Synthesis of optically active oxazoles from phosphorylated 2H-azirines and N-protected amino acids or peptides

Article abstract of DOI:10.1016/S0957-4166(02)00686-9

A simple synthesis of optically active phosphorylated oxazoles 8, 10, 11, and 12 containing amino acid residues from 2H-azirine-phosphine oxides 1 or -phosphonates 6 is described. Ring-opening reaction of 2H-azirines derived from phosphine oxides 1 and phosphonates 6 with N-protected amino acids 2 gives functionalized phosphorylated ketamides 3 and 7. Cyclization of ketamides 3 and 7 with triphenylphosphine and hexachloroethane in the presence of triethylamine leads to the formation of racemic and optically active phosphorylated oxazoles containing N-protected amino acid residues 8 and 10. Deprotection of these oxazoles gives aminoalkyl oxazoles 11 and 12. 2H-Azirines 1 and 6 also react with N-protected peptides 13 and give functionalized ketamides 14 and 15, ring closure of which leads to the formation of phosphorylated oxazoles containing peptide residues 16 and 17.

Full text of DOI:10.1016/S0957-4166(02)00686-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2541–2552
Synthesis of optically active oxazoles from phosphorylated
2H-azirines and N-protected amino acids or peptides
Francisco Palacios,* Ana Mar´ıa Ochoa de Retana, Jose´ Ignacio Gil and Jose´ Mar´ıa Alonso
Departamento de Qu´ımica Orga´nica I, Facultad de Farmacia, Universidad del Pa´ıs Vasco, Apartado 450, 01080 Vitoria, Spain
Received 20 September 2002; accepted 23 October 2002
Abstract—A simple synthesis of optically active phosphorylated oxazoles 8, 10, 11, and 12 containing amino acid residues from
2H-azirine-phosphine oxides 1 or -phosphonates 6 is described. Ring-opening reaction of 2H-azirines derived from phosphine
oxides 1 and phosphonates 6 with N-protected amino acids 2 gives functionalized phosphorylated ketamides 3 and 7. Cyclization
of ketamides 3 and 7 with triphenylphosphine and hexachloroethane in the presence of triethylamine leads to the formation of
racemic and optically active phosphorylated oxazoles containing N-protected amino acid residues 8 and 10. Deprotection of these
oxazoles gives aminoalkyl oxazoles 11 and 12. 2H-Azirines 1 and 6 also react with N-protected peptides 13 and give
functionalized ketamides 14 and 15, ring closure of which leads to the formation of phosphorylated oxazoles containing peptide
residues 16 and 17. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
phorus substituents. However, as far as we know, no
examples of racemic or optically active oxazoles with
amino acid residues and containing a phosphorus sub-
stituent have been described.
Oxazoles are widely used intermediates for functional
transformations.1 Simple oxazoles are common units in
a wide variety of polyoxazole marine natural products
possessing biological activity,2 while aminoalkyl oxa-
zoles derived from amino acids I are very important
substrates because they are constituents of peptide-
based alkaloids and antibiotics with remarkable cyto-
toxic and/or antitumor properties.3,4 Additionally,
amino acid residues play an important role in connect-
ing the heterocyclic moieties in the formation of polya-
zole natural products. Therefore, the preparation of
optically active oxazoles I is an interesting goal in
synthetic organic chemistry. Furthermore, it is known
that phosphorus substituents regulate important biolog-
ical functions,5 and that molecular modifications
involving the introduction of organophosphorus func-
tionalities could increase their biological activity, in a
similar way to that reported for other pharmaceuticals.5
For these reasons, optically active oxazoles with amino
acid residues, which contain a phosphorus substituent
(II, Fig. 1) are expected to play a similar role to that
observed in the isosteric analogues I, and could possess
biological activity and be used in the preparation of
new complex polyoxazole derivatives containing phos-
In this context, we have described new methods for the
preparation of five-6 and six-7 membered phosphorus
substituted nitrogen heterocycles from functionalized
phosphine oxides and phosphonates and the synthetic
uses of amino phosphorus derivatives as starting mate-
rials for the preparation of acyclic compounds8 and
phosphorus-containing heterocycles.9 Recently, we
reported the first asymmetric synthesis of 2H-azirines10
derived from phosphine oxides by alkaloid-mediated
Neber reaction of tosyl oximes,11,12 as well as their
dimerization to phosphorylated pyrazines13 and the ring
opening of azirines with carboxylic acids followed by
the cyclization of the corresponding adducts to oxa-
zoles IV (Scheme 1).14 Continuing with our interest in
* Corresponding author. Tel.: 34-945-013103; fax: 34-945-013049;
e-mail: qoppagaf@vc.ehu.es
Figure 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00686-9

2542
F. Palacios et al. / Tetrahedron: Asymmetry 13 (2002) 2541–2552
istry,18,19 this reaction can be used as a model for the
introduction of amino phosphorus moieties into pep-
tides. Furthermore, the functionalized ketamides gener-
ated can be used for the regioselective preparation of
the previously unknown racemic and optically active
phosphorylated oxazoles containing amino alkyl
residues.
Scheme 1.
Firstly, we explored the reaction of azirines with
racemic N-Boc protected amino acids.20 Reaction of
3-methyl-2H-azirinyl phosphine oxide 1a (R1=CH3)
with N-Boc-glycine 2a (R2=R3=H), at low tempera-
ture (−80°C) in THF led to the formation of a-
ketamide containing a phosphine oxide group in the
a-position 3aa (R1=CH3, R2=R3=H) (Scheme 2,
Table 1, entry 1). The reaction can be extended both to
Ca-substituted ( )-N-Boc-alanine 2b (R2=CH3, R3=
H; R2=H, R3=CH3) and to ( )-N-Boc-serine 2c (R2=
CH2OH, R3=H; R2=H, R3=CH2OH) obtaining (1:1)
diastereoisomeric mixtures21 of a-ketamides 3ab (R1=
CH3, R2=CH3, R3=H; R1=CH3, R2=H, R3=CH3)
and 3ac (R1=CH3, R2=CH2OH, R3=H; R1=CH3,
R2=H, R3=CH2OH) (Scheme 2, Table 1, entries 2 and
3). Spectroscopic data were in agreement with the
assigned structure of compounds 3. Mass spectrometry
of 3ab showed the molecular ion peak, while in the 31P
NMR spectrum phosphine oxide groups resonated at
lP=32.4 and 33.1 ppm for both diastereoisomers. The
formation of adducts 3 could be explained by protona-
tion of the nitrogen atom of the azirine, then nucleo-
philic addition of the carboxylate to the aziridinium
ion, followed by ring expansion of aziridine 4 to give
the zwitterionic oxazolone 5, which underwent ring
opening to form ketamides 3.
the synthesis of new phosphorus substituted heterocy-
cles, we report herein an easy and high yielding synthe-
sis of racemic and optically active 4-(2-aminoalkyloxa-
zolyl)phosphine oxides (II, Fig. 1, R=Ph) and -phos-
phonates (II, Fig. 1, R=OEt) from easily available
azirines. Azirines are thus very interesting reagents for
the activation and amidation of N-protected amino
acids via azirine–oxazolone intermediates and have
been successfully applied to peptide synthesis.15–17
2. Results and discussion
2.1. Reaction of azirines 1 and 6 with N-protected
amino acids 2. Synthesis of a-ketamides 3 and 7
Ring opening and selective cleavage of the NꢀC double
bond of amino-azirines15,16 and of phosphorus substi-
tuted azirines,14 can be achieved with carboxylic acids.
In the case of amino-azirines the process has been
extended to N-protected amino acids.15,17 As far as we
know, no ring-opening reaction of azirines containing
phosphorus substituents with N-protected amino acid
has been reported. For this reason, we explored the
reaction of phosphorylated azirines with N-protected
amino acids and peptides. Given the increasing interest
in ‘phosphapeptides’ in organic and medicinal chem-
The scope of the reaction was not limited to racemic
N-protected amino acids 3aa–3ac, given that azirine
Scheme 2.

F. Palacios et al. / Tetrahedron: Asymmetry 13 (2002) 2541–2552
2543
Table 1. a-Ketamides 3 and 7
Entry
Compound
R
R1
R2
R3
Yield (%)a
[h]2D2,b
1
2
3
4
5
6
7
8
3aa
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
H
H
73
65
65
58
62
48
66
56
68
71
66
52
72
50
–
–
–
Hc
CH3
c
(9)-3ab
(9)-3ac
(+)-3ad
(−)-3ae
(+)-3af
(−)-3ag
(−)-3ah
(9)-7ab
(+)-7ad
(−)-7ae
(−)-7ag
(+)-7bd
(−)-7bg
Hc
CH3
H
CH2OH
H
CH2OHc
H
+34.0
−34.0
+32.4
−32.4
−11.4
–
+21.0
−21.0
−11.0
+24.4
−9.5
CH3
H
CH2OH
CH2C6H5
CH3
H
CH3
CH2OH
H
CH2OH
H
c
9
Hc
10
11
12
13
14
CH3
H
H
CH3
H
a Yields refer to isolated compounds.
b Degrees (for concentration, see Section 4).
c Racemic.
phosphine oxide 1a (R1=CH3) also reacted with opti-
cally active isomers of N-Boc-(R)-alanine 2d (R2=CH3,
R3=H) or (S)-alanine 2e (R2=H, R3=CH3), of N-
Boc-(R)-serine 2f (R2=CH2OH, R3=H) or (S)-serine
2g (R2=H, R3=CH2OH) and with N-Boc-(S)-phenyl-
alanine 2h (R2=H, R3=CH2C6H5) to give, respectively,
optically active a-ketamides (+)-3ad (R1=CH3, R2=
CH3, R3=H), (−)-3ae (R1=CH3, R2=H, R3=CH3),
(+)-3af (R1=CH3, R2=CH2OH, R3=H), (−)-3ag (R1=
CH3, R2=H, R3=CH2OH) and (−)-3ah (R1=CH3,
R2=H, R3=CH2C6H5), which were obtained, as in the
case of the racemic compounds, as 1:1 diastereoiso-
meric mixtures21 (Scheme 2, Table 1, entries 4–8).
Enantiomerically enriched azirine phosphine oxide 1a
(R1=CH3)11 was also treated with optically active N-
Boc-(R)- 2d or (S)-amino acids 2e and 2g but enan-
tiomerically enriched ketamides 3 were not obtained
and (1:1) diastereoisomeric mixtures21 were obtained
instead. These results could be explained by epimeriza-
tion of Ca-carbon to the phosphine oxide group, due to
the acid character of the methinic hydrogen in this
position.
2.2. Synthesis of racemic and optically active phospho-
rus substituted aminoalkyl oxazoles 8 and 11
Next we explored the ring closure of ketamides contain-
ing a phosphine oxide 3, or phosphonate substituent 7
for the preparation of the previously unknown and
potentially useful racemic and optically active phospho-
rylated oxazoles containing amino alkyl residues II
(Fig. 1). The best results were observed when
triphenylphosphine dichloride, generated ‘in situ’ from
the reaction of the phosphine with hexachloroethane,
was used.23,24 Adducts
3
were treated with
triphenylphosphine and hexachloroethane in the pres-
ence of triethylamine in THF to give oxazole phosphine
oxides 8 in good yields and in a regioselective fashion
(Scheme 3, Table 2). Spectroscopic data were in agree-
ment with the assigned structure of compounds 8. Mass
spectrometry of (+)-8ad showed the molecular ion peak,
while in the 31P NMR spectrum the phosphine oxide
group resonated at lP=18.3 ppm. The 13C NMR spec-
trum of oxazole (+)-8ad showed doublets at lC=126.3
ppm (1JPC=141.5 Hz) for C-4, and at lC=163.8 ppm
(3JPC=17.1 Hz) for C-2. The formation of oxazoles 8
could be explained by deprotonation of ketamides 3 by
means of dichlorotriphenylphosphorane (Ph3PCl2), gen-
erated in situ from triphenylphosphine and hexa-
chloroethane,25 to give an intermediate enamide 9
(Scheme 3) followed by the loss of triphenylphosphine
oxide and subsequent ring closure.24
The process can also be extended to azirines derived
from phosphonates 6.12a In this case shorter periods of
time (2 h) and higher temperatures (70°C) were
required. Heating racemic or enantiomerically enriched
azirines 6a (R1=CH3), and 6b (R1=C2H5), with N-
Boc-protected-( )-alanine 2b, -(R)-alanine 2d or -(S)-
alanine 2e and with N-Boc-(S)-serine 2g led to the
formation22 of racemic and optically active a-ketamides
containing a diethoxyphosphoryl group in the a-posi-
tion 7ab–7bg, which were obtained, as before, as 1:1
diastereoisomeric mixtures21 (Scheme 2, Table 1, entries
9–14). This formation of phosphapeptides18,19 can be
regarded as a peptide chain elongation which intro-
duces an a-ketamine containing a phosphonate group
or a phosphine oxide to the C-terminal end of the
amino acid.
Cyclization is quite general, allowing the preparation of
racemic and optically active oxazole phosphine oxides
(4-position) bearing aminoalkyl groups in the 2-posi-
tion of the ring derived not only from glycine 8aa
(R1=CH3, R2=R3=H) (Scheme 3, Table 2, entry 1),
but also from ( )-alanine 8ab (R1=CH3, R2=CH3,
R3=H; R1=CH3, R2=H, R3=CH3), (R)-alanine (+)-
8ad (R1=CH3, R2=CH3, R3=H) or (S)-alanine (−)-
8ae (R1=CH3, R2=H, R3=CH3) (Scheme 3, Table 2,

2544
F. Palacios et al. / Tetrahedron: Asymmetry 13 (2002) 2541–2552
entries 2–4), and from (S)-phenylalanine (−)-8ah (R1=
CH3, R2=H, R3=CH2C6H5) (Scheme 3, Table 2, entry
5). As far as we know, this process represents the first
synthesis of optically active oxazoles derived from
amino acids and containing a phosphorus substituent.
Table 2, entries 7–9) when optically active ketamides
(+)-7ad, (+)-7bd, (−)-7ae were used. The deprotec-
tion of the terminal N-Boc group of oxazoles 8 and 10
was studied. In the case of oxazole phosphine oxides
8, the best results were obtained when the reaction
was performed with chlorotrimethylsilane (1 M) and
phenol (3 M) in dichloromethane26 to give (2-amino-
methyl-5-methyloxazol-4-yl) phosphine oxide 11aa
(R1=CH3, R2=R3=H) and enantiomerically pure
oxazole (−)-11ae derived from (S)-alanine (R1=CH3,
R2=H, R3=CH3) in good yields (Scheme 3, Table 2,
entries 10 and 11). However, in the case of oxazole
phosphonate 10ad the deprotection was accom-
plished27 with HCl 3 M in refluxing AcOEt and opti-
cally active oxazole (+)-12ad derived from (R)-alanine
(R1=CH3, R2=CH3, R3=H) was obtained (Scheme 3,
Table 2, entry 12).
Likewise the cyclization of functionalized ketamides
derived from a-aminophosphonates 7 with triphenyl-
phosphine–hexachloroethane and triethylamine gave
( )-oxazole 10ab (R1=CH3, R2=CH3, R3=H; R1=
CH3, R2=H, R3=CH3) (Scheme 3, Table 2, entry 6)
when racemic ketamide 7ab was used and optically
active oxazole phosphonates containing aminoalkyl
groups in the 2-position of the ring derived from (R)-
alanine (+)-10ad (R1=CH3, R2=CH3, R3=H) and (+)-
10bd (R1=C2H5, R2=CH3, R3=H) or from (S)-alanine
(−)-10ae (R1=CH3, R2=H, R3=CH3) (Scheme 3,
Scheme 3.
Table 2. Phosphorylated oxazoles 8, 10, 11 and 12
Entry
Compound
R
R1
R2
R3
Yield (%)a
[h]2D2,b
1
2
3
4
5
6
7
8
8aa
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
CH3
CH3
CH3
H
H
CH3
H
CH3
CH2C6H5
CH3
H
CH3
H
H
68
70
72
66
73
45
56
50
46
81
74
46
–
–
c
(9)-8ab
(+)-8ad
(−)-8ae
(−)-8ah
(9)-10ab
(+)-10ad
(−)-10ae
(+)-10bd
11aa
Hc
CH3
H
+43.4
−43.4
−11.0
–
+39.7
−39.7
+34.5
–
C6H5
H
c
OC2H5
OC2H5
OC2H5
OC2H5
C6H5
Hc
CH3
H
9
CH3
H
H
10
11
12
(−)-11ae
(+)-12ad
C6H5
OC2H5
CH3
H
−8.0
+15.0
CH3
a Yields refer to isolated compounds.
b Degrees (for concentration, see Section 4).
c Racemic.

F. Palacios et al. / Tetrahedron: Asymmetry 13 (2002) 2541–2552
2545
2.3. Synthesis of phosphorylated oxazoles 16 and 17
with peptide residues
(Scheme 4, Table 3, entry 5). The formation of enan-
tiomerically pure functionalized oxazoles 16 and 17
could also be explained through a similar mechanism to
that reported for oxazoles derived from amino acids 8
and 10 (Scheme 3). This strategy describes the first
preparation of optically active peptide-based oxazoles
containing phosphinoyl 16 or phosphoryl substituents
17.
The ring opening of azirines can be extended to N-pro-
tected peptides.20 Treatment of 3-methyl-2H-azirinyl
phosphine oxide 1a (R1=CH3) with both a optically
active N-protected dipeptide N-Boc-(S)-glycine-phenyl-
alanine 13a (Pep=Gly-Phe) and with a N-protected
tripeptide N-Boc-(S)-alanine-glycine-glycine 13b (Pep=
Ala-Gly-Gly) at low temperature (−80°C) in THF led
to the formation of optically active a-ketamides con-
taining a phosphine oxide group in the a-position (−)-
14aa (R1=CH3, Pep=Gly-Phe) and (+)-14ab
(R1=CH3, Pep=Ala-Gly-Gly), which were obtained as
1:1 diastereoisomeric mixtures21 in moderate yields
(Scheme 4, Table 3, entries 1 and 2). Spectroscopic data
were in agreement with the assigned structure of com-
pounds 14 and the formation of adducts 14 could be
explained, as before (Scheme 2), by formal addition of
the carboxylic acid moiety of the N-protected peptide
to the reactive carbonꢀnitrogen azirine double bond to
give an unstable aziridine intermediate, followed by
ring opening of zwitterionic oxazolone. The process can
also be extended to azirine-phosphonates. Heating at
70°C (2 h) azirine 6b (R1=C2H5) with N-Boc-(S)-
glycine-phenylalanine 13a (Pep=Gly-Phe) gave a 1:1
diastereoisomeric mixture21 of optically active a-
ketamide containing a phosphonate group in the a-
position (−)-15ba (Scheme 4, Table 3, entry 3).22 This
formation of phosphapeptides 14 and 15 can be
regarded as a peptide chain elongation which intro-
duces an a-ketamine containing a phosphine oxide or a
phosphonate group to the C-terminal end of the pep-
tide. Ketamide (−)-14aa was then treated with
triphenylphosphine and hexachloroethane in the pres-
ence of triethylamine and optically active oxazole phos-
phine oxide containing a peptide residue (−)-16aa was
obtained (Scheme 4, Table 3, entry 4). In a similar
manner oxazole phosphonate (−)-17ba was prepared
from a-ketamide (−)-15ba derived from phosphonate
3. Conclusions
In conclusion, the first asymmetric synthesis of optically
active oxazoles containing amino alkyl residues and
with phosphine oxides 8 and 11 or phosphonate groups
10 and 12 has been described. The process involves a
two-step procedure involving the ring opening of 2H-
azirines derived from phosphine oxides 1 or phospho-
nates 6 with N-protected amino acids 2, followed by
dehydration and ring closure of the first-formed a-
ketamides 3 and 7. This strategy can also be extended
to N-protected peptides 13 to give the first family of
phosphorylated optically active oxazoles 16 and 17 with
peptide side chains. Functionalized oxazoles containing
amino acid 8–12 and peptide residues 16 and 17 as well
as phosphorylated a-ketamides phosphapeptides 3, 7,
14, and 15 are important synthons in organic synthesis
and for the preparation of biologically active com-
pounds with interest in medicinal chemistry.3,4,18,19
4. Experimental
4.1. General methods
Analytical TLC was performed with Merck silica gel 60
F254 plates. Visualization was accomplished by UV
light. Flash chromatography was carried out using
Merck silica gel 60 (230–400 mesh ASTM). Melting
points were determined with an Electrothermal IA9100
Scheme 4.
Table 3. a-Ketamides 14 and 15 and phosphorylated oxazoles 16 and 17
Entry
Compound
R
R1
Peptide
Yield (%)a
[h]2D2,b
1
2
3
4
5
(−)-14aa
(+)-14ab
(−)-15ba
(−)-16aa
(−)-17ba
C6H5
C6H5
OC2H5
C6H5
OC2H5
CH3
CH3
C2H5
CH3
C2H5
(S)-Gly-Phe
(S)-Ala-Gly-Gly
(S)-Gly-Phe
(S)-Gly-Phe
(S)-Gly-Phe
55
51
48
52
50
−10.7
+3.3
−3.9
−6.6
−3.6
a Yields refer to isolated compounds.
b Degrees (for concentration, see Section 4).

2546
F. Palacios et al. / Tetrahedron: Asymmetry 13 (2002) 2541–2552
1
digital melting point apparatus and are uncorrected. H
(300 MHz), 13C (75 MHz) and 31P NMR (120 MHz)
spectra were recorded on a Varian VXR 300 MHz
spectrometer using CDCl3 solutions with TMS as an
calcd for C23H29N2O5P: C, 62.15; H, 6.58; N, 6.30.
Found C, 62.11; H, 6.60; N, 6.31.
4.2.3. ( )-2-tert-Butoxycarbonylamino-3-hydroxy-N-(1-
1
internal reference for H and 13C NMR spectra and
diphenylphosphinoyl-2-oxopropyl)propanamide
(3ac).
phosphoric acid (85%) as external standard for 31P
NMR spectra. Low-resolution mass spectra (MS) were
obtained at 50–70 eV by electron impact (EIMS) on
Hewlett–Packard 5971 and 5973 spectrometers, and
obtained by APCI on a Hewlett–Packard 1100 spec-
trometer. Infrared spectra (IR) were recorded using a
Nicolet IRFT Magna 550 spectrometer. [h]2D2 were
taken on a Perkin–Elmer 341 polarimeter using a Na/
HaI lamp. Elemental analyses were performed in a
LECO CHNS-932 apparatus. Azirines 1a11 and 6a,b12a
were synthesized according to literature procedures.
Yield 1.50 g (65%) obtained as a white solid from
compound 1a (1.28 g, 5 mmol) and ( )-N-tert-butoxy-
carbonylserine 2c (3.08 g, 15 mmol) as described in the
general procedure: mp 74–75°C (hexane/AcOEt); 1H
NMR (300 MHz, CDCl3): l 1.35 (s, 18H), 2.20 and
2.16 (2s, 6H), 3.40–3.49 and 3.69–3.77 (2m, 4H), 4.08 (t,
3
3JHH=7.5 Hz, 2H), 5.36 and 5.53 (2d, JHH=6.6 Hz,
2
3
2H), 5.80 (2dd, JPH=9.6 Hz, JHH=6.6 Hz, 2H), 7.41–
7.90 (m, 22H) ppm; 13C NMR (75 MHz, CDCl3): l
28.2, 29.5, 55.7 and 56.0, 60.6 (d, JPC=67.5 Hz), 62.4
and 62.7, 80.0, 127.8–132.8 (m), 155.6, 171.1 (d, JPC
1
3
=
13.6 Hz), 200.8 ppm; 31P NMR (120 MHz, CDCl3): l
30.7 and 31.2 ppm; IR (KBr): 3525, 3429, 3310, 3197,
3051, 2979, 1724, 1712, 1664, 1175 cm−1; MS (CI): m/z
461 (M++1, 13). Anal. calcd for C23H29N2O6P: C, 59.99;
H, 6.35; N, 6.08. Found C, 59.92; H, 6.33; N, 6.09.
4.2. General procedure for synthesis of 2-tert-butoxy-
carbonylamino-3-alkyl-N-(1-diphenylphosphinoyl-2-oxo-
propyl)alkylamide 3
To
a
−80°C solution of 3-alkyl-2H-azirin-2-yl
diphenylphosphine oxide 1 (5 mmol) in THF (5 ml), a
solution of N-protected amino acid 2 (15 mmol) in
THF (5 ml) was added under a nitrogen atmosphere.
Then, the mixture was allowed to warm to room tem-
perature and stirred for 1–4 days. The solvent was
evaporated in vacuo, and the subsequent residue was
purified by flash column chromatography eluting with
AcOEt.
4.2.4. (+)-2-(R)-tert-Butoxycarbonylamino-N-(1-diphenyl-
phosphinoyl-2-oxopropyl)propanamide (3ad). Yield 1.29
g (58%) obtained as a white solid from compound 1a
(1.28 g, 5 mmol) and N-tert-butoxycarbonyl-(R)-ala-
nine 2d (2.84 g, 15 mmol) as described in the general
procedure: [h]2D2=+34.0 (c 1.00, CH2Cl2). For spectro-
scopic data see compound 3ab.
4.2.5. (−)-2-(S)-tert-Butoxycarbonylamino-N-(1-diphenyl-
phosphinoyl-2-oxopropyl)propanamide (3ae). Yield 1.38
g (62%) obtained as a white solid from compound 1a
(1.28 g, 5 mmol) and N-tert-butoxycarbonyl-(S)-ala-
nine 2e (2.84 g, 15 mmol) as described in the general
procedure: [h]2D2=−34.0 (c 1.00, CH2Cl2). For spectro-
scopic data see compound 3ab.
4.2.1. 2-tert-Butoxycarbonylamino-N-(1-diphenylphos-
phinoyl-2-oxopropyl)acetamide (3aa). Yield 1.57 g (73%)
obtained as a white solid from compound 1a (1.28 g, 5
mmol) and N-tert-butoxycarbonylglycine 2a (2.63 g, 15
mmol) as described in the general procedure: mp 182–
1
183°C; H NMR (300 MHz, CDCl3): l 1.40 (s, 9H),
3
2.18 (s, 3H), 3.62 (m, 2H), 4.98 (d, JHH=7.5 Hz, 1H),
2
3
5.77 (dd, JPH=9.0 Hz, JHH=7.5 Hz, 1H), 7.39–7.95
4.2.6. (+)-2-(R)-tert-Butoxycarbonylamino-3-hydroxy-
N-(1-diphenylphosphinoyl-2-oxopropyl)propamide (3af).
Yield 0.64 g (28%) obtained as a white solid from
compound 1a (1.28 g, 5 mmol) and N-tert-butoxycar-
bonyl-(R)-serine 2f (3.08 g, 15 mmol) as described in
the general procedure: [h]2D2=+32.4 (c 0.87, CH2Cl2).
For spectroscopic data see compound 3ac.
(m, 11H) ppm; 13C NMR (75 MHz, CDCl3): l 28.2,
1
29.8, 44.0, 60.7 (d, JPC=65.0 Hz), 80.1, 128.4–132.8
(m), 155.7, 169.4 (d, 3JPC=4.0 Hz), 200.6 ppm; 31P
NMR (120 MHz, CDCl3): l 30.8 ppm; IR (KBr): 3423,
3211, 1724, 1699, 1668, 1228, 1182 cm−1; MS (CI): m/z
431 (M++1, 7). Anal. calcd for C22H27N2O5P: C, 61.39;
H, 6.32; N, 6.51. Found C, 61.43; H, 6.31; N, 6.53.
4.2.7. (−)-2-(S)-tert-Butoxycarbonylamino-3-hydroxy-N-
(1-diphenylphosphinoyl-2-oxopropyl)propanamide (3ag).
Yield 1.52 g (66%) obtained as a white solid from
compound 1a (1.28 g, 5 mmol) and N-tert-butoxycar-
bonyl-(S)-serine 2g (3.08 g, 15 mmol) as described in
the general procedure: [h]2D2=−32.4 (c 0.21, CH2Cl2).
For spectroscopic data see compound 3ac.
4.2.2.
( )-2-tert-Butoxycarbonylamino-N-(1-diphenyl-
phosphinoyl-2-oxopropyl)propanamide (3ab). Yield 1.44
g (65%) obtained as a white solid from compound 1a
(1.28 g, 5 mmol) and ( )-N-tert-butoxycarbonylalanine
2b (2.84 g, 15 mmol) as described in the general proce-
1
dure: mp 146–147°C (hexane/AcOEt); H NMR (300
MHz, CDCl3): l 0.88 (d, JHH=6.9 Hz, 6H), 1.38 (s,
3
18H), 2.09 and 2.15 (2s, 6H), 4.03 (m, 2H), 5.02 (2d,
3JHH=7.2 Hz, 2H), 5.76, 5.80 (2dd, 2JPH=9.6 Hz,
3JHH=7.2 Hz, 2H), 7.41–7.92 (m, 22H) ppm; 13C NMR
(75 MHz, CDCl3): l 17.8, 18.0, 28.2, 29.7, 49.8, 50.6,
4.2.8. (−)-2-(S)-tert-Butoxycarbonylamino-N-(1-diphenyl-
phosphinoyl-2-oxopropyl)phenyl propanamide (3ah).
Yield 1.46 g (56%) obtained as a white solid from
compound 1a (1.28 g, 5 mmol) and N-tert-butoxycar-
bonyl-(S)-phenylalanine 2h (3.98 g, 15 mmol) as
described in the general procedure: mp 63–64°C (hex-
1
60.4 (d, JPC=66.0 Hz), 80.0 and 80.2, 128.4–132.8 (m),
3
155.1, 172.7 (d, JPC=4.5 Hz), 200.3, 200.8 ppm; 31P
1
NMR (120 MHz, CDCl3): l 32.4 and 33.1 ppm; IR
(KBr): 3423, 3310, 3211, 3070, 2979, 1725, 1715, 1672,
1202, 1175 cm−1; MS (CI): m/z 445 (M++1, 12). Anal.
ane/AcOEt); [h]D22=−11.4 (c 1.00, CH2Cl2); H NMR
(300 MHz, CDCl3): l 1.25 (s, 18H), 2.02 and 2.16 (2s,
3
6H), 2.69 (m, 4H), 4.23 (m, 2H), 4.85 (d, JHH=7.8 Hz,

F. Palacios et al. / Tetrahedron: Asymmetry 13 (2002) 2541–2552
2547
2
3
2H), 5.76 and 5.80 (2dd, JPH=9.9 Hz, JHH=7.8 Hz,
[h]2D2=−11.0 (c 0.39, CH2Cl2); 1H NMR (300 MHz,
CDCl3): l 1.26 (m, 12H), 1.39 (s, 18H), 2.32 (2s, 6H),
2H), 7.91–7.12 (m, 32H) ppm; 13C NMR (75 MHz,
CDCl3): l 28.1, 29.7, 37.8, 55.2 and 55.9, 60.1 (d,
1JPC=66.5 Hz), 79.9, 126.6–136.3 (m), 155.1, 171.5 (d,
3JPC=13.5 Hz), 200.9 ppm; 31P NMR (120 MHz,
CDCl3): l 31.6 and 32.5 ppm; IR (KBr): 3443, 3283,
3175, 1719, 1704, 1666, 1367, 1176 cm−1; MS (CI): m/z
521 (M++1, 27). Anal. calcd for C29H33N2O5P: C, 66.91;
H, 6.39; N, 5.38. Found C, 66.86; H, 6.39; N, 5.39.
2
3.80–4.26 (m, 14H), 4.55 (s, 2H), 5.22 (dd, JPH=23.3
3
3
Hz, JHH=8.4 Hz, 2H), 5.71 (d, JHH=7.5 Hz, 2H),
7.61 (d, JHH=8.4 Hz, 2H) ppm; 13C NMR (75 MHz,
CDCl3): l 16.2, 28.2, 28.7, 55.7 (2s), 58.2 (d, JPC
3
1
=
3
141.0 Hz), 62.9, 64.0, 80.4, 155.9, 171.2 (d, JPC=5.0
Hz), 199.2 (d, 2JPC=27.7 Hz) ppm; 31P NMR (120
MHz, CDCl3): l 16.2 and 16.6 ppm; IR (NaCl): 3310,
2924, 2852, 1723, 1710, 1699, 1591, 1164 cm−1; MS
(CI): m/z 397 (M++1, 4). Anal. calcd for C15H29N2O8P:
C, 45.45; H, 7.37; N, 7.07. Found C, 45.40; H, 7.38; N,
7.08.
4.3. General procedure for synthesis of diethyl 3-alkyl-
(2-tert-butoxycarbonylaminoalkanoylamino)-2-
oxoalkylphosphonate 7
To diethyl 3-alkyl-2H-azirinyl phosphonate 6 (5 mmol)
without solvent, the N-protected amino acid 2 (7.5
mmol) was added under a nitrogen atmosphere, at
room temperature and with continuous stirring. The
mixture was heated at 70°C for 2 h. Then, the subse-
quent residue was purified by flash column chromatog-
raphy eluting with hexane/AcOEt affording 7 and a
small proportion (10–20%) of pyrazine phosphonates.13
4.3.5. Diethyl (+)-1-(2-(R)-tert-butoxycarbonylamino-
propanoylamino)-2-oxobutylphosphonate (7bd). Yield
1.42 g (72%) obtained as a colorless oil from compound
6b (1.03 g, 5 mmol) and N-tert-butoxycarbonyl-(R)-
alanine 2d (1.42 g, 7.5 mmol) as described in the general
procedure: Rf 0.48 (AcOEt); [h]2D2=+24.4 (c 0.47,
CH2Cl2); 1H NMR (300 MHz, CDCl3): l 1.03 (t,
3JHH=7.2 Hz, 6H), 1.18–1.36 (m, 18H), 1.39 (s, 18H),
3
2.52 and 2.95 (2m, 4H), 4.12 (m, 10H), 4.98 (d, JHH
=
4.3.1. Diethyl ( )-1-(2-tert-butoxycarbonylaminopro-
panoylamino)-2-oxopropylphosphonate (7ab). Yield 1.29
g (68%) obtained as a colorless oil from compound 6a
(0.96 g, 5 mmol) and ( )-N-tert-butoxycarbonylalanine
2b (1.42 g, 7.5 mmol) as described in the general
procedure: Rf 0.39 (AcOEt); 1H NMR (300 MHz,
CDCl3): l 1.28 (s, 12H), 1.39 (s, 18H), 2.36 (2s, 6H),
2
3
7.5 Hz, 2H), 5.18 (dd, JPH=22.7 Hz, JHH=8.4 Hz,
2H), 7.07 (d, JHH=8.5 Hz, 2H) ppm; 13C NMR (75
3
3
MHz, CDCl3): l 7.5, 16.2, 18.2, 28.2, 34.9 (d, JPC=3.5
Hz), 50.0 (2s), 57.0 (2d, JPC=139.5 Hz), 63.5, 80.2,
1
3
2
155.3, 172.2 (d, JPC=5.5 Hz), 202.4 (d, JPC=13.6 Hz)
ppm; 31P NMR (120 MHz, CDCl3): l 16.0 and 16.1
ppm; IR (NaCl): 3287, 2981, 2937, 2860, 1772, 1709,
1680, 1167, 977 cm−1; MS (CI): m/z 395 (M++1, 4).
Anal. calcd for C16H31N2O7P: C, 48.72; H, 7.92; N,
7.10. Found C, 48.77; H, 7.93; N, 7.09.
3
4.10 (m, 10H), 5.07 (2d, JHH=7.2 Hz, 2H), 5.76 (dd,
3
3
2JPH=23.3 Hz, JHH=8.5 Hz, 2H), 7.11 (d, JHH=8.5
Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3): l 16.2,
18.3, 28.2, 28.9 (d), 49.9 (2s), 57.1 (2d, JPC=140.5 Hz),
1
3
63.6 (2s), 80.1, 155.2, 172.3 (d, JPC=5.0 Hz), 199.2 (d,
2JPC=16.2 Hz) ppm; 31P NMR (120 MHz, CDCl3): l
15.7 and 15.8 ppm; IR (NaCl): 3270, 2861, 1725, 1709,
1679, 1590, 1165, 1113 cm−1; MS (CI): m/z 381 (M++1,
5). Anal. calcd for C15H29N2O7P: C, 47.36; H, 7.68; N,
7.36. Found C, 47.42; H, 7.67; N, 7.36.
4.3.6. Diethyl (−)-1-(2-(S)-tert-butoxycarbonylamino-3-
hydroxypropanoylamino)-2-oxobutylphosphonate (7bg).
Yield 0.89 g (35%) obtained as a colorless oil from
compound 6b (1.03 g, 5 mmol) and N-tert-butoxycar-
bonyl-(S)-serine 2g (1.54 g, 7.5 mmol) as described in
the general procedure: Rf 0.50 (AcOEt); [h]2D2=−9.5 (c
1
2.15, CH2Cl2); H NMR (300 MHz, CDCl3): l 1.03 (t,
4.3.2. Diethyl (+)-1-(2-(R)-tert-butoxycarbonylamino-
propanoylamino)-2-oxopropylphosphonate (7ad). Yield
1.35 g (71%) obtained as a colorless oil from compound
6a (0.96 g, 5 mmol) and N-tert-butoxycarbonyl-(R)-
alanine 2d (1.42 g, 7.5 mmol) as described in the general
procedure: [h]2D2=+21.0 (c 1.75, CH2Cl2). For spectro-
scopic data see compound 7ab.
3JHH=7.2 Hz, 6H), 1.27 (m, 12H), 1.40 (s, 18H), 2.54
and 2.83 (2m, 4H), 3.75–4.28 (m, 14H), 4.71 (s, 2H),
2
3
5.22 (dd, JPH=22.6 Hz, JHH3 =8.6 Hz, 2H), 5.72 (d,
3JHH=7.5 Hz, 2H), 7.60 (d, JHH=8.6 Hz, 2H) ppm;
13C NMR (75 MHz, CDCl3): l 7.3, 16.2, 28.1, 34.7,
55.7 (2s), 57.1 (d, 1JPC=140.0 Hz), 62.8, 63.6, 80.2,
3
2
155.7, 170.9 (d, JPC=5.0 Hz), 202.1 (d, JPC=24.7 Hz)
ppm; 31P NMR (120 MHz, CDCl3): l 16.4 and 16.8
ppm; IR (NaCl): 3250, 2938, 2860, 1725, 1711, 1679,
1382, 1165, 979 cm−1; MS (CI): m/z 511 (M++1, <1).
Anal. calcd for C16H31N2O8P: C, 46.83; H, 7.61; N,
6.83. Found C, 46.78; H, 7.60; N, 6.84.
4.3.3. Diethyl (−)-1-(2-(S)-tert-butoxycarbonylaminopro-
panoylamino)-2-oxopropylphosphonate (7ae). Yield 1.25
g (66%) obtained as a colorless oil from compound 6a
(0.96 g, 5 mmol) and N-tert-butoxycarbonyl-(S)-ala-
nine 2e (1.42 g, 7.5 mmol) as described in the general
procedure: [h]2D2=−21.0 (c 1.75, CH2Cl2). For spectro-
scopic data see compound 7ab.
4.4. General procedure for synthesis of (5-alkyl-2-tert-
butoxycarbonylaminoalkyl)oxazol-4-yl diphenylphos-
phine oxide 8
4.3.4. Diethyl (−)-1-(2-(S)-tert-butoxycarbonylamino-3-
hydroxypropanoylamino)-2-oxopropyl phosphonate (7ag).
Yield 1.04 g (42%) obtained as a colorless oil from
compound 6a (0.96 g, 5 mmol) and N-tert-butoxycar-
bonyl-(S)-serine 2g (1.54 g, 7.5 mmol) as described in
the general procedure: Rf 0.33 (AcOEt/MeOH 10%);
To a room temperature solution of triphenylphosphine
(1.70 g, 6.5 mmol) and hexachloroethane (1.54 g, 6.5
mmol), in THF a solution of 2-tert-butoxycarbonyl-
amino-3-alkyl-N-(1-diphenylphosphinoyl-2-oxopropyl)-

2548
F. Palacios et al. / Tetrahedron: Asymmetry 13 (2002) 2541–2552
alkylamide 3 was added under a nitrogen atmosphere.
The mixture was stirred at that temperature for 5 min.
After that, triethylamine (2.10 ml, 15 mmol) was
added dropwise for 10 min. The subsequent mixture
was heated at THF reflux for 20 h. The solvent was
evaporated in vacuo and the residue was diluted with
water and extracted with CH2Cl2. The organic layers
where dried over anhydrous MgSO4, filtered and con-
centrated in vacuo. The crude residue was purified by
flash column chromatography eluting with AcOEt.
[h]2D2=−11.0 (c 1.00, CH2Cl2); 1H NMR (300 MHz,
3
CDCl3): l 1.34 (s, 9H), 2.51 (s, 3H), 3.11 (d, JHH
=
3
7.2 Hz, 2H), 5.09 (q, JHH=7.2 Hz, 1H), 5.16 (s, 1H),
6.90–7.73 (m, 15H) ppm; 13C NMR (75 MHz, CDCl3):
l 11.5, 28.1, 39.8, 49.8, 79.9, 126.1 (d, 1JPC=141.9
2
Hz), 126.7–135.7 (m), 154.8, 159.2 (d, JPC=26.7 Hz),
3
162.0 (d, JPC=17.1 Hz) ppm; 31P NMR (120 MHz,
CDCl3): l 18.8 ppm; IR (KBr): 3250, 3058, 2979,
2939, 1719, 1188 cm−1; MS (CI): m/z 503 (M++1, 45).
Anal. calcd for C29H31N2O4P: C, 69.31; H, 6.22; N,
5.57. Found C, 69.39; H, 6.21; N, 5.56.
4.4.1.
(2-tert-Butoxycarbonylaminomethyl-5-methyl)-
4.5. General procedure for synthesis of diethyl [5-alkyl-
2-(1-tert-butoxycarbonylaminoalkyl)]oxazol-4-yl phos-
phonate 10
oxazol-4-yl diphenylphosphine oxide (8aa). Yield 1.40 g
(68%), obtained as a white solid from compound 3aa
(2.15 g, 5 mmol) as described in the general procedure:
1
mp 104–105°C (hexane/AcOEt); H NMR (300 MHz,
CDCl3): l 1.39 (s, 9H), 2.52 (s, 3H), 4.34 (d, JHH
3
To a room temperature solution of triphenylphosphine
(1.70 g, 6.5 mmol) and hexachloroethane (1.54 g, 6.5
mmol), in toluene a solution of diethyl 3-alkyl-(2-tert-
butoxycarbonylaminoalkanoylamino)-2-oxoalkylphos-
phonate 7 was added under a nitrogen atmosphere.
The mixture was stirred at that temperature for 5 min.
After that, triethylamine (2.10 ml, 15 mmol) was
added dropwise slowly for 10 min. The subsequent
mixture was heated at toluene reflux and stirred for 20
h. The solvent was evaporated in vacuo and the
residue was purified by precipitating in cold ethyl
ether. The ethereal layers were concentrated in vacuo
and the residue was ground with cold water and
filtered. The aqueous layer was concentrated again
affording the compounds 10 as colorless oils.
=
5.1 Hz, 2H), 5.28 (s, 1H), 7.82–7.36 (m, 10H) ppm;
13C NMR (75 MHz, CDCl3): l 11.6, 28.2, 37.8, 80.1,
126.3 (d, 1JPC=142.0 Hz), 128.3–133.2 (m), 155.5,
159.4 (d, 2JPC=27.1 Hz), 160.3 (d, 3JPC=17.0 Hz)
ppm; 31P NMR (120 MHz, CDCl3): l 19.3 ppm; IR
(KBr): 3264, 3078, 2980, 1712, 1553, 1275, 1188 cm−1;
MS (CI): m/z 413 (M++1, 48). Anal. calcd for
C22H25N2O4P: C, 64.07; H, 6.11; N, 6.79. Found C,
63.11; H, 6.12; N, 6.78.
4.4.2. ( )-[2-(1-tert-Butoxycarbonylaminoethyl)-5-methyl]-
oxazol-4-yl diphenylphosphine oxide (8ab). Yield 1.47 g
(69%), obtained as a white solid from compound 3ab
(2.22 g, 5 mmol), as described in the general proce-
dure: mp 120–121°C (hexane/AcOEt); H NMR (300
MHz, CDCl3): l 1.37 (s, 9H), 1.43 (d, JHH=7.2 Hz,
1
4.5.1. Diethyl ( )-[2-(1-tert-butoxycarbonylaminoethyl)-
5-methyl]oxazol-4-yl phosphonate (10ab). Yield 0.81 g
(45%), obtained as a colorless oil from compound 7ab
(1.90 g, 5 mmol), as described in the general procedure
method: Rf 0.45 (AcOEt); 1H NMR (300 MHz,
CDCl3): l 1.29 (t, 3JHH=7.0 Hz, 6H), 1.38 (s, 9H),
1.45 (d, 3JHH=7.0 Hz, 3H), 2.49 (d, 4JHH=1.8 Hz,
3
3
3H), 2.50 (s, 3H), 4.85 (q, JHH=7.2 Hz, 1H), 5.00 (s,
1H), 7.48–7.34 (m, 10H) ppm; 13C NMR (75 MHz,
1
CDCl3): l 11.7, 20.1, 28.3, 44.7, 80.0, 126.3 (d, JPC
=
2
141.5 Hz), 128.3–133.6 (m), 154.9, 159.1 (d, JPC=26.7
Hz), 163.8 (d, 3JPC=17.1 Hz) ppm; 31P NMR (120
MHz, CDCl3): l 18.3 ppm; IR (KBr): 3337, 2992,
2945, 1719, 1540, 1175 cm−1; MS (CI): m/z 427 (M++
1, 33). Anal. calcd for C23H27N2O4P: C, 64.78; H,
6.38; N, 6.57. Found C, 64.71; H, 6.37; N, 6.58.
3
3H), 4.08 (m, 4H), 4.84 (q, JHH=7.0 Hz, 1H), 5.14 (s,
1H) ppm; 13C NMR (75 MHz, CDCl3): l 11.4, 16.2
3
2
(d, JPC=6.5 Hz), 20.2, 28.2, 44.7, 62.5 (d, JPC=5.5
Hz), 79.9, 124.0 (d, 1JPC=41.5 Hz), 154.8, 158.5 (d,
2JPC=39.3 Hz), 164.1 (d, 3JPC=21.2 Hz) ppm; 31P
NMR (120 MHz, CDCl3): l 9.6 ppm; IR (NaCl):
3260, 2917, 2861, 1700, 1521, 1162, 1027 cm−1; MS
(CI): m/z 363 (M++1, 7). Anal. calcd for
C15H27N2O6P: C, 49.72; H, 7.51; N, 7.73. Found C,
49.79; H, 7.52; N, 7.72.
4.4.3. (+)-[2-(1-(R)-tert-Butoxycarbonylaminoethyl)-5-
methyl]oxazol-4-yl diphenylphosphine oxide (8ad). Yield
1.53 g (72%), obtained as a white solid from com-
pound 3ad (2.22 g, 5 mmol), as described in the gen-
eral procedure: [h]2D2=+43.4 (c 1.00, CH2Cl2). For
spectroscopic data see compound 8ab.
4.5.2. Diethyl (+)-[2-(1-(R)-tert-butoxycarbonylamino-
ethyl)-5-methyl]oxazol-4-yl phosphonate (10ad). Yield
1.01 g (56%), obtained as a colorless oil from com-
pound 7ad (1.90 g, 5 mmol), as described in the gen-
eral procedure: Rf 0.45 (AcOEt); [h]2D2=+39.7 (c 0.3,
CH2Cl2). For spectroscopic data see compound 10ab.
4.4.4. (−)-[2-(1-(S)-tert-Butoxycarbonylaminoethyl)-5-
methyl]oxazol-4-yl diphenylphosphine oxide (8ae). Yield
1.41 g (66%), obtained as a white solid from com-
pound 3ae (2.22 g, 5 mmol), as described in the gen-
eral procedure: [h]2D2=−43.4 (c 1.00, CH2Cl2). For
spectroscopic data see compound 8ab.
4.5.3. Diethyl (−)-[2-(1-(S)-tert-butoxycarbonylamino-
ethyl)-5-methyl]oxazol-4-yl phosphonate (10ae). Yield
0.91 g (50%), obtained as a colorless oil from com-
pound 7ae (1.90 g, 5 mmol), as described in the gen-
eral procedure: Rf 0.45 (AcOEt); [h]2D2=−39.7 (c 0.3,
CH2Cl2). For spectroscopic data see compound 10ab.
4.4.5. (−)-[2-(1-(S)-tert-Butoxycarbonylamino-2-phenyl-
ethyl)-5-methyl]oxazol-4-yl diphenylphosphine oxide
(8ah). Yield 1.83 g (73%), obtained as a white solid
from compound 3ah (2.60 g, 5 mmol), as described in
the general procedure: mp 115–116°C (hexane/AcOEt);

F. Palacios et al. / Tetrahedron: Asymmetry 13 (2002) 2541–2552
2549
4.5.4. Diethyl (+)-[2-(1-(R)-tert-butoxycarbonylamino-
ethyl)-5-ethyl]oxazol-4-yl phosphonate (10bd). Yield
0.87 g (46%), obtained as a colorless oil from com-
pound 7bd (1.97 g, 5 mmol), as described in the gen-
eral procedure: Rf 0.40 (AcOEt); [h]2D2=+34.5 (c 0.33,
CH2Cl2); 1H NMR (300 MHz, CDCl3): l 1.19 (t,
51). Anal. calcd for C18H19N2O2P: C, 66.25; H, 5.87;
N, 8.58. Found C, 66.21; H, 5.87; N, 8.59.
4.7. Synthesis of diethyl (+)-2-(R)-aminoethyl)-5-methyl-
oxazol-4-yl phosphonate (12ad)
3
3JHH=7.5 Hz, 3H), 1.29 (t, JHH=7.0 Hz, 6H), 1.38
To a solution of compound 10ad (1.81 g, 5 mmol) in
AcOEt, a solution of HCl 3 M (5 ml, 15 mmol) was
added dropwise slowly. The mixture was heated at
AcOEt reflux for 15 h. Then, the solution was
extracted with water and the aqueous layer was con-
centrated in vacuo. The crude residue was purified by
silica gel column chromatography eluting with AcOEt/
MeOH affording compound 12ad. 0.60 g (46%),
obtained as a white solid from compound 11ad (1.81
g, 5 mmol) as described in the general procedure: Rf
0.25 (AcOEt/MeOH 25%); [h]2D2=+15.0 (c 0.10,
3
3
(s, 9H), 1.45 (d, JHH=7.0 Hz, 3H), 2.92 (dq, JHH
=
7.5 Hz, 4JHH=1.8 Hz, 2H), 4.08 (m, 4H), 4.86 (q,
3JHH=7.0 Hz, 1H), 5.17 (s, 1H) ppm; 13C NMR (75
MHz, CDCl3): l 12.6, 16.2 (d, 3JPC=6.5 Hz), 19.1,
2
20.2, 28.2, 44.7, 62.5 (d, JPC=5.5 Hz), 79.9, 123.3 (d,
1JPC=243.9 Hz), 154.8, 163.4 (d, JPC=39.8 Hz), 164.1
2
(d, JPC=21.2 Hz) ppm; 31P NMR (120 MHz, CDCl3):
3
l 9.7 ppm; IR (NaCl): 3254, 2917, 2861, 1702, 1519,
1165, 1119 cm−1; MS (CI): m/z 377 (M++1, 10). Anal.
calcd for C16H29N2O6P: C, 51.06; H, 7.77; N, 7.44.
Found C, 50.94; H, 7.76; N, 7.45.
CH2Cl2); 1H NMR (300 MHz, CDCl3): l 1.35 (t,
3
3JHH=6.8 Hz, 6H), 1.77 (dd, 3JHH=6.1 Hz, JNH
=
4.6. General procedure for synthesis of (5-alkyl-2-
aminoalkyl)oxazol-4-yl diphenylphosphine oxide 11
42.4 Hz, 3H), 1.78 (s, 2H), 2.51 (s, 3H), 4.20 (m, 5H)
ppm; 13C NMR (75 MHz, CDCl3): l 11.5, 16.2 (d,
3JPC=6.5 Hz), 17.5, 45.1, 63.2 (d, JPC=5.0 Hz), 127.6
2
To a solution previously prepared and kept under
anhydrous Na2CO3 of chlorotrimethylsilane 1 M and
phenol 3 M in CH2Cl2 (15 mmol) a solution of pro-
tected oxazole 8 was added at room temperature and
under a nitrogen atmosphere. The mixture was stirred
at that temperature for 24 h. Then, it was washed with
a NaOH 2N solution (10 ml) and extracted with
CH2Cl2. The organic layer was dried over anhydrous
MgSO4, filtered and the solvent was evaporated under
vacuum. The crude residue was ground in hexane/
ether and, after filtering, was washed with the same
mixture of solvents. The products were crystallized
from hexane/AcOEt.
(d, 1JPC=226.1 Hz), 158.4 (d, 2JPC=36.3 Hz), 160.0
(d, JPC=22.1 Hz) ppm; 31P NMR (120 MHz, CDCl3):
3
l 10.6 ppm; IR (KBr): 3383, 3269, 1646, 1228, 1036
cm−1; MS (CI): m/z 263 (M++1, 82). Anal. calcd for
C10H19N2O4P: C, 45.80; H, 7.30; N, 10.68. Found C,
45.90; H, 7.31; N, 10.66.
4.8. General procedure for synthesis of N-Boc-peptides
13 (see Ref. 3)
4.8.1. (+)-2-(S)-[N-(2-tert-Butoxycarbonylamino)acetyl-
amino]-3-phenylpropionic acid 13a. Yield 1.29 g (80%),
obtained as a white solid from Gly-Phe (1.11 g, 5
mmol) as described in the general procedure: mp 141–
142°C (hexane/diethyl ether); [h]2D2=+31.2 (c 1.00,
4.6.1. (2-Aminomethyl-5-methyl)oxazol-4-yl diphenyl-
phosphine oxide (11aa). Yield 1.26 g (81%), obtained
as a white solid from compound 8aa (2.06 g, 5 mmol)
as described in the general procedure: mp 131–132°C
1
MeOH); H NMR (300 MHz, CDCl3): l 1.36 (s, 9H),
3
2
2.97 (q, JHH=5.4 Hz, JHHgem=13.5 Hz, 1H), 3.09 (q,
3JHH=5.4 Hz, JHHgem=13.5 Hz, 1H), 3.59 (q, JHH
=
2
3
1
2
3
(hexane/AcOEt); H NMR (300 MHz, CDCl3): l 1.66
6.3 Hz, JHHgem=16.8 Hz, 1H), 3.79 (q, JHH=6.3 Hz,
(s, 2H), 2.57 (d, 4JPH=1.8 Hz, 3H), 3.89 (s, 2H),
7.39–7.85 (m, 10H) ppm; 13C NMR (75 MHz, CDCl3):
l 11.7, 39.4, 126.2 (d, 1JPC=142.0 Hz), 128.3–133.6
2JHHgem=16.8 Hz, 1H), 4.77 (t, 3JHH=5.4 Hz, 1H),
3
5.42 (s, 1H), 6.81 (d, JHH=6.3 Hz, 1H), 7.07–7.20 (m,
5H), 9.21 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3): l
28.2, 37.3, 43.6, 45.1, 80.5, 127.0–135.8 (m), 156.3,
170.0 and 173.5 ppm; IR (KBr): 3469, 3370, 3032,
1728, 1626. 1560 cm−1; MS (CI): m/z 341 (M++3, 2),
339 (M++1, 7). Anal. calcd for C17H26N2O5: C, 60.34;
H, 7.74; N, 8.28. Found: C, 60.24; H, 7.79; N, 8.29.
2
3
(m), 159.1 (d, JPC=26.7 Hz), 163.9 (d, JPC=16.6 Hz)
ppm; 31P NMR (120 MHz, CDCl3): l 18.7 ppm; IR
(KBr): 3376, 3303, 2932, 1593, 1440, 1195, 1129 cm−1;
MS (EI): m/z 312 (M+, 77). Anal. calcd for
C17H17N2O2P: C, 65.38; H, 5.49; N, 8.97. Found C,
65.31; H, 5.49; N, 8.98.
4.8.2. (−)-2-(S)-[N-(2-tert-Butoxycarbonylaminopropi-
onylamino)acetylamino]acetic acid 13b. Yield 0.97 g
(64%), obtained a a white solid from Ala-Gly-Gly
(1.02 g, 5 mmol) as described in the general procedure:
mp 76–77°C (hexane/diethyl ether); [h]2D2=−7.9 (c 0.52,
MeOH); 1H NMR (300 MHz, CDCl3): l 1.18 (d,
3JHH=7.2 Hz, 3H), 1.36 (s, 9H), 3.67 (s, 2H), 3.74 (d,
2JHHgem=3.0 Hz, 2H), 3.88 (q, 3JHH=7.2 Hz, 1H)
ppm; 13C NMR (75 MHz, CDCl3): l 17.9, 28.7, 43.5,
52.2, 66.9, 80.9, 158.1, 171.7, 176.5 ppm; IR (KBr):
3400, 3356, 3310, 1750, 1692, 1672, 1626, 1527 cm−1;
MS (CI): m/z 304 (M++1, 8). Anal. calcd for
C12H21N3O6: C, 47.52; H, 6.98; N, 13.85. Found C,
47.47; H, 6.99; N, 13.87.
4.6.2.
(−)-[2-(1-(S)-Aminoethyl)-5-methyl]oxazol-4-yl
diphenylphosphine oxide (11ae). Yield 1.21 g (74%),
obtained as a white solid from compound 8ae (2.22 g,
5 mmol), as described in the general procedure: mp
126–127°C (hexane/AcOEt); [h]2D2=−8.0 (c 0.3,
CH2Cl2); 1H NMR (300 MHz, CDCl3): l 1.46 (d,
3JHH=6.9 Hz, 3H), 1.87 (s, 2H), 2.51 (s, 3H), 4.07 (q,
3JHH=6.9 Hz, 1H), 7.36–7.82 (m, 10H) ppm; 13C
NMR (75 MHz, CDCl3): l 11.7, 21.6, 45.5, 125.9 (d,
1JPC=142.1 Hz), 128.3–133.6 (m), 159.0 (d, JPC=26.7
2
Hz), 166.9 (d, 3JPC=17.1 Hz) ppm; 31P NMR (120
MHz, CDCl3): l 18.8 ppm; IR (KBr): 3350, 3283,
3058, 1593, 1188, 1173 cm−1; MS (EI): m/z 326 (M+,

2550
F. Palacios et al. / Tetrahedron: Asymmetry 13 (2002) 2541–2552
4.9. General procedure for synthesis of peptide
heated at 70°C for 2 h and the subsequent residue was
purified by flash column chromatography eluting with
AcOEt affording a small proportion (10–20%) of pyra-
zine phosphonates13 and 15ba (1.13 g, 43%) obtained as
colorless oil from N-Boc-(S)-GlyPhe 13a (4.83 g, 15
mmol), as described in the general procedure: Rf 0.37;
[h]2D2=−3.9 (c 1.00, CH2Cl2); 1H NMR (300 MHz,
containing a-ketamides 14
To a solution of 3-alkyl-2H-azirinyl-2-phosphine oxide
1 (1.28 g, 5 mmol) in THF (5 ml), a solution of
N-Boc-peptide 13 (15 mmol) in THF (5 ml) is added
under a nitrogen atmosphere, at −80°C and with con-
tinuous stirring. The mixture was stirred allowing to
warm to room temperature for 4 days. The solvent was
concentrated under vacuum, and the residue was
purified by flash column chromatography eluting with
AcOEt.
3
CDCl3): l 0.97 and 0.98 (2t, JHH=7.0 Hz, 6H), 1.21
(m, 12H), 1.37 and 1.38 (2s, 18H), 2.38–3.12 (m, 8H),
3.71 (m, 4H), 3.96–4.25 (m, 10H), 5.18–5.11 (2dd,
3
2JPH=22.0 and 21.5 Hz, JHH=8.2 and 8.5 Hz, 2H),
7.12–7.91 (m, 14H) ppm; 13C NMR (75 MHz, CDCl3):
3
l 7.4, 16.2, 28.2, 34.7 (d, JPC=15.6 Hz), 37.9 and 38.2,
1
4.9.1. (−)-2-(S)-(2-tert-Butoxycarbonylaminoethanoyl-
amino) - N - (1 - diphenylphosphinoyl - 2 - oxopropyl) - 3-
phenylpropanamide (14aa). Yield 1.18 g (41%) obtained
as a white solid from N-Boc-(S)-GlyPhe 13a (4.83 g, 15
mmol) as described in the general procedure: mp:110–
44.1, 53.8 and 54.1 (2s), 57.1 (d, JPC=141.5 Hz), 63.5,
80.0 (2s), 126.8–136.2 (m), 155.9, 169.5 and 169.7 (2s),
3
170.4 and 170.5 (2d, JPC=5.0 and 6.0 Hz), 202.4 (d,
2JPC=26.7 Hz) ppm; 31P NMR (120 MHz, CDCl3): l
16.0 and 16.1 ppm; IR (NaCl): 3255, 3065, 2983, 2935,
1730, 1724, 1708, 1682, 1165 cm−1; MS (CI): m/z 528
(M++1, 3). Anal. calcd for C24H38N3O8P: C, 54.64; H,
7.26; N, 7.97. Found C, 54.69; H, 7.25; N, 7.96.
1
111°C; [h]2D2=−10.7 (c 0.68, CH2Cl2); H NMR (300
MHz, CDCl3): l 1.39 (s, 18H), 1.99 and 2.11, (2s, 6H),
3
3
2.58 (d, JHH=6.3 Hz, 4H), 2.74 (dd, JHH=7.2 Hz,
2JHHgem=13.8 Hz, 2H), 2.87 (dd, 3JHH=6.9 Hz,
2JHHgem=13.8 Hz, 2H),), 3.63 (m, 4H), 4.70 and 4.80
4.11. General procedures for synthesis of peptide
containing oxazoles 16 and 17
3
(dq, JHH=7.2 Hz, 2H), 5.34 and 5.41 (2s, 2H), 5.84
and 5.76 (2dd, JPH=11.4 Hz, JHH=9.3 Hz, 2H), 6.45
2
3
3
and 6.75 (2d, JHH=6.9 Hz, 2H), 6.87–8.06 (m, 32H)
To a room temperature solution of triphenylphosphine
(1.70 g, 6.5 mmol) and hexachloroethane (1.54 g, 6.5
mmol), in toluene a solution of peptide containing
a-ketamides 14 and 15 was added under a nitrogen
atmosphere. The mixture was stirred at that tempera-
ture for 5 min. After that, triethylamine (2.10 ml, 15
mmol) was added dropwise for 10 min. The mixture
was heated at toluene reflux for 1–3 days. The solvent
was evaporated in vacuo and the residue was diluted
with water and extracted with CH2Cl2. The organic
layers where dried over anhydrous magnesium sulfate,
filtered and concentrated in vacuo. The crude residue
was purified by flash column chromatography eluting
with AcOEt.
ppm; 13C NMR (75 MHz, CDCl3): l 28.3, 29.7, 37.9,
44.0, 54.0 (2s), 60.4 (2d, 1JPC=65.5 Hz), 80.0 (2s),
3
126.8–136.1 (m), 155.9, 169.4 and 170.9 (2d, JPC=4.0
Hz), 200.6 (2s) ppm; 31P NMR (120 MHz, CDCl3): l
31.2 and 31.7 ppm; IR (KBr): 3277, 3071, 2979, 2939,
1732, 1724, 1708, 1659, 1540, 1169 cm−1; MS (CI): m/z
578 (M++1, 26). Anal. calcd for C31H36N3O6P: C, 64.46;
H, 6.28; N, 7.27. Found C, 64.44; H, 6.29; N, 7.28.
4.9.2.
panoylamino]ethanoylamino - N - (1 - diphenylphosphinoyl-
2-oxopropyl)acetamide (14ab). Yield 1.06 (38%)
(+)-2-[-2-(S)-(2-tert-Butoxycarbonylamino)pro-
g
obtained as a white solid from N-Boc-(S)-AlaGlyGly
(4.55 g, 15 mmol) as described in the general procedure:
mp 66–67°C (hexane/AcOEt); [h]2D2=+3.3 (c 1.63,
CH2Cl2); 1H NMR (300 MHz, CDCl3): l 1.33 (m,
24H), 2.02 (s, 6H), 2.53 (s, 2H), 3.59–4.06 (m, 8H), 4.20
4.11.1. (−)-2-[(1-(S)-tert-Butoxycarbonylaminoethanoy-
lamino)-2-phenylethyl]-5-methyloxazol-4-yl diphenylphos-
phine oxide 16aa. Yield 1.45 g (52%) obtained as a
white solid from compound 14aa (2.89 g, 5 mmol) as
described in the general procedure: mp 74–75°C; [h]2D2=
3
3
3
(dq, JHH=6.2 Hz, JHH=6.7 Hz, 2H), 5.61 (d, JHH
=
2
3
6.0 Hz, 2H), 5.76 (dd, JPH=10.3 Hz, JHH=9.4 Hz,
2H), 7.28 (s, 2H), 7.38–7.87 (m, 20H), 8.13 (s, 2H) ppm;
13C NMR (75 MHz, CDCl3): l 18.5, 28.3, 29.7, 42.9,
50.5, 60.8 (d, 1JPC=64.5 Hz), 80.0, 128.4–132.9 (m),
1
−6.6 (c 0.50, CH2Cl2); H NMR (300 MHz, CDCl3): l
3
1.38 (s, 9H), 2.51 (s, 3H), 3.20 (t, JHH=5.8, 4.9 Hz,
3
2H), 3.75 (m, 2H), 5.18 (s, 1H), 5.47 (q, JHH=6.0, 7.2
3
155.8, 168.8, 169.6 (d, JPC=4.0 Hz), 173.9, 200.8 ppm;
Hz), 6.83–7.77 (m, 16H) ppm; 13C NMR (75 MHz,
CDCl3): l 11.6, 28.2, 39.4, 44.3, 48.4, 80.2, 126.9–135.5
31P NMR (120 MHz, CDCl3): l 31.4 and 31.5 ppm; IR
(KBr): 3265, 3071, 2975, 2928, 1731, 1724, 1708, 1657,
1540, 1175 cm−1; MS (CI): m/z 559 (M++1, 5). Anal.
calcd for C27H35N4O7P: C, 58.06; H, 6.32; N, 10.03.
Found C, 57.93; H, 6.31; N, 10.03.
2
3
(m), 155.9, 159.3 (d, JPC=26.7 Hz), 161.5 (d, JPC
=
17.1 Hz), 169.0 ppm; 31P NMR (120 MHz, CDCl3): l
19.6 ppm; IR (KBr): 3277, 3071, 2979, 2939, 1732,
1724, 1708, 1659, 1540, 1169 cm−1; MS (CI): m/z 560
(M++1, 53). Anal. calcd for C31H34N3O5P: C, 66.55; H,
6.12; N, 7.51. Found C, 66.48; H, 6.11; N, 7.51.
4.10. Synthesis of diethyl (−)-1-[2-(S)-(2-tert-butoxy-
carbonylaminoethanoylamino)-3-phenylpropanoylamino]-
2-oxobutylphosphonate (15ba)
4.11.2. Diethyl (−)-2-[(1-(S)-tert-butoxycarbonylamino-
ethanoylamino)-2-phenylethyl]-5-ethyloxazol-4-yl phos-
phonate 17ba. Yield 1.27 g (50%) obtained as a colorless
oil from compound 15ba (2.63 g, 5 mmol) as described
in the general procedure: Rf 0.38; [h]2D2=−3.6 (c 0.30,
To diethyl 3-alkyl-2H-azirinyl phosphonate 6 (5 mmol)
without solvent, the N-Boc-peptide 13 (7.5 mmol) is
added under a nitrogen atmosphere, at room tempera-
ture and with continuous stirring. The mixture was
CH2Cl2); 1H NMR (300 MHz, CDCl3): l 1.19 (t, 3JHH
=

F. Palacios et al. / Tetrahedron: Asymmetry 13 (2002) 2541–2552
2551
3
7.5 Hz, 3H), 1.30 (q, JHH=7.1 Hz, 6H), 1.45 (s, 9H),
2000, 41, 5013–5016; (g) Vedejs, E.; Barda, D. Org. Lett.
2000, 2, 1033–1035; (h) Bertram, A.; Pattenden, G. Syn-
lett 2000, 1519–1521.
3
2.93 (m, 2H), 3.20 (d, JHH=6.3 Hz, 2H), 3.82 (m, 2H),
4.08 (m, 4H), 5.12 (s, 1H), 5.48 (q, 2JHH=7.0, 1H),
6.74–7.26 (m, 6H) ppm; 13C NMR (75 MHz, CDCl3): l
5. For reviews, see: (a) Engel, R. Handbook of Organophos-
phorus Chemistry; Marcel Dekker: New York, 1992; (b)
Kafarski, P.; Lejczak, B. Phosphorus Sulfur 1991, 63,
193–215; (c) Toy, A. D. F.; Walsh, E. N. Phosphorus
Chemistry in Everyday Living; American Chemical Soci-
ety: Washington, DC, 1987; p. 333.
6. (a) Palacios, F.; Aparicio, D.; de los Santos, J. M.;
Vicario, J. Tetrahedron 2001, 57, 1961–1972; (b) Palacios,
F.; Aparicio, D.; de los Santos, J. M. Tetrahedron 1999,
55, 13767–13778; (c) Palacios, F.; Ochoa de Retana, A.
M.; Oyarzabal, J.; Ezpeleta, J. M. Tetrahedron 1998, 54,
2281–2288; (d) Palacios, F.; Pagalday, J.; Piquet, V.;
Dahan, F.; Baceiredo, A.; Bertrand, G. J. Org. Chem.
1997, 62, 292–296.
3
12.7, 16.2 (d, JPC=4.5 Hz), 19.1, 28.3, 40.0, 48.5, 62.5
(d, 2JPC=4.5 Hz), 80.3, 123.0 (d, 1JPC=241.2 Hz),
3
127.0–135 (m), 155.8, 161.8 (d, JPC=20.7 Hz), 163.8
(d, JPC=39.8 Hz), 168.9 ppm; 31P NMR (120 MHz,
2
CDCl3): l 10.2 ppm; IR (NaCl): 3283, 2979, 2925,
1712, 1672, 1513, 1367, 1255, 1162, 1029 cm−1; MS
(CI): m/z 510 (M++1, 100). Anal. calcd for
C24H36N3O7P: C, 56.57; H, 7.12; N, 8.25. Found C,
56.62; H, 7.12; N, 8.24.
Acknowledgements
7. (a) Palacios, F.; Aparicio, D.; Garc´ıa, J.; Vicario, J.;
Ezpeleta, J. M. Eur. J. Org. Chem. 2001, 3357–3365; (b)
Palacios, F.; Aparicio, D.; Ochoa de Retana, A. M.;
Garc´ıa, J.; Oyarzabal, J. Tetrahedron 1999, 55, 3105–
3116.
8. (a) Palacios, F.; Oyarzabal, J.; Pascual, S.; Ochoa de
Retana, A. M. Org. Lett. 2002, 4, 769–772; (b) Palacios,
F.; Alonso, C.; Amezua, P.; Rubiales, G. J. Org. Chem.
2002, 67, 1941–1946; (c) Palacios, F.; Aparicio, D.; Gar-
c´ıa, J.; Rodr´ıguez, E.; Fernandez, A. Tetrahedron 2001,
57, 3131–3141; (d) Palacios, F.; Herran, E.; Rubiales, G.
J. Org. Chem. 1999, 64, 6239–6246.
The present work has been supported by the Direccio´n
General de Investigacio´n del Ministerio de Ciencia y
Tecnolog´ıa (MCYT, Madrid DGI, BQU2000-0217) and
by the Universidad del Pa´ıs Vasco (UPV, G11/99).
J.I.G. and J.M.A. thank the Universidad del Pa´ıs Vasco
and the Ministerio de Educacio´n y Cultura (Madrid)
for predoctoral fellowships.
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