Lewis acid catalyzed synthesis of N-protected diphenyl 1- aminoalkylphosphonates

Article abstract of DOI:10.1055/s-2004-837307

Diphenyl α-aminomethylphosphonates are prepared in good yields using a Lewis acid catalyzed Birum-Oleksyszyn reaction. This approach enlarges the scope of this reaction, allowing the use of aldehydes and ketones and the use of acid-labile groups in the sy

Full text of DOI:10.1055/s-2004-837307

634
PAPER
Lewis Acid Catalyzed Synthesis of N-Protected Diphenyl 1-Aminoalkyl-
phosphonates
Synthesis of
N
i
-Protec
e
ted
D
iphen
t
yl 1-A
e
minoalkylp
r
hosphonate
s
Van der Veken,a Ibrahim El Sayed,a Jurgen Joossens,a Christian V. Stevens,b Koen Augustyns,a
Achiel Haemers*a
a
Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
Fax +32(3)8202739; E-mail: achiel.haemers@ua.ac.be
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University,
b
Coupure links 653, 9000 Ghent, Belgium
Received 24 September 2004; revised 22 October 2004
which has been used invariantly since it was first pub-
lished, there are still some problems associated with it.
The first drawback consists of the rather modest yields
(typically 35–55%), together with the formation (often
Abstract: Diphenyl a-aminomethylphosphonates are prepared in
good yields using a Lewis acid catalyzed Birum–Oleksyszyn reac-
tion. This approach enlarges the scope of this reaction, allowing the
use of aldehydes and ketones and the use of acid-labile groups in the
synthesis of mono-and disubstituted diphenyl 1-aminoalkylphos- >20%) of a-hydroxyphosphonates. A second limitation is
phonates.
that the reaction conditions are incompatible with some
starting materials or products containing acid labile pro-
tecting groups. Finally, the Birum–Oleksyszyn reaction
works only for aldehydes. Finding a variant that also
works for ketones and that is compatible with acid labile
functional groups would greatly broaden the scope of ac-
cessible products. These compounds are very interesting
probes in biochemistry and medicinal chemistry as they
selectively inhibit, depending on the N-substituent, vari-
ous serine proteases.4
Key words: diphenyl 1-aminoalkylphosphonates, carbamates,
Lewis acid, aldehydes, ketones
The synthesis of mono- and disubstituted diphenyl a-ami-
nomethylphosphonates is accomplished in good yield us-
ing benzyl- or tert-butyl carbamate, an aldehyde or a
ketone and triphenyl phosphite in the presence of a Lewis
acid.
The use of Lewis acids instead of acetic acid in the
Birum–Oleksyszyn reaction has been poorly documented.
Birum mentioned the possibility to initiate the analogous
condensation reaction of urea, aldehydes and triphenyl
phosphite using BF3.2 Hudson et al. used BF3 etherate in
toluene at 85–90 °C, but did not isolate the diphenyl es-
ters. After hydrolysis in situ, the presence of a-hydroxy-
phosphonic acids as by-products of the reaction was
compared with the usual acetic acid procedure and no dif-
ference was found.5A few papers report the use of Lewis
acids as catalysts in the synthesis of dialkyl aminoalkyl-
phosphonates, but these approaches are not applicable for
diphenyl esters.6
Diphenyl 1-aminoalkylphosphonates are generally syn-
thesized using the Birum–Oleksyszyn reaction.1 We use
the name ‘Birum–Oleksyszyn reaction’ for the conden-
sation of an aldehyde, benzyl carbamate and triphenyl
phosphite in which a Z-protected diphenyl aminoalkyl-
phosphonate is formed. The term ‘Oleksyszyn reaction’
has been used in the past to designate the synthesis of ami-
noalkane phosphonates from benzyl carbamate, an alde-
hyde and phosphorous trichloride. The name ‘Birum
reaction’ has been used to describe the condensation reac-
tion of a urea derivative, an aldehyde and triphenyl phos-
phate.2 This reaction is part of a larger spectrum of
reactions in which the a-aminophosphonate function is
formed by the addition of a trivalent phosphorus nucleo-
phile to an imine carbon or an imine equivalent (e.g. pyr-
roline trimer or oxazolidine). Most of these synthetic
methodologies have been directed toward the synthesis of
free aminophosphonic acids or alkyl esters.3
We found that a Lewis acid such as ZnCl2 effectively pro-
moted the Birum–Oleksyszyn condensation at room tem-
perature. Optimal conditions for the Lewis acid were
found to be 10 mol% in dichloromethane (Scheme 1). At
5 mol%, the reaction afforded the same yield but required
longer reaction times.
The Birum–Oleksyszyn reaction is a simple and direct
route to diphenyl 1-aminoalkylphosphonates. In a typical
one-pot protocol, an aldehyde, benzyl carbamate and
triphenyl phosphite are stirred in glacial acetic acid at
80 °C. After completion of the reaction, acetic acid is re-
moved and the compound is precipitated from cold meth-
anol. In spite of the remarkably simple reaction protocol,
Lewis Acid
10 mol%
O
O
O
R1
O
P
+
+
P(OPh)3
OPh
OPh
R1
R2
R3O
N
CH2Cl2, r.t. R3O
NH2
R2
H
Scheme 1 Synthesis of diphenyl 1-aminoalkylphosphonic acids.
R1 = H, alkyl, aryl, aralkyl; R2 = alkyl, aryl, aralkenyl, aralkyl;
R1–R2 = cycloalkyl; R3 = benzyl, tert-butyl.
SYNTHESIS 2005, No. 4, pp 0634–0638
x
x
.
x
x
.2
0
0
5
Advanced online publication: 23.12.2004
DOI: 10.1055/s-2004-837307; Art ID: Z18004SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of N-Protected Diphenyl 1-Aminoalkylphosphonates
635
Table 1 Lewis Acid Catalyzed Birum–Oleksyszyn Reaction
Entry and Product Carbonyl Compound
No.
R3
Lewis Acid
Reaction Time
Yield (%)a
1
1a
2
benzaldehyde
Bn
TiCl4
20 min
140 min
70 min
120 min
120 min
120 min
240 min
30 min
70 min
70 min
120 min
100 min
48 h
87
86
94
74
91
91
68
81
82
88
84
87
44
72
69
64
benzaldehyde
Bn
ZnCl2
trans-cinnamaldehyde
dimethylaminobenzaldehyde
3-phenylpropionaldehyde
piperonal
Bn
SnCl4
3
Bn
BF3·Et2O
Cu(OTf)2
TiCl4
4
Bn
5
Bn
6
N-Boc-p-aminobenzaldehyde
benzaldehyde
Bn
Cu(OTf)2
TiCl4
7
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Bn
8
trans-cinnamaldehyde
cyclohexylaldehyde
3-methylbutyraldehyde
piperonal
SnCl4
9
SnCl4
10
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
11
12
acetophenone
13
cyclohexanone
Bn
36 h
14
pentan-2-one
Bn
48 h
15
phenylacetone
Bn
48 h
a Isolated yield.
To further validate the concept of using Lewis acids in the HBr or hydrogenolysis (cleavage conditions for the Z-
Birum–Oleksyszyn reaction, a range of aldehydes and ke- group) or in cases where the specific introduction of a Boc
tones, triphenyl phosphite and benzyl- and tert-butyl car- group is part of a protecting group strategy.
bamates were subjected to different Lewis acids. Results
To the best of our knowledge, the use of ketones instead
are summarized in Table 1. Excellent yields were ob-
of aldehydes in the Birum–Oleksyszyn reaction, which
tained in the reactions between benzyl carbamate and
would yield a,a-disubstituted diphenyl 1-aminoalkyl-
phosphonates, has never been described. The condensa-
aldehydes (entries 1–6) and only traces of a-hy-
droxyphosphonates were found. There was a remarkable
tion of acetophenone, benzyl carbamate and triphenyl
difference in the reaction time. Not completely surprising,
phosphite in acetic acid at 80 °C did not provide any target
these results roughly reflect the relative acidities of the
product after 48 hours.
different Lewis acids used. Protected 1-aminoalkyl-
Based on the results for the Birum–Oleksyszyn condensa-
phosphonates usually precipitate from a methanol solu-
tion with aldehydes, a Lewis acid promoted reaction was
tion.
investigated for ketones. Again, there was little influence
Noteworthy is the good yield when using an aldehyde
of the used catalyst on the yield of the reaction. Different
containing the acid labile Boc-protecting group (entry 6).
ketones (entries 12–15) were subjected to the Lewis acid
The stability of Boc-groups is confirmed by the use of
catalyzed Birum–Oleksyszyn reaction. The aminophos-
phonates indeed turned out to have formed in reasonable
tert-butyl carbamate (entries 7–11). Although not very
pronounced, the product yields obtained are somewhat
yields but longer reaction times were required. Yields
lower than with benzyl carbamate. Steric factors might be
were lower than those obtained with aldehydes. Ketone-
invoked to explain these observations. No deprotected
derived compounds did not show the tendency to precipi-
product was detected when a Boc-group was present. The
tate from a cold methanolic solution and had to be purified
Boc-protected compounds however did not show the ten-
using chromatographic techniques. The synthesis of the
dency to precipitate from methanol and had to be purified
free aminophosphonic acid diphenyl esters is not de-
scribed, with Z- or Boc protecting groups being easily re-
using chromatographic techniques.
The direct access to Boc-protected compounds might be moved by well known procedures.4
of use for the transformation of more complex aldehydes,
containing functional groups that are not resistant toward
in detail. We suppose that after reaction of the carbonyl
The mechanism of this reaction has not been investigated
Synthesis 2005, No. 4, 634–638 © Thieme Stuttgart · New York

636
P. Van der Veken et al.
PAPER
Diphenyl (2E)-1-{[(Benzyloxy)carbonyl]amino}-3-phenylprop-
2-enylphosphonate (2)
compound with the carbamate, the acylimine intermediate
is attacked by triphenyl phosphite with the formation of a
phosphonium intermediate5,6eand that both reactions are
catalyzed by the Lewis acid. Reaction with water affords
the target compound.
1H NMR (CDCl3, 400 MHz): d = 5.15 (AB system, 2 H, J = 12 Hz,
CH2OC), 5.21–5.35 (br m, 1 H, NCHP), 5.57 (br d, 1 H, J = 7.6 Hz,
NH), 6.31 (ddd, 1 H, J = 6.2, 12.4, 16 Hz, =CH), 6.70–6.78 (dd, 1
H, J = 3.6, 16 Hz, =CH), 7.09–7.38 (m, 20 Harom).
31P NMR (CDCl3, 109 MHz): d = 14.32.
MS (ESI): m/z = 500 (M+ + 1), 523 (M+ + Na).
In summary, Lewis acid catalysis efficiently promotes the
Birum–Oleksyszyn reaction. The yields obtained from
these reactions are significantly higher compared to the
yields obtained using the usual protocol (heating in acetic
acid). Aldehydes with acid labile Boc groups can now be
used without difficulties and tert-butyl carbamate can be
used as a reaction partner. Lewis acid catalysis also ex-
tends the scope of the Birum–Oleksyszyn reaction, allow-
ing ketones to be transformed into the corresponding
diphenyl 1-aminoalkylphosphonates.
Anal. Calcd for C29H26NO5P (499): C, 69.73; H, 5.21; N, 2.80.
Found: C, 69.81; H, 5.44; N, 2.97.
Diphenyl {[(Benzyloxy)carbonyl]amino}[4-(dimethylami-
no)phenyl]methylphosphonate (3)
1H NMR (CDCl3, 400 MHz): d = 2.94 (s, 6 H, 2 CH3), 5.09 (AB sys-
tem, 2 H, J = 12.4 Hz, CH2OC), 5.47 (dd, 1 H, J = 9.6 Hz, NCHP),
5.72 (br d, 1 H, J= 8 Hz, NH), 6.69 (d, 2 Harom, J = 8.4 Hz), 6.88 (d,
2 Harom, J = 8.8 Hz), 7.06–7.37 (m, 15 Harom).
31P NMR (CDCl3, 109 MHz): d = 15.17.
MS (ESI): m/z = 517 (M+ + 1), 539 (M+ + 1).
1H NMR and 31P NMR spectra were recorded on a Bruker
Avance DRX-400 spectrometer (400 MHz) and a Jeol
Eclipse 300 FT NMR Spectrometer (109 MHz), respec-
Anal Calcd for C29H29N2O5P (516): C, 67.44; H, 5.62; N, 5.42.
Found: C, 66.86; H, 5.59; N, 5.44.
1
tively, using TMS for H NMR and phosphoric acid for
31P NMR. ES Mass spectra were obtained on a Bruker Es-
Diphenyl 1-{[(Benzyloxy)carbonyl]amino}-3-phenylpropyl-
quire 3000 plus mass spectrometer. Column chromatogra- phosphonate (4)
1H NMR (CDCl3, 400 MHz): d = 2.00–2.23 (br m, 1 H, CH2), 2.32–
2.45 (br m, 1 H, CH2), 2.69–2.82 (br m, 1 H, CH2), 2.84–2.94 (br m,
1 H, CH2), 4.47–4.58 (m, 1 H, NCHP), 5.08–5.18 (m, 3 H, NH +
CH2OC), 7.00–7.39 (m, 20 Harom).
31P NMR (CDCl3, 109 MHz): d = 17.89.
MS (ESI): m/z = 502 (M+ + 1), 524 (M+ + Na).
phy was performed on silica gel 60 (220–440 mesh) from
Fluka Chemie. TLC was performed on precoated silica
gel plates (Polygram® SIL G/UV254). Reagents and start-
ing materials were from Acros Organics and were used
without purification.
Reaction of Aldehydes with Benzyl Carbamate; General Proce-
dure
Anal Calcd for C29H28NO5P (501): C, 69.46; H, 5.58; N, 2.79.
Found: C, 69.47; H, 5.93; N, 2.97.
Aldehyde (1.2 mmol), benzyl carbamate (1 mmol) and P(OPh)3 (1
mmol) were dissolved in well dried anhyd CH2Cl2 (2 mL). The
Lewis acid (10 mol%) was added in one portion. BF3·Et2O, TiCl4
and SnCl4 were added as 1 M solution in anhyd CH2Cl2; Cu(OTf)2
was added as such. This mixture was stirred at r.t., until TLC anal-
ysis showed the complete consumption of benzyl carbamate. Then
CH2Cl2 was evaporated and the residue dissolved in MeOH (10
mL). The product was precipitated from this solution by storing at
–20 °C for 3–6 h, followed by the collection of the precipitate by fil-
tration. Recrystallization was carried out by dissolving the product
in CHCl3 (2 mL), concentrating the CHCl3 under reduced pressure,
and adding MeOH (8 mL) to the residue. This solution was then
stored at –20 °C for 3–6 h, the precipitated product filtered off and
dried under reduced pressure (Table 1).
Diphenyl 1,3-Benzodioxol-5-yl-{[(benzyloxy)carbonyl]amino-
methylphosphonate (5)
1H NMR (CDCl3, 400 MHz): d = 5.09 (AB system, 2 H, J = 12.2
Hz, CH2OC), 5.46 (dd, 1 H, J= 9.2, 9.6 Hz, NCHP), 5.84 (br d, 1 H,
J = 6 Hz, NH), 5.93 (s, 2 H, OCH2O), 6.76 (d, 1 Harom, J = 7.6 Hz),
6.89–6.99 (m, 4 Harom), 7.06–7.37 (m, 13 Harom).
31P NMR (CDCl3, 109 MHz): d = 14.32.
MS (ESI): m/z = 518 (M+ +1), 540 (M+ + Na).
Anal Calcd for C28H24NO7P (517): C, 64.99; H, 4.64; N, 2.70.
Found: C, 65.05; H, 4.60; N, 2.86.
Diphenyl {[(Benzyloxy)carbonyl]amino}[4-(tert-butoxycarbon-
yl)aminophenyl]methylphosphonate (6)
Reaction of Aldehydes and Ketones with tert-Butyl Carbamate;
General Procedure
1H NMR (CDCl3, 400 MHz): d = 1.52 (s, 9 H, t-C4H9), 5.09 (AB
system, 2 H, J = 12 Hz, CH2OC), 5.51 (dd, 1 H, J = 10, 14 Hz,
NCHP), 5.77 (br d, 1 H, J = 7.2 Hz, NH), 6.50 (br s, 1 H, NHBoc),
6.89 (d, 2 Harom, J = 8.4 Hz), 7.05–7.44 (m, 17 Harom).
Aldehyde (1.2 mmol), tert-butyl carbamate (1 mmol) and P(OPh)3
(1 mmol) were dissolved in CH2Cl2 (2 mL). The Lewis acid (10
mol%) was added in one portion. This mixture was stirred at r.t. un-
til TLC analysis showed the complete consumption of carbamate.
The oily residue was then adsorbed onto silica gel and chromato-
graphed using hexanes–EtOAc (2:1) (Table 1).
31P NMR (CDCl3, 109 MHz): d = 14.48.
MS (ESI): m/z = 589 (M+ + 1), 611 (M+ + Na).
Anal Calcd for C32H33N2O7P (588): C, 65.30; H, 5.61; N, 4.76.
Found: C, 65.07; H, 5.91; N, 4.87.
Diphenyl [(Benzyloxycarbonyl)amino](phenyl)methylphospho-
nate (1)1a,7
1H NMR (CDCl3, 400 MHz): d = 5.05–5.22 (m, 2 H, CH2OC), 5.5–
5.69 (m, 1 H, CHP), 6.81–6.98 (br s, 1 H, NH), 6.78–6.89 (m, 2
Diphenyl [(tert-Butoxycarbonyl)amino](phenyl)methylphos-
phonate (7)
1H NMR (CDCl3, 400 MHz): d = 1.42 (s, 9 H, t-C4H9), 5.47–5.69
(br m, 2 H, NCHP + NH), 6.87 (d, 2 Harom, J = 8.0 Hz), 7.07–7.39
(m, 11 Harom) 7.41–7.48 (m, 2 Harom).
Harom), 7.05–7.43 (m, 16 Harom) 7.41–7.58 (m, 2 Harom).
MS (ESI): m/z = 488 (M+ + 1), 511 (M+ + Na).
31P NMR (CDCl3, 109 MHz): d = 15.03.
Synthesis 2005, No. 4, 634–638 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Protected Diphenyl 1-Aminoalkylphosphonates
637
MS (ESI): m/z = 440 (M+ + 1), 462 (M+ + Na).
5.08 (br s, 2 H, CH2OC), 7.07–7.18 (m, 6 Harom), 7.20–7.28 (m, 4
arom), 7.29–7.38 (m, 5 Harom).
31P NMR (CDCl3, 109 MHz): d = 19.67.
H
Anal Calcd for C24H26NO5P (439): C, 65.60; H, 5.92; N, 3.19.
Found: C, 65.46; H, 6.06; N, 3.32.
MS (ESI): m/z = 466 (M+ + 1), 488 (M+ + Na).
Diphenyl (2E)-1-[(tert-Butoxycarbonyl)amino]-3-phenylprop-
2-enylphosphonate (8)
Anal. Calcd for C26H28NO5P (465.48): C, 67.09; H, 6.06; N, 3.01.
Found: C, 67.03; H, 6.15; N, 3.09.
1H NMR (CDCl3, 400 MHz): d = 1.46 (s, 9 H, t-C4H9), 5.23 (br s, 2
H, NCHP + NH), 6.32 (ddd, 1 H, J = 6, 12, 16 Hz, =CH), 6.74 (dd,
1 H, J = 4.4, 16 Hz, =CH), 7.13–7.38 (m, 15 Harom).
Diphenyl 1-{[(Benzyloxy)carbonyl]amino}-1-methylbutylphos-
phonate (14)
31P NMR (CDCl3, 109 MHz): d = 14.89.
MS (ESI): m/z = 466 (M+ + 1), 488 (M+ + Na).
1H NMR (CDCl3, 400 MHz): d = 0.90–1.00 (m, 3 H, CH3), 1.47–
1.58 (br m, 2 H, CH2), 1.81 (d, 3 H, J = 17.6 Hz, CH3), 1.93–2.05
(m, 1 H, CH2), 2.19–2.31 (m, 1 H, CH2), 5.06 (br s, 3 H, CH2OC +
NH), 7.09–7.33 (m, 15 Harom).
Anal Calcd for C26H28NO5P (465): C, 67.10; H, 6.02; N, 3.01.
Found: C, 67.43; H, 6.12; N, 3.26.
31P NMR (CDCl3, 109 MHz): d = 20.63.
Diphenyl [(tert-Butoxycarbonyl)amino](cyclohexyl)methyl-
phosphonate (9)
MS (ESI): m/z = 454 (M+ + 1), 476 (M+ + Na).
1H NMR (CDCl3, 400 MHz): d = 1.08–1.37 (m, 6 H, 3 CH2), 1.44
(s, 9 H, t-C4H9), 1.62–1.89 (m, 3 H, CH2 + CH), 1.97–2.08 (m, 2 H,
CH2), 4.36 (2 dd, 1 H, J = 10.8 Hz, NCHP), 4.97 (dd, 1 H, J = 8.4,
10.8 Hz, NH), 7.11–7.23 (m, 6 Harom), 7.26–7.37 (m, 4 Harom).
Anal. Calcd for C25H28NO5P (453.47): C, 66.22; H, 6.22; N, 3.09.
Found: C, 66.04; H, 6.33; N, 3.16.
Diphenyl 1-Benzyl-1-{[(benzyloxy)carbonyl]amino}ethylphos-
phonate (15)
31P NMR (CDCl3, 109 MHz): d = 18.45.
MS (ESI): m/z = 446 (M+ + 1), 468 (M+ + Na).
1H NMR (CDCl3, 400 MHz): d = 1.72 (d, 3 H, J = 17.2 Hz, CH3),
3.15–3.23 (m, 1 H, CH2), 3.75–3.82 (m, 1 H, CH2), 4.98 (br s, 1 H,
NH), 5.09 (br s, 2 H, CH2OC), 7.05–7.35 (m, 20 Harom).
Anal Calcd for C24H32NO5P (445): C, 64.72; H, 7.19; N, 3.15.
Found: C, 64.96; H, 7.23; N, 3.33.
31P NMR (CDCl3, 109 MHz): d = 19.86.
MS (ESI): m/z = 502 (M+ + 1), 524 (M+ + Na).
Diphenyl 1-[(tert-Butoxycarbonyl)amino]-3-methylbutylphos-
phonate (10)
Anal. Calcd for C29H28NO5P (501.51): C, 69.45; H, 5.63; N, 2.79.
Found: C, 69.20; H, 5.64; N, 2.58.
1H NMR (CDCl3, 400 MHz): d = 0.94–1.01 (m, 6 H, 2 CH3), 1.43
(s, 9 H, t-C4H9), 1.66–1.89 (m, 3 H, CH + CH2), 4.45–4.58 (m, 1 H,
NCHP), 4.80 (d, 1 H, J = 10.4 Hz, NH), 7.12–7.22 (m, 6 Harom),
7.26–7.35 (m, 4 Harom).
Acknowledgment
31P NMR (109 MHz, CDCl3): d = 19.44.
MS (ESI): m/z = 420 (M+ + 1), 442 (M+ + Na).
P. Van der Veken and J. Joossens are fellows of the Institute of Pro-
motion and Innovation in Science and Technology of Flanders
(IWT). I. El Sayed is a visiting post-doctoral fellow of the Fund of
Scientific Research, Flanders. We thank Prof. M. Soroka (Technical
University of Wrocław, Poland) for helpful discussions.
Anal Calcd for C22H30NO5P (419): C, 63.00; H, 7.16; N, 3.34.
Found: C, 63.06; H, 7.23; N, 3.48.
Diphenyl 1,3-Benzodioxol-5-yl-[(tert-butoxycarbonyl)ami-
no]methylphosphonate (11)
References
1H NMR (CDCl3, 400 MHz): d = 1.41 (s, 9 H, t-C4H9), 5.42 (dd, 1
H, J= 8.8, 9.2 Hz, NCHP), 5.69–5.79 (br m, 1 H, NH), 5.93 (s, 2 H,
OCH2O), 6.77 (d, 1 Harom, J = 8 Hz), 6.92–7.00 (m, 4 Harom), 7.08–
7.33 (m, 8 Harom).
(1) (a) Oleksyszyn, J.; Subotkowska, L.; Mastalerz, P. Synthesis
1979, 985. (b) Oleksyszyn, J.; Tyka, R. Tetrahedron Lett.
1977, 18, 2823.
(2) (a) Oleksyszyn, J.; Tyka, R.; Mastalerz, P. Synthesis 1979,
985. (b) Birum, G. H. J. Org. Chem. 1974, 39, 209.
(3) For a review, see: Kukhar, V. P.; Hudson, H. R.
Aminophosphonic- and Aminophosphinic Acids. Chemistry
and Biological Activity; Wiley: Chichester, 2000.
(4) Examples of diphenyl 1-aminoalkylphosphonates as enzyme
inhibitors: (a) Boduszek, B.; Oleksyszyn, J.; Kam, C. M.;
Selzer, J.; Smith, R. E.; Powers, J. C. J. Med. Chem. 1994,
37, 3969. (b) Oleksyszyn, J.; Boduszek, B.; Kam, C.-M.;
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31P NMR (CDCl3, 109 MHz): d = 14.90.
MS (ESI): m/z = 484 (M+ + 1), 506 (M+ + Na).
Anal. Calcd for C25H26NO7P (483): C, 62.11; H, 5.38; N, 2.89.
Found: C, 62.15; H, 5.39; N, 3.12.
Diphenyl 1-{[(Benzyloxy)carbonyl]amino}-1-phenylethylphos-
phonate (12)
1H NMR (CDCl3, 400 MHz): d = 2.34 (d, 3 H, J = 17.6 Hz, CH3),
5.07 (br s, 2 H, CH2OC), 6.13 (d, 1 H, J = 11.2 Hz, NH), 6.80–7.62
(m, 20 Harom).
31P NMR (CDCl3, 109 MHz): d = 17.22.
MS (ESI): m/z = 488 (M+ + 1), 510 (M+ + Na).
Vedernikova, I.; Scharpé, S.; Haemers, A. J. Med. Chem.
1999, 42, 1041. (e) Nishiyama, Y.; Taguchi, H.; Luo, J. Q.;
Zhou, Y. X.; Burr, G.; Karle, S.; Paul, S. Arch. Biochem.
Biophys. 2002, 402, 281. (f) Mucha, A.; Kafarski, P.
Tetrahedron 2002, 58, 5855. (g) Grembecka, J.; Mucha, A.;
Cierpicki, T.; Kafarski, P. J. Med. Chem. 2003, 46, 2641.
(h) Joossens, J.; Van der Veken, P.; Lambeir, A.-M.;
Augustyns, K.; Haemers, A. J. Med. Chem. 2004, 47, 2411.
Anal Calcd for C28H26NO5P (487.48): C, 68.99; H, 5.38; N, 2.87.
Found: C, 69.28; H, 5.38; N, 3.00.
Diphenyl 1-{[(Benzyloxy)carbonyl]amino}cyclohexylphospho-
nate (13)
1H NMR (CDCl3, 400 MHz): d = 1.50–1.80 (m, 6 H, 3 CH2), 1.88–
1.99 (m, 2 H, CH2), 2.54–2.66 (br s, 2 H, CH2), 4.90 (br s, 1 H, NH),
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Synthesis 2005, No. 4, 634–638 © Thieme Stuttgart · New York