Synthesis, NMR conformational studies and host-guest behaviour of new (+)-tartaric acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2004.11.025

A series of dimeric α,α,α′,α′- tetraaryl-1,3-dioxolane-4,5-dimethanol TADDOLs has been prepared and host-guest interactions of these structures have been characterized using a series of ¹H NMR studies. Enantioselective recognition of the chiral alcohols glycidol and menthol was observed for phenyl and 2-naphthyl derivatives. The influence of steric bulk on the dynamic fluxional behaviour of the TADDOL structures was demonstrated by dynamic NMR.

Full text of DOI:10.1016/j.tetasy.2004.11.025

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 635–640
Synthesis, NMR conformational studies and host–guest
behaviour of new (+)-tartaric acid derivatives
a
Sacha Legrand, Hannu Luukinen, Roland Isaksson, Ilkka Kilpel a¨ inen,
b
a
c
d
a
Mikael Lindstr o¨ m, Ian A. Nicholls and C. Rikard Unelius
a,
*
a
Department of Chemistry and Biomedical Sciences, University of Kalmar, SE-39182 Kalmar, Sweden
b
Department of Chemistry, University of Oulu, PO Box 3000, FIN-90014 Oulu, Finland
Institute of Biotechnology and Department of Chemistry, University of Helsinki, PO Box 65, FIN-00014 Helsinki, Finland
c
d
STFI-Packforsk AB, PO Box 5604, SE-11486 Stockholm, Sweden
Received 29 September 2004; accepted 10 November 2004
Available online 8 January 2005
0
0
Abstract—A series of dimeric a,a,a ,a -tetraaryl-1,3-dioxolane-4,5-dimethanol TADDOLs has been prepared and host–guest inter-
actions of these structures have been characterized using a series of H NMR studies. Enantioselective recognition of the chiral alco-
1
hols glycidol and menthol was observed for phenyl and 2-naphthyl derivatives. The influence of steric bulk on the dynamic fluxional
behaviour of the TADDOL structures was demonstrated by dynamic NMR.
ꢀ
2004 Elsevier Ltd. All rights reserved.
1. Introduction
a range of other application areas, for example, for
4
chemical catalysis.
–12
Resolution is of critical importance for the preparation
of enantiomerically pure structures for use in organic
synthesis, and for the study of chiral compounds with
biological activity. Significant research effort has been
focused upon the development of systems and tech-
niques capable of the selective recognition of one of
Recently, a new generation of TADDOLs derived from
cyclohexanediones and (+)-tartaric acid has been de-
scribed, which can accommodate relatively voluminous
1
3
guests. But only a limited number of studies of this
4,15
new class of host compounds have been reported.
1
1
the enantiomers. The often remarkable molecular com-
plementarity displayed by macromolecular recognition
systems provides opportunities for application in the
resolution of racemates. TADDOLs, molecules contain-
Herein, a series of TADDOLs 3a–d (Scheme 1) derived
from the bis-ketal of diethyl (+)-tartrate and 1,4-cyclo-
hexanedione have been synthesized and the dynamic
0
0
1
ing the a,a,a ,a -tetraaryl-1,3-dioxolane-4,5-dimethanol
structure (Fig. 1), were first reported by Narasaka in
behaviour of these TADDOLs has been studied by H
NMR. Recognition of the synthetically useful small chi-
ral alcohols (ꢀ)-menthol 4a, (+)-menthol 4b, (ꢀ)-gly-
cidol 5a and (+)-glycidol 5b (Fig. 2) by the various
TADDOLs has been examined. Resolution of these par-
ticular chiral alcohols, which are used in various asym-
2
1
986, and have been shown to be useful as host mole-
3
cules for the resolution of non-voluminous racemates.
These versatile chiral auxiliaries have also been used in
1
6–23
metric syntheses,
of recent studies.
has been the focus of a number
2
4–28
Ar
Ar
R
R
O
O
OH R : alkyl or cycloalkyl
OH
2. Results and discussion
Ar
Ar
2.1. Synthesis of the new TADDOLs derived from 1,4-
cyclohexanedione and diethyl (+)-tartrate
Figure 1.
*
Corresponding author. Tel.: +46 480 446271; fax: +46 480 446262;
e-mail: rikard.unelius@hik.se
The synthesis of a series of octa-aryl substituted TADD-
OLs was achieved using the methodology developed by
0
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.025

636
S. Legrand et al. / Tetrahedron: Asymmetry 16 (2005) 635–640
Ar
Ar
HO
Ar
Ar
EtO C
OH
2
CO Et
2
EtO C
CO Et
O
2
2
O
O
O
O
O
HO
OH
ArMgBr
o
o
BF .Et O, AcOEt, 0 C
THF, 0 C
3
2
O
O
O
O
Ar
Ar
Ar
EtO C
2
CO Et
HO
OH
2
Ar
1
2 (55%)
3a : Ar = Ph (62%)
3b : Ar = 1-naphthyl (80%)
3c : Ar = 2-naphthyl (75%)
3d : Ar = 2-thiophenyl (33%)
Scheme 1. Synthesis of the TADDOLs 3a–d.
Table 1. Measured coalescence temperatures (T
constants (k
) and Gibbs free energies of activation (DG5) for the
TADDOLs 3a–d in acetone-d
C
), exchange rate
C
6
OH
OH
OH
ꢀ1 a
DG5 (kJ mol
ꢀ1 b
Entry
TADDOL
T
C
(K)
k
C
(s
)
)
d
d
1
2
3
4
3a
3b
3c
3d
220
334
217
229
nr
97
nr
69.6 ± 2
4
5
a
a
4b
5b
c
d
d
nr
210
nr
45.4 ± 2
O
O
OH
= 2.22/p
(DV þ 6J ) s
a
b
c
2
2
AB
ꢀ1
.
k
C
DG5 = 19.14T
ꢀ1
C
(10.32 + log(T
C
/k
C
)) J mol
.
Figure 2.
6
Measured in DMSO-d .
d
nr = not resolved.
1
3
Tanaka et al. The reaction between the 1,4-cyclohex-
anedione 1 and diethyl (2R,3R)-(+)-tartrate in the pres-
ence of BF ÆEt O gave the tetraester 2 in moderate yield.
vealed an AB system comprised of two apparent doublets
( J = 7.02 Hz) arising from the methine hydrogens.
Increasing the temperature resulted in coalescence of
these peaks (T = 229 K). By increasing the temperature
C
to 250 K, the resonance arising from the methine protons
was resolved into a sharp singlet (Fig. 3).
3
3
2
Subsequent reaction of the intermediate 2 with various
aryl Grignard reagents furnished the TADDOLs 3a–d
(
Scheme 1).
2
.2. Dynamic behaviour of the TADDOLs in solution
In contrast to the relatively high coalescence tempera-
ture of 3b, 334 K, the T s of the TADDOLs 3a–c were
C
1
The room temperature H NMR spectra of the 1-naph-
thyl TADDOL, 3b, demonstrated broad peaks corre-
sponding to the resonances of the aromatic and
methine protons. Spectra recorded at elevated tempera-
ture resulted in a sharpening of these peaks. This indi-
cated the presence of dynamic processes, which take
place within the NMR time frame, and suggested a clo-
ser examination of the temperature dependence of the
spectrum of 3b, and those of the other TADDOL deriv-
atives used in this study.
found between 217 and 229 K. This indicated that the
dynamic behaviour of 3b is markedly different from
the other members of this series. Indeed, the free energy
5
barrier (DG ) for the dynamic NMR process in 3b is
higher than for 3d, which we attribute to the greater ste-
ric hindrance arising from the bulkier 1-naphthyl moie-
ties, which inhibit rotation of the side chains on the C–C
bond of the five-membered rings. Interestingly, similar
spectral behaviour was observed for the methylene pro-
tons of the cyclohexane ring, (though resolution could
not be achieved within the temperature range studied)
which indicates restricted interconversion between the
two chair conformations of the cyclohexane ring.
The TADDOLs all demonstrated temperature depen-
dent dynamic behaviour from which coalescence tem-
perature (T ) could be determined for the methine
C
protons, Table 1. Exchange rate constants (k ) were cal-
C
culated for 3b and 3d using the Eyring equation, and
Gibbs free energies of activation (DG ) using k and
T . The spectra of the other TADDOLs were not suf-
C
Collectively, these observations allow us to conclude
that these TADDOLs exhibit dynamic fluxional behav-
iour in solution.
5
C
2
9
ficiently resolved at the lowest temperature studied
(
207 K) to permit the calculation of these factors.
2.3. Host–guest behaviour of the new TADDOLs
1
In the case of the TADDOL 3d, the H NMR spectrum
recorded in acetone-d at low temperature (210 K) re-
6
Previous studies have demonstrated that some TAD-
DOL derived systems can function as chiral hosts for

S. Legrand et al. / Tetrahedron: Asymmetry 16 (2005) 635–640
Table 2. Dissociation constants [K
637
d
(lM)] for complex formation
a
Entry Host (TADDOL) Guest (chiral alcohol)
d
K (lM)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
3a
3a
3a
3a
3b
3b
3b
3b
3c
3c
3c
3c
3d
3d
3d
3d
4a
4b
5a
5b
4a
4b
5a
5b
4a
4b
5a
5b
4a
4b
5a
5b
550 ± 30
100 ± 30
190 ± 60
630 ± 20
b
nc
b
nc
b
nc
b
nc
60 ± 7
0
1
2
3
4
5
6
1040 ± 30
170 ± 30
170 ± 30
30 ± 0.9
10 ± 4
10 ± 1
10 ± 1
a
Apparent dissociation constants were calculated with non-linear line
fitting to a one-site model with the software package Prism (version
3
.03, GraphPad Software, USA).
b
nc = no complexation were observed under these experimental
conditions.
1
1
0
0
.5
.0
.5
.0
1
Figure 3. Variable-temperature H NMR spectra of the methine
protons 3d in acetone-d
6
.
5
,13
1
the resolution of racemic mixture of alcohols.
H
NMR titration experiments were performed in order
to determine the nature and strength of TADDOL–
guest interactions with the small chiral alcohols (ꢀ)-
menthol 4a, (+)-menthol 4b, (ꢀ)-glycidol 5a and
(
+)-glycidol 5b (Fig. 2). By analogy to the X-ray studies
0
.0
2.5
5.0
7.5
10.0
12.5
15.0
1
3
reported by Tanaka et al., it was anticipated that in
non-polar media the guest alcohols would interact with
the TADDOLs through hydrogen bonding interactions
between the hydroxyls of the host and guest. Moreover,
the nature of the pendant side chains and the inherent
chirality of the TADDOLs themselves were expected
to influence the ligand selectivities of the host structures.
Concentration (+)-menthol (mM)
Figure 4. Binding isotherm from a TADDOL 3c/(+)-menthol 4b
titration in CDCl
3
.
TADDOL, the 1-naphthyl derivative, 3b, was perceived
to provide more steric crowding around the hydroxyls
than the 2-naphthyl case, 3c. This is reflected in the re-
sults of the dynamic NMR studies described previously.
In the case of the TADDOL, 3a, developed by Tanaka
1
3
et al., enantioselective recognition of both menthol
and glycidol was observed (Table 2, entries 1–4). In all
cases, the sequential addition of the ligand to the TAD-
DOL led to a concentration dependent downfield shift
of the TADDOL hydroxyl proton resonance. Non-lin-
ear regression analysis of the binding isotherms, Figure
4, afforded apparent dissociation constants (app. K ) for
d
the various interactions. The mechanism of interaction
in CDCl solution, that is, hydrogen bonding between li-
3
Titration studies with the 2-naphthyl derivative, 3c
(Table 2, entries 9 and 10), showed both a reversal in
selectivity for the enantiomers of menthol, as compared
to the phenyl derivative, 3a. However, in the case of gly-
cidol no enantioselectivity was observed. Interestingly,
the affinity of both (ꢀ)- and (+)-glycidol for 3c lie be-
tween the affinities of the favoured and unfavoured
enantiomers of menthol, (ꢀ) and (+), respectively. The
performance of 3c was found to be in stark contrast to
that of 3b, the 1-naphthyl derivative (Table 2, entries
gand and receptor hydroxyl moieties, is comparable to
1
3
that described by Tanaka et al. As reflected in the dif-
ferences in the app. K for the respective complexes, the
d
1
observed enantioselectivity of the TADDOL for men-
thol was superior to that for the small structure glycidol.
5–8). In this case, no changes in the H NMR spectra
of the TADDOL were observed upon ligand addition
(up to 30 mM). This lack of ligand–TADDOL interac-
In the case of the naphthyl group containing TADDOLs
tion was attributed to the excessive steric crowding
around the diol units afforded by the 1-naphthyl groups,
thus eliminating the possibility for access of the ligands
to the TADDOL hydroxyls. This observation concurs
3b and 3c the steric bulk of the pendant side chains is
greater than in the case of 3a. On account of the nature
of the point of attachment of the naphthyl group to the

638
S. Legrand et al. / Tetrahedron: Asymmetry 16 (2005) 635–640
with the inferences drawn from the dynamic NMR stud-
ies described above. The extent to which access is denied
is reflected in the fact that titrations with the small chiral
alcohol, glycidol (C H O ), induced no change in the
namic behaviour of the TADDOLs was demonstrated
by NMR. The observed enantioselectivities suggest the
use of TADDOLs as chiral selectors for chromato-
graphic stationary phase development, in particular for
the resolution of low molecular weight chiral alcohols,
which are valuable tools for use in synthetic organic
chemistry.
3
6
2
chemical shift of the TADDOL hydroxyl proton. Job-
plot analysis of the interaction between 3c and the enan-
tiomers of menthol was performed in order to establish
the stoichiometry of the host–guest system. A 1:1 com-
plex was observed for both the TADDOL 3c/(ꢀ)-men-
thol 4a (Fig. 5) and for TADDOL 3c/(+)-menthol 4b
systems. This result is in contrast to the 1:2 complex ob-
served by Tanaka et al. in X-ray diffraction studies of
4. Experimental
4.1. General
1
3
the TADDOL 3a and 2-methyl-1-butanol. The reason
for the difference in complex stoichiometry is not obvi-
ous from the experimental information available. Possi-
ble explanations may involve the bulkier nature of the
pendant side chains of 3c and the fact that the stoichio-
metries were obtained in different states (solid and
solution).
Melting points were determined on a B u¨ chi 510 instru-
ment and were not corrected. Optical rotation was mea-
sured on a Perkin–Elmer 141 polarimeter. Flash
chromatography and MPLC (medium pressure liquid
chromatography) were performed on silica gel (Merck
3
0
60). High resolution mass spectra were obtained by
electronspray ionization (ESI) or fast atom bombard-
ment (FAB). THF was dried over sodium/benzophe-
1
13
0
0
0
.25
.2
.15
.1
none. The H NMR and the
were recorded at 250/500 MHz and 63/125 MHz, respec-
C NMR spectra
0
tively. CDCl , DMSO-d and acetone-d were used as
6
3
6
solvents while the signals of the solvents served as inter-
nal standards. Chemical shifts (d) are reported in ppm
and J values given in hertz. C NMR spectra were
1
3
0
partially resolved by using DEPT experiment
(h = 135ꢁ). The IR absorptions are cited in cm
ꢀ
1
.05
0
.
4.2. (2R,3R,10R,11R)-Tetrakis(ethyl carboxylate)-1,4,9,12-
tetraoxadispiro[4.2.4.2]tetradecane 2
0
0.5
1
Molar fraction (TADDOL 3c)
Figure 5. Job-plot curve observed for the system TADDOL 3c/(ꢀ)-
menthol 4a.
To a solution of diethyl (2R,3R)-(+)-tartrate (27.7 mL,
1
62 mmol) in AcOEt (170 mL) was added the 1,4-
cyclohexanedione 1 (10 g, 89.2 mmol). The reaction mix-
ture was then cooled to 0 ꢁC and BF ÆEt O (25.7 mL,
Tanaka et al. have previously described the importance
of the pendant side chains on the capacity of TADDOL
systems to discriminate selectively between ligand struc-
3
2
202.7 mmol) was added dropwise. After stirring for 2 h
at this temperature, the reaction mixture was stirred at
rt overnight. The pH of the reaction mixture was ad-
justed to 7/8 with NaOH (2 M). Then the phases were
separated and the aqueous phase was extracted three
times with EtOAc. The combined organic phases were
1
3
tures. The results presented here provide further sup-
port for this and highlight the delicate balance
between structure and recognition characteristics avail-
able in these systems, for example, the reversal in enantio-
selectivity for menthol observed when comparing the
phenyl 3a and 2-naphthyl 3c derivatives.
dried over MgSO and evaporated in vacuo. The crude
4
product was recrystallized from EtOH to give 2 as a
¼
2
D
0
white powder (24 g, 55%). Mp = 95–96 ꢁC; ½aꢁ
1
Studies using the thiophenyl TADDOL 3d demon-
strated high affinity for both glycidol and menthol,
though no enantioselectivity was observed under these
conditions (Table 2, entries 13–16). We suggest that
the observed binding is non-specific in character, and
most probably involves hydrogen bonding-like interac-
tions between the ligands and the sulfur atoms of the
thiophenyl.
ꢀ25:6 (c 1.01, CHCl ). H NMR (500 MHz, CDCl ,
3
3
3
298 K): d 4.80 (s, 4H, 4 · CH), 4.30–4.25 (dq, J = 7.0,
3
J = 2.3, 8H, 4 · CH CH ), 1.96 (s, 8H, 4 · CH ),
2
3
2
3
13
1.33–1.30 (t, J = 7.0, 12H, 4 · CH CH ); C NMR
2
3
(66 MHz, CDCl , 298 K): d 169.7 (4 · CO), 113.2
3
(2 · OCO), 77.3 (4 · CH), 61.8 (4 · OCH CH ), 32.7
2
3
(4 · CH ), 14.0 (4 · OCH CH ); HRMS calcd for
2
2
3
+
C H O Na (M+Na) 511.1791. Found 511.1801.
2
2
32 12
Calcd for C H O : C, 54.09; H, 6.60. Found: C,
32 12
2
2
5
4.45; H, 6.50.
3. Conclusion
4.3. (2R,3R,10R,11R)-Tetrakis(hydroxydiphenylmethyl)-
1,4,9,12-tetraoxadispiro[4.2.4.2]tetradecane 3a
A series of new TADDOLs has been prepared and host–
guest interactions of these structures have been charac-
terized using a series of H NMR titration studies. The
results highlight the significance TADDOL structure
on ligand selectivity. The effect of steric bulk on the dy-
1
A solution of 2 (1 g, 2.32 mmol) in THF (4 mL) was
added to a cold solution of PhMgBr in THF (40 mL),
prepared in situ from Mg (0.9 g, 37.02 mmol) and

S. Legrand et al. / Tetrahedron: Asymmetry 16 (2005) 635–640
639
bromobenzene (5.45 g, 34.71 mmol). The mixture was
stirred for 2 h at 0 ꢁC and at rt overnight. Then a satu-
tinuous gradient from cyclohexane to EtOAc. Recrystal-
lization of the crude crystals from mixture
cyclohexane/EtOAc gave 3d as a grey powder (0.38 g,
a
rated solution of NH Cl was added with some water and
4
20
the aqueous phase was extracted three times with
EtOAc. The combined organic phases were dried over
MgSO4 and evaporated to dryness. Recrystallization
of the crude solid from EtOH gave pure 3a as a white
33%). Mp = 261–264 ꢁC; ½aꢁ ¼ þ40:4 (c 1.04, CHCl ).
D
IR (KBr): 3284. H NMR (250 MHz, CDCl , 298 K):
3
1
3
3
3
d 7.31–7.28 (dd, J = 5.1, J = 1.1, 4H, H arom), 7.26–
3
3
7.24 (dd, J = 5.13, J = 1.1, 4H, H arom), 7.20–7.18
20
3
powder (1.32 g, 62%). Mp = 267–270 ꢁC; ½aꢁ ¼ ꢀ29:6
(dd,
7.07 (dd, J = 3.6, J = 1.2, 4H, H arom), 7.02–
J = 3.6,
J = 1.2, 4H,
H
arom), 7.09–
D
3
3
(
accordance to the work published by Tanaka et al.
c 0.98, CHCl ). The spectroscopic data found were in
3
1
3
3
6.99 (dd, J = 5.1, J = 3.6, 4H, H arom), 6.95–6.91
3
3
3
dd, J = 5.1, J = 3.6, 4H, H arom), 4.70 (br s, 4H,
(
4
4
1
· OH), 4.41 (s, 4H, 4 · CH), 1.59–1.48 (m, 8H,
4.4. (2R,3R,10R,11R)-Tetrakis[hydroxydi(1-naphthyl)-
methyl]-1,4,9,12-tetraoxadispiro[4.2.4.2]tetradecane 3b
13
· CH ); C NMR (66 MHz, CDCl , 298 K): 149.7,
2
3
45.5 (both C arom), 126.6 (CH arom), 126.55 (CH
arom), 126.52 (C arom), 125.8 (CH arom), 125.7 (CH
arom), 125.5 (CH arom), 109.8 (2 · OCO), 82.5
Same procedure as for compound 3a with 1-bromo-
naphthalene (15.9 g, 76.81 mmol) instead of bromobenz-
ene. The crude product was purified by MPLC using
cyclohexane/EtOAc (1:4) as the eluent. Recrystallization
from EtOH of the resulting crystals gave 3b as a white
(
4 · CH), 75.7 (4 · C(C H ) ), 33.4 (4 · CH );
6
5 2
2
+
HRMS calcd for C H O S Na (M+Na) 999.0387.
46 40
8 8
Found 999.0363. Anal. Calcd for C H O S : C,
46 40
8 8
20
56.53; H, 4.13; S, 26.25. Found: C, 56.80; H, 4.50; S,
25.80.
powder (5.44 g, 80%). Mp = 235–240 ꢁC; ½aꢁ ¼ ꢀ47:5
D
1
(
c 1.01, CHCl ). H NMR (500 MHz, DMSO-d ,
3 6
3
53 K): d 8.00–6.70 (m, 56H, H arom), 5.50–4.90 (2 br
s, 8H, 4 · CH and 4 · OH), 2.20–1.00 (m, 8H,
4.7. Dynamic NMR
1
3
4
1
1
1
· CH ); C NMR (125 MHz, DMSO-d , 353 K): d
2
6
1
45.0, 134.0, 133.9, 133.4, 132.1, 131.9, 131.0, 128.2,
27.7, 127.6, 127.1, 126.1, 124.7, 124.4, 124.2, 124.0,
23.8, 123.7, 123.2 (all C arom or CH arom, and
H NMR spectra were recorded at 500 MHz. The sol-
vents used were acetone-d6 (99.8%) and DMSO-d6
(99.8%).
OCO), 80.1, 71.1 (4 · CH and 4 · C(C H ) ), 31.4
6
5 2
+
(
4 · CH ); HRMS calcd for C H O Na (M+Na)
2
94 72
8
4.8. NMR titrations
1
C H O : C, 84.91; H, 5.46. Found: C, 84.63; H,
5
351.5125. Found 1351.5104. Anal. Calcd for
9
4
72
8
A solution of the TADDOL (5 mM) in CDCl3 was
titrated with consecutive addition of a solution, in the
same solvent, containing the host (37.5, 50 or
100 mM) and the TADDOL (5 mM). H NMR spectra
were recorded at 250 MHz at 298 K. CDCl (99.9%) was
.67.
1
4.5. (2R,3R,10R,11R)-Tetrakis[hydroxydi(2-naphthyl)-
methyl]-1,4,9,12-tetraoxadispiro[4.2.4.2]tetradecane 3c
3
used a solvent. Apparent dissociation constants were
calculated with non-linear line fitting to a one-site model
with the software package Prism (version 3.03, Graph-
Pad Software, USA). Each regression is based on not
less than seven data points and is presented with the
Same procedure as for compound 3a with 2-bromo-
naphthalene (15.9 g, 76.81 mmol) instead of bromobenz-
ene. The crude yellow crystals were recrystallized from
EtOH to give 3c as a white powder (5.1 g, 75%).
20
1
2
Mp = 190–196 ꢁC; ½aꢁ ¼ ꢀ42:6 (c 1.22, CHCl ).
H
standard error. The goodness of fit (R ) was 0.9182 or
better in all cases.
D
3
NMR (500 MHz, CDCl , 298 K): d 8.16 (s, 4H, H
3
arom), 7.89–7.86 (m, 12H, H arom), 7.75–7.68 (m,
1
(
2H, H arom), 7.58–7.50 (m, 16H, H arom), 7.41–7.37
m, 8H, H arom), 7.28–7.24 (dd, J = 1.7, J = 8.7, 4H,
4.9. Job plot
3
3
H arom), 4.86 (s, 4H, 4 · CH), 4.55 (br s, 4H,
Samples were prepared in CDCl (99.9%) containing dif-
3
1
3
4
· OH), 1.43–1.33 (m, 8H, 4 · CH );
C NMR
2
ferent molar fractions of the TADDOL 3c and a chiral
alcohol 4a or 4b from 0 to 1.0, with a constant total con-
centration of 8.3 mM. H NMR spectra were recorded
(
66 MHz, CDCl , 298 K): d 142.6, 140.2, 132.66,
3
1
32.60, 132.56, 128.6, 128.0, 127.5, 127.31, 127.28 (all
C arom), 127.0, 126.6, 126.1, 126.0, 125.7 (all CH arom),
09.4 (2 · OCO), 80.9 (4 · CH), 78.6, 77.2 (both
C(C H ) ), 33.7 (4 · CH ); HRMS calcd for
1
at 250 MHz at 298 K.
1
6
5 2
2
+
C H O Na (M+Na) 1351.5125. Found 1351.5129.
9
4
72
8
Acknowledgements
Anal. Calcd for C H O : C, 84.91; H, 5.46. Found:
9
4
72
8
C, 84.65; H, 5.62.
We thank P a¨ ivi Joensuu and Sari Ek (University of
Oulu, Finland), and Einar Nilsson (University of Lund,
Sweden) for HRMS measurements, Ari Koskela (Insti-
tute of Biotechnology, University of Helsinki, Finland)
and Ulla Jacobsson (Royal Institute of Technology,
Stockholm, Sweden) for assistance with the DNMR
experiments, and the University of Kalmar (Sweden)
for financial support.
4.6. (2R,3R,10R,11R)-Tetrakis[hydroxydi(2-thienyl)-
methyl]-1,4,9,12-tetraoxadispiro[4.2.4.2]tetradecane 3d
Same procedure as for compound 3a with 2-bromothio-
phene (2.83 g, 17.35 mmol) instead of bromobenzene.
The crude product was purified by MPLC using a con-

640
S. Legrand et al. / Tetrahedron: Asymmetry 16 (2005) 635–640
15. Tanaka, K.; Fujiwara, T.; Urbanczyk-Lipkowska, Z. Org.
Lett. 2002, 4, 3255–3257.
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