Chiral macrocyclic polyethers incorporating a tetraoxaspiro [5.5]undecane or trioxa, azaspiro [5.5]undecane moiety

Article abstract of DOI:10.1016/S0957-4166(98)00453-4

New macrocyclic polyethers possessing chirality due to a spiro ring junction are prepared from 2,8-dihydroxymethylated (+)- 1,4,7,10- tetraoxaspiro[5.5]undecane 1 and (+)- 1,4,7-trioxa- 10-azaspiro[5.5]undecane 2, both (E,E). N-Functionalization of compounds derived from 2 is also examined. The complexing properties of representative ligands 3, 4, 5 measured by spectrophotometry in THF, for alkaline and alkaline-earth cations, indicate that these spheric positively-charged species are weakly associated.

Full text of DOI:10.1016/S0957-4166(98)00453-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4253–4265
Chiral macrocyclic polyethers incorporating a
tetraoxaspiro[5.5]undecane or trioxa-azaspiro[5.5]undecane
moiety
Christophe Garcia,a Yvon Pointud,b Georges Jeminet,a,∗ Denise Dugat a and José Luis Beltran c
aUMR 6504: Synthèse, Electrosynthèse et Etude de Systèmes à Intérêt Biologique, CNRS and Université Blaise Pascal
Clermont-Ferrand, F-63177 Aubière Cedex, France
bUPRESA 6003: Thermodynamique des Solutions et des Polymères, CNRS and Université Blaise Pascal Clermont-Ferrand,
F-63177 Aubière Cedex, France
cUniversitat de Barcelona, Departament de Quimica Analitica, Diagonal 647, E-08028 Barcelona, Spain
Received 28 October 1998; accepted 5 November 1998
Abstract
New macrocyclic polyethers possessing chirality due to a spiro ring junction are prepared from 2,8-
dihydroxymethylated (+)-1,4,7,10-tetraoxaspiro[5.5]undecane 1 and (+)-1,4,7-trioxa-10-azaspiro[5.5]undecane
2, both (E,E). N-Functionalization of compounds derived from 2 is also examined. The complexing properties
of representative ligands 3, 4, 5 measured by spectrophotometry in THF, for alkaline and alkaline-earth cations,
indicate that these spheric positively-charged species are weakly associated. © 1998 Published by Elsevier Science
Ltd. All rights reserved.
1. Introduction
We previously reported the enantioselective synthesis of 2- and 8- functionalized 1,4,7,10-
tetraoxaspiro[5.5]undecane 11 and 1,4,7-trioxa-10-azaspiro[5.5]undecane 2.2 These novel spirane
systems had structures with dianomeric axial oxygens and equatorial CH2OH substituents,3 i.e. with E,E
stereochemistry. D-α,β-Isopropylidene glycerol or (S)-Solketal, a commercially available three-carbon
precursor, was used as starting material (Scheme 1).
The proposed synthetic scheme allowed further developments, in particular towards macrocyclic
systems, if appropriate cyclizations were carried out. To begin with, we studied macrocycles constructed
with ethylenoxy units. Since the pioneering work of Pedersen,4 much attention has been focused on
∗
Corresponding author. E-mail: g.jeminet@univ-bpclermont.fr
0957-4166/98/$ - see front matter © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00453-4

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Scheme 1.
crown ethers and analogues, mainly for the design of new complexing agents for various positively-
charged species.5 In this context, crown-like structures have been used for chiral recognition of asymme-
tric species and many supporting skeletons for such chiral receptors have been studied.6 However, to our
knowledge no spirane system has ever been proposed for this purpose. Recent work describes spiroketal
based polyethers,7 but the structural approach is different, the cyclization being carried out from the
racemic 3,5-diaxial diol of 1,7-dioxaspiro[5.5]undecane.
Use of spiroacetal 1 as a starting material would give cyclic structures with C2 symmetry and a specific
chirality due to the spiro ring junction. Also, introduction of a nitrogen atom in position 10 of 2 would
afford unsymmetrical ligands that could be further functionalized.
The work reported here mainly concerns the synthesis of macrocycles, and a first example of N-
functionalization is described. For this type of multidentate ligand, it can be predicted that preorgani-
zation of the cavity is not conducive to the efficient complexation of spheric cations, judging from the
abundant previous work8 in this field. To estimate the complexing properties for IA and IIA cations, we
examined the fully oxygenated ligands 3, 4, 5, by spectrophotometric measurements with metal picrates
in THF.
We investigated the ability of these enantiopure macrocycles to selectively bind enantiomers of chiral
molecules such as protonated amines. Results obtained by electrospray mass spectrometry, and including
bicyclic analogues, will be the subject of a forthcoming paper.
2. Results and discussion
2.1. Synthesis of cyclic polyethers
Macrocyclization was envisaged by 1:1 condensation between two bifunctional systems (Scheme 2).
After examination of various experimental parameters such as temperature, reaction time, alcoholate
formation, order of mixing, and solvents, the reaction was finally carried out by treatment of diol
precursors 1 or 2 with hydride (4 equiv.) in THF followed by slow addition of ditosylate in THF in
precisely set conditions (see Experimental section).
Also, to minimize side reactions such as polycondensations, and to increase yields, two factors were
explored: (i) the choice of the alkaline hydride, (ii) the best conditions of concentration in the mean
dilution domain 10−2–10−3 mol/L.
Concentration experiments with NaH for compounds 4 and 7 led us to adopt the working domain
of 10−2 mol/L. Alkaline hydrides can induce a template effect through the cation implicated in the
alcoholate formation. Although the experiment was not carried out systematically for all the compounds,
yields shown in Table 1 indicated that NaH was preferable for the smaller ring formation (n=1, 2),
whereas KH afforded the better yield for n=3. The low-to-fair yields obtained are in the range generally
observed for this type of reaction.

C. Garcia et al. / Tetrahedron: Asymmetry 9 (1998) 4253–4265
4255
Scheme 2.
Table 1
Cyclization yields with hydrides (monomers)
With smaller rings (n=1 and 2), dimers 9–12 depicted in Scheme 3 were additionally obtained in small
amounts (Table 2).
Scheme 3.
In this case, the 2+2 condensation gave macrocycles with higher symmetry than the corresponding
monomers, i.e. D2 symmetry for X_O and C2 symmetry for X_N–C(O)–C6H5 (cis and trans isomers
formed were not separated).
Table 2
Yields of dimer formation

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2.2. Reduction of amides 7, 8
We previously showed2 that an amide function in position 10 is necessary to obtain the spiroketal
compound 2. Replacement by an amine that could be protonated during the acidic intramolecular
ketalization resulted in an incomplete cyclization of the ketodiol precursor. However, reduction of the
carbonyl group or complete amine deprotection of the tertiary amide was achieved in the subsequent
steps. It was controlled using hindered hydrides and appropriate experimental conditions. LiAlH4
afforded the benzylamine while use of LiEt3BH and subsequent hydrolysis of the tetrahedral intermediate
gave the free amine (Scheme 4). Yields ranged from 80% to 87%.
Scheme 4.
2.3. N-Functionalization
Reactivity of the chiral amines obtained was explored in compound 15 (Scheme 5).
For this first investigation, we studied the attachment of a carboxylic arm to help stabilize positively-
charged species entering the cavity. Monoalkylation to give 17 was carried out with 86% yield; inter-
estingly, excess bromo-ester induced quaternary ammonium salt formation. Further saponification with
KOH in methanol afforded the potassium salt from which recovery of the free carboxylic acid proved
difficult, probably because of the specific stability of the salt. Finally, the procedure described for similar
lariat-ethers9 by refluxing in distilled water yielded acid 18 (yield 91%).
2.4. Complexation of IA and IIA cations in THF
For this first investigation, ligands 3, 4 and 5 available in sufficient quantity were considered as
representative of the structural group studied, without considering N-functionalized macrocycles.
Of the various methods used for the determination of complexing properties, UV–visible spectropho-
tometry in tetrahydrofuran (THF) using alkaline or alkaline-earth picrates as spectroscopic probes10 was
chosen, because it is well suited for the study of associations with low stability. Additionally, it showed

C. Garcia et al. / Tetrahedron: Asymmetry 9 (1998) 4253–4265
4257
Scheme 5.
Table 3
Association constants (log β11) for ligand 5 (in THF)
a high sensitivity without consuming too much material. Details for measurements and mathematical
treatments of results using the STAR program11 are given in the Experimental section.
The following complexes between ligand (L) and metal (M) were assumed: ML, ML2 and M2L for
the statistical treatment of results, but the figures obtained for stoichiometry 1:1 (ML), corresponding
to the β11 stability constants, proved satisfactory and it was not necessary to consider higher molecular
associations.
In these experimental conditions, ligands 3 and 4 displayed no measurable complexing properties.
Macrocycle 5 with one additive ethylenoxy unit gave the results in Table 3. Some complexing properties
for alkaline cations were noted, with a selectivity for K+.
In the same experimental conditions, 18-crown-6 used as reference ligand gave for K+: log β11=5.14.
There is thus a factor of 1.9 in stability between ligand 5 and 18-crown-6, which is not surprising as the
preorganization of the cavity is severely disturbed by the spiroketal moiety. Thus the distribution of the
oxygens, which are donor centres in the macrocycle, and also the helical structure induced by the spirane
ring junction affect the complexing properties of the crown-like system.
The selectivity order of 5 for the alkaline series is closely related to the one obtained (in methanol)

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C. Garcia et al. / Tetrahedron: Asymmetry 9 (1998) 4253–4265
for 18-crown-6 (K+>Rb+>Cs+>Na+>Li+) and different from that of 21-crown-7 (Cs+>Rb+>K+»Na+).5c
This observation is in favour of a six coordinating sphere including the five oxygens of the ethylenoxy
units and one oxygen of the spiroketal function in the complex formation. This is very likely since the
simultaneous participation of both oxygens O(1) and O(7) should be excluded due to their staggered
position relatively to the polyether bridge.
If a bicyclic system is attached in place of the simple oligoethylenoxy chain to give cryptant-like
molecules, stabilities associated to the cations are increased, but, as observed here for a monocycle,
distortions are induced in the bicycle by the helical conformation of the spirane part. The characterization
of this effect will be reported in a forthcoming paper.
3. Conclusion
We have synthesized 16 new chiral crown ethers incorporating a tetraoxaspiro[5.5]undecane or
trioxa-azaspiro[5.5]undecane framework in their structure, in a single step, using 1+1 condensations
between chiral precursors 1 or 2 and di-p-tosylate of oligoethylene glycols. Three of the prepared
monomers presented a C2 symmetry (3–5) and nine no symmetry (6–8, 13–18). Interestingly, four dimers
corresponding to a 2+2 condensation were isolated, showing respectively D2 (9, 10) and C2 (11, 12)
symmetries. N-Functionalization of the interesting chiral amines 15, 16 proved straightforward. This
approach should therefore afford numerous models for the design of new receptors for various molecular
or ionic species.
4. Experimental section
4.1. General
Commercial Merck 60F254 silica gel plates were used for thin layer chromatography. Purification of
compounds was carried out by column chromatography using Geduran SI60 40–60 mm silica gel (Merck)
for the flash method and 60 0.063–0.200 mm silica gel (Merck) or neutral 90 aluminium oxide (Merck)
for a normal column. All solvents were distilled before use. Optical rotations were measured for the
sodium D line (589 nm) at 25°C with a Jasco DJP-370 polarimeter (c in g/mL). Infrared (IR) spectra
were obtained using a Perkin–Elmer 881 spectrometer, and bands are expressed in frequency units (ν
cm−1).
Mass spectra were obtained either from our own Hewlett Packard 5989B spectrometer (EI), or a ZAB-
SEQ spectrometer (EI or FAB+ for exact mass determination) at the Centre d’Analyse du CNRS, Solaize,
1
France. NMR spectra were recorded at 400 MHz for H and 100 MHz for 13C on a Bruker AC 400
spectrometer, using CDCl3 as solvent, unless otherwise stated. Chemical shifts δ are reported in ppm,
and coupling constants J in Hz. The assignments of carbons labelled with superscripts *, ‡, § are uncertain
and could be interchanged. The presence of two rotamers linked to the amide function gave broadened
1H spectra, with poor resolution, for compounds 6, 7, 8, 11 and 12.
UV spectra were run with a Uvikon 941 spectrometer. THF (spectrograde) was dried by distillation in
the presence of potassium metal, under nitrogen and with benzophenone ketyl as indicator, just before use
in spectrophotometric measurements. Metal picrates were prepared in deionized water by neutralizing
picric acid with the corresponding metal carbonates. The salts were recrystallized successively from
deionized water and from ethanol, washed with ether and finally dried under vacuum.

C. Garcia et al. / Tetrahedron: Asymmetry 9 (1998) 4253–4265
4259
4.2. Procedure for the macrocyclization reaction
A dry two-necked round bottom flask fitted with a condenser was cooled in an ice bath under argon.
The alkaline hydride (NaH or KH) (9.09 mmol, 4 equiv.) suspended in a mineral oil was carefully washed
three times with dry hexane (stored on sodium) and lastly with freshly distilled anhydrous THF; it was
then placed in the flask. A few millilitres of anhydrous THF were added to the hydride. A solution (2.27
25
mmol in 100 ml anhydrous THF) of the spiroacetal 1 {[α]D +3 (c 0.03; MeOH)} or 2 {[α]D25+35
(c 0.04; CHCl3)} prepared by methods already described1,2 was then added. The mixture was gently
heated (30–40°C) for 1.5 h, with magnetic stirring, until complete formation of the alcoholate. It was
then warmed up to THF reflux and a solution of the oligoethyleneglycol di-p-tosylate (10.0 mmol, 1.1
equiv.) in anhydrous THF (100 mL) was added slowly with an automatic syringe at a moderate rate (15
mL/h). Reflux was continued under argon for five days.
After cooling, the mixture was diluted in water (100 mL) with caution to avoid splashing. The solvent
was evaporated and the mixture extracted with ethyl acetate. After separation, the organic phase was
washed with water and the aqueous phase extracted with chloroform. The combined organic phases were
dried on MgSO4 and evaporated. The residual mixture was purified by column chromatography (eluents
are indicated for each compound).
4.3. (2R,6S,8R)-13,16,19-Trioxacyclo[92,8 ]-1,4,7,10-tetraoxaspiro[5,5]undecane (E,E) 3
Eluent for column chromatography: gradient from AcOEt to AcOEt:MeOH, 90:10. Yield 36% (with
25
22% of dimer 9, see below). Colourless oil. [α]D +4 (c 0.026; CHCl3). IR (film) νmax: 1150–1050
1
(C–O–C). HNMR δ: 3.22 (2H, d, H-5a, H-11a, J5a-5e=11.5); 3.32 (2H, pt, H-3a, H-9a, J3a-3e=11.1,
J
J
3a-2=11.1); 3.43 (2H, dd, H-12B, H-20B, J12B-12A=10.3, J12B-2=6.4); 3.58 (2H, d, H-5e, H-11e,
5e-5a=11.2); 3.59 (2H, dd, H-12A, H-20A, J12A-12B=10.3, J12A-2=4.6); 3.60–3.73 (8H, m, 2H-14, 2H-15,
2H-17, 2H-18); 3.90 (2H, dd, H-3e, H-9e, J3e-3a=11.1, J3e-2=2.6); 4.24 (2H, dddd, H-2, H-8, J2-3a=11.1,
J
2-3e=2.7, J2-12A=4.6, J2-12B=6.4). 13C NMR δ: 67.1 (C-2, C-8); 68.5 (C-3, C-9); 68.6 (C-5, C-11); 70.7
(C-14, C-18)*; 71.0 (C-12, C-20); 71.2 (C-15, C-17)*; 91.7 (C-6). MS (EI) m/z (%): 290 (22, M+·); 272
[5, (M−H20)+·]; 260 [4, (M−CH2O)+·]; 217 (3); 202 (4); 158 (6); 145 (4); 131 (12); 115 (6); 101 (20);
87 (63, C4H7O2 ); 71 (55); 57 (75); 45 (100, C2H5O+). Exact mass found: 290.1365; C13H22O7 requires
+
290.1365.
4.4. (2R,6S,8R)-13,16,19,22-Tetraoxacyclo[122,8]-1,4,7,10-tetraoxaspiro[5,5]undecane (E,E) 4
Eluent for column chromatography: gradient from AcOEt to AcOEt:MeOH, 95:5. Yield 55%
25
(with 2% of dimer 10, see below). Colourless oil. [α]D +29 (c 0.036; CHCl3). IR (CHCl3) νmax
:
1
1150–1050 (C–O–C). H NMR δ: 3.22 (2H, d, H-5a, H-11a, J5a-5e=11.5); 3.23 (2H, pt, H-3a, H-9a,
J
J
3a-3e=11.0, J3a-2=11.0); 3.47 [4H, 2H-12, 2H-23, ABX system, AB part, δB=3.44 (2H, H-12B, H-23B,
12B-12A=11.1, J12B-2=5.2); δA=3.50 (2H, H-12A, H-23A, J12A-12B=11.1, J12A-2=6.5)]; 3.54 (2H, d, H-
5e, H-11e, J5e-5a=11.5); 3.59–3.72 (12H, m, 2H-14, 2H-15, 2H-17, 2H-18, 2H-20, 2H-21); 3.84 (2H, dd,
H-3e, H-9e, J3e-3a=11.3, J3e-2=2.7); 4.39 (2H, X part, dddd, H-2, H-8, J2-3a=11.0, J2-3e=2.7, J2-12A=6.5,
J
2-12B=5.2). 13C NMR δ: 67.9 (C-2, C-3, C-8, C-9); 68.4 (C-5, C-11); 70.5 (C-15, C-20); 70.7 (C-17,
C-18); 70.8 (C-12, C-23); 71.4 (C-14, C-21); 91.7 (C-6). MS (EI) m/z (%): 334 (10, M+·); 304 (1); 274
(4); 247 [3, (M−C4H7O2)+]; 203 (4); 181 (4); 131 (20); 119 (8); 103 (20); 87 (54, C4H7O2 ); 71 (50,
+
C4H7O+); 55 (66); 45 (100, C2H5O+); 43 (68); 28 (100). Exact mass found: 334.1624; C15H26O8 requires
334.1627.

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C. Garcia et al. / Tetrahedron: Asymmetry 9 (1998) 4253–4265
4.5. (2R,6S,8R)-13,16,19,22,25-Pentaoxacyclo[152,8 ]-1,4,7,10-tetraoxaspiro[5,5]undecane (E,E) 5
25
Eluent for column chromatography same as for 4. Yield 27%. Colourless oil. [α]D +15 (c 0.015;
CHCl3). IR (film) νmax: 1150–1050 (C–O–C). 1H NMR δ: 3.25 (2H, H-5a, H-11a, J5a-5e=11.5); 3.29 (2H,
pt, H-3a, H-9a, J3a-3e=11.0, J3a-2=11.0); 3.42 (2H, H-12B, H-26B, dd, J12B-12A=10.3, J12B-2=5.1); 3.56
(2H, H-12A, H-26A, dd, J12A-12B=10.3, J12A-2=6.4); 3.61 (2H, d, H-5e, H-11e, J5e-5a=11.7); 3.63–3.72
(16H, m, 2H-14, 2H-15, 2H-17, 2H-18, 2H-20, 2H-21, 2H-23, 2H-24); 3.87 (2H, dd, H-3e, H-9e,
J
3e-3a=11.4, J3e-2=2.6); 4.36 (2H, dddd, H-2, H-8, J2-3a=11.0, J2-3e=2.6, J2-12A=6.4, J2-12B=5.1). 13C
NMR δ: 67.7 (C-2, C-8); 68.1 (C-3, C-9); 68.5 (C-5, C-11); 70.4 (C-14, C-24)*; 70.5 (C-15, C-23)*;
70.7 (C-12, C-26); 70.9 (C-17, C-21)*; 71.0 (C-18, C-20)*; 91.8 (C-6). MS (EI) m/z (%): 378 (100,
M+·); 360 (15); 347 (9); 334 (6); 322 (26); 304 (24); 289 (5); 260 (23); 247 (9); 241 (3); 217 (33); 203
(17); 173 (18); 158 (10); 133 (28); 101 (45); 87 (44); 71 (43); 55 (47); 45 (97); 29 (53). Exact mass
found: 378.1890; C17H30O9 requires 378.1890.
4.6. (2R,6S,8S)-N-Benzoyl-13,16,19-trioxacyclo[92,8 ]-1,4,7-trioxa-10-azaspiro[5,5]undecane (E,E) 6
Eluent for column chromatography same as for 4. Yield 6% (with 2% of dimer 11, see below).
25
Colourless oil. [α]D +47 (c 0.05; CHCl3). IR (film) νmax: 1640 (C_O amide); 1240 (C–O–C);
1
1150–1050 (C–O–C). H NMR δ: 2.60–4.75 (22H, unresolved massif); 7.40 (5H, Ar–H). 13C NMR
δ: 43.6 (C-9); 51.1 (C-11); 67.4 and 67.7 (C2, C8); 67.3–71.6 (C-3, C-5, C-12, C-14, C-15, C-17, C-18,
C-20); 92.0 (C-6); 127.3, 127.6, 127.8, 128.2, 128.3, 129.4 (Ar–CH); 135.2 (Ar–C); 170.4 (C_O). MS
(EI) m/z (%): 394 (7, MH+); 393 (30, M+·); 375 [2, (M−C3H5O)+·]; 336 (1); 320 (10); 278 (16); 262
(33); 235 (6); 205 (8); 190 (5); 175 (10); 161 (20); 146 (6); 131 (4); 105 (100, Ph–CO+); 77 (24, Ph+);
57 (10); 45 (10, C2H5O+). Exact mass found: 393.1783; C20H27NO7 requires 393.1787.
4.7. (2R,6S,8S)-N-Benzoyl-13,16,19,22-tetraoxacyclo[122,8]-1,4,7-trioxa-10-azaspiro[5,5]undecane
(E,E) 7
Eluent for column chromatography same as for 4. Yield 26% (with 7% of dimer 12, see below).
25
Colourless oil. [α]D +40 (c 0.04; CHCl3). IR (film) νmax: 1640 (C_O amide); 1150–1050 (C–O–C).
1H NMR δ: 2.60–4.75 (17H, unresolved massif); 7.40 (5H, Ar–H). 13C NMR δ: 43.6 and 45.7 (C-9);
49.5 and 51.1 (C-11); 67.3–72.0 (C-2, C-3, C-5, C-8, C-12, C-14, C-15, C-17, C-18, C-20, C-21, C-23);
91.9 and 92.5 (C-6); 127.3, 128.3, 129.7, 129.8 (Ar–CH); 135.1 and 135.3 (Ar–C); 171.0 and 171.2
(C_O). MS (EI) m/z (%): 437 (30, M+·); 407 (1); 364 (9); 322 (14); 306 [28, (M−C8H15O4)+]; 278 (21);
262 (36); 249 (6); 235 (13); 219 (6); 205 (16); 190 (9); 175 (15); 161 (29); 146 (6); 131 (6); 105 (100,
Ph–CO+); 77 (40, Ph+); 57 (19); 45 (25). Exact mass found: 437.2037; C22H31NO8 requires 437.2049.
4.8. (2R,6S,8S)-N-Benzoyl-13,16,19,22,25-pentaoxacyclo[152,8 ]-1,4,7-trioxa-10-azaspiro[5,5]-
undecane (E,E) 8
25
Eluent for column chromatography same as for 4. Yield 28%. Colourless oil. [α]D +50 (c 0.05;
1
CHCl3). IR (film) νmax: 1640 (C_O amide); 1240 (C–O–C); 1150–1050 (C–O–C). H NMR δ:
2.60–4.75 (30H, unresolved massif); 7.40 (5H, Ar–H). 13C NMR δ: 43.7 and 45.3 (C-9); 49.3 and
51.2 (C-11); 67.3–71.6 (C-2, C-3, C-5, C-8, C-12, C-14, C-15, C-17, C-18, C-20, C-21, C-23, C-24,
C-26); 92.0 and 92.5 (C-6); 127.3, 127.5, 128.4, 128.7, 129.2, 129.7 (Ar–CH); 135.4 (Ar–C); 171.4
(C_O). MS (EI) m/z (%): 481 (14, M+·); 438 [1, M−C2H3O)+]; 408(3); 394 [1, (M−C4H7O2)+]; 350

C. Garcia et al. / Tetrahedron: Asymmetry 9 (1998) 4253–4265
4261
[10, (M−C6H11O3)+]; 306 [18, (M−C8H15O4)+]; 278 (9); 262 (16); 262 (36); 235 (8); 205 (9); 160
(17); 131 (3); 105 (100, Ph–CO+); 77 (20, Ph+); 57 (10); 45 (17, C2H5O+). Exact mass found: 481.2318;
C24H35NO9 requires 481.2312.
4.9. (1S,5R,15R,19S,23R,33R)-3,7,10,13,17,21,25,28,31,35,37,38,39,40-Tetradecaoxatetracyclo[36,
11,5, 115,19,119,23,11,33]tetracontane (E,E),(E,E) 9
This compound was isolated simultaneously with compound 3 in the purification step of the reaction
25
mixture. Yield 22%. Colourless oil. [α]D −4 (c 0.025; CHCl3). IR (film) νmax: 1150–1050 (C–O–C).
1H NMR δ: 3.21 (4H, d, H-2a, H-18a, H-20a, H-36a, J2a-2e=11.5); 3.34 (4H, pt, H-4a, H-16a, H-22a,
H-34a, J4a-4e=11.1, J4a-5=11.1); 3.44 (4H, dd, H-6B, H-14B, H-24B, H-32B, J6B-6A=10.4, J6B-5=6.1);
3.57 (4H, d, H-2e, H-18e, H-20e, H-36e, J2e-2a=11.5); 3.58-3.68 (20H, m, H-6A, 2H-8, 2H-9, 2H-11,
2H-12, H-14A, H-24A, 2H-26, 2H-27, 2H-29, 2H-30, H-32A); 3.88 (4H, dd, H-4e, H-16e, H-22e, H-
34e, J4e-4a=11.5, J4e-5=2.6); 4.17 (4H, m, H-5, H-15, H-23, H-33). 13C NMR δ: 67.1 (C-5, C-15, C-23,
C-33); 68.4 (C-4, C-16, C-22, C-34); 68.6 (C-2, C-18, C-20, C-36); 70.6 (C-8, C-12, C-26, C-30)*; 71.0
(C-6, C-14, C-24, C-32); 71.1 (C-9, C-11, C-27, C-29)*; 91.7 (C-1, C-19). MS (EI) m/z (%): 580 (10,
M+·); 562 (3); 548 (2); 368 (4); 331 (15); 302 (3); 289 (4); 256 (22); 231 (11); 217 (12); 203 (18); 189
(4); 173 (9); 145 (16); 131 (27); 111 (30); 99 (27); 87 (73, C4H7O2 ); 71 (69, C4H7O+); 57 (88); 45 (100,
+
C2H5O+). Exact mass found: 580.2731; C26H44O14 requires 580.2731.
4.10. (1S,5R,18R,22S,26R,39R)-3,7,10,13,16,20,24,28,31,34,37,41,43,44,45,46-Hexadecaoxatetra-
cyclo[42,11,5,118,22,122,26,11,39]hexatetracontane (E,E),(E,E) 10
This compound was isolated simultaneously with compound 4 in the purification step of the reaction
25
1
mixture. Yield 2%. Colourless oil. [α]D 0 (c 0.05; CHCl3). IR (film) νmax: 1050–1150 (C–O–C). H
NMR δ: 3.26 (4H, d, H-2a, H-21a, H-23a, H-42a, J2a-2e=11.6); 3.37 (4H, pt, H-4a, H-19a, H-25a, H-40a,
J
4a-4e=11.1, J4a-5=11.1); 3.44 (4H, H-6B, H-17B, H-27B, H-38B, dd, J6B-6A=10.4, J6B-5=6.0); 3.59 (4H,
d, H-2e, H-21e, H-23e, H-42e, J2e-2a=11.6); 3.61 (4H, H-6A, H-17A, H-27A, H-38A, dd, J6A-6B=10.4,
6A-5=5.6); 3.62–3.69 (24H, m, 2H-8, 2H-9, 2H-11, 2H-12, 2H-14, 2H-15, 2H-29, 2H-30, 2H-32, 2H-
J
33, 2H-35, 2H-36); 3.89 (4H, dd, H-4e, H-19e, H-25e, H-40e, J4e-4a=11.1, J4e-5=2.6); 4.22 (4H, dddd,
H-5, H-18, H-26, H-39, J5-4a=11.1, J5-4e=2.6, J5-6A=5.6, J5-6B=6.0). 13C NMR δ: 67.2 (C-5, C-18, C-26,
C-39); 68.4 (C-4, C-19, C-25, C-40); 68.6 (C-2, C-21, C-23, C-42); 70.6 (C-8, C-15, C-29, C-36)*; 70.7
(C-9, C-14, C-30, C-35)*; 71.0 (C-6, C-17, C-27, C-38); 71.2 (C-11, C-12, C-32, C-33)*; 91.7 (C-1,
C-22). Exact mass found (FAB+): 669.3337 (MH+); C30H52O16 requires 669.3333 (MH+).
4.11. (1S,5R,15S,19S,23R,33S)-N,N0-Benzoyl-3,7,10,13,21,25,28,31,37,38,39,40-dodecaoxa-17,35-
diazatetracyclo[36,11,5 ,115,19,119,23,11,33]tetracontane (E,E),(E,E) 11
This compound was isolated simultaneously with compound 6 in the purification step of the reaction
25
mixture. Yield 12%. Colourless oil. [α]D +54 (c 0.05; CHCl3). IR (film) νmax: 1640 (C_O amide);
1150–1050 (C–O–C). 1H NMR δ: 2.60–4.75 (44H, unresolved massif); 7.40 (10H, Ar–H). 13C NMR δ:
43.9 and 45.4 (C-16, C-34); 51.4 and 52.9 (C-18, C-36); 67.7 and 68.2 (C-5, C-15, C-23, C-33); 68.8 and
71.9 (C-2, C-4, C-6, C-8, C-9, C-11, C-12, C-14, C-20, C-22, C-24, C-26, C-27, C-29, C-30, C-32); 92.1
(C-1, C-19); 127.4, 127.6, 128.4, 128.9, 129.8, 131.0 (Ar–CH); 135.5 (Ar–C); 171.4 (2 C_O). MS (EI)
m/z (%): 786 (30, M+·); 768 (7); 713 (2); 681 [16, (M−PhCO)+]; 647 (3); 611 [3, (M−C8H15O4)+]; 567
[5, (M−C10H19O5)+]; 495 (5); 434 (7); 394 (3); 357 (3); 320 (8); 278 (7); 262 (12); 205 (5); 160 (14);

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C. Garcia et al. / Tetrahedron: Asymmetry 9 (1998) 4253–4265
105 (100, PhCO+); 77 (23, Ph+); 57 (7); 45 (11). Exact mass found: 786.3578; C40H54N2O14 requires
786.3575.
4.12. (1S,5R,18S,22S,26R,39S)-N,N0-Benzoyl-3,7,10,13,16,24,28,31,34,37,43,44,45,46-tetradecaoxa-
20,41-diazatetracyclo[42,11,5 ,118,22,122,26,11,39]hexatetracontane (E,E),(E,E) 12
This compound was isolated simultaneously with compound 7 in the purification step of the reaction
25
mixture. Yield 7%. Colourless oil [α]D +32 (c 0.036; CHCl3). IR (film) νmax: 1640 (C_O amide);
1150–1050 (C–O–C). 1H NMR δ: 2.65–4.75 (52H, unresolved massif); 7.40 (10H, Ar–H). 13C NMR δ:
43.9 and 45.4 (C-19, C-40); 51.4 and 52.9 (C-21, C-42); 67.7–68.2 (C-5, C-18, C-26, C-39); 68.8–71.9
(C-2, C-4, C-6, C-8, C-9, C-11, C-12, C-14, C-15, C-17, C-23, C-25, C-27, C-29, C-30, C-32, C-33,
C-35, C-36, C-38); 92.1 (C-1, C-22); 127.4, 127.6, 128.4, 128.9, 129.8, 131.0 (Ar–CH); 135.5 (Ar–C);
171.4 (2 C_O). MS (EI) m/z (%): 875 (1, MH+); 569 (13); 551 (4); 526 (1); 496 (4); 464 (4); 438 (8);
410 (5); 394 (14); 350 (15); 322 (8); 306 (18); 278 (10); 262 (17); 249 (8); 235 (8); 219 (4); 205 (9); 190
(7); 175 (13); 161 (25); 131 (4); 105 (100, Ph–CO+); 77 (14, Ph+); 57 (8). Exact mass found (FAB+):
875.4170 (MH+); C44H62N2O16 requires 875.4177 (MH+).
4.13. (2R,6S,8S)-N-Benzyl-13,16,19,22-tetraoxacyclo[122,8]-1,4,7-trioxa-10-azaspiro[5,5]undecane
(E,E) 13
To a suspension of LiAlH4 (33 mg, 0.86 mmol, 5 equiv.) in dry THF (0.2 mL) was slowly added, at
room temperature and under argon, a solution of benzamide 7 (75 mg, 0.17 mmol) in dry THF (2mL).
The mixture was stirred for 2 h. The excess LiAlH4 was then destroyed by Mihaïlovic’s method.12
After filtration the solvent was removed and the crude material purified by chromatography on silica gel.
25
Eluent: gradient from AcOEt to AcOEt:MeOH, 95:5. Yield 87%. Colourless oil. [α]D +35 (c 0.018;
CHCl3). IR (film) νmax: 1150–1050 (C–O–C). 1H NMR δ: 1.81 (1H, pt, H-9a, J9a-9e=10.9, J9a-8=10.9);
1.85 (1H, d, H-11a, J11a-11e=11.3); 2.67 (1H, d, H-11e, J11e-11a=11.3); 2.78 (1H, br d, H-9e, J9e-9a=10.9,
J9e-8<1); 3.20 (1H, pt, H-3a, J3a-3e=11.2, J3a-2=11.2); 3.24 (1H, d, H-5a, J5a-5e=11.4); 3.38–3.80 (19H,
m, H-5e, 2H-12, 2H-14, 2H-15, 2H-17, 2H-18, 2H-20, 2H-21, 2H-23, NCH2Ph); 3.83 (1H, dd, H-3e,
J
3e-3a=11.2, J3e-2=2.6); 4.27–4.42 (2H, m, H-2, H-8); 7.20–7.40 (5H, m, 5 Ar–H). 13C NMR δ: 54.1
(C-9); 56.2 (C-11); 62.9 (NCH2Ph); 67.8 (C8); 68.2 (C-3); 69.0 (C-2); 70.3 (C-5); 70.5 (C-14)*; 70.6 (C-
15)*; 70.8 (C-20, C-21)*; 71.0 (C-23); 71.5 (C-17, C-18); 72.6 (C-12); 93.1 (C-6); 127.3 (C-40); 128.6
(C-30, C-50); 129.4 (C-20, C-60); 136.8 (C-10). MS (EI) m/z (%): 423 (26, M+·); 393 [6, (M−CH2O)+];
332 [4, (M−C7H7)+]; 292 [3, (M−C6H11O3)+]; 248 (7); 204 (5); 176 (12); 160 (67); 146 (8); 133 (12);
+
120 (28); 91 (100, C7H7 ); 73 (8); 57 (12); 45 (17). Exact mass found: 423.2242; C22H33NO7 requires
423.2257.
4.14. (2R,6S,8S)-N-Benzyl-13,16,19,22,25-pentaoxacyclo[152,8 ]-1,4,7-trioxa-10-azaspiro[5,5]-
undecane (E,E) 14
This compound was prepared from benzamide 8 (60 mg, 0.125 mmol) and LiAlH4 (24 mg, 0.625
mmol, 5 equiv.) following the procedure described for 13. Eluent for column chromatograpy: gradient
25
from AcOEt to MeOH. Yield 80%. Colourless oil. [α]D +28 (c 0.01; CHCl3). IR (film) νmax
:
1
1150–1050 (C–O–C). H NMR δ: 1.87 (1H, pt, H-9a, J9a-9e=13.9, J9a-8=13.9); 1.90 (1H, d, H-11a,
11a-11e=11.3); 2.72 (1H, d, H-11e, J11e-11a=11.3); 2.83 (1H, br d, H-9e, J9e-9a=13.9, J9e-8<1); 3.28 (1H,
d, H-5a, J5a-5e=11.4); 3.29 (1H, pt, H-3a, J3a-3e=11.0, J3a-2=11.0); 3.42 (1H, dd, H-26B, J26B-26A=10.7,
J

C. Garcia et al. / Tetrahedron: Asymmetry 9 (1998) 4253–4265
4263
J26B-8=4.7); 3.45 (1H, dd, H-12B, J12B-12A=10.4, J12B-2=5.5); 3.50–3.78 (21H, m, H-5e, H-12A, H-26A,
2H-14, 2H-15, 2H-17, 2H-18, 2H-20, 2H-21, 2H-23, 2H-24, NCH2Ph); 3.88 (1H, dd, H-3e, J3e-3a=11.2,
J
3e-2=2.6); 4.25–4.37 (2H, m, H-2, H-8); 7.20–7.35 (5H, m, 5Ar–H). 13C NMR δ: 54.1 (C-9); 56.1
(C-11); 62.8 (NCH2Ph); 67.4 (C-8); 68.4 (C-3); 68.7 (C-2); 70.3 (C-5); 70.4 (C-14, C-15)*; 70.5 (C-
17)*; 70.6 (C-18)*; 70.8 (C-12); 70.9 (C-20, C-21, C-23)*; 71.0 (C-24)*; 72.3 (C-26); 93.1 (C-6); 127.3
(C-40); 128.3 (C-30, C-50); 129.3 (C-20, C-60); 136.9 (C-10). MS (EI) m/z (%): 468 (3, MH+); 437 [2,
(M−CH2O)+]; 376 (1); 336 [1, (M−C6H11O3)+]; 292 [2, (M−C8H15O4)+]; 248 [3, M−C10H19O5)+];
+
220 (3); 204 (4); 246 (3); 176 (5); 160 (32); 134 (7); 120 (13); 91 (100, C7H7 ); 57 (23).
4.15. (2R,6S,8S)-13,16,19,22-Tetraoxacyclo[122,8 ]-1,4,7-trioxa-10-azaspiro[5,5]undecane (E,E) 15
To a solution of LiEt3BH in THF (1.37 mL, 1.37 mmol, 2 equiv., 1 M) was added dropwise under argon
a solution of benzamide 7 (300 mg, 0.68 mmol) in dry THF (7 mL). The reaction mixture was stirred for
6 h at room temperature. The excess hydride was destroyed by addition of H2O (0.25 mL, 13.7 mmol,
20 equiv.). The mixture was then heated at 60°C for 1 h in the presence of H2O2 (0.5 mL, 30 volumes) to
oxidize the boroamine intermediate. The solvent was removed and the residue was dissolved in AcOEt.
The organic layer was washed with saturated K2CO3 solution and dried on MgSO4. After evaporation of
the solvent, the residue was purified by chromatography on silica gel with AcOEt:MeOH, 50:50 as eluent.
Yield 86%. Colourless oil. [α]D +28 (c 0.01; CHCl3). IR (film) νmax: 3400 (NH); 1100 (C–O–C). 1H
25
NMR δ: 1.85 (NH); 2.48 (1H, dd, H-9a, J9a-9e=13.4, J9a-8=11.4); 2.55 (1H, d, H-11a, J11a-11e=13.5); 2.70
(1H, d, H-11e, J11e-11a=13.5); 2.95 (1H, dd, H-9e, J9e-9a=13.4, J9e-8=2.4); 3.23 (1H, pt, H-3a, J3a-3e=11.0,
J
3a-2=11.0); 3.25 (1H, d, H-5a, J5a-5e=11.6); 3.44 (1H, dd, H-23B, J23B-23A=11.2, J23B-8=5.0); 3.45 (1H,
dd, H-12B, J12B-12A=11.0, J12B-2=5.0); 3.47 (1H, dd, H-12A, J12A-12B=11.0, J12A-2=4.5); 3.52 (1H, dd,
H-23A, J23A-23B=11.2, J23A-8=7.0); 3.58-3.80 (13H, m, H-5e, 2H-14, 2H-15, 2H-17, 2H-18, 2H-20, 2H-
21); 3.87 (1H, dd, H-3e, J3e-3a=11.0, J3e-2=2.6); 4.15 (1H, dddd, H-8, J8-9a=11.0, J8-9e=2.5, J8-23A=7.0,
J
8-23B=5.0); 4.40 (1H, dddd, H-2, J2-3a=11.0, J2-3e=2.6, J2-12A=4.5, J2-12B=5.0). 13C NMR δ: 47.2 (C-9);
49.4 (C-11); 67.7 (C-2); 68.0 (C-3); 69.4 (C-8); 69.9 (C-5); 70.4 (C-17)*; 70.5 (C-18)*; 70.7 (C-15)#;
70.8 (C-20)#; 71.2 (C-23); 71.5 (C-14)§; 71.6 (C-21)§; 72.4 (C-12); 91.6 (C-6). MS (EI) m/z (%): 333
(17, M+·); 303 (6); 246 [2, (M−C4H7O2)+]; 218 (1); 202 [4, (M−C6H11O3)+]; 188 (1); 172 (3); 158
(6); 144 (3); 128 (13); 114 (6); 100 (6); 87 (20); 70 (100); 70 (41); 57 (18); 45 (32). Exact mass found:
333.1787; C15H27NO7 requires 333.1776.
4.16. (2R,6S,8S)-13,16,19,22,25-Pentaoxacyclo[152,8 ]-1,4,7-trioxa-10-azaspiro[5,5]undecane (E,E)
16
This compound was prepared from benzamide 8 (96 mg, 0.20 mmol) and LiEt3BH (0.4 mL, 0.4 mmol,
2 equiv., 1 M in THF) according to the procedure described for 15. Reaction time: 1 h. Eluent for column
25
chromatography: gradient from AcOEt:MeOH, 90:10 to pure MeOH. Yield 80%. Colourless oil. [α]D
1
+11 (c 0.05; CHCl3). IR (CHCl3) νmax: 3400 (NH); 1100 (C–O–C). H NMR δ: 1.82 (1H, br s, NH);
2.41–2.58 (2H, m, H-9a, H-11a); 2.68 (1H, d, H-11e, J11e-11a=13.4); 2.94 (1H, br d, H-9e, J9e-9a=13.0,
J9e-8<1); 3.23 (1H, d, H-5a, J5a-5e=11.6); 3.25 (1H, pt, H-3a, J3a-3e=11.1, J3a-2=11.1); 3.37 (1H, dd,
H-26B, J26B-26A=10.2, J26B-8=5.0); 3.40 (1H, dd, H-12B, J12B-12A=10.4, J12B-2=4.9); 3.51 (1H, dd, H-
26A, J26A-26B=10.0, J26A-8=8.1); 3.53 (1H, dd, H-12A, J12A-12B=10.4, J12A-2=8.2); 3.58 (1H, d, H-5e,
J
5e-5a=11.6); 3.60–3.70 (16H, m, 2H-14, 2H-15, 2H-17, 2H-18, 2H-20, 2H-21, 2H-23, 2H-24); 3.83
(1H, dd, H-3e, J3e-3a=11.1, J3e-2=2.6); 4.07 (1H, m, H-8); 4.30 (1H, dddd, H-2, J2-3a=11.1, J2-3e=2.6,
2-12A=8.2, J2-12B=4.9). 13C NMR δ: 47.3 (C-9); 49.3 (C-11); 67.3 (C-8); 68.0 (C-3); 68.8 (C-2); 69.8
J

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C. Garcia et al. / Tetrahedron: Asymmetry 9 (1998) 4253–4265
(C-5); 70.8 (C-12); 70.4, 70.5, 70.6, 70.8, 70.9 (C-14, C-15, C-17, C-18, C-20, C-21, C-23, C-24); 72.1
(C-26); 91.5 (C-6). MS (EI) m/z (%): 377 (2, M+·); 347 (6); 304 (1); 246 (3); 202 (2); 158 (5); 132 (14);
114 (7); 87 (19); 70 (71); 45 (100). Exact mass found: 377.2049; C17H31NO8 requires 377.2049.
4.17. (2R,6S,8S)-N-Methyl(ethoxycarbonyl)-13,16,19,22-tetraoxacyclo[122,8]-1,4,7-trioxa-10-
azaspiro[5,5]undecane (E,E) 17
To a suspension of amine 15 (185 mg, 0.55 mmol) and anhydrous K2CO3 (230 mg, 1.66 mmol,
3 equiv.) in dry CH3CN (9 mL) was added dropwise at room temperature and under argon, ethyl
bromoacetate (184 mL, 278 mg, 1.66 mmol, 3 equiv.). The mixture was heated at 40–50°C for 6 h.
The solvent was removed and the residue poured into water. After extraction with CH2Cl2, the organic
layer was dried on MgSO4 and evaporated. The crude material was purified by chromatography on silica-
25
gel (eluent: gradient from AcOEt to AcOEt:MeOH, 95:5). Yield 86%. Brown oil. [α]D +29 (c 0.036;
1
CHCl3). IR (film) νmax: 1740 (C_O); 1100 (C–O–C). H NMR δ: 1.26 (3H, t, 3H-28, J28-27=7.1);
2.35 (1H, pt, H-9a, J9a-9e=11.0, J9a-8=11.0); 2.40 (1H, d, H-11a, J11a-11e=11.3); 2.76 (1H, d, H-11e,
J
11e-11a=11.3); 2.82 (1H, dd, H-9e, J9e-9a=11.0, J9e-8<1); 3.28 (1H, pt, H-3a, J3a-3e=11.1, J3a-2=11.1);
3.31 (1H, d, H-5a, J5a-5e=11.5); 3.33 (2H, s, 2H-24); 3.46 (1H, dd, H-12A, J12A-12B=10.9, J12A-2=6.4);
3.50 (1H, dd, H-23A, J23A-23B=11.4, J23A-8=4.2); 3.54–3.83 (15H, m, H-5e, H-12B, 2H-14, 2H-15, 2H-
17, 2H-18, 2H-20, 2H-21, H-23B); 3.93 (1H, dd, H-3e, J3e-3a=11.1, J3e-2=2.6); 4.16 (2H, q, 2H-27,
J
J
27-28=7.1); 4.36 (1H, dddd, H-8, J8-9a=11.0, J8-9e<1, J8-23A=5.2, J8-23B=4.2); 4.42 (1H, dddd, H-2,
2-3a=11.1, J2-3e=2.6, J2-12A=5.6, J2-12B=6.4). 13C NMR δ: 14.3 (C-28); 52.8 (C-9); 54.9 (C-11); 58.4
(C-24); 60.5 (C-27); 67.5 (C-2); 68.6 (C-3); 68.9 (C-8); 70.3 (C-5); 70.5, 70.7, 70.8, 70.9 (C-15, C-17,
C-18, C-20); 71.2 (C-12); 71.4 (C-14)*; 71.6 (C-21)*; 72.3 (C-23); 93.1 (C-6); 170.1 (C-25). MS (EI)
m/z (%): 419 (37, M+·); 373 (13); 346 (100); 316 (16); 156 (52); 130 (15); 116 (18); 100 (17); 87 (15);
73 (8); 57 (9); 45 (15). Exact mass found: 419.2138; C19H33NO9 requires 419.2138.
4.18. (2R,6S,8S)-N-Methylcarboxy-13,16,19,22-tetraoxacyclo[122,8 ]-1,4,7-trioxa-10-azaspiro[5,5]-
undecane (E,E) 18
A solution of ester 17 (47 mg, 0.112 mmol) in distilled H2O (1 mL) was refluxed for 1 week. After
complete hydrolysis of the ester, the crude solution was washed with CHCl3. Evaporation of the aqueous
25
phase afforded carboxylic acid 18. Yield 91%. Brown oil. [α]D +22 (c 0.04; H2O). IR (CHCl3) νmax
:
1
1740 and 1760 (COOH); 1160–1060 (C–O–C). H NMR (D20) δ: 2.84 (1H, pt, H-9a, J9a-9e=11.3,
9a-8=11.3); 2.86 (1H, d, H-11a, J11a-11e=11.5); 3.22 (1H, pt, H-3a, J3a-3e=11.3, J3a-2=11.3); 3.30–3.63
J
(22H, m, 2H-5, H-9e, H-11e, 2H-12, 2H-14, 2H-15, 2H-17, 2H-18, 2H-20, 2H-21, 2H-23, 2H-24); 3.67
(1H, dd, H-3e, J3e-3a=11.3, J3e-2=2.6); 4.09 (1H, m, H-2); 4.26 (1H, m, H-8). 13C NMR (D20) δ: 53.3
(C-11); 55.0 (C-9); 59.6 (C-24); 67.2 (C-3); 67.3 (C-2); 68.7 (C-5); 69.6 (C-8); 70.1, 70.6, 70.7, 70.9,
71.1, 71.2, 71.9 (C-12, C-14, C-15, C-17, C-18, C-20, C-21, C-23); 93.3 (C-6); 169.9 (C-25). MS (EI)
m/z (%): 391 (16, M+·); 373 (6); 346 [91, (M−COOH)]; 332 (4); 316 (18); 304 [9, (M−C4H7O2)+]; 302
(7); 274 (5); 260 [3, (M−C6H11O3)+]; 244 (4); 230 (3); 216 (6); 200 (4); 186 (4); 172 (6); 158 (5); 144
(10); 128 (100); 100 (29); 87 (40); 73 (22); 57 (42); 45 (68). Exact mass found: 391.1842; C17H29NO9
requires 391.1839.

C. Garcia et al. / Tetrahedron: Asymmetry 9 (1998) 4253–4265
4265
4.19. Complexation experiments
An approx. 5×10−5 molar (C°m) solution of the relevant metal picrate was prepared in THF, 2 cm3
of which was placed in the spectrometer cell. More of this solution was used to prepare a 10−2 M (C°L)
solution of the ligand. Using a microsyringe, amounts of this solution were incrementally added to the cell
through a silicone septum inserted in its Teflon tap. In these conditions, the metal picrate concentration
was kept constant at molarity C°m, the ligand analytical concentration CL being variable. The CL/C°m
ratio was progressively increased first in 0.1 unit steps, then beyond 1 in 1 unit steps and beyond 10 in
10 unit steps up to a value of 100. The pure solvent was used in the reference cell. Experiments were
performed at 20°C.
The Uvikon 941 UV–visible spectrophotometer allows an accuracy better than 0.1 nm in wavelength
and better than 2×10−3 unit in absorption. The spectrum of each solution was recorded from 300 to 450
nm in 0.2 nm steps at speed 200 nm min−1 and bandwidth 2 nm.
A first analysis of the data was performed using the Easy Plot software (location of the peaks, presence
and location of the isobestic points, etc.) to suggest assumptions for further processing. Dissolved in THF,
metal picrates occur only as contact ion pairs.10 Coordination of the cation by the ligand could generate
various sorts of separated ion pairs, formation of which will correspond to more or less pronounced
bathochromic shifts. The spectral data, i.e. for each system absorption for 50 wavelengths distributed on
both sides of the isobestic point for some 20 to 30 spectra, were processed using the STAR11 program,
which provides, for a given model (number and stoichiometry of the complexes formed), both the
P
formation constants and the spectra of the species involved, by minimizing the sum ( ιri2) of the square
of the deviation of the calculated values from the experimental ones. Comparison of the values for the
various statistical parameters (standard deviation σβ, mean residual h|r|i) and residual mean hri and
consideration of the expected experimental accuracy indicates the most satisfactory model. Equilibrium
constants and associated statistical parameters are given in Table 3.
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