Preparation of enantiomerically pure C4-symmetric tetramethoxyresorcarenes by using the (-)-(S)-1-phenylethyl isocyanate chiral auxiliary

Article abstract of DOI:10.1002/ejoc.201402125

The synthesis of a series of tetramethoxyresorcarene diastereomers is reported. The reactions of inherently chiral C₄-symmetric tetramethoxyresorcarene derivatives with the chiral auxiliary (-)-(S)-1-phenylethyl isocyanate gave new diastereomeric carbamate compounds in good yields. The diastereomers were separated by simple silica chromatography and then converted by hydrolysis into their parent tetramethoxyresorcarenes to yield the optically pure (-)-(M,R)- and (+)-(P,S) enantiomers. Copyright

Full text of DOI:10.1002/ejoc.201402125

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DOI: 10.1002/ejoc.201402125
Preparation of Enantiomerically Pure C4-Symmetric Tetramethoxyresorcarenes
by Using the (–)-(S)-1-Phenylethyl Isocyanate Chiral Auxiliary
Amit S. Thakar,[a] Hitesh M. Parekh,[a] Pramod B. Pansuriya,[a] Holger B. Friedrich,[a] and
Glenn E. M. Maguire*[a]
Keywords: Resorcarenes / Asymmetric synthesis / Diastereoselectivity / Chiral resolution / Tin / Carbamates
The synthesis of a series of tetramethoxyresorcarene dia-
stereomers is reported. The reactions of inherently chiral C4-
symmetric tetramethoxyresorcarene derivatives with the chi-
ral auxiliary (–)-(S)-1-phenylethyl isocyanate gave new dia-
stereomeric carbamate compounds in good yields. The dia-
stereomers were separated by simple silica chromatography
and then converted by hydrolysis into their parent tetra-
methoxyresorcarenes to yield the optically pure (–)-(M,R)-
and (+)-(P,S) enantiomers.
asymmetry originates not from a stereogenic center but
from a stereogenic axis. By using BF3·OEt2 as a Lewis acid
catalyst, as previously done by Botta et al.[10] for the tetra-
merization of 2,6-dimethoxycinnamates in high yield, the
reaction of 3-alkoxyphenols with aldehydes renders these
tetraalkoxyresorcarenes in generally good yields (see
Scheme 1).[9,11]
Introduction
The chemistry of resorcarenes continues to be widely
studied and has provided a range of molecular assemblies
to be used for a variety of purposes. In particular, the prep-
aration of a range of calix[4]resorcarene derivatives in high
yields has provided interesting possibilities.[1] Resorcarenes
are easily prepared from resorcinol and aldehydes,[2] and as
three-dimensional macrocycles, they have been employed
for various purposes in supramolecular chemistry such as
molecular recognition.[3] Because of the ease of synthesis of
these compounds, a range of derivatization reactions have
been performed on these molecular scaffolds. By using d-
and l-valine, chiral amido[4]resorcinarenes were first syn-
thesized in enantiomerically pure form by using the chiral
unit in a BF3·OEt2-catalyzed reaction.[4] Although con-
siderable effort has been made in the synthesis of inherently
chiral calixarenes and resorcarenes, in the majority of pub-
lished examples, the products have been racemates, which
have on occasion defied resolution by advanced techniques
such as chiral HPLC.[5] Thus, only relatively small amounts
of optically pure materials have been available for use in
other investigations. Enantiomerically pure resorcarenes
have been prepared through the Mannich reaction by em-
ploying an excess amount of formaldehyde and chiral amine
or α-amino alcohol to render either 1,3-oxazine[6] or 1,3-
oxazolidine derivatives.[7] Amino acids have also been used
for this purpose with great success.[6a,8] First described by
McIldowie et al.,[9] the inherently chiral tetramethoxyresor-
carenes are a subclass of these macrocycles, in which the
Scheme 1. Formation of racemic tetramethoxyresorcarenes.
In 2003, Mattay and co-workers synthesized inherently
chiral, enantiomerically pure tetra-O-methylresorc[4]arenes
through the monofunctionalization of phenolic oxygen with
the chiral auxiliary (+)-(S)-10-camphorsulfonyl chloride.[12]
For the cyclization of the precursor, they used the BF3·OEt2
process described by McIldowie et al.[9] and obtained C4-
symmetrical rccc-tetramethoxyresorcarenes[13] as a racemic
mixture. The addition of the camphorsulfonyl moiety al-
lowed for the easy separation of the diastereomers by
HPLC with yields of 13 and 16%. After removal of the
chiral auxiliary, enantiomerically pure tetramethoxyresor-
carenes were obtained in 72 and 70% yield,[12] respectively.
[a] School of Chemistry and Physics, University of KwaZulu-
Natal,
Westville Campus, Durban 4000, South Africa
E-mail: maguireg@ukzn.ac.za
http://www.ukzn.ac.za/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402125.
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Thus, they separated the enantiomers of racemic tetrameth- analysis[17] (see Figure 1). As is the case with previously re-
oxyresorcarenes with an overall combined yield of 20%. ported examples, the derivatives demonstrate the boat con-
In a 2006 follow-up report, the absolute configuration of formation in the solid state.[9,18]
the tetra-O-functionalized camphor diastereomers of tetra-
methoxyresorcarenes were established by a combination of
NMR spectroscopic analysis and X-ray crystallographic
studies.[14] The new approach simplified the isolation of the
diastereomers from HPLC to facile column chromatog-
raphy. In this example, apart from the propyl derivative, the
yields tended to be less than 60% for the diastereomeric
preparation. In that work, the hydrolysis of diastereomeric
tetracamphorsulfonates gave a series of enantiomerically
pure tetraalkoxyresorcarenes with yields of 60–89%.
Furthermore, the (+) enantiomers of these resorcarenes
were defined with the (P,S) nomenclature, and the (–)
enantiomers were defined with the (M,R) nomenclature.[14]
The overall yields were 57, 20, 43, and 40% for propyl,
pentyl, heptyl, and undecyl derivatives, respectively.
Because of the significance of these macrocyclic species
and their potential applications[15] we plan to improve the
synthetic methods for this family of compounds. We chose a
variety of aldehydes to ensure that the approach was widely
applicable, and in the process, we created a new set of tetra-
methoxyresorcarene carbamate derivatives.
Results and Discussion
By applying the process of McIldowie et al.,[9] we studied
variable temperature effects on the reaction yield of the
tetramethoxyresorcarenes by using BF3·OEt2 as the cata-
lyst. We observed that –10 to –15 °C was the most advan-
tageous temperature. After workup, the compound was
stirred in methanol for 2 h and then filtered. Interestingly,
this solid could then be used for the next step without any
further purification. By employing this process, we obtained
more than 80% yield of a racemic mixture in each case,
the predominant isomer of which corresponded to the C4-
symmetric or rccc configuration (see Scheme 1).[16]
Figure 1. X-ray crystal structure of the racemate of 2b/2bЈ (top)[19]
and of the racemate of 2d/2dЈ[19] (bottom). Hydrogen atoms are
omitted for clarity.
Next, we examined a range of possible chiral auxiliaries.
We functionalized the phenolic hydroxy group of the tetra-
Compounds 2a–2f were obtained in excellent purity. We methoxyresorcarenes (as did Mattay and co-workers) by
also grew crystals of 2b and 2d for X-ray crystal structure using (–)-(S)-1-phenylethyl isocyanate with dibutyltin di-
Scheme 2. Resolution of racemic tetramethoxyresorcarenes through derivatization as tetracarbamates.
2
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Enantiomerically Pure C4-Symmetric Tetramethoxyresorcarenes
Table 1. Yield, diastereomeric ratio, melting point, and optical rotation data for the diastereomers.
Diastereomer
Yield
[%]
Diastereomeric ratio
[%]
Total yield
[%]
M.p.
[°C]
[α]2D0
3a (P,S,S)
3aЈ (M,S,R)
3b (P,S,S)
3bЈ (M,S,R)
3c (P,S,S)
3cЈ (M,S,R)
3d (P,S,S)
3dЈ (M,S,R)
3e (P,S,S)
42
31
41
31
36
33
32
28
34
29
32
21
57.5
42.5
57
43
52
48
53
47
54
73
72
69
60
63
53
127–129
136–138
161–162
164–165
97–98
104–105
86–87
90–91
77–79
87–88
61–62
–60.4
–78.5
–123.1
–55.2
–107.3
–39.8
–90.6
–38.8
–95.5
–47.3
–78.6
–64.1
3eЈ (M,S,R)
3f (P,S,S)
3fЈ (M,S,R)
46
60
40
68–69
laurate (DBDTL) as the catalyst (see Scheme 2) in an effort
to simplify the overall process for the enantiomeric separa-
tion. The rccc-tetramethoxyresorcarenes 2a–2f were treated
with the isocyanate reagent (8 equiv.) in dry dichlorometh-
ane with DBDTL as the catalyst at room temperature. The
reaction mixture was stirred in a pressure tube reactor at
60 °C for 72 h to lead to a mixture of tetracarbamate dia-
stereomers (see Scheme 2).[20] The separation of dia-
stereomers 3a–3f and 3aЈ–3fЈ was achieved by chromatog-
raphy on a silica gel column. The yields of the isolated
products are shown in Table 1.
Figure 2. Designation of the hydrogen atoms of compound 3a in
the NMR spectroscopic study.
Apart from the example with the undecyl group, more ference between the spectra is with regard to the chemical
than 60% total yield was obtained in each case. The best shifts for Ha (from 3a) and HaЈ (from 3aЈ) that are observed
yield was observed for the new phenylethyl compounds. The at δ = 6.46 and 6.56 ppm, respectively (see Figure 3). In the
1
diastereomers of this derivative were formed in a 60:40 example of the phenylethyl derivative, the H NMR signals
(P,S,S/M,S,R) mixture and were isolated in 42 and 31% for the (P,S,S) diastereomer are more complicated. There
yield, respectively. The spectroscopic data revealed that in are no significant differences between the δ values of the
each case the (P,S,S) diastereomer, that is 3a–3f, was first remaining protons of interest (i.e., Hb and HbЈ, Hc and
to elute by TLC,[21] and the (M,S,R) diastereomer,[21] that HcЈ, and Hd and HdЈ). The diastereomeric protons of the
is 3aЈ–3fЈ, eluted second (Scheme 2). In all examples, there 1-phenylethyl carbamate group in 3a and 3aЈ are in different
was a higher yield of the (P,S,S) diastereomer, and the environments, which lead to different chemical shifts for the
(M,S,R) diastereomer had a higher melting point (see affected proton signals.
Table 1). In each example, the product was hydrolyzed to
In an effort to further understand the nature of the dia-
generate the resolved compound. The optical rotation for stereomer conformations, we examined the NMR spectra
each resorcinarene was recorded and compared to the re- in deuterated dimethyl sulfoxide. At room temperature, a
sults for the six compounds previously reported.[14] From similar trend was observed for the δ values of the methoxy
this information, the absolute stereochemistry was then as- proton signals (δ =3.35 and 3.61 ppm for the diastereomers
signed to each of the new compounds 2a/2aЈ and 2b/2bЈ.
3a and 3aЈ, respectively; see Figure 4). For aromatic protons
The structures of the various carbamates were estab- Ha and HaЈ of 3a and 3aЈ, the signals were observed at δ
lished by using a variety of analytical techniques. The im- = 6.35 and 6.50 ppm, respectively. The remaining proton
1
portant H and 13C NMR resonances could be precisely signals for both diastereomers were almost identical.
assigned by COSY, heteronuclear single quantum corre-
Over a variable temperature range (20 to 100 °C), signal
1
lation (HSQC), and HMBC experiments. In the H NMR sharpening was observed for almost all of the proton sig-
spectra of the crude reaction mixture, the most obvious nals for both diastereomers. The amide signal moved to a
point that distinguishes the two diastereomers is the split- lower frequency in [D6]DMSO as a function of the in-
ting pattern of the methoxy protons and the presence of creased temperature (see Figures 5 and 6).
signals of the aromatic methine protons Ha and HaЈ (see
Figure 2; for spectra, see Supporting Information).
At elevated temperatures, the spectra of both compounds
are simplified, as the rate of the rotational/vibrational
In deuterated chloroform at room temperature, the movements in the molecule, including the (1-phenylethyl)-
chemical shift values for the broad signals that correspond carbamate group, becomes faster on the NMR timescale.
to the methoxy protons of diastereomers 3a and 3aЈ were δ One anticipates that all proton signals would coalesce at a
= 3.33 and 3.47 ppm respectively. Another significant dif- sufficiently high temperature (see Figure 7).
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Figure 3. Comparison of the H NMR spectra of diastereomers 3a and 3aЈ at 20 °C in CDCl3 (600 MHz).
Figure 4. Comparison of the 1H NMR spectra of diastereomers 3a and 3aЈ at 20 °C in deuterated dimethyl sulfoxide ([D6]DMSO,
600 MHz).
1
Figure 5. Comparison of the H NMR spectra of compound 3a at different temperatures in [D6]DMSO (600 MHz).
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Enantiomerically Pure C4-Symmetric Tetramethoxyresorcarenes
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Figure 6. Comparison of the H NMR spectra of compound 3aЈ at different temperatures in [D6]DMSO (600 MHz).
1
Figure 7. Comparison of the H NMR spectra of diastereomers 3a and 3aЈ at 100 °C in [D6]DMSO (600 MHz).
Because of the excess amount of isocyanate used in the
We next turned our attention to the hydrolysis of the
reaction, we obtained (S,S)-N,NЈ-bis(1-phenylethyl)urea as pure diastereomeric methyl phenylcarbamates to obtain en-
a byproduct. The purification process was complicated by antiomerically pure tetramethoxyresorcarenes. The hydroly-
the presence of this coeluting byproduct. The compound sis of the various carbamates was achieved by treatment
1
was characterized by H NMR spectroscopy, and we grew with a solution of sodium methoxide (1 m) in methanol (see
crystals for identification by X-ray crystal structure analy- Scheme 3).
sis.[19] The X-ray structure is shown in Figure 8.
After stirring at room temperature for 3 h, the starting
carbamate was no longer present in the reaction mixture
(TLC), and an intense spot was observed with the same Rf
value as the corresponding tetramethoxyresorcarenes. The
basic reaction mixture was neutralized with Amberlite IRC-
50H resin and then filtered. The filtrate was concentrated
under reduced pressure, and the resulting solid was purified
by column chromatography. The identical IR, NMR, and
HRMS spectra along with identical melting points for the
equivalent compounds clearly demonstrate the isolation of
1
the enantiomers. All H and 13C NMR spectroscopic sig-
nals could be assigned with the aid of COSY experiments.
The enantiomerically pure compounds were obtained in
good yields between 75 and 90% (see Table 2).
Figure 8. X-ray crystal structure of (S,S)-N,NЈ-bis(1-phenylethyl)-
urea. Hydrogen atoms are omitted for clarity.
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Experimental Section
General Methods: All infrared spectra were recorded with a Perkin–
Elmer Precisely Spectrometer 100 FTIR-ATR spectrometer. 1H
and 13C NMR spectroscopic data were recorded at 400.22 and
100.63 MHz, respectively, with a Bruker Avance III 400 MHz spec-
trophotometer, and for variable-temperature 1H NMR studies, a
Bruker Avance III 600 MHz spectrophotometer was used. Deuter-
ated dimethyl sulfoxide was employed as the NMR solvent, unless
otherwise stated with TMS (tetramethylsilane) as the internal refer-
ence. High-resolution mass spectrometry was performed with a
Bruker MicroTOF QII mass spectrometer in the positive mode
with an internal calibration. Melting points were recorded with an
Ernst Leitz Wetzlar hot-stage melting point apparatus. Optical ro-
tations were measured with a Perkin–Elmer 341 polarimeter that
operated at λ = 589 nm, which corresponds to the sodium D line,
and at the temperature indicated. Silica gel with mesh size 100–
200 (75–150 μm) was used as the adsorbent in all chromatographic
manipulations. The pressure tube reactor (round-bottomed flask)
that was employed was purchased from Ace glass-US (product code
8415). Reactions were monitored by thin layer chromatography on
aluminum-backed plates coated with Merck Kieselgel 60 F254 silica
gel. TLC plates were visualized by UV radiation at a wavelength
of 254 nm or by staining with a 2% potassium hypochlorite solu-
tion in water, drying of the TLC plates, spraying with a saturated
solution of o-tolidine in 2% acetic acid/0.85% KI solution (1:1 v/
v), and then charring as appropriate. Reactions that required anhy-
drous conditions were carried out with flame-dried glassware under
nitrogen, unless otherwise stated. Reaction solvents were used as
obtained commercially, unless otherwise started. Dichloromethane
was distilled from calcium hydride.
Scheme 3. Hydrolysis of the tetracarbamate resorcarenes derived
from the (–)-(S)-1-phenylethyl isocyanate chiral auxiliary.
Table 2. Yield, melting point, optical rotation data for the enantio-
mers.
Enantiomer
Yield [%] M.p. [°C]
[α]2D0
2a, (–)-(M,R)
2aЈ, (+)-(P,S)
2b, (–)-(M,R)
2bЈ, (+)-(P,S)
2c, (–)-(M,R)
2cЈ, (+)-(P,S)
2d, (–)-(M,R)
2dЈ, (+)-(P,S)
2e, (–)-(M,R)
2eЈ, (+)-(P,S)
2f, (–)-(M,R)
2fЈ, (+)-(P,S)
84
89
83
88
85
79
86
81
84
85
77
80
133–134
133–134
295–296
296–297
196–197
197–198
218–219
220–22
145–146
146–147
140–141
140–141
–46.5
+45.9
–29.9
+32.1
–87.9
+79.5
–50.9
+52.9
–63.6
+62.2
–45.0
+48.9
General Procedure 1 for the Preparation of Racemic Tetrameth-
oxyresorcarenes 2a–2f: Equivalent amounts of 3-methoxyphenol
(4.0 mmol) and the corresponding aldehyde (4.0 mmol) were dis-
solved in anhydrous dichloromethane (20 mL) under nitrogen, and
the mixture was cooled to –15 °C. Boron trifluoride–diethyl ether
(8.1 mmol) was slowly added by syringe to the reaction mixture.
The mixture was then warmed to room temperature and stirred for
48 h. After this time, dichloromethane was removed under reduced
pressure to half its volume. Methanol (20 mL) was added, and then
65–70% of the solvent was removed under reduced pressure at
40 °C. The precipitate was filtered at room temperature and then
washed with methanol to give pure 2a–2f in yields that ranged from
80 to 85%.
As expected, the hydrolysis of the first eluting dia-
stereomer from the reaction with the phenylethyl isocyanate
chiral auxiliary (i.e., 3a–3f) gave enantiomerically pure
tetramethoxyresorcarenes (i.e., 2a–2f), and each had the
same sign (–) for the optical rotation. The hydrolysis of the
second eluting diastereomer (i.e., 3aЈ–3fЈ) gave the (+) op-
tical isomer 2aЈ–2fЈ as the product.
The overall reaction yields of the synthesis and the sepa-
ration process for the phenylethyl, ethyl, propyl, pentyl,
heptyl, and undecyl derivatives were 63, 63, 57, 50, 53, and
42% respectively. In general, with an increasing number of
carbon atoms at the “feet”, the reaction yields decreased.
General Procedure 2: A 250 mL pressure tube reactor was charged
with the corresponding resorcarene (1 mmol) that was dissolved
in dry dichloromethane (100 mL) under nitrogen, and dibutyltin
dilaurate (8 mmol) added. (–)-(S)-1-Phenylethyl isocyanate
(8 mmol) was added dropwise at room temperature through a sy-
ringe. The tube was sealed under nitrogen and then the mixture
stirred at 60 °C for 72 h. After cooling, hexane (125 mL) was added
followed by a solution of ethanolamine (3.2 mL) in methanol
(30 mL). The mixture was diluted with dichloromethane (100 mL),
and the resulting solution was washed with water (3ϫ 200 mL),
dried with anhydrous magnesium sulfate, and concentrated under
reduced pressure to give a mixture of the desired carbamate com-
pounds.
Conclusions
In this study, we synthesized new inherently chiral and
enantiomerically pure C4-symmetrical tetramethoxyresor-
carenes. The first step in the isolation of each enantiomer
is to treat compounds 2a–2f with (–)-(S)-1-phenylethyl
isocyanate to give easily separable diastereomers 3a–3f and
3aЈ–3fЈ in good to high yields. After removal of the chiral
auxiliary, both enantiomeric target compounds were
obtained as 2a–2f and 2aЈ–2fЈ with the (–)-(M,R) and
(+)-(P,S) geometry, respectively, in good overall yields (see
Exp. Sect.).
General Procedure 3 for Carbamate Cleavage: The resorcarene
(0.125 mmol), which was isolated by column chromatography, was
dissolved in anhydrous methanol (3 mL), and a freshly prepared
sodium methoxide solution (1 m, 100 μL) was added. The reaction
mixture was stirred at room temperature for 2–3 h and then neu-
tralized with Amberlite IRC-50H resin. The resin was removed by
6
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Enantiomerically Pure C4-Symmetric Tetramethoxyresorcarenes
filtration through a glass wool plug and was washed with ethyl
acetate. The solvent was removed under reduced pressure, and the
crude product was purified by column chromatography to yield
enantiomerically pure tetramethoxyresorcarenes.
4 H), 4.37 (t, J = 7.40 Hz, 4 H), 3.60 (s, 12 H), 1.90 (s, 8 H), 1.46
(d, J = 6.80 Hz, 12 H), 0.74 (d, J = 6.80 Hz, 12 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 155.14, 154.42, 147.95, 145.43, 129.67,
128.06, 127.24, 127.00, 106.24, 55.75, 50.81, 36.56, 28.99, 23.94,
23.50, 12.80 ppm. HRMS (ESI+): calcd. for C76H84N4O12Na [M +
Na]+ 1267.5983; found 1267.6060.
Compounds 3a and 3aЈ: By using general procedure 2, 4,10,16,22-
tetrahydroxy-6,12,18,24-tetramethoxy-2,8,14,20-tetrakis(2-phenyl-
ethyl)resorcin[4]arene (2a; 1 g, 1.04 mmol) and (–)-(S)-1-phenyl-
ethyl isocyanate (1.23 g, 8.36 mmol) in the presence of dibutyltin
dilaurate (5.26 g, 8.34 mmol) gave a diastereomeric mixture, which
was purified by chromatography on a silica gel column (hexane/
EtOAc, 65:35) to give compound 3a (0.67 g, 42% yield) as a color-
less solid and 3aЈ (0.5 g, 31% yield) as a colorless solid. Data for
Compounds 3c and 3cЈ: By using general procedure 2, 4,10,16,22-
tetrahydroxy-6,12,18,24-tetramethoxy-2,8,14,20-tetrapropylresor-
cin[4]arene (2c; 0.35 g, 0.49 mmol) and (–)-(S)-1-phenylethyl iso-
cyanate (0.575 g, 3.92 mmol) in the presence of dibutyltin dilaurate
(2.48 g, 3.92 mmol) gave a diastereomeric mixture, which was puri-
fied by chromatography on a silica gel column (hexane/EtOAc,
75:25) to give compound 3c (0.23 g, 36% yield) as a colorless solid
and compound 3cЈ (0.21 g, 33% yield) as a colorless solid. Data
3a: M.p. 127–129 °C. [α]2D0 = –60.4 (c = 0.99, CH Cl ). IR: ν
=
˜
max
2
2
3401, 3027, 2931, 1726, 1611, 1489, 1443, 1404, 1348, 1284, 1191,
1090, 1025, 904, 844, 752, 697, 588, 540, 494 cm–1. 1H NMR
for 3c: M.p. 97–98 °C. [α]2D0 = –107.3 (c = 0.91, CH Cl ). IR: ν
˜
2
2
max
(400 MHz, CDCl3): δ = 7.31–7.13 (m, 40 H), 6.88 (s, 4 H), 6.46 (s, = 3333, 3030, 2956, 2932, 2869, 1721, 1614, 1587, 1490, 1444, 1401,
4 H), 5.24 (s, 4 H), 4.82 (t, J = 4.80 Hz, 4 H), 4.48 (d, J = 4.40 Hz, 1376, 1350, 1286, 1225, 1192, 1172, 1155, 1111, 1078, 1023, 911,
4 H), 3.33 (s, 12 H), 2.67 (d, J = 4.40 Hz, 4 H), 2.58 (d, J = 4.40 Hz,
4 H), 2.18 (d, J = 3.60 Hz, 8 H), 1.51 (d, J = 4.40 Hz, 12 H) ppm. DMSO): δ = 8.26 (d, J = 8.00 Hz, 4 H), 7.42–7.25 (m, 22 H), 7.05
844, 756, 699, 586, 539, 498 cm–1 1H NMR (400 MHz, [D6]-
.
1H NMR (400 MHz, [D6]DMSO): δ = 8.22 (d, J = 8.00 Hz, 4 H),
7.45–7.01 (m, 44 H), 6.39 (s, 4 H), 4.84 (t, J = 7.20 Hz, 4 H), 4.59
(t, J = 7.00 Hz, 4 H), 3.40 (s, 12 H), 2.47 (d, 8 H), 2.25 (s, 8 H), 1.52
(d, J = 6.80 Hz, 12 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 154.45, 153.79, 147.31, 144.91, 142.28, 129.30, 128.23, 128.17,
128.09, 127.81, 126.65, 126.41, 125.86, 125.71, 125.49, 105.00,
54.90, 50.40, 37.85, 34.39, 34.05, 23.15 ppm. HRMS (ESI+): calcd.
for C100H100N4O12Na [M + Na]+ 1572.7269; found 1572.7276.
Data for 3aЈ: M.p. 136–138 °C. [α]2D0 = –78.5 (c = 1.08, CH2Cl2).
(s, 2 H), 6.36 (s, 4 H), 4.80 (t, J = 7.40 Hz, 4 H), 4.47 (t, J =
7.20 Hz, 4 H), 3.38 (s, 12 H), 1.86 (s, 8 H), 1.48 (d, J = 6.80 Hz,
12 H), 1.23 (d, 8 H), 0.93 (t, J = 7.00 Hz, 12 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 154.42, 153.80, 147.21, 144.89, 129.08,
128.19, 127.65, 126.60, 126.40, 125.82, 125.70, 105.39, 54.89, 50.37,
37.73, 33.88, 23.11, 20.48, 13.89 ppm. HRMS (ESI+): calcd. for
C80H92N4O12Na [M + Na]+ 1323.6609; found 1323.6639. Data for
3cЈ: M.p. 104–105 °C. [α]2D0 = –39.8 (c = 0.88, CH Cl ). IR: ν
=
˜
max
2
2
3328, 3029, 2956, 2932, 2869, 1719, 1663, 1614, 1586, 1491, 1446,
IR: ν
= 3399, 3027, 2930, 1724, 1610, 1489, 1443, 1404, 1348, 1404, 1376, 1352, 1286, 1229, 1192, 1172, 1154, 1112, 1078, 1025,
˜
max
1284, 1191, 1090, 1025, 903, 843, 751, 697, 588, 493 cm–1. 1H NMR
911, 844, 756, 699, 587, 538 cm–1 1H NMR (400 MHz, [D6]-
.
(400 MHz, CDCl3): δ = 7.38–7.07 (m, 40 H), 6.89 (s, 4 H), 6.57 (s, DMSO): δ = 8.20 (d, J = 7.60 Hz, 4 H), 7.48–7.27 (m, 22 H), 7.07
4 H), 5.21 (s, 4 H), 4.86 (t, J = 4.60 Hz, 4 H), 4.46 (s, 4 H), 3.47
(s, 12 H), 2.59 (s, 4 H), 2.52 (d, J = 4.00 Hz, 4 H), 2.16 (m, 8 H),
(s, 2 H), 6.48 (s, 4 H), 4.78 (t, J = 7.00 Hz, 4 H), 4.47 (t, J =
7.20 Hz, 4 H), 3.60 (s, 12 H), 1.81 (s, 8 H), 1.46 (d, J = 6.00 Hz,
1.49 (d, J = 4.40 Hz, 12 H) ppm. 1H NMR (400 MHz, [D6]DMSO): 12 H), 1.11 (m, 8 H), 0.80 (t, J = 6.80 Hz, 12 H) ppm. 13C NMR
δ = 8.18 (d, J = 8.00 Hz, 4 H), 7.52–7.02 (m, 44 H), 6.51 (s, 4 H),
4.85 (t, J = 7.00 Hz, 4 H), 4.59 (t, J = 6.80 Hz, 4 H), 3.61 (s, 12
H), 2.41 (d, J = 8.00 Hz, 4 H), 2.34 (d, J = 8.80 Hz, 4 H), 2.22 (d,
J = 7.20 Hz, 8 H), 1.50 (d, J = 6.40 Hz, 12 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 154.57, 153.89, 147.31, 144.80, 142.18,
129.29, 128.24, 128.09, 128.04, 126.70, 126.09, 125.80, 125.45,
105.40, 55.22, 50.29, 37.94, 34.46, 34.06, 22.94 ppm. HRMS
(ESI+): calcd. for C100H100N4O12Na [M + Na]+ 1572.7269; found
1572.7197.
(100 MHz, [D6]DMSO): δ = 154.49, 153.84, 147.14, 144.78, 128.97,
128.17, 126.62, 126.40, 125.76, 125.70, 105.78, 55.20, 50.21, 37.63,
34.04, 23.34, 22.77, 20.44, 13.81 ppm. HRMS (ESI+): calcd. for
C80H92N4O12Na [M + Na]+ 1323.6609; found 1323.6653.
Compounds 3d and 3dЈ: By using general procedure 2, 4,10,16,22-
tetrahydroxy-6,12,18,24-tetramethoxy-2,8,14,20-tetrapentylresor-
cin[4]arene (2d; 0.7 g, 0.85 mmol) and (S)-(–)-1-phenylethyl iso-
cyanate (1.0 g, 6.78 mmol) in the presence of dibutyltin dilaurate
(4.28 g, 6.78 mmol) gave a diastereomeric mixture, which was puri-
fied by chromatography on a silica gel column (hexane/EtOAc,
75:25) to give compound 3d (0.38 g, 32% yield) as colorless crystals
Compounds 3b and 3bЈ: By using general procedure 2, 2,8,14,20-
tetraethyl-4,10,16,22-tetrahydroxy-6,12,18,24-tetramethoxyresor-
cin[4]arene (2b; 0.5 g, 0.76 mmol) and (–)-(S)-1-phenylethyl iso- and compound 3dЈ (0.33 g, 28% yield) as colorless crystals. Data
cyanate (0.89 g, 6.08 mmol) in the presence of dibutyltin dilaurate
(3.84 g, 6.08 mmol) gave a diastereomeric mixture, which was puri-
fied by chromatography on a silica gel column (hexane/EtOAc,
75:25) to give compound 3b (0.39 g, 41% yield) as a colorless solid
and compound 3bЈ (0.29 g, 31% yield) as a colorless solid. Data
for 3b: M.p. 161–162 °C. [α]2D0 = –123.1 (c = 1.04, CH2Cl2). 1H
for 3d: M.p. 86–87 °C. [α]2D0 = –90.6 (c = 0.99, CH Cl ). IR: ν
˜
2 2 max
= 3321, 2928, 2857, 1718, 1614, 1491, 1443, 1404, 1352, 1282, 1260,
1227, 1190, 1083, 1026, 905, 843, 797, 759, 698, 586, 540, 490,
403 cm–1 1H NMR (400 MHz, [D6]DMSO): δ = 8.25 (d, J =
.
8.00 Hz, 4 H), 7.42–7.25 (m, 22 H), 7.01 (s, 2 H), 6.37 (s, 4 H), 4.79
(t, J = 7.40 Hz, 4 H), 4.44 (t, J = 6.80 Hz, 4 H), 3.43 (s, 12 H),
NMR (400 MHz, [D6]DMSO): δ = 8.24 (d, J = 5.60 Hz, 4 H), 1.84 (s, 8 H), 1.48 (d, J = 6.80 Hz, 12 H), 1.29 (m, 24 H), 0.89 (t,
7.42–7.24 (m, 22 H), 7.06 (s, 2 H), 6.37 (s, 4 H), 4.81 (t, J = 4.80 Hz,
4 H), 4.37 (t, J = 4.80 Hz, 4 H), 3.36 (s, 12 H), 1.91 (s, 8 H), 1.50
(d, J = 4.40 Hz, 12 H), 0.85 (m, 12 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 154.98, 154.29, 147.89, 145.39, 129.66, 128.71,
12 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 154.43, 153.80,
147.20, 144.85, 129.07, 128.20, 127.94, 126.62, 125.82, 125.54,
105.47, 54.91, 50.38, 35.45, 31.41, 31.25, 28.94, 28.85, 28.65, 28.50,
27.06, 23.07, 22.05, 13.94 ppm. HRMS (ESI+): calcd. for
128.69, 127.92, 127.12, 126.91, 126.35, 126.22, 126.07, 105.76, C88H108N4O12Na [M + Na]+ 1435.7861; found 1435.7889. Data for
55.37, 50.88, 36.35, 28.94, 23.84, 23.61, 12.7 ppm. HRMS (ESI+):
calcd. for C76H84N4O12Na [M + Na]+ 1267.5983; found 1267.5988.
Data for 3bЈ: M.p. 164–165 °C. [α]2D0 = –55.2 (c = 0.816, CH2Cl2).
1H NMR (400 MHz, [D6]DMSO): δ = 8.23 (d, J = 7.60 Hz, 4 H),
7.49–7.27 (m, 22 H), 7.09 (s, 2 H), 6.49 (s, 4 H), 4.81 (t, J = 7.00 Hz,
3dЈ: M.p. 90–91 °C. [α]2D0 = –38.8 (c = 1.1, CH Cl ). IR: ν
=
˜
2
2
max
3324, 2928, 2857, 1718, 1613, 1491, 1443, 1404, 1351, 1282, 1227,
1
1190, 1117, 1083, 1026, 904, 844, 799, 757, 698, 587, 539 cm–1. H
NMR (400 MHz, [D6]DMSO): δ = 8.21 (d, J = 7.60 Hz, 4 H),
7.48–7.27 (m, 22 H), 7.03 (s, 2 H), 6.50 (s, 4 H), 4.80 (t, J = 8.00 Hz,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42125
/KAP1
Date: 17-06-14 10:41:09
Pages: 11
G. E. M. Maguire et al.
FULL PAPER
4 H), 4.44 (t, J = 7.60 Hz, 4 H), 3.61 (s, 12 H), 1.77 (s, 8 H), 1.46
(d, J = 6.40 Hz, 12 H), 1.17 (m, 24 H), 0.79 (t, 12 H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 154.49, 153.83, 147.22, 144.78,
(m, 22 H), 6.99 (s, 2 H), 6.50 (s, 4 H), 4.78 (t, J = 6.80 Hz, 4 H),
4.44 (s, 4 H), 3.60 (s, 12 H), 1.73 (s, 8 H), 1.34 (d, J = 6.00 Hz, 12
H), 1.24 (m, 72 H), 0.88 (s, 12 H) ppm. 13C NMR (100 MHz,
129.04, 128.13, 127.61, 126.58, 126.39, 125.74, 125.70, 125.53, CDCl3): δ = 155.01, 153.86, 147.09, 143.45, 130.09, 128.66, 127.31,
105.82, 55.18, 50.20, 35.40, 34.36, 31.30, 27.03, 23.34, 22.82, 126.03, 125.58, 105.56, 55.51, 50.74, 35.33, 35.16, 33.86, 31.96,
21.98, 13.82 ppm. HRMS (ESI+): calcd. for C88H108N4O12Na 30.91, 30.00, 29.90, 29.81, 29.74, 29.62, 29.41, 29.30, 29.14, 27.88,
[M + Na]+ 1435.7861; found 1435.7917.
24.83, 22.71, 22.57, 14.13 ppm. HRMS (ESI+): calcd. for
C
112H156N4O12Na [M + Na]+ 1773.1651; found 1773.1656.
Compounds 3e and 3eЈ: By using general procedure 2, 2,8,14,20-
tetraheptyl-4,10,16,22-tetrahydroxy-6,12,18,24-tetramethoxyresor-
cin[4]arene (2e; 0.5 g, 0.53 mmol) and (–)-(S)-1-phenylethyl iso-
cyanate (0.63 g, 4.26 mmol) in the presence of dibutyltin dilaurate
(2.69 g, 4.26 mmol) gave a diastereomeric mixture, which purified
by chromatography on a silica gel column (hexane/EtOAc, 70:30)
to give compound 3e (0.24 g, 34% yield) as colorless crystals and
compound 3eЈ (0.22 g, 29% yield) as colorless crystals. Data for 3e:
4,10,16,22-Tetrahydroxy-6,12,18,24-tetramethoxy-2,8,14,20-tetra-
kis(2-phenylethyl)resorcin[4]arene [(–)-(M,R)-2a]: General pro-
cedure 3 was applied by using (P,S,S)-3a (0.20 g, 0.129 mmol) and
sodium methoxide (1 m solution, 100 μL). The residue was purified
by column chromatography (hexane/EtOAc, 60:30) to obtain (–)-
(M,R)-2a (0.1 g, 84% yield) as colorless crystals; m.p. 133–134 °C.
[α]2D0 = –46.5 (c = 0.66, CH2Cl2). 1H NMR (400 MHz, [D6]DMSO):
δ = 8.44 (s, 4 H), 6.75–6.88 (m, 24 H), 6.05 (s, 4 H), 4.36 (t, J =
7.52 Hz, 4 H), 3.37 (s, 12 H), 2.12 (t, J = 7.94 Hz, 8 H), 1.81 (m,
8 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 154.92, 153.07,
142.51, 128.05, 128.04, 126.03, 125.35, 123.13, 122.56, 98.83, 55.37,
48.55, 34.10, 33.33 ppm. HRMS (ESI+): calcd. for C64H64O8Na
[M + Na]+ 983.4499; found 983.4498.
M.p. 77–79 °C. [α]2D0 = –95.5 (c = 1.2, CH Cl ). IR: ν
= 3324,
˜
max
2
2
2927, 2856, 1719, 1613, 1491, 1443, 1404, 1350, 1282, 1227, 1190,
1117, 1084, 1026, 904, 844, 757, 698, 586, 539 cm–1 1H NMR
.
(400 MHz, [D6]DMSO): δ = 8.27 (d, J = 8.40 Hz, 4 H), 7.42–7.25
(m, 22 H), 6.99 (s, 2 H), 6.37 (s, 4 H), 4.80 (t, J = 7.20 Hz, 4 H),
4.44 (t, J = 6.80 Hz, 4 H), 3.40 (s, 12 H), 1.83 (s, 8 H), 1.48 (d, J
= 6.80 Hz, 12 H), 1.30 (m, 40 H), 0.92 (m, 12 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 154.40, 153.78, 147.23, 144.83, 129.06,
128.13, 128.00, 126.61, 125.80, 125.76, 125.60, 125.50, 105.48,
54.88, 50.39, 35.53, 34.16, 33.62, 31.37, 31.25, 29.13, 28.95, 28.63,
28.49, 27.31, 23.06, 22.06, 13.86 ppm. HRMS (ESI+): calcd. for
C96H124N4O12Na [M + Na]+ 1548.9147; found 1548.9176. Data for
4,10,16,22-Tetrahydroxy-6,12,18,24-tetramethoxy-2,8,14,20-tetra-
kis(2-phenylethyl)resorcin[4]arene [(P,S)-(+)-2aЈ]: General pro-
cedure 3 was applied by using (M,S,R)-3aЈ (0.2 g, 0.129 mmol) and
sodium methoxide (1 m solution, 100 μL). The residue was purified
by column chromatography (hexane/EtOAc, 60:30) to obtain (+)-
(P,S)-2aЈ (0.11 g, 89% yield) as colorless crystals; m.p. 133–134 °C.
[α]2D0 = +45.9 (c = 0.66, CH2Cl2). 1H NMR (400 MHz, [D6]DMSO):
δ = 8.45 (s, 4 H), 6.75–6.86 (m, 24 H), 6.05 (s, 4 H), 4.36 (t, J =
7.52 Hz, 4 H), 3.37 (s, 12 H), 2.12 (t, J = 8.40 Hz, 8 H), 1.82 (m,
8 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 154.91, 153.07,
142.52, 128.06, 128.04, 126.03, 125.35, 123.14, 122.56, 98.83, 55.37,
48.55, 34.11, 33.34 ppm. HRMS (ESI+): calcd. for C64H64O8Na
[M + Na]+ 983.4499; found 983.4493.
3eЈ: M.p. 87–88 °C. [α]2D0 = –47.3 (c = 1.1, CH Cl ). IR: ν
=
˜
max
2
2
3324, 2927, 2856, 1718, 1613, 1491, 1443, 1404, 1351, 1282, 1228,
1190, 1117, 1084, 1026, 904, 844, 758, 698, 586, 540 cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.22 (d, J = 8.00 Hz, 4 H), 7.48–7.29
(m, 22 H), 7.02 (s, 2 H), 6.50 (s, 4 H), 4.80 (m, J = 7.40 Hz, 4 H),
4.44 (t, J = 7.20 Hz, 4 H), 3.61 (s, 12 H), 1.76 (s, 8 H), 1.47 (d, J
= 5.60 Hz, 12 H), 1.17 (m, 40 H), 0.86 (t, J = 7.00 Hz, 12 H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 154.49, 153.82, 147.25,
144.79, 129.07, 128.13, 127.54, 126.57, 126.40, 125.74, 125.70,
105.86, 55.18, 50.20, 35.50, 34.35, 31.25, 29.08, 28.58, 27.28, 23.33,
2 2 . 8 4 , 2 2 . 0 3 , 1 3 . 8 3 p p m . H R M S ( E S I + ) : c a l c d . fo r
C88H108N4O12Na [M + Na]+ 1548.9147; found 1548.9137.
2,8,14,20-Tetraethyl-4,10,16,22-tetrahydroxy-6,12,18,24-tetrameth-
oxyresorcin[4]arene [(–)-(M,R)-2b]: General procedure 3 was ap-
plied by using (P,S,S)-3b (0.12 g, 0.096 mmol) and sodium meth-
oxide (1 m solution, 100 μL). The residue was purified by column
chromatography (hexane/EtOAc, 75:25) to obtain (–)-(M,R)-2b
(0.052 g, 83% yield) as pink crystals; m.p. 295–296 °C. [α]2D0 = –29.9
(c = 0.87, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.53 (s, 4
H), 7.23 (s, 4 H), 6.37 (s, 4 H), 4.19 (t, J = 7.86 Hz, 4 H), 3.84 (s,
12 H), 2.24 (q, J = 7.42, 14.84 Hz, 8 H), 0.93 (t, J = 7.16 Hz, 12
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.72, 153.05, 124.56,
124.49, 123.58, 100.04, 55.87, 35.16, 26.95, 12.57 ppm. HRMS
(ESI+): calcd. for C40H48O8Na [M + Na]+ 679.3247; found
679.3280.
Compounds 3f and 3fЈ: By using general procedure 2, 4,10,16,22-
tetrahydroxy-6,12,18,24-tetramethoxy-2,8,14,20-tetraundecylresor-
cin[4]arene (2f; 0.5 g, 0.43 mmol) and (–)-(S)-1-phenylethyl iso-
cyanate (0.5 g, 3.44 mmol) in the presence of dibutyltin dilaurate
(2.17 g, 3.44 mmol) gave a diastereomeric mixture, which was puri-
fied by chromatography on a silica gel column (hexane/EtOAc,
70:30) to give compound 3f (0.24 g, 32% yield) as a glassy solid
and compound 3fЈ (0.16 g, 21% yield) as a colorless solid. Data for
3f: M.p. 61–62 °C. [α]2D0 = –78.6 (c = 1.0, CH Cl ). IR: νmax = 3320,
˜
2
2
2,8,14,20-Tetraethyl-4,10,16,22-tetrahydroxy-6,12,18,24-tetrameth-
oxyresorcin[4]arene [(+)-(P,S)-2bЈ]: General procedure 3 was ap-
plied by using (M,S,R)-3bЈ (0.12 g, 0.096 mmol) and sodium meth-
oxide (1 m solution, 100 μL). The residue was purified by column
chromatography (hexane/EtOAc, 75:25) to obtain (+)-(P,S)-2bЈ
2925, 2854, 1716, 1614, 1491, 1444, 1404, 1377, 1283, 1228, 1192,
1085, 1026, 901, 844, 800, 759, 699, 586, 539 cm–1 1H NMR
.
(400 MHz, [D6]DMSO): δ = 8.26 (d, J = 7.37 Hz, 4 H), 7.41–7.24
(m, 22 H), 6.95 (s, 2 H), 6.37 (s, 4 H), 4.79 (t, J = 6.40 Hz, 4 H),
4.44 (s, 4 H), 3.39 (s, 12 H), 1.80 (s, 8 H), 1.48 (d, J = 6.00 Hz, 12
H), 1.26 (m, 72 H), 0.88 (s, 12 H) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 154.41, 153.78, 147.24, 144.85, 129.09, 128.20, 127.93,
127.53, 126.62, 125.81, 125.40, 105.49, 54.88, 50.39, 35.56, 34.17,
33.64, 31.38, 31.25, 29.14, 28.95, 28.87, 28.70, 28.66, 28.51, 27.32,
24.49, 23.08, 22.06, 13.86 ppm. HRMS (ESI+): calcd. for
C112H156N4O12Na [M + Na]+ 1773.1651; found 1773.1657. Data
(0.055 g, 88% yield) as light pink crystals; m.p. 296–297 °C. [α]2D0
=
1
+32.1 (c = 0.86, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.54
(s, 4 H), 7.24 (s, 4 H), 6.37 (s, 4 H), 4.20 (t, J = 7.86 Hz, 4 H), 3.84
(s, 12 H), 2.25 (q, J = 7.46, 14.92 Hz, 8 H), 0.94 (t, J = 7.18 Hz, 12
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.72, 153.05, 124.57,
124.50, 123.59, 100.05, 55.88, 35.17, 26.96, 12.58 ppm. HRMS
(ESI+): calcd. for C40H49O8 [M + H]+ 657.3427; found 657.3415.
for 3fЈ: M.p. 68–69 °C. [α]2D0 = –64.1 (c = 1.2, CH Cl ). IR: ν
=
˜
max
2
2
3321, 2926, 2855, 1716, 1614, 1491, 1444, 1404, 1353, 1283, 1230,
1191, 1084, 1026, 903, 844, 758, 698, 586, 540 cm–1 1H NMR
(400 MHz, [D6]DMSO): δ = 8.21 (d, J = 5.60 Hz, 4 H), 7.46–7.27
4,10,16,22-Tetrahydroxy-6,12,18,24-tetramethoxy-2,8,14,20-tetra-
propylresorcin[4]arene [(–)-(M,R)-2c]: General procedure 3 was ap-
plied by using (P,S,S)-3c (0.081 g, 0.062 mmol) and sodium meth-
.
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42125
/KAP1
Date: 17-06-14 10:41:09
Pages: 11
Enantiomerically Pure C4-Symmetric Tetramethoxyresorcarenes
oxide (1 m solution, 50 μL). The residue was purified by column
chromatography (hexane/EtOAc, 70:30) to obtain (–)-(M,R)-2c
umn chromatography (hexane/EtOAc, 65:35) to obtain (+)-(P,S)-
2eЈ (0.099 g, 85% yield) as colorless crystals; m.p. 146–147 °C.
1
(0.038 g, 85% yield) as a colorless foam; m.p. 196–198 °C. [α]2D0
=
[α]2D0 = +62.2 (c = 1.1, CH2Cl2). H NMR (400 MHz, CDCl3): δ =
1
–87.9 (c = 1.14, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.51
7.43 (s, 4 H), 7.14 (s, 4 H), 6.26 (s, 4 H), 4.19 (t, J = 7.76 Hz, 4 H),
(s, 4 H), 7.24 (s, 4 H), 6.35 (s, 4 H), 4.31 (t, J = 7.84 Hz, 4 H), 3.84 3.75 (s, 12 H), 2.10 (d, J = 6.96 Hz, 8 H), 1.25 (m, 48 H), 0.81 (t,
(s, 12 H), 2.20 (d, J = 6.72 Hz, 8 H), 1.31 (m, 8 H), 0.99 (t, J = J = 6.52 Hz, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.60,
7.36 Hz, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.63, 152.94, 124.71, 124.60, 123.68, 99.99, 55.86, 33.96, 33.05, 31.88,
152.97, 124.67, 124.56, 123.74, 99.99, 55.88, 35.95, 32.65, 21.02, 29.66, 29.36, 28.05, 22.63, 14.09 ppm. MS (ESI+): m/z = 937.7 [M
13.97 ppm. MS (ESI+): m/z = 713.4 [M + H]+.
+ H]+.
4,10,16,22-Tetrahydroxy-6,12,18,24-tetramethoxy-2,8,14,20-tetra-
propylresorcin[4]arene [(+)-(P,S)-2cЈ]: General procedure 3 was ap-
plied by using (M,S,R)-3cЈ (0.081 g, 0.062 mmol) and sodium
methoxide (1 m solution, 50 μL). The residue was purified by col-
umn chromatography (hexane/EtOAc, 70:30) to obtain (+)-(P,S)-
2cЈ (0.035 g, 79 % yield) as a colorless foam; m.p. 197–198 °C.
4,10,16,22-Tetrahydroxy-6,12,18,24-tetramethoxy-2,8,14,20-tetra-
undecylresorcin[4]arene [(–)-(M,R)-2f]: General procedure 3 was ap-
plied by using (P,S,S)-3f (0.22 g, 0.125 mmol) and sodium meth-
oxide (1 m solution, 100 μL). The residue was purified by column
chromatography (hexane/EtOAc, 60:40) to obtain (–)-(M,R)-2f
(0.11 g, 77% yield) as a colorless foam; m.p. 140–141 °C. [α]2D0
=
[α]2D0 = +79.5 (c = 1.23, CH2Cl2). H NMR (400 MHz, CDCl3): δ
–45.0 (c = 1.12, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.51
1
1
= 7.51 (s, 4 H), 7.24 (s, 4 H), 6.35 (s, 4 H), 4.31 (t, J = 7.88 Hz, 4 (s, 4 H), 7.22 (s, 4 H), 6.35 (s, 4 H), 4.27 (t, J = 7.76 Hz, 4 H), 3.84
H), 3.84 (s, 12 H), 2.20 (d, J = 6.72 Hz, 8 H), 1.31 (m, 8 H), 0.99
(s, 12 H), 2.19 (q, J = 6.96 Hz, 8 H), 1.27 (m, 72 H), 0.90 (t, J =
(t, J = 7.34 Hz, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 6.56 Hz, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.59,
153.62, 152.96, 124.66, 124.56, 123.74, 99.99, 55.88, 35.94, 32.65,
152.94, 124.70, 124.60, 123.69, 99.98, 55.86, 33.97, 33.04, 31.95,
29.74, 29.72, 29.41, 28.07, 22.69, 14.11 ppm. MS (ESI+): m/z =
1184.9 [M + Na]+.
21.03, 13.98 ppm. MS (ESI+): m/z = 713.4 [M + H]+.
4,10,16,22-Tetrahydroxy-6,12,18,24-tetramethoxy-2,8,14,20-tetra-
pentylresorcin[4]arene [(–)-(M,R)-2d]: General procedure 3 was ap-
plied by using (P,S,S)-3d (0.18g, 0.127 mmol) and sodium meth-
oxide (1 m solution, 100 μL). The residue was purified by column
chromatography (hexane/EtOAc, 65:35) to obtain (–)-(M,R)-2d
4,10,16,22-Tetrahydroxy-6,12,18,24-tetramethoxy-2,8,14,20-tetra-
undecylresorcin[4]arene [(+)-(P,S)-2fЈ]: General procedure 3 was ap-
plied by using (M,S,R)-3fЈ (0.11 g, 0.062 mmol) and sodium meth-
oxide (1 m solution, 50 μL). The residue was purified by column
chromatography (hexane/EtOAc, 60:40) to obtain (+)-(P,S)-2fЈ
(0.09 g, 86% yield) as light pink crystals; m.p. 218–219 °C. [α]2D0
=
1
(0.058 g, 80% yield) as a colorless foam; m.p. 140–141 °C. [α]2D0
=
–50.9 (c = 0.998, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.51
(s, 4 H), 7.22 (s, 4 H), 6.35 (s, 4 H), 4.27 (t, J = 7.80 Hz, 4 H), 3.84
(s, 12 H), 2.19 (d, J = 7.04 Hz, 8 H), 1.31 (m, 48 H), 0.90 (t, J =
7.00 Hz, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.60,
152.94, 124.72, 124.63, 123.65, 99.99, 55.87, 33.94, 33.12, 31.96,
27.77, 22.69, 14.13 ppm. MS (ESI+): m/z = 825.6 [M + H]+.
1
+48.9 (c = 1.31, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.52
(s, 4 H), 7.22 (s, 4 H), 6.35 (s, 4 H), 4.27 (t, J = 7.72 Hz, 4 H), 3.84
(s, 12 H), 2.19 (q, J = 7.00 Hz, 8 H), 1.27 (m, 72 H), 0.90 (t, J =
6.56 Hz, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.59,
152.94, 124.70, 124.60, 123.68, 99.98, 55.86, 33.96, 33.04, 31.95,
29.75, 29.72, 29.41, 28.07, 22.70, 14.11 ppm. MS (ESI+): m/z =
1185.0 [M + Na]+.
4,10,16,22-Tetrahydroxy-6,12,18,24-tetramethoxy-2,8,14,20-tetra-
pentylresorcin[4]arene [(+)-(P,S)-2dЈ]: General procedure 3 was ap-
plied by using (M,S,R)-3dЈ (0.09 g, 0.063 mmol) and sodium meth-
oxide (1 m solution, 50 μL). The residue was purified by column
chromatography (hexane/EtOAc, 65:35) to obtain (+)-(P,S)-2dЈ
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR, 13C NMR, and IR spectra as well as compiled
HRMS data.
(0.042 g, 81% yield) as light pink crystals; m.p. 220–221 °C. [α]2D0
=
+52.9 (c = 1.1, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.51 (s,
4 H), 7.22 (s, 4 H), 6.35 (s, 4 H), 4.27 (t, J = 7.72 Hz, 4 H), 3.84
(s, 12 H), 2.19 (d, J = 7.08 Hz, 8 H), 1.33 (m, 48 H), 0.91 (t, J =
6.92 Hz, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.60,
152.94, 124.72, 124.63, 123.65, 99.99, 55.87, 33.94, 33.11, 31.96,
27.77, 22.69, 14.13 ppm. MS (ESI+): m/z = 825.6 [M + H]+.
Acknowledgments
The authors wish to thank Professor Jochen Mattay for his helpful
comments and encouragement of this work. Also, we want to thank
Dr. Hong Su from the Chemistry Department of the University of
Cape Town for the assistance with the X-ray data collection and
refinement and the Department of Science and Technology –
National Research Foundation, Centre of Excellence in Catalysis,
c*change for the financial support.
2,8,14,20-Tetraheptyl-4,10,16,22-tetrahydroxy-6,12,18,24-tetra-
methoxyresorcin[4]arene [(–)-(M,R)-2e]: General procedure 3 was
applied by using (P,S,S)-3e (0.19 g, 0.125 mmol) and sodium meth-
oxide (1 m solution, 100 μL). The residue was purified by column
chromatography (hexane/EtOAc, 65:35) to obtain (–)-(M,R)-2e
[1] a) C. D. Gutsche, Calixarenes, Monographs in Supramolecular
Chemistry, Royal Society of Chemistry, Cambridge, 1989; b) J.
Vicens, V. Böhmer, Calixarenes, A Versatile Class of Macro-
cyclic Compounds, Kluwer Academic Publishers, Dordrecht,
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(0.097 g, 84% yield) as colorless crystals; m.p. 145–146 °C. [α]2D0
=
1
–63.6 (c = 0.97, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.43
(s, 4 H), 7.14 (s, 4 H), 6.26 (s, 4 H), 4.19 (t, J = 7.76 Hz, 4 H), 3.75
(s, 12 H), 2.10 (d, J = 6.92 Hz, 8 H), 1.23 (m, 48 H), 0.81 (t, J =
6.52 Hz, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.60,
152.94, 124.71, 124.60, 123.68, 99.99, 55.86, 33.96, 33.05, 31.88,
29.66, 29.36, 28.05, 22.63, 14.09 ppm. MS (ESI+): m/z = 937.7 [M
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2,8,14,20-Tetraheptyl-4,10,16,22-tetrahydroxy-6,12,18,24-tetra-
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 17-06-14 10:41:09
Pages: 11
G. E. M. Maguire et al.
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Received: February 21, 2014
Published Online: ᭿
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42125
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Date: 17-06-14 10:41:09
Pages: 11
Enantiomerically Pure C4-Symmetric Tetramethoxyresorcarenes
Calixarenes
A. S. Thakar, H. M. Parekh,
P. B. Pansuriya, H. B. Friedrich,
G. E. M. Maguire* .......................... 1–11
Preparation of Enantiomerically Pure C4-
Symmetric Tetramethoxyresorcarenes by
Using the (–)-(S)-1-Phenylethyl Isocyanate
Chiral Auxiliary
An approach to enantiomerically pure C4-
symmetric tetramethoxyresorcarenes has
been developed. By employing (–)-(S)-1-
phenylethyl isocyanate as a chiral auxiliary,
the racemic resorcarenes were converted
into their corresponding diastereomeric
carbamates. A chromatographic separation
followed by hydrolysis afforded the
optically pure (–)-(M,R)- and (+)-(P,S)-
resorcarene enantiomers.
Keywords: Resorcarenes / Asymmetric syn-
thesis / Diastereoselectivity / Chiral resol-
ution / Tin / Carbamates
Eur. J. Org. Chem. 0000, 0–0
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11