Direct observation of aziridinium ions in a 2-(N,N-dibenzylamino)- to 1-(N,N-dibenzylamino)phosphonate rearrangement

Article abstract of DOI:10.1016/j.tet.2009.03.087

Aziridinium mesylates stable in the reaction medium for several hours to over a week were observed in a rearrangement of dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-mesyloxyethylphosphonates substituted at C2 with Bn, i-Pr and t-Bu to the respective 1-(N,N-d

Full text of DOI:10.1016/j.tet.2009.03.087

Tetrahedron 65 (2009) 4310–4315
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Direct observation of aziridinium ions in a 2-(N,N-dibenzylamino)- to 1-(N,N-
dibenzylamino)phosphonate rearrangement
*
´
Dorota G. Piotrowska, Andrzej E. Wroblewski
´
´
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Ło´dz, 90-151 Łodz, Muszynskiego 1, Poland
´ ´
a r t i c l e i n f o
a b s t r a c t
Article history:
Aziridinium mesylates stable in the reaction medium for several hours to over a week were observed in
a rearrangement of dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-mesyloxyethylphosphonates substituted
at C2 with Bn, i-Pr and t-Bu to the respective 1-(N,N-dibenzylamino)-2-mesyloxyethylphosphonates.
Rates of formation of these aziridinium mesylates and rates of their reactions with poorly nucleophilic
mesylate anion were governed by steric and electronic factors. The conformation of (2S,3S)-1,1-dibenzyl-
2-(tert-butyl)-3-(dimethoxyphosphoryl)aziridinium mesylate in solution was established based on 1H
and 13C NMR spectroscopic studies including a NOESY experiment.
Received 7 January 2009
Received in revised form 12 March 2009
Accepted 26 March 2009
Available online 1 April 2009
This paper is respectfully dedicated to Pro-
fessor Maria Michalska
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
aminoalcohols 1 the intermediate aziridinium mesylates 3 appeared
too reactive and, to the best of our knowledge, they have never been
It is well established that in reactions of amines substituted at the
-position with good leaving groups aziridinium ions are formed as
detected in the presence of the respective mesylates 2 and/or
products of the nucleophilic substitution 4a and/or 4b (Scheme 1).
In this paper we wish to show that direct observation of fairly stable
aziridinium ions is possible in a 2-(N,N-dibenzylamino)- to 1-(N,N-
dibenzylamino)phosphonate rearrangement.40
b
reactive intermediates (neighbouring group participation).1 For
chiral compounds the ring closure leading to aziridinium ions and
their further transformations require SN2-like displacements. The
R2
_
NR2
R'HC CHR"
OH
NR2
R'HC CHR"
OMs
NR2
R'HC CHR" +
NR2
R'HC CHR"
Nu
N
Nu
C
C
H
R"
R'
H
Nu
_
_
OMs
OMs
1
2
3
4a
4b
Scheme 1.
involvement of aziridinium ions has also been supported by kinetic
studies.2–6 Numerous aziridinium salts, e.g., perchlorates,3,5,7–19
tetrafluoroborates,15,20–23 tetraphenylborate,24 triflates,3,24–29 mesy-
lates30,31 andeveniodides3,4,13,29 or bromides30,31 have beenisolated
and characterised by 1H,3–5,7,8,13–19,23,25–28,30–37 13C7,10,25–27,33 and
19F22 NMR spectroscopy, and for some crystal structures were
obtained.24,34,38,39 Most of them are fairly stable solids mostly due to
the presence of non-nucleophilic or poorly nucleophilic counter
ions. However, under standard conditions of mesylation of 2-
2. Results and discussion
2.1. Stability of aziridinium mesylates
Dimethyl (1R
*
,2S
*
)-2-(N,N-dibenzylamino)-1-hydroxy-2-phe-
,2S
)-5a41 was treated with mesyl anhy-
nylethylphosphonate (1R
*
*
dride in the presence of triethylamine in toluene at 0 ꢀC for 30 min.
After washing ammonium salts with cold water, the toluene solu-
tion was concentrated at room temperature and the residue was
monitored by 1H and 31P NMR spectroscopy as a chloroform-d so-
lution. As judged from 31P NMR spectra after 80 min the reaction
mixture was composed of 1-O-mesylate (1R
*
,2S
*
)-6a40 (88%) and 2-
* Corresponding author. Tel.: þ48 42 677 92 33; fax: þ48 42 678 83 98.
E-mail address: andrzej.wroblewski@umed.lodz.pl (A.E. Wroblewski).
O-mesylate (1S ,2R
*
*
)-8a40 (12%) (Scheme 2). The amount of 2-O-
´
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.087

D.G. Piotrowska, A.E. Wro´blewski / Tetrahedron 65 (2009) 4310–4315
4311
Ph Ph
H
H
H
A
Hb
H
R
Bn2N
NBn2
P(O)(OMe)2
H
N
a
B
_
C
C
C C
C
C
OMs
P(O)(OMe)2
(2S,3S)-7
H
R
H
3
2
R
H
OR'
MsO
P(O)(OMe)2
H
(1R,2S)-5
(1R,2S)-6
(1S,2R)-8
R'=H
R'=OMs
a R=Ph, b R=Bn, c R=i-Pr, d R=t-Bu
Scheme 2. A 1-O-mesylate (1R,2S)-6a–d to 2-O-mesylate (1S,2R)-8a–d rearrangement.
Table 1
reached after ca. 2 h. The 1-O-mesylate (1R,2S)-6b to 2-O-mesylate
(1S,2R)-8b transformation was complete in about 5 h leading to
a 99:1 equilibrium mixture of 2-O-mesylate (1S,2R)-8b and the
The 31P NMR monitoring of a 1-O-mesylate (1R,2S)-6c to 2-O-mesylate (1S,2R)-8c
rearrangement
Compound
Reaction time [h]
aziridinium mesylate (2S,3S)-7b, as concluded from the 1H and 31
P
1.25
1.83
2.83
3.83
4.83
24
0%
1%
99%
NMR spectra taken 24 and 48 h after addition.
(1R,2S)-6b
(2S,3S)-7b
(1S,2R)-8b
76%
9%
15%
52%
11%
37%
23%
7%
70%
12%
3%
85%
0%
1%
99%
After 65 min the reaction mixture obtained by our standard
mesylation of dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-hydroxy-
3-methylbutylphosphonate (1R,2S)-5c42 31P 26.89 ppm) con-
(d
sisted of 2-O-mesylate (1S,2R)-8c (
aziridinium mesylate (2S,3S)-7c (
d
31P 29.59 ppmd35%) and the
d
31P 14.56 ppmd65%) only. The
mesylate (1S
*
,2R
*
)-8a increased to 46.5, 64 and 73% after 140, 200
and 260 min, respectively. The rearrangement was practically
complete after 24 h, since only traces of 1-O-mesylate (1R ,2S )-6a
amount of 2-O-mesylate (1S,2R)-8c grew up at the expense of
the aziridinium mesylate (2S,3S)-7c to reach an 85:15 equilibrium
mixture of (1S,2R)-8c and (2S,3S)-7c within 24 h. In order to detect
1-O-mesylate (1R,2S)-6c the mesylation was directly performed in
the NMR tube. Thus, when a solution of phosphonate (1R,2S)-5c in
chloroform-d was treated with mesyl anhydride in the presence of
triethylamine and catalytic DMAP at room temperature, mesylation
of the hydroxy group occurred immediately. In the 1H NMR spec-
trum taken after 7 min doublets of CH3CCH3 at 0.98 and 1.23 ppm
characteristic of (1R,2S)-5c completely disappeared, while two new
sets of CH3CCH3 resonances at 0.89 and 1.09 ppm [(1R,2S)-6cd30%]
and at 0.79 and 1.24 ppm [aziridinium mesylate (2S,3S)-7cd70%]
emerged. In the 31P NMR spectrum taken 3 min later the 1-O-
*
*
could be detected in 1H and 31P NMR spectra. Detailed inspection of
the 1H NMR spectrum showed that the reaction mixture also con-
tained some triethylammonium mesylate and toluene, which could
not be completely removed during work-up. However, no other
signals could be detected in the 1H and 31P NMR spectra.
When dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-hydroxy-3-
phenylpropylphosphonate (1R,2S)-5b (d
31P 27.34 ppm) was sub-
jected to our standard mesylation procedure (vide supra), 1H and
31P NMR spectra recorded 75 min after addition of mesyl anhydride
was complete clearly showed the formation of three species: 1-O-
mesylate (1R,2S)-6b (
d
31P 21.74 ppm), 2-O-mesylate (1S,2R)-8b (
d
31P
31P 26.18 ppm) and the aziridinium mesylate (2S,3S)-7b (
d
mesylate (1R,2S)-6c (d
31P 23.04 ppm) to the aziridinium mesylate
13.97 ppm) (Scheme 2). The progress of the reaction was monitored
by 1H and 31P NMR spectroscopy (Table 1). The maximum con-
centration of the aziridinium mesylate (2S,3S)-7b (ca. 11%) was
(2S,3S)-7c (d
31P 14.56 ppm) ratio changed to 12:88 but a signal of
2-O-mesylate (1S,2R)-8c was not yet present. The 1H and 31P NMR
monitoring of the reaction mixture (Fig. 1) showed that the
14.56
96 h
24 h
5.33 h
4.33 h
1.67 h
0.67 h
29.59
23.04
0.17 h
32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12
PPM
Figure 1. The 31P NMR monitoring of a 1-O-mesylate (1R,2S)-6c to 2-O-mesylate (1S,2R)-8c rearrangement.

4312
D.G. Piotrowska, A.E. Wro´blewski / Tetrahedron 65 (2009) 4310–4315
maximum concentration of the aziridinium mesylate (2S,3S)-7c (ca.
93%) was observed within 40 min and, as noticed above, an 84:16
equilibrium mixture of (1S,2R)-8c and (2S,3S)-7c was obtained
after 24 h.
to the 47–49 ppm region proving the incorporation of this atom
into a three-membered ring and a significant increase in the one-
bond C–P coupling to 173–178 Hz, when compared with the same
parameters of the 1-O-mesylate (1R,2S)-6b (dC–P 74.43 ppm, 1JC–P
¼
Taking into account the structural features of the aziridinium
mesylates 7b and 7c we hypothesised that their stability may depend
on the bulkiness of substituents R in the starting 1-O-mesylates 6. To
test this assumption dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-
hydroxy-3,3-dimethylbutylphosphonate (1R,2S)-5d was synthesi-
sed (vide infra). While application of our standard procedure of
mesylation in toluene (followed by an aqueous wash-up) to phos-
phonate (1R,2S)-5d led to the formation of complex mixture con-
taining traces of the aziridinium mesylate (2S,3S)-7d due to its poor
solubility in the reaction medium, the direct mesylation of phos-
phonate (1R,2S)-5d in a chloroform-d solution performed in the
NMR tube was successful. Within 15 min the amount of the azir-
idinium mesylate (2S,3S)-7d reached 95%, and the 1-O-mesylate
(1R,2S)-6d was the second phosphonate found in the reaction
mixture. The maximum quantity (99%) of (2S,3S)-7d was noticed
after ca. 1 h, but now 2-O-mesylate (1S,2R)-8d was detected as the
other phosphonate present. The transformation of the aziridinium
mesylate (2S,3S)-7d into the 2-O-mesylate (1S,2R)-8d was slow
and, unfortunately, decomposition products were produced on
prolonged (1 week) observation. Thus, after 24 h almost 51% of the
2-O-mesylate, 44% of the aziridinium mesylate and 5% of an un-
160.3 Hz).
Stereoheterotopic relationships have been successfully applied
in many cases to solve structural problems in organic chemistry.43
As expected, diastereotopicity of the Ha and Hb protons in the
HaCHb–N–HaCHb fragments in phosphonate (1R,2S)-5c, its mesylate
(1R,2S)-6c and the 2-O-mesylate (1S,2R)-8c was demonstrated by
the observation of two different chemical shifts for these protons.
However, in the aziridinium mesylate (2S,3S)-7c protons in the
CH2–Nþ–CH2 fragment become heterotopic and for this reason they
are expected to resonate at four different fields. This was found to
be the case in the 1H NMR spectrum of the aziridinium mesylate
(2S,3S)-7c. Furthermore, due to the inductive effect of the positively
charged N atom, signals of the heterotopic CH2–Nþ–CH2 protons in
(2S,3S)-7c are significantly (Dd¼0.4–1.2 ppm) shifted downfield in
comparison to those in CH2–N–CH2 fragments in (1R,2S)-5c,
(1R,2S)-6c and (1S,2R)-8c. Another argument for the intermediacy
of aziridinium ion came from the 13C NMR spectra, in which for
heterotopic carbons of the C–Nþ–C moiety two resonances were
observed for all aziridinium mesylates (2S,3S)-7b–d. Furthermore,
eight well-separated resonances for heterotopic carbons of two
phenyl groups were found in the 13C NMR spectra of the azir-
idinium mesylates (2S,3S)-7c–d.
identified phosphonate (d
31P 10.9 ppm) were found in the reaction
mixture. The amount of 2-O-mesylate (1S,2R)-8d reached 80% after
6 days at room temperature, but due to the formation of several
unidentified phosphonates we were unable to establish the equi-
librium ratio of the aziridinium mesylate (2S,3S)-7d to 2-O-mesy-
late (1S,2R)-8d.
Because the aziridinium mesylate (2S,3S)-7d appeared to be the
most abundant in the reaction mixtures obtained after mesylation
of hydroxyphosphonates (1R,2S)-5a–d and the slowest in decay, it
was subjected to detailed 1H NMR studies including a NOESY
spectrum at 700 MHz in order to gather information on spatial
arrangement of two phenyl groups. To identify HR–CS–HS and C6H5–
2.2. Structure of aziridinium mesylates
CS–N resonances NOESY correlations of H–CP (
first investigated. Besides the expected interactions with (CH3)3C (
1.12 ppm), the other important findings include the observation of
NOESY signals with a doublet at 7.66 ppm (ortho protons) and
with a doublet at 4.74 ppm but the appropriate signal was not
found for a doublet of doublets at 4.40 ppm (H2CS–N). Further-
more, since a doublet at 4.74 ppm correlates with a doublet at
7.66 ppm (weak) and with (CH3)3C (strong), while a doublet of
d 5.26 ppm) were
d
To prove that the aziridinium mesylates (2S,3S)-7b–d have been
formed, their 1H and 13C NMR spectroscopic data were compared
with those of the starting phosphonates (1R,2S)-5b–d, their
mesylates (1R,2S)-6b–d and the respective 2-O-mesylates (1S,2R)-
8b–d. It appeared that spectral patterns for H–C–C(P)–H, H2C–N–
CH2 and aromatic protons are identical for the aziridinium
mesylates (2S,3S)-7b–d, the only difference being the separation of
the multiplets. Since the best separation was observed in the 1H
NMR spectrum of (2S,3S)-7c, we will limit our considerations to this
case. After mesylation of HO–C1 in phosphonate (1R,2S)-5c the
signal of H–C1 was significantly shifted downfield from 4.10 ppm in
the starting material to 5.50 ppm in the 1-O-mesylate (1R,2S)-6c
due to the inductive effect of the methylsulfonyloxy group. Further
downfield shift is expected, when this group is replaced by the
positively charged ammonium residue. However, this effect is
partially compensated by the well recognised tendency for all
protons connected to three-membered rings to be shifted upfield
and for this reason H–C1 in the aziridinium mesylate (2S,3S)-7c
resonates at 5.60 ppm, still demonstrating the close vicinity of
a very strong electron-withdrawing group. In the 2-O-mesylate
(1S,2R)-8c H–C1 resonates at 3.28 ppm in agreement with previous
observations for the structurally related 1-(N,N-dibenzyl)alkyl-
phosphonates.40 A small downfield shift (Dd¼0.14 ppm) observed
d
d
d
d
d
doublets at d 4.40 ppm correlates also with a doublet at d 7.66 ppm
(strong) and with (CH3)3C (medium), one can conclude that HR–CS–
N resonates at 4.74 ppm and HS–CS–N appears at 4.40 ppm. This
d
d
assignment is further supported by the observation of a four-bond
H–P coupling, since the required W-arrangement of coupled nuclei
can only be achieved within the HS–CSNC–P moiety. It is very im-
portant to notice lack of a NOESY correlation signal between res-
onances of ortho protons in C6H5–CS–N and (CH3)3C. Taking into
account all these observations we suggest that the phenyl ring
connected to CS–N is located as far away as possible from the tert-
butyl group (Fig. 2).
Identification of HR–CR–HS and C6H5–CR–N resonances was also
accomplished by analysis of NOESY correlations. Thus, a doublet at
d
7.35 ppm comes from the ortho protons of C6H5–CR–N, because
they correlate with (CH3)3C ( 1.12 ppm), H–CCP ( 3.57 ppm) and
d
d
both H2CR–N (
d
4.46 and 4.39 ppm) but a doublet of doublets at
for H–C2 in the mesylate (1R,2S)-6c (d 2.96 ppm) in comparison
with phosphonate (1R,2S)-5c reflects the presence of the mesyloxy
group at C1. As expected, in the aziridinium mesylate (2S,3S)-7c
H–C2 is further shifted downfield (to 3.42 ppm) to accommodate
two already mentioned factors. In the acyclic mesylate (1S,2R)-8c
H
H
H
S
S
R
H
S
N
H
H
R
H
R
H
H
H–C2 resonates in low field (
contribution from the electronegative mesyloxy group.
d
¼4.80 ppm) clearly showing only the
H
P(O)(OMe)2
The most diagnostic feature found in the 13C NMR spectra of the
aziridinium mesylates (2S,3S)-7b–d is the large upfield shift of C–P
Figure 2. The most important NOESY correlations observed for (2S,3S)-7d.

D.G. Piotrowska, A.E. Wro´blewski / Tetrahedron 65 (2009) 4310–4315
4313
d
d
d
3.57 ppm (H–CCP) gave a NOESY correlation with a doublet at
4.46 only. This observation allows us to assign chemical shifts of
4.46 and 4.39 ppm to HR–CR and HS–CR, respectively. Under these
experiment. The relief in intramolecular interactions of very bulky
groups (N,N-dibenzylamino with benzyl, isopropyl or tert-butyl)
during the formation of the aziridinium mesylates 7b–d seems to
be responsible for the observed acceleration. Our NMR spectro-
scopic studies (vide supra) on the structure of the aziridinium
mesylates 7b–d fully support this conclusion.
circumstances one can suggest that the phenyl ring connected to
CR–N is located as far away as possible from the diethoxy-
phosphoryl group (Fig. 2). Two phenyl rings are not that far away in
space, because both ortho protons (
a weak NOESY correlation. Downfield shifts of the ortho and also
meta protons of C6H5–CS–N ( 7.66 and 7.51 ppm) as well as of HR–
CS–N ( 4.74 ppm) in comparison with the respective resonances of
the ortho protons in C6H5–CR–N ( 7.35 ppm) and of HS–CS–N (
4.40 ppm) as well as HR–CR–HS 4.46 and 4.39 ppm) can be at-
d
7.66 and 7.35 ppm) display
The ring opening of the aziridinium mesylates 7b–d with the
mesylate anion is purely governed by steric factors. Substitution at
the secondary centre flanked by the benzyl group is fairly fast (ca.
5 h), and the reaction at the secondary carbon substituted with
isopropyl is rather slow (ca. 1 day), but when tert-butyl is attached
to the secondary centre (neopentyl-like position) the substitution is
extremely slow (incomplete in one week).
d
d
d
d
(d
tributed to deshielding effect of the P]O group.
2.3. Synthesis of starting materials
4. Experimental
4.1. General
Dimethyl (1R
*
,2S
*
)-2-(N,N-dibenzylamino)-1-hydroxy-2-phe-
,2S )-5a and dimethyl (1R,2S)-2-(N,N-
nylethylphosphonate (1R
*
*
1H NMR spectra were taken in CDCl3 on the following spec-
trometers: Bruker Avance II Plus (700 MHz) and Varian Mercury-
300 with TMS as an internal standard. 13C and 31P NMR spectra
were recorded for CDCl3 solutions on Bruker Avance II Plus
(700 MHz) spectrometer at 176.2 and 283.5 MHz, or a Varian
Mercury-300 machine at 75.5 and 121.5 MHz, respectively. 1H{31P}
NMR, 1H–1H COSY and NOESY experiments were applied to support
spectral assignments. The spectral data of the 1-O-mesylates 6b–d,
the aziridinium mesylates 7b–d and the 2-O-mesylates 8b–d were
extracted from 1H, 13C and 31P NMR spectra of the reaction mix-
tures. For this reason in some cases it was not possible to collect
a complete set of data due to too low concentration of very reactive
compounds or superimposition of multiplets.
dibenzylamino)-1-hydroxy-3-methylbutylphosphonate (1R,2S)-5c
were obtained as described in the literature.41,42 To synthesise di-
methyl (1R,2S)-2-(N,N-dibenzylamino)-1-hydroxy-3-phenylpropyl-
phosphonates (1R,2S)-5b the procedure already described42 for
the diethyl ester was applied to give a 85:15 mixture of (1R,2S)- and
(1S,2S)-5b, from which the major phosphonate was isolated chro-
matographically followed by repeated crystallisation of appropriate
fractions. In a similar fashion phosphonylation of N,N-dibenzyl-L-
tert-leucinal44 (Scheme 3) led to the formation of an 83:17 mixture
of dimethyl (1R,2S)- and (1S,2S)-2-(N,N-dibenzylamino)-1-hy-
droxy-3,3-dimethylbutylphosphonate (1R,2S)- and (1S,2S)-5d. The
required phosphonate (1R,2S)-5d was then separated by column
chromatography.
IR spectra were measured on an Infinity MI-60 FT-IR spectro-
meter. Melting points were determined on a Boetius apparatus and
are uncorrected. Elemental analyses were performed by the Mi-
croanalytical Laboratory of this Faculty on Perkin–Elmer PE 2400
CHNS analyser. Polarimetric measurements were conducted on an
Optical Activity PolAAr 3001 apparatus.
NBn2
NBn2
NBn2
a, b
OH
P(O)(OMe)2
P(O)(OMe)2
OH
(1S,2S)-5d
+
t-Bu
t-Bu
t-Bu
OH
(1R,2S)-5d
Scheme 3. Reagents and conditions: (a) Swern oxidation; (b) (MeO)2P(O)H, NEt3.
The following adsorbents were used: column chromatography,
Merck silica gel 60 (70–230 mesh); analytical TLC, Merck TLC plastic
sheets silica gel 60 F254
.
3. Conclusions
Aziridinium mesylates observable for several hours to over
a week were detected in a 2-(N,N-dibenzylamino)- to 1-(N,N-
dibenzylamino)phosphonate rearrangement, which was studied on
2-substituted (R¼Ph, Bn, i-Pr, t-Bu) 2-(N,N-dibenzylamino)-1-
mesyloxyethylphosphonates 6a–d. The rates of formation of the
respective aziridinium mesylates 7a–d and their reactions with
poorly nucleophilic mesylate anion were governed by steric and
electronic factors. Thus, the aziridinium mesylate 7a was not ob-
served because nucleophilic substitutions at benzylic carbon are
much faster than those at non-activated carbon atoms.
In this case the rate of formation of the aziridinium mesylate is
the rate-determining step in a two-step consecutive reactions,
which can be followed (ca. 10 h) at room temperature by the 31P
NMR spectroscopy as a decay in the concentration of the 1-O-
mesylate 6a.
When the bulkiness of the substituents attached to C–C–P is
being increased (Bn, i-Pr, t-Bu) two phenomena have been noticed.
Transformation of the 1-O-mesylates 6b–d into the respective
aziridinium mesylates 7b–d is significantly accelerated, and nu-
cleophilic ring opening by the mesylate anion is dramatically
slowed down. Although the decrease in concentration of the 1-O-
mesylate 6b (R¼Bn) can still be monitored by the 31P NMR spec-
troscopy (ca. 5 h), the presence of the 1-O-mesylate 6d (R¼t-Bu)
can only be detected by 31P NMR in the first 15 min of the
4.2. Dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-hydroxy-3-
phenylpropylphosphonate (1R,2S)-5b
A mixture of a crude (S)-N,N-dibenzylphenylalaninal [obtained
after Swern oxidation of (S)-N,N-dibenzylphenylalaninol (2.32 g,
7.00 mmol)], dimethyl phosphite (0.900 mL, 7.00 mmol) and tri-
ethylamine (0.097 mL, 0.70 mmol) was left at room temperature for
20 h. The residue was twice chromatographed on a silica gel col-
umn; first with chloroform–methanol (100:1, v/v) and later with
ethyl acetate–hexanes (2:1, v/v). The appropriate fractions were
combined to give phosphonate (1R,2S)-5b (0.730 g, 24%) as an
amorphous solid, which was recrystallised from ethyl acetate to
afford (1R,2S)-5b (0.280 g, 9%) as small white needles. Mp 135–
20
135 ꢀC. [
a]
þ32.0 (c 0.9, CHCl3). IR (KBr)
n
¼3426, 3244, 2950,1452,
D
1220, 1037, 835, 748, 691 cmꢁ1
.
1H NMR (CDCl3)
d
¼7.29–7.06 (m,
15H), 4.38 (ddd, JH1–P¼9.6 Hz, JH1–HO¼7.8 Hz, JH1–H2¼1.8 Hz, 1H,
HCP), 3.92 (br s, 1H, OH), 3.86 (d, J¼14.1 Hz, 2H, PhHCHN), 3.73
and 3.69 (2ꢂd, J¼10.5 Hz, 6H, CH3OPOCH3), 3.59 (d, J¼14.1 Hz,
2H, PhHCHN), 3.34 (dddd, JH2–P¼14.9 Hz, JH2–H3b¼JH2–H3a¼7.1 Hz,
JH2–H1¼1.8 Hz, 1H, HCCP), 3.09 (d, JH3a,b–H2¼7.1 Hz, 2H,
PhHaCHbCCP). 13C NMR (CDCl3)
d
¼140.08, 139.46, 129.76, 128.86,
128.17, 128.14, 126.89, 126.01, 66.03 (d, J¼154.0 Hz, C1), 60.13 (d,
J¼5.7 Hz, C2), 54.51 (s, PhCH2N), 53.71 and 53.13 (2ꢂd, J¼7.3 Hz,
CH3OPOCH3), 32.34 (s, C3). 31P NMR (CDCl3)
d
¼27.34. Anal. Calcd for

4314
D.G. Piotrowska, A.E. Wro´blewski / Tetrahedron 65 (2009) 4310–4315
C25H30NO4P: C, 68.32; H, 6.88; N, 3.19. Found: C, 68.09; H, 6.93; N,
3.33.
2.20 (dsp, JH3–H2¼8.1 Hz, JH3–Me¼6.5 Hz, 1H, CHCCP), 1.09 and 0.89
(2ꢂd, J¼6.5 Hz, 6H, CH3CCH3). 31P NMR (CDCl3)
¼23.04.
d
4.3. Dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-hydroxy-3,3-
dimethylbutylphosphonate (1R,2S)-5d
4.4.3.3. Dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-mesyloxy-3,3-
dimethylbutylphosphonate (1R,2S)-6d. 31P NMR (CDCl3)
d¼23.46.
A mixture of a crude (S)-N,N-dibenzyl-
after Swern oxidation of (S)-N,N-dibenzyl-
L
-tert-leucinal [obtained
4.4.4. Aziridinium mesylates (2S,3S)-7b–d
L
-tert-leucinol45 (0.530 g,
1.78 mmol)], dimethyl phosphite (0.163 mL, 1.78 mmol) and tri-
ethylamine (0.073 mL, 0.53 mmol) was left at room temperature for
60 h. The residue was chromatographed on a silica gel column with
chloroform–methanol (100:1, v/v), the appropriate fractions were
collected and recrystallised from chloroform–diethyl ether to give
4.4.4.1. (2S,3S)-1,1,2-Tribenzyl-3-(dimethoxyphosphoryl)aziridinium
mesylate (2S,3S)-7b. 1H NMR (CDCl3)
d
¼7.6–7.1 (m, 15H), 5.89 (dd,
JH2–P¼7.8 Hz, JH2–H3¼3.0 Hz, 1H, HCP), 5.35 (br d, J¼14.1 Hz, 1H,
PhHaCHN), 4.65 (br d, J¼14.1 Hz, 1H, PhHACHN), 4.25 (d, J¼14.1 Hz,
1H, PhHCHBN), 4.21 (dd, J¼14.1, 4.5 Hz, 1H, PhHCHbN), 4.06 (local-
ised by COSY) (m, HCCP), 3.91 and 3.85 (2ꢂd, J¼11.1 Hz, 6H,
CH3OPOCH3), 3.58 (d, J¼14.1 Hz, 2H, PhHCHN), overlapped by sig-
nals of major components (m, 2H, PhHaCHbCCP), 2.75 (s, 3H,
phosphonate (1R,2S)-5d (0.327 g, 45%) as colourless needles. Mp
20
133–134 ꢀC. [
a
]
ꢁ27.8 (c 1.0, CHCl3). IR (KBr) ¼3232, 2956, 1494,
n
D
1453, 1222, 1058, 1017, 745, 701 cmꢁ1. 1H NMR (CDCl3):
d
¼7.40–7.20
2
(m, 10H), 4.56 (dd, JH–P¼17.7 Hz, JH1–HO¼7.2 Hz, 1H, HCP), 4.30–
3.75 (vbr s, 2H, PhHCHN), 3.86 and 3.81 (2ꢂd, J¼10.2 Hz,
6H, CH3OPOCH3), 3.45 (br d, J¼13.0 Hz, 2H, PhHCHN), 2.94 (d,
3JH2–P¼12.6 Hz, 1H, HCCP), 2.45 (dd, JP–HO¼8.1 Hz, JH1–HO¼7.2 Hz,
CH3SO2). 13C NMR (CDCl3)
d
¼resonances of aromatic carbons are
overlapped by signals of major components, 58.60 (d, J¼2.2 Hz, C3),
57.70 (s, PhCH2N), 57.41 (d, J¼1.5 Hz, PhCH2N), 55.54 and 54.82
(2ꢂd, J¼6.9 Hz, CH3OPOCH3), 47.22 (d, J¼173.2 Hz, C2), 39.77, 31.80
1H, HO), 1.00 [s, 9H, (CH3)3C]. 13C NMR (CDCl3)
d¼139.67 (br s),
(s, CCCP). 31P NMR (CDCl3)
d¼13.97.
129.48 (br s), 128.16, 127.02, 68.43 (d, 1JCP¼150.9 Hz, C1), 64.81 (d,
J¼6.0 Hz, C2) 56.96 (br s, PhCH2N), 53.56 and 53.37 (2ꢂd, J¼7.5 Hz,
4.4.4.2. (2S,3S)-1,1-Dibenzyl-3-(dimethoxyphosphoryl)-2-isopropyl
aziridinium mesylate (2S,3S)-7c. 1H NMR (CDCl3)
¼7.75–7.65 (m,
2H), 7.60–7.45 (m, 6H), 7.43–7.32 (m, 2H), 5.66 (dd, JH2–H3
CH3OPOCH3), 36.99 (C3), 29.56. 31P NMR (CDCl3)
d¼28.28. Anal.
d
Calcd for C22H32NO4P: C, 65.17; H, 7.95; N, 3.45. Found: C, 65.34; H,
7.87; N, 3.45.
¼
8.3 Hz, JH2–P¼5.4 Hz, 1H, HCP), 5.12 (br d, J¼13.5 Hz, 1H, PhHaCHN),
4.61 (br d, J¼13.8 Hz, 1H, PhHACHN), 4.37 (d, J¼13.8 Hz, 1H,
PhHCHBN), 4.23 (dd, J¼13.5, 4.2 Hz, 1H, PhHCHbN), 4.09 and 3.89
0
4.4. Mesylation of 1-hydroxyphosphonates (general
procedures)
(2ꢂd, J¼11.1 Hz, 6H, CH3OPOCH3), 3.44 (ddd, JH3–P¼15.1 Hz, JH3–H3
¼
¼
0
0
10.7 Hz, JH3–H2¼8.3 Hz,1H, HCCP),2.83(dsp,JH3–H3 ¼10.7 Hz, JH3 –Me
4.4.1. In a toluene solution
6.7 Hz, 1H, HCCCP), 2.78 (s, 3H, CH3SO2), 1.31 and 0.81 (2ꢂd,
To
a
solution of 1-hydroxyphosphonate 5b, 5c or 5d
J¼6.7 Hz, 6H, CH3CCH3). 13C NMR (CDCl3)
¼131.10, 130.89, 130.80,
d
(0.051 mmol) in toluene (1 mL) triethylamine (0.036 mL,
0.255 mmol) was added followed by mesyl anhydride (0.027 g,
0.153 mmol) at 0 ꢀC. The reaction mixture was stirred at 0–5 ꢀC for
30 min, diluted with toluene (5 mL) and washed with cold water
(2ꢂ5 mL). The organic phase was dried over MgSO4. All volatiles
were removed in vacuo at room temperature, the residue was
dissolved in CDCl3 (0.7 mL) and the solution was immediately
analysed by 1H, 31P and 13C NMR spectroscopy.
130.45, 129.69, 129.55, 129.13, 128.94, 60.60 (d, J¼2.9 Hz, C3), 57.78
(s, PhCH2N), 57.15 (s, PhCH2N), 55.73 and 54.63 (2ꢂd, J¼6.9 Hz,
CH3OPOCH3), 48.49 (d, J¼176.0 Hz, C2), 39.56, 25.82 (d, J¼3.1 Hz,
CCCP), 20.53, 19.88. 31P NMR (CDCl3)
d
¼14.56.
4.4.4.3. (2S,3S)-1,1-Dibenzyl-2-(tert-butyl)-3-(dimethoxyphosphoryl)-
aziridinium mesylate (2S,3S)-7d. 1H NMR (CDCl3)
¼7.66 (d,
d
J¼7.6 Hz, 2H), 7.51 (t, J¼7.4 Hz, 2H), 7.48 (m, 2H), 7.46 (t, J¼7.1 Hz,
2H), 7.35 (d, J¼7.4 Hz, 2H), 5.26 (dd, JH2–H3¼9.4 Hz, JH2–P¼2.3 Hz,
1H, HCP), 4.74 (d, J¼13.6 Hz, 1H, PhHaCHN), 4.46 (d, J¼13.6 Hz, 1H,
PhHACHN), 4.40 (dd, J¼13.6, 4.5 Hz, 1H, PhHCHbN), 4.39 (d,
J¼13.6 Hz, 1H, PhHCHBN), 4.00 and 3.93 (2ꢂd, J¼11.1 Hz, 6H,
CH3OPOCH3), 3.57 (dd, JH3–P¼16.7 Hz, JH3–H2¼9.4 Hz, 1H, HCCP),
4.4.2. NMR tube experiments
To
a solution of 1-hydroxyphosphonate 5b, 5c or 5d
(0.026 mmol) in CDCl3 (0.7 mL) mesyl anhydride (0.077 mmol) was
added followed by injection of NEt3 (0.13 mmol). The progress of
mesylation was monitored by 1H and 31P NMR spectroscopy.
2.68 (s, 3H, CH3SO2),1.12 [s, 9H, (CH3)3C]. 13C NMR (CDCl3)
d¼131.14,
131.04, 130.58, 130.52, 129.70, 129.56, 129.14, 129.00, 63.02 (s, C3),
59.04 (s, PhCH2N), 58.84 (s, PhCH2N), 55.36 and 54.90 (2ꢂd,
J¼6.7 Hz, CH3OPOCH3), 48.53 (d, J¼178.5 Hz, C2), 39.42, 32.59 (s,
4.4.3. 1-O-Mesylates (1R,2S)-6b–d
4.4.3.1. Dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-mesyloxy-3-phe-
CCCP), 28.35 [s, (CH3)3C]. 31P NMR (CDCl3)
4.4.5. 2-O-Mesylates (1S,2R)-8b–d
d¼13.93.
nylpropylphosphonate (1R,2S)-6b. 1H NMR (CDCl3)
d
¼7.35–7.12 (m,
15H), 5.53 (dd, JH1–P¼11.5 Hz, JH1–H2¼1.0 Hz, 1H, HCP), 3.98 (d,
J¼14.1 Hz, 2H, PhHCHN), 3.73 and 3.71 (2ꢂd, J¼10.7 Hz, 6H, CH3O-
POCH3), 3.58 (d, J¼14.1 Hz, 2H, PhHCHN), 3.55 (ddd, JH2–H3b¼JH2–
4.4.5.1. Dimethyl (1S,2R)-1-(N,N-dibenzylamino)-2-mesyloxy-3-phe-
nylpropylphosphonate (1S,2R)-8b. 1H NMR (CDCl3)
¼7.35–7.10 (m,
¼7.2 Hz, JH2–H1¼1.0 Hz,1H, HCCP), 3.27 (s, 3H, CH3SO2), 3.15–3.03
d
H3a
(m, 2H, PhHaCHbCCP). 13C NMR (CDCl3)
d
¼139.23, 138.84, 129.68,
15H), 5.27 (dddd, JH2–P¼14.7 Hz, JH2–H3a¼7.2 Hz, JH2–H3b¼6.9 Hz,
JH1–H2¼3.3 Hz, 1H, HCCP), 4.08 (dd, J¼13.5, 3.0 Hz, 2H, PhHCHN),
3.76 and 3.60 (2ꢂd, J¼10.8 Hz, 6H, CH3OPOCH3), 3.68 (d, J¼13.5 Hz,
2H, PhHCHN), 3.50 (dd, JH3a–H3b¼13.8 Hz, JH2–H3a¼7.2 Hz, 1H,
PhHaCHbCCP), 3.45 (dd, JH1–P¼21.0 Hz, JH1–H2¼3.3 Hz, 1H, HCP), 3.16
(dd, JH3a–H3b¼13.8 Hz, JH2–H3b¼6.9 Hz, 1H, PhHaCHbCCP), 2.68 (s,
128.74,128.19,128.10,126.92,126.30, 74.43 (d, J¼160.3 Hz, C1), 59.11
(d, J¼4.5 Hz, C2), 53.65 (s, PhCH2N), 53.98 and 53.36 (2ꢂd, J¼7.5 Hz,
CH3OPOCH3), 40.07, 33.22 (s, C3). 31P NMR (CDCl3)
d¼21.74.
4.4.3.2. Dimethyl
(1R,2S)-2-(N,N-dibenzylamino)-1-mesyloxy-3-
¼7.30–7.10
methylbutylphosphonate (1R,2S)-6c. 1H NMR (CDCl3)
d
3H, CH3SO2). 13C NMR (CDCl3)
d
¼138.73, 136.28, 130.01, 129.30,
(m, 10H), 5.50 (dd, JH1–P¼13.5 Hz, JH1–H2¼1.5 Hz, 1H, HCP), 3.92 (d,
J¼13.8 Hz, 2H, PhHCHN), 3.79 and 3.69 (2ꢂd, J¼10.7 Hz, 6H,
CH3OPOCH3), 3.46 (d, J¼13.8 Hz, 2H, PhHCHN), 3.19 (s, 3H, CH3SO2),
2.96 (ddd, JH2–P¼10.8 Hz, JH2–H3¼8.1 Hz, JH2–H1¼1.2 Hz, 1H, HCCP),
128.99, 128.39, 127.34, 127.34, 81.92 (d, J¼7.7 Hz, C2), 57.26 (d,
J¼147.4 Hz, C1), 56.04 (d, J¼4.9 Hz, PhCH2N), 52.83 and 52.43 (2ꢂd,
J¼6.9 Hz, CH3OPOCH3), 39.46 (s, C3), 39.27. 31P NMR (CDCl3)
d¼26.18.

D.G. Piotrowska, A.E. Wro´blewski / Tetrahedron 65 (2009) 4310–4315
4315
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4.4.5.2. Dimethyl
(1S,2R)-1-(N,N-dibenzylamino)-2-mesyloxy-3-
¼7.35–7.20
methylbutylphosphonate (1S,2R)-8c. 1H NMR (CDCl3)
d
(m, 10H), 4.85 (ddd, JH1–H2¼9.1 Hz, JH2–P¼5.4 Hz, JH2–H3¼1.6 Hz, 1H,
HCCP), 3.95 (d, J¼12.9 Hz, 2H, PhHCHN), 3.88 (dd, J¼12.9, 4.8 Hz, 2H,
PhHCHN), 3.86 and 3.82 (2ꢂd, J¼10.9 Hz, 6H, CH3OPOCH3), 3.33 (dd,
JH1–P¼15.3 Hz, JH1–H2¼9.1 Hz, 1H, HCP), 3.12 (s, 3H, CH3SO2), 2.28
(dsp, JH3–Me¼6.9 Hz, JH3–H2¼1.6 Hz, 1H, HCCCP), 1.04 and 0.31 (2ꢂd,
J¼6.9 Hz, 6H, CH3CCH3). 13C NMR (CDCl3)
¼138.44, 138.43, 129.52,
d
129.48, 128.55, 128.51, 127.60, 127.55, 85.16 (d, J¼2.6 Hz, C2), 56.22
(d, J¼134.3 Hz, C1), 55.63 (d, J¼1.7 Hz, PhCH2N), 52.28 and 52.00
(2ꢂd, J¼7.2 Hz, CH3OPOCH3), 39.50, 29.26 (d, J¼7.2 Hz, C3), 20.41 (d,
J¼1.4 Hz, CH3CCH3), 14.39 (s, CH3CCH3). 31P NMR (CDCl3)
¼29.59.
d
4.4.5.3. Dimethyl (1S,2R)-1-(N,N-dibenzylamino)-2-mesyloxy-3,3-
dimethylbutylphosphonate (1S,2R)-8d. 1H NMR (CDCl3)
d
¼7.30–7.16
(m, 10H), 4.78 (dd, JH1–H2¼3.0 Hz, JH2–P¼6.1 Hz, 1H, HCCP), 3.85 (d,
J¼13.0 Hz, 2H, PhHCHN), 3.82 (d, J¼13.0 Hz, 2H, PhHCHN), 3.81
and 3.76 (2ꢂd, J¼10.9 Hz, 6H, CH3OPOCH3), 3.45 (dd, JH1–P¼22.2 Hz,
JH1–H2¼3.0 Hz, 1H, HCP), 3.24 (s, 3H, CH3SO2), 0.69 [s, 9H, (CH3)3C].
13C NMR (CDCl3)
d
¼138.54, 129.47, 128.18, 127.32, 69.92 (s, C2),
57.70 (d, J¼142.2 Hz, C1), 55.76 (s, PhCH2N), 52.71 and 50.96 (2ꢂd,
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J¼6.6 Hz, CH3OPOCH3), 39.44, 36.39 (s, C3), 26.10 [s, (CH3)3C]. 31P
NMR (CDCl3)
d¼26.19.
Acknowledgements
Mrs. Jolanta P1ocka is acknowledged for her excellent technical
assistance. This work was supported by the Medical University of
35. Liu, Q.; Simms, M. J.; Boden, N.; Rayner, C. M. J. Chem. Soc., Perkin Trans. 1 1994,
1363–1365.
´
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qodz internal fund (503-3014-1).
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