A versatile annulation protocol toward novel constrained phosphinic peptidomimetics

Article abstract of DOI:10.1021/jo071081l

(Chemical Equation Presented) The development of a novel 3-center 2-component annulation reaction between α,ω-carbamoylaldehydes and suitably monoalkylated phosphinic acids is reported. Depending on the starting α,ω-carbamoylaldehyde, diverse phosphinic scaffolds varying in the size of their rigidity element, the nature and stereochemistry of substituents, and the participation of heteroatoms in the azacyclic ring system can be obtained in one synthetic step and in high yield. In addition, this methodology allows the synthesis of Fmoc-protected constrained aminophosphinic acids that can be easily converted to suitable pseudodipeptide building blocks compatible with the requirements of peptide synthesis on the solid phase. Finally, the careful choice of both substituents and protecting groups can provide functionally diverse, orthogonally protected constrained scaffolds for extended derivatization of the target phosphinic peptidomimetic structrures.

Full text of DOI:10.1021/jo071081l

A Versatile Annulation Protocol toward Novel Constrained
Phosphinic Peptidomimetics
Magdalini Nasopoulou,† Dimitris Georgiadis,† Magdalini Matziari,† Vincent Dive,‡ and
Athanasios Yiotakis*,†
Department of Chemistry, Laboratory of Organic Chemistry, UniVersity of Athens, Panepistimiopolis
Zografou 15771, Athens, Greece, and De´partement d’Inge´nierie et d’Etudes des Prote´ines,
CEA, 91191 Gif/YVette Cedex, France
yiotakis@chem.uoa.gr
ReceiVed May 22, 2007
The development of a novel 3-center 2-component annulation reaction between R,ω-carbamoylaldehydes
and suitably monoalkylated phosphinic acids is reported. Depending on the starting R,ω-carbamoylal-
dehyde, diverse phosphinic scaffolds varying in the size of their rigidity element, the nature and
stereochemistry of substituents, and the participation of heteroatoms in the azacyclic ring system can be
obtained in one synthetic step and in high yield. In addition, this methodology allows the synthesis of
Fmoc-protected constrained aminophosphinic acids that can be easily converted to suitable pseudodipeptide
building blocks compatible with the requirements of peptide synthesis on the solid phase. Finally, the
careful choice of both substituents and protecting groups can provide functionally diverse, orthogonally
protected constrained scaffolds for extended derivatization of the target phosphinic peptidomimetic
structrures.
SCHEME 1. Rigidification of Phosphinic Scaffolds
Introduction
Introduction of structural elements conferring rigidity in
bioactive peptides or peptidomimetics can stabilize certain
conformations of the molecule which in turn induce favorable
fit to the complementary active site of an enzyme. This drug
optimization technique can result in conformationally con-
strained derivatives with enhanced activity since entropy penal-
ties upon binding can be minimized.1 The success of the above
concept is reflected by a huge number of publications where
various types of constrained peptidomimetic inhibitors are
synthesized and evaluated.2 Interestingly, due to the lack of any
reliable synthetic technology, no such study has ever been
conducted in the field of phosphinic peptides.3
the proteolytic activity of Zn-metalloproteases and aspartyl
proteases acting as transition state analogues (TSA).4 Moreover,
it has been demonstrated that the structural features of phos-
phinic peptides can allow selective inhibition of structurally and
(2) For reviews, see: (a) Olson, G. L.; Bolin, D. R.; Bonner, M. P.;
Bos, M.; Cook, C. M.; Fry, D. C.; Graves, B. J.; Hatada, M.; Hill, D. E.;
Kahn, M.; Madison, V. S.; Rusiecki, V. K.; Sarabu, R.; Sepinwall, J.;
Vincent, G. P.; Voss, M. E. J. Med. Chem. 1993, 36, 3039. (b) Gante, J.
Angew. Chem., Int. Ed. 1994, 33, 1699. (c) Hanessian, S.; McNaughton-
Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789.
(3) For a molecular dynamics study on phosphinic cyclic hexapeptides,
see: Cuniasse, P.; Raynal, I.; Lecoq, A.; Yiotakis, A.; Dive, V. J. Med.
Chem. 1995, 38, 553.
Phosphinic peptides (Scheme 1) are able to potently inhibit
* To whom correspondence should be addressed. Phone/fax: 0030-210-
7274498.
† University of Athens.
‡ CEA, Gif/Yvette.
(1) Velazquez-Campoy, A.; Luque, I.; Freire, E. Thermochim. Acta 2001,
380, 217.
10.1021/jo071081l CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/23/2007
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J. Org. Chem. 2007, 72, 7222-7228

Constrained Phosphinic Peptidomimetics
functionally related proteases.4d In recent years, we have
exploited this property in targeting specific Zn-proteases and
overcoming the disadvantages of known broad-spectrum
inhibitors.5
SCHEME 2. Synthesis of Pipecolic Acid Phosphinic
Analogue 5a
As part of our ongoing research on selective matrix metal-
loproteinases (MMP) inhibitors, we turned our attention in
setting conformational constraints within phosphinic backbones
(Scheme 1). Hanessian et al. utilized constrained hydroxamates
to demonstrate that tight binding of the P1 position enhances
activity toward MMPs.6 Given the few crystallographic data
concerning P1-S1 interactions we decided to probe the topog-
raphy of MMPs S1 subsite by restricting the mobility of P1
entities of phosphinic inhibitors. We anticipated that optimal
unprimed interactions would favor cooperative effects in the
binding pattern of phosphinic ligands.7 In the case of phosphinic
inhibitors which bear a weak zinc binding group, these effects
are crucial in bringing out subtle differences between MMPs
and increasing selectivity factors7 as we recently pointed out
with the development of a highly selective MMP-12 inhibitor.8
In this article, we report on the development of a novel ring
formation reaction that gives access to the first series of
constrained phosphinic peptidomimetics that vary in the size
of their rigidity element, the nature and stereochemistry of
substituents, and the participation of heteroatoms in the ring.
The products can be directly transformed to Fmoc-protected
building blocks compatible with the requirements of solid-phase
peptide synthesis.9 Moreover, aiming at maximum molecular
diversity in the subsequent construction of phosphinic combi-
natorial libraries from a single precursor, a functionally diverse
and orthogonally protected proline-type scaffold was designed
and synthesized.
in our case, the desired molecular diversity would necessitate
the parallel synthesis of numerous RCM precursors which would
render the method inexpedient. Another attractive solution would
be the intramolecular amidoalkylation of monoalkylated phos-
phinic acids by R,ω-carbamoylaldehydes, a reaction which, quite
interestingly, is completely unexplored.11
To this respect, 5-aminopentanol (1) was converted to
aldehyde 3a, which was slowly added to a solution of phosphinic
acid 411b in AcCl. After stirring for 5 h at room temperature,
evaporation of the volatiles, and aqueous workup, a major
product was isolated in 69% yield, which was found to be the
Fmoc-protected aminophosphinic analogue of pipecolic acid 5a
(Scheme 2).
Prompted by the success of this model reaction we decided
to explore the scope and limitations of the transformation.
Therefore, the reactivity of a number of Fmoc-protected R,ω-
carbamoylaldehydes was screened under condensation condi-
tions.12 The versatility of the method is evident from the
numerous constrained pseudodipeptides that can be obtained
in a single step, depending on the R,ω-carbamoylaldehyde (3)
used (Table 1). In particular, unsubstituted 5-, 6-, or 7-membered
azacycles (5a-c) are efficiently produced (entries a-c), while
smaller rings, such as azetidines 5g, are not favored (entry g).
Moreover, introduction of more heteroatoms that results in
higher heterocycles such as 1,3-oxazinane 5e or piperazine 5f
is feasible. Finally, substituents of specific configuration can
be easily linked to the ring, since the necessary chiral -substi-
tuted R,ω-carbamoylaldehydes can be derived from natural
R-aminoacids (entry d). For example, the necessary aldehyde
3d for the preparation of phosphinic block 5d can be obtained
from L-phenylalanine. In particular, phthalyl-protected alcohol
6, derived from H-(L)Phe-OH according to the literature,13a,b
was oxidized in Swern conditions (Scheme 3).13c After the
Horner-Wadsworth-Emmons reaction of 7 with triethyl
phosphonoacetate,13c nickel boride reduction,5c and acidic depro-
tection, the resulting γ-aminoacid 9 was reduced with borane/
DMS complex, protected with the Fmoc group, and oxidized
toward the final aldehyde by Swern oxidation.
Results and Discussion
A convergent retrosynthetic plan that could afford a large
number of diverse rings requires the annulation to be performed
at a late stage of the synthesis. From the different disconnections
considered, ring closing metathesis (RCM) seemed adequately
general since it has been previously applied to the synthesis of
different types of constrained peptidomimetics.10 Nevertheless,
(4) For reviews, see: (a) Dive, V.; Lucet-Levannier, K.; Georgiadis, D.;
Cotton, J.; Vassiliou, S.; Cuniasse, P.; Yiotakis, A. Biochem. Soc. Trans.
2000, 28, 455. (b) Collinsova´, M.; Jira´cˇek, J. Curr. Med. Chem. 2000, 7,
629. (c) Yiotakis, A.; Georgiadis, D.; Matziari, M.; Makaritis, A.; Dive, V.
Curr. Org. Chem. 2004, 8, 1135. (d) Dive, V.; Georgiadis, D.; Matziari,
M.; Makaritis, A.; Beau, F.; Cuniasse, P.; Yiotakis, A. Cell. Mol. Life Sci.
2004, 61, 2010.
(5) Selected examples: (a) Jira´cˇek, J.; Yiotakis, A.; Vincent, B.; Checler,
F.; Dive, V. J. Biol. Chem. 1996, 271, 19606. (b) Dive, V.; Cotton, J.;
Yiotakis, A.; Michaud, A.; Vassiliou, S.; Jira´cˇek, J.; Vazeux, G.; Chauvet,
M.-T.; Cuniasse, P.; Corvol, P. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 4330.
(c) Georgiadis, D.; Vazeux, G.; Llorens-Cortes, C.; Yiotakis, A.; Dive, V.
Biochemistry 2000, 39, 1152. (d) Georgiadis, D.; Beau, F.; Czarny, B.;
Cotton, J.; Yiotakis, A.; Dive, V. Circ. Res. 2003, 93, 148. (e) Matziari,
M.; Beau, F.; Cuniasse, P.; Dive, V.; Yiotakis, A. J. Med. Chem. 2004, 47,
325.
Notably, the success of this reaction was rather unexpected
since N-alkylated carbamates should be considerably less
(6) Hanessian, S.; MacKay, D. B.; Moitessier, N. J. Med. Chem. 2001,
44, 3074.
(11) For studies on the related 3-component condensation of aldehydes,
carbamates, and phosphinic acids, see: (a) Chen, S.; Coward, J. K.
Tetrahedron Lett. 1996, 37, 4335. (b) Matziari, M.; Yiotakis, A. Org. Lett.
2005, 7, 4049.
(12) See the Supporting Information for the synthesis of the precursor
Fmoc-protected aminoalcohols.
(13) (a) Gage, J.; Evans, D. Organic Syntheses; Wiley: New Nork, 1993;
Collect. Vol. VIII, p 528. (b) Carocci, A.; Catalano, A.; Corbo, F.; Duranti,
A.; Amoroso, R.; Franchini, C.; Lentini, G.; Tortorella, V. Tetrahedron:
Asymmetry 2000, 11, 3619. (c) Damm, W.; Hoffmann, U.; Macko, L.;
Neuburger, M.; Zehnder, M.; Giese, B. Tetrahedron 1994, 50, 7029.
(7) Cuniasse, P.; Devel, L.; Makaritis, A.; Beau, F.; Georgiadis, D.;
Matziari, M.; Yiotakis, A.; Dive, V. Biochimie 2005, 87, 393.
(8) Devel, L.; Rogakos, V.; David, A.; Makaritis, A.; Beau, F.; Cuniasse,
P.; Yiotakis, A.; Dive, V. J. Biol. Chem. 2006, 281, 11152.
(9) Yiotakis, A.; Vassiliou, S.; Jira´cˇek, J.; Dive, V. J. Org. Chem. 1996,
61, 6601.
(10) (a) Fink, B. E.; Kym, P. R.; Katzenellenbogen, J. A. J. Am. Chem.
Soc. 1998, 120, 4334. (b) Hanessian, S.; Sailes, H.; Therrien, E. Tetrahedron
2003, 59, 7047. (c) Manzoni, L.; Colombo, M.; Scolastico, C. Tetrahedron
Lett. 2004, 45, 2623.
J. Org. Chem, Vol. 72, No. 19, 2007 7223

Nasopoulou et al.
SCHEME 3. Synthesis of r,ω-Carbamoylaldehyde 3d
TABLE 1. Yields for the Synthesis of Compounds 5a-g
SCHEME 4. Competition Experiments of 4 with Aldehydes
3a and 3g and CbzNH2
reactive than unsubstituted ones, such as FmocNH2 or CbzNH2.
For example, aldehyde 3g fails to form azetidine 5g but, in
addition, cross-reaction product from intermolecular condensa-
tion (i.e., 11) does not form either (Scheme 4). This implies
that an N-alkylated carbamate, such as 3g, not only fails to
cyclize but it is also unable to participate in a 3-component
condensation, a known reaction for unsubstituted carbamates
(FmocNH2, CbzNH2). The lack of reactivity of N-alkylated
carbamates toward intermolecular 3-component condensation
was further established by the observation that a mixture of
CbzNH2, aldehyde 3g, and phosphinic acid 4 leads exclusively
to 12 (Scheme 4), as was determined by MS analysis of the
crude product. The above observations dictate that the driving
force of the annulation reaction is the cyclization process of
R,ω-carbamoylaldehydes that can only lead to 5-, 6-, and
7-membered azacycles. In another competition experiment, when
a mixture of CbzNH2, aldehyde 3a, and phosphinic acid 4 was
subjected to condensation conditions only the annulation product
5a was produced with no traces of the intermolecular reaction
product 13. This means that when the size of the formed ring
allows stabilization of the intermediate species the reactivity
of N-alkylated carbamates can exceed that of unsubstituted ones.
This cyclization-induced reactivity enhancement of N-alkylated
carbamates also explains why there are no detectable traces of
3-component intermolecular condensation byproducts in all the
examples of Table 1, even under high concentration conditions
(>1.4 M).
From a mechanistic point of view, Soroka has shown that
mixtures of amides, acyl chlorides, and aldehydes form mixed
acylated O,N-hemiaminals which degrade to ylidene carboxa-
mides and react with tervalent phosphorus species.14 In addition,
it is well-known that N-carbamoyl-protected 1,4-aminoaldehydes
tend to cyclize in slightly acidic conditions to N-carbamoyl-
7224 J. Org. Chem., Vol. 72, No. 19, 2007

Constrained Phosphinic Peptidomimetics
SCHEME 5. Putative Reaction Mechanism
FIGURE 1. Proline-type scaffold 19 suitable for diversification.
SCHEME 7. Synthesis of Multifunctional Blocks 19 and 25
SCHEME 6. Synthesis of Fmoc-Protected Building Blocks
18a,c
protected 1-hydroxy pyrrolidines.15 A combination of the above
observations leads to the hypothesis that the reactive partners
in the reported intramolecular amidoalkylation are heterocycles
of type 15 and tervalent phosphonites 16, as illustrated in
Scheme 5.
For the condensation products 5 to be incorporated into
peptide backbones by means of Fmoc-synthetic solid-phase
protocol, they should be suitably protected on the hydroxy-
phosphinyl moiety. According to previous reports of our
laboratory, 1-adamantyl (Ad) protection is an excellent choice
for this case.9,16 The conversion of products 5 to the final
phosphinic building blocks 18 can be performed in 4 steps,
according to our previously described protocol.17 This includes
protection of the acidic units by the phenacyl (Pac) group,
chemoselective cleavage of the phosphinic Pac-ester, reprotec-
tion of the hydroxyphosphinyl group with the 1-Ad group, and
reductive cleavage of the carboxylic Pac-ester. These transfor-
mations proceeded smoothly, as is shown in Scheme 6 for the
cases of 5a and 5c.
side chains, as we have described before,18 or lead to triazole
analogues by means of “click” chemistry.19 Furthermore, the
azacycle of 19 (Figure 1) bears an additional carboxyl group
that can facilitate the reliable probing of the S1 subsite of MMPs,
unaffected by any side chain flexibility. Elongation of N and C
peptide extremities is also possible in solution and on the solid
phase.9 Finally, the synthetic requirements of molecule 19, and
peptide derivatives thereof, tolerate the presence of the conve-
nient adamantyl protecting group, which can be easily removed
with TFA at the end of the synthesis.16
The synthesis of target molecule 19 is outlined in Scheme 7.
The right-hand side (21) of compound 19 is directly obtained
by chemoselective Pac protecion of carboxylate 2011b in the
presence of unprotected phosphinic acid, in 63% yield (Scheme
7). For the construction of the left-hand side, the L-glutamic
acid derivative 22 is protected with a Βoc group20 and the lateral
carboxylate is selectively reduced by DIBAL-H.21 The removal
of the Boc group and the condensation was performed in a one-
pot procedure by slowly adding a solution of 23 in TFA/AcOH/
AcCl 1/1/5 into a solution of 21 in AcCl (Scheme 7). Mild
The versatility of the reported methodology allows the
introduction of additional functional groups on the phosphinic
scaffold as well as the orthogonal protection of the resulting
blocks, thus expanding diversification possibilities and widening
the scope of our strategy. Such an approach can serve as a
valuable tool for medicinally oriented chemistry where the
generation of as many compounds as possible from a single
precursor is an issue of primary importance. For example, a
multifunctional building block that could potentially serve as a
“molecular generator” for our MMPs project is shown in Figure
1. In particular, the presence of a dipolarophilic terminal alkyne
in the P1′ position of 19 can offer an effective entry to isoxazole
(18) Makaritis, A.; Georgiadis, D.; Dive, V.; Yiotakis, A. Chem. Eur. J.
2003, 9, 2079.
(19) For a review, see: Kolb, H. C.; Sharpless, K. B. Drug DiscoVery
Today 2003, 8, 1128.
(20) Xiong, H.; Huang, J.; Ghosh, S. K.; Hsung, R. P. J. Am. Chem.
Soc. 2003, 125, 12694.
(21) Kokotos, G.; Padron, J. M.; Martin, T.; Gibbons, W. A.; Martin,
V. S. J. Org. Chem. 1998, 63, 3741.
(14) Soroka, M. Liebigs Ann. Chem. 1990, 331.
(15) (a) Parr, I. B.; Boehlein, S. K.; Dribben, A. B.; Schuster, S. M.;
Richards, N. G. C. J. Med. Chem. 1996, 39, 2367. (b) Gu, X.; Tang, X.;
Cowell, S.; Ying, J.; Hruby, V. J. Tetrahedron Lett. 2002, 43, 6669.
(16) Georgiadis, D.; Dive, V.; Yiotakis, A. J. Org. Chem. 2001, 66, 6604.
(17) Nasopoulou, M.; Matziari, M.; Dive, V.; Yiotakis, A. J. Org. Chem.
2006, 71, 9525.
J. Org. Chem, Vol. 72, No. 19, 2007 7225

Nasopoulou et al.
2-Benzyl-3-[{1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-
pyrrolidinyl}(hydroxy)phosphoryl]propanoic Acid (5b). Fol-
lowing the general procedure from 4 (410 mg, 1.80 mmol), after
column purification with chloroform/methanol/acetic acid (70:3.5:
3.5) and trituration with petroleum ether 40-60 °C compound 5b
(765 mg, 82%) was obtained as a white foam. TLC Rf 0.39
(chloroform/methanol/acetic acid ) 70:5:5); HPLC tR(1) 39.28,
adamantylation of the resulting pseudodipeptide 24 toward target
19 proceeded in 44% yield (78% based on the recovered
material) with 1-AdBr/Ag2O. Finally, the Pac group can be
successfully removed by reductive cleavage, without affecting
the remaining structural entities. The utilization of multifunc-
tional compounds such as 19 in diversity oriented synthesis
(DOS) toward the development of potent and selective MMP
inhibitors is currently under way and will be reported in due
course.
1
39.94; H NMR (200 MHz, CDCl3) δ 1.53-2.52 (m, 6H), 2.54-
3.30 (m, 3H), 3.32-3.85 (m, 2H), 4.09-4.42 (m, 4H), 7.14-7.81
(m, 13H); 31P NMR (81 MHz, CDCl3) δ 54.32, 54.53, 54.93; ESMS
m/z calcd for C29H31NO6P (M + H)+ 520.2, found 520.4.
2-Benzyl-3-[{1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-
azepanyl}(hydroxy)phosphoryl]propanoic Acid (5c). Following
the general procedure from 4 (230 mg, 1.01 mmol), after column
purification with chloroform/methanol/acetic acid (70:4:4) and
trituration with petroleum ether 40-60 °C compound 5c (447 mg,
81%) was obtained as a white foam. TLC Rf 0.40 (chloroform/
methanol/acetic acid ) 70:5:5); HPLC tR(1) 42.70, 43.18; 1H NMR
(200 MHz, d6-DMSO) δ 0.61-2.18 (m, 11H), 2.33-3.08 (m, 4H),
Conclusions
In conclusion, we have presented a versatile approach for
the preparation of conformationally constrained phosphinic
peptidomimetics that can be suitably functionalized to meet the
requirements of combinatorial chemistry protocols. The pro-
posed strategy is based on a novel annulating condensation
reaction between R,ω-carbamoylaldehydes and suitably monoalky-
lated phosphinic acids. In addition, from a number of competi-
tion experiments we concluded that N-alkylated carbamates are
completely unreactive under amidoalkylation conditions but,
interestingly, this behavior is reversed when stabilization by
cyclization is feasible. Furthermore, the versatility of the
procedure was illustrated by the synthesis of a suitably func-
tionalized phosphinic scaffold for extended derivatization. Given
the well-studied application of lead optimization via constrained
analogues in drug discovery, we believe that the described
methodology will offer new perspectives to the development
of potent and selective protease inhibitors of phosphinic type.
3.23-3.80 (m, 1H), 3.83-4.72 (m, 3H), 7.03-7.95 (m, 13H); 31
P
NMR (81 MHz, d6-DMSO) δ 44.87, 45.05, 45.67, 45.82; ESMS
m/z calcd for C31H33NO6P (M - H)- 546.2, found 546.5.
2-Benzyl-3-[(5S)-5-benzyl-1-[(9H-fluoren-9-ylmethoxy)carbo-
nyl]tetrahydro-1H-pyrrol-3-yl(hydroxy)phosphoryl]propanoic
Acid (5d). Following the general procedure from 4 (57 mg, 0.25
mmol), after column purification with chloroform/methanol/acetic
acid (70:4:4) and trituration with petroleum ether 40-60 °C
compound 5d (122 mg, 80%) was obtained as a white foam. TLC
Rf 0.38 (chloroform/methanol/acetic acid ) 70:5:5); HPLC tR(1)
1
49.18, 49.75; H NMR (200 MHz, CDCl3) δ 1.35-2.38 (m, 7H),
2.40-3.21 (m, 5H), 3.61-4.23 (m, 3H), 4.43-4.85 (m, 2H), 6.57-
7.74 (m, 18H); 31P NMR (81 MHz, CDCl3) δ 54.31, 54.55; ESMS
m/z calcd for C36H37NO6P (M + H)+ 610.2, found 610.2.
2-Benzyl-3-[{4-[(9H-fluoren-9-ylmethoxy)carbonyl]-1,4-oxazi-
nan-3-yl}(hydroxy)phosphoryl]propanoic Acid (5e). Following
the general procedure from 4 (180 mg, 0.79 mmol), after column
purification with chloroform/methanol/acetic acid (70:6:6) and
trituration with petroleum ether 40-60 °C compound 5e (258 mg,
61%) was obtained as a white foam. TLC Rf 0.49 (chloroform/
Experimental Section
General Method for the Synthesis of Compounds of Type 5.
In a solution of DMSO (2.20 mmol) in anhydrous CH2Cl2 (1.0 mL),
oxalyl chloride (2 M in CH2Cl2, 0.61 mL) is slowly added at
-45 °C. The reaction is stirred for 5 min at -45 °C and then a
solution of the appropriate Fmoc-protected amino alcohol (1.00
mmol) in anhydrous CH2Cl2 (6.0 mL) is added dropwise. After
stirring for an additional 15 min at -45 °C, DIPEA (3.00 mmol,
0.5 mL) is introduced to the reaction mixture. At this time, the
reaction mixture is allowed to warm to -30 °C and stirring is
continued for 30 min. Then, the solvent is removed, and the residue
is taken up in AcOEt (30 mL), washed with H2O (10 mL), 5%
NaHCO3 (2 × 10 mL), H2O (3 × 10 mL), and brine, and dried
over Na2SO4. Evaporation of the solvent affords the crude aldehydes
of type 3 in high yield (90-100% by NMR). These products are
unstable to silica gel column purification, so further purification is
not attempted. The crude aldehyde of type 3 is dissolved in AcCl
(0.4 mL) and added to a solution of phosphinic acid 4 (1.00 mmol)
in AcCl (0.3 mL) at 0 °C. The reaction mixture is allowed to stir
at rt for 5 h, the volatiles are removed by evaporation, and the
crude product is purified by column chromatography.
2-Benzyl-3-[{1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-
piperidinyl}(hydroxy)phosphoryl]propanoic Acid (5a). Follow-
ing the general procedure from 4 (320 mg, 1.40 mmol), after column
purification with chloroform/methanol/acetic acid (70:4:4) and
trituration with petroleum ether 40-60 °C compound 5a (516 mg,
69%) was obtained as a white foam. TLC Rf 0.38 (chloroform/
methanol/acetic acid ) 70:5:5); HPLC tR(1) 41.11, 41.42;22 1H
NMR (200 MHz, CDCl3) δ 1.44-2.19 (m, 8H), 2.42-3.85 (m,
4H), 3.99-4.67 (m, 5H), 7.10-7.82 (m, 13H); 31P NMR (81 MHz,
CDCl3) δ 55.98, 56.63, 57.23; ESMS m/z calcd for C30H33NO6-
PNa (M + Na)+ 556.2, found 556.4.
1
methanol/acetic acid ) 70:20:10); HPLC tR(1) 36.34, 36.89; H
NMR (200 MHz, d6-DMSO) δ 1.38-1.75 (m, 1H), 1.78-2.12 (m,
1H), 2.63-3.08 (m, 3H), 3.10-3.85 (m, 6H), 3.90-4.57 (m, 4H),
7.12-7.91 (m, 13H); 31P NMR (81 MHz, d6-DMSO) δ 43.13,
43.75; ESMS m/z calcd for C29H31NO7P (M + H)+ 536.2, found
536.2.
2-Benzyl-3-[{1,4-bis[(9H-fluoren-9-ylmethoxy)carbonyl]-2-
piperazinyl}(hydroxy)phosphoryl]propanoic Acid (5f). Follow-
ing the general procedure from 4 (165 mg, 0.72 mmol), after column
purification with chloroform/methanol/acetic acid (70:6:6) and
trituration with petroleum ether 40-60 °C compound 5f (285 mg,
52%) was obtained as a white foam. TLC Rf 0.52 (chloroform/
methanol/acetic acid ) 70:5:5); HPLC tR(3) 39.21; 1H NMR (200
MHz, d6-DMSO) δ 1.21-1.79 (m, 1H), 1.81-2.16 (m, 1H), 2.57-
3.08 (m, 5H), 3.22-4.11 (m, 4H), 4.12-4.55 (m, 7H), 7.12-7.89
(m, 21H); 31P NMR (81 MHz, d6-DMSO) δ 43.62, 44.32, 44.40;
ESMS m/z calcd for C44H42N2O8P (M + H)+ 757.3, found 757.1.
(2S)-2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpro-
panal (7). To a solution of DMSO (855 mg, 10.9 mmol) in
anhydrous CH2Cl2 (7 mL) is slowly added oxalyl chloride (2 M in
CH2Cl2, 1.02 mL) at -45 °C. The reaction is stirred for 5 min at
-45 °C and then a solution of the phthalyl-protected amino alcohol
6 (1.4 g, 4.97 mmol) in anhydrous CH2Cl2 (5.6 mL) is added
dropwise. After stirring for an additional 15 min, DIPEA (1.93 g,
14.9 mmol) is introduced to the reaction mixture. At this point, the
reaction mixture is allowed to warm to -30 °C and stirred for an
additional 30 min. Then, the solvent is removed, and the residue is
taken up in AcOEt (100 mL), washed with H2O (40 mL), 10%
Na2CO3 (2 × 40 mL), H2O (3 × 40 mL), and brine, and dried
over Na2SO4. Evaporation of the solvent affords the pure aldehyde
(22) See the Supporting Information for HPLC experimental conditions.
7226 J. Org. Chem., Vol. 72, No. 19, 2007

Constrained Phosphinic Peptidomimetics
7 (1.36 g, 98%) as a white solid; TLC Rf 0.55 (chloroform/methanol
) 95:5); H NMR (200 MHz, CDCl3) δ 3.31 (dd, J ) 10.4, 14.3
washed with brine, and dried over Na2SO4. Evaporation of the
solvent and purification by column chromatography with chloroform/
methanol ) 98:2 afforded pure Fmoc-protected amino alcohol 10
(150 mg, 42%) as a white solid; TLC Rf 0.25 (chloroform/methanol
) 95:5); HPLC tR(3) 25.13; 1H NMR (200 MHz, CDCl3) δ 1.24-
1.74 (m, 4H), 2.77 (br d, J ) 6.4 Hz, 2H), 3.41-3.72 (m, 2H),
3.76-4.09 (m, 1H), 4.16-4.73 (m, 3H), 4.81-4.96 (m, 1H), 7.12-
7.82 (m, 13H); ESMS m/z calcd for C26H27NO3Na (M + Na)+
424.2, found 424.2.
General Method for the Synthesis of Compounds of Type
17. Phosphinic acid of type 5 (1.00 mmol) is dissolved in AcOEt
(1 mL), then cooled at 0 °C, and PacBr (4.00 mmol) is added,
followed by Et3N (4.00 mmol). After being stirred at room
temperature for 24 h the reaction mixture is diluted with AcOEt
(30 mL), washed with 1 M HCl (10 mL) and brine, and dried over
Na2SO4. Evaporation of the solvent and purification by column
chromatography, using chloroform/methanol ) 98:2 as eluent,
affords the pure Pac-diester as white foams, after trituration with
petroleum ether 40-60 °C. The above diester (1.00 mmol) is
dissolved in CH2Cl2 (1.6 mL), and TFA (6.4 mL) is added. The
reaction mixture is allowed to stir at room temperature and the
progress of the reaction is followed by TLC (reaction time: 5-24
h). Compounds of type 17 were obtained after evaporation of the
solvent and purification of the residue by column.
2-Benzyl-3-oxo-3-(2-oxo-2-phenylethoxy)propyl{1-[(9H-fluo-
ren-9-ylmethoxy)carbonyl]-2-piperidinyl}phosphinic Acid (17a).
Following the general procedure from 5a (300 mg, 0.56 mmol),
after column purification with chloroform/methanol/acetic acid (70:
2:2) and trituration with petroleum ether 40-60 °C compound 17a
(256 mg, 70%) was obtained as a white foam. TLC Rf 0.53
(chloroform/methanol/acetic acid ) 70:5:5); HPLC tR(2) 43.21; 1H
NMR (200 MHz, CDCl3) δ 1.43-2.52 (m, 8H), 2.89-3.06 (m,
1H), 3.07-3.35 (m, 3H), 3.98-4.79 (m, 5H), 5.04-5.44 (m, 2H),
7.09-7.81 (m, 18H); 31P NMR (81 MHz, CDCl3) δ 56.85, 57.53,
58.11; ESMS m/z calcd for C38H38NO7PNa (M + Na)+ 674.2, found
674.3.
1
Hz, 1H), 3.55 (dd, J ) 5.4, 14.3 Hz, 1H), 4.96 (dd, J ) 5.4, 10.4
Hz, 1H), 7.06-7.17 (m, 5H), 7.65-7.79 (m, 4H), 9.72 (s, 1H);
ESMS m/z calcd for C17H14NO3 (M + H)+ 280.1, found 280.1.
Ethyl (4R)-4-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-phe-
nylpentanoate (8). To a solution of triethyl phosphonoacetate (835
mg, 3.72 mmol) in anhydrous THF (3 mL) is added a solution of
tBuOK (418 mg, 3.72 mmol) in anhydrous THF (20 mL) at 0 °C
in one portion. The mixture is stirred at room temperature for 1 h.
Then, a solution of the phthalyl-protected amino aldehyde 7 (1.30
g, 4.65 mmol) in anhydrous THF (7 mL) is introduced slowly to
the reaction mixture at 0 °C. The mixture is stirred at room
temperature for an additional 2 h. The reaction is quenched by the
addition of 5% Na2CO3 (30 mL). The mixture is extracted with
Et2O (3 × 40 mL) and the combined organic phase is dried over
Na2SO4 and concentrated in vacuo. The crude product is purified
by column chromatography (eluent: petroleum ether 40-60 °C:
Et2O ) 2:1) to afford 1.40 g of a mixture of E and Z isomers. The
product is dissolved in THF (16 mL) and MeOH (10 mL) and NiCl2·
6H2O (2.85 g, 12 mmol) is added. The resulting mixture is cooled
at -30 °C and NaBH4 (757 mg, 20.00 mmol) is added portionwise
for 30 min. Then, the mixture is stirred at -30 °C for 10 min.
After the end of the reaction, the mixture is evaporated and the
residue is partitioned with AcOEt (30 mL) and 1 M HCl (20 mL).
The organic phase is separated, washed with H2O (10 mL), and
dried over Na2SO4. The crude product is purified by column
chromatography (eluent: petroleum ether 40-60 °C/Et2O ) 4:1)
to afford compound 8 (1.25 g, 89%) as a colorless oil. TLC Rf
0.33 (petroleum ether 40-60°/Et2O ) 2:1); [R]20 -117.7 (c 1.0,
D
1
CHCl3); H NMR (200 MHz, CDCl3) δ 1.17 (t, J ) 7.3 Hz, 3H),
2.06-2.21 (m, 1H), 2.28 (t, J ) 7.2 Hz, 2H), 2.42-2.60 (m, 1H),
3.12 (dd, J ) 6.6, 13.9 Hz, 1H), 3.34 (dd, J ) 10.3, 13.9 Hz, 1H),
4.02 (q, J ) 7.3 Hz, 2H), 4.45-4.60 (m, 1H), 7.06-7.27 (m, 5H),
7.60-7.74 (m, 4H); ESMS m/z calcd for C21H22NO4 (M + H)+
352.2, found 352.3; HRMS (ES) m/z calcd for C21H22NO4 (M +
H)+ 352.1549, found 352.1528.
2-Benzyl-3-oxo-3-(2-oxo-2-phenylethoxy)propyl{1-[(9H-fluo-
ren-9-ylmethoxy)carbonyl]-2-azepanyl}phosphinic Acid (17c).
Following the general procedure from 5c (260 mg, 0.47 mmol),
after column purification with chloroform/methanol/acetic acid (70:
2:2) and trituration with petroleum ether 40-60 °C compound 17c
(262 mg, 83%) was obtained as a white foam. TLC Rf 0.59 (CHCl3:
MeOH:AcOH ) 70:5:5); HPLC tR(3) 38.57, 39.23; 1H NMR (200
MHz, CDCl3) δ 1.15-2.37 (m, 10H), 2.92-3.36 (m, 4H), 3.53-
3.82 (m, 2H), 4.05-4.66 (m, 3H), 5.13-5.32 (m, 2H), 7.03-7.95
(m, 18H); 31P NMR (81 MHz, CDCl3) δ 55.67, 55.89, 55.58, 56.40;
ESMS m/z calcd for C39H41NO7P (M + H)+ 666.3, found 666.2.
General Method for the Synthesis of Compounds of Type
18. To a refluxing solution of a phosphinic ester of type 17 (1.00
mmol) and 1-adamantyl bromide (1.20 mmol) in CHCl3 (20 mL)
is added silver(I) oxide (1.20 mmol) portionwise over 1 h. After
the solution is refluxed overnight, the solvent is removed in vacuo
and the residue is taken up in Et2O (30 mL) and filtered through a
pad of Celite. The filtrate is evaporated and the residue is purified
by column chromatography with petroleum ether 40-60 °C:AcOEt
) 1:2 to afford the protected product as white foams. To a solution
of the resulting phosphinic diester (1.00 mmol) in MeOH:DMF
(4:1) (17 mL) are added AcOH(35.00 mmol) and magnesium
turnings (17.00 mmol). After being stirred for 4 h at room
temperature the reaction mixture is filtered. The filtrate is concen-
trated in vacuo and the residue is diluted with CH2Cl2 (40 mL),
washed with 1 M HCl (15 mL) and brine, and dried over Na2SO4.
Compounds of type 18 were obtained after evaporation of the
solvent and purification of the residue by column. 3-((1-Adaman-
tyloxy){1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-piperidinyl}-
phosphoryl)-2-benzylpropanoic acid (18a). Following the general
procedure from 17a (180 mg, 0.28 mmol), after column purification
with chloroform/methanol ) 98:2 and trituration with petroleum
ether 40-60 °C compound 18a (129 mg, 70%) was obtained as a
(4R)-4-Amino-5-phenylpentanoic acid (9). A solution of com-
pound 8 (400 mg, 1.14 mmol) in dioxane (2 mL) and 6 M HCl (15
mL) is refluxed for 15 h. After cooling to room temperature, the
mixture is washed with AcOEt (3 × 30 mL). The aqueous phase
is concentrated in vacuo to afford the product 9 (210 mg, 95%) as
a white solid. TLC Rf 0.26 (chloroform/methanol/acetic acid ) 70:
20:10); [R]20 -29.1 (c 1.0, 3 M HCl) {lit.23 [R]20 -28.2 (c 1.0,
D
D
3.4 M HCl)}; 1H NMR (200 MHz, CD3OD) δ 1.75-1.90 (m, 2H),
2.39 (br t, J ) 7.3 Hz, 2H), 2.86 (br d, J ) 6.6 Hz, 2H), 3.42-
3.63 (m, 1H), 7.18-7.34 (m, 5H); ESMS m/z calcd for C11H16NO2
(M + H)+ 194.2, found 194.2.
9H-Fluoren-9-ylmethyl N-[(1R)-1-benzyl-4-hydroxybutyl]car-
bamate (10). To a mixture of compound 9 (170 mg, 0.8 mmol) in
anhydrous THF (8 mL) is added borane dimethyl sulfide complex
(2 M in THF, 2.20 mL) at 70 °C. The mixture is refluxed for 12 h.
At this point, an additional quantity of borane dimethyl sulfide
complex (2 M in THF, 2.20 mL) is added and the reaction is
continued for 3 h. After cooling to room temperature the excess of
borane is quenched by the slow addition of 2.8 mL of a 1:1 THF:
H2O solution followed by 4 M NaOH (9.8 mL). The resulting two-
phase mixture is heated at reflux for 1 h, cooled at room
temperature, and filtered through a coarse fritted funnel. The filtrate
is extracted with CH2Cl2 (3 × 20 mL), dried over Na2SO4, and
concentrated in vacuo to afford the crude aminoalcohol, which was
diluted in dioxane (0.5 mL) and 10% Na2CO3 (3 mL). The mixture
is cooled to 0 °C and a solution of Fmoc-Cl (1.32 mmol, 341 mg)
in dioxane (1.5 mL) is slowly added. The mixture is stirred
vigorously at room temperature overnight. Then, AcOEt (30 mL)
and 1 M HCl (15 mL) are added, and the organic layer is separated,
(23) Buchschacher, P.; Cassal, J. M.; Fu¨rst, A.; Meier, W. HelV. Chim.
Acta 1977, 60, 2747.
J. Org. Chem, Vol. 72, No. 19, 2007 7227

Nasopoulou et al.
1
white foam. TLC Rf ) 0.24 (chloroform/methanol ) 95:5); H
M HCl (2 × 20 mL). The organic phase is dried over Na2SO4 and
concentrated in vacuo. The crude product is purified by column
chromatography with chloroform/methanol/acetic acid ) 70:4:4 to
afford compound 24 (500 mg, 41%) as a colorless oil; TLC Rf 0.37
(chloroform/methanol/acetic acid ) 70:5:5); HPLC tR(1) 35.90; 1H
NMR (200 MHz, CDCl3) δ 1.94-2.80 (m, 9H), 3.01-3.83 (m,
4H), 4.02-4.55 (m, 2H), 4.99-5.50 (m, 4H), 7.10-8.16 (m, 10H);
31P NMR (81 MHz, CDCl3) δ 54.16, 54.25, 54.82, 55.31; ESMS
m/z calcd for C28H30NO9PNa (M + Na)+ 578.2, found 578.3.
1-Benzyl 2-Methyl (2S)-5-((1-adamantyloxy){2-[(2-oxo-2-phe-
nylethoxy)carbonyl]-4-pentynyl}phosphoryl)tetrahydro-1H-pyr-
role-1,2-dicarboxylate (19). To a refluxing solution of compound
24 (230 mg, 0.41mmol) and silver(I) oxide (145 mg, 0.82 mmol)
in CHCl3 (8.6 mL) is added 1-adamantyl bromide(106 mg, 0.49
mmol) portionwise over 1 h. After the solution is refluxed for 3 h,
an excess of 1-AdBr (106 mg, 0.49 mmol) is added and the mixture
is stirred for 24 h in room temperature. Then, the solvent is removed
in vacuo. AcOEt (30 mL) and 1 M HCl (30 mL) are added and the
organic layer is separated and washed with 5% NaHCO3 (2 × 10
mL) (102 mg of the starting material was recovered from the
aqueous phase after acidification and extraction). The solvent is
evaporated and the residue is purified by column chromatography,
using a gradient eluent (petroleum ether 40-60 °C/AcOEt ) 7:3
f AcOEt), yielding the pure product 19 (124 mg, 44%; 78% based
on the recovered material) as a colorless oil. TLC Rf 0.70 (CHCl3:
NMR (200 MHz, CDCl3) δ 1.39-2.26 (m, 23H), 2.53-3.53 (m,
3H), 3.87-4.77 (m, 5H), 7.11-7.78 (m, 13H); 31P NMR (81 MHz,
CDCl3) δ 49.2, 50.32, 51.5, 52.00; ESMS m/z calcd for C40H47-
NO6P (M+H)+ 668.3, found 668.3; HRMS (ES) m/z calcd for
C40H47NO6P (M+H)+ 668.3141, found 668.3148.
3-((1-Adamantyloxy){1-[(9H-fluoren-9-ylmethoxy)carbonyl]-
2-azepanyl}phosphoryl)-2-benzylpropanoic Acid (18c). Follow-
ing the general procedure from 17c (145 mg, 0.22 mmol), after
column purification with chloroform/methanol ) 98:2 and tritu-
ration with petroleum ether 40-60 °C compound 18c (105 mg,
71%) was obtained as a white foam. TLC Rf 0.27 (chloroform/
1
methanol ) 95:5); H NMR (200 MHz, CDCl3) δ 1.31-2.45 (m,
25H), 2.46-3.37 (m, 5H), 3.39-3.86 (m, 1H), 4.00-4.72 (m, 3H),
7.13-8.01 (m, 13H); 31P NMR (81 MHz, CDCl3) δ 49.18, 49.37,
49.79, 51.11, 51.26, 51.94, 52.06, 52.41; ESMS m/z calcd for
C41H49NO6P (M + H)+ 682.3, found 682.4. HRMS (ES) m/z calcd
for C41H49NO6P (M + H)+ 682.3298, found 682.3290.
2-[(2-Oxo-2-phenylethoxy)carbonyl]-4-pentynylphosphinic Acid
(21). Compound 20 (1.00 g, 5.68 mmol)11b is dissolved in AcOEt
(60 mL), then cooled at 0 °C and Et3N (1.15 g, 11.00 mmol) is
added, followed by PacBr(1.02 g, 5.1 mmol). After the solution
was stirred at room temperature for 6 h the solvent is removed in
vacuo. The residue is taken up in 5% NaHCO3 (60 mL) and
extracted with Et2O (2 × 20 mL). The aqueous phase is acidified
with 3 M HCl to pH ∼1. This aqueous solution is extracted with
AcOEt (3 × 50 mL), and the combined organic layers are dried
over Na2SO4. Evaporation of the solvent affords compound 14 (1.05
g, 55%) as a colorless oil. TLC Rf 0.19 (chloroform/methanol/acetic
acid ) 70:20:10); HPLC tR(1) 19.90; 1H NMR (200 MHz, CDCl3)
δ 2.11 (t, J ) 1.6 Hz, 1H), 2.22-2.89 (m, 5H), 3.06-3.41 (m,
1H), 5.21-5.45 (m, 2H), 7.31 (d, J ) 573.4 Hz, 1H), 7.25-7.88
(m, 5H); 31P NMR (81 MHz, CDCl3) δ 35.73; ESMS m/z calcd
for C14H14O5P (M - H)- 293.1, found 293.3.
1
MeOH ) 95:5); H NMR (200 MHz, CDCl3) δ 1.41-1.60 (m,
6H), 1.70-2.20 (m, 15H), 2.21-2.79 (m, 5H), 3.30-3.78 (m, 3H),
4.10-4.43 (m, 2H), 4.96-5.57 (m, 4H), 7.09-7.96 (m, 10H); 31
P
NMR (81 MHz, CDCl3) δ 45.46, 45.67, 47.32, 47.67, 47.98, 48.12,
48.71; ESMS m/z calcd for C38H45NO9P (M + H)+ 690.3, found
690.2; HRMS (ES) m/z calcd for C38H45NO9P (M + H)+ 690.2832,
found 690.2828.
2-({(1-Adamantyloxy)[(5S)-1-[(benzyloxy)carbonyl]-5-(meth-
oxycarbonyl)tetrahydro-1H-pyrrol-2-yl]phosphoryl}methyl)-4-
pentynoic Acid (25). To a solution of compound 19 (200 mg, 0.29
mmol) in MeOH:DMF (4:1) (5 mL) are added AcOH (609 mg,
10.15 mmol) and magnesium turnings (120 mg, 4.93 mmol). After
the solution was stirred for 4 h at room temperature, CHCl3 (20
mL) and 1 M HCl (20 mL) were added. The organic layer is
separated, washed with brine, and dried over Na2SO4 and the solvent
is removed in vacuo. The crude product is purified by column
chromatography with a gradient eluent (chloroform f chloroform/
methanol ) 95:5), yielding the pure product 25 (113 mg, 68%) as
a colorless oil; TLC Rf 0.49 (CHCl3:MeOH ) 95:5); 1H NMR (200
MHz, CDCl3) δ 1.40-3.17 (m, 25H), 3.42-3.80 (m, 3H), 4.01-
4.52 (m, 2H), 4.83-5.18 (m, 2H), 7.02-7.58 (m, 5H); 31P NMR
(81 MHz, CDCl3) δ 46.74, 47.45, 49.56, 50.06, 50.62, 50,90, 51.31,
52.63, 53.12, 53.91, 55.34; ESMS m/z calcd for C30H39NO8P (M
+ H)+ 572.2, found 572.3; HRMS (ES) m/z calcd for C30H39NO8P
(M + H)+ 572.2413, found 572.2416.
Methyl (2S)-2-{[(Benzyloxy)carbonyl](tert-butoxycarbonyl)-
amino}-5-oxopentanoate (23). To a stirring solution of dimethyl
(2S)-2-{[(benzyloxy)carbonyl](tert-butoxycarbonyl)amino}-
pentanedioate (22)20 (2.00 g, 4.88 mmol) in dry ether (48.8 mL) is
added DIBAL-H (1 M in CH2Cl2, 5.37 mL) at -78 °C. The reaction
is stirred for 10 min before being quenched with H2O (0.62 mL).
The mixture is stirred for an additional 30 min, dried over Na2-
SO4, and filtered through a pad of Celite. The solvent is removed
and the crude residue is purified by column chromatography
(eluent: petroleum ether 40-60 °C/Et2O ) 3:1) to afford compound
22 (1.22 g, 66%) as a colorless oil. TLC Rf 0.46 (petroleum ether
1
40-60 °C/Et2O ) 1:2); [R]20 -32.4 (c 1.0, CHCl3); H NMR
D
(200 MHz, CDCl3) δ 1.40 (s, 9H), 2.04-2.25 (m, 1H), 2.40-2.64
(m, 3H), 3.59 (s, 3H), 4.95 (dd, J ) 4.6, 9.2 Hz, 1H), 5.18 (s, 2H),
7.25-7.51 (m, 5H), 9.71 (s, 1H); ESMS m/z calcd for C19H26NO7
(M + H)+ 380.2, found 380.1; HRMS (ES) m/z calcd for C19H26-
NO7 (M + H)+ 380.1709, found 380.1690.
Acknowledgment. This work was supported by funds from
the University of Athens and from the European Commission
(FP5RDT, QLK3-CT02-02136 and FP6RDT, LSHC-CT-2003-
503297).
(5S)-1-[(Benzyloxy)carbonyl]-5-(methoxycarbonyl)tetrahydro-
1H-pyrrol-2-yl{2-[(2-oxo-2-phenylethoxy)carbonyl]-4-pentynyl}-
phosphinic Acid (24). To a solution of compound 23 (84 mg, 2.21
mmol) in AcOH (3.3 mL) is added TFA (3.3 mL). The mixture is
stirred at room temperature for 30 min. At the end of that period,
AcCl (16 mL) is added and the solution is cooled at 0 °C. Then, a
solution of compound 21 (651 mg, 2.21 mmol) in AcCl (19 mL) is
slowly introduced to the reaction mixture. After the solution was
stirred at room temperature for 5 h, the solvents are evaporated
and the residue is diluted with AcOEt (50 mL) and washed with 1
Supporting Information Available: Copies of NMR spectra
and HPLC profiles, 13C NMR data, and experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO071081L
7228 J. Org. Chem., Vol. 72, No. 19, 2007