Lower rim functionalized chiral resorc[4]arenes derived from citronellal and carvone

Article abstract of DOI:10.1055/s-2005-872108

In our work we have provided the lower rim of resorc[4]arenes with stereogenic centers as well as with functional groups. For the synthesis of these lower rim functionalized chiral resorc[4]arenes we have used aldehydes derived from citronellal and carvone. In general, the functional group was introduced into the aldehyde compound prior to the final cyclization step. In the case of substitution of the functional group by chloride ions during the cyclization step under standard conditions (HCl-EtOH, Δ), hydrochloric acid was replaced by the conjugated acid of the functional group. Another strategy is the introduction of the iodo group at the lower rim of a resorc[4]arene, which can be easily substituted by good nucleophiles and mild bases without protection of the upper rim. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872108

PAPER
2701
Lower Rim Functionalized Chiral Resorc[4]arenes Derived from Citronellal
and Carvone
C
hira
l
Resorc[4]arenes
i
Deriv
c
edfrom Cit
hronellal and
aCarvone el Schiendorfer, Jochen Mattay*
Organische Chemie I, Fakultät für Chemie, Universität Bielefeld, Postfach 100131, 33501 Bielefeld, Germany
Fax +49(0)5211066417; E-mail: mattay@uni-bielefeld.de
Received 14 February 2005; revised 28 April 2005
using chiral amines or a-amino alcohols, the resulting di-
Abstract: In our work we have provided the lower rim of re-
sorc[4]arenes with stereogenic centers as well as with functional
groups. For the synthesis of these lower rim functionalized chiral re-
sorc[4]arenes we have used aldehydes derived from citronellal and
astereomers can also be separated by chromatography.
Chiral resorc[4]arenes can also be obtained from this type
of reaction with amino acids such as L-proline.8 One chiral
carvone. In general, the functional group was introduced into the al- resorc[4]arene with four methylene L-proline ethyl ester
substituents is known in the literature.9 Chiral C2-symmet-
dehyde compound prior to the final cyclization step. In the case of
substitution of the functional group by chloride ions during the cy-
rical resorc[4]arenes based on 1,3-oxazine rings have
clization step under standard conditions (HCl–EtOH, D), hydro-
been published by Böhmer et al.10 The synthesis and
chloric acid was replaced by the conjugated acid of the functional
chiral discrimination of chiral C4-symmetrical re-
group. Another strategy is the introduction of the iodo group at the
sorc[4]arenes (Figure 1) have been described amongst
lower rim of a resorc[4]arene, which can be easily substituted by
good nucleophiles and mild bases without protection of the upper
rim.
others by Mattay et al.11
Key words: resorcarenes, macrocycles, chirality, molecular recog-
nition, aldehydes, cyclizations
The chemistry of the resorc[4]arenes dates back to the
year 1872 when Baeyer obtained a crystalline product
formed by benzaldehyde and resorcinol under acidic con-
ditions.1 Within the following decades the structure of this
condensation product was identified as a bowl-shaped tet-
rameric macrocycle.2 Due to this structural feature the re-
sorc[4]arenes play an important role as basic skeletons for
the synthesis of host compounds for a variety of guest
molecules. They are easily available and the main struc-
ture can be modified variously to get receptors with de-
fined structure and function. Therefore they have attracted
much interest in the field of supramolecular chemistry.3
Especially, the synthesis of chiral resorc[4]arenes for in-
vestigations of chiral discrimination during host–guest in-
teractions is still a challenge. In 1996, Konishi et al.
reported the modification of only one of the eight phenolic
hydroxy groups e.g. by benzylation, which leads to a race-
mic mixture of monofunctionalized asymmetric re-
sorc[4]arenes.4 None of these racemic mixtures were
separated into enantiomerically pure compounds. Another
strategy is the monofunctionalization with a chiral com-
pound like (S)-(+)-10-camphorsulfonyl chloride.5 The
separation of both mono-O-esterified diastereomers was
achieved by RP-18 HPLC. The chiral auxiliary can be re-
moved in a suitable step of the synthetic route. A further
approach to synthesize inherently chiral resorc[4]arenes is
the preparation of 1,3-oxazolidine-6 or 1,3-oxazine7 deriv-
atives of the resorc[4]arene by Mannich reaction. When
Figure 1
Because of their capacity as host molecules, most of the
research with resorc[4]arenes relates to the upper rim (de-
fined by the eight phenolic hydroxy groups). Only a few
applications require the modification of the lower rim (de-
fined by the four methine bridges). The introduction of
sulfur groups for example is highly desirable in the case
of building self-assembled monolayers (SAMs) on gold.12
The research in building SAMs is growing rapidly be-
cause this procedure opens the possibility to modify sur-
faces for various applications. Almost any surface can be
equipped with functionalized monolayers. Especially, the
self-assembly of organosulfur adsorbates on gold has at-
tracted considerable attention, based on the strong adsorp-
tion of disulfides, sulfides and thiols. Adsorbates
containing a receptor cavity are particular interesting for
building layers capable of the selective binding of small
organic molecules, e.g. for chiral recognition. The re-
sorc[4]arenes are excellent molecules to form monolayers
as well as to realize the chiral recognition.
In this paper, we deal only with the lower rim of re-
sorc[4]arenes to introduce both chiral information and
functional groups. Instead of using a chiral auxiliary for
the modification of the upper rim we used enantiomerical-
SYNTHESIS 2005, No. 16, pp 2701–2712
Advanced online publication: 04.08.2005
DOI: 10.1055/s-2005-872108; Art ID: T01705SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5

2702
M. Schiendorfer, J. Mattay
PAPER
ly pure aldehydes in the cyclization step to get enantio-
merically pure resorc[4]arenes. As result, the
a
modification of the upper rim with non-chiral compounds
yields to separable diastereomers. Moreover, we synthe-
sized resorc[4]arenes with various functional groups at
the lower rim, in particular sulfur groups, to get a series of
resorc[4]arenes for different applications.
The aldehydes we were looking for in the literature should
have a stereogenic center at the b-position (as near to the
carbonyl group or rather the cavity as possible), carry a
functional group at the terminal position of the alkyl chain
that is stable to the cyclization conditions, and should be
accessible as easily as possible.
Scheme 1
Thus we substituted the hydroxy group of 1 with chloride
to get (3S)-6-chloro-1,1-dimethoxy-3-methylhexane (4)
as shown in Scheme 2. The reaction displayed the best
yields with N-chlorosuccinimide and triphenylphosphine
in THF. After cyclization of 4 under standard conditions
we obtained tetrachlororesorc[4]arene 5 as an oil or as a
white solid in good yield after purification by column
chromatography (CHCl3–MeOH, 10:1).
Suitable aldehydes or rather acetals were identified as
(4S)-6,6-dimethoxy-4-methyl-1-hexanol (1) derived from
commercially available S-citronellal in a two-step synthe-
sis and as both enantiomers of 3-(bromoethyl)-4-methyl-
pentanal (2), derived from commercially available
enantiomers of carvone in
(Figure 2).
a four-step synthesis
A much better leaving group than the chloro group is the
mesylate group, that can be introduced by reaction of 1
with methanesulfonyl chloride in CH2Cl2 in the presence
of triethylamine to get acetal 6. The cyclisation of 6 could
not be performed under standard conditions because of the
substitution of the mesylate group by chloride. That is
why we used methanesulfonic acid as the acid component,
so substitutions have no effect. The resulting resorc[4]ar-
ene 7 did not crystallize either, so purification was
achieved by column chromatography with the same eluent
as used for 5.
Figure 2
Citronellal-based resorc[4]arenes
S-Citronellal itself is not suitable for the resorc[4]arene
synthesis. The double bond is probably protonated in the
strong acidic media, whereby the resulting tertiary carbon
cation opens the way to build terpenoid systems.
Compound 1 was synthesized by protection of the carbo-
nyl group of S-citronellal as dimethyl acetal followed by
ozonization of the double bond with reductive treatment
as described in the literature.13 Within our work, enantio-
merically pure citronellal was not commercially available
any longer so we prepared it by oxidation of S-citronellol
with o-iodoxybenzoic acid (IBX).14 Cyclization of 1 with
resorcinol under standard conditions led to tetrahydroxy-
resorc[4]arene 3 in good yield after crystallization
(Scheme 1). The X-ray structure of 3 in comparison to the
X-ray structure of 5 will be published separately.15
Because it was too difficult to chemically differentiate be-
tween the phenolic hydroxy groups at the upper rim and
the aliphatic hydroxy groups at the lower rim, especially
in the presence of the multitude of hydroxy groups, the
modification of this resorc[4]arene was not practical.
Scheme 2
Synthesis 2005, No. 16, 2701–2712 © Thieme Stuttgart · New York

PAPER
Chiral Resorc[4]arenes Derived from Citronellal and Carvone
2703
Compound 6 is the main compound for further introduc- clization. The substitution of the mesylate group of 7 by
tions of several functional groups followed by the cycliza- thiolate ion, for example, led to deprotonation of the up-
tion process as shown in Scheme 3. The ethylthio group is per rim followed by inter- or intramolecular connection of
interesting with regard to building monolayers on gold lower rim and upper rim via ether bridges. So we synthe-
surfaces. Although monolayers of sulfide-substituted re- sized resorc[4]arenes 13 and 19 containing protected thiol
sorc[4]arenes get stabilized best by van der Waals interac- groups, the latter will be described later. Compound 13 it-
tions between long alkyl chains at the lower rim,16 we self is also an interesting compound to form monolayers
decided to introduce a short alkyl chain to prevent steric because the terminal aromatic sulfide-fragment possibly
hindrance between the methyl group at the stereogenic stabilizes a monolayer via van-der-Waals interactions.
center and the terminal alkyl chain of the sulfide. Besides, The introduction of the p-methoxybenzylthio group was
the methyl group at the stereogenic center possibly con- achieved in the same manner as the introduction of the
tributes to stabilize a monolayer in the case of denticula- ethylthio group. The p-methoxybenzylthio group is stable
tion. Intermolecular hydrogen bonds of the unsubstituted against the acidic conditions of the cyclization process
upper rim can also stabilize a monolayer supplementary if and normally can be removed with trifluoroacetic acid,
they do not promote the formation of dimeric capsules. Hg(OOCCH3)2 and H2S. Unfortunately the deprotection
Compound 8 can be obtained by substitution of the mes- reaction with compound 13 failed. Neither the product nor
ylate group of 6 by ethanethiolate followed by the cycli- 13 was obtained.
zation with resorcinol under standard conditions. We
observed that 9 forms a gel when a solution of it in
CHCl3–MeOH (10:1) was concentrated after column
chromatography. In fact, near the end of the concentration
The iodo group as another good leaving group with regard
to direct modifications at the resorc[4]arene was intro-
duced by stirring 6 with NaI in acetone at room tempera-
ture. In the case of the iodo group, the cyclization must be
process all methanol was removed and only a residue of
carried out with HI as the acid component to prevent sub-
chloroform as nonpolar solvent was left. In order to inves-
stitution by chloride. Despite of the reactive lower rim and
the reactive upper rim the resorc[4]arene, compound 15 is
astonishingly stable when stored at room temperature in
the air.
tigate the influence of the functional groups at the lower
rim and the gelation behavior of nonpolar solvents we
synthesized a resorc[4]arene with ethoxy groups at the
lower rim to distuingish between sulfur and oxygen. The
synthesis was carried out in the same way as the synthesis
of 9. Within our work we observed that all lower rim sub-
stituted resorc[4]arenes form gels of unpolar solvents
more or less in the same manner, with the exception of 3
that crystallized very well. In fact, the gelation behavior
seems to be related to the presence of functional groups at
the lower rim and the inability to crystallize. But there
must be also another reason as described later regarding
the resorc[4]arene 17.
As well as sulfides or disulfides, thiols also attracted at-
tention as organosulfur adsorbates to form monolayers.
The introduction of a thiol group in our systems is still a
challenge, however, and has not yet been successful. The
acidic cyclization of a thiol-substituted acetal with resor-
cinol e.g. led to the formation of thioacetals that are stable
Figure 3 Part of the 13C NMR spectrum of 5
against acid and consequently are not available for the cy-
Scheme 3
Synthesis 2005, No. 16, 2701–2712 © Thieme Stuttgart · New York

2704
M. Schiendorfer, J. Mattay
PAPER
Because of the stereogenic center at the lower rim, the 13C
NMR spectra (Figure 3) of all resorc[4]arenes described
Carvone-based resorc[4]arenes
in this paper show that the two quarternary carbon atom Compound 2 was synthesized from carvone in a four step
pairs 3/5 and 2/6 of the resorcinol units are not equal. At route as described in the literature.17 First the exocyclic
first glance we wanted to take advantage of this effect for double bond of carvone was hydrogenated with H2–PtO2
specific functionalization of the upper rim. Unfortunately followed by ozonization of the cyclic double bond. Treat-
the influence of the methyl group at the stereogenic center ment of the resulting lactone with gaseous HBr in metha-
is too small, as it could take an effect in the regioselective nol leads to the bromo ester (inversion of configuration),
modification of the upper rim as first experiments (meth- which can be reduced by DIBAL-H to get the desired bro-
ylation, benzylation) have shown. For these experiments mo aldehyde. The synthesis of the corresponding re-
we carried out the defunctionalization of 6 to obtain a re- sorc[4]arene 20 was carried out with HBr as the acidic
sorc[4]arene that is inert at the lower rim and only contrib- component to prevent substitution of bromide by chloride
utes the chiral information. We have obtained 17 by (Scheme 5). We synthesized both the R- and the S-enanti-
reductive substitution of the mesylate group of 6 with omers of 20. Like all lower rim functionalized re-
LiAlH4 followed by the cyclization with resorcinol under sorc[4]arenes of the citronellal system, except 3, the
standard conditions. Compound 17 as a resorc[4]arene resorc[4]arenes of the carvone system do not crystallize,
without functional groups at the lower rim neither crystal- so the purification must be achieved by column chroma-
lizes as expected nor forms a gel as observed for function- tography (CHCl3–MeOH, 10:1).
alized resorc[4]arenes.
In our work we tried to find reactions for the modification
of the lower rim of a resorc[4]arene without protection of
the upper rim (Scheme 4). Stirring of tetrachlorore-
sorc[4]arene 5 with NaI in acetone at room temperature
for seven days led to tetraiodoresorc[4]arene 15 in good
yield. The iodide ion is a very good nucleophile and a
weak base, so the upper rim did not get deprotonated. The
reaction proceeded much faster when using 7 as starting
compound. After 24 hours stirring at room temperature,
the product was obtained in high yield. As mentioned be-
Scheme 5
fore, we have synthesized resorc[4]arene 19 with four
For the introduction of the chloro group we performed the
ring opening procedure of the lactone 21 with gaseous
HCl (Scheme 6). The resulting chloro ester 22 was re-
duced by DIBAL-H in the same manner as the bromo es-
ter to get the chloro aldehyde 23. The cyclization of 23
under standard conditions led to the chloro functionalized
resorc[4]arene 24. The ring opening of the lactone 21 with
a large excess of MsOH in methanol to introduce the me-
sylate group as a good leaving group failed. The resulting
ester is methoxy functionalized.
thioester groups at the lower rim. The thioacetate is a
weak base and does not deprotonate the upper rim when
stirring with 15 for substitution of the iodo group. The cy-
clization of the thioacetate-substituted acetal 18 to obtain
resorc[4]arene 19 failed because of the strong acidic con-
ditions. These conditions led to hydrolysis of the thioace-
tate group and consequently to the release of the thiol
groups that obstruct the cyclization as described before.
As the thioester group represents a protected thiol group,
the treatment of 19 with alkali should release thiol groups
at the lower rim. After realization of the cleavage, we ob-
served the presence of unspecific disulfide groups whose
formation could not be completely prevented.
Scheme 4
Scheme 6
Synthesis 2005, No. 16, 2701–2712 © Thieme Stuttgart · New York

PAPER
Chiral Resorc[4]arenes Derived from Citronellal and Carvone
2705
2,8,14,20-Tetrakis[(2¢S)-5¢-hydroxy-2¢-methylpentyl]re-
As described for the citronellal-derived systems, the com-
pounds of the carvone system also showed that the two
quarternary carbon atom pairs 3/5 and 2/6 of the resorci-
nol units are not equal. However, the differences between
the carvone system and the citronellal system are not sig-
nificant. In order to get a carvone-based resorc[4]arene
without a functional group at the lower rim, we first pro-
tected the bromo aldehyde 2 as dimethyl acetal 25. The
bromo atom was removed by reductive substitution with
LiAlH4. Finally, the cyclization with the acetal 26 was
carried out under standard conditions to yield the re-
sorc[4]arene 27R (Scheme 7). As an alternative to this
synthetic route we found another route that saves one step.
For the first route we used the S-enantiomer of carvone
whereas the R-enantiomer was used for the following
route. Beginning with the bromo ester 28, treatment with
LiAlH4 led to the alcohol 29 that could be selectively ox-
idized to the aldehyde 30 by IBX. In the final step, the cy-
clization was carried out under standard conditions to get
the resorc[4]arene 27S. Compound 27 showed the same
behavior relating to the consistency in nonpolar solvents
which is a basis for further investigations.
sorc[4]arene (3)
To a cooled (0 °C) solution of resorcinol (1.46 g, 13.3 mmol), H2O
(2 mL) and concd aq HCl (2 mL) in EtOH (2 mL), compound 1
(2.34 g, 13.3 mmol) was added under an argon atmosphere. The
mixture was stirred at r.t. for 30 min, at 80 °C for 4 h and cooled to
r.t. The precipitate was filtered and washed with ice-cold EtOH–
H2O (1:4). The crude product was purified by crystallization from
EtOH to get 3.
Yield: 2.19 g (2.46 mmol, 74%); colorless crystals; mp 265 °C (de-
comp.); [a]D21 +9.5 (c 1.0 in MeOH).
IR (film): 3272 (OH), 2942, 1618, 1503, 1446, 1380, 1296, 1164,
1085, 1056 cm–1.
1H NMR (methanol-d4): d = 0.95 (d, 3 H, 3J = 6.3 Hz, H-13), 1.26–
1.31 (m, 1 H, H-10), 1.32–1.38 (m, 1 H, H-9), 1.44–1.51 (m, 1 H,
H-10), 1.54–1.65 (m, 2 H, H-11), 1.77 (ddd, 1 H, 2J = 13.5,
3J = 8.5, 6.2 Hz, H-8), 2.39 (ddd, 1 H, 2J = 13.5, 3J = 9.9, 4.9 Hz, H-
8), 3.55 (t, 2 H, 3J = 6.6 Hz, H-12), 4.47 (dd, 1 H, 3J = 9.9, 6.2 Hz,
H-7), 6.21 (s, 1 H, H-4), 7.18 (s, 1 H, H-1).
13C NMR (methanol-d4): d = 20.04 (prim., C-13), 31.44 (sec., C-
11), 31.93 (tert., C-7), 34.70 (sec., C-10), 42.39 (sec., C-8), 63.52
(sec., C-12), 104.03 (tert., C-4), 124.67 (quat., C-2,6), 124.99 (tert.,
C-1), 125.97 (quat., C-2,6), 152.84 (quat., C-3,5), 153.18 (quat., C-
3,5).
MALDI-TOF (matrix DHB): m/z = 889 [M + H]+, 912 [M + Na]+,
1H and 13C NMR spectra were recorded on a Bruker Am Avance
DRX 500 (500 MHz) spectrometer. IR spectra were recorded with
a Jasco FT/IR-410 spectrometer. MALDI-TOF mass spectra were
obtained with a PerSeptive Biosystems Voyager-DE mass spec-
trometer (N2-Laser, 337 nm). CI mass spectra were obtained with a
Shimadzu GC17A/GCMS-QP5050A gas chromatograph. Optical
rotation was measured with a Perkin-Elmer 341 polarimeter. The el-
ementary analyses were obtained with a Perkin-Elmer 240 appara-
tus. Mps were determined with a Büchi B-540 melting point
apparatus and are uncorrected. Chromatographic separations were
performed on silica gel 60 (SiO2, Merck, particle size 0.040–0.063
mm). Reagents were obtained from Merck, Sigma-Aldrich, Fluka
and Acros. Et2O and THF were freshly distilled from KOH and
dried (LiAlH4) if necessary. HI was freshly regenerated by distilla-
tion with phosphoric acid. CHCl3 was p. A. grade and stabilized
with amylene. All other solvents were p.A. grade and all purchased
chemicals were either p. A. grade or reagent grade and were used
without purification.
928 [M + K]+.
Anal. Calcd for C52H72O12: C, 70.24; H, 8.16. Found: C, 69.86; H,
8.40.
(3S)-6-Chloro-1,1-dimethoxy-3-methylhexane (4)
To a stirred and cooled (0 °C) solution of Ph3P (4.90 g, 18.7 mmol)
in anhyd THF (50 mL) under argon NCS (2.54 g, 19.0 mmol) was
added in portions. The mixture was stirred for a few minutes at r.t.,
and then a solution of 1 (3.00 g, 17.0 mmol) in anhyd THF (20 mL)
was dropped into the suspension. The mixture was stirred overnight
at r.t., concentrated in vacuum, mixed with n-pentane and filtered.
After thorough washing of the residue with n-pentane, the com-
bined extracts were concentrated to give the crude product of 4,
which was purified by distillation (45 °C, 0.2 mbar).
Yield: 2.49 g (12.8 mmol, 75%); [a]D22 –7.0 (c 1.0 in MeOH).
IR (film): 2958, 2834, 1462, 1380, 1192, 1125, 1054, 957, 913, 651
cm–1.
Scheme 7
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2706
M. Schiendorfer, J. Mattay
PAPER
1H NMR (CDCl3): d = 0.90 (d, 3 H, 3J = 6.6 Hz, H-9), 1.25 (dddd,
1 H, 2J = 13.2, 3J = 10.5, 7.8, 5.4 Hz, H-3), 1.37 (ddd, 1 H, 3J = 5.2,
10), 3.27 (s, 3 H, H-7/8), 3.27 (s, 3 H, H-7/8), 4.18 (t, 2 H, 3J = 6.7
Hz, H-1), 4.42 (dd, 1 H, 3J = 6.2, 3J = 5.0 Hz, H-6).
13C NMR (CDCl3): d = 19.57 (prim., C-9), 26.52 (sec., C-2), 28.60
(tert., C-4), 32.67 (sec., C-3), 37.30 (prim., C-10), 39.28 (sec., C-5),
52.52 (prim., C-7/8), 52.58 (prim., C-7/8), 70.23 (sec., C-1), 102.92
(tert., C-6).
MS (CI, NH3): m/z (%) = 255 (1) [M + H]+, 223 (100) [M – H –
CH2O]+, 159 (1) [M + H – CH3SO3H]+, 127 (10) [M + H –
CH3SO3H – MeOH]+.
3
3
2
2J = 13.2, J = 7.7 Hz, H-5), 1.43 (dddd, 1 H, J = 5.3, J = 13.2,
3J = 10.6, 5.3 Hz, H-3), 1.54–1.59 (m, 1 H, H-4), 1.60 (ddd, 1 H,
3J = 5.6, 2J = 13.2, 3J = 6.4 Hz, H-5), 1.69–1.83 (m, 2 H, H-2), 3.27
(s, 3 H, H-7/8), 3.28 (s, 3 H, H-7/8), 3.49 (dt, 2 H, 4J = 1.9, 3J = 6.7
Hz, H-1), 4.43 (dd, 1 H, 3J = 6.4, 5.2 Hz, H-6).
13C NMR (CDCl3): d = 19.65 (prim., C-9), 28.52 (tert., C-4), 30.00
(sec., C-2), 34.24 (sec., C-3), 39.33 (sec., C-5), 45.28 (sec., C-1),
52.39 (prim., C-7/8), 52.62 (prim., C-7/8), 102.94 (tert., C-6).
MS (CI, isobutane): m/z (%) = 193 (1) [M – H]+, 163/165 (100/37)
[M – H – CH2O]+, 131/133 (11/4) [M – H – CH2O – MeOH]+, 127
(6) [M – H – CH2O – HCl]+.
2,8,14,20-Tetrakis[(2¢S)-5¢-methanesulfonyl-2¢-methylpen-
tyl]resorc[4]arene (7)
To a cooled (0 °C) solution of resorcinol (1.30 g, 11.8 mmol),
MsOH (2 mL) and H2O (1 mL) in EtOH (5 mL), (4S)-6,6-
dimethoxy-4-methylhexylmethanesulfonate (6; 3.00 g, 11.8 mmol)
was added under an argon atmosphere. The mixture was stirred at
r.t. for 30 min, at 80 °C for 4 h, cooled to r.t., mixed with CHCl3 (50
mL) and washed with H2O (20 mL). The organic layer was dried
(Na2SO4), filtered, concentrated and purified by column chromatog-
raphy (silica gel; CHCl3–MeOH, 10:1) to get 7.
Anal. Calcd for C9H19ClO2: C, 55.52; H, 9.84. Found: C, 55.51; H,
9.65.
2,8,14,20-Tetrakis[(2¢S)-5¢-chloro-2¢-methylpentyl]re-
sorc[4]arene (5)
To a cooled (0 °C) solution of resorcinol (1.98 g, 18.0 mmol) and
concd aq HCl (3.5 mL) in EtOH (10 mL) 5 (3.50 g, 18.0 mmol) was
added under an argon atmosphere. The mixture was stirred at r.t. for
30 min, at 80 °C for 4 h, cooled to r.t., mixed with CHCl3 (100 mL)
and washed with H2O (30 mL). The organic layer was dried
(Na2SO4), concentrated and purified by column chromatography
(silica gel; CHCl3–MeOH, 10:1) to get 5.
Yield: 2.52 g (2.10 mmol, 71%); slightly yellow solid; mp 133–
140 °C (decomp.); [a]D23 +7.4 (c 1.0 in MeOH).
IR (KBr): 3366, 2927, 1620, 1503, 1445, 1345, 1170, 1084, 919,
812 cm–1.
1H NMR (methanol-d4): d = 0.96 (d, 3 H, 3J = 6.2 Hz, H-13), 1.33–
Yield: 4.27 g (4.43 mmol, 98%); colorless solid; mp 222 °C (de-
1.41 (m, 2 H, H-9, H-10), 1.53–1.59 (m, 1 H, H-10), 1.74 (ddd, 1 H,
comp.); [a]D22 +15.7 (c 1.0 in MeOH).
3
2J = 13.7, J = 8.3, 5.5 Hz, H-8), 1.75–1.85 (m, 2 H, H-11), 2.51
IR (KBr): 3311 (br), 2958, 1618, 1499, 1444, 1380, 1293, 1160,
1079, 845 cm–1.
(ddd, 1 H, 3J = 10.2, 3J = 3.9, 2J = 13.7 Hz, H-8), 3.03 (s, 3 H, H-
2
3
14), 4.24 (dt, 2 H, J = 1.4, J = 6.5 Hz, H-12), 4.46 (dd, 1 H,
3J = 10.2, 5.5 Hz, H-7), 6.22 (s, 1 H, H-4), 7.24 (s, 1 H, H-1).
1H NMR (methanol-d4): d = 0.95 (d, 3 H, 3J = 6.1 Hz, H-13), 1.33–
1.42 (m, 2 H, H-9, H-10), 1.53–1.60 (m, 1 H, H-10), 1.71 (ddd, 1 H,
13C NMR (methanol-d4): d = 19.81 (prim., C-13), 28.17 (tert., C-9),
31.81 (tert., C-7), 32.01 (sec., C-11), 34.16 (sec., C-10), 37.31
(prim., C-14), 41.99 (sec., C-8), 72.38 (sec., C-12), 104.08 (tert., C-
4), 124.67 (quat., C-2/6), 125.26 (tert., C-1), 126.22 (quat., C-2/6),
152.79 (quat., C-3/5), 153.22 (quat., C-3/5).
3
2J = 13.5, J = 8.5, 5.6 Hz, H-8), 1.79–1.88 (m, 2 H, H-11), 2.46
(ddd, 1 H, 3J = 10.4, 3.9 Hz, 2J = 13.5 Hz, H-8), 3.55 (t, 2 H,
3J = 6.7 Hz, H-12), 4.48 (dd, 1 H, 3J = 10.4, 5.6 Hz, H-7), 6.22 (s, 1
H, H-4), 7.18 (s, 1 H, H-1).
13C NMR (methanol-d4): d = 19.87 (prim., C-13), 31.61 (tert., C-9),
31.62 (tert., C-7), 31.78 (sec., C-11), 35.89 (sec., C-10), 42.34 (sec.,
C-8), 46.23 (sec., C-12), 104.08 (tert., C-4), 124.35 (quat., C-2/6),
125.02 (tert., C-1), 126.04 (quat., C-2/6), 152.88 (quat., C-3/5),
153.30 (quat., C-3/5).
MALDI-TOF (matrix DHB): m/z = 1021 [M – C7H15O3S]+, 1201
[M + H]+, 1223 [M + Na]+, 1239 [M + K]+.
Anal. Calcd for C56H80O20S4: C, 55.98; H, 6.71. Found: C, 54.64; H,
6.30.
MALDI-TOF (matrix DHB): m/z = 841 [M – C6H12Cl]+, 961 [M +
(3S)-6-Ethylthio-1,1-dimethoxy-3-methylhexane (8)
H]+, 983 [M + Na]+, 999 [M + K]+.
A suspension of NaH (60% in paraffin; 1.65 g, 41.3 mmol) was
washed under an argon atmosphere with anhyd n-hexane (3 × 20
mL) and suspended in anhyd THF (50 mL). The mixture was cooled
to 0 °C and a solution of ethanethiol (2.33 g, 37.5 mmol) in anhyd
THF (25 mL) was added dropwise. After stirring at r.t. for 30 min a
solution of (4S)-6,6-dimethoxy-4-methylhexylmethansulfonate (6;
6.36 g, 25.0 mmol) in anhyd THF (25 mL) was added dropwise and
stirred at r.t. overnight. The reaction mixture was cooled, washed
with aq NaOH (10%; 2 × 50 mL), diluted with Et2O (100 mL) and
washed with H2O (3 × 30 mL). The organic layer was dried
(Na2SO4), filtered, concentrated and purified by column chromatog-
raphy (silica gel; C6H6–EtOAc, 5:1) to get 8.
Anal. Calcd for C52H68Cl4O8: C, 64.86; H, 7.12. Found: C, 64.70; H,
7.37.
(4S)-6,6-Dimethoxy-4-methylhexylmethanesulfonate (6)
MsCl (4.32 g, 37.7 mmol) in anhyd CH2Cl2 (50 mL) was added to a
cooled (0 °C) solution of (4S)-6,6-dimethoxy-4-methyl-1-hexanol
(1; 6.04 g, 34.3 mmol) and Et3N (5.21 g, 51.5 mmol) in CH2Cl2 (100
mL) under an argon atmosphere over 20 min. After stirring at r.t. for
2 h, the suspension was washed successively with H2O (50 mL), sat.
aq NH4Cl (50 mL) and H2O (50 mL). The combined aq layers were
extracted with CH2Cl2 (30 mL). The combined organic layers were
dried (Na2SO4), concentrated and purified by column chromatogra-
phy (silica gel; cyclohexane–EtOAc, 1:1) to get 6.
Yield: 5.03 g (22.8 mmol, 91%); colorless liquid; [a]D27 –6.0 (c 1.0
in CHCl3).
Yield: 7.19 g (28.3 mmol, 83%); colorless oil; [a]D22 +3.7 (c 1.0 in
MeOH).
IR (film): 2930, 2829, 1458, 1378, 1262, 1192, 1125, 1055, 967,
913 cm–1.
3
IR (film): 2940, 2832, 1465, 1354, 1174, 1126, 1055, 958, 920, 826
cm–1.
1H NMR (CDCl3): d = 0.89 (d, 3 H, J = 6.4 Hz, H-9), 1.19–1.25
3
(m, 1 H, H-3), 1.22 (t, 3 H, J = 7.4 Hz, H-11), 1.35 (ddd, 1 H,
2J = 13.4, 3J = 7.7, 5.2 Hz, H-5), 1.39 (dddd, 1 H, 2J = 13.5,
3J = 10.9, 5.5, 5.5 Hz, H-3), 1.52–1.63 (m, 4 H, H-2, H-4, H-5),
2.46–2.49 (m, 2 H, H-1), 2.50 (q, 2 H, 3J = 7.4 Hz, H-10), 3.27 (d,
1H NMR (CDCl3): d = 0.90 (d, 3 H, 3J = 6.5 Hz, H-9), 1.22 (dddd,
1 H, 2J = 13.1, 3J = 10.7, 7.7, 5.4 Hz, H-3), 1.38 (ddd, 1 H,
3
2J = 10.3, J = 9.7, 5.0 Hz, H-5), 1.34–1.44 (m, 1 H, H-3), 1.54–
1.62 (m, 2 H, H-4, H-5), 1.65–1.81 (m, 2 H, H-2), 2.97 (s, 3 H, H-
Synthesis 2005, No. 16, 2701–2712 © Thieme Stuttgart · New York

PAPER
Chiral Resorc[4]arenes Derived from Citronellal and Carvone
2707
3 H, 4J = 0.5 Hz, H-7/8), 3.28 (d, 3 H, 4J = 0.5 Hz, H-7/8), 4.43 (dd,
1 H, 3J = 6.4, 5.2 Hz, H-6).
13C NMR (CDCl3): d = 14.79 (prim., C-11), 19.71 (prim., C-9),
25.91 (sec., C-10), 26.94 (sec., C-1), 28.79 (tert., C-4), 31.86 (sec.,
C-2), 36.41 (sec., C-3), 39.42 (sec., C-5), 52.32 (prim., C-7/8),
52.62 (prim., C-7/8), 103.05 (tert., C-6).
1H NMR (CDCl3): d = 0.88 (d, 3 H, 3J = 6.6 Hz, H-9), 1.16 (dddd,
2 3 3
1 H, J = 13.4, J = 10.5, 7.8, 3J = 5.4, H-3), 1.16 (t, 3 H, J = 7.0
Hz, H-11), 1.33 (dddd, 1 H, 3J = 5.4, 7.9, 2J = 11.0, 3J = 5.4 Hz, H-
3), 1.34 (ddd, 1 H, 2J = 13.6, 3J = 8.1, 5.3 Hz, H-5), 1.47–1.63 (m,
2
3
3 H, H-2, H-4), 1.61 (ddd, 1 H, J = 13.6, J = 6.6, 5.5 Hz, H-5),
4
3.26 (s, 3 H, H-7/8), 3.26 (s, 3 H, H-7/8), 3.35 (dt, 2 H, J = 1.4,
3J = 6.8 Hz, H-1), 3.43 (q, 2 H, 3J = 7.0 Hz, H-10), 4.43 (dd, 1 H,
3J = 6.6, 5.1 Hz, H-6).
MS (CI, NH3): m/z (%) = 219 (1) [M – H]+, 189 (100) [M – H –
CH2O]+, 157 (1) [M – H – CH2O – MeOH]+.
13C NMR (CDCl3): d = 15.19 (prim., C-11), 19.66 (prim., C-9),
27.09 (sec., C-3), 28.89 (tert., C-4), 33.52 (sec., C-2), 39.37 (sec.,
C-5), 52.14 (prim., C-7/8), 52.59 (prim., C-7/8), 66.02 (sec., C-10),
70.89 (sec., C-1), 102.99 (tert., C-6).
MS (CI, NH3): m/z (%) = 203 (1) [M – H]+, 173 (100) [M – H –
CH2O]+, 141 (11) [M – H – CH2O – MeOH]+, 127 (6) [M – H –
CH2O – CH3CH2OH]+.
Anal. Calcd for C11H24O2S: C, 59.95; H, 10.98. Found: C, 59.94; H,
10.68.
2,8,14,20-Tetrakis[(2¢S)-5¢-ethylthio-2¢-methylpentyl]re-
sorc[4]arene (9)
To a cooled (0 °C) solution of resorcinol (0.83 g, 7.58 mmol), concd
aq HCl (2 mL) and H2O (1 mL) in EtOH (8 mL), (3S)-6-ethylthio-
1,1-dimethoxy-3-methylhexane (8; 1.67 g, 7.58 mmol) was added
under an argon atmosphere. The mixture was stirred at r.t. for 30
min, at 80 °C for 4 h, cooled to r.t., and mixed with CHCl3 (50 mL),
sat. aq NH4Cl (30 mL) and H2O (20 mL). After phase separation the
aq layer was extracted with CHCl3 (1 × 20 mL). The combined or-
ganic layers were dried (Na2SO4), filtered, concentrated and puri-
fied by double column chromatography [silica gel; (a) CHCl3–
MeOH, 10:1; (b) C6H6–EtOH, 5:1) to get 9.
Anal. Calcd for C11H24O3: C, 64.67; H, 11.84. Found: C, 65.35; H,
11.87.
2,8,14,20-Tetrakis[(2¢S)-5¢-ethoxy-2¢-methylpentyl]re-
sorc[4]arene (11)
To a cooled (0 °C) solution of resorcinol (0.58 g, 5.26 mmol), concd
aq HCl (1 mL) and H2O (0.5 mL) in EtOH (3 mL), (3S)-6-ethoxy-
1,1-dimethoxy-3-methylhexane (10; 1.00 g, 5.26 mmol) was added
under an argon atmosphere. The mixture was stirred at r.t. for 30
min, at 80 °C for 4 h, cooled to r.t., mixed with EtOAc (50 mL) and
washed with H2O (20 mL). The organic layer was dried (Na2SO4),
filtered, concentrated and purified by column chromatography (sil-
ica gel; CHCl3–MeOH, 10:1) to get 11.
Yield: 1.53 g (1.44 mmol, 76%); as a colorless solid; mp 123–
129 °C; [a]D27 +5.4 (c 1.0 in MeOH).
IR (KBr): 3272 (br), 2927, 1620, 1501, 1449, 1387, 1293, 1161,
1093, 839 cm–1.
1H NMR (methanol-d4): d = 0.94 (d, 3 H, 3J = 6.2 Hz, H-13), 1.18–
1.26 (m, 1 H, H-10), 1.25 (t, 3 H, 3J = 7.4 Hz, H-14), 1.30–1.40 (m,
2 H, H-9, H-10), 1.52–1.66 (m, 2 H, H-11), 1.72 (ddd, 1 H,
Yield: 1.13 g (1.13 mmol, 86%); colorless solid; mp 127–131 °C;
[a]D27 +5.7 (c 1.0 in MeOH).
IR (KBr): 3258 (br), 2928, 2867, 1620, 1501, 1445, 1295, 1155,
1087, 847 cm–1.
3
2J = 13.5, J = 8.3, 5.8 Hz, H-8), 2.41–2.54 (m, 3 H, H-8, H-12),
2.54 (q, 2 H, 3J = 7.4 Hz, H-15), 4.46 (dd, 1 H, 3J = 10.3, 5.8 Hz, H-
7), 6.22 (s, 1 H, H-4), 7.18 (s, 1 H, H-1).
1H NMR (methanol-d4): d = 0.95 (d, 3 H, 3J = 6.5 Hz, H-13), 1.18
(t, 3 H, 3J = 7.0 Hz, H-14), 1.24–1.31 (m, 1 H, H-10), 1.32–1.38 (m,
1 H, H-9), 2.48 (dddd, 1 H, 2J = 12.8, 3J = 10.5, 5.2, 5.2 Hz, H-10),
13C NMR (methanol-d4): d = 15.49 (prim., C-14), 19.97 (prim., C-
13), 26.83 (sec., C-15), 27.96 (sec., C-12), 31.62 (tert., C-7/9),
31.73 (tert., C-7/9), 32.89 (sec., C-11), 37.89 (sec., C-10), 42.48
(sec., C-8), 104.06 (tert., C-4), 124.49 (quat., C-2/6), 125.01 (tert.,
C-1), 126.05 (quat., C-2/6), 152.82 (quat., C-3/5), 153.24 (quat., C-
3/5).
2
3
1.53–1.68 (m, 2 H, H-11), 1.80 (ddd, 1 H, J = 13.5, J = 8.0, 6.4
Hz, H-8), 2.34 (ddd, 1 H, 2J = 13.5, 3J = 9.6, 5.2 Hz, H-8), 3.41 (t,
2 H, 3J = 6.6 Hz, H-12), 3.47 (q, 2 H, 3J = 7.0 Hz, H-15), 4.46 (dd,
1 H, 3J = 9.6, 6.4 Hz, H-7), 6.21 (s, 1 H, H-4), 7.18 (s, 1 H, H-1).
13C NMR (methanol-d4): d = 15.56 (prim., C-14), 20.07 (prim., C-
13), 28.45 (tert., C-9), 31.69 (sec., C-11), 31.92 (tert., C-7), 34.82
(sec., C-10), 42.48 (sec., C-8), 67.16 (sec., C-15), 72.13 (sec., C-
12), 104.05 (tert., C-4), 124.79 (quat., C-2/6), 125.04 (tert., C-1),
125.91 (quat., C-2/6), 152.88 (quat., C-3/5), 153.18 (quat., C-3/5).
MALDI-TOF (matrix DHB): m/z = 919 [M – C8H17S]+, 1065 [M +
H]+, 1087 [M + Na]+, 1103 [M + K]+.
Anal. Calcd for C60H88O8S4: C, 67.63; H, 8.32. Found: C, 67.67; H,
8.67.
MALDI-TOF (matrix DHB): m/z = 871 [M – C8H17O]+, 1001 [M +
(3S)-6-Ethoxy-1,1-dimethoxy-3-methylhexane (10)
H]+, 1023 [M + Na]+, 1039 [M + K]+.
A suspension of NaH (55% in paraffin; 0.57 g, 12.9 mmol) was
washed under an argon atmosphere with anhyd n-hexane (3 × 5 mL)
and suspended in anhyd THF (20 mL). The mixture was cooled to
0 °C and a solution of EtOH (0.54 g, 11.8 mmol) in anhyd THF (10
mL) was added dropwise. After stirring at r.t. for 30 min, a solution
of (4S)-6,6-dimethoxy-4-methylhexylmethansulfonate (6; 2.00 g,
7.86 mmol) in anhyd THF (10 mL) was added dropwise and stirred
under reflux overnight. The reaction mixture was cooled, diluted
with Et2O (50 mL) and washed with brine (50 mL) and H2O (3 × 20
mL). The combined aq layers were extracted with Et2O (20 mL).
The combined organic layers were dried (Na2SO4), filtered, concen-
trated and purified by column chromatography (silica gel; C6H6–
EtOAc, 5:1) to get 10.
Anal. Calcd for C60H88O12: C, 71.97; H, 8.86. Found: C, 71.91; H,
8.90.
(3S)-6-(p-Methoxybenzyl)thio-1,1-dimethoxy-3-methylhexane
(12)
A suspension of NaH (60% in paraffin; 0.27 g, 6.60 mmol) was
washed under an argon atmosphere with anhyd n-hexane (3 × 5 mL)
and suspended in anhyd THF (20 mL). The mixture was cooled to
0 °C and a solution of p-methoxybenzylmercaptan (0.93 g, 6.00
mmol) in anhyd THF (5 mL) was added dropwise. The mixture was
stirred at r.t. for 30 min, then a solution of (4S)-6,6-dimethoxy-4-
methylhexylmethanesulfonate (6; 1.02 g, 4.00 mmol) in anhyd THF
(5 mL) was added dropwise and the mixture was stirred at r.t. over-
night. The reaction mixture was cooled, washed with aq NaOH
(10%; 2 × 20 mL), diluted with Et2O (20 mL) and washed with H2O
(3 × 10 mL). The organic layer was dried (Na2SO4), filtered, con-
centrated and purified by column chromatography (silica gel;
CHCl3–MeOH, 200:1) to get 12.
Yield: 1.23 g (6.04 mmol, 77%); colorless liquid; [a]D25 –4.8 (c 1.0
in CHCl3).
IR (film): 2936, 2855, 1458, 1378, 1193, 1122, 1055, 968, 915, 803
cm–1.
Synthesis 2005, No. 16, 2701–2712 © Thieme Stuttgart · New York

2708
M. Schiendorfer, J. Mattay
PAPER
Yield: 1.12 g (3.58 mmol, 90%); colorless liquid; [a]D27 –8.8 (c 1.0
in CHCl3).
with H2O (50 mL). The organic layer was dried (Na2SO4), concen-
trated and purified by distillation (72 °C, 0.03 mbar) to get 14.
IR (film): 2935, 2832, 1610, 1511, 1463, 1249, 1175, 1125, 1053,
830 cm–1.
Yield: 1.93 g (6.76 mmol, 86%); colorless liquid; [a]D22 –6.7 (c 1.0
in MeOH).
1H NMR (CDCl3): d = 0.87 (d, 3 H, 3J = 6.5 Hz, H-9), 1.18 (dddd,
1 H, 2J = 13.1, 3J = 10.4, 7.7, 5.4 Hz, H-3), 1.31–1.38 (m, 2 H, H-3,
H-5), 1.48–1.61 (m, 4 H, H-2, H-4, H-5), 2.35–2.38 (m, 2 H, H-1),
3.27 (s, 3 H, H-7/8), 3.28 (s, 3 H, H-7/8), 3.64 (s, 2 H, H-10), 3.77
(s, 3 H, H-17), 4.42 (dd, 1 H, 3J = 6.5, 5.2 Hz, H-6), 6.82 (d, 2 H,
3J = 8.6 Hz, H-13, H-15), 7.20 (d, 2 H, 3J = 8.6 Hz, H-12, H-16).
13C NMR (CDCl3): d = 19.68 (prim., C-9), 26.53 (sec., C-1), 28.76
(tert., C-4), 31.49 (sec., C-2), 35.64 (sec., C-10), 36.36 (sec., C-3),
39.35 (sec., C-5), 52.28 (prim., C-7/8), 52.61 (prim., C-7/8), 55.22
(prim., C-17), 102.98 (tert., C-6), 113.81 (tert., C-13 and C-15),
129.82 (tert., C-12 and C-16), 130.54 (quat., C-11), 158.49 (quat.,
C-14).
IR (film): 2936, 2829, 1460, 1381, 1222, 1193, 1124, 1056, 961,
811 cm–1.
1H NMR (CDCl3): d = 0.90 (d, 3 H, H-9), 1.23 (dddd, 1 H,
2J = 13.2, 3J = 10.2, 7.8 Hz, 5.3 Hz, H-3), 1.34–1.44 (m, 2 H, H-3,
H-5), 1.56–1.62 (m, 2 H, H-4, H-5), 1.73–1.81 (m, 2 H, H-2), 3.11–
3.19 (m, 2 H, H-1), 3.28 (s, 3 H, H-7/8), 3.29 (s, 3 H, H-7/8), 4.43
(dd, 1 H, 3J = 5.2, 6.2 Hz, H-6).
13C NMR (CDCl3): d = 7.23 (sec., C-1), 19.72 (prim., C-9), 28.29
(tert., C-4), 30.90 (sec., C-2), 37.87 (sec., C-3), 39.35 (sec., C-5),
52.42 (prim., C-7/8), 52.66 (prim., C-7/8), 102.96 (tert., C-6).
MS (CI, NH3): m/z (%) = 285 (1) [M – H]+, 255 (40) [M – H –
CH2O]+, 240 (100) [M – H – CH2O – MeOH + NH3]+, 223 (1) [M –
H – CH2O – MeOH]+, 127 (11) [M – H – CH2O – HI]+, 95 (14)
[M – H – CH2O – MeOH – HI]+.
MS (CI, NH3): m/z (%) = 313 (1) [M + H]+, 281 (22) [M + H –
MeOH]+, 159 (8) [M – SCH2PhOMe]+, 129 (35) [M – SCH2PhOMe
– CH2O]+, 127 (7) [M – SCH2PhOMe – MeOH]+, 121 (100) [p-
methoxybenzyl group]+.
Anal. Calcd for C9H19IO2: C, 37.78; H, 6.69. Found: C, 37.69; H,
6.61.
Anal. Calcd for C17H28O3S: C, 65.35; H, 9.03. Found: C, 65.36; H,
8.75.
2,8,14,20-Tetrakis[(2¢S)-5¢-iodo-2¢-methylpentyl]re-
sorc[4]arene (15)
Variant 1
2,8,14,20-Tetrakis[(2¢S)-5¢-(p-methoxybenzyl)thio-2¢-methyl-
pentyl]resorc[4]arene (13)
To a cooled (0 °C) solution of resorcinol (0.39 g, 3.50 mmol) and
concd aq HI (1 mL) in EtOH (4 mL), (3S)-6-iodo-1,1-dimethoxy-3-
methylhexane (14; 1.00 g, 3.50 mmol) was added under an argon at-
mosphere. The mixture was stirred at r.t. for 30 min, at 80 °C for 4
h, cooled to r.t., mixed with CHCl3 (50 mL) and washed with H2O
(30 mL). The organic layer was dried (Na2SO4), concentrated and
purified by column chromatography (silica gel; CHCl3–MeOH,
10:1) to get 15.
To a cooled (0 °C) solution of resorcinol (0.35 g, 3.20 mmol) and
concd aq HCl (1 mL) in EtOH (5 mL), (3S)-6(p-methoxyben-
zyl)thio-1,1-dimethoxy-3-methylhexane (12; 1.00 g, 3.20 mmol)
was added under an argon atmosphere. The mixture was stirred at
r.t. for 30 min, at 80 °C for 4 h, cooled to r.t., and mixed with CHCl3
(50 mL), sat. aq NH4Cl (30 mL) and H2O (20 mL). After phase sep-
aration the organic layer was dried (Na2SO4), filtered, concentrated
and purified by column chromatography (silica gel; CHCl3–MeOH,
10:1) to get 13.
Yield: 1.05 g (0.79 mmol, 90%); colorless solid.
Yield: 0.83 g (0.58 mmol, 72%); colorless solid; mp 124 °C;
Variant 2
[a]D27 +3.1 (c 1.0 in MeOH).
A solution of 5 (0.40 g, 0.42 mmol) and NaI (1.77 g, 11.8 mmol) in
anhyd acetone (6 mL) was stirred for 7 d under an argon atmosphere
in darkness. The suspension was mixed with CHCl3 (50 mL) and
washed with H2O (20 mL). The organic layer was dried (Na2SO4),
concentrated and purified by column chromatography (silica gel;
CHCl3–MeOH, 10:1) to get 15.
IR (KBr): 3304, 2918, 2850, 1609, 1510, 1440, 1248, 1173, 1033,
831 cm–1.
1H NMR (methanol-d4): d = 0.85 (d, 3 H, 3J = 6.3 Hz, H-21), 1.24–
1.29 (m, 2 H, H-9, H-10), 1.38–1.44 (m, 1 H, H-10), 1.52–1.58 (m,
2
2 H, H-11), 1.64 (ddd, 1 H, J = 13.5, 3J = 8.8, 5.6 Hz, H-8), 2.33
3
4
2
(dt, 2 H, J = 7.2, J = 1.3 Hz, H-12), 2.43 (ddd, 1 H, J = 13.5,
3J = 10.6, 4.0 Hz, H-8), 3.59 (s, 2 H, H-13), 3.71 (s, 3 H, H-20), 4.45
(dd, 1 H, 3J = 10.4, 5.5 Hz, H-7), 6.23 (s, 1 H, H-4), 6.78 (d, 2 H,
Yield: 0.45 g (0.34 mmol, 81%); colorless solid.
Variant 3
3J = 8.7 Hz, H-16, H-18), 7.15 (d, 2 H, J = 8.7 Hz, H-15, H-19),
A solution of 7 (2.27 g, 1.89 mmol) and NaI (7.93 g, 52.9 mmol) in
anhyd acetone (50 mL) was stirred for 24 h under an argon atmo-
sphere in darkness. The suspension was mixed with EtOAc (50 mL)
and washed with H2O (50 mL). The organic layer was dried
(Na2SO4), concentrated and purified by column chromatography
(silica gel; CHCl3–MeOH, 10:1) to get 15.
3
7.17 (s, 1 H, H-1).
13C NMR (methanol-d4): d = 19.96 (prim., C-21), 28.13 (tert., C-9),
31.65 (sec., C-12), 31.68 (tert., C-7), 32.57 (sec., C-11), 36.56 (sec.,
C-13), 37.89 (sec., C-10), 42.42 (sec., C-8), 55.70 (prim., C-20),
104.08 (tert., C-4), 114.86 (tert., C-16 and C-18), 124.41 (quat., C-
2/6), 125.05 (tert., C-1), 126.16 (quat., C-2/6), 131.04 (tert., C-15
and C-19), 131.98 (quat., C-14), 152.80 (quat., C-3/5), 153.27
(quat., C-3/5), 160.01 (quat., C-17).
Yield: 2.42 g (1.82 mmol, 96%); colorless solid; mp 174 °C (de-
comp.); [a]D22 +4.1 (c 1.0 in MeOH).
IR (KBr): 3289 (br), 2926, 1621, 1499, 1434, 1392, 1177, 1079,
835, 754 cm–1.
MALDI-TOF (matrix DHB): m/z = 1196 [M – C14H21OS]+, 1433
[M + H]+, 1455 [M + Na]+, 1471 [M + K]+.
1H NMR (methanol-d4): d = 0.95 (d, 3 H, 3J = 6.2 Hz, H-13), 1.36–
Anal. Calcd for C84H104O12S4: C, 70.36; H, 7.31. Found: C, 68.51;
H, 7.29.
1.44 (m, 2 H, H-9, H-10), 1.52–1.60 (m, 1 H, H-10), 1.69 (ddd, 1 H,
3
2J = 13.4, J = 8.7, 5.4 Hz, H-8), 1.85–1.95 (m, 2 H, H-11), 2.50
(ddd, 1 H, 2J = 13.4, 3J = 3.7, 10.7 Hz, H-8), 3.26 (t, 2 H, 3J = 6.9
Hz, H-12), 4.47 (dd, 1 H, 3J = 10.7, 5.4 Hz, H-7), 6.22 (s, 1 H, H-4),
7.19 (s, 1 H, H-1).
(3S)-6-Iodo-1,1-dimethoxy-3-methylhexane (14)
A solution of (4S)-6,6-dimethoxy-4-methylhexylmethanesulfonate
(6; 2.00 g, 7.86 mmol) and NaI (3.53 g, 23.6 mmol) in anhyd ace-
tone (20 mL) was stirred 24 h under an argon atmosphere in dark-
ness. The suspension was mixed with Et2O (50 mL) and washed
13C NMR (methanol-d4): d = 8.16 (sec., C-12), 19.90 (prim., C-13),
31.41 (tert., C-9), 31.63 (tert., C-7), 32.71 (sec., C-11), 39.60 (sec.,
C-10), 42.41 (sec., C-8), 104.12 (tert., C-4), 124.27 (quat., C-2/6),
Synthesis 2005, No. 16, 2701–2712 © Thieme Stuttgart · New York

PAPER
Chiral Resorc[4]arenes Derived from Citronellal and Carvone
(4S)-6,6-Dimethoxy-4-methylhexylethanthioate (18)
2709
124.99 (tert., C-1), 126.11 (quat., C-2/6), 152.84 (quat., C-3/5),
153.31 (C-3/5).
A solution of (4S)-6,6-dimethoxy-4-methylhexylmethanesulfonate
(6; 0.76 g, 3.00 mmol) and KSAc (0.69 g, 6.00 mmol) in anhyd
MeOH (15 mL) was stirred for 24 h under an argon atmosphere. The
suspension was mixed with Et2O (50 mL) and washed with sat. aq
NH4Cl (40 mL). The organic layer was dried (Na2SO4), concentrat-
ed and purified by column chromatography (silica gel; cyclohex-
ane–EtOAc, 4:1) to get 18.
MALDI-TOF (Matrix DHB): m/z = 1117 [M – C6H12I]+, 1329 [M
+ H]+, 1351 [M + Na]+, 1367 [M + K]+.
Anal. Calcd for C52H68I4O8: C, 47.01; H, 5.16. Found: C, 47.09; H,
5.14.
(3S)-1,1-Dimethoxy-3-methylhexane (16)
Yield: 0.60 g (2.58 mmol, 86%); colorless liquid; [a]D22 –9.7 (c 1.0
in CHCl3).
To a suspension of LiAlH4 (2.28 g, 60.0 mmol) in anhyd Et2O (50
mL), a solution of (4S)-6,6-dimethoxy-4-methylhexylmethane-
sulfonate (6; 7.63 g, 30.0 mmol) was added dropwise under an ar-
gon atmosphere and stirred under reflux for 30 min. After cooling
the mixture was diluted carefully with MeOH–Et2O (1:1, 30 mL)
and filtered (silica). The filtrate was washed with brine (50 mL),
dried, filtered, concentrated and purified by column chromatogra-
phy (silica gel; C6H6–EtOAc, 2:1) to get 16.
IR (film): 2936, 2829, 1689, 1459, 1355, 1193, 1127, 955, 913, 815
cm–1.
1H NMR (CDCl3): d = 0.88 (d, 3 H, 3J = 6.5 Hz, H-9), 1.19 (dddd,
1 H, 2J = 13.1, 3J = 10.4, 7.7, 5.5 Hz, H-3), 1.34 (ddd, 1 H,
2J = 13.2, 3J = 7.8, 5.0 Hz, H-5), 1.36 (dddd, 1 H, 3J = 5.2,
2J = 13.1, 3J = 10.5, 5.2 Hz, H-3), 1.50–1.61 (m, 4 H, H-2, H-4, H-
5), 2.29 (s, 3 H, H-11), 3.82 (dd, 2 H, 3J = 7.0, 6.7 Hz, H-1), 3.27 (d,
3 H, 4J = 0.5 Hz, H-7/8), 3.28 (d, 3 H, 4J = 0.4 Hz, H-7/8), 4.42 (dd,
1 H, 3J = 6.5, 5.0 Hz, H-6).
13C NMR (CDCl3): d = 19.63 (prim., C-9), 26.89 (sec., C-2), 28.69
(tert., C-4), 29.26 (prim., C-11), 30.60 (sec., C-3), 36.21 (sec., C-1),
39.34 (sec., C-5), 52.30 (prim., C-7/8), 52.58 (prim., C-7/8), 102.96
(tert., C-6), 195.91 (quat., C-10).
Yield: 4.18 g (26.1 mmol, 87%); colorless liquid; [a]D25 –0.8 (c 1.0
in CHCl3).
IR (film): 2929, 1466, 1380, 1192, 1118, 1056, 969, 915, 868, 802
cm–1.
1H NMR (CDCl3): d = 0.86 (t, 3 H, 3J = 7.2 Hz, H-1), 0.87 (d, 3 H,
3J = 6.6 Hz, H-9), 1.09–1.14 (m, 1 H, H-3), 1.22–1.32 (m, 2 H, H-
2, H-3), 1.33 (ddd, 1 H, 2J = 13.5, 3J = 8.2, 5.2 Hz, H-5), 1.51–1.58
(m, 1 H, H-4), 1.61 (ddd, 1 H, 2J = 13.5, 3J = 6.6, 5.5 Hz, H-5), 3.28
(s, 3 H, H-7/8), 3.29 (s, 3 H, H-7/8), 4.44 (dd, 1 H, 3J = 6.6, 5.2 Hz,
H-1).
MS (CI, NH3): m/z (%) = 233 (1) [M – H]+, 203 (2) [M – H –
CH2O]+, 159 (1) [M – H – CH3CHO]+, 129 (100) [M – H – 2
CH2O – CH3CHO]+.
13C NMR (CDCl3): d = 14.30 (prim., C-1), 19.74 (prim., C-9), 19.9
(sec., C-2), 26.90 (sec., C-3), 28.74 (tert., C-4), 39.50 (sec., C-5),
52.16 (prim., C-7/8), 52.60 (prim., C-7/8), 103.12 (tert., C-6).
Anal. Calcd for C11H22O3S: C, 56.38; H, 9.46. Found: C, 56.32; H,
9.53.
2,8,14,20-Tetrakis[(2¢S)-5¢-thioacetyl-2¢-methylpentyl]re-
sorc[4]arene (19)
MS (CI, NH3): m/z (%) = 159 (1) [M]+, 129 (100) [M – CH2O]+.
Anal. Calcd for C9H20O2: C, 67.45; H, 12.58. Found: C, 68.67; H,
12.20.
A solution of 2,8,14,20-tetrakis[(2¢S)-5¢-iodo-2¢-methylpentyl]re-
sorc[4]arene (15; 1.03 g, 0.78 mmol) and KSAc (0.71 g, 6.24 mmol)
in anhyd MeOH (100 mL) was stirred for 24 h under an argon atmo-
sphere. The suspension was mixed with CHCl3 (150 mL) and
washed with sat. aq NH4Cl–H2O (1:1, 100 mL) and sat. aq NH4Cl
(50 mL). The organic layer was dried (Na2SO4), concentrated and
purified by column chromatography (silica gel; CHCl3–MeOH,
10:1) to get 19.
2,8,14,20-Tetrakis[(2¢S)-2¢-methylpentyl]resorc[4]arene (17)
To a cooled (0 °C) solution of resorcinol (0.44 g, 4.00 mmol) and
concd aq HCl (1 mL) in EtOH (2 mL), (3S)-1,1-dimethoxy-3-meth-
ylhexane (16; 1.00 g, 4.00 mmol) was added under an argon atmo-
sphere. The mixture was stirred at r.t. for 30 min, at 80 °C for 4 h,
cooled to r.t., mixed with EtOAc (30 mL) and washed with H2O (10
mL). After phase separation the organic layer was dried (Na2SO4),
filtered, concentrated and purified by column chromatography (sil-
ica gel; CHCl3–MeOH, 10:1) to get 17.
Yield: 0.80 g (0.71 mmol, 91%); colorless solid; mp 129–141 °C;
[a]D24 +4.5 (c 1.0 in MeOH).
IR (KBr): 3355 (br), 2924, 2853, 1673, 1619, 1500, 1443, 1293,
1135, 845 cm–1.
Yield: 0.68 g (0.83 mmol, 83%); colorless solid; mp 235 °C (de-
comp.); [a]D20 +19.7 (c 1.0 in MeOH).
1H NMR (methanol-d4): d = 0.88 (d, 3 H, 3J = 6.4 Hz, H-13), 1.27–
1.34 (m, 1 H, H-10), 1.36–1.48 (m, 1 H, H-9 and H-10), 1.51–1.59
(m, 1 H, H-11), 1.61–1.69 (m, 2 H, H-8, H-11), 2.37 (s, 3 H, H-14),
IR (KBr): 3258 (br), 2928, 2867, 1620, 1501, 1445, 1295, 1155,
1087, 847 cm–1.
2
3
2.59 (ddd, 1 H, J = 13.4, J = 4.7, 10.3 Hz, H-8), 2.79 (ddd, 1 H,
2J = 13.3, 3J = 8.7, 6.0 Hz, H-12), 2.95 (ddd, 1 H, 2J = 13.3,
3J = 8.8, 6.4 Hz, H-12), 4.45 (dd, 1 H, 3J = 10.3, 5.7 Hz, H-7), 6.22
(s, 1 H, H-4), 7.42 (s, 1 H, H-1).
1H NMR (methanol-d4): d = 0.91 (d, 3 H, 3J = 6.2 Hz, H-13), 0.95
3
(t, 3 H, J = 7.3 Hz, H-12), 1.33–1.46 (m, 5 H, H-9, H-10, H-11),
2
3
1.58 (ddd, 1 H, J = 13.4, J = 8.6, 5.3 Hz, H-8), 2.34 (ddd, 1 H,
2J = 13.4, 3J = 10.9, 3.6 Hz, H-8), 4.46 (dd, 1 H, 3J = 10.9, 5.3 Hz,
H-7), 6.21 (s, 1 H, H-4), 7.17 (s, 1 H, H-1).
13C NMR (methanol-d4): d = 19.82 (prim., C-13), 28.69 (tert., C-9),
30.07 (sec., C-11), 31.05 (sec., C-12), 31.25 (prim., C-14), 31.83
(tert., C-7), 37.72 (sec., C-10), 41.61 (sec., C-8), 104.02 (tert., C-4),
124.78 (quat., C-2/6), 125.64 (tert., C-1), 126.38 (quat., C-2/6),
152.69 (quat., 3/5), 153.08 (quat., C-3/5), 197.65 (quat., C-15).
13C NMR (methanol-d4): d = 14.99 (prim., C-12), 20.12 (prim., C-
13), 21.62 (sec., C-11), 31.50 (tert., C-9), 31.57 (tert., C-7), 41.49
(sec., C-10), 42.36 (sec., C-8), 104.04 (tert., C-4), 124.30 (quat., C-
2/6), 125.05 (tert., C-1), 126.20 (quat., C-2/6), 152.76 (quat., C-3/
5), 153.25 (quat., C-3/5).
MALDI-TOF (matrix DHB): m/z = 961 [M – C8H15OS]+, 1121
[M + H]+, 1143 [M + Na]+, 1159 [M + K]+.
MALDI-TOF (matrix DHB): m/z = 739 [M – C6H13]+, 825 [M +
Anal. Calcd for C60H80O12S4: C, 64.26; H, 7.19. Found: C, 63.97; H,
7.44.
H]+, 847 [M + Na]+, 863 [M + K]+.
Anal. Calcd for C52H72O8: C, 75.69; H, 8.80. Found: C, 75.51; H,
8.87.
Synthesis 2005, No. 16, 2701–2712 © Thieme Stuttgart · New York

2710
M. Schiendorfer, J. Mattay
PAPER
2,8,14,20-Tetrakis[(2¢S)-2¢-(2¢¢-bromoethyl)-3¢-methylbutyl]re-
sorc[4]arene (20S)
After phase separation the organic layer was washed with NaHCO3
(50 mL) and H2O (50 mL). The combined aqueous phases were ex-
tracted with CH2Cl2 (3 × 30 mL). The combined organic layers
were dried (Na2SO4), filtered, concentrated and purified by column
chromatography (silica gel; CH2Cl2) to get 23.
Yield: 3.69 g (22.7 mmol, 78%); colorless liquid; [a]D22 –16.7
(c 1.0 in CHCl3).
To a cooled (0 °C) solution of resorcinol (0.28 g, 2.50 mmol) and
HBr (47%, 0.5 mL) in EtOH (1.5 mL), (3S)-3-(2¢-bromoethyl)-4-
methylpentanal (2; 0.52 g, 2.50 mmol) was added under an argon at-
mosphere. The mixture was stirred at r.t. for 30 min, at 80 °C for 4
h, cooled to r.t., mixed with CHCl3 (50 mL), washed with brine (20
mL) and H2O (20 mL). After phase separation the organic layer was
dried (Na2SO4), filtered, concentrated and purified by column chro-
matography (silica gel; CHCl3–MeOH, 10:1) to get 20.
IR (film): 2967, 1708, 1466, 1413, 1390, 1371, 1290, 1101, 727,
656 cm–1.
1H NMR (CDCl3): d = 0.84 (d, 3 H, 3J = 6.8 Hz, H-5/6), 0.87 (d, 3
Yield: 0.52 g (0.43 mmol, 69%); colorless solid; mp 145 °C (de-
H, 3J = 6.9 Hz, H-5/6), 1.65 (dddd, 1 H, 2J = 14.3, 3J = 6.4, 7.3, 7.3
comp.); [a]D21 +21.0 (c 1.0 in MeOH).
2
Hz, H-7), 1.70–1.78 (m, 1 H, H-4), 1.84 (dddd, 1 H, J = 14.3,
IR (film): 3377 (OH), 2964, 2877, 1621, 1501, 1441, 1370, 1295,
1164, 1087 cm–1.
3J = 5.9, 7.2, 7.2 Hz, H-7), 2.09–2.15 (m, 1 H, H-3), 2.26 (ddd, 1 H,
2J = 16.7, 3J = 7.3, 2.3 Hz, H-2), 2.42 (ddd, 1 H, 2J = 16.7, 3J = 5.7,
2.0 Hz, H-2), 3.47–3.57 (m, 2 H, H-8), 9.75 (t, 1 H, 3J = 2.2 Hz, H-
1).
3
1H NMR (methanol-d4): d = 0.87 (d, 3 H, J = 6.9 Hz, H-11, 12),
0.95 (d, 3 H, 3J = 6.9 Hz, H-11, 12), 1.29–1.30 (m, 1 H, H-9), 1.82–
1.94 (m, 4 H, H-8, H-10, H-13), 2.20 (ddd, 1 H, 2J = 13.5, 3J = 9.0,
5.2 Hz, H-8), 3.39–3.49 (m, 2 H, H-14), 4.53 (dd, 1 H, 3J = 9.0, 7.0
Hz, H-7), 6.24 (s, 1 H, H-4), 7.17 (s, 1 H, H-1).
13C NMR (CDCl3): d = 18.34 (prim., C-5/6), 19.40 (prim., C-5/6),
29.85 (tert., C-4), 34.41 (sec., C-7), 35.72 (tert., C-3), 43.01 (sec.,
C-8), 45.02 (sec., C-2), 202.54 (tert., C-1).
MS (CI, isobutane): m/z (%) = 163/165 (89/28) [M + H]+, 145/147
(100/30) [M + H – H2O]+, 127 (45) [M + H – HCl]+, 109 (40) [M +
H – HCl – H2O]+.
13C NMR (methanol-d4): d = 19.31 (prim., C-11,12), 19.71 (prim.,
C-11,12), 30.39 (tert., C-10), 31.50 (tert., C-9), 33.48 (sec., C-13),
35.49 (sec., C-14), 36.95 (sec., C-8), 41.60 (tert., C-7), 104.75 (tert.,
C-4), 124.17 (quat., C-2,6), 124.36 (tert., C-1), 125.01 (quat., C-
2,6), 153.39 (quat., C-3,5), 153.47 (quat., C-3,5).
Anal. Calcd for C8H15ClO: C, 59.07; H, 9.30. Found: C, 59.05; H,
9.66.
MALDI-TOF (matrix DHB): m/z = 1197 [M + H]+, 1219 [M +
Na]+, 1235 [M + K]+.
2,8,14,20-Tetrakis[(2¢S)-2¢-(chloroethyl)-3¢-methylbutyl]re-
sorc[4]arene (24)
Methyl-(3S)-3-(chloroethyl)-4-methylpentanoate (22)
Through a solution of (4R)-4-isopropyltetrahydro-2H-pyran-2-one
(21; 27.1 g, 189 mmol) in anhyd MeOH (100 mL) was passed gas-
eous HCl until saturation while keeping the mixture under 35 °C.
After stirring at r.t. for 1 h the solution was diluted with Et2O (300
mL) and H2O (200 mL) and neutralized with concd aq NaOH. After
phase separation the aq layer was extracted with Et2O (3 × 50 mL).
The combined organic layers were dried (Na2SO4), filtered, concen-
trated and purified by column chromatography (silica gel; CH2Cl2)
to get 22.
To a cooled (0 °C) solution of resorcinol (1.10 g, 10.0 mmol) and
concd aq HCl (2 mL) in EtOH (6 mL) (3S)-3-(chloroethyl)-4-meth-
ylpentanal (23; 1.63 g, 10.0 mmol) was added under an argon atmo-
sphere. The mixture was stirred at r.t. for 30 min, at 80 °C for 8 h,
cooled to r.t., mixed with CHCl3 (150 mL), washed with brine (50
mL) and H2O (50 mL). After phase separation the organic layer was
dried (Na2SO4), filtered, concentrated and purified by column chro-
matography (silica gel; CHCl3–MeOH, 10:1) to get 24.
Yield: 1.94 g (1.90 mmol, 76%); colorless solid; mp: 208 °C (de-
comp.); [a]D22 +11.5 (c 1.0 in MeOH).
Yield: 24.1 g (125 mmol, 66%); colorless liquid; [a]D22 –7.1 (c 1.0
in CHCl3).
IR (film): 3389 (br), 2958, 2871, 1619, 1499, 1290, 1164, 1087,
838, 759 cm–1.
IR (film): 2965, 2879, 1738, 1435, 1371, 1336, 1273, 1195, 1157,
1020 cm–1.
3
1H NMR (methanol-d4): d = 0.88 (d, 3 H, J = 6.9 Hz, H-11/12),
3
0.95 (d, 3 H, J = 6.8 Hz, H-11/12), 1.71–1.93 (m, 5 H, H-8, H-9,
1H NMR (CDCl3): d = 0.84 (d, 3 H, 3J = 6.9 Hz, H-5/6), 0.86 (d, 3
H-10, H-13), 2.13 (ddd, 1 H, 2J = 13.6, 3J = 9.1, 5.5 Hz, H-8), 3.43–
3.53 (m, 2 H, H-14), 4.44 (dd, 1 H, 3J = 11.0, 9.1 Hz, H-7), 6.16 (s,
1 H, H-4), 7.09 (s, 1 H, H-1).
H, 3J = 6.9 Hz, H-5/6), 1.67 (dddd, 1 H, 2J = 14.1, 3J = 6.3, 7.7, 7.7
2
Hz, H-7), 1.68–1.75 (m, 1 H, H-3), 1.81 (dddd, 1 H, J = 14.1,
3J = 5.7, 7.0, 8.0 Hz, H-7), 1.92–1.98 (m, 1 H, H-4), 2.15 (dd, 1 H,
2J = 15.3, 7.7 Hz, H-2), 2.31 (dd, 1 H, 2J = 15.3, 3J = 5.9 Hz, H-2),
3.47–3.56 (m, 2 H, H-8), 3.65 (s, 3 H, H-9).
13C NMR (methanol-d4): d = 19.59 (prim., C-11/12), 19.98 (prim.,
C-11/12), 30.78 (tert., C-10), 31.77 (tert., C-9), 35.41 (sec., C-8),
37.22 (sec., C-13), 40.59 (tert., C-7), 45.14 (sec., C-14), 103.82
(tert., C-4), 124.47 (quat., C-2/6), 125.43 (tert., C-1), 125.88 (quat.,
C-2/6), 153.69 (quat., C-3/5), 153.80 (quat., C-3/5).
13C NMR (CDCl3): d = 18.46 (prim., C-5/6), 19.13 (prim., C-5/6),
29.84 (tert., C-4), 34.29 (sec., C-7), 35.43 (sec., C-2), 38.48 (tert.,
C-3), 43.15 (sec., C-8), 51.60 (prim., C-9), 173.77 (quat., C-1).
MALDI-TOF (matrix DHB): m/z = 883 [M – C7H14Cl]+, 1017 [M +
MS (CI, isobutane): m/z (%) = 193/195 (100/42) [M + H]+, 157 (8)
H]+, 1039 [M + Na]+, 1055 [M + K]+.
[M – HCl]+.
Anal. Calcd for C56H76Cl4O8: C, 66.01; H, 7.52. Found: C, 66.19; H,
7.59.
Anal. Calcd for C9H17ClO2: C, 56.10; H, 8.89. Found: C, 56.06; H,
9.07.
(3S)-3-(2¢-Bromoethyl)-1,1-dimethoxy-4-methylpentanal (25)
A solution of (3S)-3-(2¢-bromoethyl)-4-methylpentanal (2; 4.50 g,
21.7 mmol) and PPTS (0.10 g) in anhyd MeOH (100 mL) was
stirred under an argon atmosphere at r.t. The mixture was diluted
with Et2O (200 mL) and washed with half-sat. aq NaHCO3 (100
mL) and brine (2 × 50 mL). The organic layer was dried (Na2SO4),
concentrated and purified by distillation (64 °C, 0.2 mbar) to get 25.
(3S)-3-(Chloroethyl)-4-methylpentanal (23)
To a cooled (–75 °C) solution of methyl (3S)-3-(chloroethyl)-4-
methylpentanoate (21; 5.59 g, 29.0 mmol) in anhyd CH2Cl2 a solu-
tion of diisobutylaluminum hydride in CH2Cl2 (1 M, 32 mL, 32
mmol) was added under an argon atmosphere during a period of
30 min. After stirring for 2 h at –75 °C MeOH (2 mL) was added to
the solution. The cooling bath was replaced by an ice bath and the
solution was acidified with concd aq HCl during vigorously stirring.
Synthesis 2005, No. 16, 2701–2712 © Thieme Stuttgart · New York

PAPER
Chiral Resorc[4]arenes Derived from Citronellal and Carvone
2711
Yield: 3.87 g (15.3 mmol, 71%); colorless liquid; [a]D22 +1.5 (c 1.0
in CHCl3).
IR (KBr): 3389 (br), 2958, 2871, 1620, 1499, 1444, 1294, 1156,
1082, 760 cm–1.
3
IR (film): 2963, 1466, 1369, 1320, 1259, 1123, 957, 912, 803, 640
cm–1.
1H NMR (methanol-d4): d = 0.81 (t, 3 H, J = 7.5 Hz, H-14), 0.85
(d, 3 H, 3J = 6.9 Hz, H-11/12), 0.93 (d, 3 H, 3J = 6.8 Hz, H-11/12),
1.24–1.30 (m, 2 H, H-9, H-10), 1.36 (ddq, 1 H, 3J = 7.1, 2J = 14.5,
3J = 7.3, H-13), 1.54 (ddq, 1 H, 3J = 6.6, 2J = 14.5, 3J = 7.3 Hz, H-
13), 1.70 (ddd, 1 H, 2J = 16.1, 3J = 2.4, 7.3 Hz, H-8), 2.46 (ddd, 1 H,
2J = 16.1, 3J = 2.4, 3J = 5.6 Hz, H-8), 4.42 (dd, 1 H, 3J = 11.4, 4.7
Hz, H-7), 6.17 (s, 1 H, H-4), 7.13 (s, 1 H, H-1).
1H NMR (CDCl3): d = 0.82 (d, 3 H, 3J = 6.9 Hz, H-5/6), 0.85 (d, 3
2
H, 3J = 6.9 Hz, H-5/6), 1.38 (ddd, 1 H, J = 14.0, 3J = 5.6, 7.5 Hz,
2
H-2), 1.48–1.54 (m, 1 H, H-3), 1.60 (ddd, 1 H, J = 14.0, 3J = 5.7,
5.6 Hz, H-2), 1.69–1.79 (m, 3 H, H-7, H-4), 3.29 (s, 3 H, H-9/10),
3.30 (s, 3 H, H-9/10), 3.34–3.44 (m, 2 H, H-8), 4.40 (t, 1 H, 3J = 5.7
Hz, H-1).
13C NMR (CDCl3): d = 18.46 (prim., C-5/6), 18.90 (prim., C-5/6),
29.28 (tert., C-4), 32.37 (sec., C-7), 33.19 (sec., C-2), 34.49 (sec.,
C-8), 38.48 (tert., C-3), 52.48 (prim., C-9/10), 52.99 (prim., C-9/
10), 103.52 (tert., C-1).
13C NMR (methanol-d4): d = 12.01 (prim., C-14), 18.95 (prim., C-
11/12), 21.05 (prim., C-11/12), 23.85 (sec., C-13), 30.27 (tert., C-
10), 31.41 (tert., C-9), 35.78 (sec., C8), 43.69 (tert., C-7), 104.03
(tert., C-4), 124.11 (quat., C-2/6), 125.29 (tert., C-1), 126.41 (quat.,
C-2/6), 152.81 (quat., C-3/5), 153.41 (quat., C-3/5).
MALDI-TOF (matrix DHB): m/z = 781 [M – C8H17]+, 881 [M +
MS (CI, NH3): m/z (%) = 221/223 (82/80) [M – CH2O]+, 206/208
H]+, 903 [M + Na]+, 919 [M + K]+.
(25/24) [M – CH2O – CH3]+, 177/179 (7/7) [M – CH2O – C2H4O]+.
Anal. Calcd for C56H80O8: C, 76.33; H, 9.15. Found: C, 76.11; H,
9.01.
Anal. Calcd for C10H21BrO2: C, 47.44; H, 8.51. Found: C, 47.44; H,
8.51.
(3S)-3-Ethyl-4-methyl-1-pentanol (29)
(3R)-3-Ethyl-1,1-dimethoxy-4-methylpentane (26)
To a cooled (0 °C) solution of (3R)-methyl 3-(2¢-bromoethyl)-4-
methylpentanoate (28; 7.35 g, 31.0 mmol) in anhyd THF (100 mL),
a solution of LiAlH4 in THF (1 M, 31.0 mL, 31.0 mmol) was added
under an argon atmosphere. After stirring for 1 h at r.t., the mixture
was diluted carefully with a mixture of THF–H2O (1:1; 20 mL) at
0 °C. The mixture was further diluted with Et2O (100 mL) and aq
HCl (10%; 50 mL). The aq layer was extracted with Et2O (50 mL).
The combined organic layers were dried (Na2SO4), concentrated,
purified primarily by distillation (72 °C, 10 mbar) and afterwards
by column chromatography (silica gel; CH2Cl2) to get 29.
To
a cooled (0 °C) solution of (3S)-3-(2¢-bromoethyl)-1,1-
dimethoxy-4-methylpentanal (25; 3.00 g, 11.8 mmol) in anhyd THF
(30 mL), a solution of LiAlH4 in THF (1 M, 11.8 mL, 11.8 mmol)
was added under an argon atmosphere. After stirring for 3 h at r.t.,
the mixture was diluted carefully with a mixture of THF–H2O (1:1;
20 mL) at 0 °C. The mixture was diluted with Et2O (100 mL) and
washed with sat. aq NH4Cl (50 mL). The aq layer was extracted
with Et2O (50 mL). The combined organic layers were dried
(Na2SO4), concentrated and purified by column chromatography
(silica gel; CH2Cl2) or distillation (71 °C, 10 mbar) to get 26.
Yield: 3.23 g (24.8 mmol, 80%); colorless liquid; [a]D25 –3.3 (c 1.0
in CHCl3).
Yield: 1.62 g (9.29 mmol, 79%); colorless liquid; [a]D25 +1.3 (c 1.0
in CHCl3).
IR (film): 3337 (OH), 2964, 1463, 1385, 1368, 1200, 1178, 1115,
1057, 877 cm–1.
IR (film): 2964, 2833, 1466, 1386, 1368, 1192, 1124, 1060, 998,
880 cm–1.
1H NMR (CDCl3): d = 0.80 (d, 3 H, 3J = 6.8 Hz, H-5/6), 0.82 (d, 3
1H NMR (CDCl3): d = 0.80 (d, 3 H, 3J = 6.9 Hz, H-5/6), 0.83 (d, 3
3
3
H, J = 6.8 Hz, H-5/6), 0.84 (t, 3 H, J = 7.4 Hz, H-8), 1.08–1.14
(m, 1 H, H-3), 1.20 (ddq, 1 H, 3J = 7.0, 2J = 14.1, 3J = 7.4 Hz, H-7),
1.30 (ddq, 1 H, 3J = 6.8, 2J = 14.1, 3J = 7.4 Hz, H-7), 1.39 (dddd, 1
3
3
H, J = 6.7 Hz, H-5/6), 0.85 (t, 3 H, J = 7.0 Hz, H-8), 1.18–1.23
2
(m, 1 H, H-3), 1.23–1.33 (m, 2 H, H-7), 1.37 (ddd, 1 H, J = 14.3,
3J = 5.3, 7.6 Hz, H-2), 1.57 (ddd, 1 H, 2J = 14.3, 3J = 5.3, 6.6 Hz, H-
2), 1.69–1.77 (m, 1 H, H-4), 3.28 (s, 3 H, H-9/10), 3.29 (s, 3 H, H-
9/10), 4.43 (dd, 1 H, 3J = 6.6, 5.3 Hz, H-1).
2
H, J = 13.6, 3J = 7.9, 5.9, 7.7 Hz, H-2), 1.52–1.58 (m, 1 H, H-2),
1.65–1.75 (m, 1 H, H-4), 3.60 (ddd, 1 H, 2J = 10.3, 3J = 7.9, 6.8 Hz,
H-1), 3.64 (ddd, 1 H, 2J = 10.3, 3J = 8.3, 5.9 Hz, H-1).
13C NMR (CDCl3): d = 11.81 (prim., C-8), 18.53 (prim., C-5/6),
19.28 (prim., C-5/6), 23.14 (sec., C-7), 28.73 (tert., C-4), 32.86
(sec., C-2), 41.03 (tert., C-3), 52.13 (prim., C-9/10), 52.68 (prim.,
C-9/10), 103.67 (tert., C-1).
13C NMR (CDCl3): d = 11.91 (prim., C-8), 18.70 (prim., C-5/6),
19.38 (prim., C-5/6), 23.29 (sec., C-7), 29.02 (tert., C-4), 33.32
(sec., C-2), 41.99 (tert., C-3), 61.96 (sec., C-1).
MS (CI, NH3): m/z (%) = 148 (100) [M + NH4]+, 129 (3) [M]+, 111
MS (CI, NH3): m/z (%) = 173 (1) [M – H]+, 143 (100) [M – CH2O]+,
(5) [M – H2O]+.
128 (20) [M – CH2O – CH3]+, 99 (19) [M – CH2O – C2H4O]+.
Anal. Calcd for C8H18O: C, 73.78; H, 13.93. Found: C, 72.88; H,
13.53.
Anal. Calcd for C10H22O2: C, 68.92; H, 12.72. Found: C, 68.83; H,
12.52.
(3S)-3-Ethyl-4-methylpentanal (30)
2,8,14,20-Tetrakis[(2¢R)-2¢-ethyl-3¢-methylbutyl]re-
To a solution of IBX (4.90 g, 17.5 mmol) in DMSO (25 mL, solva-
tion process takes a few minutes), (3S)-3-ethyl-4-methyl-1-pen-
tanol (29; 1.51 g, 11.6 mmol) was added and stirred at r.t. overnight.
The milky suspension was diluted with H2O (50 mL) and filtered.
The aq layer of the filtrate was extracted with Et2O (3 × 50 mL) as
well as the filter residue (2 × 50 mL). The combined organic layers
were dried (Na2SO4), concentrated and purified by column chroma-
tography (silica gel; cyclohexane–EtOAc, 80:20) to get 30.
sorc[4]arene (27)
To a cooled (0 °C) solution of resorcinol (0.57 g, 5.16 mmol), H2O
(1 mL) and concd aq HCl (1 mL) in EtOH (5 mL), (3R)-3-ethyl-1,1-
dimethoxy-4-methylpentane (26; 0.66 g, 5.16 mmol) was added un-
der an argon atmosphere. The mixture was stirred at r.t. for 30 min
and at 80 °C for 8 h. After cooling to r.t., a petalled, shimmery com-
pound was accumulated. The suspension was diluted with EtOAc
(50 mL) and washed with brine (20 mL) and H2O (20 mL). The or-
ganic layer was dried (Na2SO4), concentrated and purified by col-
umn chromatography (silica gel; CHCl3–MeOH, 10:1) to get 27.
Yield: 1.36 g (10.6 mmol, 91%); colorless liquid; [a]D22 –3.9 (c 1.0
in MeOH).
Yield: 0.82 g (0.93 mmol, 72%); colorless solid; mp 277 °C (de-
IR (film): 2961, 2875, 2816, 2713, 1725, 1464, 1412, 1388, 1369,
1023 cm–1.
comp.); [a]D22 +39.8 (c 1.0 in MeOH).
Synthesis 2005, No. 16, 2701–2712 © Thieme Stuttgart · New York

2712
M. Schiendorfer, J. Mattay
PAPER
1H NMR (CDCl3): d = 0.81 (d, 3 H, 3J = 6.8 Hz, H-5/6), 0.84 (d, 3
H, 3J = 6.8 Hz, H-5/6), 0.85 (t, 3 H, 3J = 7.3 Hz, H-8), 1.23 (ddq, 1
(8) (a) Schneider, U.; Schneider, H.-J. Chem. Ber. 1994, 127,
2455. (b) Matsushita, Y.; Matsui, T. Tetrahedron Lett. 1993,
34, 7433.
(9) Fox, O. D.; Dalley, N. K.; Harrison, R. G. J. Inclusion
Phenom. Macrocycl. Chem. 1999, 33, 403.
(10) Shivanyuk, A.; Schmidt, C.; Böhmer, V.; Paulus, E. F.;
Lukin, O.; Vogt, W. J. Am. Chem. Soc. 1998, 120, 4319.
(11) (a) McIldowie, M. J.; Mocerino, M.; Skelton, B. W.; White,
A. H. Org. Lett. 2000, 2, 3869. (b) Klaes, M.; Agena, C.;
Köhler, M.; Inoue, M.; Wada, T.; Inoue, Y.; Mattay, J. Eur.
J. Org. Chem. 2003, 1404. (c) Boxhall, J. Y.; Page, P. C. B.;
Elsegood, M. R. J.; Chan, Y.; Heaney, H.; Holmes, K. E.;
Mc Grath, M. J. Synlett 2003, 1002. (d) Mehdizadeh, A.;
Letzel, M. C.; Klaes, M.; Agena, C.; Mattay, J. Eur. J. Mass
Spectrom. 2004, 10, 649.
3
2
3
3
H, J = 7.1, J = 14.6, J = 7.3 Hz, H-7), 1.38 (ddq, 1 H, J = 6.6,
3
2J = 14.6, J = 7.3 Hz, H-7), 1.69–1.79 (m, 2 H, H-3, H-4), 2.21
(ddd, 1 H, 2J = 16.3, 3J = 2.4, 7.3 Hz, H-2), 3.60 (ddd, 1 H,
2J = 16.3, 3J = 2.4, 5.6 Hz, H-2), 3.64 (t, 1 H, 3J = 2.4 Hz, H-1).
13C NMR (CDCl3): d = 11.75 (prim., C-8), 18.42 (prim., C-5/6),
19.72 (prim., C-5/6), 24.18 (sec., C-7), 29.62 (tert., C-4), 40.34
(tert., C-3), 45.20 (sec., C-2), 203.67 (tert., C-1).
MS (CI, NH3): m/z (%) = 146 (18) [M + NH4]+, (128) [M]+, 100 (10)
[M – CH2O]+.
Anal. Calcd for C8H16O: C, 74.94; H, 12.58. Found: C, 74.58; H,
12.37.
(12) (a) Van Velzen, E. U. T.; Engbersen, J. F. J.; Reinhoudt, D.
N. Synthesis 1995, 989. (b) Adams, H.; Davis, F.; Stirling,
C. J. M. J. Chem. Soc., Chem. Commun. 1994, 2527.
(c) Wink, T.; van Zuilen, S. J.; Bult, A.; van Bennekom, W.
P. Analyst 1997, 122, 43R. (d) Davis, F.; Neogi, P.; Stirling,
C. J. M. J. Chem. Soc., Chem. Commun. 1994, 1199.
(e) Van Velzen, E. U. T.; Engbersen, J. F. J.; de Lange, P. J.;
Mahy, J. W. G.; Reinhoudt, D. N. J. Am. Chem. Soc. 1995,
117, 6853. (f) Eckel, R.; Ros, R.; Decker, B.; Mattay, J.;
Anselmetti, D. Angew. Chem. Int. Ed. 2005, 44, 484; Angew.
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Bartz, P.; Decker, B.; Agena, C.; Schäfer, C.; Molter, S.;
Ros, R.; Bach, M.; Neumann, M.; Anselmetti, D.; Mattay, J.;
Heinzmann, U.; Drescher, M. J. Biotechnol. 2004, 112, 139.
(13) (a) Tietze, L. F.; Denzer, H.; Holdgrün, X.; Neumann, M.
Angew. Chem. 1987, 99, 1309. (b) Boutellier, M.; Wallach,
D.; Tamm, C. Helv. Chim. Acta 1993, 76, 2515.
Acknowledgment
Financial support by the Deutsche Forschungsgemeinschaft (DFG),
the Fonds der Chemischen Industrie, and the Innovationsfonds der
Universität Bielefeld is gratefully acknowledged.
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Synthesis 2005, No. 16, 2701–2712 © Thieme Stuttgart · New York