Synthesis of phosphinodepsipeptides via the pseudo-four-component condensation reaction

Article abstract of DOI:10.1016/j.tet.2013.04.032

Phosphinodepsipeptides are recognized as an important class of enzyme inhibitors as tetrahedrally structural transition-state analogues to natural peptides. A series of phosphinodepsipeptides was synthesized in satisfactory yields via pseudo-four-component condensation reaction of 2-(N- benzoxycarbonylamino)alkanamides/peptide amides, aldehydes, and aryldichlorophosphines, followed by alcoholysis with hydroxyl esters.

Full text of DOI:10.1016/j.tet.2013.04.032

Tetrahedron 69 (2013) 4944e4952
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of phosphinodepsipeptides via the pseudo-four-
component condensation reaction
*
Fanhua Meng, Jiaxi Xu
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology,
Beijing 100029, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Phosphinodepsipeptides are recognized as an important class of enzyme inhibitors as tetrahedrally
structural transition-state analogues to natural peptides. A series of phosphinodepsipeptides was syn-
thesized in satisfactory yields via pseudo-four-component condensation reaction of 2-(N-benzox-
ycarbonylamino)alkanamides/peptide amides, aldehydes, and aryldichlorophosphines, followed by
alcoholysis with hydroxyl esters.
Received 5 February 2013
Received in revised form 29 March 2013
Accepted 8 April 2013
Available online 13 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amino amide
Alcoholysis
Four-component condensation
Peptide
Phosphinodepsipeptide
1. Introduction
phosphinodepsipeptides show generally better stability than the
corresponding phosphonopeptides and phosphinopeptides, re-
Phosphonopeptides as important phosphorus analogs of natu-
rally occurring peptides have received considerable attention in
bioorganic, biological, and medicinal chemistry due to the fact that
they can be considered as stable mimetics of tetrahedral transition
states in ester and amide hydrolysis and formation.1e4 Phosphono-
peptide is a general name for peptides containing a phosphonamide
linkaged bond or 1-aminoalkylphosphonic acid at their C-terminal.
Phosphinopeptides are peptides involving a phosphinamide bond
or 1-aminoalkylphosphinic acid at their C-terminal. Phosphono-
depsipeptides are peptides involving the phosphonate junction and
phosphinodepsipeptides contain the phosphinate connection in the
peptides or peptides containing a 1-hydroxyalkylphosphonic acid or
1-hydroxyalkylphosphinic acid at their C-terminal, respectively.5 All
of them have been widely used as enzyme inhibitors,1e4,6e10 hap-
tens for production of catalytic antibodies,11 antibacterials,1,12 and
herbicidal agents,1 and potential antihypertensive agents.13 Re-
cently, it was shown that vancomycin-resistant bacteria canproduce
spectively. Thus, the new phosphonodidepsipeptides and phosphi-
nodidepsipeptides are interesting candidates for use as inhibitors of
VanX D,D-dipeptidase.
Phosphonopeptides and phosphinopeptides have been widely
prepared and applied in organic and biological chemistry fields.1e4
Phosphonodepsipeptides have also been synthesized via the re-
action of N-protected aminoalkylphosphonochloridates with hydroxy
esters,6b,7,9,10,14 via the condensation of N-protected amino-
aklylphosphonic acids or their monoester with hydroxy esters using
coupling reagents, such as DIAD/PPh3,11b,15 DPPA, BOP, PyBOP, BOP-Cl.
HBTU, BroP, TPyCIU, etc.6a,11a,16 Alternatively, they were synthesized
via condensation of the corresponding phosphonous acids and hy-
droxy esters with DCC as a coupling reagent followed by oxidation
with sodium periodate17 or via the reaction of the corresponding
phosphonous chlorides and hydroxy esters and subsequent oxidation
with sodium periodate.18 They were also prepared via nucleophilic
displacement of the corresponding phosphonate sodium salts and
ethyl 2-trifluoromethanesulfonyloxyalkanoates12 and our recent
phosphorus-Mannich-type reactions of carbamates, aldehydes, and
chlorophosphites, and subsequent alcoholysis with hydroxy esters.19
However, the synthesis of phosphinodepsipeptides has not been re-
ported to date. Recently, we reported a novel method for the prepa-
ration of phosphinopeptides or hybrid sulfonophosphinopeptides via
the Mannich-type condensation of N-Cbz protected amino amides/
peptide amides or N-Cbz protected aminoalkanesulfonamides,
D
-Ala-
-Ala-
D
-lactate didepsipeptide instead of
D-Ala-D-Ala dipeptide.
D
D-lactate didepsipeptide not only binds much more weakly to
vancomycin but also can be incorporated into the peptidoglycan
layer.11,14 On the other hand, phosphonodepsipeptides and
* Corresponding author. Tel./fax: þ86 10 64435565; e-mail address: jxxu@
mail.buct.edu.cn (J. Xu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.032

F. Meng, J. Xu / Tetrahedron 69 (2013) 4944e4952
4945
aldehydes, aryldichlorophosphines, and subsequent aminolysis with
amino acid esters/peptide esters or hydrolysis in high yields.20,21 We
herein present the first and facile synthesis of phosphinodepsipep-
tides via the pseudo-four-component condensation reaction, which is
a convergent and atom-economic synthetic strategy.
improve the yield of the phosphinodepsipeptide 4. Further using
shorter reaction time, the yield of 4 was improved obviously to 51%
and 68% (Table 1, entries 3 and 4). However, when the Mannich
reaction was shortened to 0.5 h, the yield of 4 decreased to 60%
(Table 1, entry 5). In each of cases, we can recover some N-Cbz-
glycinamide (1a) after workup. To improve the conversion of N-
Cbz-glycinamide (1a), we increased the amount of phenyl-
dichlorophosphine (3a) to 1.33 and 1.67 equiv to N-Cbz-glycina-
mide (1a), respectively. However, the yield of the desired product 4
was improved slightly to 70% and 71% (Table 1, entries 6 and 7).
Therefore, the optimized reaction conditions are that N-Cbz-ami-
noamide (1a), aldehyde (2a), and aryldichlorophosphine (3a) in
a molar ratio of 1.0:1.2:1.3:2.0 were refluxed in anhydrous aceto-
nitrile under a nitrogen atmosphere for 1 h and then the resulting
mixture was alcoholyzed for another 6 h.
2. Results and discussion
Several N-benzyloxycarbonyl(Cbz)-amino amides and an N-Cbz
protected peptide amide (N-Cbz-glycylglycinamide) were prepared
from the corresponding acids by the mixed anhydride method via
activation with ethyl chloroformate and aminolysis with ammonia.
The reaction of N-Cbz-glycinamide (1a), benzaldehyde (2a), and
phenyldichlorophosphine (3a) followed by alcoholysis with etha-
nol in the presence of triethylamine was selected to optimize the
reaction conditions. It is worth mentioning that it is not easy to
detect the reaction progress by TLC as the intermediate (N-Cbz-
glycyl)-1-aminophenylmethylphosphinic chloride is sensitive to
water and possesses weak UV absorbance. Thus, on the basis of our
previous investigations,20,21 we chose 1.0:1.2:1.2:2.0 as the molar
ratio of N-Cbz-glycinamide (1a), benzaldehyde (2a), phenyl-
dichlorophosphine (3a), and ethanol, and conducted the reaction in
anhydrous acetonitrile, in which N-Cbz amino amides show good
solubility. A mixture of N-Cbz-glycinamide (1a), benzaldehyde (2a),
and phenyldichlorophosphine (3a) was refluxed in anhydrous
acetonitrile under a nitrogen atmosphere for 12 h and alcoholyzed
for another 24 h. After sequential washing with saturated sodium
bicarbonate and brine to remove the corresponding phosphinic
acid, the residue was separated by flash column chromatography to
obtain the desire phosphinodepsipeptide 4 in a low yield of 36%.
The aqueous solution was adjusted to pH 1 and extracted with ethyl
acetate. After removal of the solvent, the residue was crystallized to
give the corresponding phosphinic acid 5a in 38% yield (Table 1,
entry 1). Similar to the mechanism described in our and others’
previously published papers,22,23 the acid 5a should be generated
from the corresponding phosphinic anhydride via alcoholysis with
ethanol. It is possible to reduce its formation to improve the yield of
the desired product 4 by avoiding the formation of the phosphinic
anhydride, which is formed from the corresponding phosphinic
chloride and phosphinic acid 5a. The acid 5a should be generated
via the addition of phenylphosphonous acid to the in situ generated
imine in the reaction mixture or via hydrolysis of the phosphinic
chloride during workup (Scheme 1). So we tried to optimize the
reaction conditions. When we shortened the Mannich reaction to
6 h and the alcoholysis to 12 h, the yield of the product 4 was
improved to 42%, and the yield of 5a was reduced simultaneously
(Table 1, entry 2). It is obvious that using shorter reaction time,
especially the first step Mannich reaction time, is beneficial to
Under the optimized conditions, a series of phosphinodep-
sipeptides, including a phosphinotetradepsipeptide, was prepared
using different aldehydes, N-Cbz-amino amides, aryldi-
chlorophosphines, and hydroxyl esters. The results are summarized
in Table 2. The results indicate that different aldehydes, N-Cbz-
amino amides, aryldichlorophosphines, and hydroxyl esters do not
affect the yields obviously. All reactants used work very well for the
reaction (Table 2, entries 1e11). Aromatic aldehydes show slightly
higher yields than aliphatic aldehyde. Both electron-rich and
electron-deficient aromatic aldehydes and aryldichlorophosphines
gave rise to the phosphinodepsipeptides in similar yields. The
structures of all phosphinodepsipeptides 7 and the corresponding
byproduct phosphinic acids 4 were characterized by 1H NMR, 13
C
NMR, 31P NMR, and MS spectrometries.
As for the reaction mechanism, in a manner similar to previous
one in the synthesis of N-Cbz-1-amino-1-arylalkylphosphonate
mixed diesters,22 it is assumed that an aminoamide 1 first attacks
an aldehyde 2 to form an N-acylaminohydrin adduct 8, which fur-
ther reacts with an aryldichlorophosphine 3 to produce an aryl-
chlorophosphinate 9. The phosphinate 9 undergoes an elimination
to give rise to an imine 10 and an arylchlorophosphonous acid 11,
which can tautomerize into a relatively stable arylphosphinic
chloride 110 and exists in an equilibrium between the aryl-
chlorophosphonous acid 11 and the arylphosphinic chloride 110.
Alternatively, the reaction of the N-acylaminohydrin 9 and the
arylchlorophosphonous acid 11 yields arylphosphinic monoester
12, which undergoes an elimination to form the imine 10 and an
arylphosphonous acid 13. Similarly, the arylphosphonous acid 13
exists in an equilibrium between the arylphosphonous acid 13 and
an arylphosphinic acid 130. Both the arylchlorophosphonous acid 11
and arylphosphonous acid 13 undergo an addition to the imine 10
to produce an aminoalkylphosphinic chloride 14 and the phos-
phinic acid 5, respectively. The aminoalkylphosphinic chloride 14
Table 1
Optimizing reaction conditions for the synthesis of phosphinodepsipeptide from N-Cbz-glycinamide, benzaldehyde, phenyldichlorophosphine, and ethanol.
O
Ph
O
Ph
O
80 o
C
EtOH
CbzHN
OEt
CbzHN
OH
CbzHN
+ PhCHO + PhPCl2
N
H
P
N
H
P
NH2
MeCN Et3N
O
Ph
O
Ph
1a
2a
3a
4
5
Entry
1:2:3:EtOH (mmol)
Reaction time (h)
Yield of 4 (%)a
Yield of 5 (%)a
Mannich reaction
Alcoholysis
1
2
3
4
5
6
7
3.0:3.5:3.5:6.0
3.0:3.5:3.5:6.0
3.0:3.5:3.5:6.0
3.0:3.5:3.5:6.0
3.0:3.5:3.5:6.0
3.0:3.5:4.0:6.0
3.0:3.5:5.0:6.0
12
6
4
1
0.5
1
24
12
12
6
6
6
36
38
42 (56)
51 (56)
68 (74)
60 (63)
70 (72)
71 (75)
23 (30)
21 (24)
18 (20)
22 (24)
19 (20)
19 (21)
1
6
a
Isolated yield, the yield in parentheses based on the consumed starting N-Cbz-glycinamide.

4946
F. Meng, J. Xu / Tetrahedron 69 (2013) 4944e4952
Ar
P
Cl
O
Cl
OH
OH
O
O
P
Ar
ArPCl2
3
CbzHNAA
CbzHNAA
N
N
R1
R1
O
CbzHNAA
CbzHNAA
N
H
O
OH
R1
R1CHO
10
11
-HCl
9
CbzHNAA
1
NH2
CbzHNAA
N
H
-HCl
2
Ar
OH
8
P
ArP(OH)Cl
11
O
HO
O
O
P
Ar
R1
R1
Ar
H
O
N
H
P
12
10
13
OH
13'
R1
O
HO
Cl
OH
OH
CbzHNAA
CbzHNAA
N
H
P
P
R1
Ar
P
Ar
13
O
Ar
O
O
5
HCl
CbzHNAA
R2
N
H
P
O
CbzHNAA
N
10
R1
2
O
R1
Ar
O
15
OH
P
Ar
11
Cl
N
H
O
14
R2
HO
CO2Et
6
Ar
H
O
P
HO
CO2Et
6
Cl
O
11'
R1
O
R1
Ar
O
R1
Ar
O
CO2Et
OH
O
CO2Et
CbzHNAA
N
P
CbzHNAA
N
H
P
CbzHNAA
N
H
P
H
Ar
7
O
R2
O
O
R2
5
7
Scheme 1. Proposed mechanism in the synthesis of phosphinodepsipeptides 7.
Table 2
Synthesis of phosphinodepsipeptides 7.
R2
O
R1
O
R1
O
HO
CO2Et
MeCN
6
O
CO2Et
OH
O
R1CHO
ArPCl2
CbzHNAA
N
H
P
CbzHNAA
N
P
CbzHNAA
NH2
H
5
Ar
7
O
2
R2
Ar
1
3
Entry
Peptide
AA
R1
Ar
Ph
p-MePh
p-ClPh
Ph
Ph
Ph
Ph
Ph
R2
Yield of 7 (%)
Dr (syn:anti)a
Yield of 5 (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
Gly
Gly
Gly
Gly
Gly
Gly
Gly
Gly
Ph
Ph
Ph
p-MePh
p-ClPh
iPr
p-MePh
p-MePh
Ph
H
H
H
H
H
H
64
60
65
66
61
59
62
66
60
50
56
60:40
69:31
66:34
66:34
62:38
69:31b
50:26:12:12b,c
NAd
18
23
18
26
21
25
24
25
22
18
20
(S)-CH3
(S)-Ph
H
H
H
9
10
11
b-Ala
Ph
Ph
Ph
76:24
NA
77:23
7j
7k
(S)-Val
Gly-Gly
p-MePh
p-MePh
a
Diastereomeric ratio syn:anti on the basis of isolated yield.
b
c
Diastereomeric ratio on the basis of integration in 31P NMR analysis.
(R,RP,S):(S,SP,S):(R,SP,S):(S,RP,S)¼50:26:12:12.
Not available.
d
undergoes an alcoholysis with a hydroxyl ester 6 to afford the de-
sired product phosphinodepsipeptide 7, or it reacts with the
phosphinic acid 5 to generate the phosphinic anhydride 15, which
is followed by alcoholysis with the hydroxyl ester 6 to generate the
phosphinodepsipeptide 7 and the byproduct phosphinic acid 5
(Scheme 1). The intermediates were observed previously in 31P
NMR tracing experiments.22,23
The stereochemistry of the product phosphinodepsipeptides is
discussed below. Most phosphinodepsipeptides 7aee,i,k were sep-
arated into their diastereomers by silica gel column and the di-
astereomeric ratio values were determined on the basis of the
isolated yields. Although phosphinodepsipeptides 7f and 7g, and 7h
and 7j possess two and three chiral carbon atoms, respectively, they
are inseparable. For 7h and 7j, they even show single peaks in 31P
NMR analysis possibly due to the close similarity of their di-
astereomers. The diastereomeric ratios of the phosphinodepsipep-
tides 7f,g were measured as 50:26:12:12 and 69:31, respectively, on
the basis of their integrations in 31P NMR analyses (Table 2, entry 7).
Low diastereoselectivities were observed in the addition step of
arylchlorophosphonous acid 11 to the N-acyl imine 10 in the reaction
because the chiral center in optically active amino amides is too far
away from the reactive center. The syn-products were assumed as

F. Meng, J. Xu / Tetrahedron 69 (2013) 4944e4952
4947
major diastereomers in the products on the basis of the reaction
mechanism (Scheme 1). The reaction of N-Cbz-glycinamide (1a), p-
methylbenzaldehyde (2b), phenyldichlorophosphine (3a), and ethyl
(S)-(ꢀ)-lactate (6b) was selected as an example to illustrate the re-
action diastereoselectivity. As mentioned above, the reaction pro-
duces an N-acyl imine 10b and phenylchlorophosphonous acid (11a)
firstly. Phenylchlorophosphonous acid (11a) is a chiral compound.
The (R)- and (S)-isomers of phenylchlorophosphonous acid (11a)
predominately attack the imine 10b from its Si and Re sides, re-
spectively, producing (S,SP)- and (R,RP)-N-(N-Cbz-glycinyl)-1-amino-
(4-methylphenyl)methylphosphinic chlorides (S,SP)-14b and (R,RP)-
14b, which undergo alcoholysis with ethyl (S)-lactate (6b) to gen-
erate the products phosphinodepsipeptides (S,SP,S)-7g and (R,RP,S)-
7g through the backside attack via a pentacoordinate phosphorus
transition state on the basis of the reported stereochemical in-
vestigation on the alcoholysis.24 Although the configuration of the
phosphorus atom undergoes an inversion during the alcoholysis, its
configuration still keeps original assignment according to the IUPAC
nomenclature rule. The (R,RP,S)-7g should be the major product as its
all substituents are in anti-position and the yield of (S,SP,S)-7g should
be ranked in the second one because phenyl and methyl locate in
more steric hindrance syn-position. Similarly, the (R)- and (S)-iso-
mers of phenylchlorophosphonous acid (11a) can also attack the
imine 10b from its Re and Si sides, respectively, to produce (R,SP)-
during alcoholysis, the syn-products are major diastereomers in the
products.
3. Conclusion
In conclusion, a series of phosphinodepsipeptides was synthe-
sized in satisfactory yields via a facile pseudo-four-component
condensation reaction of 2-(N-benzoxycarbonylamino)alka-
namides/peptide amides, aldehydes, and aryldichlorophosphines,
and subsequent alcoholysis with hydroxy esters. The current syn-
thetic route is convergent and atom-economic method. It is an ef-
ficient pathway to prepare phosphonodepsipeptides from simple
starting materials.
4. Experimental section
4.1. General
Melting points were measured on a Yanaco MP-500 melting
point apparatus and are uncorrected. 1H, 13C and 31P NMR spectra
were recorded on a Brucker 400 NMR spectrometer at 400 MHz,
100 MHz, and 162 MHz, or a Varian 300 NMR spectrometer at
300 MHz, 75 MHz,121 MHz, respectively, in CDCl3 or DMSO-d6 with
TMS as an internal standard and 85% H3PO4 as an external standard
for 31P NMR. HRMS data was carried out on an Agilent LC/MSD TOF
mass spectrometer. IR spectra were determined on a Nicolet AVA-
TAR 330 FTIR spectrometer.
Aryldichlorophosphines were prepared according to literature
procedure25 and their analytical data are identical to those reported
previously.25,26 The analytical data of known phosphinopeptides 5
are identical to those reported previously.20b Acetonitrile was
and
(S,RP)-N-(N-Cbz-glycinyl)-1-amino-(4-methylphenyl)methyl-
phosphinic chlorides (R,SP)-14b and (S,RP)-14b followed by alcohol-
ysis with ethyl (S)-lactate (6b) to afford (R,SP,S)-7g and (S,RP,S)-7g,
respectively, in lower yields (Scheme 2). Because the addition step is
the stereoselective step, generating anti-phosphinic chlorides as
major intermediates on the basis of the conformational analysis
(Scheme 2), and the phosphorus center undergoes an inversion
HO
Cl
Cl
Cl
N
PhMe-
p
NH2
P
P
Ph
3a
CbzHN
+ HCl
CbzHN
p
-MePhCHO
Ph
11a
O
O
10b
1a
2b
Ph
O
O
H
N
P
OEt
CbzHN
O
H
O
PhMe-
p
O
CbzNHCH2CONH
Ph
PhMe-p
(S,S ,S)-7g 16%
P
Cl
OEt
Et3N
HO
More stable anti conformation
O
O
P
6b
Ph
H
O
Ph
Si
Cl
N
P
H
N
addition
attack from the back
Cl
CbzHN
Cl
PhMe-
PhMe-
p
CbzHN
CbzHN
O
p
O
O
H
H
N
PhMe-
p
P
(S,S )-14b
P
CbzHN
OH
Re
Ph
H
O
H
N
O
10b
H
Ph
(R)-11a
attack from the front
addition
PhMe-
p
N
P
CbzHN
Cl
O
P
O
PhMe-
p
(R,S )-14b
P
Cl
Ph
OEt
O
H
Et3N
HO
CbzNHCH2CONH
Cl
PhMe-p
O
6b
Ph
O
Ph
H
N
P
OEt
CbzHN
O
Less stable gauche conformation
O
PhMe-
p
O
7.5%
7g
(R,S ,S)-
P
Scheme 2. Diastereoselectivity in the synthesis of phosphinodepsipeptide 7g.

4948
F. Meng, J. Xu / Tetrahedron 69 (2013) 4944e4952
CO2Et
OEt
HO
O
Ph
Ph
H
N
O
O
O
H
N
P
O
Ph
O-
P
OEt
CbzHN
Cl
PhMe-p
6b
CbzHN
R
P
-Cl-
O
O
PhMe-p
O
H+NEt3
NEt3
Cl
(S,S )-14b
P
(S,S ,S)-7g
P
Pentacoordinate
transitaion state
Inversion of the phosphorus configuration through the backside attack
H
N
= R
CbzHN
O
Ph
O
H
N
P
OEt
CbzHN
O
O
H
O
PhMe-p
O
CbzNHCH2CONH
Cl
PhMe-p
Ph
(S,R ,S)-7g 7.5%
P
OEt
HO
Less stable gauche conformation
O
O
6b
O
P
O
Ph
H
N
Cl
Ph
P
Si
H
CbzHN
Cl
PhMe-p
addition
N
attack from the back
Ph
PhMe-p
CbzHN
CbzHN
O
O
H
H
(S,R )-14b
P
N
PhMe-p
P
CbzHN
OH
Re
H
N
O
H
Ph
Cl
O
10b
H
Cl
(S)-11a
attack from the front
PhMe-p
addition
N
P
CbzHN
HO
O
P
O
PhMe-p
Cl
Ph
(R,R )-14b
P
O
CbzNHCH2CONH
Ph
PhMe-p
OEt Et3N
O
Cl
6b
Ph
O
H
H
N
More stable anti conformation
P
OEt
CbzHN
O
O
PhMe-p
O
7g
(R,R ,S)-
31.5%
P
Scheme 2. (Continued)
refluxed with calcium hydride and freshly distilled prior to use. All
reactions were performed under a nitrogen atmosphere.
another 6 h. After removal of the solvent, the residue was dis-
solved in ethyl acetate. The solution was washed with saturated
aqueous sodium bicarbonate (50 mLꢂ3), saturated brine
(50 mLꢂ2), and dried over anhydrous sodium sulfate. After
concentration at reduced pressure, the residue was separated on
a silica gel column with a mixture of petroleum ether (30e60 ꢁC)
and ethyl acetate as an eluent with gradient elution to give the
desired product phosphinodepsipeptide 7. (Caution: The silica gel
column was buffered by 0.5% triethylamine before the sample
was loaded. The desired peptide 7 shows very weak fluorescent
intensity under UV light. It is better to monitor collective frac-
tions in the column separation after concentration). The aqueous
solution was adjusted to pH 1 with 6 mol/L HCl and extracted
with ethyl acetate (50 mLꢂ3), the organic phase was dried over
anhydrous sodium sulfate. After concentration at reduced pres-
sure, the residue was crystallized from a mixture of ethyl acetate
4.2. General procedure for synthesis of phosphinodepsipep-
tides 7
To a solution of an N-Cbz-2-aminoalkanamide 1 (3.0 mmol)
and aldehyde 2 (3.5 mmol) in dried acetonitrile (15 mL) was
added aryldichlorophosphine 3 (4.0 mmol) under stirring and
a nitrogen atmosphere. After the N-Cbz-2-aminoalkanamide 2
was dissolved completely, the resulting solution was stirred in
refluxing acetonitrile at 80 ꢁC for 1 h. The reaction mixture was
allowed to cool to room temperature under stirring. Hydroxyl
ester 6 or ethanol (6.0 mmol) was added dropwise. After stirring
for 15 min, triethylamine (1.67 mL, 1.22 g, 12 mmol) was added
dropwise and the resulting reaction mixture was stirred for

F. Meng, J. Xu / Tetrahedron 69 (2013) 4944e4952
4949
and hexanes or methanol (ethanol) and diethyl ether to afford
the corresponding phosphinic acid 5.
(d, JPeC¼10.0 Hz), 133.47, 133.5, 136.3, 143.9, 156.5, 168.7 (d,
JPeC¼5.2 Hz), 169.0 (d, JPeC¼6.2 Hz); 31P NMR (121.5 MHz, CDCl3)
d:
41.5 (85% H3PO4 as an external standard); HRMS (ESI) calcd for
4.2.1. Ethyl anti-/syn-phenyl[N-[N-benzyloxycarbonylglycinyl]-1-
aminophenylmethyl]phosphinate (4). White solid, mp 155e157 ꢁC;
Rf¼0.67 (Silica gel plate, ethyl acetate), mixture of diastereomers
(anti:syn 15:1). IR (KBr) v (cmꢀ1): 1713 (C]O),1675 (C]O),1202 (P]
C28H32N2O7P [MþH]þ m/z 539.1942; found 539.1949.
4.2.5. Ethyl anti-[[4-methylphenyl[N-[N-benzyloxycarbonylglycinyl]-1-
aminophenylmethyl]phosphinyl]oxy]acetate (minor) (anti-7b). White
solid, mp 96e98 ꢁC; Rf¼0.29 (Silica gel plate, ethyl acetate:hexanes
1:1, v/v). IR (KBr) v (cmꢀ1): 1761 (C]O), 1734 (C]O), 1676 (C]O),
O); 1H NMR (300 MHz, CDCl3)
d
: 1.04(t, J¼7.2Hz, 3H, CH3, anti),1.30 (t,
J¼7.2 Hz, 3H, CH3, syn), 3.60e4.00 (m, 4H, NCH2 & POCH2), 4.98 (s, 2H,
OCH2, anti), 5.05 (s, 2H, OCH2, syn), 5.62e5.80 (m, 2H, POCH &
1218 (P]O); 1H NMR (300 MHz, CDCl3)
d
: 1.17 (t, J¼7.1 Hz, 3H, CH3,
CO2NH), 7.25e7.91 (m, 15H, ArH), 9.07 (d, J¼9.6 Hz, 1H, CONH); 13
C
major rotamer), 1.18 (t, J¼7.1 Hz, 3H, CH3, minor rotamer), 2.32 (s, 3H,
CH3, minor rotamer), 2.38 (s, 3H, CH3, major rotamer), 3.80e4.0 (m,
2H, NCH2), 4.13 (q, J¼7.1 Hz, 2H, CO2CH2, major rotamer), 4.14 (q,
J¼7.1 Hz, 2H, CO2CH2, minor rotamer), 4.25e4.40 (m, 2H, POCH2),
5.04 (s, 2H, OCH2, major rotamer), 5.10 (s, 2H, OCH2, minor rotamer),
5.71e5.80 (m, 2H, POCH & CO2NH), 7.18e7.65 (m, 14H, ArH), 8.70 (s,
NMR (50 MHz, CDCl3)
d
: 16.2 (d, JPeC¼5.9 Hz), 44.1, 52.2 (d,
JPeC¼109.3 Hz), 62.2 (d, JPeC¼7.3 Hz), 66.7,127.61,127.63,127.9,128.0,
128.01, 128.07, 128.4, 128.5, 128.57, 128.7, 128.76, 131.7, 131.9, 132.8,
132.88,134.49, 134.5, 136.3, 156.1, 168.7; 31P NMR (121.5 MHz, CDCl3)
d
: 37.4, 39.5 (85%H3PO4 asanexternalstandard); HRMS(ESI) calcd for
C25H28N2O5P [MþH]þ m/z 467.1730; found 467.1719.
br, 1H, CONH); 13C NMR (75 MHz, CDCl3)
d: 13.9, 21.2 (minor
rotamer), 21.7 (major rotamer), 44.04 (minor rotamer), 44.08 (major
rotamer), 53.0 (d, JPeC¼95.7 Hz), 61.0 (d, JPeC¼6.5 Hz), 61.6 (major
rotamer), 61.63 (minor rotamer), 67.7, 125.2, 127.9, 127.93, 128.0,
128.3, 128.4, 128.5, 128.9, 129.0, 129.2, 129.4, 131.9 (d, JPeC¼10.5 Hz),
132.3 (d, JPeC¼9.7 Hz), 134.2, 136.3, 143.8, 156.1, 168.5 (d,
4.2.2. Ethyl syn-[[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-
aminophenylmethyl]phosphinyl]oxy] acetate (major) (syn-7a). White
solid, mp 126e128 ꢁC; Rf¼0.51 (Silica gel plate, ethyl acetate:hex-
anes 2:1, v/v). IR (KBr) v (cmꢀ1): 1734 (C]O), 1718 (C]O), 1684 (C]
O), 1216 (P]O); 1H NMR (300 MHz, CDCl3)
d
: 1.18 (t, J¼7.1 Hz, 3H,
JPeC¼5.5 Hz), 168.7 (d, JPeC¼7.1 Hz); 31P NMR (112.0 MHz, CDCl3)
d:
CH3), 3.78e3.89 (m, 2H, NCH2), 4.13 (q, J¼7.1 Hz, 2H, CO2CH2), 4.26
(dd, J¼10.3, 16.1 Hz, 1H in POCH2), 4.34 (dd, J¼10.1, 16.1 Hz, 1H in
POCH2), 5.04 (s, 2H, OCH2), 5.65 (s, br, 1H, CO2NH), 5.77 (dd, J¼9.9,
13.0 Hz, 1H, POCH), 7.20e7.77 (m, 15H, ArH), 8.69 (dd, J¼3.7, 9.7 Hz,
40.5, 40.6 (85% H3PO4 as an external standard); HRMS (ESI) calcd for
C28H32N2O7P [MþH]þ m/z 539.1942; found 539.1935.
4.2.6. Ethyl syn-[[4-chlorophenyl[N-[N-benzyloxycarbonylglycinyl]-1-
aminophenylmethyl]phosphinyl]oxy]acetate (major) (syn-7c). White
solid, mp 140e141 ꢁC; Rf¼0.37 (Silica gel plate, ethyl acetate:hex-
anes 1:1, v/v). IR (KBr) v (cmꢀ1): 1761 (C]O), 1727 (C]O), 1686 (C]
1H, CONH); 13C NMR (75 MHz, CDCl3)
d: 13.7, 43.8, 52.4 (d,
JPeC¼107.7 Hz), 61.0 (d, JPeC¼6.2 Hz), 61.3, 66.4, 126.7, 127.6, 127.6,
127.9, 128.1, 128.2, 128.3, 131.4, 131.5, 131.7, 132.9, 133.8, 136.2, 155.9,
167.8 (d, JPeC¼4.3 Hz), 168.7 (d, JPeC¼5.3 Hz); 31P NMR (121.5 MHz,
O), 1215 (P]O); 1H NMR (400 MHz, CDCl3)
d
: 1.19 (t, J¼7.1 Hz, 3H,
CDCl3)
d
: 40.3 (85% H3PO4 as an external standard); HRMS (ESI)
CH3), 3.82e3.88 (m, 2H, NCH2), 4.15 (q, J¼7.0 Hz, 2H, CO2CH2),
4.24e4.36 (m, 2H, POCH2), 5.06 (s, 2H, OCH2), 5.60 (s, br, 1H, CONH),
5.72 (dd, J¼9.7, 13.0 Hz,1H, POCH), 7.23e7.65 (m, 14H, ArH), 8.50 (br,
calcd for C27H30N2O7P [MþH]þ m/z 525.1785; found 525.1784.
4.2.3. Ethyl anti-[[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-
aminophenylmethyl]phosphinyl]oxy] acetate (minor) (anti-7a). White
solid, mp 139e140 ꢁC; Rf¼0.64 (Silica gel plate, ethyl acetate:hexanes
2:1, v/v). IR (KBr) v (cmꢀ1): 1734 (C]O), 1725 (C]O), 1675 (C]O),
1H, CONH); 13C NMR (100.6 MHz, CDCl3)
d: 13.9, 44.2, 53.0 (d,
JPeC¼106.8 Hz), 61.1 (d, JPeC¼5.9 Hz), 61.8, 66.9, 125.7, 127.0, 127.9,
128.1, 128.3, 128.4, 128.5, 128.8, 128.9, 133.3, 133.4, 133.8, 136.3,
139.8, 139.9, 156.2, 168.6, 168.7 (d, JPeC¼6.7 Hz); 31P NMR
1215 (P]O); 1H NMR (300 MHz, CDCl3)
d
: 1.21 (t, J¼7.1 Hz, 3H, CH3),
(162.0 MHz, CDCl3) d: 39.0 (85% H3PO4 as an external standard);
3.94e4.05 (m, 2H, NCH2), 4.17 (q, J¼7.1 Hz, 2H, CO2CH2), 4.44 (dd,
J¼10.7, 16.1 Hz, 1H in POCH2), 4.59 (dd, J¼9.8, 16.1 Hz, 1H in POCH2),
5.12 (s, 2H, OCH2), 5.68 (dd, J¼9.4,13.4 Hz,1H, POCH), 5.78 (dd, J¼4.6,
4.7 Hz, 1H, CO2NH), 7.16e7.69 (m, 15H, ArH), 8.23 (dd, J¼4.2, 9.2 Hz,
HRMS (ESI) calcd for C27H28ClN2O7P [MþNa]þ m/z 581.1215; found
581.1210.
4.2.7. Ethyl anti-[[4-chlorophenyl[N-[N-benzyloxycarbonylglycinyl]-1-
aminophenylmethyl]phosphinyl]oxy]acetate (minor) (anti-7c). White
solid, mp 135e136 ꢁC; Rf¼0.42 (Silica gel plate, ethyl acetate:hexanes
1:1, v/v). IR (KBr) v (cmꢀ1): 1760 (C]O), 1724 (C]O), 1686 (C]O),
1H, CONH); 13C NMR (75.5 MHz, CDCl3)
d: 13.7, 43.8, 52.4 (d,
JPeC¼107.2 Hz), 61.0 (d, JPeC¼6.5 Hz), 61.3, 66.3, 126.7, 127.6, 127.9,
128.1, 128.2, 128.3, 128.4, 131.5, 131.7, 132.9, 133.8, 136.2, 155.9, 167.8
(d, JPeC¼5.0 Hz), 168.8 (d, JPeC¼6.2 Hz); 31P NMR (121.5 MHz, CDCl3)
1216 (P]O); 1H NMR (400 MHz, CDCl3)
d
: 1.23 (t, J¼7.1 Hz, 3H, CH3),
d
: 41.1 (85% H3PO4 as an external standard); HRMS (ESI) calcd for
3.95 (dd, J¼5.3, 16.9 Hz, 1H in NCH2), 4.03 (dd, J¼5.9, 16.9 Hz, 1H in
NCH2), 4.18 (q, J¼7.1 Hz, 2H, CO2CH2), 4.43 (dd, J¼11.2, 16.2 Hz, 1H in
POCH2), 4.57 (dd, J¼10.1, 16.2 Hz, 1H in POCH2), 5.13 (d, J¼12.3 Hz,1H
in OCH2), 5.16 (d, J¼12.3 Hz, 1H in OCH2), 5.61 (d, J¼5.4 Hz, 1H,
CONH), 5.63 (dd, J¼9.4, 13.4 Hz, 1H, POCH), 7.22e7.61 (m, 14H, ArH),
C27H30N2O7P [MþH]þ m/z 525.1785; found 525.1780.
4.2.4. Ethyl syn-[[4-methylphenyl[N-[N-benzyloxycarbonylglycinyl]-1-
aminophenylmethyl]phosphinyl]oxy]acetate (major) (syn-7b). White
solid, mp 143e144 ꢁC; Rf¼0.21 (Silica gel plate, ethyl acetate:hexanes
1:1, v/v). IR (KBr) v (cmꢀ1): 1761 (C]O), 1733 (C]O), 1674 (C]O),
7.90 (s, br, 1H, CONH); 13C NMR (100.6 MHz, CDCl3)
d: 14.0, 44.4, 53.2
(d, JPeC¼103.8 Hz), 61.3 (d, JPeC¼6.6 Hz), 61.7, 66.9, 125.4, 126.7, 127.9,
128.0, 128.1, 128.14, 128.4, 128.5, 128.7, 128.9, 133.3, 133.4, 133.5,
136.2, 139.7, 139.77, 156.5, 168.2 (d, JPeC¼4.7 Hz), 168.9 (d,
1217 (P]O); 1H NMR (300 MHz, CDCl3)
d: 1.21 (t, J¼7.1 Hz, 3H, CH3),
2.29 (s, 3H, CH3, minor rotamer), 2.34 (s, 3H, CH3, major rotamer),
3.96e4.02 (m, 2H, NCH2), 4.151 (q, J¼7.1 Hz, 2H, CO2CH2, major
rotamer), 4.155 (q, J¼7.1 Hz, 2H, CO2CH2, minor rotamer), 4.37 (dd,
J¼10.6, 16.0 Hz, 1H in POCH2, major rotamer), 4.38 (dd, J¼10.5,
16.2 Hz, 1H in POCH2, minor rotamer), 4.49 (dd, J¼9.8, 15.5 Hz, 1H in
POCH2, major rotamer), 4.50 (dd, J¼9.9, 16.2 Hz, 1H in POCH2, minor
rotamer), 5.11 (s, 2H, OCH2), 5.63 (dd, J¼9.5, 13.3 Hz, 1H, POCH), 5.78,
5.98, & 6.07 (br, 1H, CO2NH), 7.17e7.71 (m, 14H, ArH), 8.25 (m, 1H,
JPeC¼6.0 Hz); 31P NMR (162.0 MHz, CDCl3)
d: 39.4 (85% H3PO4 as an
external standard); HRMS (ESI) calcd for C27H28ClN2O7P [MþNa]þ m/
z 581.1215; found 581.1210.
4.2.8. Ethyl syn-[[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-amino(4-
methylphenyl)methyl]phosphinyl]oxy]acetate (major) (syn-7d). White
solid, mp 149e150 ꢁC; Rf¼0.56 (Silica gel plate, ethyl acetate:hexanes
2:1, v/v). IR (KBr) v (cmꢀ1): 1761 (C]O), 1725 (C]O), 1678 (C]O),
CONH); 13C NMR (100.6 MHz, CDCl3)
d: 14.0, 21.7, 44.5, 53.3 (d,
JPeC¼102.2 Hz), 61.0 (d, JPeC¼6.4 Hz), 61.7, 67.0, 126.6, 128.0, 128.1,
1214 (P]O); 1H NMR (400 MHz, CDCl3)
2.31 (s, 3H, CH3), 3.82 (dd, J¼3.8,17.0 Hz,1H in NCH2), 3.85 (dd, J¼3.8,
d
: 1.18 (t, J¼7.1 Hz, 3H, CH3),
128.13, 128.4, 128.5, 128.8, 129.2, 129.3, 132.0 (d, JPeC¼10.3 Hz), 132.5

4950
F. Meng, J. Xu / Tetrahedron 69 (2013) 4944e4952
17.0 Hz, 1H in NCH2), 4.13 (q, J¼7.1 Hz, 2H, CO2CH2), 4.29 (d, J¼9.9,
16.0 Hz, 1H in POCH2), 4.30 (d, J¼10.1, 16.0 Hz, 1H in POCH2), 5.0 (s,
2H, OCH2), 5.63 (s, br, 1H, CO2NH), 5.72 (dd, J¼10.1, 12.6 Hz, 1H,
POCH), 7.03e7.77 (m, 14H, ArH), 8.57 (dd, J¼3.5, 9.6 Hz, 1H, CONH);
IR (KBr) v (cmꢀ1): 1762 (C]O), 1727 (C]O), 1681 (C]O), 1213 (P]
O); 1H NMR (400 MHz, CDCl3)
d: 1.05 (d, J¼6.6 Hz, 6H, 2CH3), 1.22 (t,
J¼7.1 Hz, 3H, CH3), 2.40 (dheptet, J¼5.1, 6.6 Hz, 1H, CH), 3.69 (dd,
J¼5.2,16.5 Hz 1H in NCH2), 3.78 (dd, J¼4.7, 16.7 Hz,1H in NCH2), 4.17
(q, J¼7.1 Hz, 2H, CO2CH2), 4.31 (dd, J¼9.0,15.8 Hz,1H in POCH2), 4.59
(dd, J¼10.5, 15.8 Hz, 1H in POCH2), 4.61 (ddd, J¼5.1, 11.1, 16.0 Hz, 1H,
POCH), 5.03 (d, J¼12.4 Hz, 1H in OCH2), 5.06 (d, J¼12.4 Hz, 1H in
13C NMR (100.6 MHz, CDCl3)
d: 13.9, 21.1, 44.1, 52.7 (d,
JPeC¼106.5 Hz), 61.1 (d, JPeC¼6.4 Hz), 61.6, 66.7, 127.3, 127.9, 127.94,
128.36, 128.4, 128.5, 129.1, 131.0, 131.8, 131.9, 133.0, 136.3, 137.9, 156.1,
168.5 (d, JPeC¼5.0 Hz), 168.6 (d, JPeC¼6.9 Hz); 31P NMR (162.0 MHz,
OCH2), 5.75 (s, br, 1H, CO2NH), 7.30e7.80 (m, 11H, ArH & CONH); 13
C
CDCl3)
d
: 39.7 (85% H3PO4 as an external standard); HRMS (ESI) calcd
NMR (100.6 MHz, CDCl3)
d
: 13.9, 18.4 (d, JPeC¼4.8 Hz), 20.7 (d,
for C28H31N2NaO7P [MþNa]þ m/z 561.1761; found 561.1757.
JPeC¼9.7 Hz), 28.5, 44.0, 52.4 (d, JPeC¼112.2 Hz), 60.8 (d,
JPeC¼6.5 Hz), 61.5, 66.8, 127.6, 127.9, 128.0, 128.4, 128.5, 128.8, 131.8,
131.9, 132.9, 136.3, 156.2, 167.8 (d, JPeC¼6.5 Hz), 169.2; 31P NMR
4.2.9. Ethyl anti-[[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-
amino(4-methylphenyl)methyl]phosphinyl]oxy]acetate (minor) (anti-
7d). White solid, mp 111e112 ꢁC; Rf¼0.67 (Silica gel plate, ethyl
acetate:hexanes 2:1, v/v). IR (KBr) v (cmꢀ1): 1761 (C]O), 1724 (C]
(162.0 MHz, CDCl3) d: 42.9 (85% H3PO4 as an external standard);
HRMS (ESI) calcd for C24H31N2NaO7P [MþNa]þ m/z 513.1761; found
513.1758.
O), 1685 (C]O), 1214 (P]O); 1H NMR (400 MHz, CDCl3)
d: 1.21 (t,
J¼7.1 Hz, 3H, CH3), 2.25 (s, 3H, CH3), 3.96 (dd, J¼5.6, 16.9 Hz, 1H in
NCH2), 4.03 (dd, J¼5.3, 16.9 Hz, 1H in NCH2), 4.17 (q, J¼7.1 Hz, 2H,
CO2CH2), 4.43 (dd, J¼10.6, 16.1 Hz, 1H in POCH2), 4.59 (dd, J¼9.8,
16.1 Hz,1H in POCH2), 5.12 (s, 2H, OCH2), 5.65 (dd, J¼9.2, 13.1 Hz,1H,
POCH), 5.77 (s, br, 1H, CO2NH), 6.96e7.69 (m, 14H, ArH), 8.15 (dd,
4.2.13. Ethyl (S)-2-[[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-
amino(4-methylphenyl)methyl]phosphinyl]oxy]propionate (mixture
of (R,SP,S):(S,SP,S):(S,RP,S):(R,RP,S)¼50:26:12:12) (7g). Pale yellow oil;
Rf¼0.35 (Silica gel plate, ethyl acetate:hexanes 1:1, v/v). IR (KBr) v
(cmꢀ1): 1728 (C]O), 1676 (C]O), 1513 (C]O), 1211 (P]O); 1H
J¼3.2, 8.8 Hz, 1H, CONH); 13C NMR (100.6 MHz, CDCl3)
d: 14.0, 21.0,
NMR (400 MHz, CDCl3)
d: 1.04, 1.09, & 1.24 (t, J¼7.1 Hz, 3H, CH3),
44.4, 52.9 (d, JPeC¼103.0 Hz), 61.1 (d, JPeC¼6.6 Hz), 61.6, 66.9, 126.9,
1.16, 1.45, & 1.53 (d, J¼6.9 Hz, 3H, CH3), 2.23, 2.25, & 2.36 (s, 3H,
CH3), 3.71, 3.94, & 3.96 (dd, J¼5.2, 16.5 Hz, 1H in NCH2), 3.79, 3.94, &
3.96 (dd, J¼4.7, 16.7 Hz, 1H in NCH2), 4.00, 4.05, & 4.18 (dq, J¼10.8,
7.1 Hz, 1H in POCH2), 4.01, 4.08, & 4.20 (dq, J¼10.9, 7.1 Hz, 1H in
POCH2), 4.60 & 4.86 (dq, J¼15.6, 7.2 Hz, 1H, CH), 5.04 (s, 2H, OCH2),
5.10 (d, J¼12.4 Hz, 1H in OCH2), 5.14 (d, J¼12.4 Hz, 1H in OCH2), &
5.13 (d, J¼12.3 Hz,1H in OCH2), 5.16 (d, J¼12.3 Hz,1H in OCH2), 5.04,
5.54e5.72 (s, br, & m, 1H, CO2NH), 5.61e5.75 (m, 1H, POCH),
6.90e7.90 (m, 14H, ArH), 8.10 (s, br, 1H, CONH); 13C NMR
127.97, 128.0, 128.3, 128.4, 128.41, 128.49, 130.4, 132.0, 132.1, 133.0,
136.3, 137.1, 156.4, 168.5 (d, JPeC¼4.7 Hz), 168.8 (d, JPeC¼6.0 Hz); 31
P
NMR (162.0 MHz, CDCl3) d: 40.6 (85% H3PO4 as an external stan-
dard); HRMS (ESI) calcd for C28H31N2NaO7P [MþNa]þ m/z 561.1761;
found 561.1762.
4.2.10. Ethyl syn-[[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-
amino(4-chlorophenyl)methyl]phosphinyl]oxy]acetate (major) (syn-
7e). White solid, mp 145e147 ꢁC; Rf¼0.34 (Silica gel plate, ethyl
acetate:hexanes 1:1, v/v). IR (KBr) v (cmꢀ1): 1761 (C]O), 1727 (C]
(100.6 MHz, CDCl3) d: 13.8, 13.84, 14.0; 18.86, 18.9, 19.6; 21.1, 21.2;
44.2, 44.5, 44.6; 52.4 (d, JPeC¼109.2 Hz), 53.0 (d, JPeC¼101.0 Hz),
53.2 (d, JPeC¼105.0 Hz); 61.4, 61.5, 61.9; 66.9, 69.5, 70.35; 67.0,
69.54, 70.4; 127.8, 127.9, 128.05, 128.1, 128.2, 128.3, 128.4, 128.45,
128.5, 128.6, 129.0, 129.2, 129.3, 129.4, 130.4, 130.8, 131.07, 131.1,
131.8, 131.9, 132.2, 132.3, 132.8, 132.9, 138.3, 137.59, 137.6, 137.7,
137.8, 137.97, 137.99, 156.2, 156.4, 168.4 (d, JPeC¼6.9 Hz), 168.5, 168.8
(d, JPeC¼6.8 Hz), 170.4 (d, JPeC¼3.5 Hz), 170.5 (d, JPeC¼4.4 Hz), 171.1
O), 1687 (C]O), 1215 (P]O); 1H NMR (400 MHz, CDCl3)
d: 1.19 (t,
J¼7.0 Hz, 3H, CH3), 3.70e3.92 (m, 2H, NCH2), 4.13e4.17 (m, 2H,
CO2CH2), 4.30 (dd, J¼10.6, 15.9 Hz, 1H in POCH2), 4.43 (dd, J¼10.0,
15.9 Hz, 1H in POCH2), 5.05 (s, 2H, OCH2), 5.62 (s, br, 1H, CO2NH),
5.71 (dd, J¼9.8, 13.1 Hz, 1H, POCH), 7.18e7.71 (m, 14H, ArH), 8.61 (s,
br, 1H, CONH); 13C NMR (100.6 MHz, CDCl3)
d: 13.9, 44.1, 52.5 (d,
JPeC¼106.4 Hz), 61.1 (d, JPeC¼5.8 Hz), 61.8, 66.9, 126.8, 127.9, 128.0,
128.4, 128.6, 128.7, 129.8, 131.8, 131.9, 132.7, 133.3, 134.08, 134.1,
136.3, 156.2, 168.5 (d, JPeC¼3.8 Hz), 168.8 (d, JPeC¼6.8 Hz); 31P NMR
(d, JPeC¼3.1 Hz); 31P NMR (162.0 MHz, CDCl3)
d: 39.0, 39.4, 40.2
(85% H3PO4 as an internal standard); HRMS (ESI) calcd for
C29H34N2O7P [MþH]þ m/z 553.2098; found 553.2092.
(162.0 MHz, CDCl3) d: 39.5 (85% H3PO4 as an external standard);
HRMS (ESI) calcd for C27H28ClN2NaO7P [MþNa]þ m/z 581.1220;
4.2.14. Ethyl anti/syn-[[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-
amino(4-methylphenyl)methyl]-phosphinyl]oxy]-(S)-2-phenylacetate
(7h). White solid, mp 149e150 ꢁC; Rf¼0.37 (Silica gel plate, ethyl
acetate:hexanes 1:1, v/v). IR (KBr) v (cmꢀ1): 1754 (C]O), 1728 (C]
found 581.1225.
4.2.11. Ethyl anti-[[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-
amino(4-chlorophenyl)methyl]phosphinyl] oxy]acetate (minor) (anti-
7e). White solid, mp 214e215 ꢁC; Rf¼0.40 (Silica gel plate, ethyl
acetate:hexanes 1:1, v/v). IR (KBr) v (cmꢀ1): 1725 (C]O), 1693 (C]
O), 1681 (C]O), 1212 (P]O); 1H NMR (400 MHz, CDCl3)
d: 1.00 (t,
J¼7.1 Hz, 3H, CH3), 2.30 (s, 3H, CH3), 3.61 (dd, J¼5.0, 16.7 Hz, 1H in
NCH2), 3.68 (dd, J¼4.9, 17.3 Hz, 1H in NCH2), 3.97 (q, J¼7.1 Hz, 2H,
CO2CH2), 5.05 (s, 2H, OCH2), 5.29 (dd, J¼4.7, 4.7 Hz, 1H, CO2NH),
5.36 (d, J¼8.7 Hz, 1H, OCH), 5.70 (dd, J¼10.6, 12.1 Hz, 1H, POCH),
6.90e7.97 (m, 19H, ArH), 8.06 (s, br, 1H, CONH); 13C NMR
O), 1581 (C]O), 1128 (P]O); 1H NMR (400 MHz, CDCl3)
d: 1.20 (t,
J¼7.1 Hz, 3H, CH3), 3.91e4.03 (m, 2H, NCH2), 4.14 (q, J¼7.1 Hz, 2H,
CO2CH2), 4.38 (dd, J¼11.0, 16.0 Hz, 1H in POCH2), 4.51 (dd, J¼10.1,
16.0 Hz,1H in POCH2), 5.11 (s, 2H, OCH2), 5.58 (dd, J¼9.2,13.5 Hz,1H,
POCH), 5.79 (s, br, 1H, CO2NH), 6.99e7.92 (m, 14H, ArH), 8.31 (s, br,
(100.6 MHz, CDCl3)
d
: 13.7, 21.1, 43.9, 52.2 (d, JPeC¼109.6 Hz), 61.6,
66.7, 75.1 (d, JPeC¼6.5 Hz), 127.0, 127.9, 128.2, 128.4, 128.5, 128.55,
128.6, 128.62, 128.7, 129.1, 129.2, 130.66, 130.68, 131.8, 131.9, 133.0,
134.8, 134.9, 136.4, 137.7, 156.0, 168.7; 31P NMR (162.0 MHz, CDCl3)
1H, CONH); 13C NMR (100.6 MHz, CDCl3)
d: 14.0, 44.4, 52.8 (d,
JPeC¼102.4 Hz), 61.2 (d, JPeC¼6.6 Hz), 61.8, 67.0, 126.4, 127.7, 128.0,
128.3, 128.4, 128.5, 128.6, 128.9, 129.4, 129.45, 131.9, 132.0, 132.1,
133.3, 133.98, 134.0, 135.1, 136.3, 156.5, 168.3 (d, JPeC¼4.3 Hz), 169.1
d
: 36.8 (85% H3PO4 as an external standard); HRMS (ESI) calcd for
C34H35N2NaO7P [MþNa]þ m/z 637.2074; found 637.2069.
(d, JPeC¼6.3 Hz); 31P NMR (162.0 MHz, CDCl3)
d: 40.3 (85% H3PO4 as
an external standard); HRMS (ESI) calcd for C27H28ClN2NaO7P
4.2.15. Ethyl syn-[[phenyl[N-[N-benzyloxycarbonyl-b-alaninyl]-1-
[MþNa]þ m/z 581.1220; found 581.1225.
aminophenylmethyl]phosphinyl]oxy]acetate (7i). White solid, mp
156e158 ꢁC; Rf¼0.51 (Silica gel plate, ethyl acetate:hexanes 2:1, v/
v). IR (KBr) v (cmꢀ1): 1760 (C]O), 1720 (C]O), 1673 (C]O), 1230
4.2.12. Ethyl syn-[[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-amino-
2-methylpropyl]phosphinyl]oxy]acetate (syn-7f). White solid, mp
123e125 ꢁC; Rf¼0.18 (Silica gel plate, ethyl acetate:hexanes 1:1, v/v).
(P]O); 1H NMR (400 MHz, CDCl3)
2.52e2.55 (m, 2H, CH2CO), 3.46 (dt, J¼5.8, 5.8 Hz, 2H, NCH2), 4.17 (q,
d
: 1.21 (t, J¼7.1 Hz, 3H, CH3),

F. Meng, J. Xu / Tetrahedron 69 (2013) 4944e4952
4951
J¼7.1 Hz, 2H, CO2CH2), 4.48 (dd, J¼10.1, 16.1 Hz, 1H in POCH2), 4.58
(dd, J¼9.6, 16.1 Hz, 1H in POCH2), 5.06 (s, 2H, OCH2), 5.63 (s, br, 1H,
CO2NH), 5.70 (dd, J¼9.3, 13.6 Hz, 1H, POCH), 7.16e7.65 (m, 15H,
CDCl3) d: 40.7 (85% H3PO4 as an internal standard); HRMS (ESI)
calcd for C30H35N3O8P [MþH]þ m/z 596.2156; found 596.2153;
calcd for C30H34N3NaO8P [MþNa]þ m/z 618.1981; found 618.1971.
ArH), 7.87 (s, br, 1H, CONH); 13C NMR (100.6 MHz, CDCl3)
d: 13.9,
35.7, 37.1, 53.2 (d, JPeC¼102.8 Hz), 61.1 (d, JPeC¼6.5 Hz), 61.7, 66.4,
4.2.19. Phenyl[N-[N-benzyloxycarbonylglycinyl]-1-amino-2-methyl-
propyl]phosphinic acid (5f). White solid, mp 274 ꢁC (dec); IR (KBr) v
(cmꢀ1): 1728.5 (C]O), 1660.1 (C]O), 1236.3 (P]O); 1H NMR
126.9, 127.9, 128.07, 128.1, 128.3, 128.5, 131.9 (JPeC¼9.8 Hz), 133.0,
133.8, 136.6, 156.4, 168.5 (d, JPeC¼5.2 Hz), 171.3 (d, JPeC¼5.7 Hz); 31
P
NMR (162.0 MHz, CDCl3)
d
: 40.6 (85% H3PO4 as an external stan-
(400 MHz, DMSO-d6)
J¼5.2 Hz, 3H, CH3), 2.15 (m, 1H, CH), 3.46 (d, J¼12 Hz, 1H in COCH2),
3.65 (d, J¼12 Hz, 1H in COCH2) 4.08 (m, 1H, CHPO), 5.02 (s, 2H,
d
: 0.87 (d, J¼5.2 Hz, 3H, CH3), 0.95 (d,
dard); HRMS (ESI) calcd for C28H31N2NaO7P [MþNa]þ m/z 561.1761;
found 561.1765.
OCH2), 6.26 (s, br, 1H, NH), 7.34e7.70 (m, 12H, ArH, POH & NH); 13
C
4.2.16. Ethyl syn-[[phenyl[N-[(S)-N-benzyloxycarbonylvalinyl]-1-
amino(4-methylphenyl)methyl]-phosphinyl]oxy]acetate (7j). White
solid, mp 164e166 ꢁC; Rf¼0.47 (Silica gel plate, ethyl acetate:hex-
anes 1:1, v/v). IR (KBr) v (cmꢀ1): 1764 (C]O),1722 (C]O),1661 (C]
NMR (100.6 MHz, DMSO-d6)
d
: 18.2 (d, JPeC¼4.0 Hz), 20.9 (d,
JPeC¼15 Hz), 27.9, 43.3, 52.8 (d, JPeC¼108 Hz), 65.4, 127.6, 127.7,
128.0 (d, JPeC¼12 Hz), 128.3, 131.3 (d, JPeC¼10 Hz), 131.5, 132.6 (d,
JPeC¼7 Hz), 133.8 (d, JPeC¼5 Hz), 137.1, 156.3, 169.1; 31P NMR
O), 1217 (P]O); 1H NMR (400 MHz, CDCl3)
d: 0.62 (d, J¼6.7 Hz, 3H,
(162.0 MHz, DMSO-d6) d: 23.5, 26.4 (85% H3PO4 as an internal
CH3), 0.72 (d, J¼6.7 Hz, 3H, CH3), 1.21 (t, J¼7.1 Hz, 3H, CH3),
1.83e1.91 (m, 1H, CH), 2.32 (s, 3H, CH3), 3.09 (dd, J¼5.0, 7.1 Hz, 1H,
NCH), 4.16 (q, J¼7.1 Hz, 2H, CO2CH2), 4.29 (dd, J¼10.2, 16.2 Hz, 1H in
POCH2), 4.34 (dd, J¼9.9, 19.6 Hz, 1H in POCH2), 5.02 (d, J¼12.2 Hz,
1H in OCH2), 5.05 (d, J¼12.2 Hz, 1H in OCH2), 5.42 (d, J¼8.9 Hz, 1H,
CONH), 5.67 (dd, J¼9.7,13.1 Hz,1H, POCH), 7.04e7.89 (m,11H, ArH &
standard); HRMS (ESI) calcd for C20H26N2O5P [MþH]þ 405.1573;
found 405.1577.
Acknowledgements
This work was supported by the National Basic Research Pro-
gram of China (No. 2013CB328900) and the National Natural
Science Foundation of China (Project No. 20972013).
CONH), 8.00 (s, br, CONH); 13C NMR (100.6 MHz, CDCl3)
d: 14.0, 17.0,
19.1, 21.1, 31.7, 45.8, 52.7 (d, JPeC¼106.9 Hz), 61.0 (d, JPeC¼6.4 Hz),
61.6, 66.8, 127.5, 127.68, 127.7, 127.9, 128.4, 128.5, 128.7, 128.76,
128.8, 129.2, 129.25, 131.1, 132.0, 132.1, 132.3, 132.4, 133.0, 133.8,
Supplementary data
136.3, 137.8, 156.2, 168.6 (d, JPeC¼5.4 Hz), 171.7 (d, JPeC¼7.4 Hz); 31
P
NMR (162.0 MHz, CDCl3) d: 30.6, 40.0 (85% H3PO4 as an internal
Analytical data of representative phosphinopeptides 5, copies of
the 1H NMR and 13C NMR spectra of phosphinopeptide 4, phos-
phinodepsipeptides 7, and phosphinopeptides 5. Supplementary
data associated with this article can be found in the online version,
at http://dx.doi.org/10.1016/j.tet.2013.04.032. These data include
MOL files and InChiKeys of the most important compounds de-
scribed in this article.
standard); HRMS (ESI) calcd for C31H37N2NaO7P [MþNa]þ m/z
603.2231; found 603.2234.
4.2.17. Ethyl syn-[[phenyl[N-[N-[N-benzyloxycarbonylglycinyl]glycinyl]-
1-amino(4-methylphenyl)methyl]phosphinyl]-oxy]acetate (major) (syn-
7k). White solid, mp 152e154 ꢁC; Rf¼0.21 (Silica gel plate, ethyl ace-
tate). Pure syn-7k cannot be obtained. The analytic data shown here
from a mixture of syn-7k and anti-7k in a ratio of anti:syn¼6.81:1. IR
(KBr) v (cmꢀ1): 1727 (C]O), 1725 (C]O), 1658 (C]O), 1578 (C]O),
References and notes
1088 (P]O); 1H NMR (400 MHz, CDCl3)
d
: 1.21 & 1.24 (t, J¼7.1 Hz, 3H,
1. Kafardki, P.; Lejczak, B. In Aminophosphonic and Aminophosphinic Acids: Chem-
istry and Biological Activity; Kukhar, V. P., Hudson, H. R., Eds.; John Wiley:
Chichester, UK, 2000; Chapter 12, pp 407e442.
2. Yiotakis, A. D.; Georgiadis, D.; Matziari, M.; Makaritis, A.; Dive, V. Curr. Org.
Chem. 2004, 8, 1135e1158.
3. Jouin, P.; Coste, J.; Galeotti, N.; Campagne, J. M.; Bedos, P.; Guillou, L. Lett. Pept.
Sci. 1995, 2, 233e238.
4. Mucha, A.; Kafarski, P.; Berlicki, L. J. Med. Chem. 2011, 54, 5955e5980.
5. He, F. D.; Meng, F. H.; Song, X. Q.; Hu, W. X.; Xu, J. X. Org. Lett. 2009, 11,
3922e3925.
6. (a) Picha, J.; Budesinsky, M.; Hanclova, I.; Sanda, M.; Fiedler, P.; Vanek, V.;
Jiracek, J. Tetrahedron 2009, 65, 6090e6103; (b) Picha, J.; Budesinsky, M.; Sanda,
M.; Jiracek, J. Tetrahedron Lett. 2008, 49, 4366e4368; (c) Giannousis, P. P.;
Bartlett, P. A. J. Med. Chem. 1987, 30, 1603e1609; (d) Picha, J.; Budesinsky, M.;
Fiedler, P.; Sanda, M.; Jiracek, J. Amino Acids 2010, 39, 1265e1280.
7. (a) Bartlett, P. A.; Giangiordano, M. A. J. Org. Chem. 1996, 61, 3433e3438; (b)
Bartlett, P. A.; Hanson, J. E.; Giannousis, P. P. J. Org. Chem. 1990, 55, 6268e6274.
8. (a) Tsukamoto, T.; Flanary, J. M.; Rojas, C.; Slusher, B. S.; Valiaevab, N.; Cowardb,
J. K. Bioorg. Med. Chem. Lett. 2002, 12, 2189e2192; (b) Phillips, M. A.; Kaplan, A.
P.; Rutter, W. J.; Bartlett, P. A. Biochemistry 1992, 31, 959e963.
9. Bartlett, P. A.; Lamden, L. A. Bioorg. Chem. 1986, 14, 356e377.
10. Sampson, N. S.; Bartlett, P. A. Biochemistry 1991, 30, 2255e2263.
11. (a) Isomura, S.; Ashley, J. A.; Wirsching, P.; Janda, K. D. Bioorg. Med. Chem. Lett.
2002, 12, 861e864; (b) Wagner, J.; Lerner, R. A.; Barbas, C. F., III. Bioorg. Med.
Chem. 1996, 4, 901e916.
CH3), 2.25 & 2.29 (s, 3H, CH3), 3.82e3.95 (m 2H, NCH2), 3.95e4.06 (m,
2H, NCH2), 4.18 & 4.22 (q, J¼7.1 Hz, 2H, CO2CH2), 4.33 & 4.37 (dd, J¼11.2,
17.3 Hz, 1H in POCH2), 4.46e4.58 (m, 1H in POCH2), 5.11 & 5.14 (s, 2H,
OCH2), 5.57 (dd, J¼9.4,13.3 Hz,1H, POCH), 5.75 & 5.83 (s, br,1H, CONH),
6.98e7.60 (m, 14H, ArH), 8.20 (s, br, 1H, CONH); 13C NMR (100.6 MHz,
CDCl3)
d
: 13.9, 21.1, 42.8, 44.2, 53.1 (d, JPeC¼105.4 Hz), 61.0 (d,
JPeC¼6.3 Hz), 61.7, 67.0, 127.2, 127.9, 128.0, 128.3, 128.32, 128.4, 128.44,
128.5,129.2,130.3,130.9,131.9,132.0,133.1,136.3,137.9,156.6,168.3 (d,
JPeC¼7.1 Hz),168.8 (d, JPeC¼4.6 Hz),169.4; 31P NMR (162.0 MHz, CDCl3)
d
: 40.3, 40.9 (85% H3PO4 as an internal standard); HRMS (ESI) calcd for
C30H35N3O8P [MþH]þ m/z 596.2156; found 596.2153; calcd for
C30H34N3NaO8P [MþNa]þ m/z 618.1981; found 618.1971.
4.2.18. Ethyl anti-[[phenyl[N-[N-[N-benzyloxycarbonyl-glycinyl]gly-
cinyl]-1-amino(4-methylphenyl) methyl]phosphinyl]-oxy]acetate
(minor) (anti-7k). White solid, mp 66e67 ꢁC; Rf¼0.26 (Silica gel
plate, ethyl acetate). IR (KBr) v (cmꢀ1): 1735 (C]O), 1719 (C]O),
1707 (C]O),1685 (C]O),1220 (P]O); 1H NMR (400 MHz, CDCl3)
d:
12. Meyer, J. H.; Bartlett, P. A. J. Am. Chem. Soc. 1998, 120, 4600e4609.
13. Elliott, R. L.; Marks, N.; Berg, M. J.; Portoghese, P. S. J. Med. Chem. 1985, 28,
1208e1216.
14. Yang, K. W.; Brandt, J. J.; Chatwood, L. L.; Crowder, M. W. Bioorg. Med. Chem. Lett.
2000, 10, 1085e1087.
15. (a) Malachowski, W. P.; Coward, J. K. J. Org. Chem. 1994, 59, 7625e7634; (b)
Campbell, D. A. J. Org. Chem. 1992, 57, 6331e6335; (c) Campbell, D. A.; Bermak,
J. C. J. Org. Chem. 1994, 59, 658e660; (d) Campbell, D. A.; Bermak, J. C. J. Am.
Chem. Soc. 1994, 116, 6039e6040.
16. (a) Campagne, J. M.; Coste, J.; Jouin, P. J. Org. Chem. 1995, 60, 5214e5223; (b)
Galeotti, N.; Coste, J.; Bedos, P.; Jouin, P. Tetrahedron Lett. 1996, 37, 3997e3998;
(c) Campagne, J. M.; Coste, J.; Jouin, P. Tetrahedron Lett. 1995, 36, 2079e2082.
17. Sampson, N. S.; Bartlett, P. A. J. Org. Chem. 1988, 53, 4500e4503.
1.21 (t, J¼7.1 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 3.97 (d, J¼5.6 Hz, 2H,
NCH2), 3.97e4.10 (m, 2H, NCH2), 4.17 (q, J¼7.1 Hz, 2H, CO2CH2), 4.38
(dd, J¼10.8, 16.2 Hz, 1H in POCH2), 4.55 (dd, J¼9.7, 16.2 Hz, 1H in
POCH2), 5.13 (s, 2H, OCH2), 5.59 (dd, J¼9.4, 12.8 Hz, 1H, POCH), 5.91
(s, br, 1H, CO2NH), 6.93 (s, br, 1H, CONH), 6.98e7.68 (m, 14H, ArH),
7.98 (s, br, 1H, CONH); 13C NMR (100.6 MHz, CDCl3)
d: 14.0, 21.1,
43.1, 44.5, 53.1 (d, JPeC¼102.8 Hz), 61.1 (d, JPeC¼6.3 Hz), 61.9, 67.2,
127.0, 127.9, 128.0, 128.1, 128.2, 128.3, 128.5, 128.54, 128.6, 129.2,
130.2, 132.1, 132.2, 133.1, 136.2, 137.9, 137.94, 156.6, 168.3 (d,
JPeC¼2.4 Hz), 169.1 (d, JPeC¼4.9 Hz), 169.6; 31P NMR (162.0 MHz,

4952
F. Meng, J. Xu / Tetrahedron 69 (2013) 4944e4952
18. de Fatima, M.; Fernandez Vlaar, C. P.; Fan, H.; Liu, Y. H.; Fronczek, F. R.; Hammer,
R. P. J. Org. Chem. 1995, 60, 7390e7391.
19. (a) Fu, N. Y.; Zhang, Q. H.; Duan, L. F.; Xu, J. X. J. Pept. Sci. 2006, 12, 303e309; (b)
Xu, J. X.; Gao, Y. H. Synthesis 2006, 783e788; (c) Liu, H.; Cai, S. Z.; Xu, J. X. J. Pept.
Sci. 2006, 12, 337e340.
20. (a) Li, B. N.; Cai, S. Z.; Du, D. M.; Xu, J. X. Org. Lett. 2007, 9, 2257e2260; (b) Meng,
F. H.; Xu, J. X. Amino Acids 2010, 39, 533e538.
21. Meng, F. H.; He, F. D.; Song, X. Q.; Zhang, L. L.; Hu, W. X.; Liu, G.; Xu, J. X. Amino
22. Xu, J. X.; Fu, N. Y. J. Chem. Soc., Perkin Trans. 1 2001, 1223e1226.
23. Hirschmann, R.; Yager, K. M.; Taylor, C. M.; Witherington, J.; Sprengeler, P. A.;
Phillips, B. W.; Moore, W.; Smith, A. B., III. J. Am. Chem. Soc. 1997, 119,
8177e8190.
24. (a) Koizumi, T.; Yanada, R.; Takagi, H.; Hirai, H.; Yoshii, E. Tetrahedron Lett. 1981,
22, 477e480; (b) Chen, R. Y.; Liu, L. Z. Studies on Organophosphorus Chemistry;
Higher Education: Beijing, China, 2001; Chapter 2.250e58.
25. Buchner, B.; Lockhart, H. J. Am. Chem. Soc. 1951, 73, 755e756.
26. Weinberg, K. G. J. Org. Chem. 1975, 40, 3586e3589.
Acids 2012, 43, 423e429.