Novel polyaminocarboxylate chelates derived from 3-aroylcoumarins

Article abstract of DOI:10.1016/S0040-4020(01)00168-5

We have devised efficient reaction pathways to attach aminopolycarboxylate subunits to the 3-aroylcoumarin chromophore. Two series of compounds were thus prepared in which the chelating arms were directly bonded to the coumarin ring (series A) or to the 3

Full text of DOI:10.1016/S0040-4020(01)00168-5

TETRAHEDRON
Pergamon
Tetrahedron 57 42001) 3105±3116
Novel polyaminocarboxylate chelates derived from
3-aroylcoumarins
p
Ernesto Brunet, Marõa Teresa Alonso, Olga Juanes, Oscar Velasco and
Â
Juan Carlos Rodrõguez-Ubis
Â
p
  Â
Departamento de Quõmica, Organica C-1, Facultad de Ciencias, Universidad Autonoma de Madrid, 28049 Madrid, Spain
Received 24 October 2000; revised 14 December 2000; accepted 5 February 2001
AbstractÐWe have devised ef®cient reaction pathways to attach aminopolycarboxylate subunits to the 3-aroylcoumarin chromophore. Two
series of compounds were thus prepared in which the chelating arms were directly bonded to the coumarin ring 4series A) or to the 3-aroyl
moiety 4series B). The corresponding Eu4III) and Tb4III) chelates were easily formed and their photophysical properties measured. In all the
cases, lanthanide emission lifetimes were in the range of ms. Unfortunately, quantum yields were relatively low. Measurement of T1 states
gave too low range of values to sensitize Tb4III). In fact, the metal emission of Tb4III) chelates of series A was not observed. However, series
B was able to sensitize both metals. The absorption/energy-transfer/emission mechanisms are discussed. q 2001 Elsevier Science Ltd. All
rights reserved.
1. Introduction
even though these complexes were ¯uorescent, not kineti-
cally stable and the crown ethers did not provide a perfect
isolation to the lanthanide ions from the water molecules.
In turn, subsequent preliminary studies showed that the
replacement of crowns by iminodiacetic subunits conferred
to the corresponding Eu31 and Tb31 coumarin complexes
quite promising properties.8 In this article, we give a full
account of our results concerning complexation and photo-
physical properties of lanthanide complexes of 3-aroyl-
coumarins. The bis-iminodiacetic chelating units for the
lanthanide metals have been attached to either ring A or B
4Fig. 1; series A and B in the sequel) to check the best
relative arrangement between the absorbing coumarin and
the emitting metals.
The luminescence of lanthanide4III) compounds is widely
applied in various ®elds, in particular time-resolved ¯uoro-
immunoassay 4TR-FIA).1 We are currently involved in the
development of Eu31 and Tb31 complexes of organic
ligands bearing suitable chromophoric groups. The high
ef®ciency of lanthanide emission sought in these complexes
obliges to comply with quite stringent structural and photo-
physical features, namely high emission quantum yield,
high kinetic stability, and good water solubility. Among
the various chromophore units tried, 2,6-bis4N-pyrazolyl)-
pyridine was one of the most successful.2 On the other hand,
the use of aminopolycarboxylate subunits appears to be an
excellent choice to achieve effective isolation of the metal
ion from solvent molecules,3 which is the main cause for
undesirable, nonradiative decay of the luminescent level.4
2. Results and discussion
2.1. Synthesis of the ligands
It has been reported in the literature excellent intersystem-
crossing yields for 3-aroylcoumarins that, used as ef®cient
triplet sensitizers,5 may induce lanthanide emission if the
chromophore is provided with adequate chelating moieties.
The single example existing to our knowledge of this approach
is based in a proton-ionizable 7-hydoxycoumarin deriva-
tive,6 whose photophysical results show a low lanthanide-
sensitization ef®ciency. In contrast, in a previous paper, we
reported that crown-ether derived 3-aroylcoumarins resulted
reasonably ef®cient triplet sensitizers of lanthanide emission,7
The 3-aroylcoumarins described in this paper can be
prepared by Claisen condensation of a salicylaldehyde
with an aroylacetate. We thus envisaged the bis-ethoxy-
carbonylmethyl ether of 3,4-dihydroxyacetophenone, easily
obtained from pyrocatechol,9 as a common starting material
for both series A and B of compounds with iminodiacetic
Keywords: polycarboxylates; lanthanide chelates; coumarins; lumines-
cence.
p
Corresponding authors. Tel.: 134-91-397-3926; fax: 134-91-397-3966;
e-mail: ernesto.brunet@uam.es
Figure 1. Rings A and B in coumarin moiety.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020401)00168-5

3106
E. Brunet et al. / Tetrahedron 57 02001) 3105±3116
Scheme 1.
units 4Scheme 1). In the case that iminodiacetates are to be
bound to ring A, the acetyl group can be transformed into
OH by Baeyer±Villiger oxidation and hydrolysis of the
resulting acetate. Subsequent carbonylation and Claisen
reaction with an aroylacetate would yield the corresponding
3-aroylcoumarin with suitable precursors of iminodiacetate
groups in ring A. Series B can be prepared by Claisen reac-
tion of the acetophenone with diethylcarbonate to give the
necessary aroylacetate to be condensed with salycilalde-
hyde.
bonate was Claisen condensed in good yield. The resulting
b-ketoester reacted with substituted salicylaldehydes to
form the coumarins 3. The building of the coumarin nucleus
was performed prior to the transformation of hydroxy
groups in methane sulphonates to avoid undesired reactions
with the b-ketoester enol form. The tetraacid ligands 4a±d
were prepared by substitution of the mesylated coumarin
with di-tert-butyliminodiacetate. The resulting tert-butyl
esters were easily cleaved to the corresponding acids with
tri¯uoroacetic acid in dichloromethane.
The synthesis of series B was accomplished 4Scheme 2) as it
was foreseen. Thus, 3,4-dihydroxyacetophenone was alkyl-
ated with 2equiv. of methylbromoacetate to yield the
diester 1. Ketone protection, reduction of esters, and depro-
tection yielded the diol derivative 2 to which diethyl car-
The anticipated synthesis in Scheme 1 of coumarins of
series A had to be slightly modi®ed 4Scheme 3) since the
Baeyer±Villiger rearrangement occurred with low yield
starting from acetophenone diester 1. We then decided to
start from the aldehyde 5, whose one-step triple LAH
Scheme 2.

E. Brunet et al. / Tetrahedron 57 02001) 3105±3116
3107
Scheme 3.
reduction led to diol 6, which yielded coumarins by Claisen
condensation and lactonization with differently substituted
aroylacetates.5 Finally, the tetra-acid ligands 8a±d were
prepared following the same methodology described as in
Scheme 2.
shift was observed whereas series B suffered a batho-
chromic shift.
The elegant measurement of the excited-state dipole
moments of several 7-aminocoumarins performed very
recently10 indicates that these compounds increase their
polarity when excited. However, albeit the increment was
larger than 6 D in some cases, additional evidence pointed
out that it was a too low change to support true internal
charge-transfer 4ICT) species in the excited state as it was
previously proposed.11 Therefore, the excited state of
coumarins may be explained in simpler terms by a superior
contribution of charge-separated resonance forms as
compared to the ground state 4Scheme 4).
2.2. Lanthanide complexes
The complexes of Eu31 and Tb31 of coumarin series A and
B were prepared in methanol. In all cases spectrometric
titration of ligands with increasing amounts of EuCl3 or
TbCl3 evidenced that complexes with 1:1 stoichiometry
were formed. The UV±Vis spectra of complexes 8a±d
and 4a±d 4Table 1) of Eu31 and Tb31 showed similar,
small shifts as compared to the free ligands but, noticeably,
with a different tendency: for series A, an hypsochromic
The hypsochromic 4series A) and bathochromic 4series B)
shifts observed upon complexation are in excellent agreement
Table 1. Absorption data for ligands of series A and B and their Eu31 and Tb31 complexes 4e l mol21 cm21
)
Coumarin
Series
Ligands
max 4nm)
Lanthanide complexes
Dlmax 4nm) 4complex-ligand)
l
e£103
l
max 4nm)
e£103
Eu31
Tb31
A
A
A
A
B
B
B
B
8a
8b
8c
8d
4a
4b
4c
4d
363
377
381
358
317
343
358
421
9.0
12.2
13.4
10.3
13.6
20.4
19. 5
32.8
359
367
367
357
320
347
359
427
8.0
11.2
12.6
10.0
12.8
19.2
18.5
30.7
±
±
±
±
12.6
19.0
18.5
30.6
24
210
214
21
13
14
11
16
Scheme 4.

3108
E. Brunet et al. / Tetrahedron 57 02001) 3105±3116
Table 2. Fluorescence maxima 4nm), quantum yields 4f) and Stokes' shifts 4nm)
Entry
Free ligands lems 4nm) 4f)
Eu31/Tb31 complexes
ems 4nm) 4f)
Stokes' shifts 4nm)
Eu31/Tb31 complexes
l
Free ligands
1
2
3
4
5
4d
8a
8b
8c
8d
49245%)
490 44%)
482 42%)
479 41%)
456 40.1%)
450 41%)
71
63
123
112
89
482 43%)
481 42%)
463 40.2%)
460 41%)
119
104
82
10293
with this assertion. Thus, the formation of the chelate close
to ring B, where electronic density is likely to increase in the
excited state, should stabilize it displacing the maxima bath-
ochromically. The small effects observed 4average13.5 nm)
excluded the direct interaction of lanthanides with the car-
bonyl groups of the 3-aroylcoumarin system12 but, despite
the remoteness of the metal, the system appears to be quite
sensitive to far off electronic changes.
benzoyl derivative 8d 4entry 5). In contrast, the unsubstitued
compound 8a 4entry 2) and those with electron-withdrawing
groups 48b and c; entries 3 and 4) showed the opposite
tendency, i.e. a complexation-induced increase of their
Stokes' shift, which was higher for the nitro compounds.
A plausible explanation is outlined in Fig. 2.
We mentioned earlier that the these compounds have a rela-
tively high-polar excited state S1 that, upon complexation,
was destabilized or stabilized depending on which series A
or B, respectively, one considers. Additionally, it is reason-
able to assume that at room temperature in a polar,
non-viscous solvent as methanol, solvation interactions are
relatively fast and reach equilibrium prior to emission.14
Therefore, after excitation, the solvent layer surrounding
the ¯uorophore should reorganize in a process named
solvent relaxation that stabilizes the excited state 4Fig. 2).
But in the cases where the S1 state gains stability upon
complexation 4stabilized complex in Fig. 2), the role of
solvation should be somewhat less important compared to
the free ligand, and Stokes' shift should be lower. This is the
situation of 8d and 4d that, upon complexation, exhibited in
absorption 4Table 1), a negligible hypsochromic and the
highest bathochromic shifts, respectively, and a decrease
of Stokes' shifts in ¯uorescence 4Table 2). On the contrary,
destabilization of S1 by complexation 4destabilized complex
in Fig. 2) should intensify the need for solvent relaxation
thus making Stokes' shift larger. This should be the case of
compounds 8a±c where complexation gave rise to fairly
large hypsochromic shifts in absorption 4Table 1) and
increased Stokes' shifts in emission 4Table 2).
On the other hand, the presence of the metal cation close
to ring A, where a positive charge density presumably
develops when the chromophore absorbs light, should
destabilize the excited state shifting the maxima hypso-
chromically. The observed shifts in this case were larger
4average27 nm) suggesting that the phenol oxygens, in
direct conjugation with the coumarin chromophore, might
play a secondary but important role in the chelation of the
metal. The most sensitive compounds to the presence of the
metal in series A and B were those bearing the strongest
electron acceptor 48b, 30-NO2 and 8c, 40-NO2) and electron
donor groups 44d, 7-NMe2), respectively, that should favour
the highest internal charge displacement. This fact rein-
forces our assumption of stabilization 4series B) or destabili-
zation 4series A) of the highly polar excited state by the
lanthanide cation.
2.3. Fluorescence
Coumarins of series B exhibited no ¯uorescence in metha-
nol at room temperature except when the strong electron-
donor diethylamino group is present 44d). On their part,
coumarins 8 4series A) resulted ¯uorescent 48a and b) or
moderately ¯uorescent 48c and d; cf. Table 2). The quantum
yields of ¯uorescence 4f) in series A decreased in the order
8a.8b.8d.8c.
2.4. Luminescence
Table 3 collects the relevant photophysical data in methanol
of the studied Eu4III) and Tb4III) complexes. We measured
in the corresponding Gd4III) complexes,15 the energy of the
Complexation with Eu4III) and Tb4III) changed very little
¯uorescence f values. The presence of the metals, that in
principle provides new pathways for energy transfer, did
not affect drastically the deactivation of the ligand by
¯uorescence.
The variation of Stokes' shifts upon complexation deserves
some comments. This is a complex phenomenon that has
been largely discussed in related compounds.13 Fortunately,
the strong regularities found in our systems allowed us to
venture a relatively simple explanation. Thus, we observed
that compounds with donor substituents at either end of the
3-aroyl-coumarin structure suffered a diminution of their
Stokes' shifts with complexation. This is the case of diethyl-
aminocoumarin 4d 4Table 2, entry 1) and 40-methoxy
Figure 2. Schematic representation of the excited states of ligands and
complexes.

E. Brunet et al. / Tetrahedron 57 02001) 3105±3116
3109
Table 3. Energy of triplet-state level 4T1), excitation maxima 4lexc), lumi-
nescence lifetimes 4t), and quantum yields 4f) of the lanthanide complexes
of the coumarins studied in this work
able for Europium complexes due to the relative ease of
Eu31/Eu21 reduction which drastically degrades quantum
yield of metal emission. Besides, complexes 8a±d exhibited
¯uorescence 4see above). Our data suggests that this radia-
tive pathway competes with the A±ET±E process because
the more ¯uorescent the complex 48a.8b.8d.8c; cf.
Table 2), the lower the metal emission 48a#8b,8d,8c;
cf. Table 3).
Compound
T1 4cm21
)
lexc [lmax] 4nm)
t 4ms)
f 4%)
4a
22 500
Eu31
Tb31
292 [320]
252 [320]
0.73
1.45
0.6
2.0
4b
20 900
20 400
18 100
Eu31
Tb31
348 [347]
278 [347]
0.71
0.98
2.0
0.6
Another fact that is worthy of comment is that terbium
complexes of ligands 4 and the europium complex of 4a
and d 4all belonging to series B), showed excitation
pro®les strongly different from their absorption spectra
4cf. Table 3).17
4c
Eu31
Tb31
359 [359]
280 [359]
0.66
1.15
0.9
0.8
4d
Eu31
Tb31
257 [427]
281 [427]
0.76
1.71
0.4
1.2
Besides concerning triplet states, it is remarkable that
terbium complex of 4d, whose T1 level 418 100 cm21) is
well below the D4 emitting level of the metal, displayed a
5
8a
Eu31
20 000
20 100
19 900
20 400
359 [359]
367 [367]
367 [367]
357 [359]
0.84
0.90
1.01
1.45
,0.1
,0.1
0.7
quantum yield of emission similar or even higher to those of
its counterparts in the series, whose T1 values were higher
and therefore better placed in principle to transfer energy to
the metal. These ®ndings and the long emission lifetimes
observed, specially in the case of Tb4III) complexes, suggest
that, after all, there should be a viable energy-transfer
mechanism from the chromophore to terbium.
8b
Eu31
8c
Eu31
8d
Eu31
0.2
The situation is similar to what we have found in other
coumarin derived ligands.18 Semiempirical calculations at
the AM1 level of 3-benzoylcoumarin showed that the
preferred conformation of the 3-benzoyl moiety is very far
away from planarity with the coumarin nucleus, both in the
ground and the excited states. Should this occur in our
complexes of series B, conjugation between coumarin and
aroyl parts is severed and these chromophores might be
considered as independently absorbing.19 Thus, levels S1
and T1, formally coumarin-centered, were too low lying
and their energy could be transferred to europium but not
at all to terbium. On the other hand, previous results20
showed that 3,4-dioxaacetophenone chromophore behaved
as an excellent sensitizer for terbium. Therefore, in ligands 4
there should be higher levels, formally belonging to the
3-aroyl moiety, adequately located for energy transfer to
terbium. However, this process does not result very ef®cient,
given the low quantum yields measured.
lowest triplet state 4Table 3) in order to shed additional
understanding to the expected absorption/energy-transfer/
emission 4A±ET±E) process between the chromophore
and the metal. This is of paramount importance in our
current task of developing novel, ef®cient lanthanide
chelates.
Except for the Tb4III) complexes of compounds 8a±d,
where no metal emission was observed 4see below), the
studied lanthanide chelates gave the typical well-structured,
narrow-band emission of Eu4III) and Tb4III), centered at
621 and 525 nm, respectively.
It may be seen 4Table 3) that emission lifetimes resulted in
the range of ms what, in principle, makes these complexes
adequate for time-resolved techniques. However, lumines-
cence quantum yields resulted deceptively low. Other
authors and we have found that polycarboxylates provide
the metal with an effective shield towards solvent O±H
oscillators that thermically deactivates it. Therefore, the
low quantum yields should be attributed to some ¯aws in
the A±ET±E process.
3. Conclusion
We have attached aminopolycarboxylate subunits to the
3-aroylcoumarin chromophore following expeditious
synthesis schemes. Reaction of the prepared compounds
with Eu4III) and Tb4III) salts easily led to the corresponding
lanthanide chelates. Metal emission was observed in almost
all cases with long lifetimes in the range of ms. However,
the general poor matching between the measured T1 levels
of the ligands and the metal emitting levels led to
low quantum yields. Various absorption/energy-transfer/
emission mechanisms can be at play, in which the coumarin
and 3-aroyl chromophores could be formally considered as
independently absorbing. Further modi®cation of the
coumarin is in progress, in order to improve the energy
transfer to the lanthanides.
First of all, we referred above that the metal of Tb4III)
complexes 8a±d did not emit at all. This is easily under-
stood in terms of the energy of their triplet state 419900±
20400 cm21), which resulted clearly below the 5D4 emitting
level of Tb31 420490 cm21).16 Unfortunately, although they
were above the emitting 5D0 level of Eu4III) 417400 cm21),
the emission of this metal for 8a±d was very poor 4Table 3).
In previous studies,14 we found that the best quantum yields
were achieved when the triplet state of the chromophore laid
closely above the 5D2 state of Eu4III) 421400 cm21) which is
not the case. Therefore, other non-radiative mechanisms of
energy transfer should be preferred, namely ligand-to-
metal-charge transfer 4LMCT), which is specially favour-

3110
E. Brunet et al. / Tetrahedron 57 02001) 3105±3116
4. Experimental
mixture of the dimesyl derivative 40.5 mmol), 4tert-butoxy-
carbonylmethyl-amino)-acetic acid tert-butyl ester, sodium
iodide 41.50 mmol) and sodium carbonate 45.05 mmol) in
40 mL of acetonitrile was stirred at 1208C 4autoclave) under
argon for 4 days. The solvent was then removed and
the resulting residue ¯ash-chromatographed on silica-gel
4dichloromethane/methanol 95:5). The fractions containing
the tetraester were collected, the solvent removed and in
some cases chromatographed again on silica-gel 4ethyl
acetate/hexane 2:1). The tetraester was obtained as yellow
oil. Yield 28±43%.
4.1. General
1H and 13C NMR: Bruker AC-200 4Departamento de
Â
Quõmica Organica, DCO) and AMX-300 4Servicio Inter-
departamental de Invesigacion, SIdI). M.S.: VG Autospec
Â
Â
spectrometer 4SIdI) in FAB mode 4L-SIMS1). Absorption
spectra: Lambda
6 Perkin±Elmer spectrophotometer
4DCO). Excitation and emission spectra: LS50 Perkin±
Elmer spectro¯uorometer 4DCO). The excitation spectra
were automatically corrected, and the emission spectra
were corrected according to the instrument guidebook.2
Elemental analyses: Perkin±Elmer CHN 2400 automatic
analyzers 4SIdI). All solvents were puri®ed prior to their
use. Lanthanide chlorides and oxides were purchased from
Aldrich and used as received. IUPAC names of compounds
were obtained from ChemWeb: 4http://cwgen.chemweb.-
com/autonom/autonomsearch.html).
4.2.4. Hydrolysis of tetra*tert-butyl)esters. A solution of
tetraester 40.13 mmol) and TFA 40.18 mL) in dichloro-
methane 44 mL) was stirred at rt for 18 h. The solvent
was then removed under vacuo, the residue crushed in
acetone and the resulting white-yellow solid ®ltered off.
Yield 96±98%.
4.3. Compounds series B
4.1.1. Synthesis of Eu*III) and Tb*III) complexes and
luminescence measurements. The complexes were formed
by addition of equimolecular amounts of the corresponding
lanthanide4III) chloride salt in methanol 41022 M) to the
tetraacids solutions 43.2£1025 M). Luminescence para-
meters were analyzed from the same spectroscopic grade
solvent. The emission quantum yields were measured by a
relative method using the Eu31 and Tb31 complexes of
N,N,N0,N0-46,600-aminomethyl-40-phenyl-2,20:60,200-terpyri-
dine) tetrakis 4acetic acid) as a standard and referenced to
quinine sulphate. The expected errors of this measurement
are within 30%. The total luminescence intensities of
complexes were determined by integrating the emissions of
each lanthanide chelate. Emission lifetimes were measured as
previously described and estimated errors are 10%.2
4.3.1. 3-[3,4-Bis-*2-hydroxy-ethoxy)-phenyl]-3-oxo-propi-
onic acid ethyl ester. A suspension of potassium tert-butox-
ide 47.90 g, 66.7 mmol) in diethyl carbonate 480 mL)
was stirred in an ultrasound bath for 5 min. 1-[3,4-Bis-42-
hydroxy-ethoxy)-phenyl]-ethanone17 42 in Scheme 2) was
added 46.00 g, 25 mmol) and the mixture was kept in the
ultrasound bath for 4 h under Ar. Hexane was added
450 mL) and the orange solid was ®ltered and dissolved in
water. HCl 10% was added until pHˆ2. The aqueous layer
was extracted with CH2Cl2 44£100 mL), dried over sodium
sulphate and the solvent evaporated. The product was
obtained as a yellow solid 46.82g), yield 87%; mp 88±
1
898C. H NMR 4CDCl3) 4corresponding to major tautomer
of b-ketoester): d 7.57 4dd, 1H, Jˆ2.1 and 8.8 Hz, H-6); 7.57
4d, 1H, Jˆ2.1 Hz, H-2); 6.93 4d, 1H,Jˆ8.8 Hz, H-5); 4.53
4brs, 2H, CH2OH); 4.21 4q, 2H, Jˆ7.1 Hz, CH3CH2O); 4.18±
4.14 4m, 4H, ArOCH2); 4.02±3.95 4m, 4H, CH2OH); 3.94 4s,
2H, COCH2CO); 1.26 4t, 3H, Jˆ7 Hz, CH3CH2O). 13C NMR
4CDCl3) 4corresponding to major tautomer of b-ketoester): d
190.9 4ArCO); 167.6 4CO2Et); 153.24C-4); 148.1 4C-3);
129.0 4C-1); 123.7 4C-6); 112.3 4C-2); 111.4 4C-5); 70.5;
70.3 4ArOCH2); 61.24CH 3CH2O); 60.5; 60.3 4CH2OH);
45.3 4COCH2CO); 13.8 4CH3CH2O). Anal. calcd for
C15H20O7: C, 57.69; H, 6.41. Found: C, 57.86; H, 6.57.
4.2. General methods
4.2.1. Synthesis of the coumarin ring. The corresponding
salicylaldehyde 40.25 mmol) and the b-ketoester
40.25 mmol) were dissolved in 3 mL of ethanol. Piperidine
43 drops) was added, and the mixture was re¯uxed for 4 h.
Filtration of the cooled mixture yielded the coumarin as
analytically pure crystals. In selected cases, a second crop
of coumarin could be obtained by total evaporation of
solvent followed by column chromatography 4dichoro-
metane/methanol 95:5). Yield 50±80%.
4.3.2. 3-[3,4-Bis-*2-hydroxy-ethoxy)-benzoyl]-chromen-
2-one *3a). It was obtained as a yellow solid following the
general method starting from 3-[3,4-bis-42-hydroxy-
ethoxy)-phenyl]-3-oxo-propionic acid ethyl ester and
salicylaldehyde. Yield 72%; mp 185±1878C. 1H NMR
4CDCl311 drop of CD3OD) d: 8.06 4s, 1H, H-4); 7.73±
4.2.2. Mesylation of coumarins. A solution of the
coumarin-diol derivative 42.08 mmol) and triethylamine
46.25 mmol) in dichloromethane 410 mL) was stirred
under argon in an ice bath. Methanesulfonyl chloride
44.58 mmol) was then slowly added and the resulting
mixture was stirred for 20 min. A portion 410 mL) of
crushed ice was added to the reaction mixture and the
organic layer was washed with 10% hydrochloric acid
43£8 mL), saturated sodium hydrogenocarbonate 43£8 mL)
and brine 43£8 mL), dried over sodium sulphate, and the
solvent evaporated. The residue was crushed in ether and the
resulting white solid ®ltered off. Yield 70±95%.
7.624m, H2 , H-5, H-7); 7.57 4d, 1H,
Jˆ2.1 Hz, H-20);
7.47 4dd, 1H, Jˆ2.1 and 8.5 Hz, H-60); 7.45±7.36 4m, 2H,
H-8, H-6); 6.93 4d, 1H, Jˆ8.5 Hz, H50); 4.20±4.15 4m, 4H,
ArOCH2); 3.99±3.94 4m, 4H, CH2OH). 13C NMR
4CDCl311 drop of CD3OD) d: 190.7 4CO); 159.3 4C-2);
154.7 4C-9); 154.3 4C-40); 148.9 4C-30); 145.24C-4);
133.9 4C-7); 129.5 4C-101C-5); 127.0 4C-10); 126.2 4C-
60); 125.5 4C-6); 118.4 4C-3); 117.0 4C-8); 113.5 4C-20);
111.8 4C-50); 71.0; 70.8 4ArOCH2); 60.6; 60.5 4CH2OH).
Anal. calcd for C20H18O7: C, 64.86; H, 4.86. Found: C,
64.73; H 4.69.
4.2.3. Reaction of mesylated derivatives with *tert-butoxy-
carbonylmethyl-amino)-acetic acid tert-butyl ester. A

E. Brunet et al. / Tetrahedron 57 02001) 3105±3116
3111
4.3.3. 3-[3,4-Bis-*2-hydroxy-ethoxy)-benzoyl]-7-methoxy-
chromen-2-one *3b). It was synthesized as a dark-yellow
solid following the general method starting from 3-[3,4-bis-
42-hydroxy-ethoxy)-phenyl]-3-oxo-propionic acid ethyl
ester and 4-methoxysalicylaldehyde. Yield 86%; mp 195±
1978C. 1H NMR 4CDCl311 drop of CD3OD) d: 8.05 4s, 1H,
H-4); 7.53 4d, 1H, Jˆ2.0 Hz, H-20); 7.53 4d, 1H, Jˆ8.5 Hz,
H-5); 7.46 4dd, 1H, Jˆ2.0 and 8.3 Hz, H-60); 6.95 4dd, 1H,
Jˆ2.3 and 8.5 Hz, H-6); 6.93 4d, 1H, Jˆ8.3 Hz, H-50); 6.91
4d, 1H, Jˆ2.3 Hz, H-8); 4.19±4.15 4m, 4H, ArOCH2); 4.00±
3.93 4m, 4H, CH2OH); 3.94 4s, 3H, OCH3). 13C NMR
4CDCl311 drop of CD3OD) d: 190.6 4CO); 164.4 4C-7);
159.1 4C-2); 156.6 4C-9); 153.4 4C-40); 148.24C-3 0);
145.8 4C-4); 130.24C-5); 192.4 4C-1 0); 125.5 4C-60);
122.5 4C-3); 113.5 4C-6); 113.3 4C-20); 111.6 4C-10);
111.3 4C-50); 100.4 4C-8); 70.6; 70.4 4ArOCH2); 60.2;
60.0 4CH2OH); 55.8 4OCH3). Anal. calcd for C21H20O8: C,
63.00; H, 5.00. Found: C, 62.80; H, 4.86.
84%; mp 166±1688C. 1H NMR 4CDCl311 drop of
CD3OD) d: 8.09 4s, 1H, H-4); 7.73±7.624m, H2 , H-5,
H-7); 7.56 4d, 1H, Jˆ2.0 Hz, H-20); 7.50 4dd, 1H, Jˆ2.0
and 8.4 Hz, H-60); 7.48±7.35 4m, 2H, H-8, H-6); 6.94 4d,
1H, Jˆ8.4 Hz, H50); 4.66±4.60 4m, 4H, CH2OSO2);
4.38±4.33 4m, 4H, ArOCH2); 3.18 4s, 3H, CH3S); 3.16 4s,
3H, CH3S). 13C NMR 4CDCl311 drop of CD3OD) d: 191.7
4CO); 160.3 4C-2); 155.5 4C-9); 153.9 4C-40); 148.8 4C-30);
146.3 4C-4); 134.8 4C-7); 131.0 4C-10); 130.24C-5); 127.7
4C-10); 127.0 4C-60); 126.1 4C-6); 119.1 4C-3); 117.9 4C-8);
0
115.0 4C-20); 113.24C-5 ); 69.0; 68.7; 68.2; 67.9 4CH2O);
38.6 4CH3S). Anal. calcd for C22H22O11S2: C, 50.19; H, 4.18.
Found: C, 49.79; H, 3.98.
4.3.7. Methanesulfonic acid 2-[2-*2-methanesulfonyloxy-
ethoxy)-5-*7-methoxy-2-oxo-2H-chromene-3-carbonyl)-
phenoxy]-ethyl ester. A white solid in 97% yield was
obtained following the general method starting from 3b;
1
mp 142±1438C. H NMR 4CDCl311 drop of CD3OD) d:
4.3.4. 3-[3,4-Bis-*2-hydroxy-ethoxy)-benzoyl]-5,7-
dimethoxy-chromen-2-one *3c). It was prepared as a
yellow solid following the general method starting from
3-[3,4-bis-42-hydroxy-ethoxy)-phenyl]-3-oxo-propionic
acid ethyl ester and 4,6-methoxysalicylaldehyde. Yield
89%; mp 217±2188C. 1H NMR 4CDCl311 drop of
CD3OD) d: 8.34 4s, 1H, H-4); 7.51 4d, 1H, Jˆ2.0 Hz,
H-20); 7.45 4dd, 1H, Jˆ2.0 and 8.5 Hz, H-60); 6.95 4d, 1H,
Jˆ8.5 Hz, H-50); 6.524d, 1H, Jˆ2.1 Hz, H-8); 6.38 4d, 1H,
Jˆ2.1 Hz, H6); 4.20±4.15 4m, 4H, ArOCH2); 3.99±3.93 4m,
4H, CH2OH); 3.93 4s, 6H, OCH3). 13C NMR 4CDCl311
drop of CD3OD) d: 190.3 4CO); 165.8 4C-7); 159.3 4C-2);
8.10 4s, 1H, H-4); 7.56 4d, 1H, Jˆ8.6 Hz, H-5); 7.53 4d, 1H,
Jˆ2.1 Hz, H-20); 7.51 4dd, 1H, Jˆ2.1 and 8.4 Hz, H-60);
6.96 4dd, 1H, Jˆ2.3 and 8.6 Hz, H-6); 6.96 4d, 1H,
Jˆ8.4 Hz, H-50); 6.91 4d, 1H, Jˆ2.3 Hz, H-8); 4.67±4.60
4m, 4H, CH2OSO2); 4.39±4.33 4m, 4H, ArOCH2); 3.95 4s,
3H, OCH3); 3.19 4s, 3H, CH3S); 3.18 4s, 3H, CH3S). 13C
NMR 4CDCl311 drop of CD3OD) d: 190.5 4CO); 164.7
4C-7); 159.1 4C-2); 156.9 4C-9); 152.5 4C-40); 147.6
4C-30); 146.4 4C-4); 130.4 4C-5); 129.8 4C-10); 125.7
4C-60); 122.5 4C-3); 114.1 4C-6); 113.7 4C-20); 112.1
4C-50); 111.7 4C-10); 100.5 4C-8); 67.9; 67.7; 67.0; 66.8
4CH2O); 55.9 4OCH3); 37.6 4CH3S). Anal. calcd for
C23H24O12S2: C, 49.64; H, 4.32. Found: C, 49.41; H, 4.29.
0
158.0 4C-5); 157.3 4C-9); 153.24C-4 ); 148.1 4C-30); 141.7
0
4C-4); 129.5 4C-10); 125.3 4C-60); 119.7 4C-3); 113.24C-2 );
0
70.24ArOCH ); 60.1; 60.0 4CH2OH); 55.7 4OCH3). Anal.
111.24C-5 ); 103.24C-10); 95.0 4C-6); 92.5 4C-8); 70.4;
4.3.8. Methanesulfonic acid 2-[5-*5,7-dimethoxy-2-oxo-
2H-chromene-3-carbonyl)-2-*2-methanesulfonyloxy-
ethoxy)-phenoxy]-ethyl ester. It was synthesized following
the general method from 3c as a white solid in 95% yield;
2
calcd for C22H22O9: C, 61.39; H, 5.12. Found: C, 60.94; H,
5.24.
1
mp 180±1818C. H NMR 4CDCl311 drop of CD3OD) d:
4.3.5. 3-[3,4-Bis-*2-hydroxy-ethoxy)-benzoyl]-7-diethyl-
amino-chromen-2-one *3d). It was obtained as a yellow
solid following the general method starting from 3-[3,4-
bis-42-hydroxy-ethoxy)-phenyl]-3-oxo-propionic acid ethyl
ester and 4-diethylaminosalicylaldehyde. Yield 84%; mp
8.41 4s, 1H, H-4); 7.51 4d, 1H, Jˆ2.0 Hz, H-20); 7.49 4dd,
1H, Jˆ2.0 and 8.4 Hz, H-60); 6.96 4d, 1H, Jˆ8.4 Hz, H-50);
6.51 4d, 1H, Jˆ2.1 Hz, H-8); 6.37 4d, 1H, Jˆ2.1 Hz, H6);
4.67±4.61 4m, 4H, CH2OSO2); 4.39±4.33 4m, 4H,
ArOCH2); 3.93 4s, 6H, OCH3); 3.19 4s, 3H, CH3S); 3.18
4s, 3H, CH3S). 13C NMR 4CDCl311 drop of CD3OD) d:
190.5 4CO); 165.9 4C-7); 159.1 4C-2); 158.1 4C-5); 157.5
4C-9); 152.2 4C-40); 147.4 4C-30); 142.2 4C-4); 130.4 4C-10);
125.5 4C-60); 120.5 4C-3); 114.2 4C-20); 112.1 4C-50); 103.8
4C-10); 95.24C-6); 9.28 4C-8); 67.9; 67.7; 67.1; 66.8
4CH2O); 56.1 4OCH3); 37.8 4CH3S).
1
121±1228C. H NMR 4CDCl311 drop of CD3OD) d: 8.04
4s, 1H, H-4); 7.48 4d, 1H, Jˆ2.0 Hz, H-20); 7.47 4dd, 1H,
Jˆ2.0 and 8.0 Hz, H-60); 7.38 4d, 1H, Jˆ9.0 Hz, H-5); 6.92
4d, 1H, Jˆ8.0 Hz, H-50); 6.66 4dd, 1H, Jˆ2.5 and 9.0 Hz,
H-6); 6.53 4d, 1H, Jˆ2.5 Hz, H-8); 4.19±4.14 4m, 4H,
ArOCH2); 3.99±3.924m, 4H, C H2OH); 3.48 4q, 4H,
Jˆ7.1 Hz, CH3CH2N); 1.26 4t, 6H, Jˆ7.1 Hz, CH3CH2N).
13C NMR 4CDCl311 drop of CD3OD) d: 191.3 4CO); 160.2
4C-7); 157.8 4C-2); 152.9 4C-9); 152.5 4C-40); 147.9 4C-30);
147.3 4C-4); 130.7 4C-5); 130.4 4C-10); 125.0 4C-60); 117.2
4C-3); 113.8 4C-20); 111.4 4C-50); 109.6 4C-6); 107.5 4C-10);
96.6 4C-8); 70.7; 70.4 4ArOCH2); 60.3; 60.1 4CH2OH);
44.9 4CH3CH2N); 12.1 4CH3CH2N). Anal. calcd for
C24H27NO7´0.5H2O: C, 64.00; H, 6.22; N, 3.11. Found: C,
63.69; H, 5.81; N, 3.16.
4.3.9. Methanesulfonic acid 2-[4-*7-diethylamino-2-oxo-
2H-chromene-3-carbonyl)-2-*2-methanesulfonyloxy-
ethoxy)-phenoxy]-ethyl ester. It was prepared from 3d
following the general method. A yellow solid was obtained
in 99% yield; mp 136±1388C. 1H NMR 4CDCl3) d: 8.09 4s,
1H, H-4); 7.49 4dd, 1H, Jˆ1.9 and 8.1 Hz, H-60); 7.47 4d,
1H, Jˆ1.9 Hz, H-20); 7.38 4d, 1H, Jˆ8.9 Hz, H-5); 6.90 4d,
1H, Jˆ8.1 Hz, H-50); 6.64 4dd, 1H, Jˆ2.4 and 8.9 Hz, H-6);
6.51 4d, 1H, Jˆ2.4 Hz, H-8); 4.64±4.58 4m, 4H, CH2OSO2);
4.35±4.31 4m, 4H, ArOCH2); 3.47 4q, 4H, Jˆ7.1 Hz,
CH3CH2N); 3.16 4s, 3H, CH3S); 3.15 4s, 3H, CH3S); 1.25
4t, 6H, Jˆ7.1 Hz, CH3CH2N). 13C NMR 4CDCl3) d: 190.8
4CO); 159.8 4C-7); 157.9 4C-2); 152.1 4C-9); 151.8 4C-40);
4.3.6. Methanesulfonic acid 2-[2-*2-methanesulfonyloxy-
ethoxy)-5-*2-oxo-2H-chromene-3-carbonyl)-phenoxy]-
ethyl ester. It was synthesized from 3a as a white solid
following the general method described above. Yield

3112
E. Brunet et al. / Tetrahedron 57 02001) 3105±3116
147.3 4C-301C-4); 131.3 4C-10); 130.9 4C-5); 125.1 4C-60);
117.8 4C-3); 114.3 4C-20); 112.1 4C-50); 109.9 4C-6); 108.0
4C-10); 97.1 4C-8); 68.1; 67.9; 66.9; 66.7 4CH2O); 45.2
4CH3CH2N); 37.6 4CH3S); 12.3 4CH3CH2N). Anal. calcd
for C26H31NO11S2 C, 52.26; H, 5.19; N, 2.34. Found: C,
52.05; H, 4.95; N, 2.23.
80.9 4CCH3); 68.5; 68.0 4CH2O); 56.9; 56.6 4NCH2CO2);
55.9 4OCH3); 53.1 4CH2CH2N); 28.0 4CCH3). MS4L-
SIMS1): 885.4 4M1H1, 8%); 907.5 4M1Na1, 5%); 661.3
4M1H1244C4H8), 9%); 233.1 4coumarin CO1, 50%).
4.3.13. *{2-[2-[2-*Bis-tert-butoxycarbonylmethyl-amino)-
ethoxy]-5-*7-diethylamino-2-oxo-2H-chromene-3-carbonyl)-
phenoxy]-ethyl}-tert-butoxycarbonylmethyl-amino)-acetic
acid tert-butyl ester. It was synthesized following the
general method starting from the corresponding dimesylated
derivative. Yellow oil, 35% yield. 1H NMR 4CDCl3) d: 7.96
4s, 1H, H-4); 7.45 4d, 1H, Jˆ1.9 Hz, H-20); 7.41 4dd, 1H,
4.3.10. *{2-[2-[2-*Bis-tert-butoxycarbonylmethyl-amino)-
ethoxy]-5-*2-oxo-2H-chromene-3-carbonyl)-phenoxy]-
ethyl}-tert-butoxycarbonylmethyl-amino)-acetic acid
tert-butyl ester. It was synthesized following the general
method starting from the corresponding dimesylated deriva-
1
0
0
tive. Yellow oil, 33% yield. H NMR 4CDCl3) d: 7.96 4s,
Jˆ1.9 and 8.2Hz, H-6 ); 7.34 4d, 1H, Jˆ8.9 Hz, H-5); 6.88
1H, H-4); 7.65±7.57 4m, 2H, H-5, H-7); 7.50 4d, 1H,
Jˆ1.9 Hz, H-20); 7.44±7.29 4m, 3H, H-60, H-8, H-6); 6.89
4d, 1H, Jˆ8.5 Hz, H-50); 4.23±4.13 4m, 4H, ArOCH2); 3.55
4s, 8H, NCH2CO2); 3.22±3.16 4m, 4H, NCH2); 1.43 4s, 36H,
4d, 1H, Jˆ8.2Hz, H-5 ); 6.61 4dd, 1H, Jˆ2.4 and 8.9 Hz,
H-6); 6.51 4d, 1H, Jˆ2.4 Hz, H-8); 4.23±4.13 4m, 4H,
ArOCH2); 3.56 4s, 8H, NCH2CO2); 3.46 4q, 4H, Jˆ7.1 Hz,
CH3CH2N); 3.23±3.17 4m, 4H, NCH2); 1.44 4s, 36H,
CCH3); 1.24 4t, 6H, Jˆ7.1 Hz, CH3CH2N). 13C NMR
t
CCH3). 13C NMR 4CDCl3) d:189.6 4CO); 170.4 4CO2 Bu);
t
158.1 4C-2); 154.2 4C-9); 153.5 4C-40); 148.3 4C-30); 143.9
4C-4); 133.0 4C-7); 128.7 4C-101C-5); 127.0 4C-10); 125.1
4C-60); 124.6 4C-6); 117.9 4C-3); 116.4 4C-8); 112.6 4C-20);
111.1 4C-50); 80.7 4CCH3); 68.0 4CH2O); 56.7;
56.5 4NCH2CO2); 52.9 4CH2CH2N); 27.8 4CCH3).
MS4L-SIMS1): 825.1 4M1H1, 21%); 847.1 4M1Na1,
4%); 601.3 4M1H1244C4H8), 19%); 173.0 4coumarin
CO1, 25%)
4CDCl3) d: 191.1 4ArCO); 170.7 4CO2 Bu); 159.7 4C-7);
157.9 4C-2); 152.8 4C-9); 152.2 4C-40); 148.1 4C-30);
146.7 4C-4); 130.6; 130.3 4C-10, C-5); 124.7 4C-60); 118.5
4C-3); 113.3 4C-20); 111.24C-5 0); 109.4 4C-6); 107.6 4C-10);
96.9 4C-8); 81.0; 80.9 4CCH3); 67.9 4CH2O); 56.8; 56.6
4NCH2CO2); 53.1 4CH2CH2N); 45.0 4CH3CH2N); 28.1
4CCH3); 12.4 4CH3CH2N). MS4L-SIMS1): 896.6 4M1H1,
28%); 918.6 4M1Na1, 9%); 672 .3 4M1H1244C4H8),
27%); 244.1 4coumarin CO1, 80%).
4.3.11. *{2-[2-[2-*Bis-tert-butoxycarbonylmethyl-amino)-
ethoxy]-5-*7-methoxy-2-oxo-2H-chromene-3-carbonyl)-
phenoxy]-ethyl}-tert-butoxycarbonylmethyl-amino)-
acetic acid tert-butyl ester. It was synthesized following the
general method starting from the corresponding dimesylated
derivative. Yellow oil, 30% yield. 1H NMR 4CDCl3) d: 7.98
4s, 1H, H-4); 7.51 4d, 1H, Jˆ8.5 Hz, H-5); 7.49 4d, 1H,
Jˆ1.9 Hz, H-20); 7.43 4dd, 1H, Jˆ1.9 and 8.4 Hz, H-60);
6.90 4d, 1H, Jˆ8.4 Hz, H-50); 6.90 4dd, 1H, Jˆ2.4 and
8.5 Hz, H-6); 6.84 4d, 1H, Jˆ2.4 Hz, H-8); 4.25±4.15 4m,
4H, ArOCH2); 3.91 4s, 3H, OCH3); 3.58 4s, 8H, NCH2CO2);
3.28±3.20 4m, 4H, NCH2); 1.45 4s, 36H, CCH3). 13C NMR
4.3.14. *{2-[2-[2-*Bis-carboxymethyl-amino)-ethoxy]-5-
*2-oxo-2H-chromene-3-carbonyl)-phenoxy]-ethyl}-carboxy-
methyl-amino)-acetic acid *4a). It was synthesized follow-
ing the general method starting from the corresponding tert-
butyl tetraester. Dark-yellow solid, 97% yield; mp
1
162±1648C. H NMR 4DMSO-d6) d: 8.324s, 1H, H-4);
7.85±7.67 4m, 2H, H-5, H-7); 7.56±7.37 4m, 4H, H-20,
H-60, H-8, H-6); 7.05 4d, 1H, Jˆ8.4 Hz, H-50); 4.22±4.10
4m, 4H, ArOCH2); 3.60; 3.58 4s, s, 8H, NCH2CO2);
3.15±3.024m, 4H, NCH ). MS4L-SIMS1): 601.0 4M1H1,
2
6%); 623.0 4M1Na1, 2%); 543.0 44M1H1)2CHCO2H, 1%);
173.0 4coumarin CO1, 6%). Anal. calcd for C28H28N2O13: C,
56.00; H, 4.67; N, 4.67. Found: C, 56.19; H, 4.96; N, 4.86.
t
4CDCl3) d: 190.0 4CO); 170.4 4CO2 Bu); 163.9 4C-7); 158.4
4C-2); 156.4 4C-9); 153.1 4C-40); 148.0 4C-30); 144.9 4C-4);
130.0 4C-5); 129.0 4C-10); 124.8 4C-60); 122.9 4C-3); 113.0
4C-6); 112.6 4C-20); 111.5 4C-50); 110.9 4C-10); 100.3 4C-8);
80.6 4CCH3); 67.7 4CH2O); 56.6; 56.4 4NCH2CO2); 55.6
4OCH3); 52.8 4CH2CH2N); 27.8 4CCH3). MS4L-SIMS1):
855.24M 1H1, 9%); 877.24M 1Na1, 6%); 631.3
4M1H1244C4H8), 10%); 203.1 4coumarin CO1, 45%).
4.3.15. *{2-[2-[2-*Bis-carboxymethyl-amino)-ethoxy]-5-
*7-methoxy-2-oxo-2H-chromene-3-carbonyl)-phenoxy]-
ethyl}-carboxymethyl-amino)-acetic acid *4b). It was
synthesized following the general method starting from
the corresponding tert-butyl tetraester. Dark-yellow solid,
1
96% yield; mp 158±1608C. H NMR 4DMSO-d6) d: 8.27
4.3.12. *{2-[2-[2-*Bis-tert-butoxycarbonylmethyl-amino)-
ethoxy]-5-*5,7-dimethoxy-2-oxo-2H-chromene-3-carbonyl)-
phenoxy]-ethyl}-tert-butoxycarbonylmethyl-amino)-acetic
acid tert-butyl ester. It was synthesized following the general
method starting from corresponding dimesylated derivative.
4s, 1H, H-4); 7.75 4d, 1H, Jˆ8.6 Hz, H-5); 7.48 4dd, 1H,
Jˆ1.8 and 8.3 Hz, H-60); 7.43 4d, 1H, Jˆ1.8 Hz, H-20); 7.08
4d, 1H, Jˆ2.2 Hz, H-8); 7.04 4d, 1H, Jˆ8.3 Hz, H-50); 7.01
4dd, 1H, Jˆ2.2 and 8.6 Hz, H-6); 4.14±4.08 4m, 4H,
ArOCH2); 3.89 4s, 3H, OCH3); 3.54 4s, 8H, NCH2CO2);
3.16±3.05 4m, 4H, NCH2). MS4L-SIMS1): 631.0 4M1H1,
15%); 653.0 4M1Na1, 17%); 573.0 44M1H1)2CHCO2H,
8%); 203.0 4coumarin CO1, 31%). Anal. calcd for
C29H30N2O14: C, 55.24; H, 4.76; N, 4.44. Found: C, 55.02;
H, 4.52; N, 4.10.
1
Yellow oil, 28% yield. H NMR 4CDCl3) d: 8.31 4s, 1H, H-
4); 7.8 4d, 1H, Jˆ2.0 Hz, H-20); 7.41 4dd, 1H, Jˆ2.0 and
8.4 Hz, H-60); 6.89 4d, 1H, Jˆ8.4 Hz, H-50); 6.46 4d, 1H,
Jˆ2.1 Hz, H-8); 6.31 4d, 1H, Jˆ2.1 Hz, H6); 4.24±4.14 4m,
4H, ArOCH2); 3.90 4s, 6H, OCH3); 3.56 4s, 8H, NCH2CO2);
3.23±3.17 4m, 4H, NCH2); 1.44 4s, 36H, CCH3). 13C NMR
4CDCl3) d: 190.4 4CO); 170.6 4CO2tBu); 165.4 4C-7); 158.9
4.3.16. *{2-[2-[2-*Bis-carboxymethyl-amino)-ethoxy]-5-
*5,7-dimethoxy-2-oxo-2H-chromene-3-carbonyl)-phen-
oxy]-ethyl}-carboxymethyl-amino)-acetic acid *4c). It
was synthesized following the general method starting
0
4C-2); 158.0 4C-5); 157.5 4C-9); 153.1 4C-40); 148.24C-3 );
141.0 4C-4); 129.60 4C-10); 124.9 4C-60); 120.8 4C-3); 113.0
4C-20); 111.24C-5 ); 103.4 4C-10); 94.9 4C-6); 92.6 4C-8);

E. Brunet et al. / Tetrahedron 57 02001) 3105±3116
3113
from the corresponding tert-butyl tetraester. Yellow solid,
98% yield; mp 139±1418C. 1H NMR 4DMSO-d6) d: 8.15 4s,
1H, H-4); 7.46±7.35 4m, 2H, H-20, H-60); 7.04 4d, 1H,
Jˆ8.3 Hz, H-50); 6.69 4d, 1H, Jˆ2.0 Hz, H-8); 6.57 4d,
1H, Jˆ2.0 Hz, H-6); 4.17±4.11 4m, 4H, ArOCH2); 3.90
4s, 3H, OCH3); 3.88 4s, 3H, OCH3); 3.61 4s, 8H,
NCH2CO2); 3.16±3.05 4m, 4H, NCH2). MS4L-SIMS1):
661.0 4M1H1, 5%); 683.0 4M1Na1, 3%); 603.0
44M1H1)2CHCO2H, 2%); 233.0 4coumarin CO1, 22%).
Anal. calcd for C30H32N2O15: C, 54.54; H, 4.85; N, 4.24.
Found: C, 54.16; H, 4.57; N, 3.88.
CH3CH2O); 1.30 4t, 3H, Jˆ6.6 Hz, CH3CH2O).
MS4L-SIMS1): 327.1 4M1H1, 100%); 298.1 4M2CHO,
41%)
4.4.3. 3,4-Bis-*2-hydroxy-ethoxy)-phenol. LiAlH4 41 g,
27.6 mmol) was added in small portions to a suspension
of the previous formiate 43 g, 9.2mmol) in 70 mL of dry
THF at 08C. The mixture was stirred for 3 h and after this
period it was added to 2.2 mL of 10% NaOH and heated at
re¯ux for 4 h. The mixture was ®ltered and the salts washed
with water 42£75 mL). The combined layers 4THF and
water) were acidi®ed and extracted with ethyl acetate
43£50 mL). Work-up of the organic layer yielded 1.74 g
4.3.17. *{2-[2-[2-*Bis-carboxymethyl-amino)-ethoxy]-5-
*7-diethylamino-2-oxo-2H-chromene-3-carbonyl)-phen-
oxy]-ethyl}-carboxymethyl-amino)-acetic acid *4d). It
was synthesized following the general method starting
from the corresponding tert-butyl tetraester. Yellow solid,
1
488%) of a brown solid; mp 123±1248C. H NMR 4D20)
d: 6.78 4d, 1H, Jˆ8.4 Hz, H-5); 6.41 4d, 1H, Jˆ2.0 Hz,
H-2); 6.30 4dd, 1H, Jˆ8.4 and 2.0 Hz, H-6); 3.65±3.75
4m, 4H, ArOCH2); 3.90±4.00 4m, 4H, OCH2CH2O). 13C
NMR 4CDCl3/CD3OD, 10%) d: 151.5 4C-1); 149.0 4C-3);
140.7 4C-4); 116.0 4C-2); 106.2 4C-6); 101.8 4C-5); 70.0;
69.9 4ArOCH2); 60.0; 59.9 4CH3CO). MS4EI1): 214.1 4M1,
24%); 170.1 4M12C2H4O, 19%); 126.1 4M12C4H8O2,
100%). Anal. calcd for C10H14O5: C, 56.07; H, 6.59.
Found: C, 55.76; H, 6.86.
1
97% yield; mp 154±1568C. H NMR 4CD3OD) d: 8.16 4s,
1H, H-4); 7.53 4d, 1H, Jˆ8.9 Hz, H-5); 7.524dd, 1H, Jˆ2.2
and 9.0 Hz, H-60); 7.51 4d, 1H, Jˆ2.2 Hz, H-20); 7.11 4d,
1H, Jˆ9.0 Hz, H-50); 6.83 4dd, 1H, Jˆ2.5 and 8.9 Hz, H-6);
6.624d, 1H, Jˆ2.5 Hz, H-8); 4.46±4.42 4m, 4H, ArOCH2);
4.16 4s, 4H, NCH2CO2); 4.11 4s, 4H, NCH2CO2); 3.75±3.70
4m, 4H, NCH2); 3.57 4q, 4H, Jˆ7.1 Hz, CH3CH2N); 1.27 4t,
6H, Jˆ7.1 Hz, CH3CH2N). MS4L-SIMS1): 672.1 4M1H1,
2%); 694.0 4M1Na1, 2%); 614.1 44M1H1)2CHCO2H,
1%); 244.0 4coumarin CO1, 7%). Anal. calcd for
C32H37N3O13´CF3CO2H: C, 51.97; H, 4.84; N, 5.35.
Found: C, 51.52; H, 4.39; N, 4.98.
4.4.4. 2-Hydroxy-4,5-bis-*2-hydroxy-ethoxy)-benzalde-
hyde. A mixture of 3,4-bis42-hydroxyethoxy)phenol 41 g,
4.6 mmol) and hexamethylenetetramine 40.654 g, 4.6 mmol)
in TFA 411 mL) was heated at 908C for 3 h. The mixture
was cooled at rt, water 420 mL) was added and the reaction
heated again for 4 h. The pH was adjusted to 7 with sat.
solution of sodium hydrogencarbonate and the mixture
extracted with ethyl acetate 42£50 mL). The resulting oily
residue after usual work-up of the organic layer was puri®ed
by ¯ash chromatography 4dichloromethane/methanol 95:5)
yielding 0.628 g 455%) of the product as a yellow solid; mp
4.4. Series A
4.4.1. *5-Formyl-2-methoxycarbonylmethoxy-phenoxy)-
acetic acid methyl ester. A mixture of 3,4-dihydroxyben-
zaldehyde 410 g, 72.4 mmol), ethyl bromoacetate 422.6 g,
159.3 mmol) and potassium carbonate 430 g, 217.2 mmol)
in 300 mL of acetone was re¯uxed for 1 h. The salts were
then ®ltered off and washed with dichloromethane. The
®ltrate was washed with water 3£25 mL, dried over sodium
sulphate and the solvent evaporated. The product was
obtained in 81% yield as yellow oil, which solidi®ed on
1
105±1068C. H NMR 4CDCl311 drop of CD3OD) d: 9.70
4s, 1H, HCO); 7.08 4s, 1H, H-2); 6.494s, 1H, H-6); 4.08±
4.19 4m, 4H, ArOCH2); 3.89±4.00 4m, 4H, OCH2CH2O).
13C NMR 4CDCl3/CD3OD, 10%) d: 193.7 4CO);158.7
4C-1); 155.9 4C-3); 141.24C-4); 114.7 4C-6); 113.0 4C-5);
100.3 4C-2); 70.3; 69.8 4ArOCH2); 59.5; 59.1 4CH3CO).
MS4EI1): 242.1 4M1, 60%); 198.1 4M12C2H4O, 41%);
154.0 4M12C4H8O2, 100%). Anal. calcd for C11H14O6: C,
54.54; H, 5.83. Found: C, 53.65; H, 5.91.
1
standing at rt; mp 55±568C. H NMR 4CDCl3) d: 9.84 4s,
1H, HCO); 7.50 4dd, 1H, Jˆ8.4 and 2.0 Hz, H-6), 7.40 4d,
1H, Jˆ2Hz, H-2); 6.93 4d, 1H, Jˆ8.4 Hz, H-5); 4.81; 4.79
4s, 2H, CH2CO); 4.70 4s, 2H, CH2CO); 4.29 4q, 2H,
Jˆ6.6 Hz, CH3CH2O); 1.30 4t, 3H, Jˆ6.6 Hz, CH3CH2O).
MS4L-SIMS1): 311.1 4M1H1, 100%); 136.0 4M2C8H14O4,
51%).
4.4.5. 3-Benzoyl-6,7-bis-*2-hydroxy-ethoxy)-4a,8a-dihydro-
chromen-2-one *7a). It was synthesized following the
general method starting using ethyl benzoylacetate. Yellow
solid, 83% yield; mp 184±1858C. 1H NMR 4CDCl31drop of
CD3OD) d: 8.10 4s, 1H, H-4); 7.90 4d, 2H, Jˆ8.3 Hz, H-20,
H-60); 7.61±7.70 4m, 2H, H-30, H-50); 7.49±7.59 4m, 1H,
H-40); 7.18 4s, 1H, H-5); 6.99 4s, 1H, H-8); 4.18±4.30 4m,
4H, ArOCH2); 4.00±4.11 4m, 4H, OCH2CH2O). 13C NMR
4CDCl3/CD3OD, 10%) d: 192.1 4CO); 159.0 4C-2); 154.5
4C-7); 151.6 4C-9); 146.4 4C-6); 146.0 4C-4); 136.4 4C-10);
133.4 4C-40); 129.4 4C-20, C-60); 128.4 4C-30, C-50); 122.9
4C-3); 111.3 4C-10); 110.9 4C-5); 100.7 4C-8); 71.4; 71.0
4ArOCH2); 60.3; 60.0 4CH2OH). MS4EI1): 370.1 4M1,
69%); 326.1 4M12C2H4O, 15%); 282.1 4M12C4H8O2,
13%); 105 4COPh, 100%).
4.4.2. *5-Formyloxy-2-methoxycarbonylmethoxy-phen-
oxy)-acetic acid methyl ester. To a stirred suspension of
aldehyde 5 418 g, 58.0 mmol) in 100 mL of dichloro-
methane, m-chloroperbenzoic acid was added in small
portions 418.7 g, 87.0 mmol). The mixture was stirred over-
night at rt and ®ltered. The ®ltrate was washed with 10%
solution of sodium hydrogensulphite 42£25 mL), saturated
solution of potassium hydrogencarbonate 43£25 mL) and
brine 42£25 mL). Usual work-up of the organic layer
afforded a red-brown oil which was crushed in cold hexane
yielding 13.4 g 471%) of a red-orange solid; mp 62±638C 1H
NMR 4CDCl3) d: 8.28 4s, 1H, HCO); 6.95 4d, 1H, Jˆ8.4 Hz,
H-5); 6.77 4dd, 1H, Jˆ8.4 and 2.0 Hz, H-6); 6.73 4d, 1H,
Jˆ2 Hz, H-2); 4.71 4s, 2H, CH2CO); 4.29 4q, 2H, Jˆ6.6 Hz,
4.4.6. 6,7-Bis-*2-hydroxy-ethoxy)-3-*3-nitro-benzoyl)-
4a,8a-dihydro-chromen-2-one *7b). It was synthesized

3114
E. Brunet et al. / Tetrahedron 57 02001) 3105±3116
following the general method using ethyl 3-nitrobenzoyl-
acetate. Yellow solid, 95% yield; mp 206±2078C. 1H
NMR 4CDCl311 drop of CD3OD) d: 8.54 4t, 1H,
Jˆ2.0 Hz, H-20); 8.38 4dt, 1H, Jˆ8.3 and 2.0 Hz, H-40);
8.23 4s, 1H, H-4); 8.06 4dt, 2H, Jˆ8.3 and 2.0 Hz, H-60);
7.61 4t, 2H, Jˆ8.3 Hz, H-50); 7.024s, 1H, H-5); 6.89 4s, 1H,
H-8); 4.02±4.16 4m, 4H, ArOCH2); 3.87±3.98 4m, 4H,
OCH2CH2O). 13C NMR 4CDCL3/CD3OD, 10%) d: 190.2
4CO); 159.2 4C-2); 155.4 4C-7); 152.2 4C-9); 148.4 4C-4);
147.9 4C-30); 146.3 4C-6); 138.3 4C-10); 134.6 4C-60); 129.4
4C-5); 127.1 4C-40); 123.8 4C-20); 121.1 4C-3); 111.1 4C-10);
111.0 4C-5); 100.5 4C-8); 71.2; 71.0 4ArOCH2); 60.2; 50.8
4CH2OH). MS4EI1): 415.1 4M1, 78%); 371.1 4M2C2H4O,
14%) 353.1 4M2NO3, 61%); 327.1 4M2C4H8O2, 36%);
205.0 4M2C10H13O2, 30%); 150.0 4NO2Ph1, 100%). Anal.
calcd for C20H17NO9: C, 57.83; H, 4.13; N, 3.37. Found: C,
57.30; H, 4.18; N, 3.34.
Anal. calcd for C22H22O11S2: C, 50.19; H, 4.21; S, 12.18.
Found: C, 49.92; H, 4.19; S, 12,29.
4.4.10. Methanesulfonic acid 2-[7-*2-methanesulfonyl-
oxy-ethoxy)-3-*3-nitro-benzoyl)-2-oxo-4a,8a-dihydro-2H-
chromen-6-yloxy]-ethyl ester. It was synthesized follow-
ing the general method. Yellow solid, 88% yield; mp 141±
1428C. 1H NMR 4CDCl311 drop of CD3OD) d: 8.74 4t, 1H,
Jˆ2.0 Hz, H-20); 8.40 4dt, 1H, Jˆ8.3 and 2.0 Hz, H-40);
8.35 4s, 1H, H-4); 8.19 4dt, 2H, Jˆ8.3 and 2.0 Hz, H-60);
7.74 4t, 2H, Jˆ8.3 Hz, H-50); 7.224s, 1H, H-5); 7.024s, 1H,
H-8); 4.62±4.73 4m, 4H, ArOCH2); 4.35±4.47 4m, 4H,
OCH2CH2O); 3.20 4s, 6H, SO2CH3). 13C NMR 4CDCl3/
CD3OD, 10%) d: 190.0 4CO); 158.7 4C-2); 154.3 4C-7);
152.3 4C-9); 148.0 4C-4); 147.8 4C-30); 145.5 4C-6); 138.2
4C-10); 134.6 4C-60); 129.6 4C-5); 127.4 4C-40); 124.1
4C-20); 122.1 4C-3); 112.6 4C-10); 111.5 4C-5); 101.2 4C-
8); 67.8; 67.6 4ArOCH2); 67.2; 67.0 4CH2OS); 37.6; 37.5
4CH3S). MS4L-SIMS1): 572.1 4M1H1, 42%), 307.1
4M1H122CH2OSO21, 25%); 77.0 4Ph1, 27%). Anal.
calcd for C22H21O13NS2: C, 46.23; H, 3.71; N, 2.45; S,
11.20. Found: C, 46.47; H, 3.92; N, 2.25; S, 11.05.
4.4.7.
6,7-Bis-*2-hydroxy-ethoxy)-3-*4-nitro-benzoyl)-
4a,8a-dihydro-chromen-2-one *7c). It was synthesized
following the general method using ethyl 4-nitrobenzoyl-
acetate. Yellow solid, 94% yield; mp 181±1828C. 1H
NMR 411 drop of CD3OD) d: 8.30 4d, 2H, Jˆ8.4 Hz,
H-30, H-50); 8.29 4s, 1H, H-4); 7.90); 7.94 4d, 2H,
Jˆ8.4 Hz, H-20, H-60); 7.05 4s, 1H, H-5); 6.90 4s, 1H,
H-8); 4.09±4.20 4m, 4H, ArOCH2); 3.91±4.01 4m, 4H,
OCH2CH2O). 13C NMR 4CDCl3) d: 190.9 4CO); 159.1 4C-
2); 155.5 4C-7); 152.3 4C-9); 150.0 4C-10); 148.5 4C-4);
146.4 4C-6); 142.1 4C-40); 129.8 4C-30, C-5); 123.4 4C-6,
C-20); 121.0 4C-3); 111.1 4C-10); 110.9 4C-5); 100.5 4C-8);
71.0; 71.24ArOCH 2); 59.8; 60.1 4CH2OH). MS4EI1): 415.2
4M1, 100%); 371.1 4M2C2H4O, 22%); 353.1 4M12NO3,
77%); 327.1 4M2C4H8O2, 42%); 150.1 4NO2Ph1, 89%).
Anal. calcd for C20H17NO9: C, 57.83; H, 4.13; N, 3.37.
Found: C, 57.95; H, 4.09; N, 3.32.
4.4.11. Methanesulfonic acid 2-[7-*2-methanesulfonyl-
oxy-ethoxy)-3-*4-nitro-benzoyl)-2-oxo-4a,8a-dihydro-2H-
chromen-6-yloxy]-ethyl ester. It was synthesized following
the general method. Yellow solid, 87% yield; mp 170±
1
1718C. H NMR 4CDCl311 drop of CD3OD) d: 8.34 4d,
2H, Jˆ8.4 Hz, H-30, H-50); 8.30 4s, 1H, H-4); 7.98 4d, 2H,
Jˆ8.4 Hz, H-20, H-60); 7.15 4s, 1H, H-5); 6.95 4s, 1H, H-8);
4.62±4.74 4m, 4H, ArOCH2); 4.34±4.45 4m, 4H,
OCH2CH2O); 3.20 4s, 6H, SO2CH3). MS4EI1): 571.1 4M1,
1
9%); 353.1 4M22CH2OSO2, 37%); 150.1 4COPhNO2
,
100%). Anal. calcd for
1
27%); 123.0 4PhNO2
,
C22H21O13NS2: C, 46.23; H, 3.71; N, 2.45, S, 11.20. Found:
C, 45.76; H, 3.63; N, 2.22; S, 10.95.
4.4.8. 6,7-Bis-*2-hydroxy-ethoxy)-3-*4-methoxy-benzoyl)-
4a,8a-dihydro-chromen-2-one *7d). It was synthesized
following the general method using ethyl 4-methoxy-
benzoylacetate. Yellow solid, 83% yield; mp 181±1828C.
1H NMR 4CDCl311 drop of CD3OD) d: 8.00 4s, 1H, H-4);
7.87 4d, 2H, Jˆ8.3 Hz, H-20, H-60); 7.05 4s, 1H, H-5); 6.95
4d, 2H, Jˆ8.3 Hz, H-30, H-50); 6,924s, 1H, H-8); 4.11±4.23
4m, 4H, ArOCH2); 3.95±4.06 4m, 4H, OCH2CH2O); 3.80 4s,
3H, OCH3). 13C NMR 4CDCl3/CD3OD, 10%) d: 189.6
4CO); 162.9 4C-40); 158.4 4C-2); 153.2 4C-7); 150.1 4C-9);
145.0 4C-6); 144.5 4C-4); 130.9 4C-20, C-60); 128.0 4C-10);
122.1 4C-3); 112.6 4C-30, C-50); 110.0 4C-10); 109.9 4C-5);
4.4.12. Methanesulfonic acid 2-[7-*2-methanesulfonyl-
oxy-ethoxy)-3-*4-methoxy-benzoyl)-2-oxo-4a,8a-dihydro-
2H-chromen-6-yloxy]-ethyl ester. It was synthesized
following the general method. Yellow solid, 94% yield;
1
mp 195±1968C. H NMR 4CDCl311 drop of CD3OD) d:
8.024s, 1H, H-4); 7.89 4d, 2H, Jˆ8.3 Hz, H-20, H-60); 7.13
4s, 1H, H-5); 7.00 4d, 2H, Jˆ8.3 Hz, H-30, H-50); 6.99 4s,
1H, H-8); 4.60±4.724m, 4H, ArOCH 2); 4.31±4.44 4m, 4H,
OCH2CH2O); 3.80 4s, 3H, OCH3); 3.10 4s, 6H, SO2CH3).
MS4EI1): 556.1 4M1, 4%); 338.1 4M2CH2OSO2CH3,
43%); 135 4COPhOMe1, 100%). Anal. calcd for
C23H24O12S2: C, 49.63; H, 4.35; S, 11.50. Found: C,
49.40; H, 4.41; S, 11.64.
99.5 4C-8); 70.1; 69.8 4ArOCH2); 59.1; 58.8 4CH2OH); 54.2
4CH3O). MS4EI1): 400.24M 1, 16%); 135 4COPhNO2
1
,
100%). Anal. calcd for C21H20O8: C, 62.98; H, 5.04.
Found: C, 62.88; H, 5.14.
4.4.13.
[*2-{3-Benzoyl-7-[2-*bis-tert-butoxycarbonyl-
methyl-amino)-ethoxy]-2-oxo-4a,8a-dihydro-2H-chromen-
6-yloxy}-ethyl)-tert-butoxycarbonylmethyl-amino]-acetic
acid tert-butyl ester. It was synthesized following the
4.4.9. Methanesulfonic acid 2-[3-benzoyl-7-*2-methane-
sulfonyloxy-ethoxy)-2-oxo-4a,8a-dihydro-2H-chromen-6-
yloxy]-ethyl ester. It was synthesized following the general
method. Yellow solid, 78% yield; mp 189±1908C. 1H NMR
4CDCl311 drop of CD3OD) d: 8.07 4s, 1H, H-4); 7.89 4d,
2H, Jˆ8.3 Hz, H-20, H-60); 7.69±7.78 4m, 2H, H-30, H-50);
7.46±7.43 4m, 1H, H-40); 7.08 4s, 1H, H-5); 6.91 4s, 1H,
H-8); 4.60±4.71 4m, 4H, ArOCH2); 4.30±4.41 4m, 4H,
OCH2CH2O); 3.17 4s, 6H, SO2CH3). MS4L-SIMS1):
527.0 4M1H1, 34%), 307.0 4M1H122CH2OSO21, 17%).
1
general method. Yellow oil, 43% yield. H NMR 4CDCl3)
d: 8.05 4s, 1H, H-4); 7.87 4d, 2H, Jˆ8.3 Hz, H-20, H-60);
7.55±7,64 4m, 2H, H-30, H-50); 7.41±7.51 4m, 1H, H-40);
7.05 4s, 1H, H-5); 6.90 4s, 1H, H-8); 4.14±4.28 4m, 4H,
ArOCH2); 3.57 4s, 8H, NCH2CO2); 3.14±3.28 4m, 4H,
NCH2); 1.44 4s, 36H, CCH3). 13C NMR 4CDCl3) d: 192.1
t
4CO); 170.7 4CO2 Bu); 159.0 4C-2); 154.6 4C-7); 151.6
4C-9); 146.5 4C-6); 146.24C-4); 136.8 4C-1 0); 133.2

E. Brunet et al. / Tetrahedron 57 02001) 3105±3116
3115
4C-40); 129.4 4C-20, C-60); 128.3 4C-30, C-50); 122.8 4C-3);
110.8 4C-10); 110.7 4C-5); 100.4 4C-8); 81.0 4CCH3), 68.9
4CH2O); 57.0; 56.9 4NCH2CO2); 53.0; 52.9 4CH2CH2N);
28.0 4CCH3). MS4L-SIMS1): 825.3 4M1H1, 8%); 160.0
ethyl)-carboxymethyl-amino]-acetic acid *8a). It was
synthesized following the general method. Yellow solid,
98% yield; H NMR 4DMSO-d6) d: 8.31 4s, 1H, H-4);
7.89 4d, 2H, Jˆ8.3 Hz, H-20, H-60); 7.61±7.724m, 2H, H-
30, H-50); 7.58±7.49 4m, 1H, H-40); 7.41 4s, 1H, H-5); 7.19
4s, 1H, H-8); 4.00±4.30 4m, 4H, ArOCH2); 3.5 4s, 8H,
NCH2CO2); 3.00±3.20 4m, 4H, NCH2). High resol. MS:
C28H28N2O13: 600.1591. Found: C28H29N2O13: 601.1678.
1
t
4M1H12PhCO12O4CH2)2N4CH2CO2 Bu)224CH2)2N-
t
4CH2CO2 Bu)2, 100%).
4.4.14. *{2-[7-[2-*Bis-tert-butoxycarbonylmethyl-amino)-
ethoxy]-3-*3-nitro-benzoyl)-2-oxo-4a,8a-dihydro-2H-
chromen-6-yloxy]-ethyl}-tert-butoxycarbonylmethyl-
amino)-acetic acid tert-butyl ester. It was synthesized
4.4.18. *{2-[7-[2-*Bis-carboxymethyl-amino)-ethoxy]-3-
*3-nitro-benzoyl)-2-oxo-4a,8a-dihydro-2H-chromen-6-
yloxy]-ethyl}-carboxymethyl-amino)-acetic acid *8b). It
was synthesized following the general method. Yellow
1
following the general method. Yellow oil, 43% yield. H
NMR 4CDCl3) d: 8.71 4t, 1H, Jˆ2.0 Hz, H-20); 8.41 4dt,
1H, Jˆ8.3 and 2.0 Hz, H-40); 8.28 4s, 1H, H-4); 8.03 4dt,
2H, Jˆ8.3 and 2.0 Hz, H-60); 7.66 4t, 2H, Jˆ8.3 Hz, H-50);
7.11 4s, 1H, H-5); 6.90 4s, 1H, H-8); 4.15±4,30 4m, 4H,
ArOCH2); 3.57 4s, 8H, NCH2CO2); 3.15±3.28 4m, 4H,
NCH2); 1.45 4s, 36H, CCH3). 13C NMR 4CDCl3) d: 190.3
1
solid, 97% yield. H NMR 4DMSO-d6) d: 8.59 4t, 1H,
Jˆ2.0 Hz; H-20); 8.50 4dt, 1H, Jˆ8.3 and 2.0 Hz; H-40);
8.49 4s, 1H, H-4); 8.29 4dt, 2H, Jˆ8.3 and 2.0 Hz, H-60);
7.81 4t, 2H, Jˆ8.3 Hz, H-50); 7.48 4s, 1H, H-5); 7.20 4s, 1H,
H-8); 4.15±4.30 4m, 4H, ArOCH2); 3.59 4s, 8H, NCH2CO2);
3.10±3.20 4m, 4H, NCH2). High resol. MS: C28H27N3O15:
645.1442. Found: C28H28N3O15: 646.1523.
t
4CO); 170.7 4CO2 Bu); 159.1 4C-2); 155.4 4C-7); 152.3
4C-9); 148.5 4C-4); 148.0 4C-30); 146.4 4C-6); 138.6 4C-
10); 134.7 4C-60); 129.4 4C-5); 127.1 4C-40); 124.0 4C-20);
121.1 4C-3); 110.9 4C-10); 110.8 4C-5); 100.4 4C-8); 81.1
4CCH3); 69.0 4CH2O); 57.1; 57.0 4NCH2CO2); 52.9
4CH2CH2N); 28.1 4CCH3)
4.4.19. *{2-[7-[2-*Bis-carboxymethyl-amino)-ethoxy]-3-
*4-nitro-benzoyl)-2-oxo-4a,8a-dihydro-2H-chromen-6-
yloxy]-ethyl}-carboxymethyl-amino)-acetic acid *8c). It
was synthesized following the general method. Yellow
1
solid, 98% yield. H NMR 4DMSO-d6) d: 8.50 4s, 1H,
4.4.15. *{2-[7-[2-*Bis-tert-butoxycarbonylmethyl-amino)-
ethoxy]-3-*4-nitro-benzoyl)-2-oxo-4a,8a-dihydro-2H-
chromen-6-yloxy]-ethyl}-tert-butoxycarbonylmethyl-
amino)-acetic acid tert-butyl ester. It was synthesized
H-4); 8.31 4d, 2H, Jˆ8.5 Hz, H-30, H-50); 8.09 4d, 2H,
Jˆ8.5 Hz, H-20, H-60); 8.49 4s, 1H, H-5); 7.20 4s, 1H,
H-8); 4.05±4.30 4m, 4H, ArOCH2); 3.59 4s, 8H,
NCH2CO2); 3.10±3.20 4m, 4H, NCH2). High resol. MS:
C28H27N3O15: 645.1442. Found: C28H28N3O15: 646.1536.
1
following the general method. Yellow oil, 36% yield. H
NMR 4CDCl3) d: 8.324d, 2H, Jˆ8.5 Hz, H-30, H-50); 8.30
4s, 1H, H-4); 7.96 4d, 2H, Jˆ8.5 Hz, H-20, H-60); 7.11 4s,
1H, H-5); 6.924s, 1H, H-8); 4.16±4.30 4m, 4H, ArOCH2);
3.60 4s, 8H, NCH2CO2); 3.15±3.30 4m, 4H, NCH2); 1.45 4s,
36H, CCH3). 13C NMR 4CDCl3) d: 190.9 4CO); 170.7
4.4.20. *{2-[7-[2-*Bis-carboxymethyl-amino)-ethoxy]-3-
*4-methoxy-benzoyl)-2-oxo-4a,8a-dihydro-2H-chromen-
6-yloxy]-ethyl}-carboxymethyl-amino)-acetic acid *8d).
It was synthesized following the general method. Yellow
t
4CO2 Bu); 159.0 4C-2); 155.5 4C-7); 152.4 4C-9); 150.0
1
4C-10); 148.5 4C-4); 146.4 4C-6); 142.4 4C-40); 129.9
4C-30, C-5); 136.4 4C-6, C-20); 121.0 4C-3); 110.9 4C-10);
110.8 4C-5); 100.4 4C-8); 81.1 4CCH3); 69.0 4CH2O); 56.9;
57.0 4NCH2CO2); 52.9 4CH2CH2N); 28.1 4CCH3).
solid, 95% yield. H NMR 4DMSO-d6) d: 8.22 4brs, 1H,
H-4); 7.85 4d, 2H, Jˆ8.7 Hz, H-20, H-60); 7.36 4brs, 1H,
H-5); 7.17 4brs, 1H, H-8); 7.04 4d, 2H, Jˆ8.7 Hz, H-30, H-
50); 4.35±4.00 4m, 4H, ArOCH2); 3.90 4s, 3H, OCH3); 3.70±
3.20 4m, 8H, NCH2CO2, 4H, NCH2). High resol. MS:
C29H30N2O14: 630.169704. Found: C29H31N2O14: 631.176349.
4.4.16. *{2-[7-[2-*Bis-tert-butoxycarbonylmethyl-amino)-
ethoxy]-3-*4-methoxy-benzoyl)-2-oxo-4a,8a-dihydro-2H-
chromen-6-yloxy]-ethyl}-tert-butoxycarbonylmethyl-
amino)-acetic acid tert-butyl ester. It was synthesized
Acknowledgements
1
following the general method. Yellow oil, 36% yield. H
Â
Financial support from Comision Interministerial de Cien-
cia y Tecnologõa of Spain 4CICYT; grants PB90-0176,
PB93-0264, PB95-0172, PB98-0103) and indirect funding
from FYSE-ERCROS S.A. are gratefully acknowledged.
NMR 4CDCl3) d: 8.00 4s, 1H, H-4); 7.89 4d, 2H,
Jˆ8.3 Hz, H-20, H-60); 7.05 4s, 1H, H-5); 6.96 4d, 2H,
Jˆ8.3 Hz, H-30, H-50); 6.90 4s, 1H, H-8); 4.15±4.30 4m,
4H, ArOCH2); 3.90 4s, 3H, OCH3); 3.59 4s, 8H,
NCH2CO2); 3.15±3.30 4m, 4H, NCH2); 1.45 4s, 36H,
CCH3). 13C NMR 4CDCl3) d: 190.5 4CO); 170.6
Â
t
4CO2 Bu); 163.8 4C-40); 159.1 4C-2); 154.2 4C-7); 151.3
References
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4NCH2CO2); 55.4 4CH3O); 53.0; 52.9 4CH2CH2N); 28.0
4CCH3). MS4L-SIMS1): 855.7 4M1H1, 13%); 160.1
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