A new synthesis of protected phosphonodipeptides with an N-terminal amino acid

Article abstract of DOI:10.1016/S0040-4020(00)00283-0

A new simple protocol for the direct synthesis of phosphonodipeptides from N-protected amino acids, diethyl 1-azidoalkylphosphonates and tertiary alkyl phosphine (Bu₃P, Me₃P) was developed. The method is general and the coupling occurred with good yield (42-97%). Depending on the phosphine used and/or mechanism operating during the condensation, the reaction can be accomplished at room temperature, or on heating in toluene. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00283-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3755±3761
A New Synthesis of Protected Phosphonodipeptides
with an N-Terminal Amino Acid
*
Dorota Sikora and Tadeusz Gajda
Ç
Institute of Organic Chemistry, Technical University (Politechnika), Zeromskiego St. 116, 90-924 Lodz, Poland
Received 28 January 2000; revised 13 March 2000; accepted 30 March 2000
AbstractÐA new simple protocol for the direct synthesis of phosphonodipeptides from N-protected amino acids, diethyl 1-azidoalkyl-
phosphonates and tertiary alkyl phosphine (Bu3P, Me3P) was developed. The method is general and the coupling occurred with good yield
(42±97%). Depending on the phosphine used and/or mechanism operating during the condensation, the reaction can be accomplished at
room temperature, or on heating in toluene. q 2000 Elsevier Science Ltd. All rights reserved.
Phosphonate analogs of a-amino acids and their deriva-
tives1 have received considerable attention in bioorganic
and medicinal chemistry due to their unique biological
activities.2 In turn, the peptide mimeticsÐphosphonopep-
tides can be obtained by different methods3 but generally,
the reactions employed in the formation of the peptide bond
between 1-aminoalkylphosphonates and amino acids are
similar to those used in standard peptide chemistry. Thus,
the diester of the 1-aminoalkylphosphonate is directly
coupled with the N-protected amino acid mostly by means
of dicyclohexylcarbodiimide as condensation agent, or the
carboxylic moiety is activated by formation of mixed
anhydrides prior to condensation.4
enables the synthesis of N-protected amines without the
necessity of azide reduction prior to coupling.
Results and Discussion
In connection with our interest in the chemistry of bifunc-
tional organic compounds containing both phosphorus and
nitrogen moieties we have recently become engaged in the
application of diethyl 1-azidoalkylphosphonates17 1 in the
synthesis of diethyl 1-(isothiocyano)alkylphosphonates18
and derivatives of 1-[1-(diethoxyphosphoryl)alkyl]-1H-
1,2,3-triazoles.19
An alternative synthesis of carboxamides from carboxylic
acids could also be realized in a one-pot reaction of a
carboxylic acid, azide and tertiary alkyl or aryl phosphine
under non-acidic conditions, by taking advantage of the
Staudinger reaction (formation of phosphine imines from
azides and tertiary phosphines).5 In this way, several
carboxamides and small peptides were successfully
obtained.6±13 Also carboxylic mixed anhydrides were
successfully applied as substrates in the synthesis of small
peptides from azidoesters and trialkylphosphines.14,15 The
above mentioned reactions were proved to proceed without
the epimerisation at the stereogenic center of the a-amino
acid.8,15
Herein, we wish to report a new application of the above-
mentioned reagent 1 in the synthesis of phosphonopeptides
6 with N-terminal amino acids (Scheme 1). To the best of
our knowledge there are no reports20 on the application of
Staudinger reaction based methodology for the preparation
of phosphonopeptides.
Starting diethyl 1-azidoalkylphosphonates17 1 are easily
available from diethyl 1-hydroxyalkylphosphonates21 and
hydrazoic acid by the Mitsunobu reaction.22 The above-
mentioned azides 1 are stable, distillable liquids and can
be stored for unlimited periods of time in a refrigerator
without any signs of decomposition. Several N-benzyloxy-
carbonyl and N-t-butyloxycarbonyl amino acids 4 as well as
N-t-butyloxycarbonyl-N-methyl valine were used as acid
components.
Since azides16 are excellent and often used precursors of the
amino group, the above presented synthetic approach
Thus, according to Scheme 1, diethyl 1-azidoalkylphospho-
nate 1 was converted by the Staudinger reaction5 with
appropriate phosphine 2 into the respective iminophosphor-
ane 3. This in turn, by reaction with an N-protected amino
acid 4, was transformed via the intermediate salt 5 into the
Keywords: phosphonopeptides; diethyl 1-azidoalkylphosphonates; amino
acids; phosphines; phosphine imines; Staudinger reaction.
* Corresponding author. Tel.: 148-42-631-3146; fax: 148-42-636-5530;
e-mail: tmgajda@ck-sg.p.lodz.pl
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00283-0

3756
D. Sikora, T. Gajda / Tetrahedron 56 (2000) 3755±3761
Scheme 1. Reagents and conditions: (a) Toluene, room temperature, 1.5 h; (b) Toluene, 80±858C or re¯ux, 3±12 h or room temperature, 24 h±3 days.
Table 1. Phosphonopeptides 6aa±6bd prepared via the iminophosphorane route
Entry
Compound
R3P
R1
PG-Aa-OH
Reaction conditions
(time, temp 8C)
Yield (%)a
[a]D (c) (MeOH)
1
2
3
4
5
6
7
8
6aa
6ab
6ac
6ad
6ae
6af
6ag
6ah
6ai
Bu3P
H
Z-Gly-OH
12h, 80±85
3 h, 80±85
58
63
92
±
Boc-(l)-Ala-OH
Z-(l)-Ala-OH
Z-(l)-Val-OH
222.69 (1.04)
223.28 (0.76)
222.40 (0.54)
211.11e (0.62)
123.18 (0.91)
214.33 (1.05)
27.30 (0.78)
257.13 (0.74)
165.06 (0.77)
222.12 (2.26)
210.50 (3.34)
256.46 (1.81)
214.88h (0.77)
255.71 (0.14)
±
8 h, 80±85
12 h, 80±85
76
Z-(l)-Phe-OH
12 h, 80±85b
4 h, 80±85
67c,d
97
Boc-(d)-Met-OH
Z,Z-(l)-Lys-OH
Boc-(l)-Trp-OH
Z-(l)-Pro-OH
Boc-(d)-N(Me)-Val-OH
Z-(l)-Ala-OH
Z-(l)-Phe-OH
Z-(l)-Pro-OH
Z-(l)-Ala-OH
Z-(l)-Pro-OH
Boc-(D,L)-N(Me)-Val-OH
Z-(l)-Ala-OH
Z-(l)-Pro-OH
4 h, 80±85
4 h, 80±85
12 h, 80±85
5 h, re¯ux
24 h, room temperature
24 h, room temperature
48 h, room temperature
8 h, 80±85
10 h, re¯ux
5 h, re¯ux
68
73
93
63
63
62
9
10
11
12
13
14
15
16
17
18
19
6aj
6ac
6ae
6ai
6ba
6bb
6bc
6ba
6bb
6bd
Me3P
Bu3P
Me3P
H
59
Me
Me
42f,g
63
62
65
70
67
3 days, room temperature
3 days, room temperature
3 days, room temperature
29.42h (1.21)
243.26 (1.04)
22.19 (0.73)
Z-(l)-Phe-OH
a Yields of pure phosphonopeptides 6, based on 1.
b No peptide formation was observed after 24 h at room temperature.
c Also independently synthesized from Z-Phe-OH and diethyl aminomethylphosphonate25 via mixed anhydride method24 with i-BuOCOCl; yield: 47%, mp
100±1028C, [a]Dˆ210.94 (c 0.8, MeOH).
d For the reaction with Ph3P instead of Bu3P about 65% of conversion was achieved after 12 h in boiling toluene.
e Lit.26: [a]Dˆ29.8 (EtOH).
f Also independently synthesized from Z-Phe-OH and diethyl 1-aminoethylphosphonate25 via mixed anhydride method24 with i-BuOCOCl; yield: 55%, oil,
[a]Dˆ215.18 (c 0.9, MeOH).
g For the reaction with Ph3P instead of Bu3P about 40% of conversion was achieved after 24 h in boiling toluene.
h Lit.27: [a]Dˆ29.8 (MeOH).

D. Sikora, T. Gajda / Tetrahedron 56 (2000) 3755±3761
3757
corresponding phosphonodipeptide 6. The above-mentioned
reaction was performed in toluene at room temperature or
on heating, depending on the reactivity of the iminophos-
phorane 3 used. The results are summarized in Table 1. All
phosphonodipeptides 6 thus formed were isolated in good
overall yields (42±93%) and their structures were unequi-
to give the expected peptides 6ae and 6ba with 47 and
55% yield, respectively, (see footnote c and f to Table 1).
The products resulting from these two methods were in all
cases shown to be identical by their optical rotation values
1
and 31P and H NMR spectroscopy.
1
vocally con®rmed by 31P and H NMR spectroscopy.
The progress of the reactions shown in Scheme 1 can be
easily monitored by 31P NMR spectroscopy. Thus, after
mixing the diethyl 1-azidoethylphosphonate17 1b
(dPˆ22.8 ppm) with Bu3P 2b (dPˆ230.0 ppm) and the
evolution of N2 at room temperature, the signals of
substrates disappeared and the new set of absorption of
iminophosphorane 3 was observed at dPˆ28.05d and
30.55d ppm respectively with Jˆ30.38 Hz. The signals of
3 vanished, after the addition of N-(benzyloxycarbonyl)-(l)-
alanine and two new doublets of the salt 5 appeared at
dPˆ24.68d and 58.16d ppm, respectively (Jˆ8.1 Hz).
Heating of the reaction mixture caused slow transformation
of 5 into the ®nal product 6ba (dPˆ25.83 and 25.94 ppm)
and tributylphosphine oxide (dPˆ49.2 ppm). Unfortunately
no additional pentacovalent phosphorus intermediate was
observed in 31P NMR spectroscopy.7,8,11,28
The coupling of 1 with 4 by means of tributylphosphine 2b
needs heating of the reaction mixture in toluene at 80±858C
or in re¯ux. The condensation of amino acids 4 by means of
Bu3P 2b with the more hindered diethyl 1-azidoethyl-
phosphonate 1b requires heating of the reaction mixture in
boiling toluene for completion (Table 1, entry 15 and 16).
At the temperature 80±858C the desired phosphonodi-
peptide 6ba was also formed but with a lower yield
(Table 1, entry 14). Triphenylphosphine is less reactive
than Bu3P (see footnote d and g to Table 1).
The replacement Bu3P 2b with Me3P23 2a enables the
coupling at room temperature (Table 1, entry 11±13 and
17±19), however prolonged time is necessary for com-
pleting the reaction. The application of Me3P eliminates
the need for chromatography as the way of isolating the
®nal product 6 since the by-product, trimethylphosphine
oxide, can be simply washed away with water. The scope of
the above mentioned synthesis can be easily broadened to the
derivatives of N-methyl amino acids (Table 1, entry 10 and 16).
On the other hand Inazu et al.12,13 have suggested that the
formation of the amide bond from glycosyl azide and
N-protected amino acids by means of trialkylphosphine
has occurred via the intermediate triazaphosphadiene5b,c,15
instead of iminophosphorane at 2788C. Following this and
other observations15,28 we found that if the reaction between
diethyl 1-azidoalkylphosphonates 1, N-protected amino
acids 4, and tributylphosphine 2b has been accomplished
in toluene at 2158C to room temperature, the appropriate
phosphonodipeptide 6 was formed in moderate yield, as
depicted in Scheme 2. The results are summarized in
Table 2.
To compare the methodology proposed here with the
existing methods4 compounds 6ae and 6ba were addition-
ally synthesized via the mixed anhydride method.24 Thus,
the mixed anhydride from N-(benzyloxycarbonyl)-(l)-
phenylalanine and isobutyl chloroformate was coupled
with diethyl azidomethyl- and 1-azidoethylphosphonate25
Scheme 2. Reagents and conditions: (a) Toluene, 2158C, 30 min; (b) Toluene, 2158C to room temperature, 24 h.

3758
D. Sikora, T. Gajda / Tetrahedron 56 (2000) 3755±3761
Table 2. Phosphonopeptides (6ae±6ca) obtained via the triazaphosphadiene approach
Entry
Compound
R1
PG-Aa-OH
Reaction conditions
(time, temp 8C)
Yield (%)a
[a]D (c) (MeOH)
1
2
3
6ae
6af
6ba
H
H
Me
Z-(l)-Phe-OH
Boc-(d)-Met-OH
Z-(l)-Ala-OH
24 h, room temperature
24 h, room temperature
24 h, room temperature
55
52
46
210.14 (0.54)
122.08 (1.0)
215.83 (1.0)
a Yields of pure phosphonopeptides 6, based on 1.
It should be stressed that in this case, unlike the reactions
described in Scheme 1, the formation of the amide bond
with the participation of Bu3P 2b occurs at room tempera-
ture. According to the literature,12,13 we assume that the
generation of 6 would proceed via the intermediate triaza-
phosphadiene 7 as a result of the concerted evolution of
nitrogen, intramolecular amide formation, and elimination
of tributylphosphine oxide from 8 (Scheme 2).
diethyl 1-azidoalkylphosphonates,17 (1) were prepared
according to the literature procedure.
Preparation of phosphonopeptides (6aa±6bd) via the
iminophosphorane routeÐgeneral procedure
Reaction with tributylphosphine. Bu3P (2b) (0.0021 mol,
0.425 g) was added in one portion to a cooled (ice-water
bath) solution of the diethyl 1-azidoalkylphosphonate (1)
(0.002 mol) in anhydrous toluene (5 mL). Vigorous evolu-
tion of the nitrogen took place. The water bath was removed
and the solution was stirred for 1.5 h at room temperature.
Then the N-protected amino acid (4) (0.0021 mol) was
added in one portion. The solution was heated at 80±858C
or under re¯ux for the time given (see Table 1 for details).
The resulting mixture was evaporated under reduced
pressure. The oily residue was dissolved in CH2Cl2
(25 mL), washed successively with H2O (5 mL), 5%HCl
aq. (5 mL), H2O (5 mL), 5% NaHCO3 aq. (2£5 mL), and
H2O (5 mL). Organic layer was dried over anhydrous
Na2SO4, and the residue was subjected to ¯ash chroma-
tography to give pure phosphonodipeptide (6) (Table 1) as
a yellow oil or colorless solid.
Conclusions
In summary the protocol described here provides a new and
simple access to phosphonodipeptides with N-terminal
amino acids from readily accessible starting materials.
The method is general and the coupling occurred with
good yield. Several differentially N-protected amino acids
were used without the necessity of activation of the carboxyl
group. The reaction can be also extended to N-methyl
derivatives of amino acids. Generally coupling is not very
sensitive to steric hindrance on the a-substituent of the
amino acid moiety, and the presence of an alkyl group on
the a-carbon of the azidophosphonate has insigni®cant
in¯uence on the yields of condensation. Depending on the
phosphine used and/or mechanism operating during the
condensation, reaction can be conducted at room tempera-
ture or at elevated temperature. Additionally the application
of the trimethylphosphine allows elimination of chroma-
tography as a method of isolation of ®nal products.
Reaction with trimethylphosphine. Me3P (2a) (0.004 mol,
1 M solution in toluene) was slowly added via syringe to a
cooled (ice-water bath) solution of the diethyl 1-azido-
alkylphosphonate (1) (0.003 mol) in anhydrous toluene
(5 mL). The vigorous evolution of the nitrogen took place.
The water bath was removed and the solution was stirred for
1 h at room temperature. Then the N-protected amino acid
(4) (0.0036 mol) was added in one portion, and the solution
was stirred at room temperature for the time given (see
Table 1 for details). The excess of Me3P was removed
under reduced pressure. The residue was diluted with
toluene (100 mL), washed successively with H2O (2 mL),
5% HCl aq. (2 mL), H2O (2 mL), 5% NaHCO3 aq.
(2£2 mL), H2O (2 mL), and dried over anhydrous Na2SO4.
Toluene was evaporated and the rest of volatile material was
removed at 408C/0.04 Torr to give pure phosphonodi-
peptides (6) (Table 1).
Experimental
NMR spectra were recorded on a Bruker DPX 250 instru-
1
ment at 250.13 MHz for H and 101.3 MHz for 13P NMR,
respectively, in CDCl3 solution, using tetramethylsilane as
internal and 85% H3PO4 as ext. standard, respectively. Posi-
tive chemical shifts are down®eld from ext. 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 Electron (Ukraine) Modell MI 12001E mass spectro-
meter equipped with a FAB ion source (thioglycerol
matrix). IR spectra were measured on a Specord M80
(Zeiss) instrument and are reported in wavenumbers
(cm21). Optical rotations were measured in 1 dm cell on a
Horiba polarimeter. Flash chromatography was performed
with glass column packed with Baker silica gel (30±
60 mm). Eluents: CH2Cl2/MeOH 90/10 (A); Acetone/
MeOH 30/1 (B); AcOEt/MeOH 30/1 (C); AcOEt/MeOH
15/1 (D); Acetone/hexanes 10/1 (E); CH2Cl2/MeOH 95/5
(F); Acetone (G). Melting points were determined in open
capillaries and are uncorrected. All reagents were purchased
from Fluka and used without further puri®cation. The
Preparation of phosphonopeptides (6ae±6ca) via the
triazaphosphadiene routeÐgeneral procedure
Bu3P (2b) (0.0022 mol, 0.445 g) was slowly added (10 min)
to a cooled to 2158C solution of the diethyl 1-azidoalkyl-
phosphonate (1) (0.002 mol), and the N-protected amino
acid (4) (0.0022 mol) in anhydrous toluene (5 mL). The
resulting solution was kept for 15 min at this temperature
and the mixture was stirred for 24 h at room temperature
(see Table 2 for details). The solution was diluted with
CH2Cl2 (25 mL), washed successively with H2O (5 mL),

D. Sikora, T. Gajda / Tetrahedron 56 (2000) 3755±3761
3759
5% HCl aq. (5 mL), H2O (5 mL), 5% NaHCO3 aq.
(2£5 mL), and H2O (5 mL). Organic layer was dried over
anhydrous Na2SO4, and the residue was subjected to ¯ash
chromatography to give pure phosphonodipeptides
(6ae±6ba) (Table 2).
A of the AB system, Jˆ12.25 Hz, 1H, CH), 5.07 (part B of
the AB system, Jˆ12.25 Hz, 1H, CH), 5.44 (bd, Jˆ8.0 Hz,
1H, NH), 6.47±6.53 (m, 1H, NH), 7.15±7.40 (m, 10Harom);
31P NMR: dˆ22.58; IR (®lm): nˆ3264, 3064, 2984, 1720,
1698, 1668, 1536, 1456, 1252, 1028, 760, 704; FAB/MS m/z
(%): 449 (55); Anal. Calcd for C22H29N2O6P (448.45): C;
58.92; H: 6.52; N: 6.25. Found: C; 58.89; H: 6.44; N: 6.14.
Diethyl (N-benzyloxycarbonyl-glycyl)aminomethylphos-
phonate29 (6aa). Yield: 58%, colorless oil; Rfˆ0.50 (A); 1H
NMR: dˆ1.31 (t, Jˆ7.25 Hz, 6H, 2CH3), 3.70 (dd, Jˆ5.75,
12.0 Hz, 2H, CH2), 3.92 (d, Jˆ5.25 Hz, 2H, CH2), 4.11 (qu,
Jˆ7.25 Hz, 4H, 2CH2), 5.12 (s, 2H, CH2), 5.69 (bs, 1H,
NH), 6.88 (bs, 1H, NH), 7.28±7.36 (m, 5Harom); 31P NMR:
dˆ22.85; IR (®lm): nˆ3264, 1720, 1700, 1600, 1532, 1456,
1392, 1248, 1160, 1024, 976, 740, 700; FAB/MS m/z (%):
359 (59); Anal. Calcd for C15H23N2O6P (358.33): C; 50.28;
H: 6.47; N: 7.82. Found: C; 50.09; H: 6.31; N: 7.70.
Diethyl (N-t-butyloxycarbonyl-d-methionyl)aminomethyl-
phosphonate (6af ). Yield: 97%, colorless needles, mp 79±
1
818C; Rfˆ0.30 (C); H NMR: dˆ1.33, 1.34 (2t, Jˆ7.0 Hz,
6H, 2CH3), 1.45 (s, 9H, 3CH3), 1.82±2.20 (m, 2H, CH2),
2.11 (s, 3H, CH3), 2.55±2.62 (m, 2H, CH2), 3.63±3.85 (m,
2H, CH2), 4.07±4.20 (m, 4H, 2CH2), 4.25±4.35 (m, 1H,
CH), 5.16±5.22 (m, 1H, NH) 6.60 (bs, 1H, NH); 31P
NMR: dˆ22.76; IR (®lm): nˆ3272, 3080, 2976, 1712,
1660, 1556, 1528, 1392, 1248, 1204, 1168, 1024, 784;
FAB/MS m/z (%): 399 (18); Anal. Calcd for
C15H31N2O6PS (398.46): C; 45.21; H: 7.84; N: 7.03.
Found: C; 45.10; H: 7.71; N: 6.90.
Diethyl (N-t-butyloxycarbonyl-l-alanyl)aminomethylphos-
phonate30 (6ab). Yield: 63%, colorless oil; Rfˆ0.58 (B); 1H
NMR: dˆ1.33 (t, Jˆ7.0 Hz, 6H, 2CH3), 1.37 (d, Jˆ
5.25 Hz, 3H, CH3), 1.45 (s, 9H, 3CH3), 3.71 (dd, Jˆ6.25,
12.25 Hz, CH2), 4.14 (q, Jˆ7.0 Hz, 4H, 2 CH2), 4.16±4.23
(m, 1H, CH), 4.98 (d, Jˆ6.75 Hz, 1H, NH), 6.62 (bs, 1H,
NH); 31P NMR: dˆ22.99; IR (neat): nˆ3296, 2984, 1712,
1696, 1528, 1448, 1368, 1248, 1192, 1024, 976; FAB/MS
m/z (%): 339 (72); Anal. Calcd for C13H27N2O6P (338.34):
C; 46.15; H: 8.04; N: 8.28. Found: C; 46.02; H: 7.90; N:
8.01.
Diethyl [N,N-bis(benzyloxycarbonyl)-l-lysyl]aminomethyl-
phosphonate (6ag). Yield: 68%, colorless ¯akes, mp 110±
1128C; Rfˆ0.68 (E); 1H NMR: dˆ1.28, 1.29 (2t, Jˆ7.1 Hz,
6H, 2CH3), 1.33±1.45 (m, 2H, CH2), 1.45±1.56 (m, 2H,
CH2), 1.61±1.74 (m, 2H, CH2), 1.75±1.91 (m, 2H, CH2),
3.16±3.25 (m, 2H, CH2), 3.60±3.80 (m, 2H, CH2), 4.03±
4.15 (m, 4H, 2CH2), 4.15±4.25 (m, 1H, CH), 4.96±5.07 (m,
1H, NH), 5.05±5.15 (m, 4H, 2CH2), 5.55±5.61 (m, 1H,
NH), 6.69 (bs, 1H, NH), 7.30±7.40 (m, 10Harom); 31P
NMR: dˆ22.32; IR (CCl4): nˆ3304, 3072, 2920, 1716,
1652, 1456, 1280, 1244, 1196, 1104, 1056, 1044, 1024,
944, 760, 704; FAB/MS m/z (%): 564 (24); Anal. Calcd
for C27H38N3O8P (563.58): C; 57.54; H: 6.79; N: 7.45.
Found: C; 57.41; H: 6.62; N: 7.33.
Diethyl (N-benzyloxycarbonyl-l-alanyl)aminomethylphos-
phonate31 (6ac). Yield: 92%, colorless needles, mp 69±
708C, (lit.31 mp 72±748C); Rfˆ0.27 (C); 1H NMR:
dˆ1.31 (t, Jˆ7.0 Hz, 6H, 2CH3), 1.39 (d, Jˆ7.25 Hz, 3H,
CH3), 3.69 (dd, Jˆ5.75, 12.0 Hz, CH2), 4.05±4.17 (m, 4H,
2CH2), 4.30 (bqu, Jˆ7.25 Hz, 1H, CH), 5.08 (part A of the
AB system, Jˆ12.0 Hz, 1H, CH), 5.12 (part B of the AB
system, Jˆ12.0 Hz, 1H, CH), 5.51 (bd, Jˆ8.25 Hz, 1H,
NH), 6.82 (bs, 1H, NH), 7.31±7.37 (m, 5Harom); 31P NMR:
dˆ22.89; IR (®lm): nˆ3264, 3064, 2984, 1720, 1700, 1672,
1528, 1452, 1252, 1160, 1024, 976, 776, 696; FAB/MS m/z
(%): 373 (54); Anal. Calcd for C16H25N2O6P (372.35): C;
51.61; H: 6.77; N: 7.52. Found: C; 51.50; H: 6.66; N: 7.33.
Diethyl (N-t-butyloxycarbonyl-l-tryptyl)aminomethyl-
phosphonate (6ah). Yield: 73%, colorless solid, mp 80±
1
858C; Rfˆ0.38 (C); H NMR: dˆ1.26 (t, Jˆ7.25 Hz, 6H,
2CH3), 1.41 (s, 9H, 3CH3), 3.15±3.34 (m, 2H, CH2), 3.58
(dd, Jˆ6.0, 12.0 Hz, 2H, CH2), 3.95±4.20 (m, 4H, 2CH2),
4.40±4.50 (m, 1H, NH), 5.02±5.12 (m, 1H, NH), 6.15±6.22
(m, 1H, NH), 7.06±7.23 (m, 2Harom), 7.36 (bd, Jˆ7.75 Hz,
P
Diethyl (N-benzyloxycarbonyl-l-valyl)aminomethylphos-
phonate (6ad). Yield: 76%, colorless needles, mp 96±
1Harom), 7.64 (bd, Jˆ7.75 Hz, 1Harom), 8.19 (bs, 1Harom); 31
NMR: dˆ22.76; IR (CCl4): nˆ3320, 3064, 2984, 1768,
1676, 1496, 1392, 1248, 1168, 1024, 996; FAB/MS m/z
(%): 454 (5); Anal. Calcd for C21H32N3O6P (453.47):
C; 55.62; H: 7.11; N: 9.27. Found: C; 55.51; H: 7.00; N:
9.16.
1
988C; Rfˆ0.37 (C); H NMR: dˆ0.92 (d, Jˆ7.0 Hz, 3H,
CH3), 0.97 (d, Jˆ7.0 Hz, 3H, CH3), 1.30 (t, Jˆ7.0 Hz,
6H, 2CH3), 2.03±2.25 (m, 1H, CH), 3.60±3.84 (m, 2H,
CH2), 4.05±4.21 (m, 5H, 2CH2, CH), 5.10 (bs, 2H, CH2),
5.52 (bd, Jˆ8.75 Hz, 1H, NH), 6.78 (bs, 1H, NH), 7.33±
7.40 (m, 5Harom); 31P NMR: dˆ22.85; IR (®lm): nˆ3280,
2960, 1720, 1700, 1536, 1388, 1232, 1144, 1024, 968, 744,
700; FAB/MS m/z (%): 401 (55); Anal. Calcd for
C18H29N2O6P (400.41): C; 53.99; H: 7.30; N: 7.00. Found:
C; 53.90; H: 7.21; N: 6.89.
Diethyl (N-benzyloxycarbonyl-l-prolyl)aminomethylphos-
1
phonate (6ai). Yield: 93%, colorless oil; Rfˆ0.41 (F); H
NMR: dˆ1.31 (bt, Jˆ7.0 Hz, 6H, 2CH3), 1.74±2.05 (m,
4H, 2CH2), 3.40±3.62 (m, 2H, CH2), 3.70 (dd, Jˆ6.0,
12.0 Hz, 2H, CH2), 4.05±4.18 (m, 4H, 2CH2), 4.35±4.43
(m, 1H, CH), 5.14 (part A of the AB system, Jˆ13.25 Hz,
1H, CH), 5.17 (part B of the AB system, Jˆ13.25 Hz, 1H,
CH), 6.25±6.40 (m, 1H, NH), 7.15±7.45 (m, 5Harom); 31P
NMR: dˆ23.10; IR (®lm): nˆ3272, 3064, 2984, 1708,
1680, 1536, 1416, 1356, 1216, 1192, 1168, 1120, 1028,
976, 768, 696; FAB/MS m/z (%): 399 (72); Anal. Calcd
for C18H27N2O6P (398.39): C; 54.27; H: 6.83; N: 7.03.
Found: C; 54.11; H: 6.71; N: 6.96.
Diethyl (N-benzyloxycarbonyl-l-phenylalanyl)amino-
methylphosphonate26 (6ae). Yield: 67%, pale yellow
needles, mp 100±1028C; (lit.26 mp 102±1048C); Rfˆ0.38
1
(C); H NMR: dˆ1.27, 1.28 (2t, Jˆ7.1 Hz, 6H, 2CH3),
2.99±3.15 (m, 2H, CH2), 3.56 (ddd, Jˆ5.6, 12.1, 15.8 Hz,
1H, CH), 3.70 (ddd, Jˆ6.3, 12.5, 15.8 Hz, 1H, CH), 4.00±
4.14 (m, 4H, 2CH2), 4.48 (bq, Jˆ7.0 Hz, 1H, CH), 5.04 (part

3760
D. Sikora, T. Gajda / Tetrahedron 56 (2000) 3755±3761
Diethyl (N-t-butyloxycarbonyl-N-methyl-d-valyl)amino-
methylphosphonate (6aj). Yield: 63%, colorless oil;
Acknowledgements
1
Rfˆ0.55 (C); H NMR: dˆ0.87, 0.94 (2d, Jˆ6.50 Hz, 6H,
The partial ®nancial support of this work by the Polish
Committee of Scienti®c Research (KBN) under grant
number 3 T09A 103 14 is gratefully acknowledged.
2CH3), 1.32 (t, Jˆ7.25 Hz, 6H, 2CH3), 1.48 (s, 9H, 3CH3),
2.21±2.36 (m, 1H, CH), 2.80 (s, 3H, CH3), 3.69 (dd,
Jˆ5.75, 11.50 Hz, 2H, CH2), 4.13 (bqu, Jˆ7.25 Hz, 4H,
2CH2), 6.46 (bs, 1H, NH); 31P NMR: dˆ23.05; IR (®lm):
nˆ3264, 2976, 1680, 1552, 1480, 1444, 1392, 1368, 1336,
1252, 1156, 1028; FAB/MS m/z (%): 381 (38); Anal. Calcd
for C16H33N2O6P (380.42): C; 50.52; H: 8.74; N: 7.36.
Found: C; 50.42; H: 8.64; N: 7.27.
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Diethyl 1-(N-benzyloxycarbonyl-l-alanyl)aminoethylphos-
phonate27 (6ba). Yield: 42%, colorless oil; Rfˆ0.48 (C);
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1
(the 1:1 mixture of diastereomers); H NMR: dˆ1.25±
1.35 (m, 9H, 3CH3), 1.38, 1.39 (2d, Jˆ7.00 Hz, 3H, CH3),
4.00±4.20 (m, 4H, 2CH2), 4.21±4.33 (m, 1H, CH), 4.37±
4.60 (m, 1H, CH), 5.11 (s, 2H, CH2), 5.29±5.32 (m, 1H,
NH), 6.28±6.32, 6.45±6.52 (2m, 1H, NH), 7.33±7.40 (m,
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nˆ3272, 3064, 2984, 1720, 1696, 1680, 1532, 1448,
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phonate24 (6bb). Yield: 63%, pale yellow oil; Rfˆ0.56 (G);
(the mixture of diastereomers); 1H NMR: dˆ1.12±1.31 (m,
9H, 3CH3), 1.85±2.25 (m, 4H, 2CH2), 3.40±3.60 (m, 2H,
CH2), 4.05±4.20 (m, 4H, 2CH2), 4.25±4.52 (m, 2H, 2CH2),
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968, 788; FAB/MS m/z (%): 413 (19); Anal. Calcd for
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Â
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Â
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È
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Diethyl 1-(N-t-butyloxycarbonyl-N-methyl-d,l-alanyl)-
aminoethylphosphonate (6bc). Yield: 62%, colorless
prisms, mp 113±1158C; Rfˆ0.53 (C); (the mixture of
diastereomers); 1H NMR: dˆ0.79, 0.82, 0.87 (3d, Jˆ
6.5 Hz, 6H, 2CH3), 1.23, 1.24 (2t, Jˆ7.0 Hz, 6H, 2CH3),
1.30 (dd, Jˆ16.75, 7.5 Hz, 3H, CH3), 1.41 (bs, 9H, 3CH3),
3.95±4.13 (m, 5H, 2CH2, CH), 4.30±4.51 (m, 1H, CH),
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Â
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Â
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Diethyl 1-(N-benzyloxycarbonyl-l-phenylalanyl)amino-
ethylphosphonate30,31 (6bd). Yield: 67%, pale yellow oil;
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6H, 2CH3), 2.95±3.15 (m, 2H, CH2), 3.90±4.15 (m, 4H,
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5.40, 5.56 (2bd, Jˆ8.25 Hz, 1H, NH), 6.34, 6.60 (2bd,
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