Synthesis of norleucine-derived phosphonopeptides

Article abstract of DOI:10.1016/j.tetlet.2008.05.028

The synthesis of norleucine-derived phosphonopeptides was achieved by BOP-catalyzed coupling of the monobenzyl ester of a N-CBz-protected phosphonate derivative of norleucine with hydroxyl moieties of derivatized lactic or glycolic acids. The complete deprotection of the product esters/carbamates was achieved in good yields by one-step Pd-catalyzed hydrogenolysis.

Full text of DOI:10.1016/j.tetlet.2008.05.028

Tetrahedron Letters 49 (2008) 4366–4368
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Synthesis of norleucine-derived phosphonopeptides
*
ˇ
´
ˇ
ˇ
Jan Pícha, Miloš Budešínsky, Miloslav Šanda, Jirí Jirácek
Institute of Organic Chemistry and Biochemistry, v.v.i., Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of norleucine-derived phosphonopeptides was achieved by BOP-catalyzed coupling of the
monobenzyl ester of a N-CBz-protected phosphonate derivative of norleucine with hydroxyl moieties of
derivatized lactic or glycolic acids. The complete deprotection of the product esters/carbamates was
achieved in good yields by one-step Pd-catalyzed hydrogenolysis.
Received 2 April 2008
Revised 25 April 2008
Accepted 7 May 2008
Available online 10 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Phosphinopeptides1,2 and phosphonopeptides3,4 (also called
depsipeptides5) have found important applications in biology and
medicine primarily as inhibitors of metalloenzymes. The replace-
ment of a hydrolysable peptide bond by non-hydrolysable phosph-
inate6 or phosphonate7,8 moieties mimics the hypothetical
transition state of the substrate upon hydrolysis and may result
in potent inhibition of the respective peptidases.
We present here an efficient solution synthesis of a novel type
of pseudopeptide mimicking the sequences Nle-Ala(Gly) or Nle-
Ala(Gly)-Val with all the examples containing the phosphonate
analogue of norleucine at the N-terminus. These compounds may
represent potential inhibitors of methionine or leucine aminopep-
tidases. The proposed pseudopeptide sequences should fulfill the
structural requirements of methionine aminopeptidases Nle or
Met at P1 and a small aliphatic residue, such as Ala or Gly, in the
P01 position. The C-terminal Val at the P02 position was chosen based
on our recent results with statine pseudopeptides as inhibitors of
methionine aminopeptidases.9
In the present work, we modified the previously published
methodology for the preparation of phosphonopeptides described
by Campagne et al.10 The first step of our approach was the
synthesis of the protected phosphonate analogue of norleucine 4
(Scheme 1). (R,S)-Diphenyl 1-(3-phenylthioureido)pentanephospho-
nate 1 was synthesized from valeraldehyde, triphenyl phosphite,
and N-phenylthiourea according to the procedure described by
Stec et al.11 This was converted to (R,S)-1-aminopentanephosphon-
ic acid 2 by refluxing in concentrated hydrochloric acid followed by
treatment with propylene oxide. Reaction of 2 with benzyl chloro-
formate afforded the Z-protected phosphonate, and heating this
free acid with 2 equiv of N,N0-diisopropyl-O-benzylisourea12 in a
mixture of benzene and DMF (1:5) gave the corresponding dibenz-
yl ester 3.13 The key intermediate 4 was obtained in high yield after
base-catalyzed hydrolysis14 of 3.
The above-mentioned N-CBz-protected phosphonate monoester
4 was used as a starting material for the synthesis of a series of
phosphodipeptides and phosphonotripeptides 5–12 (Scheme 2).
O
S
a
O
P(OPh)3
P
OPh
H2N
NHPh
OPh
PhHN
NH
S
1
O
P
O
O
P
OH
b
e
P
OH
c,d
OBn
OBn
NH
OH
OBn
NH
BnO
NH2
BnO
O
4
O
3
2
Scheme 1. Reagents, conditions, and yields: (a) AcOH, 80 °C, 3 h (81%); (b) 35% HCl and AcOH, reflux for 20 h, then 1,2-epoxypropane, ethanol (58%); (c) benzyl chlorofor-
mate, Na2CO3, water, and dioxane, 0 °C, 2 h then at rt overnight (88%); (d) N,N0-diisopropyl-O-benzylisourea, benzene, and DMF, 80 °C, 8 h (75%); (e) DABCO, toluene, 80 °C,
8 h (92%).
* Corresponding author. Tel.: +420 220183441; fax: +420 220183571.
ˇ
E-mail address: jiracek@uochb.cas.cz (J. Jirácek).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.028

J. Pícha et al. / Tetrahedron Letters 49 (2008) 4366–4368
4367
R
R
H
O
H
O
O
OBn
b
OH
a
P
O
P
O
OBn
NH
O
OH
BnO
NH2
5a, R = H
5b, R = CH3
6a, R = H
6b
O
, R = CH3
R
H
O
R
O
P
H
O
OCH3
OCH3
O
c
d
P
O
OBn
NH
OH
O
BnO
NH2
7a, R = H
8a, R = H
8b
O
7b
, R = CH3
, R = CH3
4
R
H
R
H
O
O
P
O
NH2
NH2
O
e
P
O
f
OBn
NH
O
OH
BnO
NH2
9a, R = H
9b
10a, R = H
O
, R = CH3
10b
, R = CH3
O
O
R
R
H
O
H
O
H
N
H
N
O
P
O
P
O
OBn
h
O
OH
g
OBn
NH
OH
NH2
BnO
12a, R = H
12b
11a, R = H
O
, R = CH3
11b
, R = CH3
Scheme 2. Reagents, conditions, and yields: (a) benzyl glycolate or benzyl (S)-lactate, BOP, TEA, DMF, rt, overnight, R = H (88%), R = CH3 (86%); (b) 10% Pd/H2, methanol, rt,
overnight, R = H (70%), R = CH3 (69%); (c) methyl glycolate or methyl (S)-lactate, BOP, TEA, DMF, rt, overnight, R = H (85%), R = CH3 (82%); (d) 10% Pd/H2, methanol, rt,
overnight, R = H (78%), R = CH3 (73%); (e) glycolamide or (S)-lactamide, BOP, TEA, DMF, rt, overnight, R = H (74%), R = CH3 (70%); (f) 10% Pd/H2, methanol, rt, overnight, R = H
(77%), R = CH3 (64%); (g) HOCH2CONHCH(S-iPr)COOBn or HOCH(S–CH3)CONHCH(S-iPr)COOBn, BOP, TEA, DMF, rt, overnight, R = H (70%), R = CH3 (72%); (h) 10% Pd/H2,
methanol, rt, overnight, R = H (65%), R = CH3 (56%).
Compound 4 was esterified easily with the benzyl ester, methyl
of the Czech Republic (to J.J.) and by Research Project Z4 055 0506
of the Academy of Sciences of the Czech Republic.
ester or amide forms of glycolic or L-lactic acids using the activat-
ing agent BOP10 to give the mixed diesters 5a, 5b, 7a, 7b, 9a, and 9b
as outlined in Scheme 2. To obtain compounds 11a and 11b, pre-
cursor 4 was reacted with the previously prepared15 dipeptides
References and notes
1. Dive, V.; Georgiadis, D.; Matziari, M.; Makaritis, A.; Beau, F.; Cuniasse, P.;
Yiotakis, A. Cell. Mol. Life Sci. 2004, 61, 2010.
composed of benzyl L-valine and glycolic or L-lactic acid. All the
mixed diester precursors were fully deprotected by hydrogenoly-
sis. After HPLC purifications, we obtained target compounds 6a,
6b, 8a, 8b, 10a, 10b, 12a, and 12b. All the intermediates and final
products gave correct spectra. As examples, the NMR spectra for
compounds 12a and 12b are given.16
The synthetic route presented for phosphonate pseudopeptides
is convenient, mainly for masking the amino and hydroxy groups
with a non-polar protecting group, which permits easy work-up
of the intermediates. Condensation of 4 with esters or amides of
glycolic and lactic acid proceeds without sensitivity to steric hin-
drance, and the final step of the synthesis enables the complete re-
moval of the protecting groups under mild conditions. At present,
we are investigating the application of the N-Fmoc-protected
derivatives of 6a and 6b as building blocks for solid-phase peptide
synthesis, providing a tool for the development of phosphonic
peptide libraries.
2. Yiotakis, A.; Georgiadis, D.; Matziari, M.; Makaritis, A.; Dive, V. Curr. Org. Chem.
2004, 8, 1135–1158.
3. Kafarski, P.; Lejczak, B. In Aminophosphinic and Aminophosphonic Acids.
Chemistry and Biological Activity; Kukhar, V. P., Hudson, H. R., Eds.; Synthesis
of Phosphono- and Phosphinopeptides; John Wiley & Sons Ltd: Chichester,
2000; pp 173–203.
4. Kafarski, P.; Lejczak, B. In Aminophosphinic and Aminophosphonic Acids,
Chemistry and Biological Activity; Kukhar, V. P., Hudson, H. R., Eds.; The
Biological Activity of Phosphono- and Phosphinopeptides; John Wiley & Sons
Ltd: Chichester, 2000; pp 407–442.
5. Isomura, S.; Ashley, J. A.; Wirsching, P.; Janda, K. D. Bioorg. Med. Chem. Lett.
2002, 12, 861.
6. Collinsova, M.; Jiracek, J. Curr. Med. Chem. 2000, 7, 629.
7. Hanson, J. E.; Kaplan, A. P.; Bartlett, P. A. Biochemistry 1989, 28, 6294.
8. Phillips, M. A.; Kaplan, A. P.; Rutter, W. J.; Bartlett, P. A. Biochemistry 1992, 31,
959.
9. Mitra, S.; Dygas-Holz, A. M.; Jiracek, J.; Zertova, M.; Zakova, L.; Holz, R. C. Anal.
Biochem. 2006, 357, 43.
10. Campagne, J. M.; Coste, J.; Jouin, P. Tetrahedron Lett. 1995, 36, 2079.
11. Kudzin, Z. H.; Stec, W. J. Synthesis 1978, 469.
12. Davies, J. S.; Howe, J.; Lebreton, M. J. Chem. Soc., Perkin Trans. 2 1995, 2335.
13. Hoffmann, M. J. Prakt. Chem. 1988, 330, 820.
14. Hoffmann, M. Phosphorus Sulfur Silicon Relat. Elem. 1998, 134, 109.
15. Toth, I.; Anderson, G. J.; Hussain, R.; Wood, I. P.; Fernandez, E. D.; Ward, P.;
Gibbons, W. A. Tetrahedron 1992, 48, 923.
Acknowledgments
16. Compound 12a: mixture of diastereoisomers ꢀ2:1; only signals of the
major isomer are given: 1H NMR (600 MHz, DMSO): 0.86 (3H, t, J = 7.3, CH3);
0.89 (6H, d, J = 6.8, 2 ꢁ CH3); 1.26 (2H, m, CH2); 1.40 (2H, m, CH2); 1.57 and
1.76 (2H, m, CH2); 2.08 (1H, m, CH); 2.96 (1H, m, N–CH–P); 4.18 (1H, dd, J = 8.2
This project was supported by Grant 203/06/1405 (to J.J.) of the
Grant Agency of the Czech Republic, by Chemical Genetics Consor-
tium No. LC060777 of the Ministry of Education, Youth and Sports

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J. Pícha et al. / Tetrahedron Letters 49 (2008) 4366–4368
and 5.3, N–CH–CO); 4.37 (2H, m, O–CH2–CO); 7.98 (2H, b, NH2); 8.32 (1H, d,
m, CH2); 2.09 (1H, m, CH); 3.08 (1H, m, N–CH–P); 4.14 (1H, dd, J = 8.4 and
5.6, N–CH–CO); 4.84 (1H, dq, J = 6.8 and 7.6, O–CH–CO); 8.08 (2H, b, NH2);
8.18 (1H, d, J = 8.4, NH); 13C NMR (150.9 MHz, DMSO): 13.91 (CH3); 18.19 and
19.32 (2 ꢁ CH3); 20.46 (d, J(C, P) = 5.1, CH3); 22.08 (CH2); 27.77 (d, J(C, P) = 7.8,
CH2); 28.38 (CH2); 30.10 (CH); 47.70 (d, J(C, P) = 147.2, N–CH–P); 57.46 (N–
CH); 70.89 (d, J(C, P) = 6.0, O–CH); 172.29 (d, J(C, P) = 3.2, CO–N); 172.83
J = 8.2, NH); 13C NMR (150.9 MHz, DMSO): 13.98 (CH3); 18.01 and 19.29
(2 ꢁ CH3); 22.20 (CH2); 28.02 (d, J(C, P) = 7.8, CH2); 28.66 (CH2); 30.15 (CH);
48.02 (d, J(C, P) = 143.5, N–CH–P); 57.30 (N–CH); 62.88 (d, J(C, P) = 6.0, O–CH2);
170.91 (CO–N); 172.79 (COOH). HRMS (ESI) calcd for C12H26O6N2P1 [M+H]+
325.1523; found: 325.1525. Compound 12b: 1H NMR (600 MHz, DMSO):
0.85 (3H, t, J = 7.4, CH3); 0.89 (6H, d, J = 6.8, 2 ꢁ CH3); 1.26 (2H, m, CH2);
1.36 and 1.42 (2H, m, CH2); 1.38 (3H, d, J = 6.8, CH3); 1.61 and 1.77 (2H,
(COOH). HRMS (ESI) calcd for
339.1678.
C13H28O6N2P1 [M+H]+ 339.1680; found: