Synthesis of isocyanide derivatives of α-aminoalkylphosphonate diphenyl esters

Article abstract of DOI:10.1016/j.tetlet.2006.04.058

This letter describes the first example of the synthesis of isocyanide derivatives of α-aminoalkylphosphonate diphenyl esters. This method produces the title compounds in high purity and in very good yields. It also permits the generation of an α-aminopho

Full text of DOI:10.1016/j.tetlet.2006.04.058

Tetrahedron Letters 47 (2006) 4209–4211
Synthesis of isocyanide derivatives of
a-aminoalkylphosphonate diphenyl esters
*
´
´
Marcin Sienczyk, Maciej Kliszczak and Jozef Oleksyszyn
Division of Medicinal Chemistry and Microbiology, Chemistry Department, Wroclaw University of Technology,
Wybrzez_e Wyspian´skiego 27, 50-370 Wrocław, Poland
Received 22 February 2006; revised 3 April 2006; accepted 10 April 2006
Available online 9 May 2006
Abstract—This letter describes the first example of the synthesis of isocyanide derivatives of a-aminoalkylphosphonate diphenyl
esters. This method produces the title compounds in high purity and in very good yields. It also permits the generation of an a-amino-
phosphonate-based library of biologically active phosphonopeptides. Preliminary experiments demonstrate their application as sub-
strates for the Ugi-type multicomponent condensation.
Ó 2006 Elsevier Ltd. All rights reserved.
For several years a-aminoalkylphosphonates—phos-
phonic analogues of amino acids—have interested bio-
chemists, due to their broad spectrum application as
herbicides, apoptosis inducers and neuroactive agents.1
Special attention has been paid to their activity as
enzyme inhibitors, especially serine proteases inhibitors.2
To date, many phosphonate diphenyl esters and their
peptide derivatives have been used as potent and selec-
tive enzyme inhibitors.3 The synthesis of phosphonopep-
tides uses classical coupling procedures such as mixed
carboxylic-carbonic anhydride (MCA), dicyclohexyl-
carbodiimide (DCC), and active ester and active chlo-
ride methods.4 Very little attention has been paid to
the four-component condensation, formally known as
the Ugi reaction for the preparation of phosphonopep-
tides in one step.5 We have found only two reports in
the literature describing such an approach which uses
commercially available 1-isocyanomethanephosphonate
diethyl ester.6 This is the first example of the synthesis
of pseudopeptides with an a-aminoalkylphosphonate
diphenyl ester moiety at the C-terminus in one step
using isocyanide derivatives as the substrates.
condensation reactions opens the way for the synthesis
of large numbers of new biologically active compounds.
It also provides a powerful tool for one-pot syntheses of
diverse and complex peptides with aminophosphonate
moieties at the C-terminus in great numbers. No other
single method enables chemists to create such large
numbers of chemicals as is provided by multicomponent
reactions combining simple raw materials, such as car-
bonic acids, amines, aldehydes and isocyanides.7 ‘If
for example, 40 each of different components are reacted
with one another, the result is 404 = 2,560,000 reaction
products.’8 Here we present a simple method for
the preparation of isocyanide derivatives of a-amino-
alkylphosphonate diphenyl esters. We also report our
preliminary results of their application for phosphono-
peptide synthesis in the Ugi-type multicomponent
condensation.9
The synthetic approach is outlined in Scheme 1. The
starting Cbz-N-protected a-aminophosphonate diphen-
yl esters 1a–j were prepared using the method described
in the literature.10 Compounds 1a–j were obtained as
racemic mixtures upon condensation of triphenyl phos-
phite, benzyl carbamate and an aldehyde. The synthesis
of Phth-N-protected 5-amino-1-pentanal began with the
protection of the amino group of 5-amino-1-pentanol
with phthalic anhydride. Subsequent oxidation under
Swern conditions gave the desired aldehyde.11 The syn-
thesis of N-phthaloyl-4-amino-1-butanal started with
the protection of the amino group of 4-aminobutyralde-
hyde diethyl acetal with N-ethoxycarbonylphthalimide,
The possibility of using isocyanide derivatives of a-
aminophosphonate diphenyl esters in multicomponent
Keywords: a-Aminoalkylphosphonates; Isocyanides; Phosphonopep-
tides; Ugi-type condensation.
*
Corresponding author. Tel.: +48 71 320 40 27; fax: +48 71 328 40
64; e-mail: marcin.sienczyk@pwr.wroc.pl
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.058

4210
M. Sien´czyk et al. / Tetrahedron Letters 47 (2006) 4209–4211
Table 1. The N-formyl derivatives of a-aminoalkylphosphonate
diphenyl esters
R
R
O
O
Cbz
O
O
i
O
R
HBr*H2N
P
N
H
P
70 - 90%
O
O
O
O
H
P
N
H
O
2a-j
1a-j
Compound
R
Yield (%)
ii
> 90%
3a
3b
3c
3d
3e
3f
–CH3
–CH2CH2CH3
–CH(CH3)2
–CH2CH(CH3)2
–Ph
–CH2Ph
95
91
97
99
96
99
99
99
93
90
O
R
R
iii
O
O
O
O
H
P
P
N
N
C
H
3g
3h
3i
–CH2CH2Ph
> 85%
O
O
–CH2CH2CH2NPhth
–CH2CH2CH2CH2NPhth
–CH2CH2SCH3
4a-j
3j
3a-j
Scheme 1. Preparation of 1-isocyanoalkylphosphonate diphenyl esters
4a–j. is an aromatic or aliphatic side–chain. Reagents and
conditions: (i) 33% HBr/AcOH; (ii) Et3N, acetic formic anhydride,
CH2Cl2; (iii) Et3N, POCl3, CH2Cl2, N2, À20 °C.
it was dried with Na2SO4 and evaporated to give 4a–j
as oils with a characteristic isocyanide odour in yields
greater than 85% (see Table 2).17
R
Initial experiments clearly demonstrated the application
of 1-isocyanoalkylphosphonate diphenyl esters in the
Ugi-type multicomponent condensation for the prepara-
tion of phosphonic pseudopeptides. The yields were in
the range of 44–70% as diastereomeric mixtures.18 We
are currently at advanced stages in the synthesis of a
phosphonopeptide-based library using the multicompo-
nent condensations. Complete data for the condensation
products obtained as well as their biological activities
will be published in due course.
followed by acidic hydrolysis in THF.12 Deprotection of
a-aminoalkylphosphonate diphenyl esters 1a–j using
33% HBr in acetic acid gave the corresponding hydro-
bromide salts of the a-aminoalkylphosphonates 2a–j.
The typical method for preparing N-formylated a-amino-
phosphonates is a two-step process, with a total yield of
about 70%.13 First, hydrobromide salts are transformed
into hydrochloride salts. Formylation is then achieved
using EDC/formic anhydride in dichloromethane at
0 °C in the presence of N-methylmorpholine. The dura-
tion of the reaction is rather long, and the temperature
needs to be kept constant throughout the duration.
In conclusion, we have presented a very efficient route
for the synthesis of N-formyl-1-aminoalkylphosphonate
diphenyl esters compared to the method described in the
literature.13 We have also shown that N-formyl deriva-
tives can be easily dehydrated, giving their isocyanide
derivatives—a new class of compounds, which could
be used in the preparation of very large number of phos-
Here we present a fast, efficient and simple method for
the synthesis of N-formylated a-aminoalkylphospho-
nate diphenyl esters. To a suspension of 2a–j (1 equiv)
in dichloromethane, Et3N (1.2 equiv) was added at
room temperature. After the hydrobromide salt had dis-
solved completely, acetic formic anhydride14 was added
as the formylating agent (2.0 equiv). The reaction was
complete within 30 min. The reaction mixture was then
evaporated to dryness, dissolved in ethyl acetate, and
the hydrobromide salt of triethylamine, which usually
precipitates, was filtered off. The organic phase was
washed with 5% NaHCO3, dried with Na2SO4 and
evaporated, giving 3a–j in very high yields.15 The struc-
tures of the N-formyl derivatives 3a–j are presented in
Table 1.
Table 2. The isocyanide derivatives of a-aminoalkylphosphonate
diphenyl esters
R
O
P
N
O
C
O
Compound
R
Yield (%)
4a
4b
4c
4d
4e
4f
–CH3
–CH2CH2CH3
–CH(CH3)2
–CH2CH(CH3)2
–Ph
–CH2Ph
95
87
85
98
85
91
99
86
94
85
For the synthesis of isocyanides 4a–j, N-formylated
derivatives 3a–j were dissolved in dichloromethane.
After adding Et3N (5 equiv), the reaction mixture (N2
atmosphere) was cooled to À22 °C and POCl3 (2 equiv)
was added slowly.16 The reaction was complete within
2 h. a-Aminoalkylphosphonate diphenyl esters are quite
stable under strongly acidic conditions.2 After washing
the organic phase with saturated NaHCO3 and brine,
4g
4h
4i
–CH2CH2Ph
–CH2CH2CH2(NPhth)
–CH2CH2CH2CH2(NPhth)
–CH2CH2SCH3
4j

M. Sien´czyk et al. / Tetrahedron Letters 47 (2006) 4209–4211
4211
12. Teshima, T.; Matsumoto, T.; Wakamiya, T.; Shiba, T.;
Aramaki, Y.; Nakajima, T.; Kawai, N. Tetrahedron 1991,
47, 3305–3312.
phonic pseudopeptides designed to inhibit enzyme activ-
ity or to examine enzyme specificity.
13. Chen, F. M.; Benoiton, N. Synthesis 1979, 709–710.
14. (a) Krimen, L. I. In Organic Synthesis; John Wiley: New
York, 1988; Vol. 6, pp 8–9; (b) Strazzolini, P.; Giumanini,
A. G.; Cauci, S. Tetrahedron 1990, 46, 1081–1118.
15. 1H, 13C NMR and 31P NMR spectra were recorded at
600.58, 151.03 and 243.11 MHz, respectively. Spectro-
scopic data of all synthesized N-formylated a-amino-
alkylphosphonate diphenyl esters can be found in the
Supplementary data.
Acknowledgements
This work was supported by the State Committee for
Scientific Research Grant 2 P05A 039 28.
Supplementary data
Compound 3a: White crystals, mp 75 °C; 31P NMR
1
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.04.058.
(CDCl3): 18.10 (s); H NMR (CDCl3): 1.52 (dd, J = 7.8,
18.3 Hz, 3H), 4.95–5.03 (m, 1H), 7.09–7.37 (m, Ar–H,
NH, 11H), 8.07 (s, 1H); 13C NMR (CDCl3): 16.63, 40.17
(d, J = 161.6 Hz), 120.49 (d, J = 4.5 Hz), 125.49, 125.62,
129.93 (d, J = 6.0 Hz), 149.98. (d, J = 10.6 Hz), 150.26 (d,
J = 10.6 Hz), 160.70 (d, J = 7.6 Hz). IR (KBr, cmÀ1):
3430, 3255, 3035, 2880, 1685, 1590, 1535, 1490, 1380, 1255,
1210, 1185, 1165, 1070, 950, 930, 780, 690. MS (ESI)
m/z = 328.8 (M++Na).
References and notes
1. (a) Kafarski, P.; Lejczak, B.; Tyka, R.; Koba, L.;
Pliszczak, E.; Wieczorek, P. J. Plant Growth Regul. 1995,
´
´
14, 199–203; (b) Dra˛g, M.; Sienczyk, M.; Marcinkowska,
16. Zhao, G.; Bughin, C.; Bienayme, H.; Zhu, J. Synlett 2003,
´
A.; Dra˛g-Zalesinska, M.; Wysocka, T.; Oleksyszyn, J. Pol.
8, 1153–1154.
J. Chem. 2005, 79, 593–602; (c) Lunn, W. H. W.; Schoepp,
D. D.; Calligaro, D. O.; Vasileff, R. T.; Heinz, L. J.;
Salhoff, C. R.; O’Malley, P. J. J. Med. Chem. 1992, 35,
4608–4612.
17. 1H, 13C NMR and 31P NMR spectra were recorded at
600.58, 151.03 and 243.11 MHz, respectively. Spectro-
scopic data of all synthesized isocyanide derivatives of a-
aminoalkylphosphonate diphenyl esters can be found in
the Supplementary data.
2. Oleksyszyn, J.; Powers, J. C. In Methods Enzymology;
Academic Press, 1994; Vol. 244, pp 423–441.
3. (a) Oleksyszyn, J.; Powers, J. C. Biochemistry 1991, 30,
485–493; (b) Boduszek, B.; Oleksyszyn, J.; Kam, C.-M.;
Selzler, J.; Smith, R.; Powers, J. J. Med Chem. 1994, 37,
3969–3976; (c) Joossens, J.; Van der Veken, P.; Lambeir,
A.-M.; Augustyns, K.; Haemers, A. J. Med. Chem. 2004,
47, 2411–2413.
4. Kafarski, P.; Lejczak, B. In Aminophosphonic and Amino-
phosphinic Acids; John Wiley & Sons Ltd: Chichester,
2000; pp 173–203.
5. Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8–21.
6. (a) Rachon, J. Chimia 1983, 37, 299–301; (b) Rachon, J.
Compound 4a: Amber oil; 31P NMR (CDCl3): 9.70 (s); 1H
NMR (CDCl3): 1.82 (dd, J = 7.2, 16.8 Hz, 3H), 4.23–4.29
(m, 1H), 7.26–7.38 (m, Ar–H, 10H); 13C NMR (CDCl3):
16.48 (d, J = 4.5 Hz), 45.77 (d, J = 161.6 Hz), 120.41 (dd,
J = 4.5, 12.1 Hz), 125.96 (d, J = 13.6 Hz), 130.06 (d,
J = 9.1 Hz), 149.68 (d, J = 9.1 Hz), 149.94 (d, J = 9.1 Hz),
161.06 (d, J = 4.5 Hz). IR (neat, cmÀ1): 3285, 3070, 2935,
2139, 1685, 1595, 1590, 1490, 1455, 1390, 1320, 1270, 1250,
1200, 1160, 1070, 1025, 1010, 930. MS (ESI) m/z = 310.5
(M++Na).
18. 1H and 31P NMR spectra were recorded at 600.58 and
243.11 MHz, respectively. Spectroscopic data of the
derivative of 4d—N-Cbz-Ala-(N-n-butyl)-Val-LeuP(OPh)2
obtained by Ugi-type condensation as the diastereo-
isomeric mixture: Yield 48%; colourless oil; 31P NMR
(CDCl3): 19.69 (26%), 19.79 (20%), 20.07 (26%), 20.45
´
´
Synthesis 1984, 3, 219–222.
7. Do¨mling, A. Chem. Rev. 2006, 106, 17–89.
8. Ugi, I.; Steinbruckner, C. Chem. Ber. 1961, 94, 734–742.
¨
9. This work is the subject of patent applications P 379013
and P 379083.
1
(28%); H NMR (CDCl3): 0.71–0.87 (m, 15H), 1.05–1.15
10. Oleksyszyn, J.; Subotkowska, L.; Mastalerz, P. Synthesis
1979, 985–986.
11. Jackson, D. S.; Fraser, S. A.; Ni, L.-M.; Kam, C.-M.;
Winkler, U.; Johnson, S. A.; Froelich, C. J.; Hudig, D.;
Powers, J. C. J. Med. Chem. 1998, 41, 2289–2301.
(m, 2H), 1.17–1.27 (m, 4H), 1.49–1.62 (m, 3H), 1.68–1.81
(m, 2H), 2.43 (s, 1H), 3.12–3.27 (m, 2H), 4.14–4.30 (m,
1H), 4.46–4.61 (m, 1H), 4.77–4.97 (m, 1H), 5.00–5.15
(m, 2H), 5.77 (s, 1H), 6.95–7.23 (m, Ar–H, 15H). MS (ESI)
m/z = 702.5 (M++Na).