Direct synthesis of phosphinopeptides containing C-terminal α-aminoalkylphosphinic acids

Article abstract of DOI:10.1007/s00726-009-0469-7

A series of phosphinopeptides containing C-terminal α- aminoalkylphosphinic acids were prepared in good yields directly in one-pot reactions of 2-(N-benzoxycarbonylamino)alkanamides/peptide amides, aldehydes, and aryldichlorophosphines, followed by hydrolysis. In the current method, the peptide bond was formed in a Mannichtype reaction. Springer-Verlag 2010.

Full text of DOI:10.1007/s00726-009-0469-7

Amino Acids (2010) 39:533–538
DOI 10.1007/s00726-009-0469-7
ORIGINAL ARTICLE
Direct synthesis of phosphinopeptides containing
C-terminal a-aminoalkylphosphinic acids
•
Fanhua Meng Jiaxi Xu
Received: 29 November 2009 / Accepted: 27 December 2009 / Published online: 22 January 2010
Ó Springer-Verlag 2010
Abstract
A
series of phosphinopeptides containing
1981; Thorsett et al. 1982; Elliott et al. 1985; Bartlett and
Lamden 1986; Musiol et al. 1994; Sampson and Bartlett
1988; Mucha et al. 1994; de Fatima Fernandez et al. 1995),
direct condensation of phosphonate monoesters with amino
acid esters or peptide esters in the presence of coupling
reagents (Galeotti et al. 1996; Campbell and Bermak
1994a, b; Karanewsky and Badia 1986), and our Mannich-
type condensation of benzyl carbamate, aldehydes, alkyl
dichlorophosphite, and subsequent aminolysis with amino
esters (Fu et al. 2006) or alcoholysis with hydroxyl esters
(Xu and Gao 2005; Liu et al. 2006).
C-terminal a-aminoalkylphosphinic acids were prepared in
good yields directly in one-pot reactions of 2-(N-benzoxy-
carbonylamino)alkanamides/peptide amides, aldehydes,
and aryldichlorophosphines, followed by hydrolysis. In the
current method, the peptide bond was formed in a Mannich-
type reaction.
Keywords Amino amide Á Mannich reaction Á
Peptide Á Phosphinopeptide Á Synthesis
The phosphinamidate bond in the phosphinopeptides
have been generally formed by the reaction of phosphi-
nochlorides with amino acid esters or peptide esters (Moree
et al. 1993; Mucha et al. 1994), direct condensation of
phosphinic acids with amino acid esters or peptide esters in
the presence of coupling reagents (Elhaddadi et al. 1991),
the enzyme-catalyzed condensation of phosphinate ethyl
esters and amino esters (Natchev 1991), and our Mannich-
type condensation of N-Cbz protected amino amides/
peptide amides, aldehydes, aryldichlorophosphines, and
subsequent aminolysis with amino acid esters/peptide
esters (Li et al. 2007; He et al. 2009).
Introduction
Phosphonopeptides and phosphinopeptides are important
phosphorus analogues of naturally occurring peptides.
They have been widely used as enzyme inhibitors and as
haptens for catalytic antibody research because they
can be considered as stable mimetics of tetrahedral
transition states in ester and amide hydrolysis and for-
mation (Kafarski and Lejczak 2000a, b; Cunningham
et al. 2008). Several phosphonopeptides have also
shown potent antibacterial activity (Kafarski and Lejczak
2000a, b).
Phosphonopeptides and phosphinopeptides containing
C-terminal a-aminoalkylphosphonic acids or a-amino-
alkylphosphinic acids have been synthesized by coupling
of N-protected amino acids or their active esters with dial-
kyl a-aminoalkylphosphonates/alkyl a-aminoalkylphosphi-
nates (Vassiliou et al. 2008; Ravaschino et al. 2006;
Atherton et al. 1986), or their free acids in organic media or
in aqueous-organic media (Kafarski and Lejczak 1988;
Solodenko et al. 1991; Lukas et al. 2002). An alternative
method for the synthesis of these type of phosphonopep-
tides is ammonolysis or aminolysis of 1-(N-chloroacetyla-
mino)alkylphosphonic acids (Kudzin et al. 2008), which
The phosphonamidate bond in the phosphonopeptides
have been generally formed by the reaction of phospho-
nochloridates with amino acid esters or peptide esters
(Kafarski and Lejczak 2000a, b; Jacobsen and Bartlett
F. Meng Á J. Xu (&)
State Key Laboratory of Chemical Resource Engineering,
Department of Organic Chemistry, Faculty of Science,
Beijing University of Chemical Technology,
100029 Beijing, People’s Republic of China
e-mail: jxxu@mail.buct.edu.cn
123

534
F. Meng, J. Xu
were prepared from aminoalkylphosphonates and chloro-
acetic acid.
Aryldichlorophosphines were prepared according to lit-
erature procedure (Buchner and Lockhart 1951) and their
analytical data are identical to reported ones (Buchner and
Lockhart 1951; Weinberg 1975).
Although several methods are available for the prepa-
ration of phosphinopeptides containing C-terminal a-amino-
alkylphosphinic acids, most of them use the phosphinic
acid derivatives as starting materials, which were generally
synthesized in multi-step procedure (Kukhar et al. 1994;
Soloshonok et al. 1992; Xu and Yu 1999). These methods
have some disadvantages, such as complicated multi-step
procedure of preparation, product isolation and purifica-
tion. The overall yields from the synthesis of the phos-
phinic acid derivatives to the desired peptide products are
seldom satisfactory. It is therefore worthy to develop a new
synthetic method for the preparation of this type of
important phosphinopeptides. Recently we reported novel
methods for the preparation of phosphonic acid derivatives
via phosphorus-Mannich-type reactions (Xu and Fu 2000,
2001; Xu and Wei 2001; Liu and Xu 2005). We also
reported the Mannich-type condensation of N-Cbz pro-
tected amino amides/peptide amides, aldehydes, aryldi-
chlorophosphines, and subsequent aminolysis with amino
acid esters/peptide esters to synthesize phosphinopeptides,
in which the phosphinochloride intermediates were reacted
with amino esters as nucleophiles (Li et al. 2007). More-
over, to optimize the reaction conditions, the hydrolysis of
a phosphinochloride was presented, but only for one
example. We herein present its extension in the direct
synthesis of phosphinopeptides containing C-terminal
a-aminoalkylphosphinic acids.
General procedure for the preparation of N-Cbz-amino
amides or peptide amide (Kline et al. 2008)
To a solution of N-Cbz-amino acids (42 mmol) and
triethylamine (6.4 mL, 4.24 g, 42 mmol) in dried THF
(60 mL), dropwise ethyl chloroformate was added (4.2
mL, 4.54 g, 42 mmol) under stirring at 0°C. The resulting
solution was stirred at the same temperature for 30 min.
After addition of ammonia (10.8 mL), the reaction mixture
was stirred for another 30 min. After removal of solvent,
the residue was dissolved in ethyl acetate. The solution was
washed with 20 mL of water. After concentration and
cooling, colorless crystalline product was afforded from the
solution. Their analytical data are identical to reported ones
(N-Cbz-L-Ala amide, Kline et al. 2008; N-Cbz-L-Val
amide, Dziedzic et al. 2006; N-Cbz-L-Phe amide, Hiskey
and Jung 1963; N-Cbz-b-Ala amide, Rapport et al. 1947;
N-Cbz-Gly-Gly amide, Huang and Niemann 1950).
General procedure for the direct synthesis
of phosphinopeptides
To a solution of N-Cbz-aminoalkanamide (3.0 mmol)
and aldehyde (3.5 mmol) in dried acetonitrile (10 mL),
arylphosphine dichloride was added (3.5 mmol) under the
nitrogen atmosphere. The resulting solution was stirred at
80°C for 12 h (for N-Cbz-Gly-Gly amide, stirred for 36 h).
After cooling and addition of water (0.05 mL), the reaction
mixture was stirred for another 12 h. After removal of
solvent, the residue was separated on a pretreated active
carbon powder column with a mixture of petroleum ether
(30–60°C) and ethyl acetate (2:1, v/v) as an eluent to
remove impurities, finally with methanol as an eluent
to afford desired product, which was recrystallized
from methanol (or ethanol) or a mixture of methanol
(ethanol) and diethyl ether to give colorless crystal
phosphinopeptide.
Materials and methods
Melting points were obtained on a Yanaco melting point
1
apparatus and are uncorrected. The HNMR, 13C NMR,
and 31P NMR spectra were recorded on a Varian Mercury
Plus 300 (300 MHz) or Bruker 400 (400 MHz) spec-
trometer with TMS as an internal standard in the CDCl3
solution. 31P NMR spectra were obtained with the use of
1
broad-band H decoupling; chemical shifts are reported as
ppm referenced to 85% phosphoric acid with positive
shift downfield. The IR spectra were taken on a Nicolet
5700 FT-IR spectrophotometer in KBr. Mass spectra were
obtained on a Bruker ESQUIRE * LCTM ESI ion trap
spectrometer. HRMS data were obtained with an Agilent
LC/MSD TOF mass spectrometer. TLC separations were
performed on silica gel G plates with petroleum ether
(60–90°C)/ethyl acetate (1:1, v/v), and the plates were
visualized with UV light.
Phenyl[N-(R,S)-[N-(S)-benzyloxycarbonylalaninyl]-1-
aminophenylmethyl]-phosphinic acid (2a)
Colorless crystals, mp 314°C (dec.), yield 75%.
IR (KBr) v (cm-1): 1,654.9 (C=O), 1,592.6 (C=O), 1,169.0
(P=O).
Commercially available active carbon powder was
washed with 2 mol/L HCl, ethanol twice, water twice,
ethanol, deionized water, and dried at 80°C before the use
in chromatography.
1H NMR (400 MHz, DMSO-d6) d: 1.76 (s, 3H, CH3),
4.89 (m, 2H, CH & CHP), 5.01 (m, 2H, OCH2), 6.69
(s, 1H, NH), 7.01–7.93 (m, 15H, ArH), 7.99 (s, 1H, NH),
10.03 (s, br, 1H, POH).
123

Direct synthesis of phosphinopeptides
535
13C NMR (100.6 MHz, DMSO-d6) d: 21.2, 23.0, 60.2,
65.6, 125.9, 127.0, 127.1, 127.8, 128.1, 128.2, 128.3,
128.8, 130.0, 130.4, 133.0, 137.5, 137.6, 140.9, 170.8,
172.0.
31P NMR (162.0 MHz, DMSO-d6) d: 22.9.
HRMS (ESI) Calcd. for C24H25N2O5NaP [M ? Na]?
475.1393; Found 475.1376.
HRMS (ESI) Calcd. for C30H30N2O5P [M ? H]?
529.1886; Found 529.1891.
Phenyl[N-(R,S)-[N-benzyloxycarbonyl-b-alaninyl]-1-
aminophenylmethyl]-phosphinic acid (2d)
Colorless crystals, mp 126–132°C, yield 88%.
IR (KBr) v (cm-1): 1,715.5 (C=O), 1,675.0 (C=O), 1,252.6
(P=O).
1H NMR (400 MHz, DMSO-d6) d: 2.28 (s, 2H,
CH2CO), 2.99 (s, 2H, NCH2), 5.01 (s, 2H, OCH2), 5.40 (s,
1H, CHP), 7.05 (s, 1H, NH), 7.34–7.60 (m, 15H, ArH),
7.70 (s, 1H, NH), 8.86 (s, 1H, POH).
Phenyl[N-(R,S)-[N-(S)-benzyloxycarbonylvalinyl]-1-
aminophenylmethyl]-phosphinic acid (2b)
Colorless crystals, mp 188–196°C, yield 65%.
(S,S):(R,S) = 57:43.
IR (KBr) v (cm-1): 1,690.8 (C=O), 1,649.2 (C=O), 1,239.0
13C NMR (100.6 MHz, DMSO-d6) d: 35.8, 37.5, 53.3
(d, J = 104.7 Hz), 65.7, 127.5, 128.2, 128.5, 128.8, 128.9,
132.1, 132.1, 133.37, 133.44, 136.6, 137.7, 156.3, 170.2.
31P NMR (162.0 MHz, DMSO-d6) d: 31.3.
(P=O).
1H NMR (400 MHz, DMSO-d6) major epimer d: 0.46
(d, J = 6.8 Hz, 3H, CH3), 0.55 (d, J = 6.4 Hz, 3H, CH3),
1.74 (dqq, J = 6.4, 6.8, 8.4 Hz, 1H, CH), 3.93 (dd,
J = 8.4, 8.8 Hz, 1H, NCH), 4.97 (d, J = 12.4 Hz, 1H in
OCH2), 5.04 (d, J = 12.4 Hz, 1H in OCH2), 5.31 (dd,
J = 10, 14.4 Hz, 1H, CHPO), 7.10–7.52 (m, 15H, ArH),
7.68–7.73 (m, 1H, NH), 8.72 (d, J = 7.6 Hz, 1H, NH).
31P NMR (162.0 MHz, DMSO-d6) major epimer
d: 28.6.
HRMS (ESI) Calcd. for C24H26N2O5P [M ? H]?
453.1573; Found 453.1577.
4-Methylphenyl[N-(R,S)-[N-benzyloxycarbonyl-b-
alaninyl]-1-aminophenyl-methyl]phosphinic acid (2e)
Colorless crystals, mp 179–186°C, yield 87%.
IR (KBr) v (cm-1): 1,688.8 (C=O), 1,636.2 (C=O), 1,182.2
(P=O).
1H NMR (400 MHz, DMSO-d6) d: 2.26 (t, J = 5.6 Hz,
2H, CH2CO), 2.39 (s, 3H, CH3), 2.97 (t, J = 5.6 Hz, 2H,
CH2N), 4.99 (s, 2H, OCH2), 5.32 (dd, J = 10, 14.4 Hz, 1H,
CHP), 7.04 (s, 1H, NH), 7.23–7.57 (m, 15H, ArH & NH),
8.79 (s, 1H, POH).
1H NMR (400 MHz, DMSO-d6) minor epimer d: 0.64
(d, J = 6.8 Hz, 3H, CH3), 0.68 (d, J = 6.8 Hz, 3H, CH3),
1.74 (dqq, J = 6.0, 6.8, 6.8 Hz, 1H, CH), 4.02 (dd,
J = 6.0, 9.6 Hz, 1H, NCH), 4.97 (d, J = 12.8 Hz, 1H in
OCH2), 5.01 (d, J = 12.8 Hz, 1H in OCH2), 5.34 (dd,
J = 10.0, 14.8 Hz, 1H, CHP), 7.10–7.52 (m, 15H, ArH),
7.68–7.73 (m, 1H, NH), 8.6 (d, J = 9.6 Hz, 1H, NH).
31P NMR (162.0 MHz, DMSO-d6) minor epimer d:
29.1.
13C NMR (100.6 MHz, DMSO-d6) d: 21.1, 35.2, 37.0,
52.8 (JP–C = 97.3 Hz), 65.2, 126.9, 127.3, 127.3, 127.5,
127.6, 127.7, 127.8, 128.3, 128.3, 128.4, 128.4, 128.5,
131.6, 131.7, 136.3, 137.1, 140.2, 140.8 155.8, 169.7.
31P NMR (162.0 MHz, DMSO-d6) d: 31.3.
13C NMR (100.6 MHz, DMSO-d6) d: 17.5, 18.8, 19.4,
19.6, 30.95, 30.99, 53.2 (d, JP–C = 104 Hz) 53.3 (d,
JP–C = 105 Hz), 59.9, 60.8, 65.8, 65.9, 127.5, 128.0,
128.1, 128.2, 128.3, 128.4, 128.5, 128.72, 128.78, 128.82,
128.87, 128.9, 132.0, 132.1, 132.2, 132.3, 133.5, 136.7 (d,
JP–C = 9 Hz), 156.3, 171.3 (d, JP–C = 6 Hz), 156.4, 171.4
(d, JP–C = 6 Hz).
HRMS (ESI) Calcd. for C25H28N2O5P [M ? H]?
467.1730; Found 467.1729.
Phenyl[N-(R,S)-[N-benzyloxycarbonylglycinyl]-1-amino-
2-methylpropyl]-phosphinic acid (2f)
HRMS (ESI) Calcd. for C26H30N2O5P [M ? H]?
481.1886; Found 481.1878.
Colorless crystals, mp 274°C (dec.), yield 81%.
IR (KBr) v (cm-1): 1,728.5 (C=O), 1,660.1 (C=O), 1,236.3
(P=O).
Phenyl[N-(R,S)-[N-(S)-benzyloxycarbonylphenylalaninyl]-
1-aminophenyl-methyl]phosphinic acid (2c)
1H NMR (400 MHz, DMSO-d6) d: 0.87 (d, J = 5.2 Hz,
3H, CH3), 0.95 (d, J = 5.2 Hz, 3H, CH3), 2.15 (m, 1H,
CH(CH3)2), 3.46 (d, J = 12 Hz, 1H in COCH2), 3.65 (d,
J = 12 Hz, 1H in COCH2) 4.08 (m, 1H, CHPO), 5.02 (s,
2H, OCH2), 6.26 (s, br, 1H, NH), 7.34–7.70 (m, 12H, ArH,
POH & NH).
Colorless crystals, mp 275°C (dec.) °C, yield 70%.
IR (KBr) v (cm-1): 1,685.8 (C=O), 1,654.8 (C=O), 1,191.3
(P=O).
1H NMR (400 MHz, DMSO-d6) d: 2.70 (m, 2H, CH2),
4.30 (m, 1H, CH), 4.93 (m, 3H, OCH2 & CHP), 7.02–7.76
(m, 22H, ArH & 2NH).
13C NMR (100.6 MHz, DMSO-d6) d: 18.2 (d,
JP–C = 4.0 Hz), 20.9 (d, JP–C = 15 Hz), 27.9, 43.3, 52.8
31P NMR (162.0 MHz, DMSO-d6) d: 20.4.
123

536
F. Meng, J. Xu
(d, JP–C = 108 Hz), 65.4, 127.6, 127.7, 128.0 (d,
JP–C = 12 Hz), 128.3, 131.3 (d, JP–C = 10 Hz), 131.5,
132.6 (d, JP–C = 7 Hz), 133.8 (d, JP–C = 5 Hz), 137.1,
156.3, 169.1.
31P NMR (162.0 MHz, DMSO-d6) d: 23.5.
HRMS (ESI) Calcd. for C20H26N2O5P [M ? H]?
405.1573; Found 405.1577.
byproducts were eluted with a mixture of petroleum ether
(30–60°C) and ethyl acetate (2:1, v/v). Polar peptide
product was obtained with methanol as an eluent. After
recrystallized from a mixture of methanol and diethyl ether
or methanol, colorless crystal product was obtained in good
yield. Under optimized conditions, a series of phosphino-
peptides were prepared by the use of different aldehydes,
N-Cbz-amino amides, and aryldichlorophosphines. The
results are summarized in Table 1. The results indicated
that the side-chain of the amino amides affects the yields
obviously. Low yields were obtained for the amino amides
with bulky substituents (Table 1, entries 2–3). Aliphatic
aldehydes also work for the reaction (Table 1, entry 6). The
reaction was further extended to an N-Cbz protected pep-
tide amide, a phosphinotripeptide was afforded in a good
yield of 80% (Table 1, entry 7). The structures of all
Phenyl[N-(R,S)-[N-[N-
benzyloxycarbonylglycinyl]glycinyl]-
1-aminophenyl-methyl]phosphinic acid (2g)
Colorless crystals, mp 292°C (dec.), yield 80%.
IR (KBr) v (cm-1): 1,684.9 (C=O), 1,653.8 (C=O), 1,635.8
(C=O), 1,235.9 (P=O).
1H NMR (400 MHz, DMSO-d6) d: 3.68 (m, 4H,
2NHCH2), 4.89 (m, 1H, CHP), 5.03 (s, 2H, OCH2), 7.05–
7.65 (m, 16H, ArH & NH), 8.27 (s, br, 1H, NH).
13C NMR (100.6 MHz, DMSO-d6) d: 42.1, 43.3, 55.4
(JP–C = 94 Hz), 65.5, 125.5, 126.8, 126.9, 127.6, 127.7,
128.0, 128.2, 129.5, 132.1 (JP-C = 7.5 Hz), 136.8, 139.1,
156.4, 168.3, 169.2.
31P NMR (162.0 MHz, DMSO-d6) d: 20.1.
HRMS (ESI) Calcd. for C25H27N3O6P [M ? H]?
496.1632; Found 496.1632.
1
phosphonopeptides 1 were characterized by H NMR, 13C
NMR, 31P NMR, and MS spectrometries (Scheme 1).
On stereochemistry of the product phosphinopeptides,
for N-Cbz-b-Ala amide and N-Cbz-Gly-Gly amide, race-
mic phosphinopeptides 2d–g were obtained. For optically
active N-Cbz-L-Ala amide, N-Cbz-L-Val amide, and
N-Cbz-L-Phe amide, low degree of asymmetric induction
was observed because the chiral center is too far away from
the reactive center in the addition step of the aryl-
chlorophosphonous acid to the N-acyl imine in the reaction
(Scheme 2). N-Cbz-L-Val amide shows the highest stere-
oselectivity in the reaction to afford phosphinopeptide 2b
with a diastereomeric ratio of 57:43 on the basis of inte-
gration in 31P NMR analysis (only one peak was observed
in 31P NMR spectra of products 2a and 2c possibly because
the chiral center of the amino acid moiety in these two
products play an unconspicuous effect to their phosphorus
atom due to long distance). Phenyl[N-(S)-[N-(S)-benzy-
loxycarbonylvalinyl]-1-aminophenylmethyl]phosphinic
acid (2b) was assumed as major diastereomer on the basis
of the reaction mechanism (Scheme 2). The amide, benz-
aldehyde, and phenyldichlorophosphine react to produce an
N-acylimine and phenylchlorophosphonous acid as previ-
ous report (Li et al. 2007). The phenylchlorophosphonous
acid then attacks the imine favorably from its Si side
Results and discussion
Several a-N-benzyloxycarbonyl(Cbz)-amino amides,
a
b-N-Cbz-amino amide (b-N-Cbz-alaninamide), and an
N-benzyloxycarbonyl protected peptide amide (N-Cbz-
glycylglycinamide) were prepared from the corresponding
acids by the mixed anhydride method via activation with
ethyl chloroformate and aminonolysis with ammonia. The
reaction of L-a-N-Cbz-alaninamide, benzaldehyde, and
phenyldichlorophosphine followed by hydrolysis was
selected to optimize the reaction conditions. On the basis of
our previous investigation (Li et al. 2007), acetonitrile is a
suitable solvent because it shows good solubility for most
N-Cbz amino amides. After a mixture of L-a-N-Cbz-alan-
inamide, benzaldehyde, and phenyldichlorophosphine was
refluxed in anhydrous acetonitrile for 12 h and hydrolyzed
for 6 h at room temperature, the desired phosphinopeptide
was generated in a good yield on the basis of TLC and ESI
mass spectral analyses. However, the purification met some
problem because the desired peptide is a strong polar
compound, which shows strong absorbance on silica gel.
After several attempts, we found that the active carbon
powder is an appropriate stationary phase for such strong
polar compound. After reaction and removal of solvent, the
residue was separated on an active carbon powder column
with gradient elute. Weak polar starting materials and
Table 1 Direct synthesis of phosphinopeptides
Entry Phosphinopeptide AA
R
Ar
Yield (%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
L-Ala
L-Val
L-Phe
b-Ala
b-Ala
Gly
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
75
65
70
88
4-MePh 87
Me2CH Ph
Ph
81
80
2g
GlyGly Ph
123

Direct synthesis of phosphinopeptides
537
.
Scheme 1 Direct synthesis of
phosphinopeptides
O
O
ClCO2Et
Et3N
NH3 H2O
CbzNH-AA
OH
CbzNH-AA
NH2
1
β
AA = Gly, L-Ala, L-Val ,L-Phe , -Ala,GlyGly
O
R
O
Ar
H2O
MeCN
ArPCl2
RCHO
CbzNH-AA
N
H
P
CbzNH-AA
NH2
OH
O
1
2
Scheme 2 Formation
mechanism and stereostructures
of diastereomeric
Cl
Cl
P
HO
Cl
N
Ph
Cl
+ PhCHO +
NH2
P
CbzHN
+
CbzHN
Ph
-HCl
Ph
phosphinopeptide 2b
O
O
attack from the back
O
O
Ph
P
H
N
Si addition
Cl
HO
Ph
H
N
Ph
P
H
N
P
CbzHN
+
CbzHN
Cl
Ph
favorably
Ph
CbzHN
O
O
Ph
O
Ph
O
H
H2O
N
P
CbzHN
OH
O
Ph
major (S,S)-2b
attack from the front
O
Ph
H
Re addition
Cl
HO
N
Ph
H
N
P
P
CbzHN
+
CbzHN
Cl
N
Ph
unfavorably
Ph
CbzHN
O
O
Ph
O
P
O
H
Ph
O
H
Cl
H2O
Ph
N
P
CbzHN
OH
O
Ph
minor (S,R)-2b
because the isopropyl group exists and subsequent proton
transfer affords the key intermediate as the aminoalkyl-
phosphinic chloride, which undergoes hydrolysis to gen-
erate the product phosphinopeptide with S,S configuration
as major product. Similarly, the phenylchlorophosphonous
acid attacks the imine unfavorably from its Re side to
afford the phosphinopeptide with S,R configuration as
minor product (Scheme 2).
phosphinic acids from simple starting materials has been
developed. Using this approach, phosphinopeptides con-
taining C-terminal a-aminoalkylphosphinic acids can be
conveniently prepared in good yields directly from simple
chemicals. The method should prove to be valuable for
organic and biological chemists interested in and required
the preparation of this type of phosphorus containing
peptides.
On comparison with the previously reported methods,
the current method is thus a direct synthetic route to these
valuable peptide mimics and is a very useful and conve-
nient method for the preparation of phosphinopeptides
containing C-terminal a-aminoalkylphosphinic acids. The
protocol is very simple and practical.
Acknowledgments The project was supported partly by National
Natural Science Foundation of China (No. 20092013 and 20772005).
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F. Meng, J. Xu
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