O-Ethyl 1-azidoalkylphosphonic acids - Versatile reagents for the synthesis of protected phosphonamidate peptides

Article abstract of DOI:10.1016/S0040-4020(00)01143-1

A new methodology for the synthesis of protected phosphonamidate peptides from O-ethyl 1-azidoalkylphosphonic acids and amino acids esters was developed. The method is general and the corresponding N-Boc protected phosphonopeptides as well as their azido

Full text of DOI:10.1016/S0040-4020(00)01143-1

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1619±1625
O-Ethyl 1-azidoalkylphosphonic acidsÐversatile reagents for the
synthesis of protected phosphonamidate peptides
Dorota Sikora, Tomasz Nonas and Tadeusz Gajdap
Ç
Institute of Organic Chemistry, Technical University (Politechnika), Zeromskiego St. 116, 90-924 Lodz, Poland
Received 29 September 2000; revised 10 November 2000; accepted 30 November 2000
AbstractÐA new methodology for the synthesis of protected phosphonamidate peptides from O-ethyl 1-azidoalkylphosphonic acids and
amino acids esters was developed. The method is general and the corresponding N-Boc protected phosphonopeptides as well as their azido
analogs have been obtained in good yields. An ef®cient preparation of O-ethyl 1-azidoalkylphosphonic acids is also presented. q 2001
Elsevier Science Ltd. All rights reserved.
Among peptidomimetics, considerable attention is paid to
the phosphonopeptides1 obtained by the incorporation of an
aminoalkylphosphonic unit into the peptide framework.
Substitution of an amide bond for phosphonamidate bond
in the peptides leads to the phosphonopeptides in which
a tetrahedral phosphorus atom is a stable analog of the
tetrahedral transition states for many enzyme-catalyzed
reactions.1b
azide moieties we have recently become involved in the
application of diethyl 1-azidoalkylphosphonates30 in the
synthesis of diethyl 1-(isothiocyano)alkylphosphonates31
and phosphonopeptides with an N-terminal amino acid.32
In this context, we wish to report a new methodology for the
preparation of phosphonamidate peptides. To the best of
our knowledge there are no reports33 on the application of
O-ethyl 1-azidoalkylphosphonic acids as key reagents in the
synthesis of the above-mentioned phosphonopeptides.
The azido group is easily converted into an amine, thus
azidophosphonates can be considered to be azide-masked
equivalents of aminophosphonates or their N-protected
derivatives.
The syntheses of phosphonopeptides have been recently
reviewed.1a Most often phosphonamidate peptides are
prepared by coupling monoalkyl or monoaryl N-protected
aminoalkylphosphonochloridates with an appropriate amino
acid ester or suitably protected peptide.1a Phosphonochlori-
dates in turn have been usually obtained by reaction of
phosphonic monoesters with thionyl or oxalyl chloride,2±12
although cleavage of a single ester linkage in N-protected
phosphonate diesters by means of phosphorus penta-
chloride11,13±15 or oxidative chlorination of phosphinate
esters with carbon tetrachloride, using the Atherton±Todd
procedure were also reported.12,16
1.1. O-Ethyl 1-azidoalkylphosphonic acids 2
The preparation of phosphonic monoesters from the corre-
sponding symmetrical diesters usually involves either an
alkaline hydrolysis2,9b,13a,34±37 of such diesters or their selec-
tive dealkylation under non-hydrolytic conditions by means
of sodium iodide,38 lithium bromide39 and azide,40 tert-
butylamine8,41 or tertiary amines.42
On the other hand the utility of azides as masking groups for
amines has been demonstrated in many ®elds of organic synthe-
sis.17,18 The application of the azido acid derivatives as conveni-
ent reagents in peptide synthesis is also well documented.19±29
So far, O-alkyl 1-azidoalkylphosphonic acids have not been
systematically studied and a survey of the literature on this
subject reveals few publications.43±45 Initially a method for
selective dealkylation of diethyl 1-azidoalkylphosphonates
1 was developed. The starting diethyl 1-azidoalkylphos-
phonates30 1 are readily available from diethyl 1-hydro-
xyalkylphosphonates46 and hydrazoic acid by the
Mitsunobu reaction.18
1. Results and discussion
In connection with our interest in the chemistry of bifunc-
tional organic compounds containing both phosphorus and
Thus, treatment of diethyl 1-azidoalkylphosphonate 1 with
lithium bromide39b at 105±1108C, in 2-pentanone as a
solvent gave the corresponding lithium salt of 2. This in
turn was simply converted into a free acid 2 by the action
Keywords: phosphonopeptides; phosphonamidates; diethyl 1-azidoalkyl-
phosphonates; amino acids; O-ethyl 1-azidoalkylphosphonic acids.
Corresponding author. Tel.: 148-42-631-3146; fax: 148-42-636-5530;
p
e-mail: tmgajda@ck-sg.p.lodz.pl
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01143-1

1620
D. Sikora et al. / Tetrahedron 57 (2001) 1619±1625
in the presence of triethylamine as a base (Scheme 2). All
azido derivatives 5 thus formed were isolated in good yields
(50±70%) after ¯ash chromatography as an inseparable
mixture of isomers. Their structure was unequivocally
1
con®rmed by 31P and H NMR spectroscopy (Table 2).
Unmasking of the azide-masked amino group of an azido-
phosphonate often involves a catalytic reduction of the
azide moiety.47 Hence the azido derivative 5 was hydro-
genated at room temperature over 10% Pd/C under
3.06 atm pressure in the presence of di-tert-butyl dicarbo-
nate to give an analytically pure phosphonamidate peptide 6
in good yield (62±83%) after ¯ash chromatography. Our
attempt to resolve the diastereomeric mixture was unsuc-
cessful. The results are summarized in Table 2.
Scheme 1. Reagents and conditions: (a) LiBr/2-pentanone, 105±1108C,
2 h; (b) HCl aq./CH2Cl2.
of aqueous hydrogen chloride prior to which the removal of
traces of unreacted substrate with diethyl ether takes place
(Scheme 1). The monodealkylation described here is
general and O-ethyl 1-azidoalkylphosphonic acids 2 were
isolated in high yields (70±97%) and with good analytical
purity. The results are summarized in Table 1.
2. Conclusions
A new methodology (`azide approach') for the synthesis of
phosphonamidate peptides as well as their azido analogs
was developed. The method is general and novel phospho-
nopeptides were formed in good yields. Readily available
O-ethyl 1-azidoalkylphosphonic acids were used in this
protocol as stable azide-masked equivalents of N-protected
1-aminoalkylphosphonate derivatives. The advantage of
such an approach lies in the fact that no N-protection of
the phosphonic component is needed before the coupling
reaction. To improve the value of the above-mentioned
methodology an ef®cient synthesis of O-ethyl 1-azidoalkyl-
phosphonic acids was also developed.
Additionally, some O-ethyl 1-azidoalkylphosphonic acids 2
were also prepared under hydrolytic conditions by heating
diethyl 1-azidoalkylphosphonates 1 and aqueous potassium
hydroxide in ethanol. However, besides lower yields, the
above-mentioned procedure is limited to azidophosphonates
1 with alkyl substituents at C-1 only (Table 1, footnote b and
c, respectively). For the phenyl analog 1f the decomposition
of azide takes place under the reaction conditions (Table 1,
footnote d).
1.2. Phosphonamidate peptides 6
Having achieved an ef®cient synthesis of O-ethyl 1-
azidoalkylphosphonic acids 2, we proceeded with the syn-
thesis of phosphonamidate peptides 6 via the phosphono-
chloridate1a approach.
3. Experimental
NMR spectra were recorded on a Bruker AVANCE DPX
1
250 instrument at 250.13 MHz for H and at 62.9 MHz for
13C and 101.3 MHz for 13P NMR, respectively, in CDCl3
solution, using tetramethylsilane as internal and 85%
H3PO4 as external standard. Positive chemical shifts are
down®eld from external 85% H3PO4 for 31P NMR spectra.
Chemical shifts (d) are indicated in ppm and coupling
constants (J) in Hz. FAB/MS were recorded on a APO Elec-
tron (Ukraine) model MI 12001E mass spectrometer
equipped with a FAB ion source (thioglycerol matrix). IR
spectra were measured on a Specord M80 (Zeiss) instrument
and are reported in wavenumbers (cm21). Flash chroma-
tography was performed with glass column packed with
Baker silica gel (30±60 mm). Eluents: AcOEt (A); AcOEt/
MeOH 30/1 (B); CH2Cl2/MeOH 95/5 (C); CH2Cl2/MeOH
90/10 (D); Acetone (E). Melting points were determined in
open capillaries and are uncorrected. All reagents were
purchased from Fluka and used without further puri®cation.
The diethyl 1-azidoalkylphosphonates 1 were prepared
according to the literature procedure.30
For this purpose O-ethyl 1-azidoalkylphosphonic acid 2 was
quantitatively converted by means of oxalyl chloride7,8 into
O-ethyl 1-azidoalkylphosphonochloridate 3 (31P NMR:
dPˆ32.3 ppm for 3a) within two hours at room temperature.
Crude 3, after the removal of the excess of chlorinating
agent, was immediately coupled with an amino acid methyl
ester hydrochloride 4 to afford the corresponding azide-
masked phosphonopeptide 5. The above-mentioned reaction
was performed in methylene chloride at room temperature
Table 1. O-Ethyl 1-azidoalkylphosphonic acids 2a±g prepared
Entry
Compound
R1
Reaction
conditions
(time h,
Yield (%)a
temp 8C)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
H
Me
Et
i-Bu
i-Pr
Ph
p-BrC6H4
2, 105±110
2, 105±110
2, 105±110
2, 105±110
2, 105±110
2, 105±110
2, 105±110
97b
90c
73
82
77
78d
70
3.1. O-Ethyl 1-azidoalkylphosphonic acids (2a±g)Ð
general procedure
2g
a
Yields of pure 2 based on 1.
b
c
d
LiBr (0.0072 mol, 0.63 g) was added in one portion to a
solution of diethyl 1-azidoalkylphosphonate (1)
(0.006 mol) in 2-pentanone (3 mL). The mixture was heated
at 105±1108C for 2 h. Then the solvent was evaporated
Heating of 1a and aqueous KOH for 2 h in ethanol gave 2a in 78% yield.
Heating of 1b and aqueous KOH for 2 h in ethanol gave 2b in 83% yield.
Decomposition of the azide 1f occurred on heating with aqueous KOH in
ethanol.

D. Sikora et al. / Tetrahedron 57 (2001) 1619±1625
1621
Scheme 2. Reagents and conditions: (a) (COCl)2/DMF(cat.)/CH2Cl2, 08C to room temperature, 2 h; (b) Et3N/CH2Cl2, 08C to room temperature, 24 h; (c) H2/
10% Pd±C/Boc2O/AcOEt, 3.06 atm, room temperature, 4 h.
under reduced pressure, and the solid residue was washed
with diethyl ether (3£5 mL). The crude lithium salt of 2 was
suspended in CH2Cl2 (10 mL) and 20% HCl aq. was added
to the suspension until pH,1 was reached. Solid NaCl
(2.0 g) was added to the two-phase mixture, the organic
layer was separated and the aqueous layer extracted with
CH2Cl2 (2£5 mL). The combined extracts were dried over
anhydrous Na2SO4, the solvent evaporated under reduced
pressure and the rest of the volatile material was removed
at 308C/0.1 Torr to give analytically pure O-ethyl 1-
azidoalkylphosphonate 2 as a colorless or yellow oil
(Table 1).
3.1.1. O-Ethyl azidomethylphosphonic acid (2a).43 Yield:
1
97%, colorless oil; H NMR: dˆ1.39 (t, Jˆ7.25 Hz, 3H,
CH3), 3.50 (d, Jˆ12.26 Hz, 2H, CH2N3), 4.20 (qu,
Table 2. Azidophosphonamidates 5 and phosphonopeptides 6 prepared
Entry
Compound
R1
R2
Reaction conditions
(time h, temp 8C)
Yield (%)a
d.r.b
1
2
3
4
5
6
7
8
5aa
5ab
5ba
5bb
5da
5db
5fa
5fb
6aa
6ab
6ba
6bb
6da
6db
6fa
H
H
H
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
24, room temperature
24, room temperature
24, room temperature
24, room temperature
24, room temperature
24, room temperature
24, room temperature
24, room temperature
4, room temperature
4, room temperature
4, room temperature
4, room temperature
4, room temperature
4, room temperature
4, room temperature
4, room temperature
70
50
57
58
75
73
75
70
68
62
74
83
78
76
70
63
±
52:48
52:48
26:26:48
50:50
74:26
Me
Me
i-Bu
i-Bu
Ph
Ph
H
H
Me
Me
i-Bu
i-Bu
Ph
50:50
50:25:25
±
55:45
52:48
28:26:29:17
43:57
22:27:29:22
50:50
25:50:25
9
10
11
12
13
14
15
16
6fb
Ph
Me
a
Yields of pure azide 5 based on 1, or phosphonopeptide 6 based on 5.
Diastereomer ratio based on 31P NMR spectra of the crude reaction mixture. In some cases the signals overlap.
b

1622
D. Sikora et al. / Tetrahedron 57 (2001) 1619±1625
Jˆ7.25 Hz, 2H, CH2O), 11.68 (bs, 1H, OH); 31P NMR:
1H, CHN3), 6.47 (bs, 1H, OH), 7.31±7.40 (m, 5Harom); 31P
3
3
dˆ22.03; 13C NMR: dˆ16.28 (d, JPCˆ5.90 Hz, CH3),
NMR: dˆ21.11; 13C NMR: dˆ16.50 (d, JPCˆ5.91 Hz,
45.30 (d, 1JPCˆ158.68 Hz, CH2N3), 63.06 (d,
2JPCˆ6.81 Hz, CH2O); IR (®lm) nˆ2992, 2096, 1248,
1168, 1040; FAB/MS m/z (%): 166(100); Anal. Calcd for
C3H8N3O3P (165.09): C: 21.83; H: 4.88; N: 25.45. Found:
C: 21.70; H: 4.79; N: 25.32.
CH3), 61.75 (d, JPCˆ160.15 Hz, CHN3), 63.86 (d,
1
2JPCˆ7.30 Hz, CH2O), 128.58±132.67 (Carom); IR (®lm);
nˆ2984, 2104, 1240, 1112, 1040; FAB/MS m/z (%):
242(52); Anal. Calcd for C9H12N3O3P (241.19): C: 44.82;
H: 5.02; N: 17.42. Found: C: 44.71; H: 4.90; N: 17.33.
3.1.7. O-Ethyl azido(4-bromophenyl)methylphosphonic
3.1.2. O-Ethyl 1-azidoethylphosphonic acid (2b). Yield:
1
1
acid (2g). Yield: 70%, yellow oil; H NMR: dˆ1.27 (t,
90%, colorless oil; H NMR: dˆ1.38 (t, Jˆ7.25 Hz, 3H,
Jˆ7.00 Hz, 3H, CH3), 3.91±4.08 (m, 2H, CH2O), 4.64 (d,
Jˆ16.76 Hz, 1H, CHN3), 7.20±7.55 (m, 4H, AA0XX0 of p-
BrC6H4), 9.18 (bs, 1H, OH); 31P NMR: dˆ20.55; 13C NMR:
CH3), 1.49 (dd, Jˆ7.21,17.26 Hz, 3H, CH3), 3.58 (dq,
Jˆ7.25, 14.51 Hz, 1H, CHN3), 4.22 (qu, Jˆ7.25 Hz, 2H,
CH2O), 11.45 (bs, 1H, OH); 31P NMR: dˆ25.15; 13C
3JPCˆ5.89 Hz,
CH3),
60.67
(d,
2
dˆ16.16
(d,
NMR: dˆ13.69 (d, JPCˆ1.51 Hz, CH3), 16.36 (d,
2
1JPCˆ160.05 Hz, CHN3), 63.56 (d, JPCˆ7.38 Hz, CH2O),
122.78±131.65 (Carom); IR (®lm): nˆ2984, 2104, 1248,
1164, 1016, 788; FAB/MS m/z (%): 320/322(1); Anal.
Calcd for C9H11N3O3PBr (320.08): C: 33.77; H: 3.46; N:
13.13. Found: C: 33.63; H: 3.35; N: 12.99.
1
3JPCˆ5.98 Hz, CH3), 52.12 (d, JPCˆ161.14 Hz, CHN3),
2
62.92 (d, JPCˆ7.30 Hz, CH2O); IR (®lm): nˆ2984, 2120,
1208, 1128, 1036; FAB/MS m/z (%): 180(84); Anal. Calcd
for C4H10N3O3P (179.11): C: 26.82; H: 5.63; N: 23.46.
Found: C: 26.70; H: 5.54; N: 23.29.
3.1.3. O-Ethyl 1-azidopropylphosphonic acid (2c). Yield:
3.2. N-[Ethoxy(1-azidoalkyl)phosphinyl] amino acids
methyl esters (5aa±5fd)Ðgeneral procedure
1
73%, colorless oil; H NMR: dˆ1.11 (t, Jˆ7.25 Hz, 3H,
CH3), 1.38 (t, Jˆ7.00 Hz, 3H, CH3), 1.69±2.00 (m, 2H,
CH2), 3.28±3.43 (m, 1H, CHN3), 4.16±4.28 (m, 2H,
CH2O), 9.30 (bs, 1H, OH); 31P NMR: dˆ25.22; 13C
Oxalyl chloride (0.005 mol, 0.635 g, 0.44 mL) was added
via syringe to a cooled to 08C solution of O-ethyl 1-
azidoalkylphosphonic acid 2 (0.0025 mol) and DMF
(50 mL) in dry CH2Cl2 (8 mL). The mixture was stirred
for 30 min at 08C, and 1.5 h at room temperature. Then
the volatile material was carefully evaporated under reduced
pressure. The crude phosphonochloridate 3 was dissolved in
dry CH2Cl2 (5 mL) and the solution was added dropwise to
the mixture of amino acid methyl ester hydrochloride 4
(0.003 mol) and Et3N (0.02 mol, 2.02 g) in CH2Cl2
(15 mL), cooled to 08C. The resulting mixture was stirred
for 24 h at room temperature. The solvent and an excess of
Et3N were then evaporated, CHCl3 (50 mL) was added to
the semi-solid residue, and the mixture was successively
washed with water (5 mL), 1 M NaOH aq. (2£5 mL),
water (2£5 mL), 5% HCl aq. (2£5 mL), 5% NaHCO3 aq.
(2£5 mL) and water (2£5 mL). Organic layer was dried
over anhydrous MgSO4, solvent removed under reduced
pressure and the crude azide subjected to ¯ash chroma-
tography to give analytically pure N-[ethoxy(1-azidoalkyl)-
phosphinyl] amino acid methyl ester 5 as a yellow oil (Table
2).
2
NMR: dˆ11.22 (d, JPCˆ14.08 Hz, CH3), 16.26 (d,
3JPCˆ5.82 Hz, CH3), 21.85 (s, CH3), 58.89 (d,
2
1JPCˆ158.56 Hz, CHN3), 62.80 (d, JPCˆ7.29 Hz, CH2O);
IR (®lm): nˆ2976, 2104, 1230,1196, 1040; FAB/MS m/z
(%): 194(73); Anal. Calcd for C5H12N3O3P (193.14): C:
31.09; H: 6.26; N: 21.76. Found: C: 31.01; H: 6.20; N:
21.65.
3.1.4. O-Ethyl 1-azido-3-methylbutylphosphonic acid
1
(2d).44 Yield: 82%, pale yellow oil; H NMR: dˆ0.94,
0.99 (2d, Jˆ6.75 Hz, 6H, 2CH3), 1.39 (t, Jˆ7.00 Hz, 3H,
CH3), 1.53±1.96 (m, 3H, CH2, CH), 3.40±3.58 (m, 1H,
CHN3), 4.13±4.37 (m, 2H, CH2O), 10.11 (bs, 1H, OH);
31P NMR: dˆ25.83; 13C NMR: dˆ16.32 (d,
3JPCˆ5.74 Hz, CH3), 20.78 (s, CH3), 23.06 (s, CH3), 24.91
3
(d, JPCˆ13.74 Hz, CH), 36.55 (s, CH2), 55.25 (d,
2
1JPCˆ158.77 Hz, CHN3), 62.85 (d, JPCˆ7.32 Hz, CH2O);
IR (®lm): nˆ2960, 2104, 1216, 1084, 1048; FAB/MS m/z
(%): 222(66); Anal. Calcd for C7H16N3O3P (221.19): C:
38.01; H: 7.29; N: 19.00. Found: C: 37.93; H: 7.20; N:
18.91.
3.2.1. Methyl N-[ethoxy(azidomethyl)phosphinyl] glyci-
1
3.1.5. O-Ethyl 1-azido-2-methylpropylphosphonic acid
nate (5aa). Yield: 70%, pale yellow oil; Rfˆ0.25 (A); H
1
(2e). Yield: 77%, colorless oil; H NMR: dˆ1.07, 1.11
NMR: dˆ1.37 (t, Jˆ7.25 Hz, 3H, CH3), 3.24±3.35 (m, 1H,
NH), 3.50 (four lines, 1H, Jˆ15.0, 11.76 Hz, part A of the
ABX system, CH2P), 3.58 (four lines, 1H, Jˆ15.00,
11.76 Hz, part B of the ABX system, CH2P), 3.76 (s, 3H,
CH3O), 3.85 (dd, Jˆ7.00, 11.00 Hz, NCH2), 4.06±4.30 (m,
2H, CH2O); 31P NMR: dˆ24.35; IR (®lm) nˆ3456, 2960,
2096, 1752, 1256, 1112, 1036; FAB/MS m/z (%): 237 (100);
Anal. Calcd for C6H13N4O4P (236.17): C: 30.51; H: 5.55; N:
23.72. Found: C: 30.31; H: 5.51; N: 23.52.
(2d, Jˆ6.75 Hz, 6H, 2CH3), 1.37 (t, Jˆ7.25 Hz, 3H, CH3),
2.09±2.27 (m, 1H, CH), 3.37 (dd, Jˆ13.00, 5.25 Hz, 1H,
CHN3), 4.20 (qu Jˆ7.25 Hz, 2H, CH2O), 10.26 (bs, 1H,
OH); 31P NMR: dˆ24.36; 13C NMR: dˆ16.32 (d,
3
3JPCˆ6.06 Hz, CH3), 18.38 (d, JPCˆ6.43 Hz, CH3), 20.93
3
(d, JPCˆ10.59 Hz, CH3), 29.09 (bs, CH), 62.33 (d,
1
2JPCˆ7.28 Hz, CH2O), 64.07 (d, JPCˆ156.63, CHN3); IR
(®lm): nˆ2968, 2104, 1248, 1128, 1040; FAB/MS m/z (%):
208(39); Anal. Calcd for C6H14N3O3P (207.17): C: 34.78;
H: 6.81; N: 20.28. Found: C: 34.69; H: 6.72; N: 20.14.
3.2.2. Methyl N-[ethoxy(azidomethyl)phosphinyl]-l-
alanate (5ab). Yield: 50%; pale yellow oil; Rfˆ0.34 (B);
(the mixture of diastereomers); 1H NMR: dˆ1.36, 1.37 (2t,
Jˆ7.25 Hz, 3H, CH3), 1.43, 1.46 (2d, Jˆ6.75 Hz, 3H, CH3),
3.25±3.60 (m, 3H, CH2P, NH), 3.75, 3.76 (2s, 3H, CH3O),
3.1.6. O-Ethyl azidophenylmethylphosphonic acid (2f).
1
Yield: 78%, yellow oil; H NMR: dˆ1.24 (t, Jˆ7.05 Hz,
3H, CH3), 3.91±4.06 (2m, 2H, CH2O), 4.63 (d, Jˆ17.00 Hz,

D. Sikora et al. / Tetrahedron 57 (2001) 1619±1625
1623
4.05±4.26 (m, 3H, CH2O, NCH); 31P NMR: dˆ22.76, 23.59
(52:48); IR (®lm) nˆ3184, 2984, 2096, 1748, 1252, 1152,
1036; FAB/MS m/z (%): 251 (100); Anal. Calcd for
C7H15N4O4P (250.20): C: 33.60; H: 6.04; N: 22.39.
Found: C: 33.40; H: 5.92; N: 22.23.
1036, 700; FAB/MS m/z (%): 313(78); Anal. Calcd for
C12H17N4O4P (312.26); C: 46.16; H: 5.49; N: 17.94.
Found: C: 46.03; H: 5.38; N: 17.81.
3.2.8. Methyl N-[ethoxy(azidophenylmethyl)phosphinyl]-
l-alanate (5fb). Yield: 70%, yellow oil; Rfˆ0.49 (B); (the
mixture of diastereomers); 1H NMR: dˆ1.14±1.39 (m, 6H,
2CH3), 3.02±3.40 (m, 1H, NH), 3.70, 3.71, 3.72 (3s, 3H,
CH3O), 3.75±4.23 (m, 3H, OCH2, NCH), 4.70, 4.73, 4.79,
4.80 (4d, Jˆ16.00 Hz, 1H, N3CH), 7.33±7.44 (m, 5Harom);
31P NMR: dˆ22.06, 22.34, 22.78 (50:25:25); IR (®lm):
nˆ3216, 3080, 2104, 1744, 1456, 1224, 1152, 1032, 700;
FAB/MS m/z (%): 327(76); Anal. Calcd for C13H19N4O4P
(326.29); C: 47.85; H: 5.87; N: 17.17. Found: C: 47.68; H:
5.79; N: 17.12.
3.2.3. Methyl N-[ethoxy(1-azidoethyl)phosphinyl] glyci-
nate (5ba). Yield: 57%; yellow oil; Rfˆ0.50 (B); (the
mixture of diastereomers); 1H NMR: dˆ1.37 (bt,
Jˆ7.00 Hz, 3H, CH3), 1.45, 1.52 (2dd, Jˆ7.25, 16.25 Hz,
3H, CH3), 3.18±3.26 (m, 1H, NH), 3.51±3.76 (m, 1H,
CHP), 3.78, 3.81 (2s, 3H, CH3O), 3.82±3.91 (m, 2H,
NCH2), 4.10±4.30 (m, 2H, CH2O); 31P NMR: dˆ27.19,
27.52 (52:48); IR (®lm) nˆ3190, 2985, 2100, 1750, 1250,
1140, 1038; FAB/MS m/z (%): 251 (100); Anal. Calcd for
C7H15N4O4P (250.19): C: 33.60; H: 6.04; N: 22.39. Found:
C: 33.52; H: 5.99; N: 22.21.
3.3. N-[Ethoxy(1-N-t-butoxycarbonylaminoalkyl)phosphinyl]
amino acids methyl esters 6aa±6fbÐgeneral procedure
3.2.4. Methyl N-[ethoxy(1-azidoethyl)phosphinyl]-l-
alanate (5bb). Yield: 58%; yellow oil; Rfˆ0.41 (B); (the
A solution of N-[ethoxy(1-azidoalkyl)phosphinyl] amino
acid methyl ester 5 (0.001 mol) in ethyl acetate (30 mL)
was hydrogenated at room temperature for 4 h over 10%
Pd/C (70 mg) under a pressure of 3.06 atm in the presence
of di-tert-butyl dicarbonate (0.0012 mol, 0.262 g). The cata-
lyst was removed by ®ltration through Celite, and the ®ltrate
was successively washed with 1 M KHSO4 (2£5 mL), water
(5 mL), 5% NaHCO3 aq. (2£5 mL) and water (5 mL).
The organic layer was dried over anhydrous MgSO4, the
solvent removed under reduced pressure and the crude phos-
phonopeptide was subjected to ¯ash chromatography to
give analytically pure N-[ethoxy(1-N-t-butoxycarbonyl-
aminoalkyl)phosphinyl] amino acid methyl ester 6 as a
yellow oil or colorless crystals (Table 2).
1
mixture of diastereomers); H NMR: dˆ1.23, 1.24 (2t,
Jˆ7.25 Hz, 3H, CH3), 1.30±1.54 (m, 6H, CH3, CH3CP),
3.18±3.30 (m, 1H, NH), 3.37±3.65 (m, 1H, CHP), 3.72,
3.73, 3.74 (3s, 3H, CH3), 4.03±4.20 (m, 3H, CH2O, CH);
31P NMR: dˆ25.71, 26.51, 26.69 (26:26:48); IR (®lm)
nˆ3256, 2992, 2120, 1744, 1204, 1152, 1024; FAB/MS
m/z (%): 265 (100); Anal. Calcd for C8H17N4O4P
(264.22): C: 36.37; H: 6.49; N: 21.20. Found: C: 36.17;
H: 6.38; N: 21.07.
3.2.5. Methyl N-[ethoxy(1-azido-3-methylbutyl)phos-
phinyl] glycinate (5da). Yield: 75%, yellow oil; Rfˆ0.45
(B); (the mixture of diastereomers); 1H NMR: dˆ0.94, 0.95,
0.98, 1.00 (4d, Jˆ6.50 Hz, 6H, 2CH3), 1.36, 1.37 (2t,
Jˆ7.00 Hz, 3H, CH3), 1.57±1.60 (m, 1H, CH), 1.60±1.98
(m, 2H, CH2), 3.20±3.35 (m, 1H, NH), 3.38±3.63 (m, 1H,
CHN3), 3.76, 3.77 (2s, 3H, CH3O), 3.80±3.96 (m, 2H,
NCH2), 4.06±4.30 (m, 2H, OCH2); 31P NMR: dˆ27.35,
27.48 (50:50); IR (®lm): nˆ3208, 2960, 2112, 1756,
1440, 1216, 1152, 1036; FAB/MS m/z (%): 293(100);
Anal. Calcd for C10H21N4O4P (292.27): C: 41.09; H: 7.24;
N: 19.17. Found: C: 40.94; H: 7.12; N: 19.03.
3.3.1. Methyl N-[ethoxy(N-t-butoxycarbonylamino-
methyl)phosphinyl] glycinate(6aa). Yield: 68%; colorless
1
prisms, mp 77±798C; Rfˆ0.21 (C); H NMR: dˆ1.32 (t,
Jˆ7.00 Hz, 3H, CH3), 1.44 (s, 9H, 3CH3), 3.15 (bs, 1H,
NH), 3.35±3.70 (m, 2H, CH2P), 3.74 (s, 3H, CH3O),
3.74±3.84 (m, 2H, NCH2), 4.04±4.21 (m, 2H, CH2O),
5.16 (bs, 1H, NHBoc); 31P NMR: dˆ27.75; IR (®lm)
nˆ3304, 2974, 1752, 1712, 1528, 1368, 1204, 1152,
1040; FAB/MS m/z (%): 311 (25); Anal. Calcd for
C11H23N2O6P (310.29): C:42.58; H: 7.47; N: 9.03. Found:
C: 42.42; H: 7.31; N: 8.89.
3.2.6. Methyl N-[ethoxy(1-azido-3-methylbutyl)phos-
phinyl]-l-alanate (5db). Yield: 73%, yellow oil; Rfˆ0.42
(C); (the mixture of diastereomers); 1H NMR: dˆ0.93, 0.94,
0.98, 1.00 (4d, Jˆ6.50 Hz, 6H, 2CH3), 1.35, 1.37 (2t,
Jˆ7.00 Hz, 3H, CH3), 1.41±1.47 (m, 3H, CH3), 1.53±1.90
(m, 3H, CH2, CH), 3.10±3.60 (m, 2H, NCH, NH), 3.75, 3.76
(2s, 3H, CH3O), 4.00±4.25 (m, 3H, OCH2, N3CH); 31P
NMR: dˆ25.86, 26.67 (74:26); IR (®lm): nˆ3200, 2960,
2112, 1748, 1448, 1220, 1156, 1036; FAB/MS m/z (%):
307(89); Anal. Calcd for C11H23N4O4P (306.30); C: 43.13;
H: 7.57; N: 18.29. Found: C: 43.00; H: 7.48; N: 18.11.
3.3.2. Methyl N-[ethoxy(N-t-butoxycarbonylamino-
methyl)phosphinyl]-l-alanate (6ab). Yield: 62%; yellow
1
oil; Rfˆ0.57 (E); (the mixture of diastereomers), H NMR:
dˆ1.26, 1.31 (2t, Jˆ7.25 Hz, 3H, CH3), 1.39, 1.42 (2d,
Jˆ7.00 Hz, 3H, CH3), 1.44, 1.45 (2s, 9H, 3CH3), 3.25±
3.69 (m, 3H, CH2P, NH), 3.74 (s, 3H, CH3O), 4.02±4.16
(m, 3H, CH2O, CH), 4.96, 5.08 (2bs, 1H, NHBoc); 31P
NMR: dˆ26.55, 27.20 (55:45); IR (®lm) nˆ3344, 2984,
1812, 1752, 1712, 1512, 1368, 1256, 1212, 1120, 1068;
FAB/MS m/z (%): 325 (17); Anal. Calcd for C12H25N2O6P
(324.32): C: 44.44; H: 7.77; N: 8.64. Found: C: 44.25; H:
7.61; N: 8.52.
3.2.7. Methyl N-[ethoxy(azidophenylmethyl)phosphinyl]
glycinate (5fa). Yield: 75%, yellow oil; Rfˆ0.55 (D); (the
1
mixture of diastereomers); H NMR: dˆ1.31, 1.34 (2t,
Jˆ7.00 Hz, 3H, CH3), 3.07±3.18 (m, 1H, NH), 3.53±3.70
(m, 2H, NCH2), 3.73 (s, 3H, CH3O), 4.01±4.28 (m, 2H,
OCH2), 4.77, 4.82 (2d, Jˆ15.76 Hz, 1H, CHN3), 7.35±
7.47 (m, 5Harom); 31P NMR: dˆ23.01, 23.26 (50:50); IR
(®lm): nˆ3328, 2984, 2104, 1752, 1496, 1216, 1148;
3.3.3. Methyl N-[ethoxy(1-N-t-butoxycarbonylamino-
ethyl)phosphinyl] glycinate (6ba). Yield: 74%; colorless
needles, mp 86±888C (dec); Rfˆ0.38 (B); (the mixture of
diastereomers); 1H NMR: dˆ1.31, 1.32 (2t, Jˆ7.00 Hz, 3H,

1624
D. Sikora et al. / Tetrahedron 57 (2001) 1619±1625
CH3), 1.36 (dd, Jˆ7.25, 16.75 Hz, 3H, CH3), 1.43, 1.45 (2s,
9H, 3CH3), 3.10±3.24 (m, 1H, NH), 3.74, 3.75 (2s, 3H,
CH3O), 3.76±3.85 (m, 2H, NCH2), 3.98±4.21 (m, 3H,
CH2O, CHP), 4.76, 5.00 (2bd, Jˆ8.75 Hz, 1H, NHBoc);
31P NMR: dˆ30.04, 30.88 (52:48); IR (®lm) nˆ3330,
1750, 1715, 1521, 1261, 1214, 1162, 1043; FAB/MS m/z
(%): 325 (47); Anal. Calcd for C12H25N2O6P (324.32): C:
44.44; H: 7.77; N: 8.64. Found: C: 44.31; H: 7.63; N: 8.49.
3.3.8. Methyl N-[ethoxy(N-t-butoxycarbonylaminophenyl-
methyl)phosphinyl]-l-alanate (6fb). Yield: 63%, colorless
needles, mp 102±1048C; Rfˆ0.68 (B); (the mixture of
diastereomers); 1H NMR:dˆ1.04±1.20 (m, 3H, CH3),
1.26±1.33 (m, 3H, CH3), 1.41 (bs, 9H, 3CH3), 2.95±3.35
(m, 1H, NH), 3.67, 3.68, 3.72, 3.74 (4s, 3H, OCH3), 3.82±
3.96 (m, 1H, NCH), 4.01±4.17 (m, 2H, OCH2), 4.92±5.03
(m, 1H, PhCH), 5.54±5.80 (m, 1H, NHBoc), 7.30±7.40 (m,
5Harom); 31P NMR: dˆ25.48, 25.80, 25.90 (25:50:25); IR
(®lm): nˆ3328, 3088, 1748, 1684, 1496, 1208, 1160,
1044, 788; FAB/MS m/z (%): 401(12); Anal. Calcd for
C18H29N2O6P (400.41); C: 53.99; H: 7.30; N: 7.00. Found:
C: 53.81; H: 7.22; N: 6.89.
3.3.4. Methyl N-[ethoxy(1-N-t-butoxycarbonylamino-
ethyl)phosphinyl]-l-alanate (6bb). Yield: 83%; colorless
solid, mp 94±968C (dec); Rfˆ0.41 (B); (the mixture of
1
diastereomers); H NMR: dˆ1.28±1.45 (m, 18H, 6CH3),
3.13±3.27 (m, 1H, NH), 3.74, 3.75 (2s, 3H, CH3O), 3.90±
4.20 (m, 4H, CH2O, NCH, CHP), 4.60±4.75, 4.80±4.95
(2m, 1H, NHBoc); 31P NMR: dˆ28.85, 29.39, 30.01,
30.27 (28:26:29:17); IR (®lm) nˆ3368, 3200, 2960, 1736,
1728, 1708, 1696, 1688, 1516, 1300, 1276, 1160, 1048;
FAB/MS m/z (%): 339 (37); Anal. Calcd for C13H27N2O6P
(338.34): C: 46.15; H: 8.04; N: 8.28. Found: C: 45.95; H:
7.84; N: 8.18.
Acknowledgements
The ®nancial support of this work by the Polish State
Committee for Scienti®c Research under grant number 3
T09A 103 14 is gratefully acknowledged.
3.3.5. Methyl N-[ethoxy(1-N-t-butoxycarbonylamino-3-
methylbutyl)phosphinyl] glycinate (6da). Yield: 78%,
colorless solid, mp 105±1088C; Rfˆ0.42 (B); (the mixture
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