Straightforward synthesis of depsiphosphonopeptides via Mannich-type multicomponent condensation

Article abstract of DOI:10.1055/s-2006-926324

A straightforward method for the synthesis of depsiphosphonopeptides via a Mannich-type multicomponent condensation of simple starting materials, such as benzyl carbamate, aldehydes, and 1-carbethoxyalkyl phosphorodichloridites, was developed. Compared to

Full text of DOI:10.1055/s-2006-926324

PAPER
783
Straightforward Synthesis of Depsiphosphonopeptides via Mannich-Type
Multicomponent Condensation
Synthesis
i
of
D
eps
a
iphosphon
x
opeptide
s
i Xu,* Yuanhe Gao
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, College of Chemistry and Molecular
Engineering, Peking University, Beijing 100871, P. R. of China
Fax 86(10)62751708; E-mail: jxxu@pku.edu.cn
Received 22 August 2005; revised 15 September 2005
PyBOP, BOP-Cl, HBTU, BroP, TPyCIU, etc. and
Abstract: A straightforward method for the synthesis of depsi-
Mitsunobu8 strategies have also been developed. An alter-
native method for synthesizing depsiphosphonopeptides
involves the DCC–DMAP-mediated condensation of N-
phosphonopeptides via a Mannich-type multicomponent condensa-
tion of simple starting materials, such as benzyl carbamate,
aldehydes, and 1-carbethoxyalkyl phosphorodichloridites, was de-
veloped. Compared to previous methods, our strategy provides a protected aminoalkylphosphonous acids and hydroxy es-
more efficient, convenient, and practical route for the preparation of
ters, followed by oxidation of the resulting aminoalkyl-
phosphonous monoester by sodium periodate.9
depsiphosphonopeptides under mild reaction conditions with good
yields. Such a strategy avoids the initial synthesis of 1-aminoalkyl-
Depsiphosphonopeptides are generally more stable than
phosphonopeptides and have been widely used as struc-
tural analogues of phosphonopeptides. Although several
methods have been developed for the synthesis of depsi-
phosphonopeptides, to date, all of the methods require
aminoalkylphosphonic acid or aminoalkylphosphonous
acid derivatives as starting materials and the overall yields
from the synthesis of aminoalkylphosphonic acid or
phosphonous acid derivatives to the desired depsi-
phosphonopeptides are not satisfactory in most cases.1–3
Thus, it is necessary to seek a new synthetic route to pre-
pare depsiphosphonopeptides efficiently. Herein, we
present our strategy for the direct preparation of depsi-
phosphonopeptides from simple starting materials.
phosphonic acid or 1-aminoalkylphosphonous acid derivatives as
starting materials.
Key words: depsiphosphonopeptides, Mannich reactions, multi-
component condensations, peptides, phosphonates, phosphonopep-
tides
Phosphonopeptides (phosphonamidate-linked phospho-
nopeptides) and depsiphosphonopeptides (phosphonate-
linked phosphonopeptides) are very important tetrahedral
analogues of naturally occurring peptides. They are recog-
nized as an important class of enzyme inhibitors either as
transition-state analogues, or as nonhydrolyzable phos-
phonate surrogates,1 and are of great interest in the devel-
opment of haptens for the production of catalytic
antibodies.2
Recently, multicomponent condensations have been
widely used in synthetic organic chemistry, especially in
combinatorial synthesis.10 They show high efficiency in
syntheses with structurally diverse products. The three-
component Mannich-type reaction of amines (or carbam-
ates), aldehydes, and phosphites has been widely utilized
in the synthesis of aminoalkylphosphonic acids11a and
their derivatives, including monoesters11 and diesters.12
The Mannich-type reaction followed by alcoholysis and
aminolysis has also been used in the preparation of ami-
noalkylphosphonic mixed diesters,13 depsiphosphonopep-
tides,14 phosphonamidates,15 and phosphonopeptides.14
However, the yields of the desired products are generally
low because aminoalkylphosphonic acid monoester
byproducts always form.13–15 Very recently, we found that
side-chain hydroxymethyl functionalized depsiphospho-
nopeptides can be prepared from the Mannich-type reac-
tion of benzyl carbamate, aldehydes, and a cyclic
monochlorophosphite, diethyl (R,R)-2-chloro-1,3,2-diox-
aphospholane-4,5-dicarboxylate, and subsequent water-
mediated ring-opening reaction of 2-oxo-1,3,2-dioxa-
phospholane intermediates generated in the Mannich-type
reaction.
Phosphonopeptides and depsiphosphonopeptides are gen-
erally prepared by the reaction of N-protected aminoalkyl-
phosphonochloridates with amino esters or hydroxy esters
(or peptide esters or hydroxy acyl esters), respectively;3
use of the monochloridates is more common. The
phosphonochloridates in turn are prepared by the reaction
of N-protected aminoalkylphosphonate diesters with one
equivalent of phosphorus pentachloride,1b,1c,3f,3g by treat-
ment of N-protected aminoalkylphosphonic acid mo-
noesters with thionyl chloride1a,1c,1d,3e,4 or oxalyl
chloride,3b,3d,3h,4 or by oxidative chloridation of N-protect-
ed aminoalkylphosphinate esters with carbon tetrachlor-
ide.5 In addition, the syntheses of phosphonopeptides
from N-protected aminoalkylphosphonic acid hydroxy-
benzotriazole esters and phosphonochloridates under sil-
ver ion catalysis have also been reported.6
Depsiphosphonopeptides have also been prepared from
N-protected aminoalkylphosphonic acids or their mo-
noesters using coupling reagents,7 such as DPPA, BOP,
SYNTHESIS 2006, No. 5, pp 0783–0788
x
x
.
x
x
.2
0
0
6
Advanced online publication: 07.02.2006
DOI: 10.1055/s-2006-926324; Art ID: F13905SS
© Georg Thieme Verlag Stuttgart · New York

784
J. Xu, Y. Gao
PAPER
In our current strategy, N-Cbz-protected depsiphospho-
nopeptides were prepared via the Mannich-type multiple
component condensation of benzyl carbamate, aldehydes,
and 1-carbethoxyalkyl phosphorodichloridites, followed
by hydrolysis. Such a strategy for the preparation of dep-
siphosphonopeptides avoids the initial synthesis of phos-
phonic acid or phosphonous acid derivatives found in
conventional depsiphosphonopeptide synthesis.3
Table 1 Straightforward Synthesis of Depsiphosphonopeptides 2
Entry
1
Peptide
2a
R1
R2
H
Yielda (%) anti/syn
Ph
86
87
87
78
2
2b
2c
4-ClPh
4-BrPh
4-MeOPh
Ph
H
3
H
4
2d
2e
H
1-Carbethoxyalkyl phosphorodichloridites 1 were readily
prepared from the corresponding hydroxy esters and
phosphorous trichloride according to a known proce-
dure.16 They were mixed and stirred with benzyl carba-
mate and an aldehyde in anhydrous benzene. After stirring
for six hours, hydrolysis furnished the desired depsi-
phosphonopeptides in good yields following crystalliza-
tion or chromatographic separation (Scheme 1 and
Table 1). Thus, depsiphosphonopeptides were synthe-
sized in a straight forward manner from simple starting
materials with the Mannich-type multicomponent con-
densation as a key step. Unlike previous synthetic meth-
ods where they were obtained by carefully selective
hydrolysis of phosphonate diester linkage,3b by condensa-
tion of phosphonic acid with hydroxy esters,7 or by
oxidation of phosphonous monoester linkage depsi-
phosphonopeptides;9 the current strategy provides a fast
5
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
72
81
86
66
89
86
82
87
86
88:12
88:12
87:13
87:13
86:14
84:16
84:16
NA
6
2f
4-ClPh
4-BrPh
4-MeOPh
Ph
7
2g
8
2h
2i
9
10
11
12
13
2j
4-ClPh
4-BrPh
4-MeOPh
Ph
2k
2l
2m
85:15
a Isolated yield after crystallization or column chromatography.
and practical way to prepare depsiphosphonopeptides in dicated that depsiphosphonopeptide 2m was obtained as
two diastereomers in a 85:15 ratio on the basis of 31P
one pot under mild reaction conditions with good yields,
NMR analysis. After saponification, 1-Cbz-amino-1-phe-
nylmethylphosphonic acid 3 was obtained with a negative
optical rotation. From a previous publication,17 we con-
cluded that the major isomer of N-Cbz-amino phosphonic
acid 3 should have an S-configuration. To further confirm
this, N-Cbz-amino phosphonic acid 3 was deprotected un-
der hydrogenolysis in the presence of Pd/C to yield free 1-
amino-1-phenylmethylphosphonic acid 4 with a positive
optical rotation, which also indicates that (S)-1-amino-1-
phenylmethylphosphonic acid 4 is the major component
on the basis of the reported results.18 Thus, the (S,R)-dia-
stereomer is the major depsiphosphonopeptide 2m isomer
formed, with the (R,R)-isomer as the minor component
(namely 1,4-anti/1,4-syn, 85:15) (Scheme 2). For pep-
tides 2e–l, 1,4-anti isomers predominate with the anti/syn
ratio ranging from 84:16 to 88:12 on the basis of 31P NMR
analyses.
and could be considered as a pseudo-four-component con-
densation as hydrolysis occurs in situ after the Mannich
reaction. To the best of our knowledge, this is the shortest
route to depsiphosphonopeptides to date. The reaction
works very well for aromatic aldehydes, however, for ali-
phatic aldehydes, only low yields were obtained.
R2
OEt
HO
O
PCl3
R2
O
O
OEt
+
+
Cl2PO
R1
H
Ph
O
NH2
O
1
1a: R2 = H, 1b: R2 = Me, 1c: R2 = Ph
Next we looked at the mechanism, 1-carbethoxyalkyl
phosphorodichloridites 1 are dehydrating agents and
could promote the formation of imines from benzyl car-
bamate and aldehydes. They are converted into hydroxyl
phosphorochloridite intermediates, which then undergo
addition to the imines formed, proton transfer, and hydro-
lysis yield depsiphosphonopeptides 2. For 1-carbethoxy-
alkyl phosphorodichloridites 1b and 1c, for example, (R)-
1c, Si face addition is more favorable than Re face addi-
tion due to the steric hindrance imposed by the methyl or
phenyl group. Thus, the 1,4-anti-depsiphosphonopeptides
anti-2e–l are the major products along with 2m possessing
a newly formed S chiral center (Scheme 3).
R2
O
OH
O
(1) benzene, r.t.
(2) H2O
H
Ph
O
N
P
OEt
O
R1
O
2
R
R
1 = Ph, 4-ClPh, 4-BrPh, 4-MeOPh
2 = H, Me, Ph
Scheme 1 Straightforward synthesis of depsiphosphonopeptides 2
via Mannich-type multicomponent condensation
In order to identify the relative configuration of the two
chiral carbon atoms in depsiphosphonopeptides 2e–l, an
optically pure hydroxyl ester, ethyl (R)-mandelate was
employed in the three-component reaction. The results in-
Synthesis 2006, No. 5, 783–788 © Thieme Stuttgart · New York

PAPER
Synthesis of Depsiphosphonopeptides
785
Ph
The desired depsiphosphonopeptides could be used di-
rectly as anionic type tetrahedral analogues of naturally
occurring peptides, esters, and amides because they are
easily converted into their anionic forms when they are
dissolved in a weak basic buffer. This method could find
applicability in the fields of chemistry, biochemistry, and
enzymology.
O
O
(1) benzene, r.t.
(2) H2O
OEt
+
+
Cl2PO
(R)-1c
Ph
O
NH2
Ph
H
O
Ph
Ph
O
P
OH
O
O
OH
O
H
N
H
N
Ph
O
OEt
Ph
O
P
OEt
+
O
Ph
O
O
Ph
O
anti-2m major
syn-2m minor
Mps were obtained on a Yanaco melting point apparatus and are un-
corrected. 1H NMR and 31P NMR spectra were recorded on a Varian
Mercury 300 Plus spectrometer with TMS as an internal standard or
85% H3PO4 as an external standard in CDCl3. The IR spectra were
taken on a Bruker Vector 22 FT-IR spectrophotometer. Mass spec-
tral data were recorded on a VG-ZAB spectrometer or a Bruker ES-
QUIRE-LCTM ESI ion trap spectrometer. CHN analyses were
recorded on an Elementar Vario EL analyzer. Optical rotations were
measured on a Perkin-Elmer Model 341LC polarimeter with a ther-
mally jacketed 10 cm cell (concentration c given as g/100 mL). TLC
were performed on silica gel GF254 plates and were visualized with
UV light. Benzene was refluxed with sodium and freshly distilled
prior to use. All reactions were performed under a nitrogen atmo-
sphere. Petroleum ether with a bp range 30–60 °C was used.
O
OH
OH
O
OH
OH
H
H
NaOH
EtOH
Ph
O
N
P
Ph
O
N
P
+
O
Ph
O
Ph
(R)-3 minor
(S)-3 major
O
OH
OH
O
OH
OH
H2, Pd/C
HOAc
H2N
P
H2N
P
+
Ph
(S)-4 major
Ph
(R)-4 minor
Scheme 2 Determination of the relative configuration of depsiphos-
phonopeptides 2e–l via chemical correlation
1-Carbethoxyalkyl Phosphorodichloridites (1); General Proce-
dure
Hydroxy ester (0.15 mol) was added dropwise to PCl3 (42 g, 0.30
mol) in an ice–water bath over 2 h. After addition, the resulting mix-
ture was stirred for 6 h, and then allowed to warm to r.t. After re-
moval of excess PCl3, the residue was distilled to afford 1-
carbethoxyalkyl phosphorodichloridite as a colorless liquid.
Ph
O
O
benzene
r.t.
OEt
+
+
Cl2PO
(R)-1c
Ph
Ph
O
O
NH2
Ph
H
O
Si-face favored
HO Cl
Ph
H+ transfer
Carbethoxymethyl Phosphorodichloridite (1a)
Colorless liquid; yield: 66%; bp 69–70 °C/10 mmHg (Lit.16 91–
92 °C/13 mmHg).
1H NMR (300 MHz, CDCl3): d = 4.72 (d, JPH = 9.3 Hz, 1 H, POCH2),
4.29 (q, J = 6.9 Hz, 2 H, OCH2), 1.32 (t, J = 6.9 Hz, 3 H, CH3).
31P NMR (121.5 MHz, CDCl3): d = 180.1.
EI-MS: m/z = 204 (M+).
N
Ph
P
OEt
+
O
O
O
Re-face disfavored
Ph
Cl
Ph
O
O
Cl
O
H
N
H
N
H2O
Ph
Ph
O
P
OEt
+
Ph
O
P
OEt
O
O
Ph
O
O
Ph
O
Re-face addition product, minor
Si-face addition product, major
HRMS: m/z calcd for C4H7Cl2O3P: 203.9510; found: 203.9512.
Ph
Ph
O
OH
O
O
OH
O
H
H
1-Carbethoxyethyl Phosphorodichloridite (1b)
Colorless liquid; yield: 54%; bp 113–115 °C/10 mmHg.
O
N
P
OEt
Ph
O
N
P
OEt
+
O
Ph
O
O
Ph
O
IR (KBr): 1718 (C=O), 1097, 1025 (POC) cm–1.
syn-2m minor
anti-2m major
1H NMR (300 MHz, CDCl3): d = 5.16 (sext, J = 6.9 Hz, 1 H,
POCH), 4.25 (q, J = 7.0 Hz, 2 H, OCH2), 1.60 (d, J = 6.9 Hz, 3 H,
CH3), 1.31 (t, J = 7.0 Hz, 3 H, CH3).
31P NMR (121.5 MHz, CDCl3): d = 178.7.
EI-MS: m/z = 218 (M+).
Scheme 3 Proposed formation mechanism of depsiphosphonopep-
tide 2m
In summary, a straightforward method for the synthesis of
depsiphosphonopeptides using Mannich-type multiple
component condensation of simple starting materials,
benzyl carbamate, aldehydes, and 1-carbethoxyalkyl
phosphorodichloridites was developed. Compared to pre-
vious methods, our strategy provides an efficient, conve-
nient, and practical route for the preparation of
Anal. Calcd for C5H9Cl2O3P (219.00): C, 27.42; H, 4.14. Found: C,
27.13; H, 4.32.
1-Carbethoxy-1-phenylmethyl Phosphorodichloridite (1c)
Colorless liquid; yield: 48%; bp 133–135 °C/10 mmHg.
IR (KBr): 1720 (C=O), 1098, 1024 (POC) cm–1.
depsiphosphonopeptides in one-pot under mild reaction 1H NMR (300 MHz, CDCl3): d = 7.53–7.37 (m, 5 H, Ph), 6.01 (d,
conditions with good yields. It can also be applied to pre-
pare optically active depsiphosphonopeptides with opti-
cally active hydroxyl esters. Such a strategy avoids the
need for the synthesis of aminoalkylphosphonic acid or
phosphonous acid derivatives first as starting materials.
JPH = 14.4 Hz, 1 H, POCH), 4.25 (d, J = 7.0 Hz, 2 H, OCH2), 1.25
(t, J = 7.0 Hz, 3 H, CH3).
31P NMR (121.5 MHz, CDCl3): d = 168.1.
EI-MS: m/z = 280 (M+).
Synthesis 2006, No. 5, 783–788 © Thieme Stuttgart · New York

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J. Xu, Y. Gao
PAPER
Ethyl 2-[({1-[(Benzyloxycarbonyl)amino]-(4-methoxyphen-
yl)methyl}hydroxyphosphoryl)oxy]acetate (2d)
Colorless crystals; yield: 78%; mp 115–117 °C; Rf 0.14 (EtOAc–
MeOH, 2:1).
Anal. Calcd for C10H11Cl2O3P (281.07): C, 42.73; H, 3.94. Found:
C, 42.67; H, 4.08.
Depsiphosphonopeptides (2); General Procedure
2-Carbethoxyalkyl phosphorodichloridite 1 (2 mmol) was slowly
added dropwise to a stirred mixture of benzyl carbamate (0.30 g, 2
mmol) and aldehyde (2 mmol) in anhyd benzene (10 mL) in an ice–
water bath and then allowed to warm to r.t. under stirring. After stir-
ring the reaction mixture for 6 h at r.t., H2O (0.1 mL) was added
dropwise and the resulting reaction mixture was allowed to stir for
2 h. After removal of the solvent, the residue was crystallized from
petroleum ether–EtOAc to afford depsiphosphonopeptides 2 except
for 2i and 2l, which were separated by column chromatography (pe-
troleum ether–acetone, 5:1).
IR (KBr): 3333 (NH, POH), 1720 (C=O), 1246 (P=O), 1098, 1028
(POC) cm–1.
1H NMR (300 MHz, CDCl3): d = 10.26 (br s, 1 H, POH), 7.30–6.82
(m, 9 H, Ph), 6.48 (br s, 1 H, NH), 5.24 (d, JPH = 20.1 Hz, 1 H,
PCH), 5.08 (s, 2 H, OCH2), 4.45–4.27 (m, 2 H, OCH2), 4.19 (q,
J = 7.2 Hz, 2 H, CH2), 3.76 (s, 3 H, CH3O), 1.24 (t, J = 7.2 Hz, 3 H,
CH3).
31P NMR (121.5 MHz, CDCl3): d = 20.88.
ESI-MS: m/z = 438 (MH+).
Anal. Calcd for C20H24NO8P (437.38): C, 54.92; H, 5.53; N, 3.20.
Found: C, 55.14; H, 5.30; N, 3.01.
Ethyl 2-[({1-[(Benzyloxycarbonyl)amino]phenylmethyl}hy-
droxyphosphoryl)oxy]acetate (2a)
Colorless crystals; yield: 86%; mp 113–115 °C; Rf 0.25 (EtOAc–
MeOH, 2:1).
Ethyl 2-[({1-[(Benzyloxycarbonyl)amino]phenylmethyl}hy-
droxyphosphoryl)oxy]propionate (2e)
Colorless crystals; yield: 72%; mp 122–125 °C; anti/syn, 88:12; Rf
IR (KBr): 3313 (NH, POH), 1719 (C=O), 1236 (P=O), 1099, 1025
(POC) cm–1.
1H NMR (300 MHz, CDCl3): d = 10.27 (br s, 1 H, POH), 7.37–7.17
(m, 10 H, Ph), 6.55 (br s, 1 H, NH), 5.29 (d, JPH = 21.0 Hz, 1 H,
PCH), 5.08 (s, 2 H, OCH2), 4.42–4.24 (m, 2 H, OCH2), 4.19 (q,
J = 7.0 Hz, 2 H, CH2), 1.24 (t, J = 7.0 Hz, 3 H, CH3).
31P NMR (121.5 MHz, CDCl3): d = 21.61.
ESI-MS: m/z = 408 (MH+).
0.18 (EtOAc–MeOH, 2:1).
IR (KBr): 3319 (NH, POH), 1726 (C=O), 1239 (P=O), 1053, 1009
(POC) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.22 (br s, 1 H, POH), 7.41–7.27
(m, 10 H, Ph), 6.41, 6.25 (br s, 1 H, NH), 5.30–5.10 (m, 1 H, CHP),
5.10 (d, JPH = 2.9 Hz, 2 H, CH2O), 4.66, 4.53 (dq, JPH = 7.0 Hz,
J = 7.2 Hz, 1 H, POCH), 4.18, 4.15 (q, J = 7.2 Hz, 2 H, OCH2),
1.38, 1.31 (d, J = 7.2 Hz, 3 H, CH3), 1.24, 1.22 (t, J = 7.0 Hz, 3 H,
CH3).
Anal. Calcd for C19H22NO7P (407.35): C, 56.02; H, 5.44; N, 3.44.
Found: C, 55.78; H, 5.56; N, 3.62.
31P NMR (121.5 MHz, CDCl3): d = 21.49, 20.90 (88:12).
FAB-MS: m/z = 422 (MH+).
Ethyl 2-[({1-[(Benzyloxycarbonyl)amino]-(4-chlorophen-
yl)methyl}hydroxyphosphoryl)oxy]acetate (2b)
Colorless crystals; yield: 87%; mp 137–139 °C; Rf 0.16 (EtOAc–
MeOH, 2:1).
Anal. Calcd for C20H24NO7P (421.38): C, 57.01; H, 5.74; N, 3.32.
Found: C, 57.22; H, 5.63; N, 3.10.
IR (KBr): 3320 (NH, POH), 1708 (C=O), 1239 (P=O), 1093, 1015
(POC) cm–1.
1H NMR (300 MHz, CDCl3): d = 11.13 (br s, 1 H, POH), 7.34–7.24
(m, 9 H, Ph), 6.75 (br s, 1 H, NH), 5.28 (d, JPH = 22.5 Hz, 1 H,
PCH), 5.07 (s, 2 H, OCH2), 4.44–4.28 (m, 2 H, OCH2), 4.19 (q,
J = 7.0 Hz, 2 H, CH2), 1.24 (t, J = 7.0 Hz, 3 H, CH3).
31P NMR (121.5 MHz, CDCl3): d = 21.00.
ESI-MS: m/z = 442 (MH+).
Ethyl 2-[({1-[(Benzyloxycarbonyl)amino]-(4-chlorophen-
yl)methyl}hydroxyphosphoryl) oxy]propionate (2f)
Colorless crystals; yield: 81%; mp 127–129 °C; anti/syn, 88:12; Rf
0.14 (EtOAc–MeOH 2:1).
IR (KBr): 3319 (NH, POH), 1725 (C=O), 1239 (P=O), 1053, 1014
(POC) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.59 (br s, 1 H, POH), 7.38–7.27
(m, 9 H, Ph), 6.56, 6.36 (br s, 1 H, NH), 5.32–5.07 (m, 1 H, CHP),
5.09 (d, JPH = 2.7 Hz, 2 H, CH2O), 4.72, 4.48 (dq, JPH = 7.0 Hz,
J = 6.9 Hz, 1 H, POCH), 4.19, 4.17 (q, J = 7.2 Hz, 2 H, OCH2),
1.40, 1.36 (d, J = 6.9 Hz, 3 H, CH3), 1.24, 1.23 (t, J = 7.2 Hz, 3 H,
CH3).
31P NMR (121.5 MHz, CDCl3): d = 20.58, 19.60 (88:12).
FAB-MS: m/z = 456 (MH+).
Anal. Calcd for C19H21ClNO7P (441.80): C, 51.65; H, 4.79; N, 3.17.
Found: C, 51.89; H, 5.00; N, 2.96.
Ethyl 2-[({1-[(Benzyloxycarbonyl)amino]-(4-bromophen-
yl)methyl}hydroxyphosphoryl)oxy]acetate (2c)
Colorless crystals; yield: 87%; mp 139–40 °C; Rf 0.28 (EtOAc–
MeOH, 2:1).
Anal. Calcd for C20H23ClNO7P (455.83): C, 52.70; H, 5.09; N, 3.07.
Found: C, 52.53; H, 5.13; N, 3.10.
IR (KBr): 3344 (NH, POH), 1722 (C=O), 1240 (P=O), 1098, 1021
(POC) cm–1.
1H NMR (300 MHz, CDCl3): d = 9.95 (br s, 1 H, POH), 7.45–7.28
(m, 9 H, Ph), 6.65 (br s, 1 H, NH), 5.27 (d, JPH = 22.2 Hz, 1 H,
PCH), 5.08 (s, 2 H, OCH2), 4.49–4.24 (m, 2 H, OCH2), 4.21 (q,
J = 7.2 Hz, 2 H, CH2), 1.25 (t, J = 7.2 Hz, 3 H, CH3).
Ethyl 2-[({1-[(Benzyloxycarbonyl)amino]-(4-bromophen-
yl)methyl}hydroxyphosphoryl)oxy]propionate (2g)
Colorless crystals; yield: 86%; mp 124–126 °C; anti/syn, 87:13; Rf
0.21 (EtOAc–MeOH, 2:1).
31P NMR (121.5 MHz, CDCl3): d = 20.94.
ESI-MS: m/z = 486 (MH+).
IR (KBr): 3316 (NH, POH), 1719 (C=O), 1238 (P=O), 1099, 1053
(POC) cm–1.
1H NMR (300 MHz, CDCl3): d = 10.45 (br s, 1 H, POH), 7.44–7.25
(m, 9 H, Ph), 6.64, 6.44 (br s, 1 H, NH), 5.30–5.13 (m, 1 H, PCH),
5.08 (d, JPH = 2.1 Hz, 2 H, OCH2), 4.73, 4.58 (m, 1 H, OCH), 4.16
(q, J = 7.0 Hz, 2 H, CH2), 1.40, 1.35 (d, J = 6.9 Hz, 3 H, CH3), 1.23,
1.21 (t, J = 7.0 Hz, 3 H, CH3).
Anal. Calcd for C19H21BrNO7P (486.25): C, 46.93; H, 4.35; N, 2.88.
Found: C, 47.09; H, 4.03; N, 3.12.
Synthesis 2006, No. 5, 783–788 © Thieme Stuttgart · New York

PAPER
Synthesis of Depsiphosphonopeptides
787
31P NMR (121.5 MHz, CDCl3): d = 20.40, 19.63 (87:13).
ESI-MS: m/z = 500 (MH+).
1H NMR (300 MHz, CDCl3): d = 9.50 (br s, 1 H, POH), 7.40–7.17
(m, 14 H, Ph), 6.45 (br s, 1 H, NH), 5.39 (d, JPH = 7.5 Hz, 1 H,
OCH), 5.20 (d, JPH = 24.9 Hz, 1 H, PCH), 5.05 (s, 2 H, OCH2), 4.10
(q, J = 7.5 Hz, 2 H, CH2), 1.10 (t, J = 7.5 Hz, 3 H, CH3).
31P NMR (121.5 MHz, CDCl3): d = 20.88, 19.60 (84:16).
ESI-MS: m/z = 562 (MH+).
Anal. Calcd for C20H23BrNO7P (500.28): C, 48.02; H, 4.63; N, 2.80.
Found: C, 47.82; H, 4.89; N, 3.02.
Ethyl 2-[({1-[(Benzyloxycarbonyl)amino]-(4-methoxyphen-
yl)methyl}hydroxyphosphoryl)oxy]propionate (2h)
Colorless crystals; yield: 66%; mp 116–119 °C; anti/syn, 87:13; Rf
0.24 (EtOAc–MeOH, 2:1).
Anal. Calcd for C25H25BrNO7P (562.35): C, 53.40; H, 4.48; N, 2.49.
Found: C, 53.19; H, 4.59; N, 2.66.
IR (KBr): 3319 (NH, POH), 1720 (C=O), 1245 (P=O), 1053, 1009
(POC) cm–1.
Ethyl 2-[({1-[(Benzyloxycarbonyl)amino]-(4-methoxyphen-
yl)methyl}hydroxyphosphoryl)oxy]phenylacetate (2l)
Colorless viscous oil; yield: 87%; Rf 0.13 (EtOAc–MeOH, 2:1).
1H NMR (300 MHz, CDCl3): d = 7.37–7.27 (m, 7 H, Ph), 6.85 (d,
J = 8.6 Hz, 2 H, Ph), 6.37, 6.20 (br s, 1 H, NH), 5.13–5.04 (m, 1 H,
CHP), 5.09 (d, JPH = 2.4 Hz, 2 H, CH2O), 4.71, 4.56 (dq, JPH = 7.0
Hz, J = 6.9 Hz, 1 H, POCH), 4.18, 4.16 (q, J = 7.0 Hz, 2 H, OCH2),
3.78 (s, 3 H, MeO), 1.40, 1.33 (d, J = 6.9 Hz, 3 H, CH3), 1.24, 1.23
(t, J = 7.2 Hz, 3 H, CH3).
31P NMR (121.5 MHz, CDCl3): d = 21.61, 20.70 (87:13).
FAB-MS: m/z = 452 (MH+).
IR (KBr): 3333 (NH, POH), 1729 (C=O), 1248 (P=O), 1058, 1028
(POC) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.84 (br s, 1 H, POH), 7.44–7.75
(m, 14 H, Ph), 6.50, 6.35 (br s, 1 H, NH), 5.63 (d, JPH = 8.1 Hz,
OCH), 5.40 (d, JPH = 6.9 Hz, 1 H, OCH), 5.26, 5.19 (d, JPH = 20.1
Hz, 1 H, PCH), 4.10 (q, J = 7.2 Hz, 2 H, OCH2), 3.74 (s, 3 H,
CH3O), 1.12 (t, J = 7.2 Hz, 3 H, CH3).
31P NMR (121.5 MHz, CDCl3): d = 20.82, 20.30 (inseparable).
ESI-MS: m/z = 514 (MH+).
Anal. Calcd for C21H26NO8P (451.41): C, 55.88; H, 5.81; N, 3.10.
Found: C, 55.80; H, 5.65; N, 3.22.
Anal. Calcd for C26H28NO8P (513.48): C, 60.82; H, 5.50; N, 2.73.
Found: C, 60.71; H, 5.72; N, 2.80.
Ethyl 2-[({1-[(Benzyloxycarbonyl)amino]phenylmethyl}hy-
droxyphosphoryl)oxy]phenylacetate (2i)
Colorless crystals; yield: 89%; mp 45–48 °C; anti/syn, 86:14; Rf
0.11 (EtOAc–MeOH, 2:1).
Ethyl 2-[([1-[(Benzyloxycarbonyl)amino]-(S)-phenylmethyl]hy-
droxyphosphoryl)oxy]-(R)-phenylacetate (2m)
Colorless crystals; yield: 86%; anti/syn, 85:15; mp 47–48 °C; Rf
0.11 (EtOAc–MeOH, 2:1).
IR (KBr): 3348 (NH, POH), 1734 (C=O), 1221 (P=O), 1058, 1026
(POC) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.62 (br s, 1 H, POH), 7.41–6.10
(m, 15 H, Ph), 6.51, 6.33 (br s, 1 H, NH), 5.60 (d, JPH = 8.4 Hz, 1 H,
OCH), 5.37 (d, JPH = 7.2 Hz, 1 H, OCH), 5.05 (s, 2 H, OCH2), 5.29,
5.24 (d, J = 20.4 Hz, 1 H, CHP), 4.10 (q, J = 6.9 Hz, 2 H, OCH2),
1.12, 1.11 (t, J = 6.9 Hz, 3 H, CH3).
31P NMR (121.5 MHz, CDCl3): d = 23.56, 22.40 (86:14).
ESI-MS: m/z = 484 (MH+).
IR (KBr): 3348 (NH, POH), 1734 (C=O), 1221 (P=O), 1058, 1026
(POC) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.62 (br s, 1 H, POH), 7.41–6.10
(m, 15 H, Ph), 6.51, 6.33 (br s, 1 H, NH), 5.60 (d, JPH = 8.4 Hz, 1 H,
OCH), 5.37 (d, JPH = 7.2 Hz, 1 H, OCH), 5.05 (s, 2 H, OCH2), 5.29,
5.24 (d, J = 20.4 Hz, 1 H, CHP), 4.10 (q, J = 6.9 Hz, 2 H, OCH2),
1.12, 1.11 (t, J = 6.9 Hz, 3 H, CH3).
31P NMR (121.5 MHz, CDCl3): d = 23.56, 22.40 (85:15).
ESI-MS: m/z = 484 (MH+).
Anal. Calcd for C25H26NO7P (483.45): C, 62.11; H, 5.42; N, 2.90.
Found: C, 62.00; H, 5.68; N, 3.13.
Anal. Calcd for C25H26NO7P (483.45): C, 62.11; H, 5.42; N, 2.90.
Found: C, 62.09; H, 5.19; N, 3.07.
Ethyl 2-[({1-[(Benzyloxycarbonyl)amino]-(4-chlorophen-
yl)methyl}hydroxyphosphoryl)oxy]phenylacetate (2j)
Colorless crystals; yield: 86%; mp 147–150 °C; anti/syn, 84:16; Rf
0.18 (EtOAc–MeOH, 2:1).
1-Benzyloxycarbonylamino-1-Phenylmethylphosphonic Acid
(3)
IR (KBr): 3330 (NH, POH), 1725 (C=O), 1220 (P=O), 1090, 1015
(POC) cm–1.
1H NMR (300 MHz, CDCl3): d = 10.41 (br s, 1 H, POH), 7.28–7.20
(m, 14 H, Ph), 6.45 (br s, 1 H, NH), 5.40 (d, JPH = 7.5 Hz, 1 H,
OCH), 5.22 (d, JPH = 23.4 Hz, 1 H, PCH), 5.05 (s, 2 H, OCH2), 4.11
(q, J = 7.0 Hz, 2 H, CH2), 1.11 (t, J = 7.0 Hz, 3 H, CH3).
31P NMR (121.5 MHz, CDCl3): d = 20.94, 19.80 (84:16).
ESI-MS: m/z = 518 (MH+).
Depsiphosphonopeptide 2m (1.69 g, 3.5 mmol) was dissolved in a
solution of NaOH (1 M, EtOH; 10 mL) and stirred at r.t. overnight.
The pH was adjusted to 2–3 by the addition of HCl (2 M), the result-
ing mixture was extracted with Et2O (3 × 50 mL), and dried over an-
hyd Na2SO4. After removal of the solvent, the residue was
crystallized from CHCl3.
Colorless crystals; yield: 0.71 g (63%); mp 143–145 °C; [a]D20 –27
20
(c 1.0, DMSO-d6), {Lit.17a mp 142–143 °C; [a]D –19.4 (c 2.0, 1
M NaOH)}.
IR (KBr): 3394 (NH, POH), 1717 (C=O), 1184 (P=O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.52–7.10 (m, 10 H, Ph), 5.49
(br s, 1 H, NH), 4.90 (br s, 3 H, OCH2, CHP).
31P NMR (121.5 MHz, DMSO-d6): d = 17.85.
ESI-MS: m/z = 322 (MH+).
Anal. Calcd for C25H25ClNO7P (517.90): C, 57.98; H, 4.87; N, 2.70.
Found: C, 58.17; H, 4.99; N, 2.61.
Ethyl 2-[({1-[(Benzyloxycarbonyl)amino]-(4-bromophen-
yl)methyl}hydroxyphosphoryl)oxy]phenylacetate (2k)
Colorless crystals; yield: 82%; mp 140–143 °C; anti/syn, 84:16; Rf
0.30 (EtOAc–MeOH, 2:1).
Anal. Calcd for C15H16NO5P (321.27): C, 56.08; H, 5.02; N, 4.36.
Found: C, 56.09; H, 5.29; N, 4.17.
IR (KBr): 3335 (NH, POH), 1720 (C=O), 1223 (P=O), 1058, 1011
(POC) cm–1.
Synthesis 2006, No. 5, 783–788 © Thieme Stuttgart · New York

788
J. Xu, Y. Gao
PAPER
Witherington, J.; Phillips, B. W.; Smith, A. B. III J. Am.
(S)-1-Amino-1-phenylmethylphosphonic Acid (4)
To a solution of phosphonic acid 3 (0.64 g, 2 mmol) in AcOH (2.5
mL) was added Pd/C (10%; 0.1 g), and the resulting mixture was
stirred under a hydrogen atmosphere at r.t. for 14 h. After filtration
and removal of the solvent, the residue was crystallized from H2O.
Colorless crystals; yield: 0.337 g (90%); mp 282–284 °C (Lit.18
287–288 °C); [a]D20 +12 (c 1.0, 1 M NaOH) {Lit18 [a]D20 +18 (c 2,
1 M NaOH)}.
Chem. Soc. 1995, 117, 6370. For phosphonopeptides, see:
(g) Hariharan, M.; Chaberek, S.; Martell, A. E. Synth.
Commun. 1973, 3, 375. (h) Yamauchi, K.; Mitsuda, Y.;
Kinoshita, M. Bull. Chem. Soc. Jpn. 1975, 48, 3285.
(i) Morgan, B. P.; Holland, D. R.; Matthews, B. W.; Bartlett,
P. A. J. Am. Chem. Soc. 1994, 116, 3251.
(4) Vo-Quang, Y.; Gravey, A. M.; Simonneau, R.; Vo-Quang,
L.; Lacoste, A. M.; Le Goffic, F. Tetrahedron Lett. 1987, 28,
6167.
(5) (a) Sampson, N. S.; Bartlett, P. A. J. Org. Chem. 1988, 53,
4500. (b) Mucha, A.; Kafarski, P.; Plenat, F.; Cristau, H. J.
Tetrahedron 1994, 50, 12743. (c) Bartlett, P. A.;
Giangiordano, M. A. J. Org. Chem. 1996, 61, 3433.
(6) Musiol, H. J.; Grams, F.; Rudolph-Bohner, S.; Moroder, L.
J. Org. Chem. 1994, 59, 6144.
Acknowledgment
This work was supported in part by the National Natural Science
Foundation of China (Project Nos. 20472005 and 20272002), Min-
istry of Education of China (SRF for ROCS and EYTP), and Peking
University (President Grant).
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Synthesis 2006, No. 5, 783–788 © Thieme Stuttgart · New York