Active methylene phosphinic peptides: A new diversification approach

Article abstract of DOI:10.1021/ol060575m

Simple, rapid, and efficient methods for P₁′ diversification of phosphinic peptides have been developed, employing alkylation and Knoevenagel-type condensation reactions with active methylene phosphinic scaffolds, thus leading to a wide variety

Full text of DOI:10.1021/ol060575m

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2317-2319
Active Methylene Phosphinic Peptides:
A New Diversification Approach
Magdalini Matziari, Magdalini Nasopoulou, and Athanasios Yiotakis*
UniVersity of Athens, Department of Chemistry, Laboratory of Organic Chemistry,
Panepistimiopolis Zografou 15771, Athens, Greece
yiotakis@chem.uoa.gr
Received March 8, 2006
ABSTRACT
Simple, rapid, and efficient methods for P1′ diversification of phosphinic peptides have been developed, employing alkylation and Knoevenagel-
type condensation reactions with active methylene phosphinic scaffolds, thus leading to a wide variety of diversified phosphinic and
dehydrophosphinic peptides.
We have recently reported synthetic strategies focused on
the post-modification of phosphinopeptidic precursors, which
can give access to a wide variety of diversified structures.
Thus, diversification of phosphinic di- or tripeptides that bear
a dehydrolanine residue1 at the P1′ position2 provided potent
and selective cysteine-analogue inhibitors of MMP-11,3 and
a propargyl glycine analogue at the same position allowed
the identification of potent isoxazole-containing phosphi-
nopeptidic inhibitors of MMP-13 and -14.4 Most recently,
selective isoxazole phosphinic inhibitors of MMP-12 were
identified, using combinatorial chemistry.5
phosphinic peptide chemistry is the synthesis of the Pheψ-
[P(O)(OH)CH2]Arg dipeptide isostere.7
In this Letter we report a new and efficient strategy for
diversification of phosphinic peptides, using â-phosphinoyl
malonates of type 3 (Scheme 1), namely active methylene
phosphinic scaffolds, which give access to a wide variety of
P1′-substituted phosphinic peptides, through alkylation and
subsequent decarboxylation (compounds of type 7, Scheme
4). Alternatively, building blocks 3 can be submitted to
Knoevenagel-type condensation reactions, providing dehy-
drophosphinic peptides of type 4 (Scheme 3). Such com-
pounds are of great interest, as useful intermediates for
enantioselective hydrogenation. Most importantly compounds
4 are useful in their own right, as metalloprotease inhibitors
that exhibit a preference for dehydro substrates at the P1′
position, such as renal dipeptidase.8 Actually, P1′ dehydro-
phosphinic inhibitors have been synthesized9 and evaluated,10
exhibiting inhibitory potencies in the low nanomolar range.
Active methylene compounds have been widely used in
organic synthesis as highly versatile reagents for carbon-
carbon bond formation.6 A useful example of their use in
(1) Matziari, M.; Georgiadis, D.; Dive, V.; Yiotakis, A. Org. Lett. 2001,
3, 659.
(2) Schechter, I.; Berger, A. Biochem. Biophys. Res. Commun. 1967, 27,
157.
(3) Matziari, M.; Beau, F.; Cuniasse, P.; Dive, V.; Yiotakis, A. J. Med.
Chem. 2004, 47, 325.
(4) Makaritis, A.; Georgiadis, D.; Dive, V.; Yiotakis, A. Chem. Eur. J.
2003, 9, 2079.
(5) Devel, L.; Rogakos, V.; David, A.; Makaritis, A.; Beau, F.; Cuniasse,
F.; Yiotakis, A.; Dive, V.; J. Biol. Chem. 2006, in press.
(6) Trost, B. M. In ComprehensiVe Organic Synthesis; Tietze, L., Beifuss,
U., Eds.; Pergamon Press: New York, 1991; Vol. 2, pp 341-388.
(7) Kende, A. S.; Dong, H.-Q.; Liu, X.; Ebetino, F. H. Tetrahedron Lett.
2002, 43, 4973.
10.1021/ol060575m CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/05/2006

Scheme 1. Synthesis of Active Methylene Phosphinic Peptide
Scaffolds 3
Scheme 2. Selective Protection and Deprotection Conditions
for Blocks 3e-h
Methylenemalonates 2 (Scheme 1), serving as the Michael
acceptors, were synthesized by a Knoevenagel-type conden-
sation of HCHO with malonate esters, using Cu(OAc)2 as
catalyst (reactions not shown).11 Both HMDS (using
1,1,1,3,3,3-hexamethyldisilazane) and TMS (chlorotrimeth-
ylsilane) activation of 112 were applied, providing the active
methylene phosphinic scaffolds of type 3. Yields, protecting
groups, and side chains are shown in Table 1.
Phosphinic pseudodipeptide 3g′, namely the S isomer at
the P1 position, was subjected to Knoevenagel-type conden-
sations with aldehydes (Scheme 3), leading to variously P1′
Scheme 3. Knoevenagel Type Condensation of 3g′ with
Aldehydes
Table 1. Yields, Protecting Groups, and Side Chains of Blocks
3
entry
R1
R2
R3
R4
yields (%)
3a
3a
3a′
3b
3c
3d
PhCH2
PhCH2
(S) PhCH2
PhCH2
PhCH2
Cbz
Cbz
Cbz
Boc
Cbz
Cbz
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
But
Et
77a
69b
74a,c
58a
62a
51a
diversified dehydrophosphinic peptides of type 4 in yields
shown in Table 2. Aromatic and aliphatic aldehydes react
readily with 3g′, though ketones do not, as expected on the
basis of their reduced reactivity and increased steric hin-
drance.
(CH3)2CH
a HMDS activation. b TMS activation. c S stereochemistry at the P1
position.
Scheme 4. Alkylation of 3e with Alkylbromides
Selective protection and deprotection conditions of phos-
phinoyl malonates 3a and 3c (Scheme 2) lead to various
useful intermediates. Diethyl ester 3a can be converted to
diacid 3g by saponification or to ethyl ester 3f under milder
conditions. 3c provides 3f and 3h under acidic and basic
treatment, respectively. Fully protected pseudodipeptidic
block 3e is afforded by 3a, using 1-AdBr. These building
blocks can be used accordingly, depending on the require-
ments of the particular synthetic plan.
(8) Barrett, A. J.; Rawlings, N. D.; Woessner, J. F. In Handbook of
Proteolytic Enzymes; Hooper, N. M., Ed.; Elsevier: London, UK, 2004;
pp 994-997.
(9) Gurulingappa, H.; Buckhaults, P.; Kumar, S. K.; Kinzler, K. W.;
Vogelstein, B.; Khan, S. R. Tetrahedron Lett. 2003, 44, 1871.
(10) Gurulingappa, H.; Buckhaults, P.; Kinzler, K. W.; Vogelstein, B.;
Khan, S. R. Biorg. Med. Chem. Lett. 2004, 14, 3531.
(11) Takagi, Y.; Asahara, T. J. Chem. Soc. Jpn. 1953, 56, 901.
(12) Baylis, E. K.; Campbell, C. D.; Dingwall, J. D. J. Chem. Soc., Perkin
Trans. 1 1984, 2845.
2318
Org. Lett., Vol. 8, No. 11, 2006

Figure 1. HPLC chromatogram and 31P NMR of compound 4d.
The E/Z ratio depends on the aldehyde used, varying from
the exclusive formation of the one isomer (4b) to a nearly
1/1 ratio (4d), as indicated by RP-HPLC analyses and 31P
NMR. Separation of the two isomers of 4d can be achieved
by RP-HPLC as shown in Figure 1.
mentioning that the synthesis of 7a with previously reported
synthetic strategies16 provided an overall yield of 6.5%,
whereas the method introduced herein provides the same
compound in 54% overall yield.
In summary we have described here a new diversification
synthetic strategy of phosphinic peptide precursors of metal-
loprotease inhibitors, via Knoevenagel-type condensation and
alkylation of active methylene phosphinic scaffolds. Subtle
modifications within the structure of phosphinic blocks can
give rise to potent but mostly selective inhibitors of zinc-
metalloproteases. These modifications can be conveniently
and efficiently achieved by employing the strategy outlined
herein.
Table 2. Yields and Side Chains of Compounds 4
entry
R1′
yields (%)
E/Z ratio13
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
Ph
Ph(CH2)2
PhCH2OCH2
(CH3)2CHCH2
4-imidazole
p-chlorophenyl
p-benzoic(OBut)
p-benzoic
55
66
57
55
62
75
53
56
71
100:0
67:33
56:44
54:46
77:23
100:0
100:0
100:0
Acknowledgment. We thank Dr. Maria Halabalaki for
the 2D-NMR measurements. This work was supported in
part by the European Commission (FP5RDT, QLK3-CT02-
02136 and FP6RDT, LSHC-CT-2003-503297), by funds
from the Laboratory of Organic Chemistry and Special
Account for Research Grants of National Athens University
(NKUA).
Asymmetric reduction of 4a was attempted with rhodium
catalysts.14 In the best case Rh(COD)2OTf was used with
the chiral ligand (S,S)-DuPHOS,15 at 55 psi, providing the
hydrogenated product in excellent yield (91%), but in poor
diastereomeric excess (22%). Further experiments are under
way.
Supporting Information Available: Detailed experi-
mental procedures, spectroscopic and analytical data for all
compounds, and copies of HPLC chromatograms for com-
pounds 4 and 7. This material is available free of charge via
the Internet at http://pubs.acs.org.
Alternatively,7 alkylation of 3e with alkylbromides leads
to variously diversified phosphinic blocks. It is worth
OL060575M
(15) Rh(COD)2OTf: bis-(1,5-cyclooctadiene)rhodium(I) trifluoromethane-
sulfonate. DuPHOS: (+)-1,2-bis[(2S,5S)-2,5-diethylphospholanobenzene.
(16) Vassiliou, S.; Mucha, A.; Cuniasse, P.; Georgiadis, D.; Lucet-
Levannier, K.; Beau, F.; Kannan, R.; Murphy, G.; Knauper, V.; Rio, M.
C.; Basset, P.; Yiotakis, A.; Dive, V. J. Med. Chem., 1999, 42, 2610.
(13) Schoen W. R.; Parsons W. H. Tetrahedron Lett. 1988, 41, 5201,
and based on COSY, NOESY, and HMQC NMR measurements.
(14) Berg, M.; Minnaard, A. J.; Schudde, E. P.; Esch. J.; de Vries, A.
H.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539.
Org. Lett., Vol. 8, No. 11, 2006
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