Synthesis of N-phosphopeptides coupled by dichlorotriphenyl-phosphorane

Article abstract of DOI:10.1081/SCC-100104428

Coupling of N-phosphoamino acids 2 and amino acid methyl esters by dichlorotriphenylphosphorane 3 produced N-phosphopeptide methyl esters 5, which were sequentially hydrolyzed in triethylamine or dilute NaOH aqueous solution. The target products N-phospho

Full text of DOI:10.1081/SCC-100104428

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SYNTHESIS OF N-PHOSPHOPEPTIDES COUPLED BY
DICHLOROTRIPHENYLPHOSPHORANE
Shu-Zhi Dong a , Hua Fu a & Yu-Fen Zhao b
a State Laboratory of Bioorganic Phosphorus Chemistry of Education Ministry, Department
of Chemistry , School of Life Sciences and Engineering, Tsinghua University , Beijing,
100084, P.R. China
b State Laboratory of Bioorganic Phosphorus Chemistry of Education Ministry, Department
of Chemistry , School of Life Sciences and Engineering, Tsinghua University , Beijing,
100084, P.R. China
Published online: 09 Nov 2006.
To cite this article: Shu-Zhi Dong , Hua Fu & Yu-Fen Zhao (2001) SYNTHESIS OF N-PHOSPHOPEPTIDES COUPLED BY
DICHLOROTRIPHENYLPHOSPHORANE, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:13, 2067-2075, DOI: 10.1081/SCC-100104428
To link to this article: http://dx.doi.org/10.1081/SCC-100104428
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SYNTHETIC COMMUNICATIONS, 31(13), 2067–2075 (2001)
SYNTHESIS OF N-PHOSPHOPEPTIDES
COUPLED BY DICHLOROTRIPHENYL-
PHOSPHORANE
Shu-Zhi Dong, Hua Fu, and Yu-Fen Zhao*
State Laboratory of Bioorganic Phosphorus Chemistry of
Education Ministry, Department of Chemistry, School of
Life Sciences and Engineering, Tsinghua University,
Beijing 100084, P.R. China
ABSTRACT
Coupling of N-phosphoamino acids 2 and amino acid methyl
esters by dichlorotriphenylphosphorane 3 produced N-phos-
phopeptide methyl esters 5, which were sequentially hydro-
lyzed in triethylamine or dilute NaOH aqueous solution.
The target products N-phosphodipeptides 6 were obtained
in reasonable yields and high purity after isolation using
extraction method. The convenient and efficient approach
could be generally used for synthesis of polypeptides.
Derivatives of N-phosphopeptides are of pharmaceutical and biologi-
cally active interest.1–4 They are continuing to be increasingly important as
mechanistic probes for proteases,5 potent inhibitors of peptidases as tetra-
hedral transition-state or high-energy intermediate analogs,6 useful tools for
*Corresponding author. Fax: 86-10-62781695; E-mail: tp-dch@mail.tsinghua.edu.cn
2067
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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DONG, FU, AND ZHAO
the investigation of phosphorylation, or as important posttranslational
modification of peptides and proteins.7
In order to decipher the role of many phosphopeptides and explore
their biological activities, a facile method to acqurie multi-gram quantities
of phosphopeptides is in high demand. In general, N-(dialkoxyphosphor-
yl)peptides were prepared by phosphorylating the peptides obtained by the
deprotection of N-protected peptides such as N-Boc-peptides.4 However,
N-(dialkoxyphosphoryl)amino acids have hardly been used for the synthesis
of N-(dialkoxyphosphoryl)peptides, probably because it is difficult to
synthesize and purify them. Fortunately, an efficient method to prepare
highly pure and large quantities of N-phosphoamino acids has been devel-
oped in our lab.8
Furthermore, it has been proved that the phosphinic carboxylic mixed
anhydride method had the superiority in peptide synthesis9 than the mixed
carboxylic anhydride method for the faster coupling rate, more regiospeci-
ficity in nucleophilic attack and more thermal stability to disproportiona-
tion. Hence, the methodology of N-phosphopeptide synthesis starting from
N-phosphoamino acid and using dichlorotriphenylphosphorane 3 as the
coupling reagent was investigated.
RESULTS AND DISCUSSION
Synthesis of N-(Diisopropyloxyphosphoryl)dipeptide Methyl Esters
5(N-DIPP-dipeptide Methyl Esters)
Dichlorotriphenylphosphorane 3, which was assigned to the ionised
form according to 31P NMR spectrum (dP ¼ 61.1 ppm), is either commer-
cially available or can readily be prepared by the reaction of tri-
phenylphosphinewithhexachloroethane withoutanyundesirablephosphorus
by-product (Scheme 1).10
Scheme 1. Synthetic Pathway of Dichlorotriphenylphosphorane 3.
1.5 equivalents of in-situ generated dichlorotriphenylphosphorane 3
was added to 1 equivalent of N-(diisopropyloxyphosphoryl)amino acid 2
(N-DIPP-amino acid 2), amino acid methyl ester and triethylamine
(Et3N) in CH2Cl2 at room temperature. The mixture was stirred for 1 h,

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2069
and compound 2 and amino acid ester almost transferred into N-DIPP-
dipeptide methyl ester 5 in quantitative amount (indicated by the single
signal at about 31P NMR 6.8 ppm of compound 5) (Scheme 2). The activa-
tion mechanism was proposed that dichlorotriphenylphosphorane 3 phos-
phorylated N-DIPP-amino acid 2 to give the phosphinic carboxylic mixed
anhydride 4, followed by the nucleophilic attack of amino acid methyl ester
resulting into the formation of peptide bond.11 Excessive dichlorotriphenyl-
phosphorane 3 would consume the remnant water to guarantee the anhy-
drous environment and make the coupling reaction complete. Moreover, it
would not bring in further by-products because 3 can react with H2O to
form triphenylphosphine oxide, which is the same as the product yielded in
coupling reaction.
Scheme 2. Synthetic Pathway of N-DIPP-dipeptide Methyl Esters 5.
Hydrolysis of N-DIPP-dipeptide Methyl Esters 5
In order to avoid the side reactions on N-protecting group DIPP
(diisopropyloxyphosphoryl), triethylamine, as a weak base, was the first
choice to catalyze the hydrolysis of compound 5 (Scheme 3).12 Yet it was
only efficient for the hydrolysis of compound 5a, 5b and 5c. Hydrolysis of
compound 5d, 5e, 5f, however, was completed in a stronger base, dilute
NaOH aqueous solution, with a longer time as shown in Table 1. Table 1
shows that the only difference between 5a, 5b, and 5d, 5e, 5f lies in the side
chain of the amino acid residue on C-terminal. And the nuance between
compound 5c and 5e is the addition of phenyl on the side-chain of the first
amino acid residue. These show that the hydrolysis reaction is strongly
dependent upon the dual side-chains.
The hydrolysis reaction was carried out in aqueous-organic mixed sol-
vents to facilitate the tracing of reaction process by 31P NMR techniques.
N-DIPP-dipeptide methyl esters 5 are organic soluble species, while the

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DONG, FU, AND ZHAO
Scheme 3. Synthetic Pathway of N-DIPP-dipeptides 6.
Table 1. Hydrolysis of N-DIPP-dipeptide Methyl Esters 5
Final
Poduct 6
Time
(h)
Overall
Yield (%)
R1
R2
Base
DIPP-Phe-Gly a
DIPP-Phe-Ala b
DIPP-Ala-Phe c
DIPP-Phe-Leu d
DIPP-Phe-Phe e
DIPP-Phe-Val f
-CH2-Ph
-CH2-Ph
-CH3
-CH2-Ph
-CH2-Ph
-CH2-Ph
-H
-CH3
-CH2-Ph
-CH2-Pr1
-CH2-Ph
-Pr1
Et3N
Et3N
Et3N
NaOH (0.17 N)
NaOH (0.17 N)
NaOH (0.65 N)
3.5
3.5
3.5
7.0
7.0
9.0
85.2
60.7
60.0
80.3
75.8
88.2
basic hydrolyzed products 6 are the corresponding salts which are aqueous
soluble. As the hydrolysis proceeding the signal at about 31P NMR 6.8 ppm of
compound 5 in organic phase decreased. At the end point there was no com-
pound 5 left, therefore no 31P NMR signal of compound 5 could be detected in
the organic phase. Whilst triphenylphosphine oxide was imprisoned in
organic phase (the signal at about 31P NMR 28.0 ppm of Ph3P ¼ O only
existed in the organic phase). So the major impurity was removed completely.
Dichlorotriphenylphosphorane 3 gives cleaner reactions due to the high
sensitivity towards the atmosphere and the exclusive resultant triphenyl-
phosphine oxide. Hence after eliminating the main impurity Ph3P ¼ O, we
got highly pure N-phosphodipeptides 6a–f using simple extraction workup.
The purity and structure of compounds 6a–f were determined by
1H NMR, 13C NMR, 31P NMR and ESI-MS methods. Each target product
gave only one 31P NMR signal implying that no racemization occurred
during this peptide bond formation.13 These highly optical pure N-DIPP-
dipeptides 6a–f could be used for elongation of N-phosphopeptides or/and
test for biological activities.
In conclusion, dichlorotriphenylphosphorane 3 is an effective coupling
reagent for synthesis of N-phosphopeptides. The present method enables
us to obtain N-phosphopeptides on a large-scale and highly pure production
because of its availability, convenience and low racemization. Further,
the N-phosphopeptides could be deprotected under acid conditions14 to
yield the corresponding peptides. Thus the convenient and efficient approach
could be also applied for the synthesis of polypeptides.

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2071
EXPERIMENTAL
General Procedure
All glassware was dried in an oven for at least 3 h at 120ꢀC prior to use.
Air sensitive materials were transferred under a nitrogen atmosphere.
Dichloromethane and triethylamine were dried over P2O5 and CaH2
1
respectively. H MNR and 13C NMR spectra were recorded on Bruker
AM 500 spectrometer. TMS (d ¼ 0.0) and CDCl3 (d ¼ 77.0 ppm) were
1
references for H and 13C NMR spectra respectively. 13C NMR spectra
1
were all taken under H decoupled and 31P coupled conditions. 31P NMR
spectra were taken on Bruker AC 200 spectrometer at 81 MHz under
1H decoupled conditions. 31P NMR chemical shifts are reported in ppm
downfield (þ) or upfield (ꢁ) from external 85% H3PO4 as reference. Mass
spectra were conducted on Bruker Esquire-LC mass spectrometer in positive
and negative ion mode.
Synthesis of Diisopropyl Phosphite (DIPPH) 1
The starting material DIPPH 1 was prepared according to the pub-
lished procedure.15 Yield: 75%. 31P NMR: 4.4 ppm.
Synthesis of N-(Diisopropyloxyphosphoryl)amino Acids 2
N-DIPP-amino acid 2 was synthesized by adding diisopropyl
phosphite 1 to an aqueous-organic mixture containing the amino acid,
water, carbon tetrachloride, triethylamine and ethanol, well stirring the
mixture at 0–20ꢀC for a few hours, and quenching the reaction by acidifica-
tion.8 Yields: DIPP-Ala, 89%; DIPP-Phe, 93%. 31P NMR: 7.1, 6.9 ppm
respectively.
Synthesis of Dichlorotriphenylphosphorane 3
According to literature,10 under a nitrogen atmosphere, 2 mmol
triphenylphosphine in 3 mL dry CH2Cl2 was added dropwise to a stirred
2 mmol hexachloroethane in 3 mL dry CH2Cl2 in an ice-water bath.
After five minutes, the bath was removed. The reaction was stirred continu-
ously for 1 h at room temperature, then dichlorotriphenylphosphorane 3 was
produced. Yield: 90% (by 31P NMR spectral integral). 31P NMR: 61.1 ppm.

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DONG, FU, AND ZHAO
Synthesis of N-(Diisopropyloxyphosphoryl)dipeptide Methyl Esters 5
Under a nitrogen atmosphere, 1.2 mmol dichlorotriphenylphosphor-
ane 3 in CH2Cl2 was added dropwise to a stirred dry CH2Cl2 (5 mL) solution
of 0.8 mmol N-(diisopropyloxyphosphoryl)amino acid 2, 0.8 mmol
amino acid methyl ester and 350 mL dry Et3N at room temperature. Extra
addition of adequate Et3N was followed after half an hour. The stirring was
continued for 1 h. After the removal of solvent the resultant residue was
dissolved in 15 mL ethyl acetate, then followed by the filtration of residue
triethylamine hydrochloride. The filtrate was washed with 4 mL 1 mol/L
citric acid, 4 mL saturated NaCl solution, 4 mL 5% NaHCO3 solution,
and 4 mL H2O.
Synthesis of N-(Diisopropyloxyphosphoryl)dipeptides 6
Method A: The above filtrate by ethyl acetate was evaporated to dry-
ness. A mixture of 3.5 mL Et3N and 3.5 mL H2O was added to the resulting
residue containing N-(diisopropyloxyphosphoryl)dipeptide methyl ester 5
and stirred at 40ꢀC for 3.5 h. The water layer was washed with Et3N
(3 ꢂ 4 mL) followed by addition of 1.5 equivalents NaOH. The mixture
was stirred for ten minutes, then washed with CH2Cl2 (3 ꢂ 5 mL) and acid-
ified to pH 3 with 1 mol/L HCl in an ice-water bath. The nepheloid solution
was extracted with ethyl acetate (3 ꢂ 15 mL). The organic layer was washed
with water, brine and dried over anhydrous MgSO4. Removal of the solvent
afforded the pure products 6a–c as white solid.
Spectral data for compounds 6a–c
N-DIPP-Phe-Gly 6a, yield: 85.2%. 31P NMR (81.0 MHz, AcOEt), d
1
(ppm): 6.95. H NMR (500 MHz, CDCl3), d (ppm): 1.09–1.25 (m, 12H,
(P(OCH(CH3)2)2), 2.97–3.11 (m, 2H, CH2Ph), 3.78–3.83 (m, 2H,
CH2COOH), 4.04–4.16 (br, 1H, CO-NH), 4.19 (q, J ¼ 5.7 Hz,
3JP-H ¼ 18.6 Hz, 1H, CHCH2Ph), 4.27–4.38 (m, 2H, P(OCH(CH3)2)2),
7.18–7.29 (m, 6H, P-NH, Ph). 13C NMR (125 MHz, CDCl3), d (ppm): 23.52
3
(br, OCH(CH3)2), 40.30 (d, JP-C ¼ 5.0 Hz, CH2Ph), 41.49 ( CH2COOH), 56.78
(CHCH2Ph), 71.07 (q, 2JP-C ¼ 6.1 Hz, P(OCH(CH3)2)2), 126.80–136.53 (Ph),
3
172.23 (COOH), 172.40 (d, JP-C ¼ 4.4 Hz, CO-NH). Positive-ion ESI-MS
(m/z): 387.1 (M þ H)þ. Negative-ion ESI-MS (m/z): 385.1 (M-H)ꢁ.
N-DIPP-Phe-Ala 6b, yield: 60.7%. 31P NMR (81.0 MHz, AcOEt), d
(ppm): 7.21. 1H NMR (500 MHz, CDCl3), d (ppm): 1.12 (d, J ¼ 6.0 Hz, 3H,
CHCH3), 1.15–1.31 (m, 12H, (P(OCH(CH3)2)2), 3.01–3.08 (m, 2H, CH2Ph),
3.74 (t, 1H, CHCH3), 4.06 (br, 1H, CO-NH), 4.28–4.41 (m, 2H

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2073
(P(OCH(CH3)2)2), 4.41–4.54 (m, 1H, CHCH2Ph), 7.19–7.48 (m, 6H, P-NH,
Ph). 13C NMR (125 MHz, CDCl3), d (ppm): 18.13 (CHCH3), 23.51–23.60
(m, (P(OCH( CH3)2)2), 39.59 (d, 3JP-C ¼ 5.5 Hz, CH2Ph), 48.14 (CHCOOH),
56.54 ( CHCO-NH), 72.00 (q, 2JP-C ¼ 5.8 Hz, (P(OCH(CH3)2)2), 126.83–136.25
(Ph), 171.99 (d, 3JP-C ¼ 4.4 Hz, CO-NH), 175.16 (COOH). Positive-ion ESI-
MS (m/z): 401 (M þ H)þ. Negative-ion ESI-MS (m/z): 399 (M-H)ꢁ.
N-DIPP-Ala-Phe 6c, yield: 60.0%. 31P NMR (81.0 MHz, AcOEt), d
(ppm): 6.85. 1H NMR (500 MHz, CDCl3), d (ppm): 1.21 (d, J ¼ 4.5 Hz, 3H,
CHCH3, 1.26–1.30 (m, 12H, (P(OCH(CH3)2)2), 2.93 (d, J ¼ 7.5 Hz, 2H,
CH2Ph), 4.54 (m, 1H, CHCOOH), 4.54 (br, 1H, CO-NH), 4.58–4.61 (m,
2H, (P(OCH(CH3)2)2), 4.80 (m, 1H, CHCH3), 7.19–7.26 (m, 6H, P-NH, Ph).
13C NMR (125 MHz, CDCl3), d (ppm): 20.67 (CHCH3), 23.57–23.73
((P(OCH( CH3)2)2), 37.45 (CH2Ph), 51.42 (CHCOOH), 53.27 (CHCH3),
2
72.06 (q, JP-C ¼ 5.3 Hz, (P(OCH(CH3)2)2), 126.77–136.55 (Ph), 173.12 (d,
3JP-C ¼ 5.5 Hz, CO-NH), 174.20 (COOH). Positive-ion ESI-MS (m/z): 401
(M+H)+. Negative-ion ESI-MS (m/z): 399 (M-H)ꢁ.
Method B: The above filtrate by ethyl ecetate was evaporated to
dryness. A mixture of 6 mL NaOH aqueous solution (0.17 mol/L for
6d and 6e, 0.65 mol/L for 6f) and 3 mL CH2Cl2 was added to the resulting
residue containing N-(diisopropyloxyphosphoryl)dipeptide methyl ester
5 and stirred at room temperature for 7 h. The water layer was washed
with CH2Cl2 (3 ꢂ 4 mL). The following isolation procedure was the same
as that of method A.
Spectral data for compounds 6d–f.
N-DIPP-Phe-Leu 6d, yield: 80.3%. 31P NMR (81.0 MHz, AcOEt), d
(ppm): 7.28. 1H NMR (500 MHz, CDCl3), d (ppm): 0.89 (q, J ¼ 6.5, 16.5 Hz,
6H, CH2CH(CH3)2), 1.13–1.25 (m, 12H, P(OCH(CH3)2)2), 1.44–1.55 (m,
2H, CH2CH(CH3)2), 1.59–1.64 (m, 1H, CH2CH(CH3)2), 3.00–3.15 (m,
2H, CH2Ph), 3.58 (t, 1H, CHCOOH), 4.07 (br, 1H, CO-NH), 4.32–4.43
3
(m, 2H, P(OCH(CH3)2)2), 4.59 (q, J ¼ 7.8 Hz, JP-H ¼ 13.8 Hz, 1H,
CHCH2pH), 7.19–7.38 (m, 6H, P-NH, Ph). 13C NMR (125 MHz, CDCl3),
d (ppm): 22.29, 22.65 (CH2CH(CH3)2), 23.50–23.65 (P(OCH(CH3)2)2), 24.52
3
(CH2CH(CH3)2), 39.30 (d, JP-C ¼ 4.5 Hz, CH2Ph), 41.51 (CH2CH(CH3)2),
2
50.83 (CHCOOH), 56.62 (CHCH2Ph), 71.92–72.13 (q, JP-C ¼ 5.9 Hz,
3
P(OCH(CH3)2)2), 126.84–136.26 (Ph), 171.85 (d, JP-C ¼ 5.4 Hz, CO-NH),
175.26 (COOH). Positive-ion ESI-MS (m/z): 443.3 (M+H)+. Negative-ion
ESI-MS (m/z): 441.3 (M-H)ꢁ.
N-DIPP-Phe-Phe 6e, yield: 75.8%. 31P NMR (81.0 MHz, AcOEt), d
1
(ppm): 6.93. H NMR (500 MHz, CDCl3), d (ppm): 1.03–1.23 (m, 12H,
(P(OCH(CH3)2)2), 2.89–3.07 (m, 4H, 2(CH2Ph)), 3.83 (t, J ¼ 10.8 Hz, 1H,

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DONG, FU, AND ZHAO
CHCOOH), 3.99 (br, 1H, CO-NH), 4.26–4.38 (m, 2H, (P(OCH(CH3)2)2),
3
4.79 (q, J ¼ 6.5 Hz, JP-C ¼ 12.5 Hz, 1H, CHCO-NH), 7.07–7.39 (m, 11H,
P-NH, 2Ph). 13C NMR (125 MHz, CDCl3), d (ppm): 23.45–23.54
3
((P(OCH(CH3)2)2), 37.52 (PhCH2CHCOOH), 39.51 (d, JP-C ¼ 4.9 Hz,
PhCH2CHCONH), 53.46 (CHCOOH), 56.83 (CHCONH), 71.00 (q,
2JP-C ¼ 6.1 Hz, (P(OCH(CH3)2)2), 126.69–126.48 (2 Ph), 172.06 (d,
3JP-C ¼ 5.1 Hz, CO-NH), 173.70 (COOH). Positive-ion ESI-MS (m/z): 477
(M+H)+. Negative-ion ESI-MS (m/z): 475 (M-H)ꢁ.
31
N-DIPP-Phe-Valf 6f, yield: 88.2%. P NMR (81.0 MHz, AcOEt), d
(ppm): 6.89. 1H NMR (500 MHz, CDCl3), d (ppm): 0.86 (dd, J ¼ 7.0,
14.0 Hz, 6H, CHCH(CH3)2), 1.08–1.19 (m, 12H, (P(OCH(CH3)2)2),
2.13–2.18 (m, 1H, CHCH(CH3)2), 2.96–3.04 (m, 2H, CH2Ph), 4.10 (m, 1H,
CHCOOH), 4.12 (br, 1H, CO-NH), 4.18–4.37 (m, 2H, (P(OCH(CH3)2)2),
3
4.45 (q, J ¼ 5.0 Hz, JP-H ¼ 8.5 Hz, 1H, CHCH2Ph), 7.12–7.40 (m, 6H,
P-NH, Ph). 13C NMR (125 MHz, CDCl3), d (ppm): 17.72, 18.53
(CHCH(CH3)2),23.35–23.46((P(OCH(CH3)2)2),30.92(CHCH(CH3)2),39.67
(d, 3JP-C ¼ 5.1 Hz, CH2Ph), 56.58 (CHCOOH), 57.34 (CHCH2Ph), 71.64 (q,
2JP-C ¼ 5.8 Hz, (P(OCH(CH3)2)2), 126.59– 136.41 (Ph), 172.85 (d,
3JP-C ¼ 4.3 Hz, CO-NH), 174.96 (COOH). Positive-ion ESI-MS (m/z): 429
(M+H)+. Negative-ion ESI-MS (m/z): 427 (M-H)ꢁ.
ACKNOWLEDGMENTS
The authors would like to thank the financial supports from the
Chinese National Natural Science Foundation (No. 29902003), the Ministry
of Science and Technology, the Chinese Education Ministry and
Tsinghua University.
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Received in the Netherlands September 14, 2000

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