Towards convenient precursors for α-phosphonylated aziridinium ions

Article abstract of DOI:10.1080/10426500902719867

Mixtures of the respective 2-(N,N-dibenzylamino)-1-chloro- and 1-(N,N-dibenzylamino)-2-chlorophosphonates were obtained after mesylation of dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-hydroxy-3-methylbutylphosphonate and diethyl (1R,2S)-2-(N,N-dibenzylamino)-1-hydroxy-3-phenylpropylphosphonate with mesyl chloride in the presence of tetraethylammonium chloride. These mixtures are considered as useful precursors to-phosphonylated aziridinium ions.

Full text of DOI:10.1080/10426500902719867

This article was downloaded by: [Heriot-Watt University]
On: 03 January 2015, At: 18:08
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Towards Convenient Precursors
for α -Phosphonylated
Aziridinium Ions
Dorota G. Piotrowska a & Andrzej E. Wróblewski a
a Bioorganic Chemistry Laboratory, Faculty of
Pharmacy , Medical University of Łódź , Łódź,
Poland
Published online: 26 Mar 2009.
To cite this article: Dorota G. Piotrowska & Andrzej E. Wróblewski (2009) Towards
Convenient Precursors for α -Phosphonylated Aziridinium Ions, Phosphorus, Sulfur, and
Silicon and the Related Elements, 184:4, 998-1016, DOI: 10.1080/10426500902719867
To link to this article: http://dx.doi.org/10.1080/10426500902719867
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.

This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 184:998–1016, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902719867
Towards Convenient Precursors for α-Phosphonylated
Aziridinium Ions
´
Dorota G. Piotrowska and Andrzej E. Wroblewski
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical
University of Lꢀ o´dz´, Lꢀ o´dz´, Poland
Mixtures of the respective 2-(N,N-dibenzylamino)-1-chloro- and 1-(N,N-dibenzy-
lamino)-2-chlorophosphonates were obtained after mesylation of dimethyl (1R,2S)-
2-(N,N-dibenzylamino)-1-hydroxy-3-methylbutylphosphonate and diethyl (1R,2S)-
2-(N,N-dibenzylamino)-1-hydroxy-3-phenylpropylphosphonate with mesyl chloride
in the presence of tetraethylammonium chloride. These mixtures are considered as
useful precursors to α-phosphonylated aziridinium ions.
Keywords 2-Amino-1-hydroxyphosphonates; aziridinium ions; 1-chlorophosphonates;
2-chlorophosphonates; regioselectivity
INTRODUCTION
Synthetic organic chemistry involving aziridinium ions has re-
mained an active field of research for decades.1 Recently, we
have demonstrated that the transformation of the readily
available dimethyl (1R*,2S*)-2-(N,N-dibenzylamino)-1-hydroxy-2-
phenylethylphosphonate2 (1R*,2S*)-1 into 2-substituted dimethyl
(1S*,2R*)-1-(N,N-dibenzylamino)-2-phenylethylphosphonates
(1S*,
2R*)-3 could be accomplished in good yields and also occurred via
aziridinium ion 2 (Scheme 1).3 It would be interesting to investigate the
scope of this reaction. In this article, we report on the synthesis of 1-O-
mesylates of the 2-(N,N-dibenzylamino)-1-hydroxyethylphosphonates
4 (R = H, i-Pr, Bn) and on their reaction with tetraethylammonium
Received 28 December 2007; accepted 6 February 2008.
Dedicated to Professor Marian Mikolꢀajczyk from the CBMiM PAN in Lꢀ o´dz´, Poland,
on the occasion of his 70th birthday.
We thank the Medical University of Lꢀ o´dz´ for financial support under internal grant
503-3014-1 and Mrs. Jolanta Plꢀocka for excellent technical assistance.
Address correspondence to Dorota G. Piotrowska, Bioorganic Chemistry Laboratory,
Faculty of Pharmacy, Medical University of Lꢀ o´dz´, Muszyn´skiego 1, 90-151 Lꢀ o´dz´, Poland.
E-mail: dorota@ich.pharm.am.lodz.pl
998

Precursors of α-Phosphonylated Aziridinium Ions
999
SCHEME 1
chloride in order to prepare the corresponding β-chloroamines 5 and/or
6 as a convenient reservoir1p of α-phosphonylated aziridinium ions 7
(Scheme 2).
SCHEME 2
RESULTS AND DISCUSSION
Standard benzylation of 2-aminoethanol gave N,N-dibenzyla-
minoethanol 84 in 79% yield after chromatographic purification
(Scheme 3). This compound was subjected to Swern oxidation to
SCHEME 3

1000
D. G. Piotrowska and A. E. Wro´blewski
provide N,N-dibenzylaminoacetaldehyde 9,5 which was immediately
reacted with dimethyl or diethyl phosphites in the presence of cat-
alytic amounts of triethylamine to afford racemic dimethyl or diethyl 2-
(N,N-dibenzylamino)-1-hydroxyethylphosphonates 10a or 10b in 79%
and 74% yield, respectively. When phosphonate 10a was treated with
mesyl chloride at 0◦C, the 1-O-mesylate 11a was formed quantita-
tively. Inspection of the 1H and 31P NMR spectra of the crude 11a
proved that it was pure enough to be used in the next step. Addi-
tion of tetraethylammonium chloride to the dichloromethane solution
of crude 11a triggered transformation of the 1-O-mesylate 11a into
dimethyl 1-(N,N-dibenzylamino)-2-chloroethylphosphonate 12a. Moni-
toring of this reaction by 31P NMR spectroscopy showed a new signal
at 26.5 ppm formed at the expense of the resonance at 20.2 ppm, which
completely disappeared after 10 days at room temperature. The crude
2-chlorophosphonate 12a was slightly (less than 10%) contaminated
by an unidentified impurity (δ31P = 22.3 ppm). After chromatographic
purification, phosphonate 12a was separated in 22% yield.
When the 1-O-mesylate 11a was treated with benzylamine at 60◦C
for 7 h, significant demethylation of the phosphonate residue occurred,
as indicated by the appearance of 31P NMR signals at 19.8 and 18.7
ppm in the spectrum of the crude product. However, the presence of the
31P NMR resonance at 30.0 ppm, showing the formation of the desired
dimethyl 1-(N,N-dibenzylamino)-2-(N-benzylamino)ethylphosphonate,
encouraged us to prepare O,O-diethyl ester 10b. Indeed, when 1-
O-mesylate 11b was reacted with benzylamine at 70–75◦C for 20
h, diethyl 1-(N,N-dibenzylamino)-2-(N-benzylamino)ethylphosphonate
13b (δ31P = 27.1 ppm) was produced together with several im-
purities, but the formation of dealkylation products was not ob-
served. Chromatographic purification allowed us to obtain 13b in 30%
yield.
Phosphonylation of N,N-dibenzyl-L-valinal 146 with lithium O,O-
dimethyl phosphonate at –70◦C proceeded in a highly stereos-
elective manner to produce almost exclusively dimethyl (1R,2S)-
2-(N,N-dibenzylamino)-1-hydroxy-3-methylbutylphosphonate (1R,2S)-
15a (δ31P = 26.9 ppm) (Scheme 4). Another signal at 26.4 ppm in the
31P NMR spectrum of the crude product (ca. 2%) could be assigned to
(1S,2S)-15b, but due to the low amount, this compound was not sepa-
rated and characterized. The absolute configuration at C1 of the ma-
jor diastereoisomer was deduced from the known stereochemical out-
come of the nucleophilic additions to 2-(N,N-dibenzylamino)aldehydes.7
It was further supported by our studies on phosphonylation of N,N-
dibenzyl-L-phenylglycinal.3

Precursors of α-Phosphonylated Aziridinium Ions
1001
SCHEME 4
Treatment of phosphonate (1R,2S)-15a with mesyl chloride in
the presence of triethylamine and tetraethylammonium chloride at
room temperature for 24 h led to the formation of (1S,2R)-1-(N,N-
dibenzylamino)-2-chloro-3-methylbutylphosphonate (1S,2R)-16 and
(1S,2S)-2-(N,N-dibenzylamino)-1-chloro-3-methylbutylphosphonate
(1S,2S)-17 in a 90:10 ratio (Scheme 5), which did not change when the
reaction time was extended. Unfortunately, this mixture could not be
separated, giving fractions enriched in (1S,2S)-17, at best, up to 20%.
SCHEME 5
Triethylamine-catalyzed phosphonylation of N,N-dibenzyl-L-
phenylalaninal 187 with diethyl phosphite (Scheme 6) gave a
83:17 mixture of the known8 diethyl (1R,2S)- and (1S,2S)-2-(N,N-
dibenzylamino)-1-hydroxy-3-phenylpropylphosphonates (1R,2S)-19a
(δ31P = 25.1 ppm) and (1S,2S)-19b (δ31P = 24.5 ppm). Diastereos-
electivity of the triethylamine-catalyzed addition is slightly higher
than that observed earlier for the phosphonylation of 18 with tert-
butyldimethylsilyl diethyl phosphite (74:26).8 The major phosphonate
(1R,2S)-19a was isolated by silica gel chromatography and finally
purified by crystallization.
SCHEME 6

1002
D. G. Piotrowska and A. E. Wro´blewski
When (1R,2S)-19a was treated with mesyl chloride followed
by tetraethylammonium chloride as described for (1R,2S)-15a, a
50:50 equilibrium mixture of diethyl (1S,2R)-1-(N,N-dibenzylamino)-
2-chloro-3-phenylpropylphosphonate (1S,2R)-20 and diethyl (1S,2S)-2-
(N,N-dibenzylamino)-1-chloro-3-phenylpropylphosphonate (1S,2S)-21
was obtained (Scheme 7). Unfortunately, all attempts to separate the
regioisomeric phosphonates (1S,2R)-20 and (1S,2S)-21 on a silica gel
column failed despite trying several solvent mixtures as eluents.
SCHEME 7
Alternatively, phosphonates (1S,2R)-20 and (1S,2S)-21 were formed
(also in a 50:50 ratio) from diethyl (1S,2R)-1-(N,N-dibenzylamino)-2-
mesyloxy-3-phenylpropylphosphonate (1S,2R)-23 after treatment with
tetraethylammonium chloride (Scheme 7). We found that a chlo-
roform solution containing ca. 95% of the 2-mesyloxyphosphonate
(1S,2R)-23 (δ31P = 23.5 ppm) was obtained when phosphonate (1R,2S)-
19a was subjected to mesylation with mesyl chloride in toluene at
0◦C, ammonium salts were quickly washed out with cold water,
and the resulting mixture was left at room temperature for 48 h.
Undoubtedly, the 1-mesyloxyphosphonate (1R,2S)-22 was produced
first, and it was later transformed into the 2-mesyloxyphosphonate
(1S,2R)-23 in
a
similar manner as described earlier.3 How-
ever, after chromatographic purification of a 50:50 mixture of

Precursors of α-Phosphonylated Aziridinium Ions
1003
chlorophosphonates (1S,2R)-20 and (1S,2S)-21 prepared from (1S,2R)-
23, it appeared that they were contaminated with two other phospho-
nates, namely the starting 1-hydroxyphosphonate (1R,2S)-19a (δ31P
= 25.1 ppm) (ca. 2%) and the 2-hydroxyphosphonate (1S,2R)-24 (δ31P
= 29.7 ppm) (ca. 5%). Moisture present in tetraethylammonium chlo-
ride is probably the most likely cause of their formation. To prove the
structure of (1S,2R)-24, we returned to our previous observation of the
functional group transposition.3 Based on this experience, the crude 2-
mesyloxyphosphonate (1S,2R)-23 was left on silica gel for 48 h. Indeed,
the 2-hydroxyphosphonate (1S,2R)-24 was the major product of the re-
action mixture, which in addition contained the 1-hydroxyphosphonate
(1R,2S)-19a, minute quantities of both chlorophosphonates (1S,2R)-20
and (1S,2S)-21, and traces of an unidentified phosphonate (δ31P = 28.4
ppm). After careful examination of the 1H and 31P NMR spectra of the
crude (1S,2R)-23, it became apparent that chlorophosphonates (1S,2R)-
20 and (1S,2S)-21 were formed even during mesylation with mesyl
chloride in toluene at 0◦C.
In structural studies of all new compounds, comparisons of
several 1H and 13C NMR spectroscopic features were employed.
Transformations of 2-(N,N-dibenzylamino)phosphonates into 1-(N,N-
dibenzylamino)phosphonates resulted in significant upfield shifts of
HCP and CP, because the nitrogen atom is less electronegative
than the oxygen atom (OH, OMs) attached to C1 in the start-
ing materials. Thus, HCP in 1-(N,N-dibenzylamino)phosphonates
12a, 13b, (1S,2R)-16, (1S,2R)-20, (1S,2R)-23, and (1S,2R)-24 res-
onated at 3.12–3.42 ppm, while the signals of the same proton
in 2-(N,N-dibenzylamino)phosphonates 10a, 10b, (1R,2S)-15a, and
(1R,2S)-19a appeared between 3.98–4.32 ppm. Other NMR param-
eters of 1-(N,N-dibenzylamino)phosphonates and the starting ma-
terials useful in structural assignments include the CP 13C NMR
shifts (55–61 ppm vs. 64–66 ppm) and one-bond CP coupling con-
stants (131–147 Hz vs. 154–167 Hz). The presence of three-bond
PhCH2NCP coupling constants (1.5–4.8 Hz) also supported the for-
mation of 1-(N,N-dibenzylamino)phosphonates. For the identification
of 1-chlorophosphonates (1S,2S)-17 and (1S,2S)-21, CP 13C NMR shifts
were extremely diagnostic, since they appeared at around 51 ppm,9,10
far upfield compared to those of the respective 1-hydroxyphosphonates
(1R,2S)-15a and (1R,2S)-19a (around 66 ppm).
Configurational assignments in 1-chlorophosphonates (1S,2S)-17
and (1S,2S)-21, 2-chlorophosphonates (1S,2R)-16 and (1S,2R)-20, as
well as in phosphonates (1S,2R)-23 and (1S,2R)-24 are based on the
stereochemistry of their formation via intermediate aziridinium ions
25 (Scheme 8). The ring closure in 1-mesyloxyphosphonates (1R,2S)-26

1004
D. G. Piotrowska and A. E. Wro´blewski
takes place with inversion of configuration at C1 and leads to the ions
25. The nucleophiles (Cl¯ , water, MsO¯ ) can attack C1 to give 2-(N,N-
dibenzylamino)phosphonates 27 [in this article: (1S,2S)-17, (1S,2S)-21,
and (1R,2S)-19a] or C2 to afford 1-(N,N-dibenzylamino)phosphonates
28, exemplified here by (1S,2R)-16, (1S,2R)-20, (1S,2R)-23, and (1S,2R)-
24. These openings also occur with the inversion of configuration.1
SCHEME 8
Additional support for these conclusions comes from the conforma-
tional analysis of (1S,2R)-16. This acyclic phosphonate exists in a pre-
ferred conformation shown in Scheme 9, in which HC1 and HC2 are
3
antiperiplanar (3JH1H2 = 9.9 Hz and JPH2 = 8.1 Hz),11,12 HC2 and
HC3 are gauche oriented (3JH2H3 = 2.7 Hz),11 and HC3 and the phos-
phorus atom are situated in plane (4JPH3 = 1.5 Hz, W-coupling).13 Al-
3
though in this conformer, JPC would be expected to exceed 10 Hz to
conform with the antiperiplanar arrangement of CCCP atoms,14 the
lower value of the observed coupling (7.5 Hz) probably arises from the
influence of two electron-withdrawing substituents present along the
coupling pathway.15
SCHEME 9

Precursors of α-Phosphonylated Aziridinium Ions
1005
CONCLUSIONS
Treatment of 2-(N,N-dibenzylamino)-1-hydroxyphosphonates 4 (R = i-
Pr, Bn) with mesyl chloride followed by tetraethylammonium chloride
led to the formation of mixtures of 1-(N,N-dibenzylamino)-2-chloro- and
2-(N,N-dibenzylamino)-1-chlorophosphonates 5 and 6, while from 2-
(N,N-dibenzylamino)-1-hydroxyethylphosphonate 4 (R = H), 1-(N,N-
dibenzylamino)-2-chloroethylphosphonate 5 (R = H) was produced
(Scheme 2). Both carbon sites in the intermediate aziridinium ions 7 (R
= i-Pr, Bn) are attacked by chloride. Alternatively, in the aziridinium
ion 7 (R = H), less hindered C2 is preferrebly attacked. Despite the lack
of regioselectivity mixtures of 1-(N,N-dibenzylamino)-2-chloro- and 2-
(N,N-dibenzylamino)-1-chlorophosphonates, 5 and 6 (R = i-Pr, Bn) will
be converted to the same aziridinium ions before reacting with stronger
nucleophiles. Thus, the immediate precursors to several aziridinium
phosphonates became easily available.
EXPERIMENTAL
1H NMR spectra were recorded with a Varian Mercury-300 spectrom-
eter; chemical shifts δ in ppm are given with respect to TMS; coupling
constants J are given in Hz. 13C and 31P NMR spectra were recorded
with a Varian Mercury-300 instrument at 75.5 and 121.5 MHz, respec-
tively. IR spectral data were measured with an Infinity MI-60 FT-IR
spectrophotometer. Melting points were determined on a Boetius ap-
paratus and are uncorrected. Elemental analyses were performed by
the Microanalytical Laboratory of this faculty with a Perkin Elmer
PE 2400 CHNS analyzer. Polarimetric measurements were conducted
with a Perkin Elmer 241 MC apparatus. The following absorbents were
used: for column chromatography—Merck silica gel 60 (70−230 mesh);
for analytical TLC—Merck TLC plastic sheets silica gel 60 F254
.
N,N-Dibenzylaminoethanol 8
To a solution of 2-aminoethanol (6.11 g, 100 mmol) in acetonitrile (100
mL) containing potassium carbonate (27.7 g, 200 mmol) and tetra-
butylammonium iodide (3.7 g, 10 mmol), benzyl bromide (23.8 mL,
200 mmol) was added dropwise at room temperature, and the suspen-
sion was stirred for 20 h. After the addition of chloroform (15 mL),
the solid was filtered off and washed with chloroform (2 × 10 mL).
All volatiles were carefully evaporated, and the crude product (19.2
g) was subjected to chromatography on a silica gel column with ethyl
acetate:hexanes (4:1, v/v) to give N,N-dibenzylaminoethanol 8 (26.26 g,

1006
D. G. Piotrowska and A. E. Wro´blewski
79%) as a colorless oil. 1H NMR (CDCl3): δ = 7.36–7.20 (m, 10H), 3.63
(s, 4H, PhCH2N), 3.58 (t, J = 5.4 Hz, 2H, H2C1), 2.66 (t, J = 5.4 Hz,
2H, H2C2), 2.60 (br s, 1H, HO).
N,N-Dibenzylaminoacetaldehyde 9
To
a solution of oxalyl chloride (0.497 mL, 5.82 mmol) in
dichloromethane (15 mL) cooled to –70◦C, a solution of dimethyl
sulfoxide (0.895 mL, 12.6 mmol) in dichloromethane (10 mL)
was added dropwise. After stirring for 15 min at this tempera-
ture, N,N-dibenzylaminoethanol 8 (1.20 g, 4.85 mmol) dissolved in
dichloromethane (15 mL) was slowly transferred via cannula to the
Swern reagent, and the reaction mixture was stirred for another 30
min. Then triethylamine (2.03 mL, 14.5 mmol) was added dropwise,
and the mixture was stirred at –70◦C for 1.5 h. After the addition
of saturated sodium bicarbonate (17 mL), the solution was allowed
to warm up to room temperature. The phases were separated, and
the aqueous layer was extracted with dichloromethane (20 mL). The
combined organic extracts were washed with brine (10 mL) and dried
over MgSO4. All volatiles were evaporated at room temperature to af-
ford the crude N,N-dibenzylaminoacetaldehyde 9 (1.16 g, 100%) as a
1
colorless oil, which was immediately used in the next step. H NMR
(CDCl3) δ = 9.53 (t, J = 2.0 Hz, 1H, CHO), 7.40–7.23 (m, 10H), 3.70
(s, 4H, PhCH2N), 3.19 (d, J = 2.0 Hz, 2H, H2CCHO).
Dimethyl 2-(N,N-Dibenzylamino)-1-hydroxyethylphosphonate
10a
To a solution of the crude aldehyde 9 prepared as described above
(4.85 mmol) and dimethyl phosphite (0.445 mL, 4.85 mmol) in
dichloromethane (2 mL), triethylamine (0.068 mL, 0.049 mmol) was
added. The reaction mixture was stirred at room temperature for 8 h,
diluted with dichloromethane (10 mL), and washed with water (10 mL).
The aqueous phase was extracted with dichloromethane (2 × 10 mL).
The organic phases were collected, washed with water (2 × 15 mL),
and dried over MgSO4. All volatiles were removed in vacuo, and the
crude phosphonate was chromatographed on a silica gel column with
chloroform:methanol (100:1, v/v) to give phosphonate 10a (1.393 g,
79%) as a colorless oil. IR (film) ν = 3306, 3028, 2954, 1495, 1453,
1237, 1033 cm–1. 1H NMR (CDCl3) δ = 7.37–7.18 (m, 10H), 3.98 (ddd,
3JH2aH1 = 10.8 Hz, 3JPH1 = 5.7 Hz, 3JH2bH1 = 3.6 Hz, 1H, HCP), 3.83 (d,
J = 13.5 Hz, 2H, PhHCHN), 3.72 (d, J = 10.2 Hz, 3H, CH3OPOCH3),

Precursors of α-Phosphonylated Aziridinium Ions
1007
3.67 (d, J = 10.2 Hz, 3H, CH3OPOCH3), 3.51 (d, J = 13.5 Hz, 2H,
3
3
PhHCHN), 2.95 (ddAB, JAB = 13.2 Hz, JH2aH1 = 10.8 Hz, JPH
=
3
10.2 Hz, 1H, HaCHCP), 2.84 (ddAB, JAB = 13.2 Hz, JH2bH1 = 3.6
Hz, JPH = 2.4 Hz, 1H, HCHbCP). 13C NMR (CDCl3): δ = 137.9 (brs),
3
1
129.2, 128.6, 127.6, 63.8 (d, JPC = 167.5 Hz, C1), 58.3 (CH2Ph), 53.8
(d, J = 3.5 Hz, C2), 53.7 (d, J = 6.6 Hz, CH3OPOCH3), 53.2 (d, J =
6.6 Hz, CH3OPOCH3). 31P NMR (CDCl3): δ = 26.2. Anal. Calcd for
C18H24NO4P: C, 61.88; H, 6.92; N, 4.01. Found: C, 61.70; H, 7.14; N,
4.06%.
Diethyl 2-(N,N-Dibenzylamino)-1-hydroxyethylphosphonate
10b
As described above, the crude product obtained from aldehyde 9 (14.0
mmol) and diethyl phosphite (1.79 mL, 14.0 mmol) in the presence of
triethylamine (0.15 mL, 1.4 mmol) was purified on a silica gel column
with chloroform:methanol (50:1, v/v). The appropriate fractions were
collected to afford phosphonate 10b (3.95 g, 74%) as a colorless oil. IR
(film) ν = 3307, 2982, 2928, 1602, 1495, 1453, 1231, 1052, 1027, 968
–1
cm
.
1H NMR (CDCl3): δ = 7.36–7.21 (m, 10H), 4.15–3.92 (m, 5H,
CH2OPOCH2 and HCP), 3.84 (d, J = 13.2 Hz, 2H, PhHCHN), 3.47 (d,
J = 13.2 Hz, 2H, PhHCHN), 2.92 (ddAB, JAB = 13.2 Hz, J = 10.8 Hz, J =
10.2 Hz, 1H, HaCHCP), 2.80 (ddAB, JAB = 13.2 Hz, J = 3.6 Hz, J = 2.4
Hz, 1H, HCHbCP), 1.24 (t, J = 7.2 Hz, 3H, CH3CH2OPOCH2CH3), 1.17
(t, J = 7.2 Hz, 3H, CH3CH2OPOCH2CH3). 13C NMR (CDCl3): δ = 137.8
(brs), 129.0, 128.4, 127.3, 63.7 (d, J = 167.4 Hz, C1), 62.8 (d, J = 7.2 Hz,
CH2OPOCH2), 62.4 (d, J = 7.2 Hz, CH2OPOCH2), 58.0 (CH2Ph), 53.4
(d, J = 3.7 Hz, C2), 16.4 (d, J = 5.7 Hz, CH3CH2OPOCH2CH3), 16.3 (d,
J = 5.7 Hz, CH3CH2OPOCH2CH3). 31P NMR (CDCl3): δ = 23.1. Anal.
Calcd for C20H28NO4P: C, 63.65; H, 7.48; N, 3.71. Found: C, 63.50; H,
7.27; N, 3.63%.
Dimethyl 2-(N,N-Dibenzylamino)-1-
mesyloxyethylphosphonate 11a
To a solution of the hydroxyphosphonate 10a (0.21 g, 0.59 mmol) con-
taining triethylamine (0.245 mL, 1.77 mol) in dichloromethane (1.5
mL) cooled to 0◦C, mesyl chloride (0.055 mL, 0.71 mmol) was added
dropwise. The reaction mixture was stirred at this temperature for
30 min, allowed to warm to 20◦C over 20 min, and finally it was
diluted with dichloromethane (10 mL). The solution was washed
with cold water (10 mL), and the aqueous phase was extracted with

1008
D. G. Piotrowska and A. E. Wro´blewski
dichloromethane (20 mL). The organic extracts were washed with
cold water (15 mL), dried over MgSO4, and all volatiles were re-
moved in vacuo at room temperature to leave crude 1-O-mesylate 11a
1
(0.24 g, 100%) as a colorless oil. H NMR (CDCl3): δ = 7.42–7.20 (m,
2
3
3
10H), 5.09 (ddd, JPH = 10.2 Hz, JHH = 9.6 Hz, JHH = 2.4 Hz, 1H,
HCP), 3.85 (d, J = 13.5 Hz, 2H, PhHCHN), 3.76 (d, J = 10.5 Hz, 3H,
CH3OPOCH3), 3.73 (d, J = 10.5 Hz, 3H, CH3OPOCH3), 3.50 (d, J = 13.5
Hz, 2H, PhHCHN), 3.15 (s, 3H, CH3SO2), 3.06 (ddAB, JAB = 15.0 Hz,
3
3JHH = 9.6 Hz, JPH = 6.0 Hz, 1H, HaCHCP),) 2.89 (ddAB, JAB = 15.0
3
3
Hz, JPH = 4.2 Hz, JHH = 2.4 Hz, 1H, HCHbCP). 31P NMR (CDCl3):
δ = 20.2.
Dimethyl 1-(N,N-Dibenzylamino)-2-chloroethylphosphonate
12a
A solution of crude 1-O-mesylate 11a (0.61 g, 1.4 mmol) in
dichloromethane (5 mL) containing tetraethylammonium chloride (0.20
g, 1.2 mmol) was stirred at room temperature for 10 d. The reaction
mixture was diluted with dichloromethane (10 mL), washed with water
(10 mL), and the aqueous phase was extracted with dichloromethane
(20 mL). The organic extracts were washed with water (15 mL) and
dried over MgSO4. The oily residue obtained after evaporation of the
solvent (0.43 g) was twice chromatographed on silica gel with ethyl
acetate:hexane (2:1, v/v) to give phosphonate 12a (0.114 g, 22%) as col-
–1
orless oil. IR (film) ν = 2953, 2924, 2852, 1495, 1455, 1249, 1038 cm
.
1H NMR (CDCl3): δ = 7.45–7.16 (m, 10H), 3.95 (s, 4H, PhCH2N), 3.87
3
3
(ddAB, JAB = 12.0 Hz, JHH = 9.6 Hz, JPH = 5.4 Hz, 1H, HaCHCP),
3
3.82 (tAB, JAB = 12.0 Hz, JHH
=
3JPH = 4.2 Hz, 1H, HCHbCP),
3.73 (d, J = 10.5 Hz, 3H, CH3OPOCH3), 3.71 (d, J = 10.5 Hz, 3H,
2
3
3
CH3OPOCH3), 3.42 (ddd, JPH = 19.5 Hz, JHH = 9.6 Hz, JHH = 4.2
Hz, 1H, HCP). 13C NMR (CDCl3): δ = 138.9 (br s), 129.4, 129.1, 128.3,
127.3, 57.4 (d, 1JPC = 136.6 Hz, C1), 55.1 (d, J = 3.0 Hz, PhCH2N), 52.9
(d, J = 7.5 Hz, CH3OPOCH3), 52.3 (d, J = 7.5 Hz, CH3OPOCH3), 41.8
(d, JPC = 21.9 Hz, C2). 31P NMR (CDCl3): δ = 26.5. Anal. Calcd for
2
C18H23ClNO3P: C, 58.78; H, 6.30; N, 3.81. Found: C, 58.68; H, 6.02; N,
3.76%.
Diethyl 1-(N,N-Dibenzylamino)-2-
(N-benzylamino)ethylphosphonate 13b
Crude diethyl 2-(N,N-dibenzylamino)-1-mesyloxyethylphosphonate
11b was obtained as described above from phosphonate 10b (0.329 g,

Precursors of α-Phosphonylated Aziridinium Ions
1009
0.855 mmol), triethylamine (0.356 mL, 2.56 mmol), and mesyl chlo-
ride (0.100 mL, 1.28 mmol). 1H NMR (CDCl3): δ = 7.40–7.19 (m,
10H), 5.08 (dt, J = 9.6 Hz, J = 2.4 Hz, 1H, HCP), 4.20–4.00 (m, 4H,
CH2OPOCH2), 3.86 (d, J = 13.5 Hz, 2H, PhHCHN), 3.51 (d, J = 13.5
Hz, 2H, PhHCHN), 3.17 (s, 3H, CH3SO2), 3.05 (ddAB, JAB = 15.0 Hz,
3
3JHH = 9.6 Hz, JPH = 5.7 Hz, 1H, HaCHCP), 2.88 (tAB, JAB = 15.0
3
Hz, JHH
=
3JPH = 2.4 Hz, 1H, HCHbCP), 1.27 (t, J = 7.2 Hz, 3H,
CH3CH2OPOCH2CH3), 1.25 (t, J = 7.2 Hz, 3H, CH3CH2OPOCH2CH3).
31P NMR (CDCl3): δ = 17.7.
A solution of the crude 11b in toluene (2 mL) containing benzylamine
(0.093 mL, 0.86 mmol) and triethylamine (0.12 mL, 0.86 mmol) was
kept at 70–75◦C for 20 h. All volatiles were evaporated and the residue
was twice chromatographed on silica gel with ethyl acetate:hexane
(2:1, v/v) to give phosphonate 13b (0.136 g, 30%) as a colorless oil. IR
(film): ν = 3472, 3062, 3028, 2981, 2927, 2907, 2851, 1603, 1495, 1453,
1242, 1051, 1027 cm–1. 1H NMR (CDCl3): δ = 7.35–7.15 (m, 15H), 4.20–
4.05 (m, 4H, CH2OPOCH2), 3.93 (AB, JAB = 13.2 Hz, 2H, PhHCHN),
4
3.88 (dAB, JAB = 13.2 Hz, JPH = 3.9 Hz, 2H, PhHCHN), 3.49 (d, J =
13.5 Hz, 1H, PhHCHN), 3.34 (d, J = 13.5 Hz, 1H, PhHCHN), 3.30
2
3
3
(ddd, JPH = 16.5 Hz, JHH = 9.9 Hz, JHH = 3.9 Hz, 1H, HCP), 3.02
3
3
(ddAB, JAB = 12.9 Hz, JHH = 9.9 Hz, JPH = 6.3 Hz, 1H, HaCHCP),
3
2.81 (tAB, JAB = 12.9 Hz, JHH
=
3JPH = 3.9 Hz, HCHbCP), 1.33
(t, J = 7.2 Hz, 3H, CH3CH2OPOCH2CH3), 1.32 (t, J = 7.2 Hz, 3H,
CH3CH2OPOCH2CH3). 13C NMR (CDCl3): δ = 139.8 (br s), 139.6, 129.3,
128.5, 128.2, 127.3, 127.0, 61.8 (d, J = 6.9 Hz, CH2OPOCH2), 61.5 (d,
J = 6.9 Hz, CH2OPOCH2), 55.3 (d, J = 2.3 Hz, PhCH2N), 55.1 (d, J =
131.7 Hz, C1), 52.2 (PhCH2N), 46.4 (d, J = 11.2 Hz, C2), 17.0 (d, J = 6.0
Hz, CH3CH2OPOCH2CH3), 16.9 (d, J = 6.0 Hz, CH3CH2OPOCH2CH3).
31P NMR (CDCl3): δ = 27.1. Anal. Calcd for C27H35N2O3P: C, 69.51; H,
7.56; N, 6.00. Found: C, 69.72; H, 7.38; N, 5.83%.
Dimethyl (1R,2S)-2-(N,N-Dibenzylamino)-1-hydroxy-3-methyl
butylphosphonate (1R,2S)-15a
To
a solution of oxalyl chloride (0.592 mL, 6.92 mmol) in
dichloromethane (10 mL) cooled to –70◦C, a solution of dimethyl sul-
foxide (1.06 mL, 15,0 mmol) in dichloromethane (5 mL) was added
dropwise. After stirring for 15 min at this temperature, N,N-dibenzyl-
L-valinol (1.64 g, 5.77 mmol) dissolved in dichloromethane (5 mL) was
slowly transferred via cannula to the Swern reagent and the reac-
tion mixture was stirred for another 40 min. Then triethylamine (2.41
mL, 17.3 mmol) was added dropwise and the mixture was stirred at

1010
D. G. Piotrowska and A. E. Wro´blewski
–70◦C for 30 min. A solution of lithium O,O-dimethyl phosphonate
[prepared from dimethyl phosphite (0.635 mL, 6.92 mmol), diisopropy-
lamine (0.970 mL, 6.92 mmol), and 1.6 M BuLi (4.33 mL, 6.92 mmol)]
in THF (10 mL) cooled to –70◦C was slowly transferred via cannula
into the solution of the crude aldehyde at –70◦C. After stirring for
1.5 h at this temperature, saturated ammonium chloride (14 mL) was
added, and the reaction mixture was allowed to warm up to room tem-
perature. The phases were separated, and the aqueous layer was ex-
tracted with dichloromethane (3 × 10 mL). The combined organic ex-
tracts were washed with brine (10 mL) and dried over MgSO4. All
volatiles were evaporated at room temperature to afford a crude phos-
phonate 15a, which was subjected to chromatography on a silica gel
column with chloroform:methanol (50:1, v/v). The appropriate fractions
were combined and crystallized from a chloroform/hexane mixture to
give phosphonate (1R,2S)-15a (1.13 g, 50%) as an amorphous solid. Mp
119.5–120.8◦C. [α]2D0 = –36.2 (c 1.5, AcOEt). IR (KBr): ν = 3277, 2953,
1454, 1218, 1057, 1035, 747, 700 cm–1. H NMR (CDCl3): δ = 7.40–
1
2
7.25 (m, 10H), 4.10 (dd, JPH = 9.6 Hz, JHH = 4.2 Hz, 1H, HCP), 3.88
(d, J = 13.3 Hz, 2H, PhHCHN), 3.78 (d, J = 13.3 Hz, 2H, PhHCHN),
3.71 (d, J = 10.5 Hz, 3H, CH3OPOCH3), 3.70 (d, J = 10.5 Hz, 3H,
CH3OPOCH3), 2.82 (ddd, 3JPH = 27.3 Hz, JHH = 9.6 Hz, 3JHH = 4.2 Hz,
3
3
1H, HCCP), 2.45 (dsp, JHH = 9.6 Hz, JHH = 6.6 Hz, 1H, HCCCP),
3
3
1.23 (d, JHH = 6.6 Hz, 3H, CH3CCH3), 0.98 (d, JHH = 6.6 Hz, 3H,
CH3CCH3). 13C NMR (CDCl3): δ = 139.6, 129.5, 128.4, 127.2, 66.4 (d,
1JPC = 154.6 Hz, C1), 65.7 (d, J = 4.0 Hz, C2) 55.3 (PhCH2N), 53.2
(d, J = 7.4 Hz, CH3OPOCH3), 53.1 (d, J = 7.4 Hz, CH3OPOCH3),
28.2 (C3), 22.9, 21.7. 31P NMR (CDCl3): δ = 26.9. Anal. Calcd for
C21H30NO4P: C, 64.44; H, 7.72; N, 3.58. Found: C, 64.22; H, 7.90;
N, 3.66%.
Dimethyl (1S,2R)-1-(N,N-Dibenzylamino)-2-chloro-3-methyl
butylphosphonate (1S,2R)-16 and Dimethyl (1S,2S)-2-(N,N-
Dibenzylamino)-1-chloro-3-methylbutylphosphonate
(1S,2S)-17
To a solution of phosphonate (1R,2S)-15a (0.100 g, 0.255 mmol) in
methylene chloride (2 mL) containing triethylamine (0.178 mL, 1.28
mmol) and powdered molecular sieves 4A (0.30 g) cooled to 0◦C, me-
syl chloride (0.060 mL, 0.77 mmol) was slowly injected followed by the
addition of tetraethylammonium chloride (0.085 g, 0.51 mmol). The
suspension was stirred at room temperature for 24 h. After filtration
through a layer of Celite, the solution was concentrated and subjected

Precursors of α-Phosphonylated Aziridinium Ions
1011
to chromatography on a silica gel column with chloroform:methanol
(100:1, v/v) to give several fractions containing various mixtures
(from 94:6 to 80:20) of dimethyl (1S,2R)-1-(N,N-dibenzylamino)-2-
chloro-3-methylbutylphosphonate (1S,2R)-16 and dimethyl (1S,2S)-
2-(N,N-dibenzylamino)-1-chloro-3-methylbutylphosphonate (1S,2S)-17
(total 0.075 g, 72%) as colorless oils. Anal. Calcd for C21H29ClNO3P:
C, 61.54; H, 7.13; N, 3.42. Found: C, 61.79; H, 7.06; N,
3.34%.
Dimethyl (1S,2R)-1-(N,N-Dibenzylamino)-2-chloro-3-methyl
butylphosphonate (1S,2R)-16
1H NMR (CDCl3): δ = 7.36–7.21 (m, 10H), 4.06 (ddd, JH2H1 = 9.9 Hz,
3JPH2 = 8.1 Hz, JH2H3 = 2.7 Hz, 1H, HCCP), 3.92 (AB, J = 13.5 Hz,
2H, PhCH2N), 3.88 (AB, J = 13.5 Hz, 2H, PhCH2N), 3.87 (d, J =
11.0 Hz, 3H, CH3OPOCH3), 3.84 (d, J = 11.0 Hz, 3H, CH3OPOCH3),
2
3.31 (dd, JPH1 = 15.6 Hz, JH1H2 = 9.9 Hz, 1H, HCP), 2.55 (spdd,
3
4
3JHH = 6.5 Hz, JH3H2 = 2.7 Hz, JPH3 = 1.5 Hz, 1H, HCCCP), 0.92
3
3
(d, JHH = 6.5 Hz, 3H, CH3CCH3), 0.26 (d, JHH = 6.5 Hz, 3H,
CH3CCH3). 13C NMR (CDCl3): δ = 138.9, 129.7, 128.5, 127.5, 66.1
1
(d, J = 5.5 Hz, C2), 59.9 (d, JPC = 137.5 Hz, C1), 55.8 (d, J = 1.5
Hz, PhCH2N), 52.6 (d, J = 7.5 Hz, CH3OPOCH3), 52.0 (d, J = 7.5 Hz,
CH3OPOCH3), 29.2 (d, J = 7.5 Hz, C3), 20.1, 15.1. 31P NMR (CDCl3):
δ = 30.7.
Dimethyl (1S,2S)-2-(N,N-Dibenzylamino)-1-chloro-3-methyl
butylphosphonate (1S,2S)-17
2
1H NMR (CDCl3): δ = 7.36–7.21 (m, 10H), 4.12 (dd, JPH1 = 9.6 Hz,
JH1H2 = 4.2 Hz, 1H, HCP), 3.89 (d, J = 13.5 Hz, 2H, PhHCHN), 3.78 (d,
J = 13.5 Hz, 2H, PhHCHN), 3.72 (d, J = 10.5 Hz, 3H, CH3OPOCH3),
3
3.70 (d, J = 10.5 Hz, 3H, CH3OPOCH3), 2.82 (ddd, JPH2 = 28.8 Hz,
3
3
JH2H3 = 10.5 Hz, JH2H1 = 4.2 Hz, 1H, HCCP), 2.46 (dsp, JH3H2
=
3
3
10.5 Hz, JHH = 6.5 Hz, 1H, HCCCP), 1.23 (d, JHH = 6.5 Hz, 3H,
CH3CCH3), 0.98 (d, 3JHH = 6.5 Hz, 3H, CH3CCH3). 13C NMR (CDCl3):
δ = 139.6, 129.5, 128.4, 127.3, 65.7 (d, J = 4.0 Hz, C2) 55.3 (PhCH2N),
53.2 (d, J = 7.5 Hz, CH3OPOCH3), 53.0 (d, J = 7.5 Hz, CH3OPOCH3),
51.5 (d, JPC = 150.9 Hz, C1), 28.3 (C3), 23.0, 21.8. 31P NMR (CDCl3):
1
δ = 27.4.

1012
D. G. Piotrowska and A. E. Wro´blewski
Diethyl (1R,2S)-and (1S,2S)-2-(N,N-Dibenzylamino)-1-hydroxy-
3-phenylpropyl-phosphonates (1R,2S)-19a and (1S,2S)-19b
A mixture of a crude (S)-N,N-dibenzylphenylalaninal 18 [obtained af-
ter Swern oxidation of (S)-N,N-dibenzylphenylalaninol (1.98 g, 5.97
mmol)], diethyl phosphite (0.769 mL, 5.97 mmol), and triethylamine
(0.083 mL, 0.060 mmol) was left at room temperature for 20 h. The
residue was chromatographed on a silica gel column with ethyl ac-
etate:hexane (2:1, v/v). The appropriate fractions of the less polar com-
pound were combined to give phosphonate (1S,2S)-19b (0.243 g, 9%) as
a colorless oil, which solidified at 5◦C.8 IR (KBr): ν = 3215, 2995, 2801,
1495, 1454, 1199, 1053, 1022, 978, 745, 701 cm–1. 1H NMR (CDCl3): δ =
7.45–7.36 (m, 4H), 7.35–7.29 (m, 1H), 7.29–7.19 (m, 6H), 7.10–7.00 (v
br s, 4H), 4.95 (br d, J = 18.3 Hz, 1H, HO), 4.22–4.00 (m, 2H, H2COP),
3.95–3.65 (m, 5H), 3.55–3.25 (m, 4H), 2.99 (dd, J = 14.7 Hz, J = 10.5
Hz, 1H, HCHbCCP), 1.28 (t, J = 6.9 Hz, 3H, CH3CH2OP), 1.09 (t, J = 6.9
Hz, 3H, POCH2CH3). 13C NMR (CDCl3): δ = 140.2, 138.2, 129.7, 129.4,
129.0, 128.8, 128.7, 128.5, 128.2, 127.5, 126.6, 66.7 (d, J = 167.2 Hz, C1),
63.2 (d, J = 7.5 Hz, CH2OPOCH2), 62.6 (d, J = 7.5 Hz, CH2OPOCH2),
59.8 (d, J = 4.0 Hz, C2), 53.6 (s, PhCH2N), 34.5 (s, C3), 16.7 (d, J = 5.7
Hz, CH3CH2OPOCH2CH3), 16.7 (d, J = 5.7 Hz, CH3CH2OPOCH2CH3).
31P NMR (CDCl3): δ = 24.5. Anal. Calcd for C27H34NO4P: C, 69.36; H,
7.33; N, 3.00. Found: C, 69.28; H, 7.08; N, 2.88%.
Further fractions (0.97 g, 36%) contained various mixtures of
diastereoisomeric phosphonates (1R,2S)-19a and (1S,2S)-19b. In the
final fractions, more polar phosphonate (1.49 g, 54%) was collected
and was crystallized from ethyl acetate to afford (1R,2S)-19a (0.79 g,
28%). IR (KBr): ν = 3299, 2982, 1454, 1217, 1057, 1026, 976, 745, 698
–1
cm
.
1H NMR (CDCl3): δ = 7.30–7.05 (m, 15H), 4.32 (ddd, JPH1
=
9.6 Hz, JH1HO = 7.2 Hz, JH1H2 = 2.1 Hz, 1H, HCP), 4.17–3.95 (m,
4H, CH2OPOCH2), 3.87 (d, J = 13.8 Hz, 2H, PhHCHN), 3.57 (d, J =
13.8 Hz, 2H, PhHCHN), 3.38 (dddd, 1H, JPH2 = 14.4 Hz, JH2H3b = 9.3
Hz, JH2H3a = 5.1 Hz, JH2H1 = 2.1 Hz, HCCP), 3.11 (dAB, JAB = 14.4
Hz, JH3aH2 = 5.1 Hz, 1H, PhHaCHCCP), 3.05 (dAB, JAB = 14.4 Hz,
JH3bH2 = 9.3 Hz, 1H, PhHCHbCCP), 2.96 (dd, JHOH1 = 7.2 Hz, JPOH
=
4.2 Hz, 1H, HO), 1.27 (t, J = 6.9 Hz, 3H, CH3CH2OPOCH2CH3), 1.24
(t, J = 6.9 Hz, 3H, CH3CH2OPOCH2CH3). 13C NMR (CDCl3): δ =
140.3, 139.6, 129.8, 128.1, 128.0, 126.8, 125.9, 66.3 (d, J = 153.8 Hz,
C1), 63.1 (d, J = 7.2 Hz, CH3CH2OPOCH2CH3), 62.6 (d, J = 7.2 Hz,
CH3CH2OPOCH2CH3), 59.9 (d, J = 6.0 Hz, C2), 54.5 (s, PhCH2N),
32.5 (s, C3), 16.8 (d, J = 5.5 Hz, CH3CH2OPOCH2CH3). 31P NMR
(CDCl3): δ = 25.1. Anal. Calcd for C27H34NO4P: C, 69.36; H, 7.33; N,
3.00. Found: C, 69.01; H, 7.23; N, 3.20%.

Precursors of α-Phosphonylated Aziridinium Ions
1013
Diethyl (1S,2R)-1-(N,N-Dibenzylamino)-2-chloro-3-phenyl
propylphosphonate (1S,2R)-20 and (1S,2S)-2-(N,N-Dibenzyl
amino)-1-chloro-3-phenylpropylphosphonate (1S,2S)-21
To a solution of phosphonate (1R,2S)-19a (0.050 g, 0.11 mmol) in
methylene chloride (1 mL) containing triethylamine (0.075 mL, 0.54
mmol) and powdered molecular sieves 4A (0.15 g) cooled to 0◦C, me-
syl chloride (0.025 mL, 0.32 mmol) was slowly injected followed by
the addition of tetraethylammonium chloride (0.035 g, 0.21 mmol).
The suspension was stirred at room temperature for 48 h. Af-
ter filtration through a layer of Celite, the solution was concen-
trated and subjected to chromatography on a silica gel column with
chloroform:methanol (100:1, v/v) to give several fractions contain-
ing 1:1 mixtures of diethyl (1S,2R)-1-(N,N-dibenzylamino)-2-chloro-
3-phenylpropylphosphonate (1S,2R)-20 and diethyl (1S,2S)-2-(N,N-
dibenzylamino)-1-chloro-3-phenylpropylphosphonate (1S,2S)-21 (total
0.037 g, 71%) as colorless oils. Anal. Calcd for C27H33ClNO3P: C, 66.73;
H, 6.84; N, 2.88. Found: C, 66.83; H, 6.66; N, 2.95%.
Diethyl (1S,2R)-1-(N,N-Dibenzylamino)-2-chloro-3-phenyl
propylphosphonate (1S,2R)-20
1H NMR (CDCl3): δ = 7.34–6.95 (m, 15H), 4.39 (dddd, 3JPH2 = 15.6 Hz,
JH2H3b = 9.3 Hz, JH2H3a = 6.0 Hz, JH2H1 = 5.4 Hz, 1H, HCCP), 4.27–
4.11 and 4.09–3.98 (m, 2H, CH2OPOCH2), 4.14 (AB, J = 13.5 Hz, 2H,
2
PhCH2N), 3.82 (AB, J = 13.5 Hz, 2H, PhCH2N), 3.71 (dd, JH3aH3b
=
2
14.1 Hz, JH3aH2 = 6.0 Hz, 1H, HaCHCCP), 3.37 (dd, JPH1 = 21.3 Hz,
2
JH1H2 = 5.4 Hz, 1H, HCP), 2.76 (dd, JH3bH3a = 14.1 Hz, JH3bH2 = 9.3
Hz, 1H, HCHbCCP), 1.30 (t, J = 7.1 Hz, 3H, CH3CH2OPOCH2CH3),
1.21 (t, J = 7.1 Hz, 3H, CH3CH2OPOCH2CH3). 13C NMR (CDCl3): δ =
139.5, 138.3, 129.5, 128.7, 128.1, 127.3, 126.9, 126.2, 62.1 (d, J = 7.5
1
Hz, CH2OPOCH2), 61.8 (d, J = 7.5 Hz, CH2OPOCH2), 60.7 (d, JPC
=
147.5 Hz, C1), 60.4 (d, J = 7.4 Hz, C2), 56.1 (d, J = 4.0 Hz, PhCH2N),
43.2 (d, J = 4.0 Hz, C3), 16.9 (d, J = 6.0 Hz, CH3CH2OPOCH2CH3),
16.8 (d, J = 6.0 Hz, CH3CH2OPOCH2CH3). 31P NMR (CDCl3): δ = 24.8.
Dimethyl (1S,2S)-2-(N,N-Dibenzylamino)-1-chloro-3-phenyl
propylphosphonate (1S,2S)-21
2
1H NMR (CDCl3): δ = 7.34–6.95 (m, 15H), 4.54 (dd, JPH1 = 15.6
Hz, JH1H2 = 0.9 Hz, 1H, HCP), 4.27–4.11 and 4.09–3.98 (m, 4H,
CH2OPOCH2), 4.03 (AB, JAB = 14.1 Hz, 2H, PhCH2N), 3.43 (AB,
JAB = 14.1 Hz, 2H, PhCH2N), 3.80–3.70 (m, 1H, HCCP), 3.16

1014
D. G. Piotrowska and A. E. Wro´blewski
2
(dAB, JH3aH3b = 14.4 Hz, JH3aH2 = 4.2 Hz, 1H, HaCHCCP), 3.12
2
(dAB, JH3aH3b = 14.4 Hz, JH3bH2 = 9.9 Hz, 1H, HCHbCCP), 1.36
(t, J = 7.1 Hz, 3H, CH3CH2OPOCH2CH3), 1.34 (t, J = 7.1 Hz, 3H,
CH3CH2OPOCH2CH3). 13C NMR (CDCl3): δ = 139.1, 139.0, 129.9,
129.4, 128.6, 128.4, 128.2, 126.9, 64.1 (d, J = 7.5 Hz, CH2OPOCH2),
63.6 (d, J = 7.5 Hz, CH2OPOCH2), 58.3 (d, J = 2.6 Hz, C2), 53.9 (s,
1
PhCH2N), 51.3 (d, JPC = 151.8 Hz, C1), 34.7 (s, C3), 16.7 (d, J = 5.3
Hz, CH3CH2OPOCH2CH3), 16.6 (d, J = 5.3 Hz, CH3CH2OPOCH2CH3).
31P NMR (CDCl3): δ = 20.8.
Reaction of Crude Diethyl (1S,2R)-1-(N,N-Dibenzylamino)-2-
mesyloxy-3-phenylpropyl-phosphonate (1S,2R)-23 with
Tetraethylammonium Chloride
To a solution of phosphonate (1R,2S)-19a (0.100 g, 0.214 mmol) in
toluene (1 mL) cooled to 0◦C, triethylamine (0.090 mL, 0,64 mmol)
was added followed by slow injection of mesyl chloride (0.025 mL, 0.32
mmol) at this temperature. After 30 min of stirring at 0◦C, toluene (5
mL) was added, the mixture was washed with cold water (2 × 5 mL),
dried over MgSO4, and concentrated in vacuo at room temperature.
The oily residue was dissolved in chloroform and left at room temper-
ature for 48 h to provide a crude product containing ca. 95% of the 2-
mesyloxyphosphonate (1S,2R)-23. 1H NMR (CDCl3): δ = 7.40–7.10 (m,
15H), 5.22 (dtd, JPH2 = 13.5 Hz, JH2H3a
=
JH2–H3b = 6.6 Hz, JH2H1 =
3.3 Hz, HCCP), 4.20–4.00 (m, 5H, CH2OPOHCH, PhHCHN), 4.00–3.85
(m, 1H, CH2OPOHCH), 3.71 (d, J = 13.5 Hz, 2H, PhHCHN), 3.50 (dd,
JH3aH3b = 13.5 Hz, JH3aH2 = 6.6 Hz, 1H, HaCHCCP), 3.43 (dd, JPH1
24.0 Hz, JH1H2 = 3.3 Hz, 1H, HCP), 3.16 (dd, JH3bH3a = 13.5 Hz, JH3bH2
=
=
6.6 Hz, 1H, HCHbCCP), 2.65 (s, 3H, CH3SO2), 1.32 (t, J = 7.1 Hz, 3H,
CH3CH2OPOCH2CH3), 1.30 (t, J = 7.1 Hz, 3H, CH3CH2OPOCH2CH3).
13C NMR (CDCl3): δ = 138.8, 136.3, 130.0, 129.2, 128.9, 128.3, 127.2,
82.1 (d, J = 8.6 Hz, C2), 62.2 (d, J = 6.8 Hz, CH2OPOCH2), 61.9 (d,
J = 6.8 Hz, CH2OPOCH2), 57.7 (d, J = 147.1 Hz, C1), 56.1 (d, J =
4.8 Hz, PhCH2N), 39.3 (s, C3), 39.0 (s, CH3SO2), 16.8 (d, J = 6.0 Hz,
CH3CH2OPOCH2CH3), 16.7 (d, J = 6.0 Hz, CH3CH2OPOCH2CH3). 31
NMR (CDCl3): δ 23.5.
P
To a solution of the crude 2-mesyloxyphosphonate (1S,2R)-23 (0.100
g, 0.183 mmol) in methylene chloride (1 mL) containing triethylamine
(0.077 mL, 0.549 mmol), tetraethylammonium chloride (0.061 g, 0.37
mmol) was added, and the mixture was left at room temperature for
48 h. After dilution with methylene chloride (5 mL), the solution was
washed with water (3 × 3 mL), dried over MgSO4, and concentrated.

Precursors of α-Phosphonylated Aziridinium Ions
1015
The oily residue was chromatographed on a silica gel column with chlo-
roform:methanol (100:1, v/v) to give a colorless oil (0.080 g), which
was identified as a 1:1 mixture of chlorophosphonates (1S,2R)-20
and (1S,2S)-21 contaminated with the starting 1-hydroxyphosphonate
(1R,2S)-19a (ca. 2%) and the 2-hydroxyphosphonate (1S,2R)-24
(ca. 5%).
Reaction of Crude Diethyl (1S,2R)-1-(N,N-Dibenzylamino)
-2-mesyloxy-3-phenylpropyl phosphonate (1S,2R)-23 with
Water on Silica Gel
A solution of the 2-mesyloxyphosphonate (1S,2R)-23 prepared from
phosphonate (1R,2S)-19a (0.050 g, 0.11 mmol) in chloroform (1
mL) was left on a silica gel column for 48 h. Elution with chloro-
form:methanol (20:1, v/v) gave a colorless oil (0.042 g), which was
identified as a mixture of five compounds: diethyl (1S,2R)-1-(N,N-
dibenzylamino)-2-hydroxy-3-phenylpropylphosphonate (1S,2R)-24 (ca.
86%), diethyl (1R,2S)-2-(N,N-dibenzylamino)-1-hydroxy-3-phenylpro-
pylphosphonate (1S,2R)-19a (ca. 8%), diethyl (1S,2R)-1-(N,N-diben-
zylamino)-2-chloro-3-phenylpropylphosphonate (1S,2R)-20 (ca. 4%),
diethyl (1S,2S)-2-(N,N-dibenzylamino)-1-chloro-3-phenylpropylphos-
phonate (1S,2S)-21 (ca. 4%), and ca. 2% of an unidentified phosphonate
(δ31P = 28.4 ppm).
Diethyl (1S,2R)-1-(N,N-Dibenzylamino)-2-hydroxy-3-phenyl
propylphosphonate (1S,2R)-24
1H NMR (CDCl3): δ = 7.38–7.04 (m, 15H), 4.27–3.98 (m, 5H,
CH3CH2OPOCH2CH3, HCCP), 3.98 (dd, J = 13.8 Hz, J = 4.2 Hz, 2H,
PhHCHN), 3.89 (d, J = 13.8 Hz, 2H, PhHCHN), 3.32 (dd, JH3aH3b = 14.1
Hz, JH3aH2 = 3.3 Hz, 1H, HaCHCCP), 3.12 (dd, JPH1 = 17.1 Hz, JH1H2
7.2 Hz, 1H, HCP), 2.93 (d, J = 5.7 Hz, 1H, HO), 2.44 (dd, JH3bH3a
=
=
14.1 Hz, JH3bH2 = 9.0 Hz, 1H, HCHbCCP), 1.39 (t, J = 6.9 Hz, 3H,
CH3CH2OPOCH2CH3), 1.32 (t, J = 6.9 Hz, 3H, CH3CH2OPOCH2CH3).
13C NMR (CDCl3): δ = 139.3 (s, Cipso), 138.9 (d, J = 1.7 Hz, NCH2Cipso),
129.5, 129.3, 128.6, 128.4, 127.3, 126.5, 71.8 (d, J = 4.9 Hz, C2), 61.9
(d, J = 7.4 Hz, CH2OPOCH2), 61.8 (d, J = 7.4 Hz, CH2OPOCH2),
61.2 (d, J = 132.3 Hz, C1), 56.1 (d, J = 2.9 Hz, NCH2Ph), 42.1
(d, J = 8.3 Hz, C3), 17.0 (d, J = 5.7 Hz, CH3CH2OPOCH2CH3),
16.9 (d, J = 5.7 Hz, CH3CH2OPOCH2CH3). 31P NMR (CDCl3): δ =
29.7.

1016
D. G. Piotrowska and A. E. Wro´blewski
REFERENCES
[1] For the selected references, see: (a) M. D’hooghe, K. Vervisch, and N. De Kimpe, J.
Org. Chem., 72, 7329 (2007); (b) Q. Perron and A. Alexakis, Tetrahedron: Asymmetry,
18, 2503 (2007); (c) C. Couturier, J. Blanchet, T. Schlama, and J. Zhu, Org. Lett., 8,
2183 (2006); (d) J. Turconi, L. Lebeau, J.-M. Paris, and C. Mioskowski, Tetrahedron,
62, 8109 (2006); (e) L.-X. Liu and P.-Q. Huang, Tetrahedron: Asymmetry, 17, 3265
(2006); (f) J. M. Concello´n, P. L. Bernad, J. R. Sua´rez, S. Garcia-Granda, and M. R.
Diaz, J. Org. Chem., 70, 9411 (2005); (g) M. Periasamy, M. Seenivasaperumal, and V.
D. Rao, Tetrahedron: Asymmetry, 15, 3847 (2004); (h) C. McKay, R. J. Wilson, and C.
M. Rayner, Chem. Commun., 1080 (2004); (i) C. Carter, S. Fletcher, and A. Nelson,
Tetrahedron: Asymmetry, 14, 1995 (2003); (j) M. E. Bunnage, A. J. Burke, S. G.
Davies, N. L. Millican, R. L. Nicholson, P. M. Roberts, and A. D. Smith, Org. Biomol.
Chem., 1, 3708 (2003); (k) R. N. Salvatore, A. S. Nagle, and K. W. Jung, J. Org.
Chem.,67, 674 (2002); (l) P. OꢀBrien and T. D. Towers, J. Org. Chem., 67, 304 (2002);
(m) E. Curthbertson, P. OꢀBrien, and T. D. Towers, Synthesis, 693 (2001); (n) T.
Chuang and K. B. Sharpless, Org. Lett., 2, 3555 (2000) and references cited therein;
(o) K. Weber, S. Kuklinski, and P. Gmeiner, Org. Lett., 2, 647 (2000); (p) T. Chuang
and K. B. Sharpless, Org. Lett., 1, 1435 (1999); (q) T. Katagiri, M. Takahashi, Y.
Fujiwara, H. Ihara, and K. Ureyama, J. Org. Chem., 64, 7323 (1999); (r) B. Colman,
S. E. de Sousa, P. OꢀBrien, T. D. Towers, and W. Watson, Tetrahedron: Asymmetry,
10, 4173 (1999); (s) S. R. Anderson, J. T. Ayers, K. M. DeVries, F. Ito, D. Mendenhall,
and B. C. Vanderplas, Tetrahedron: Asymmetry,10, 2655 (1999).
[2] A. E. Wro´blewski and D. G. Piotrowska, Tetrahedron: Asymmetry, 12, 2977 (2001).
[3] D. G. Piotrowska and A. E. Wro´blewski, Tetrahedron, 59, 8405 (2003).
[4] J. M. Andre´s, R. Barrio, M. A. Martinez, R. Pedrosa, and A. Pe´rez-Encabo, J. Org.
Chem., 61, 4210 (1996).
[5] J. D. White and J. D. Hansen, J. Org. Chem., 70, 1963 (2005).
[6] S. Bastin, M. Ginj, J. Brocard, L. Pelinski, and G. Novogrocki, Tetrahedron: Asym-
metry, 14, 1701 (2003).
[7] M. T. Reetz, Chem. Rev., 99, 1121 (1999).
[8] T. Yokomatsu, T. Yamagishi, and S. Shibuya, Tetrahedron: Asymmetry, 4, 1401
(1993).
[9] B. Iorga, F. Eymery, and P. Savignac, Synthesis, 576 (2000).
[10] S. Kumaraswamy, R. S. Selvi, and K. C. K. Swamy, Synthesis, 207 (1997).
[11] C. Altona and M. Sundaralingam, J. Am. Chem. Soc. 95, 2333 (1973).
[12] C. Benezra, J. Am. Chem. Soc. 95, 6890 (1973).
[13] J. G. Verkade and L. D. Quin, Eds., Phosphorus-31 NMR Spectroscopy in Stereo-
chemical Analysis (VCH Publishers, Weinheim, 1987), Chap. 11, p. 383.
[14] J.-R. Neeser, J. M. J. Tronchet, and E. J. Charollais, Can. J. Chem. 61, 2112 (1983).
[15] P. Sohar, Nuclear Magnetic Resonance Spectroscopy (CRC Press, Boca Raton, 1984),
Chap. 1.