to remove excess of (S)-(+)-p-
toluensulfinamide and purified by column chromatography (diethyl ether : acetone, 20:1).
4.3.1. (1S, 2R, Ss )-2-(diethoxyphosphoryl)-cyclopropylmethylidene-p-toluenesulfinamide 15a
20
A colorless oil. Yield: 0.316 g (75%), [α]D = −155 (c 3.5, acetone); IR (KBr) 3030, 2975, 2860,
1
1560, 1230, 1025 cm-1; 31P NMR (81 MHz, CDCl3): δ 25.7; H NMR (200 MHz, CDCl3): δ
0.80−0.98 (m, 2H, 3’-CH2), 1.21–1.29 (m, 1H, 2’-CH), 1.31 (t, J = 7.1 Hz, 3H, CH3CH2O), 1.32 (t,
J = 7.1 Hz, 3H, CH3CH2O), 1.50−1.55 (m, 1H, 1’-CH), 2.39 (s, 3H, C6H4CH3), 4.01–4.17 (m, 4H,
13
CH3CH2O), 7.29 (d, J = 8.0 Hz, HAr), 7.52 (d, J = 7.9 Hz, HAr), 7.68 (d, J = 7.2, 1H, CH=N); C
NMR (50 MHz, CDCl3): δ 13.4 (d, J = 196.4 Hz), 16.3 (d, J = 5.9 Hz), 21.2, 26.1, 30.2, 62.3, 124.4,
125.3, 129.5, 129.8, 165.6; MS (CI) m/z = 344 (M + H)+; HR MS(EI) 343.1007 calcd for
C15H22NO4PS. Found: 343.1014.
4.3.2. (1R, 2S, Ss)-2-(diethoxyphosphoryl)-cyclopropylmethylidene-p-toluenesulfinamide 15b
20
A colorless oil. Yield: (70%), [α]D = +152 (c 1.2, acetone); IR (film) 3030, 2980, 2875, 1560,
1230, 1025 cm-1; 31P NMR (81 MHz, CDCl3): δ 25.7; 1H NMR (200 MHz, CDCl3): δ 0.84−1.29 (m,
2H, 3’-CH2), 1.21–1.29 (m, 1H, 2’-CH), 1.30 (t, J = 7.1 Hz, 3H, CH3CH2O), 1.32 (t, J = 7.1 Hz,
3H, CH3CH2O), 1.45−1.69 (m, 1H, 1’-CH), 2.40 (s, 3H, C6H4CH3), 4.02–4.18 (m, 4H, CH3CH2O),
7.30 (d, J = 8.1 Hz, HAr), 7.53 (d, J = 8.2 Hz, HAr), 7.69 (d, J = 7.4 Hz, 1H, CH=N); 13C NMR (50
MHz, CDCl3): δ 13.3 (d, JC-P = 190.2 Hz), 16.1 (d, JC-P = 5.5 Hz), 21.1, 26.1,30.4, 62.1, 124.3,
125.6, 128.7, 129.3, 165.4; MS (CI) m/z = 344 (M + H)+; HR MS(EI) 343.1007 calcd for
C15H22NO4PS. Found: 343.1001.
4.4. Preparation of [(S)-N-p-toluenesulfinyl]-2-amino-2-[diethoxyphosphorylcyclopropyl]-
ethanenitrile 16
In an oven-dried double-neck round-bottom flask equipped with a magnetic stirring bar, a rubber
septum, and an argon balloon was placed the solution of sulfininime (0.140 g, 0.409 mmol, 1 eq) in
o
THF (7 mL) and cooled to −78 C. In a separate single-neck round-bottom flask equipped with
magnetic stirring bar, a rubber septum, and an argon balloon was added a solution of
diethylaluminium cyanide (0.211 g, 0.189 mmol, 0.25 mL, 4.6 eq) in THF (2 mL). The solution was

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cooled to −78 oC, and i-PrOH (0.051 g, 0.818 mmol, 0.064 mL, 2 eq) was added. The mixture was
allowed to reach room temperature, stirred for 30 min, and cannulated to the solution of sulfinimine
o
at −78 C. After the reaction the mixture was brought to room temperature, and stirred for 24 h, it
o
was cooled to −78 C, and quenched with saturated NH4Cl solution (5 mL). The suspension was
filtered through Celite, extracted with EtOAc (5 x 5 mL), washed with brine (3 x 5 mL), dried over
MgSO4 and concentrated to give a mixture of aminonitriles (diastereomeric ratio: 5 : 2) (83%),
which was purified by column chromatography (acetyl acetate : diethyl ether : Et3N, 1:1: traces)
4.4.1. (2S)-[(S)-N-p-toluenesulfinyl]-2-amino-(1’S,2’R)-2-[diethoxyphosphorylcyclopropyl]-
ethanenitrile 16a
20
A colorless oil. Yield: 0.081g (54%), [α]D = +41 (c 0.75, acetone); IR (film) 3440, 3030, 2980,
2230, 1230, 1020 cm-1; 31P NMR (81 MHz, CDCl3): δ 26.7; 1H NMR (200 MHz, CDCl3): δ 1.05 (t,
J = 7.3 Hz, 3H, CH3CH2O), 1.22 (t, J = 7.0 Hz, 3H, CH3CH2O), 1.00−1.38 (m, 3H, 1’-CH, 3’-CH2),
1.77−1.87 (m, 1H, 2’-CH), 2.37 (s, 3H, CH3C6H5), 3.81 (dd, J = 8.7, 6.5 Hz, 1H, CHCN),
4.01−4.12 (m, 4H, CH3CH2O), 5.83 (d, J = 8.8 Hz, 1H, NH), 7.28 (d, J = 8.1 Hz, 2HAr), 7.54 (d, J =
8.1 Hz, 2HAr); 13C NMR (125 MHz, CDCl3): δ 9.9 (d, J = 34.2 Hz), 14.7 (d, JC-P= 194.5 Hz), 16.3,
20.5, 21.3, 29.6, 43.6, 62.4 (m), 116.9, 126.1, 129.9,139.3, 142.2; MS (CI) m/z = 371 (M + H)+; HR
MS(FAB) 370.1116 calcd for C16H23N2O4PS. Found: 370.1111.
4.4.2. (2S)-[(S)-N-p-toluenesulfinyl]-2-amino-(1’R,2’S)-2-[diethoxyphosphorylcyclopropyl]-
ethanenitrile 16c
20
A colorless oil. Yield: (67%), [α]D = +44 (c 1, acetone); IR (KBr) 3430, 3030, 2980, 2225, 1225,
1030 cm-1; 31P NMR (81 MHz, CDCl3): δ 26.6; 1H NMR (200 MHz, CDCl3): δ 0.99−1.10 (m, 3H,
2’-CH, 3’-CH2), 1.28 (t, J = 7.3 Hz, 3H, CH3CH2O), 1.40 (t, J = 7.3 Hz, 3H, CH3CH2O), 1.89−1.94
(m, 1H, 1’-CH), 2.41 (s, 3H, CH3C6H5), 3.87 (dd, J = 7.3, 6.9 Hz, 1H, CHCN), 4.01−4.12 (m, 4H,
CH3CH2O), 5.43 (d, J = 6.9 Hz, 1H, NH), 7.28 (d, J = 8.1 Hz, 2HAr), 7.53 (d, J = 8.2 Hz, 2HAr); 13C
NMR (125 MHz, CDCl3): δ 8.6 (3’C), 9.4 (d, JC-P = 194.3 Hz, 2’C), 16.3 (d, JC-P=5.5 Hz,
CH3CH2O), 20.4 (1’C), 21.2, 43.3 (C-CN), 62.3 (d, JC-P= 5.8 Hz, CH3CH2O), 116.7 (CN), 126.0
(CAr-H), 130.0 (CAr-H), 139.1 (CAr-C), 142.5 (CAr-S); MS (CI) m/z = 371 (M + H)+; HR MS(FAB)
370.1116 calcd for C16H23N2O4PS. Found: 370.1122.
4.5. Procedure for hydrolysis of the aminonitriles to amino acids
In single-neck round-bottom flask equipped with magnetic stirring bar and a water condenser were
placed the appropriate aminonitrile (0.0811g, 0.219 mmol, 1eq ) and 6N HCl aq, (6 mL). The
solution was refluxed for 24 h. The reaction mixture was cooled to room temperature and extracted

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with diethyl ether (5 x 5 mL), and the aqueous phase was concentrated. The crude product was
purified by preparative TLC (methanol, 2% of acetic acid).
4.5.1. (2S,1’S,2’R)-2-(2’-phosphonocyclopropyl)glycine 7
o
20
A white powder, m.p. 246−248 C. Yield: 16,8 mg (39%), [α]D = −9.3 (c 0.72, H2O); IR (KBr)
31
1
3100, 2985, 2130, 1230 cm-1; P NMR (81 MHz, D2O): δ 25.8; H NMR (200 MHz, D2O): δ
0.95−1.12 (m, 2H, 3’-CH2), 1.25−1.27 (m, 1H, 1’-CH), 1.39−1.48 (m, 1H, 2’-CH), 3.43 (d, J = 10.1
Hz, 2-CH); 13C NMR (125 MHz, D2O): δ 8.7, 12.5 (d, JC-P = 184.6 Hz), 16.7, 56.0, 170.8; MS (CI)
m/z = 195 (M + H)+ HR MS(FAB) 195.0296 calcd for C5H10NO5P. Found: 195.0274.
4.5.2. (2S,1’R,2’S)-2-(2’-phosphonocyclopropyl)glycine 8
o
20
A white powder, m.p. 235−237 C. Yield: (40%), [α]D = +78.5 (c 0.95, H2O); IR (KBr) 3100,
31
2980, 2120, 1230 cm-1; P NMR (81 MHz, D2O): δ 23.2; 1H NMR (200 MHz, D2O): δ 1.00−1.06
(m, 2H, 3’-CH2), 1.10−1.17 (m, 1H, 1’-CH), 1.43−1.50 (m, 1H, 2’-CH), 3.36 (d, J = 9.5 Hz, 2-CH);
13C NMR (125 MHz, D2O): δ 8.9, 12.2 (d, JC-P = 183.5 Hz), 16.9, 56.3, 171.1; MS (CI) m/z = 195
(M + H)+ HR MS(FAB) 195.0296 calcd. for C5H10NO5P. Found: 195.0304
4.6. Preparation of 1-dimethoxyphosphoryl-2-carbomethoxy-3-phenylcyclopropane
To the solution of 772 mg (2 mmol) of 1-dimethoxyphosphoryl-1-p-tolylsulfinyl-2-carbomethoxy-
3-phenylcyclopropane in methanol (20 mL) Na2HPO4 (1.5 g) was added as a buffer. To this mixture,
o
cooled to −20 C, sodium amalgam (1 g) was added and reaction mixture was stirred for 1 h and
o
then allowed to warm up to 0 C. At this temperature 10 mL of water was added and solution was
extracted with chloroform (5 x 20 mL) The combined organic phases was dried over MgSO4, and
concentrated to give crude product (444 mg, 78% yield). The crude product was purified by
chromatography.
4.6.1. (1R,2S,3S)- 1-Dimethoxyphosphoryl-2-carbomethoxy-3-phenylcyclopropane 18a
20
A colorless oil 280 mg (50 % yield). [α]D +47.7 (c 1.7, acetone); IR (KBr) 3030, 1770, 1580,
31
1
1530, 1235, 1210, 1020 cm-1; P NMR (80 MHz, CDCl3) δP = 25.8 ppm; H NMR (500 MHz,
CDCl3) δ: 1.93 (ddd, 1H, JP-H = 3.0 Hz, JH-H = 10.1, 5.8 Hz, CHP), 2.78 (ddd, 1H, JP-H = 15.5 Hz,
JH-H = 5.8, 5.6, Hz, CHCO2), 2.98 (ddd, 1H, JP-H = 15.7 Hz, JH-H = 10.1, 5.7 Hz, CHPh), 3.37 (d,
3H, J = 10.9 Hz, CH3OP), 3.40 (d, 3H, JP-H = 11.0 Hz, CH3OP), 3.76 (s, 3H, CH3O2C), 7.21−7.37
(m, 5H, C6H5); 13C NMR (50 MHz, CDCl3) 21.8 (d, JC-P = 193.6 Hz), 23.6 (CCO2), 29.8 (d, JC-P
6.2 Hz, CPh), 52.0 (d, JC-P = 6.0 Hz), 52.3 (d, JC-P = 6.5 Hz), 52.4, 127.3, 128.1, 129.0, 134.4 (d, JC-
=

ACCEPTED MANUSCRIPT
= 6.2 Hz), 172.1 (d, JC-P = 3.6 Hz, C=O),; MS (CI) m/z = 285 (M + H)+; Anal. Calcd for
P
C13H17O5P C, 54.93; H, 6.03; Found C, 54.75; H, 5.98.
NOE: H3
H1 7.5%;
4.6.2.
(1S,2S,3S)- 1-Dimethoxyphosphoryl-2-carbomethoxy-3-phenylcyclopropane 18b
A colorless oil 135 mg (23.7 % yield). [α]D20 +16.7 (c 2.3, acetone); IR (KBr) 3035, 1765, 1220 cm-
1; 31P NMR (80 MHz, CDCl3) δP = 26.4 ppm; 1H NMR (500 MHz, CDCl3) δ: 1.68 (ddd, 1H, JP-H
=
1.2 Hz, JH-H = 9.9, 7.2 Hz, CHP), 2.36 (ddd, 1H, JP-H = 11.0 Hz, JH-H = 9.9, 5.9 Hz, CHCO2), 3.16
(ddd, 1H, JP-H = 17.5, JH-H = 7.2, 5.9 Hz, CHPh), 3.77 (d, 3H, J = 11.1 Hz, CH3OP), 3.77 (s, 3H,
CH3O2C), 3.78 (d, 3H, J = 11.0 Hz, CH3OP), 7.11−7.35 (m, 5H, C6H5); 13C NMR (50 MHz, CDCl3)
22.4 (d, JC-P = 194.1 Hz), 28.3 (d, JC-P = 6.0 Hz), 28.7 (d, JC-P = 2.5 Hz), 52.3, 52.7 (d, JC-P = 6.2
Hz), 52.9 (d, JC-P = 6.1 Hz), 96.1, 126.4, 127.3, 128.7, 137.5 (d, JC-P = 3.2 Hz), 169.5 (d, JC-P = 8.5
Hz, C=O),; MS (CI) m/z = 257 (M + H)+; HR MS calcd for C13H17PO5. Found 256.0853.
NOE: H2 H1 5%
4.7. Preparation of 1-dimethoxyphosphoryl-2-hydroksymethyl-3-phenylcyclopropane
To the solution of methyl 2-(dimethoxyphosphoryl)-3-phenylcyclopropanecarboxylate (624 mg, 3
mmol) and methanol (0.4 mL) in THF (15 mL) was added slowly LiBH4 (5eq, 7.5 mL, 2 M solution
in THF). The reaction was stirred vigorously for 24 hours at room temperature, and then 10 ml of
water was added. The mixture was a acidified by the addition of 5% solution of HCl aq to pH 3 and
extracted (5 x 10 mL) with CHCl3. The combined organic layers were dried with anhydrous MgSO4
and evaporated. Product was purified by column chromatography on silica gel (diethyl ether).
4.7.1. (1R,2S,3S)- 1-Dimethoxyphosphoryl-2-hydroksymethyl-3-phenylcyclopropane 19
A colorless oil 400 mg (yield 81%). [α]D +64.5 (c 3.7, acetone); IR (KBr) 3640, 3030, 2985, 1590,
1510, 1320, 1230 cm-1; 31P NMR (80 MHz, CDCl3) δP = 29.5 ppm; 1H NMR (200 MHz, CDCl3) δ:
1.26−1.34 (m, 1H, CHP), 2.16−2.40 (m, 1H, CH), 2.43−2.62 (m, 1H, CH), 3.36 (d, 3H, J = 11.0 Hz,
CH3OP), 3.39 (d, 3H, J = 11.0 Hz, CH3OP), 3.57−3.66 (m, 1H, CH2OH), 3.79−3.88 (m, 1H,
CH2OH), 7.18−7.36 (m, 5H, C6H5); 13C NMR (50 MHz, CDCl3) 17.6 (d, JC-P = 195 Hz), 25.1 (d, JC-
= 4.0 Hz), 26.3 (d, JC-P = 5.4 Hz), 51.9 (d, JC-P = 6.1 Hz), 52.2 (d, JC-P = 6.5 Hz), 64.2 (d, JC-P
=
P
34.4 Hz), 126.8, 127.9, 129.3, 136.2 (d, JC-P = 6.6); MS (CI) m/z = 257 (M + H)+; HR MS(EI)
256.0861 calcd for C12H15O4P. Found 256.0853.
4.8. Preparation of dimethoxyphosphoryl 2-formyl-3-phenylcyclopropane

ACCEPTED MANUSCRIPT
To the solution of 1-dimethoxyphosphoryl-2-hydroksymethyl-3-phenylcyclopropane (508 mg, 2
mmol) in 25 mL of dichloromethane, complex of CrO3 in pyridine (800 mg) was added and stirred
12 hours at room temperature. Reaction was monitored by TLC and finished until the spot of
alcohol disappeared. Solvent was evaporated and brown precipitate was washed with diethyl ether
(3 x 10 mL) and filtrated by Celite. Filtrate was evaporated in vacuum. Crude product was purified
by flash chromatography using diethyl ether as eluent.
4.8.1. (1R,2S,3S)-Dimethoxyphosphoryl-2-formyl-3-phenylcyclopropane 20
20
A colorless oil 486 mg (95 % yield) [α]D +136.4 (c 10.5, acetone); IR (film) 3030, 2985, 1740,
31
1
1610, 1590, 1520, 1230 cm-1; P NMR (80 MHz, CDCl3) δP = 24.8 ppm; H NMR (200 MHz,
CDCl3) δ: 2.01−2.10 (m, 1H, CHP), 2.95−3.12 (m, 2H, CH), 3.38 (d, 3H, J = 10.8 Hz, CH3OP),
3.41 (d, 3H, J = 10.8 Hz, CH3OP), 7.23−7.35 (m, 5H, C6H5), 9.58 (d, 1H, J = 3.1 Hz, CHO); 13C
NMR (50 MHz, CDCl3) 23.2 (d, JC-P = 195.8 Hz), 30.2 (d, JC-P = 4.6 Hz), 32.0, 52.5 (d, JC-P = 6.0
Hz), 52.6 (d, JC-P = 6.3 Hz), 127.6, 128.3, 129.1, 133.8, 197.8; MS (CI) m/z = 255 (M + H)+; HR
MS(EI) 254.0697 calcd for C12H15O4P. Found 254.0692.
4.9. Preparation
toluenesulfinamide
of
N-(2-dimethoxyphosphoryl)-(3-phenyl)cyclopropylmethylidene-p-
To the mixture of aldehyde (254 mg, 1 mmol, 1eq) and (+)- (S)-p-tolylsulfinamide (310 mg, 2
mmol, 2eq) in CH2Cl2 (30 mL) was added slowly Ti(OEt)4 (7eq). Reaction was stirred for 24 hours
o
at room temperature and quenched at 0 C by slow addition of 20 mL of water. White gel was
filtrated by Celite and washed with CH2Cl2 (2 x 20 mL). Water phase was extracted (2 x 15 mL)
with CH2Cl2 and combined organic fraction was dried over MgSO4. Solvent was evaporated in
vacuum and crude product was purified by column chromatography on silica gel (Et2O) to remove
unreacted sulfinamide.
4.9.1. (1S,2R,3S,SS) N-(2-Dimethoxyphosphoryl)-(3-phenyl)cyclopropylmethylidene-p-
toluenesulfinamide 21a
Product was isolated as colorless oil 310 mg (79 % yield). [α]D +157.4 (c 2.0, acetone); IR (film)
1
3030, 2985, 1620, 1585, 1460, 1230, 1025 cm-1; 31P NMR (80 MHz, CDCl3) δP = 25.3 ppm; H

ACCEPTED MANUSCRIPT
NMR (200 MHz, CDCl3) δ: 2.01−2.10 (m, 1H, CHP), 2.95−3.12 (m, 2H, CH), 3.38 (d, 3H, J = 10.8
Hz, CH3OP), 3.41 (d, 3H, J = 10.8 Hz, CH3OP), 7.23−7.35 (m, 5H, C6H5), 9.58 (d, 1H, J = 3.1 Hz,
CHO); 13C NMR (50 MHz, CDCl3) 19.3 (d, JC-P = 194 Hz), 21.5, 25.4, 27.6, 44.1, 52.4 (d, JC-P = 6.0
Hz), 52.6 (d, JC-P = 6.3 Hz), 126.4, 127.0, 128.2, 128.3, 129.1, 131.1, 138.1, 142.7, 166.3. Anal.
calcd for C19H22NO4PS C, 58.30; H, 5.67; Found C, 58.51; H, 5.58;
4.9.2. (1R,2S,3S,SS) N-(2-Dimethoxyphosphoryl)-(3-phenyl)cyclopropylmethylidene-p-
toluenesulfinamide 21b
A colorless oil. Yield 77%; [α]D −136.1 (c 2.1, acetone); IR (film) 3030, 2985, 1620, 1575, 1510,
1460, 1230, 1025 cm-1; 31P NMR (80 MHz, CDCl3) δP = 25.2 ppm; 1H NMR (200 MHz, CDCl3) δ:
2.01−2.11 (m, 1H, CHP), 2.96−3.11 (m, 2H, CH), 3.37 (d, 3H, J = 10.8 Hz, CH3OP), 3.40 (d, 3H, J
= 10.8 Hz, CH3OP), 7.21−7.34 (m, 5H, C6H5), 9.58 (d, 1H, J = 3.1 Hz, CHO); 13C NMR (50 MHz,
CDCl3) 19.5 (d, JC-P = 191 Hz), 21.3, 25.7, 27.1, 44.5, 52.2 (d, JC-P = 6.0 Hz), 52.8 (d, JC-P = 6.2 Hz),
126.4, 127.1, 128.3, 129.2, 129.3, 131.3, 138.2, 142.8, 166.2. Anal. Calcd for C19H22NO4PS C,
58.30; H, 5.67; Found C, 58.56, H, 5.54.
4.10. Preparation of [(S)-N-p-toluenesulfinyl]-2-amino-2-[2’-dimethoxyphosphoryl-3’-
phenyl]cyclopropyl-ethanenitrile
To the solution of Et2AlCN (202 mg 1.82 mmol, 2 eq) was added i-PrOH (60 mg 0.91 mmol, 1 eq)
in 20 mL THF at –78 oC. The mixture was warmed to room temperature and stirred for 30 minutes.
o
Next, reaction was cooled to –78 C and added to cyclopropylsulfinimine (354 mg 0.91 mmol)..
After then, the mixture was warmed to r.t. and stirred vigorously for 24 hours. The reaction was
o
quenched –78 C by addition of 10 mL of sat. NH4Cl. The mixture was filtrated by Celite. The
water phase was extracted with ethyl acetate (3 x 20 mL). Combined organic phase was washed
with sat. NaCl and dried over MgSO4. The solvent was evaporated. The crude product was obtained
as a mixture of two diastereomers in 3:1 ratio (83% yield) and purified by column chromatography
(ethyl acetate/petroleum ether/Et3N 1 : 1 : traces).
4.10.1. (2S,1’S,2’R,3’S,SS)-[(N-p-toluenesulfinyl)-2-amino]-2-[2’-dimethoxyphosphoryl-3’-
phenyl]cyclopropyl-ethanenitrile 22a
20
The major diastereomer was isolated as yellow oil 220 mg (58 % yield). [α]D +200.2 (c 2.1,

ACCEPTED MANUSCRIPT
acetone); IR (film) 3430, 3030, 2985, 2230, 1600, 1580, 1440, 1230, 1025 cm-1; 31P NMR (80 MHz,
CDCl3) δP = 26.6 ppm; 1H NMR (500 MHz, CDCl3) δ: 1.54 (dd, 1H, J = 10.1, 6.1 Hz, CH), 2.42 (s,
3H, C6H4CH3), 2.51 (ddd, 1H, J = 16.1, 6.1, 6.1 Hz, CH), 2.73 (ddd, J = 13.6, 10.1, 6.1 Hz, 1H,
CH), 3.38 (d, 3H, J = 11.2 Hz, CH3OP), 3.40 (d, 3H, J = 11.2 Hz, CH3OP), 4.30 (dd, 1H, J = 6.5,
6.5 Hz CH), 5.52 (d, 1H, J = 6.5 Hz CH), 7.21−7.36 (m, 7H (C6H5 + 2H C6H4CH3)), 7.61 (d, 2H, J
= 8.1 Hz, C6H4CH3); 13C NMR (125 MHz, CDCl3) 18.0 (d, JC-P = 195.6 Hz), 21.4, 25.8, 27.9, 43.6,
52.4 (d, JC-P = 6.0 Hz), 52.5 (d, JC-P = 6.3 Hz), 116.3, 126.1, 127.4, 128.2, 129.1, 130.0, 134.2,
138.3, 142.5; MS (EI) m/z = 419 (M)+; Anal. Calcd for C20H23N2O4PS C, 57.41; H, 5.54; S 7.66;
Found C, 57.21; H, 5.68, S 7.79.
4.10.2. (2S,1’R,2’S,3’R,SS)-[(N-p-toluenesulfinyl)-2-amino]-2-[2’-dimethoxyphosphoryl-3’-
phenyl]cyclopropyl-ethanenitrile 22c
20
A colorless oil. Yield 55%; [α]D +38.5 (c 2.0, acetone); IR (film) 3440, 3030, 2985, 2230, 1610,
31
1
1575, 1450, 1230, 1025 cm-1; P NMR (80 MHz, CDCl3) δP = 26.5 ppm; H NMR (500 MHz,
CDCl3) δ: 1.62 (dd, 1H, J = 10.1, 6.0 Hz, CH), 2.43 (s, 3H, C6H4CH3), 2.52 (ddd, 1H, J = 16.2,
13.7, 6.0 Hz, CH), 2.72 (ddd, 1H, J = 13.7, 10.1, 6.0 Hz, CH), 3.36 (d, 3H, J = 11 Hz, CH3OP), 3.43
(d, 3H, J = 11 Hz, CH3OP), 4.00 (dd, 1H, J = 7.5, 7.5 Hz CH), 5.43 (d, 1H, J = 7.5 Hz CH),
7.22−7.37 (m, 7H, (C6H5 + 2H C6H4CH3)), 7.61 (d, 2H, J = 8.1 Hz, C6H4CH3); 13C NMR (125
MHz, CDCl3) 19.8 (d, JC-P = 194.5 Hz), 21.4; 26.2, 28.0, 43.9, 52.4 (d, JC-P = 7.1 Hz), 116.8, 126.2,
127.5, 128.3, 129.0, 130.1, 134.3, 138.7, 142.5; MS (CI) m/z = 419 (M + H)+; Anal. Calcd for
C20H23N2O4 PS C, 57.41; H, 5.54; S, 7.66; Found C, 57.23; H, 5.64; S, 7.76
4.11. Preparation of 2-(2’-phosphono-3’-phenylcyclopropyl)glycine.
o
Cyclopropane 22 (77 mg 0.184 mmol) was dissolved in 10 mL of 6N HCl and heated at 95 C for
24 hours. The solution was evaporated in vacuum. Product was purified by resin Dowex – X 50W.
4.11.1. (2S,1’S,2’R,3’S)-2-(2’-Phosphono-3’-phenylcyclopropyl)glycine 23
o
A white powder, m.p. 247−251 C. 28 mg (56 % yield). [α]D20 +79.5 (c 1.1, H2O); IR (KBr) 3120,
3030, 2985, 2120, 1630, 1520, 1440, 1230, cm-1; 31P NMR (80 MHz, D2O) δP = 21.9 ppm; 1H NMR
(200 MHz, D2O) δ: 1.45 (dd, 1H, J = 10.0, 6.4, CH), 2.02−2.12 (m, 1H, CH), 2.53–2.59 (m, 1H,
CH), 3.61 (d, 1H, J = 10.1 Hz, NH), 7.09–7.35 (m, 5H C6H5); 13C NMR (50 MHz, D2O) 21.1, 21.7
(d, JC-P = 189.7 Hz), 27.4, 27.9, 57.8, 127.1, 128.5, 129.7, 136.8, 173.1; MS (CI) m/z = 272 (M +
H)+ HR MS(FAB) 271.0609 calcd for C11H14NO5P. Found: 271.0621.

ACCEPTED MANUSCRIPT
4.11.2. (2S,1’R,2’S,3’R)-2-(2’-Phosphono-3’-phenylcyclopropyl)glycine 24
o
A white powder m.p. 229−234 C. [α]D20 −31.8 (c 1.0, H2O); IR (KBr) 3130, 3030, 2980, 2120,
1640, 1590, 1520, 1440, 1230, cm-1; 31P NMR (80 MHz, D2O) δP = 21.8 ppm; 1H NMR (200 MHz,
D2O) δ: 1.45 (dd, 1H, J = 10.0, 3.7 Hz, CH), 1.96−2.10 (m, 1H, CH), 2.53–2.59 (m, 1H, CH), 3.59
(d, 1H, J = 10.0 Hz, NH), 7.08–7.25 (m, 5H, C6H5); 13C NMR (50 MHz, D2O) 19.2, 21.9, (d, JC-P
=
189.7 Hz), 27.5, 27.9, 57.8, 127.1, 128.5, 129.2, 135.8, 170.1; MS (CI) m/z = 272 (M + H)+. HR
MS(FAB) 271.0609 calcd for C11H14NO5P. Found: 271.0614.
Acknowledgment
Financial support by the Ministry of Education and Science (Grant No N N204257938) is gratefully
acknowledged
Notes and references
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1992, 227, 361−362.
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Ouazzani, F., Tetrahedron: Asymmmetry 1998, 9, 2329–2332.

ACCEPTED MANUSCRIPT
8.
9.
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P. J., Bioorg. Med. Chem. Lett. 2000, 10, 1241–1244.
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Asymmetry 2010, 21, 1486−1493.
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R., Bioorg. & Med. Chem. 2007, 15, 3161–3170.
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16. The relative configuration of cyclopropanes was established based on the coupling constants
3
3JHP between phosphorus and proton and JCP phosphorus and carbonyl carbon atom in the
corresponding 1H and 13C NMR spectra
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19. Midura, W. H.; Mikołajczyk, M., Tetrahedron Lett. 2002, 43, 3061–3065.
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