Selective O-functionalization of phenolic α-amino acids with crown ethers bearing cyclophosphazene sub-units

Article abstract of DOI:10.1016/j.tet.2011.01.053

Cyclophosphazenes (CyP) containing a crown ether and an α-amino acid unit have been prepared starting from diphosphaza[16]crown-6 (PNP16C6). Nucleophilic substitution of one (or both) residual ansa-chlorine atom(s) of bis-spiro substituted PNP16C6 by α-ar

Full text of DOI:10.1016/j.tet.2011.01.053

Tetrahedron 67 (2011) 2096e2102
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selective O-functionalization of phenolic
bearing cyclophosphazene sub-unitsq
a-amino acids with crown ethers
,
a
b
,
,
z
Michele Penso a , Angelamaria Maia , Vittoria Lupi y, Giovanni Tricarico b
*
a CNR-Istituto di Scienze e Tecnologie Molecolari (ISTM), Via Golgi 19, I-20133 Milano, Italy
Dipartimento di Chimica Organica e Industriale dell’Universita, Via Venezian 21, I-20133 Milano, Italy
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 October 2010
Received in revised form 30 December 2010
Accepted 18 January 2011
Available online 26 January 2011
Cyclophosphazenes (CyP) containing a crown ether and an
starting from diphosphaza[16]crown-6 (PNP16C6). Nucleophilic substitution of one (or both) residual
ansa-chlorine atom(s) of bis-spiro substituted PNP16C6 by -arylsulfonamido esters containing a
phenolic function leads to the target compounds. These new polyfunctionalized CyP are lariat ethers,
potentially useful as starting materials for the preparation of ‘pH-controlled active ion carriers’ in liquid
membranes.
a-amino acid unit have been prepared
a
Keywords:
Cyclophosphazenes
Ó 2011 Elsevier Ltd. All rights reserved.
a
-Amino acids
Nucleophilic substitution
Lariat ethers
Ion carriers
1. Introduction
containing a certain number of crown moieties linked to the same
CyP central unit.6 With these polymacrocycles the binding of
cations slightly exceeding the size of the cavity afforded sandwich-
complexes (2:1) instead of 1:1 complexes. These compounds are of
1.1. Cyclophosphazenes. General
Cyclophosphazenes (CyP) and polyorganophosphazenes (POP),
the latter obtained by thermal polymerization and functionaliza-
tion with organic molecules of the former, have stimulated an
increasing interest both as innovative plastic materials and, in
supramolecular technology, for the study of biomimetic systems.1
great potential interest since they may allow new insights into the
possibility of organized systems (‘molecular stacking’) for the
formation of nanotubes in the design of artificial ionic channels.6
Since the sixties,
a number of POP with different physico-
chemical characteristics have been synthesized by nucleophilic
mono- or poly-substitution of the chlorine atoms of hexa-
chlorocyclophosphazene (1).2,3 In particular, the full substitution
with polyether chains affords CyP polypodands, a new class of
‘octopus molecules’ (2).4 These many-armed ligands, due to the
‘cooperative effect’ of all the polyether chains, are powerful com-
plexing agents of alkali metal salts even in low polarity media and
hence very efficient phase transfer catalysts.5 An analogous co-
operative effect was found with multisite receptors 3 (Fig. 1)
q
In memory of Krystyna Brandt.
* Corresponding author. Tel.: þ39 02 503 14161; fax: þ39 02 503 14159; e-mail
address: michele.penso@istm.cnr.it (M. Penso).
y
Present address: Nerviano Medical Sciences, Viale Pasteur 10, I-20014 Nerviano,
Italy.
z
Present address: Galapagos NV, Industriepark Mechelen Noord, Generaal De
Wittelaan L11 A3, B-2800 Mechelen, Belgium.
Fig. 1. ‘CyP’ multisite receptors 2e4 derived from hexachlorophosphazene 1.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.053

M. Penso et al. / Tetrahedron 67 (2011) 2096e2102
2097
In recent years, much attention has been paid to the synthesis of
functional crown ethers that can be regarded as enzyme models
because their reactivity is remarkably affected by the cation com-
plexed inside the macrocyclic cavity and the catalytic activity de-
pends on the size fit of the hosteguest complex with the substrate.
Both are typical properties of the enzyme chemistry.7 In this
line, functional crowns, like diphosphaza[16]crown-6 (PNP16C6) 4,
synthesized by incorporating the Cyp 1 sub-unit into the polyether
backbone (Fig. 1), are particularly promising ligands.8 They com-
bine, in fact, the versatile reactivity of 12,3 with the complexing
ability of crown ethers,9 and hence can be regarded as potential
anion activators in nucleophilic substitution reactions. In previous
studies, we have revealed the crucial role that the metal ion plays
in determining the product distribution in the nucleophilic sub-
stitution reactions of 4 with a series of alkali and alkaline-earth
metal 4-nitrophenates.10,11 In particular, in apparent contrast with
the rules of classical phosphazene chemistry, we found that lith-
ium, sodium, and calcium salts gave exclusively the product of
mono-substitution at one of the ‘Pansa’ atoms, such as 5 (Scheme 1),
in the position geminal to the macrocycle.12
a NePansa bond. The features of these molecules are a free car-
boxylic acid function and a very crowded -amino group, as a result
a
of the phosphazenic ring proximity. The reaction under homoge-
neous conditions of 4 with the N-free amino esters 6a,b (Scheme 2,
path i) gave only minor amounts of the corresponding mono-ansa
substituted compounds 7a,b, together with mono-spiro and poly-
substituted CyP that were not isolated from the reaction crude. In
an attempt to use more powerful nitrogen nucleophiles, 4 was
reacted with nosylamido esters of valine and serine 8a,b, under
heterogeneous conditions. As previously found in the N-alkylation
of these a
-amino acid derivatives,21 the reactivity of the nucleo-
philic center is strongly conditioned by the steric hindrance of the
electrophilic counterpart: 8a,b did not react with PNP16C6 4,
neither with potassium carbonate, under solideliquid phase
transfer catalysis (SL-PTC) conditions, nor using a stronger base in
a heterogeneous non-catalyzed system, but slowly decomposed
(Scheme 2, path ii). In addition, to check the reactivity of sulfona-
mido nucleophiles, 4 was reacted with TsNH2 under SL-PTC, but
the starting materials were recovered unchanged after prolonged
reaction time.
Scheme 1.
Scheme 2. i) DIPEA, DCM, 20 ꢁC, 48 h. (ii) K2CO3, TEBAcat, MeCN, 25 ꢁC (SL-PTC), 14
1.2. Cyclophosphazenes containing amino functions
days or NaH, THF, 60 ꢁC, 7 days.
CyP bearing one or more amino derivative side arms are found
to display interesting structural properties, finding remarkable
applications in different fields of inorganic, organic, and medicinal
chemistry.13e20 In spite of this, only a few papers describing com-
pounds of this class have appeared in a relatively large span of time.
Brandt reported the synthesis of PNP-crown polytopic receptors
by reaction of PNP16C6 (4) and polymethylene-diamines: three
classes of new compoundsdansaeansa, bino-ansa, and bis-bino-
ansadhave been screened as metal-cation complexing agents.13
Labarre et al. studied CyP-lariats and their stable gadolinium
cryptates, for NMR-imaging applications.14 C¸ iftc¸ i analyzed the syn/
anti conformational polymorphism of spermine-bridged bis-CyP
derivatives.15 Siwy prepared and studied in vitro the cytostatic and
anti-leukemic activity of some poly-aziridinyl-PNP-crowns.16 In
the sixties, Kropacheva reported CyP-glycinate esters for the first
time,17 to our knowledge, and some 20 years later, Smaardijk
prepared a few compounds of this type, which may serve as anti-
cancer drug precursors.18 Sohn described CyP bearing poly(oxy-
3. Results and discussion
Considering the above findings and the good reactivity of al-
kaline phenoxides toward chlorophosphazenes, due to the forma-
tion in the condensation products of energetically more favored
PeO bonds (PeO w336 kJ molꢀ1; PeN w230 kJ molꢀ1),22 we de-
cided to change the synthetic approach. With this objective in
mind, L-tyrosine and D-4-hydroxy-phenylglycine derivatives 9a,b
and 10a,b (Fig. 2),23 which contain a phenol function, were chosen
as nucleophiles for the condensation with 4.
ethylene) and
a-amino acid or oligopeptide units, as potential
thermosensitive drug delivery systems.19 Recently, the synthesis
and the properties of a novel star-shaped CyP, containing glycine
ester units linked to the phosphazenic ring by phenolic spacers,
have been reported by Li.20 Stimulated by the features of these new
functionalized CyP, we studied the strategy for an original regio-
selective synthesis of new PNP-crowns bearing
on the phosphazene ring.
a-amino acid units
2. Preliminary results
A series of reactions on 4 were carried out to link optically pure
Fig. 2. L-Tyrosine and D-4-hydroxy-phenylglycine derivatives 9a,b and 10a,b used as
a
-amino acid derivative units to the PNP16C6 moiety through
nucleophiles.

2098
M. Penso et al. / Tetrahedron 67 (2011) 2096e2102
As expected, in the reaction of 4 with the
L-tyrosine derivative
The reaction of 13 with -NsTyrOMe (9a), under heterogeneous
L
9a (Scheme 3), the nucleophilic attack was completely O-chemo-
selective. However, a mixture of mono-OPansa 1124 and mono-
OPspiro 1225 (as major, less hindered product) formed with this
nucleophile, under both SL-PTC (path i) and non-catalyzed het-
erogeneous conditions (path ii).
conditions by using anhydrous sodium carbonate as a solid base
(Scheme 5), gave the mono-OPansa derivative 15a (path i), after
Scheme 3. i) L-NsTyrOMe (9a), K2CO3, TEBAcat, MeCN, 25 ꢁC, 24 h. (ii) 9a, Na2CO3, THF,
25 ꢁC, 48 h.
Scheme 5. i) L-NsTyrOMe (9a), Na2CO3, MeCN, 40 ꢁC, 6 days. (ii) L-TsTyrOMe (9b),
Na2CO3, MeCN, 40 ꢁC, 4 days. (iii) D-NsHpgOMe (10a), Na2CO3, MeCN, 30 ꢁC, 24 h. (iv)
D-TsHpgOMe (10b), Na2CO3, MeCN, 25 ꢁC, 5 days.
In order to introduce the amino acid unit exclusively on the
Pansa atom, the Pspiro position was ‘blocked’ by forming the (ꢂ)-1,10-
bi(2-naphthol) (13) or 4-nitrophenol (14) bis-spiro derivatives
(Scheme 4).
prolonged heating at 40 ꢁC. The N-tosyl derivative
showed a similar behavior and reactivity (path ii). Much more re-
active (Scheme 5) were the -4-hydroxy-phenylglycine derivatives
L-TsTyrOMe (9b)
D
D
-NsHpgOMe (10a) (path iii) and
D
-TsHpgOMe (10b) (path iv),
which reacted with 13 at 25e30 ꢁC. Analogous reactions were
performed on the bis-spiro-4-nitrophenol derivative 14 (Scheme
6), which showed a reactivity toward the
a-amino acid de-
rivatives 9a,b and 10a,b similar to that of 13.
Scheme 6. i) L-NsTyrOMe (9a), Na2CO3, MeCN, 40 ꢁC, 5 days. (ii) L-TsTyrOMe (9b),
Na2CO3, MeCN, 40 ꢁC, 4 days. (iii) D-NsHpgOMe (10a), Na2CO3, MeCN, 60 ꢁC, 48 h. (iv)
D-TsHpgOMe (10b), Na2CO3, MeCN, 40 ꢁC, 3 days.
In order to substitute both the chlorine atoms on the ansa-po-
Scheme 4. i) (R)-1,10-bi-(2-naphthol) (13), K2CO3, MeCN, 60 ꢁC, 21 h. (ii) 4-NO2
sition, 13 was reacted with excess -NsTyrOMe (9a) and Na2CO3
(Scheme 7).
L
-
C6H4OK, MeCN, 25 ꢁC, 2 h.

M. Penso et al. / Tetrahedron 67 (2011) 2096e2102
2099
amounts of four diastereoisomers. These latter result from the
attack of the nucleophile on one of the two Pansa atoms of the CyP
ring, bearing one of the two enantiomeric bi(2-naphthol) sub-
stituents (R or S), e.g., 16a exists as a mixture of
D-R-P1, D-R-P2, D-S-
P1, and
D
-S-P2 isomers (Fig. 4).26
The bis-spiro 4-nitrophenoxy mono-ansa derivatives 17, 18
derive from the achiral CyP 14 and therefore exist as couple of
diastereoisomers, e.g.,
Finally the bis-ansa derivative 19 is an equimolar mixture of the
two diastereoisomers -R- and -S-
(Fig. 6).28
D-P1 and D
-P2 of 18a (Fig. 5).27
L
L
L
L
Scheme 7. i) L-NsTyrOMe (9a) (2 mol equiv), Na2CO3 (6 mol equiv), MeCN, 60 ꢁC, 6
days. (ii) L-NsTyrOMe (9a) (3 mol equiv), NaH (5 mol equiv), MeCN, 40 ꢁC, 24 h.
Under the usual heterogeneous conditions (path i), the bis-
substitution is only partial and the target compound 19 was iso-
lated together with a relevant quantity of mono-ansa compound
15a. The use of sodium hydride (path ii), resulted in milder reaction
conditions and very good yields of bis-ansa CyP 19.
The bis-substitution in the presence of the stronger base NaH is
likely favored by the formation of the complex A (Fig. 3), i.e., the N-
sodium salt of the mono-ansa substituted intermediate 15a. The so-
dium cation, coordinated by the oxygen atoms of the crown ether, is
brought in close proximity to the residual ansa-chlorine atom that,
consequently, is activated toward a second nucleophilic O-attack by
the B dianion.
Fig. 4. Mono-ansa Cyp 16a isomers formed.
Fig. 5. Mono-ansa Cyp 18a regioisomers formed.
Fig. 3. Proposed mechanism for the bis-substitution on substrate 13.
4. Stereochemical considerations
As reported above, the racemic mixture (ꢂ)-1,10-bi(2-naphthol)
has been used in the synthesis of the bis-spiro derivative 13 that, in
turn, is racemic. The reaction of 13 with a stoichiometric amount of
an achiral nucleophile produces two racemic mono-ansa di-
astereoisomers, whereas the products 15, 16 of mono-substitution
of 13 with the optical pure nucleophiles 9, 10 are equimolar
Fig. 6. Bis-substituted Cyp 19 diastereoisomers formed.

2100
M. Penso et al. / Tetrahedron 67 (2011) 2096e2102
5. Conclusions
(10.43 g, 30 mmol) in anhydrous THF (150 mL) was added NaH 60%
(2.64 g, 66 mmol). This suspension was stirred under nitrogen at
room temperature while tetraethyleneglycol (5.85 g, 30 mmol) was
added in 3 h by syringe pump, then the suspension was stirred 1 h
more. TLC control (Et2O; staining with I2 then CAM) indicated that no
furtherstartingmaterialswerepresentandevidencedproduct4asan
orange spot. The reaction mixture was quenched with water (0.2 mL)
and filtered over Celite. AfterremovalofTHFunder vacuum, awhitish
oil was obtained (13.74 g). Product 4 (4.22 g, 30%) was isolated by FCC
(Et2O) as white solid; mp 91.4e92.0 ꢁC (lit.8 85.9 ꢁC); dH (300 MHz,
CDCl3) 4.48e4.20 (4H, m), 3.86e3.73 (4H, m), 3.73e3.63 (8H, m); dP
(121 MHz, CDCl3) 25.7 (1Pspiro (Cl2), dd, J 65.0, 70.0 Hz), 19.4 (1Pansa
(Cl, OCH2), d, J 65.0 Hz), 19.4 (1Pansa (Cl, OCH2), d, J 70.0 Hz).
In conclusion, products 15e19 can be considered lariat ethers29
in which amido esters residues are linked to the macrocyclic ring
via the phosphorus in the ‘ansa’ position. Due to their topology,
these compounds could give stable inclusion complexes, especially
with alkali metal and alkaline-earth metal cations, in organic sol-
vents and hence could behave as good potential carriers for cations
in analogy with crown ethers and the related open-chain analogs.
The unprotected derivatives of these compounds should be exactly
defined ‘proton-ionizable lariat ethers’ due to the presence in the
molecule of a pendent amino acid group.29,30 Such a property is
known to be very useful because the complexation and the release
of the cation are controlled by the pH of the medium (‘proton
switch’) and the metal ion extraction does not involve transfer of
the aqueous phase anion into the organic phase.30 More in general,
these lariat ethers could be potentially useful as ‘pH-controlled
active ion carriers’ in liquid membranes. In addition, it is also pos-
sible to introduce hydrophobic chains in both the ‘spiro’ and the left
‘ansa’ positions so obtaining functionalized crown ethers capable to
form aggregates in aqueous media and hence to behave as active
‘liquid ion carriers’.31 Alternatively, the potential stacking of two or
more phosphazenic rings, by linking difunctionalized lipophilic
chains of appropriate length, could provide the driving force to form
channel-like structures.32 Very recently, bis-PNP-lariat ethers were
6.3. Reaction of PNP16C6 4 with L-NsTyrOMe 9a: synthesis
of mono-ansa 11 and mono-spiro 12 derivatives
In a screw cap vial, anhydrous, finely ground K2CO3 (31 mg,
0.225 mmol) was added to a solution of 4 (70 mg, 0.15 mmol),
L-NsTyrOMe 9a (57, 0.15 mmol), and TEBA (3.4 mg, 0.015 mmol) in
anhydrous acetonitrile (0.75 mL). This heterogeneous mixture was
stirred at room temperature for 24 h (TLC, DCM/PE/MeOHd19:10:1)
andthenfilteredonCelite. Afterremovalof thesolventundervacuum,
the crude (yellow oil,115 mg) was purified by FCC (Et2O/AcOEtd6:1).
Mono-ansa derivative 11 (17 mg,14%); colorless oil; dH (300 MHz,
CDCl3) 7.97 (1H, dd, J 9.0, 2.4 Hz), 7.89 (1H, dd, J 7.1,1.9 Hz), 7.78e7.68
(2H, m), 7.10e7.02 (4H, m), 6.01 (1H, br s), 4.42e4.39 (1H, m),
4.33e3.90(4H, m), 3.82e3.59(12H, m), 3.51(3H, s), 3.13(1H, dd, J 5.2,
5.0 Hz), 3.00 (1H, dd, J 14.2, 7.0 Hz); dP (121 MHz, CDCl3) 26.9 (1Pspiro
(Cl2), dd, J 77.2, 75.0 Hz), 22.3 (1Pansa (Cl, OCH2), dd, J 77.2, 70.2 Hz),
9.3 (1Pansa (OAr0, Cl), dd, J 75.0, 70.2 Hz). IR (Nujol, cmꢀ1) 3286, 2925,
2855,1786,1554,1343,1326,1200,1165,1109, 905, 604. HRMS, calcd
for C24H32Cl3N5O12P3S (MþHþ): 812.0047; found 812.0045.
Mono-spiro derivative 12 (71 mg, 58%); colorless oil; dH
(300 MHz, CDCl3) 7.94 (1H, dd, J 9.4, 2.4 Hz), 7.86 (1H, dd, J 7.3,
1.8 Hz), 7.74e7.64 (2H, m), 7.17e7.09 (4H, m), 6.10 (1H, br s),
4.46e4.17 (5H, m), 3.85e3.60 (12H, m), 3.54 and 3.52 (3H, sþs), 3.16
(1H, dd, J 14.2, 5.3 Hz), 3.03 (1H, dd, J 14.0, 7.1 Hz); dP (121 MHz,
CDCl3) 21.7 (2Pansa (Cl, OCH2), d, J 77.2 Hz), 17.8 (1Pspiro (OAr0, Cl), t, J
77.2 Hz). IR (Nujol, cmꢀ1) 3291, 2918, 2863, 1780, 1544, 1358, 1326,
1196, 1159, 1108, 910, 599. HRMS, calcd for C24H32Cl3N5O12P3S
(MþHþ): 812.0047; found 812.0047.
found to behave as efficient ion carriers for heavy metal (Zn2þ, Cd2þ
,
Pb2þ) transport across polymer inclusion membranes, in particular
for lead(II), due to the formation of ‘sandwich’ complexes with the
macrocycle.33 Finally, since PNP-crown amido esters 15e19 contain
optically active
a-amino acid residues the possibility of stereo-
selective interactions with chiral guests could also be envisaged.
6. Experimental section
6.1. General
All reactions were carried out in oven-dried glassware with
magnetic stirring. Isolated yields refer to homogeneous materials
(TLC, HPLC, NMR). Arylsulfonamido esters 9a,b and 10a,b were
prepared as previously described.23 Reagent-grade commercially
available reagents and solvents were used; anhydrous solvents
were used as purchased. DCM indicated dichloromethane, and PE
is petroleum ether having bp 40e60 ꢁC. Tetraethyleneglycol was
ꢁ
distilled from anhydrous K2CO3 and stored over 4 A molecular
6.4. Synthesis of 1,3-[oxy(tetraethyleneoxy)]-5,5-
sieves. The reactions were monitored by TLC on silica gel 60 F254
(Merck, 0.15e0.20 mm), and visualized by UV-254 light and CAM
staining. Reaction mixtures were purified by flash column (FCC)
and medium pressure liquid chromatography (MPLC) using silica
gel 60 (Merck, 0.040e0.063 mm). Melting points were determined
(1,10-binaphthalene-2,20-dioxy)cyclotriphosphazene (13)
Anhydrous, finely ground K2CO3 (655 mg, 4.74 mmol) was
added to a solution of 4 (708 mg, 1.51 mmol) and (ꢂ)-1,10-binaph-
thol (452 mg, 1.58 mmol) in anhydrous acetonitrile (9 mL), placed
in a screw cap vial. The heterogeneous mixture was stirred at 60 ꢁC
for 20 h (TLC, Et2O/AcOEtd6:1), then cooled to room temperature
and filtered on Celite. After removal of MeCN under vacuum,
a yellow solid (1.05 g) was obtained. The bis-spiro derivative 13
(942 mg, 91%) was isolated by FCC (Et2O) as white solid; mp 130 ꢁC
(lit.34 135 ꢁC); dH (300 MHz, CDCl3) 8.02 (1H, d, J 8.8 Hz), 8.00 (1H, d,
J 8.8 Hz), 7.94 (1H, d, J 8.2 Hz), 7.92 (1H, d, J 8.2 Hz), 7.56 (1H, d, J
8.8 Hz), 7.55 (1H, d, J 8.8 Hz), 7.49e7.38 (4H, m), 7.31e7.25 (2H, m),
4.40e4.21 (4H, m), 3.89e3.62 (12H, m); dP (121 MHz, CDCl3) 24.6
(2Pansa (Cl, OCH2), d, J 78.7 Hz), 22.2 (1Pspiro (OAr2), t, J 78.7 Hz). IR
(Nujol, cmꢀ1) 3325, 2880, 1207, 1159, 1111, 600.
€
with a Buchi B-540 apparatus and are uncorrected. IR spectra were
recorded on a Jasco FT-IR-4100 spectrophotometer, using KBr cells,
and are reported in frequency of absorption (cmꢀ1). Optical rota-
tions were determined on a PerkineElmer 241 polarimeter oper-
ating at 589 nm, using a (10 cmꢃ5 mL) cell; c is in g/100 mL. NMR
spectra were recorded on Bruker AC-300 and AMX-300 spec-
trometers, operating at 300 MHz, 75 MHz, and 121 MHz for 1H, 13C,
and 31P, respectively. TMS was used as external reference. Chemical
shifts are given on the
d scale (ppm). Coupling constants (J) are
given in hertz. Electrospray ionization (ESI) HRMS were obtained
with a Bruker Daltonics ICR-FTMS APEX II at the Unimi-CIGA
Interdepartmental Analytical Centre.
6.5. Synthesis of 1,3-[oxy(tetraethyleneoxy)]-5,5-
bis(4-nitrophenoxy)cyclotriphosphazene (14)
6.2. Synthesis of PNP16C6 (4)
PNP16C6 (4) was preparedfollowing a modification of the synthesis
In a screw cap vial, 4 (469 mg, 1.0 mmol) in anhydrous aceto-
nitrile (1.6 mL), was reacted with potassium 4-nitrophenate
described by Brandt.8 To a solution of hexachlorocyclophosphazene

M. Penso et al. / Tetrahedron 67 (2011) 2096e2102
2101
(354 mg, 2.0 mmol) for 2 h at room temperature, under stirring
(TLC, DCM/AcOEtd3:1). After filtration on Celite and removal of
MeCN under vacuum, the resultant yellow oil (670 mg) was puri-
fied by FCC (AcOEt/PEd1:1). The bis-spiro derivative 14 (440 mg,
65%) was isolated as yellow solid; mp 108e110 ꢁC (we previously10
reported 14 as a wax); dH (300 MHz, CDCl3) 8.29 (2H, d, J 9.1 Hz),
8.28 (2H, d, J 9.0 Hz), 7.43 (2H, d, J 9.1 Hz), 7.42 (2H, d, J 9.0 Hz),
4.35e4.20 (2H, m), 4.20e4.05 (2H, m), 3.75e3.65 (4H, m),
3.64e3.50 (8H, m); dP (121 MHz, CDCl3) 23.5 (2Pansa (Cl, OCH2), d, J
84.4 Hz), 4.8 (1Pspiro (OAr2), t, J 84.4 Hz). IR (Nujol, cmꢀ1) 3310,
2895, 2850, 1528, 1324, 1201, 1160, 1113, 850, 600.
(32 mg, 0.30 mmol); 5 days at 25 ꢁC; the crude is an uncolored wax
(89 mg); FCC eluant (Et2O); 16b (72 mg, 73%) wax; dH (300 MHz,
CDCl3) 8.06e6.91 (20H, m), 5.76, 5.74, 5.70, and 5.65 (1H, NH, br
sþbr sþbr sþbr s), 5.10e4.98 (1H, m), 4.60e3.40 (16H, m), 3.540,
3.538, 3.518, and 3.516 (3H, sþsþsþs), 2.36 and 2.34 (3H, sþs); dP
(121 MHz, CDCl3) 28.0e24.8 (1Pansa (Cl, OCH2) þ1Pspiro (OAr2), m),
14.0e10.0 (1Pansa (OAr0), m). IR (Nujol, cmꢀ1) 3326, 2912, 1724,
1349, 1199, 1154, 1116, 910, 606. HRMS, calcd for C44H45ClN4O12P3S
(MþHþ): 981.1656; found 981.1653.
6.6.5. Synthesis of mono-ansa(L-NsTyrOMe) bis-spiro(4-nitrophenoxy)
derivative 17a. Bis-spiro derivative 14 (56 mg, 0.083 mmol), sulfo-
namido ester 9a (32 mg, 0.083 mmol), MeCN (0.35 mL), Na2CO3
(26 mg, 0.25 mmol); 5 days at 40 ꢁC; the crude is a yellowish oil
(93 mg); FCC eluant (Et2O/AcOEtd6:1); 17a (67 mg, 81%) yellow oil;
dH (300 MHz, CDCl3) 8.26 (2H, d, J 9.6 Hz), 8.15 (2H, d, J 9.1 Hz),
7.99e7.68 (4H, m), 7.44 (2H, d, J 9.0 Hz), 7.27 (2H, d, J 8.8 Hz),
7.18e7.02 (4H, m), 6.01 (1H, d, J 8.8 Hz), 4.41e4.38 (1H, m),
4.35e3.92 (4H, m), 3.80e3.53 (12H, m), 3.50 and 3.49 (3H, sþs), 3.13
(1H, dd, J 5.3, 5.1 Hz), 3.00 (1H, dd, J 14.1, 7.0 Hz); dP (121 MHz,
CDCl3) 25.7 (1Pansa (Cl, OCH2), dd, J 94.1, 74.4 Hz), 10.5 (1Pansa (OAr0),
dd, J 94.8, 74.4 Hz), 7.7 (1Pspiro (OAr2), dd, J 94.8, 94.1 Hz). IR (Nujol,
cmꢀ1) 3322, 2906, 2853, 1781, 1549, 1340, 1319, 1203, 1162, 1109,
899, 853, 602. HRMS, calcd for C36H40ClN7O18P3S (MþHþ):
1018.1052; found 1018.1050.
6.6. General procedure for the synthesis of mono-ansa
derivatives 15e18
In a screw cap vial, a heterogeneous mixture of the bis-spiro
derivative 13, 14 and the sulfonamido ester 9, 10 solution in anhy-
drous acetonitrile, and lyophilized Na2CO3 (0.3 mol equiv) was
stirred until no further starting materials were detected by TLC
analysis (DCM/PE/MeOHd19:10:1). After filtration on Celite and
evaporation under vacuum of the solvent, the crude was purified by
FCC. Starting materials and solvent, reaction time and temperature,
amount of the crude, FCC eluant, product yield, physical, spectro-
scopic and analytical data are as follows.
6.6.1. Synthesis of mono-ansa(L-NsTyrOMe) bis-spiro(binaphthoxy) de-
rivative 15a. Bis-spiro derivative 13 (137 mg, 0.2 mmol), sulfonamido
ester 9a (76 mg, 0.2 mmol), MeCN (0.6 mL), Na2CO3 (64 mg,
0.6 mmol); 6 days at 40 ꢁC; the crude is a yellow oil (197 mg); FCC
eluant (Et2O/AcOEtd7:1); 15a (152 mg, 74%) white wax; dH (300 MHz,
CDCl3) 8.02e6.98 (20H, m), 6.10e5.97 (1H, NH, m), 4.60e4.08 (5H, m),
3.95e3.53 (12H, m), 3.521, 3.517, 3.498, and 3.478 (3H, sþsþsþs),
3.25e2.95 (2H, m); dP (121 MHz, CDCl3) 28.5e25.0 (1Pansa (Cl, OCH2)þ
1Pspiro (OAr2), m), 12.5e10.7 (1Pansa (OAr0), m). IR (Nujol, cmꢀ1) 3330,
2912, 2853, 1783, 1551, 1340, 1203, 1156, 1113, 899, 602. HRMS, calcd
for C44H44ClN5O14P3S (MþHþ): 1026.1507; found 1026.1508.
6.6.6. Synthesis of mono-ansa(L-TsTyrOMe) bis-spiro(4-nitrophenoxy)
derivative 17b. Bis-spiro derivative 14 (58 mg, 0.086 mmol), sulfo-
namido ester 9b (30 mg, 0.086 mmol), MeCN (0.35 mL), Na2CO3
(27 mg, 0.26 mmol); 4 days at 40 ꢁC; the crude is a yellow oil
(86 mg); FCC eluant (Et2O); 17b (69 mg, 82%) wax; dH (300 MHz,
CDCl3) 8.24 (2H, d, J 9.1 Hz), 8.15 (2H, d, J 9.1 Hz), 7.63 (2H, d, J
8.3 Hz), 7.43 (2H, d, J 9.1 Hz), 7.28e7.24 (4H, m), 7.04e6.95 (4H, m),
5.20 and 5.14 (1H, dþd, J 9.2þ8.3 Hz), 4.35e3.90 (5H, m), 3.90e3.50
(12H, m), 3.46 and 3.45 (3H, sþs), 3.02 (1H, dd, J 15.0, 6.0 Hz), 2.92
(1H, dd, J 15.0, 6.0 Hz), 2.39 (3H, s); dP (121 MHz, CDCl3) 25.7 (1Pansa
(Cl, OCH2), dd, J 94.4, 74.5 Hz), 10.5 (1Pansa (OAr0), dd, J 95.5,
6.6.2. Synthesis of mono-ansa(
L
-TsTyrOMe) bis-spiro(binaphthoxy)
74.5 Hz), 7.7 (1Pspiro (OAr2), dd, J 95.5, 94.4 Hz). IR (Nujol, cmꢀ1
)
derivative 15b. Bis-spiro derivative 13 (96 mg, 0.14 mmol), sulfo-
namido ester 9b (49 mg, 0.14 mmol), MeCN (0.6 mL), Na2CO3
(45 mg, 0.42 mmol); 4 days at 40 ꢁC; the crude is an uncolored oil
(148 mg); FCC eluant (Et2O); 15b (123 mg, 88%) wax; dH (300 MHz,
CDCl3) 8.10e7.00 (20H, m), 5.12, 5.11, 5.09, and 5.08 (1H, NH, br
sþbr sþbr sþbr s), 4.60e4.05 (5H, m), 3.92e3.57 (12H, m), 3.451,
3.433, 3.425, and 3.398 (3H, sþsþsþs), 3.06e3.02 (2H, m), 2.36 (3H,
s); dP (121 MHz, CDCl3) 28.0e25.2 (1Pansa (Cl, OCH2)þ1Pspiro (OAr2),
m), 12.5e10.9 (1Pansa (OAr0), m). IR (Nujol, cmꢀ1) 3318, 2910, 1778,
1353, 1205, 1165, 1110, 901, 611. HRMS, calcd for C45H47ClN4O12P3S
(MþHþ): 995.1813; found 995.1811.
3308, 2898, 2844, 1780, 1533, 1361, 1324, 1199, 1159, 1113, 900, 850,
612. HRMS, calcd for C37H43ClN6O16P3S (MþHþ): 987.1358; found
987.1359.
6.6.7. Synthesis of mono-ansa(L-NsHpgOMe) bis-spiro(4-nitro-
phenoxy)derivative 18a. Bis-spiro derivative 14 (101 mg, 0.15 mmol),
sulfonamido ester 10a (55 mg, 0.15 mmol), MeCN (0.45 mL), Na2CO3
(48 mg, 0.45 mmol); 48 h at 60 ꢁC; the crude is a yellow oil (157 mg);
FCC eluant (Et2O/AcOEtd7:1); 18a (96 mg, 64%) wax; dH (300 MHz,
CDCl3) 8.24 (2H, d, J 9.1 Hz), 8.11 (2H, d, J 8.6 Hz), 7.90 (1H, d, J 7.5 Hz),
7.87 (1H, d, J 7.5 HZ), 7.63e7.60 (2H, m), 7.42 (2H, d, J 8.9 Hz), 7.27
(2H, d, J 9.4 Hz), 7.22 (1H, d, J 8.6 Hz), 7.21 (1H, d, J 8.6 Hz), 7.06 (2H,
d, J 8.4 Hz), 6.65 and 6.60 (1H, dþd, J 7.9þ7.7 Hz), 5.18 and 5.16 (1H,
dþd, J 7.9þ7.7 Hz), 4.25e3.45 (19H, m); dP (121 MHz, CDCl3) 25.6
(1Pansa (Cl, OCH2), dd, J 93.6, 77.2 Hz), 10.7 (1Pansa (OAr0), dd, J 94.3,
6.6.3. Synthesis of mono-ansa(L-NsHpgOMe) bis-spiro(binaphthoxy)
derivative 16a. Bis-spiro derivative 13 (55 mg, 0.08 mmol), sulfo-
namido ester 10a (29 mg, 0.08 mmol), MeCN (0.3 mL), Na2CO3
(25 mg, 0.24 mmol); 24 h at 30 ꢁC; the crude is a yellowish oil
(71 mg); FCC eluant (Et2O/AcOEtd7:1); 16a (72 mg, 89%) uncolored
oil; dH (300 MHz, CDCl3) 7.99e6.99 (20H, m), 6.69, 6.66, 6.60, and
6.55 (1H, NH, br sþbr sþbr sþbr s), 5.33e5.19 (1H, m), 4.60e4.18
(4H, m), 4.12e3.56 (12H, m), 3.605, 3.594, 3.586, and 3.583 (3H,
sþsþsþs); dP (121 MHz, CDCl3) 27.1e24.8 (1Pansa (Cl, OCH2)þ1Pspiro
(OAr2), m), 12.6e10.7 (1Pansa (OAr0), m). IR (Nujol, cmꢀ1) 3316, 2898,
2860, 1736, 1537, 1355, 1200, 1148, 1109, 910, 610. HRMS, calcd for
C43H42ClN5O14P3S (MþHþ): 1012.1350; found 1012.1354.
77.2 Hz), 7.7 (1Pspiro (OAr2), dd, J 94.3, 93.6 Hz). IR (Nujol, cmꢀ1
)
3299, 2888, 2860, 1735, 1534, 1528, 1350, 1326,1200, 1145, 1113, 909,
844, 614. HRMS, calcd for C35H38ClN7O18P3S (MþHþ): 1004.0895;
found 1004.0893.
6.6.8. Synthesis ofmono-ansa(L-TsHpgOMe) bis-spiro(4-nitrophenoxy)
derivative 18b. Bis-spiro derivative 14 (67 mg, 0.10 mmol), sulfona-
mido ester 10b (34 mg, 0.10 mmol), MeCN (0.45 mL), Na2CO3
(32 mg, 0.30 mmol); 3 days at 40 ꢁC; the crude is a yellow
oil (96 mg); FCC eluant (Et2O); 18b (69 mg, 71%) pale yellow oil; dH
(300 MHz, CDCl3) 8.25 (2H, d, J 9.1 Hz), 8.17 (2H, d, J 8.4 Hz), 7.68
(2H, d, J 8.4 Hz), 7.42 (2H, dd, J 9.1, 1.5 Hz), 7.30e7.22 (4H, m),
7.18 (2H, dd, J 8.6, 1.5 Hz), 7.08 (2H, d, J 8.6 Hz), 5.67 and 5.66 (1H,
6.6.4. Synthesis of mono-ansa(L-TsHpgOMe) bis-spiro(binaphthoxy)
derivative 16b. Bis-spiro derivative 13 (68 mg, 0.10 mmol), sulfo-
namido ester 10b (34 mg, 0.10 mmol), MeCN (0.45 mL), Na2CO3

2102
M. Penso et al. / Tetrahedron 67 (2011) 2096e2102
7. (a) Suelter, C. H. In Metal Ions in Biological Systems; Sigel, H., Ed.; Marcel Dekker:
New York, NY, 1974; Vol. 3, Chapter 7; (b) Suh, J. Acc. Chem. Res. 1992, 25,
273.
8. Brandt, K.; Kupka, T.; Drodz, J.; Van de Grampel, J. C.; Meetsma, A.; Jekel, A. P.
Inorg. Chim. Acta 1995, 228, 187.
9. (a) Gokel, G. W. Crown Ethers and Cryptands, Monographs in Supramolecular
Chemistry; The Royal Society of Chemistry: London, 1991; (b) Landini, D.; Maia,
A.; Penso, M. In Comprehensive Supramolecular Chemistry; Lehn, J. M., Ed.;
Pergamon: New York, NY, 1996; Vol. 1, Chapter 11; (c) Landini, D.; Maia, A.
Encyclopedia of Supramolecular Chemistry; Marcel Dekker: New York, NY, 2004;
939e949.
dþd, J 7.9þ7.8 Hz), 4.94 and 4.93 (1H, dþd, J 7.9þ7.8 Hz), 4.22e3.92
(4H, m), 3.90e3.44 (12H, m), 3.52 (3H, br s), 2.41 (3H, s); dP
(121 MHz, CDCl3) 25.7 (1Pansa (Cl, OCH2), dd, J 94.3, 75.6 Hz), 10.7
(1Pansa (OAr0), dd, J 94.4, 75.6 Hz), 7.7 (1Pansa (OAr2), dd, J 94.4,
94.3 Hz). IR (Nujol, cmꢀ1) 3330, 2889, 2861, 1730, 1529, 1517, 1328,
1199, 1151, 1109, 910, 842, 614. HRMS, calcd for C36H41ClN6O16P3S
(MþHþ): 973.1201; found 973.1198.
6.7. Synthesis of bis-ansa(L-NsTyrOMe) bis-spiro
10. Maia, A.; Landini, D.; Penso, M.; Brandt, K.; Siwy, M.; Schroeder, G.; Gierczyk, B.
New J. Chem. 2001, 25, 1078.
(binaphthoxy) derivative 19
11. Maia, A.; Landini, D.; Penso, M.; Brandt, K. New J. Chem. 2002, 26, 1817.
12. These results have been rationalized on the basis of a transition state in which
the metal cation interacts with the oxygen atoms of the polyether 4 (‘hoste
guest’ complex) while the ion-paired anion simultaneously attacks the adjacent
phosphorous atoms following a concerted mechanism.10,11 As an important
consequence, an appropriate choice of the metal cation Mnþ allows to access to
species otherwise unlikely to be obtainable.
In a screw cap vial flushed with argon, 60% NaH (30 mg,
0.45 mmol) was rinsed with anhydrous pentane (3ꢃ1 mL), then
a solution of 13 (102 mg, 0.15 mmol) and 9a (171 mg, 0.45 mmol) in
anhydrous THF (1 mL) was added at room temperature. This het-
erogeneous mixture was stirred for 24 h at 40 ꢁC. After cooling, the
13. (a) Brandt, K.; Porwolik, I.; Siwy, M.; Kupka, T.; Shaw, R. A.; Davies, D. B.;
Hursthouse, M. B.; Sykara, G. D. J. Am. Chem. Soc. 1997, 119, 1143; (b) Brandt, K.;
Porwolik-Czomperlik, I.; Siwy, M.; Kupka, T.; Shaw, R. A.; Ture, S.; Clayton, A.;
Davies, D. B.; Hursthouse, M. B.; Sykara, G. D. J. Org. Chem. 1999, 64, 7299.
reaction was quenched with water (50 mL), the solvent was evap-
orated under vacuum, and the crude was purified by FCC (AcOEt/
PEd3:1). Bis-ansa derivative 19 (158 mg, 77%) was isolated as wax;
dH (300 MHz, CDCl3) 8.01e6.56 (28H, m), 6.13e5.95 (2H, NH, m),
4.45e4.19 (6H, m), 3.89e3.66 (12H, m), 3.53, 3.51, 3.46, and 3.44
(6H, sþsþsþs), 3.23e2.95 (4H, m); dP (121 MHz, CDCl3) 27.6 (1Pspiro
(OAr2), t, J 94.7 Hz), 13.77 (2Pansa (OAr0), d, J 94.7 Hz). IR (Nujol,
cmꢀ1) 3325, 2912, 1774, 1547, 1340, 1218, 1148, 1119, 900. HRMS,
calcd for C60H59N7O21P3S2 (MþHþ): 1370.2418; found 1370.2418.
ꢂ
14. Valerio, C.; Labarre, M.-C.; Labarre, J.-F. J. Mol. Struct. 1993, 299, 171.
15. C¸ iftc¸ i, G. Y. Inorg. Chem. Commun. 2004, 7, 1258.
16. (a) Porwolik-Czomperlik, I.; Siwy, M.; Sȩk, D.; Kaczmarczyk, B.; Nasulewicz, A.;
Jaroszewicz, I.; Pelczyska, M.; Opolski, A. Acta Pol. Pharm. 2004, 61, 267; (b)
Siwy, M.; Sȩk, D.; Kaczmarczyk, B.; Jaroszewicz, I.; Nasulewicz, A.; Pelczyska,
M.; Nevozhay, D.; Opolski, A. J. Med. Chem. 2006, 49, 806.
17. Kropacheva, A. A.;Kashnikova, N. M.; Parshina, V. A. Zh. Obshch. Khim.1964, 34, 530.
18. Smaardijk, A. A.; de Ruiter, B.; Van der Huizen, A. A.; Van de Grampel, J. C. Recl.
Trav. Chim. Pays-Bas 1982, 101, 270.
19. Lee, S. B.; Song, S.-C.; Jin, J.-I.; Sohn, Y. S. J. Am. Chem. Soc. 2000, 122, 8315.
20. Bing, B.-C.; Li, B. Sci. China, Ser. B 2009, 52, 2186.
Acknowledgements
21. Albanese, D.; Landini, D.; Lupi, V.; Penso, M. Eur. J. Org. Chem. 2000, 1443.
22. Dorfman, Ya. A.; Abdreimova, R. R.; Doroshkevich, D. M. Theor. Exp. Chem.1991, 27,
571.
23. Penso, M.; Albanese, D.; Landini, D.; Lupi, V.; Tricarico, G. Eur. J. Org. Chem. 2003,
4513.
This research was carried out within the framework of the
National Project ‘Nuovi sistemi catalitici stereoselettivi e sintesi
stereoselettive di molecole funzionali’, and it is supported by MIUR
(Rome) and CNR (Italy).
24. Mono-ansa derivative 11a is
a diastereomeric mixture as a result of the
nucleophilic substitution of the chlorine atom in both the ‘ansa’ positions.
25. Mono-spiro derivative 12a is a mixture of isomers syn/anti, relative to the
crown ether ring.
26. These diastereoisomers show four methyl ester signals in the region 3.6e3.
Supplementary data
4 ppm of the compounds 15, 16 1H NMR spectra.
27. In the case of the 17, 18 diastereoisomers several 1H NMR signals are doubled
(see Experimental).
28. The presence of two diastereoisomers of 19 is confirmed by two couples of
methyl ester signals in the region 3.53e3.44 ppm.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.01.053.
29. (a) Gokel, G. W.; Schall, O. F. In Comprehensive Supramolecular Chemistry;
Reinhoudt, D. N., Ed.; Pergamon: New York, NY, 1996; Vol. 10, Chapter 6; (b)
Bartsch, R. A.; Lee, E. K.; Elkarim, N.; Brandt, K.; Porwolik-Czomperlik, I.; Siwy,
References and notes
̃
M.; Lach, D.; Silbening, J. J. Chem. Soc., Perkin Trans. 2 2002, 442.
1. Allcock, H. R. Chem. Eng. News 1985, 63, 22.
2. Allen, C. W. Chem. Rev. 1991, 91, 119.
̃
30. Bartsch, R. H.; Hwang, H.-S.; Talanov, V. S.; Talanova, G. G.; Purkiss, D. W.;
Rogers, R. D. J. Org. Chem. 1999, 64, 5341.
3. Allcock, H. R.; Al-Shali, S.; Ngo, D. C.; Visscher, K. B.; Parvez, H. J. Chem. Soc.,
31. De Jong, F.; Visser, H. C. In Comprehensive Supramolecular Chemistry; Reinhoudt,
D. N., Ed.; Pergamon: New York, NY, 1996; Vol. 10, Chapter 2.
32. Fyles, T. M.; Van Straaten-Nijenhuis, W. F. In Comprehensive Supramolecular
Chemistry; Reinhoudt, D. N., Ed.; Pergamon:NewYork, NY,1996; Vol.10, Chapter 3.
33. Kozlowski, C. A.; Kozlowska, J. J. Membr. Sci. 2009, 326, 215.
Dalton Trans. 1995, 3521.
4. Corda, L.; Anchisi, C.; Podda, G.; Traldi, P.; Gleria, M. Heterocycles 1986, 24, 2821.
5. (a) Landini, D.; Maia, A.; Corda, L.; Maccioni, A.; Podda, G. Tetrahedron 1991, 47,
1285; (b) Gobbi, A.; Landini, D.; Maia, A.; Delogu, G.; Podda, G. J. Org. Chem.
1994, 59, 5059 and references therein.
34. Brandt, K.; Porwolik-Czomperlik, I.; Siwy, M.; Kupka, T.; Shaw, R. A.; Davies, D.
B.; Hursthouse, M. B.; Sykara, G. D. J. Am. Chem. Soc. 1997, 119, 12432.
6. Hochart, F.; Mouveaux, C.; Levalois-Mitjaville, J.; De Jaeger, R. Tetrahedron Lett.
1998, 39, 6171.