The diastereoselective formation of tetraalkoxy[4]resorcinarenes derived from (-)-(2R)-2-methoxy-2-phenylethanol and proof of absolute configurations

Article abstract of DOI:10.1002/ejoc.201100733

The preparation of optically pure (-)-3-[(2R)-2-methoxy-2-phenylethoxy] phenol from resorcinol monobenzoate and its conversion into diastereoisomeric tetraalkoxyresorcin[4]arenes together with proof of the absolute configurations of the products is reported. The results of the study indicate that diastereoselective ring closure of linear tetrameric intermediates is controlled by the steric demand of the alkyl group in the precursor 3-alkoxyphenol.

Full text of DOI:10.1002/ejoc.201100733

FULL PAPER
DOI: 10.1002/ejoc.201100733
The Diastereoselective Formation of Tetraalkoxy[4]resorcinarenes Derived from
(–)-(2R)-2-Methoxy-2-phenylethanol and Proof of Absolute Configurations
Philip C. Bulman Page,[a] Yohan Chan,[a] Harry Heaney,*[b] Matthew J. McGrath,[b] and
Eduardo Moreno[b]
Keywords: Calixarenes / Configuration determineation / Chirality / Diastereoselectivity / Macrocycles
The preparation of optically pure (–)-3-[(2R)-2-methoxy-2-
phenylethoxy]phenol from resorcinol monobenzoate and its
conversion into diastereoisomeric tetraalkoxyresorcin[4]-
arenes together with proof of the absolute configurations of
the products is reported. The results of the study indicate that
diastereoselective ring closure of linear tetrameric intermedi-
ates is controlled by the steric demand of the alkyl group in
the precursor 3-alkoxyphenol.
selective formation of tetrakis(benzoxazines), derived from
a number of resorcin[4]arenes. Methylation of the residual
phenolic hydroxy groups was performed to preclude dia-
stereoisomerization and loss of axial chirality after ring
opening of the 1,3-oxazine ring and removal of the chiral
auxiliary.[10] The formation of a racemic tetramethoxyresor-
cinarene by the boron trifluoride catalyzed reaction of oc-
tanal with resorcinol monomethyl ether, reported by Mo-
cerino and co-workers,[11] provided an important advance
in the chemistry of axially chiral C4-symmetric resorcin[4]-
arenes. We showed, subsequently, that the desymmetri-
zation of resorcinol could be achieved in high yields[12] to
give a wide range of 3-alkoxyphenol derivatives starting
from 3-iodophenol, using alkanols and copper(I) iodide/
9,10-phenanthroline catalysis,[13] or from resorcinol mono-
benzoate using alcohols in Mitsunobu reactions,[14] fol-
lowed by base-catalyzed alcoholysis. We were thus able to
access a range of other racemic tetraalkoxyresorcinarene
derivatives in good to excellent yields by the interaction of
boron trifluoride with 1,1-dimethoxyalkanes and, for exam-
ple, the 3-alkoxyphenol derivatives.[15] We also recently re-
ported the conversion of a number of racemic tetraalk-
oxyresorcinarenes into diastereoisomeric mixtures of tet-
rakis(1,3-benzoxazine) derivatives, together with the separa-
tion of the diastereoisomers and proof of their absolute
configurations.[16]
Introduction
A large number of studies of calixarenes have concen-
trated on inherently chiral C1-symmetric systems where the
dissymmetry generated by unsymmetrical substitution[1] is
recognized as being related to the nonplanar structures of
the parent compounds as a result of blocked curvature.[2]
Considerable effort has been devoted to the synthesis of in-
herently chiral calixarenes, but, in the majority of published
examples, the products have been obtained as racemates
that could not be resolved except by using chiral HPLC
techniques; this has inevitably meant that only very small
amounts of optically pure material has been available for
use in other investigations. The ready availability of resor-
cin[4]arenes as the rccc (all-cis) C4v-symmetric cyclic tetra-
mers, which are prepared in high yields by the acid-cata-
lyzed interaction of a number of aldehydes with resorcinol,
has made the study of those compounds particularly at-
tractive.[3] Derivatives of the parent tetramers have been
used for a wide variety of purposes.[4] The use of aldehydes,
other than formaldehyde and acetaldehyde, in the prepara-
tion of resorcin[4]arenes, prevents racemization by pro-
cesses involving “through-the-annulus rotation”.[5] The ob-
servation of axial chirality (sometimes referred to as cyclo-
chirality) was first noted by Prelog in connection with cy-
clopeptides,[6] and has subsequently been studied in a
number of other areas, including rotaxanes.[7] Cyclochiral-
ity, as applied to resorcinarenes, has been discussed in sev-
eral recent reviews.[8] Our studies have concentrated on axi-
ally chiral C4-symmetric resorcin[4]arenes; for example,
studies carried out by us[9a] and others[9b–9d] using optically
pure α-methylbenzylamines resulted in the highly diastereo-
Results and Discussion
The method developed by Mocerino[11] provided, in prin-
ciple, a route to diastereoisomeric resorcinarene derivatives
by using suitable optically pure 3-alkoxyphenols. During
the course of our investigation, the Mocerino protocol was
used to prepare diastereoisomeric tetrakis(2-methylbutyl-
oxy)resorcin[4]arenes in a 3:2 ratio using 3-methylbutanal,
and in a 1:1 ratio using dodecanal.[17] However, as far as
[a] School of Chemistry, University of East Anglia,
Norwich, Norfolk, NR4 7TJ, U.K
[b] Department of Chemistry, Loughborough University,
Loughborough, Leicestershire, LE11 3TU, U.K
E-mail: h.heaney@lboro.ac.uk
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H. Heaney et al.
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Scheme 1. Preparation of (–)-3-[(2R)-2-methoxy-2-phenylethoxy]phenol (5).
we are aware, the absolute configurations of the products phenyl benzoate (4) in 78% yield. Hydrolysis of the esters
have not been confirmed. Our investigation required a via- gave (–)-3-[(2R)-2-methoxy-2-phenylethoxy]phenol (5) in
ble route to quantities of (–)-3-[(2R)-2-methoxy-2-phenyl- excellent yields. The sequence of reactions is shown in
ethoxy]phenol. We showed that hydroxycarboxylic acids Scheme 1.
could be converted in excellent yields into the related ether–
Reactions using (–)-3-[(2R)-2-methoxy-2-phenylethoxy]-
esters using dimsyllithium in dimethyl sulfoxide (DMSO) phenol (5) were carried out using hexanal (or 1,1-dimeth-
and methyl iodide; we prepared (–)-methyl (2R)-2-methoxy- oxyhexane) and 2-phenylpropanal (or 1,1-dimethoxy-3-
2-phenylacetate (1) in an essentially quantitative yield by phenylpropane), together with boron trifluoride–diethyl
using that method with no loss of optical purity.[18] Re- ether (Scheme 2). Unfortunately, reactions carried out un-
duction of the ester using lithium aluminium hydride in der apparently identical reaction conditions at ambient
tetrahydrofuran (THF) gave (–)-(2R)-2-methoxy-2-phenyl- temperature, using the aldehydes or the related dimethyl
ethanol (2) in 92% yield. Although the Mitsunobu reaction acetals, behaved capriciously. The yields of a mixture of the
using (–)-(2R)-2-methoxy-2-phenylethanol proceeded ef- diastereoisomers 6a and 6b varied from 20–70%, typically
ficiently using commercial resorcinol monoacetate, the li- 60%. The yields of the boron trifluoride catalyzed reactions
quid resorcinol monoacetate used, which is known to be a using (–)-3-[(2R)-2-methoxy-2-phenylethoxy]phenol and 3-
mixture of monoacetate, diacetate and resorcinol, resulted phenylpropanal, or the related dimethyl acetal, resulted in
in the isolation of (–)-3-[(2R)-2-methoxy-2-phenylethoxy]- the formation of a mixture of diastereoisomers 7a and 7b,
phenyl acetate (3) in only 50% yield. However, using the but in only 20–25% yield.
commercially available pure crystalline resorcinol mono-
We prefer to reserve the use of the term “inherent chiral-
benzoate gave (–)-3-[(2R)-2-methoxy-2-phenylethoxy]- ity” to calixarenes that are not Cn-symmetric. We also pre-
Scheme 2. Diastereoselective formation of C4-symmetric (P)- and (M)-tetraalkoxyresorcin[4]arenes from (–)-3-[(2R)-2-methoxy-2-phenyl-
ethoxy]phenol.
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The Diastereoselective Formation of Calixarenes
fer to use the term “axial chirality” rather than “cyclochi- 6a/b using a variety of Mitsunobu protocols or using diazo-
rality” and the configurational symbols (M) and (P) for axi- methane failed. Finally, when either of the diastereoisomers
ally chiral C4-symmetric resorcinarenes,[16] as recommended 6a or 6b was heated to reflux in acetonitrile using methyl
by the Cahn–Ingold–Prelog system.[19] The configurational p-toluenesulfonate and potassium carbonate, the corre-
symbol (M) refers to an anticlockwise sequence of groups sponding methyl ethers were obtained in 70% yield from
around the chiral axis as defined by the Cahn–Ingold–Pre- the major diastereoisomer 6b, and in 55% yield from the
log system and the configurational symbol (P) to a clock- minor diastereoisomer 6a, respectively. We have noted pre-
wise sequence; in each case, the sequence is determined viously that diastereoisomeric tetraalkoxyresorcin[4]arenes
either by viewing the groups from inside the cavity of the frequently show different reactivities, especially when steri-
resorcin[4]arene or from above the upper polar rim; both cally demanding alkoxy groups are present.[16,21] To estab-
operations give the same configurational symbol. When de- lish the absolute configurations of the diastereoisomers 6a
termining the correct sequence it is also important to note and 6b it was necessary to prepare compounds 11 and 12,
that the pendant groups (R) occupy pseudo-axial orienta- with known absolute configurations, by alkylating the enan-
tions.
tiomerically pure tetramethoxyresorcin[4]arenes (–)-(M,R)-
1
Inspection of the H NMR spectra of the crude reaction 8 and (+)-(P,S)-8, derived from 3-methoxyphenol and hexa-
mixtures showed that the diastereoisomer ratio for 6a and nal, which we had prepared and fully characterized pre-
6b was typically 1:3 for reactions using 1,1-dimethoxyhex- viously, and to compare these compounds with those pre-
ane, and 1:2 for reactions using hexanal. The diastereoiso- pared by the methylation of 6a and 6b.[22] We chose to opti-
mer ratios for reactions using 3-phenylpropanal were typi- mize the alkylation of the racemic tetramethoxyresorcin[4]-
cally 1:2. The formation of tetraalkoxyresorcin[4]arenes is arene (Ϯ)-8 using the mesylate 9 and tosylate 10 (the enanti-
thought to involve the reversible formation of a series of omer of which has been reported previously)[23] prepared in
linear dimeric and tetrameric intermediates,[12] and the final 87 and 75% yields, respectively, from (–)-(2R)-2-methoxy-
cyclization of linear tetrameric diastereoisomers, with dif- 2-phenylethanol (2), as shown in Scheme 3.
fering steric demands, accounts for the observed diastereo-
selectivities in the reactions recorded here. When the reac-
tions leading to the formation of compounds 6a and 6b
were carried out at –78 °C, no improvement in yields or
diastereoisomer ratios was observed. Separation of the mix-
tures was achieved by using flash chromatography on silica
gel, with the slower eluting diastereoisomer being obtained
in larger amounts in each case (Scheme 3). Despite numer-
ous attempts, we were unable to obtain crystalline deriva-
tives of the pure diastereoisomers in order to establish their
Scheme 3. Preparation of methane- and p-toluenesulfonates from
(–)-(R)-2-methoxy-2-phenylethanol.
A series of experiments showed that alkylation of the ra-
absolute configurations by X-ray crystallographic analysis. cemic tetramethoxyresorcin[4]arene (Ϯ)-8 using tosylate 10
Our unambiguous proof of structures of the (+) and (–) gave slightly higher yields of the diastereoisomers 11 and
enantiomers for a range of tetraalkoxyresorcin[4]arenes 12 than when mesylate 9 was used. The reactions proceeded
provided a method for establishing the configurations of the very slowly when heated to reflux in acetonitrile in the pres-
diastereoisomers 6a/b and 7a/b that did not rely on X-ray ence of either potassium or cesium carbonate. The results
crystallography.[20] Attempted methylation of a mixture of of the alkylation experiments are shown in Scheme 4.
Scheme 4. Proof of absolute configurations of diastereoisomers 6a and 6b using alkylation reactions.
Eur. J. Org. Chem. 2011, 5347–5354
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H. Heaney et al.
FULL PAPER
tomed flask under a flux of nitrogen from an inverted funnel. Li-
AlH4 (2.3 g, 60.7 mmol, 1.3 equiv.) was then added in small por-
tions to the solution under the flux of nitrogen. The grey reaction
mixture was stirred at room temperature for 2 h, after which time
anhydrous sodium sulfate (10 g) was added. Water (10 mL) was
cautiously added, and the mixture was stirred for a further 30 min,
after which time the suspension became white. The mixture was
filtered through a pad of Celite, and the filtrate was concentrated
under reduced pressure to give 2 as a pale-yellow liquid (6.5 g,
91%). [α]D = –15.4 (c = 2.0, CHCl3). HRMS: calcd. for C9H12O2
Alkylation of (+)-(P,S)-8 using the mesylate 9 gave the
derivative (M,R,R)-12, which was shown to be identical to
the product obtained by methylation of the major dia-
stereoisomer 6b. As anticipated, we found that alkylation of
(–)-(M,R)-8, even using tosylate 10, proceeded more slowly
to form the derivative (P,S,R)-11, and in lower yield than
the similar reaction using (+)-8. In this way we were able to
establish and confirm unambiguously the absolute configu-
rations of the tetraalkoxyresorcin[4]arenes (P,S,R)-6a and
(M,R,R)-6b. The results obtained from the methylation of [M]+ 152.0837; found 152.0835. IR (CH Cl ): ν
= 3427, 2978,
˜
max
2
2
2932, 2871, 2834, 1453, 1112, 759 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 2.52 (br. s, 1 H, OH), 3.33 (s, 3 H, OCH3), 3.69 (m, 2
H, CH2OH), 4.33 (dd, J = 8.6, 4.0 Hz, 1 H, CHOMe), 7.28–7.42
(m, 5 H, PhH) ppm. 13C NMR (100 MHz, CDCl3): δ = 56.9 (CH3),
67.4 (CH2OH), 84.6 (CHOMe), 126.9 (CArH), 128.2 (CArH), 128.6
(CArH), 138.2 (CAr) ppm.
the diastereoisomers 6a and 6b and the differential ease of
formation and yields of diastereoisomeric camphorsulfon-
ates,[22] and trifluoromethanesulfonates,[21] obtained from
sterically demanding racemic tetraalkoxyresorcin[4]arenes
[prepared, for example, from 3-(isopropyloxy)phenol and 3-
(cyclopentyloxy)phenol], allows us to draw general conclu-
sions concerning diastereoisomer formation when tetraalk-
oxyresorcin[4]arenes are prepared from optically pure 3-alk-
oxyphenol derivatives. Although we have not carried out
experiments to establish the absolute configurations of
compounds 7a and 7b using tetramethoxyresorcin[4]arene
derivatives of known absolute configurations, it is not un-
reasonable to conclude that the major diastereoisomer is
(M,R,R)-7b.
3-[(2R)-2-Methoxy-2-phenylethoxy]phenyl Acetate (3): (R)-2-Meth-
oxy-2-phenylethanol (2; 11.3 g, 85.5 mmol, 1.0 equiv.), resorcinol
monoacetate (16.9 g, 111 mmol, 1.3 equiv.) and triphenylphos-
phane (31.6 g, 138 mmol, 1.6 equiv.) were dissolved in anhydrous
THF (150 mL) in a 500 mL oven-dried round-bottomed flask un-
der nitrogen, and the mixture was cooled to 0 °C. Diisopropyl azo-
dicarboxylate (23 mL, 117 mmol, 1.4 equiv.) was then added drop-
wise over 30 min. The solution was warmed to room temperature
and stirred at room temperature for 12 h. The solvent was then
removed under reduced pressure, and the residue was triturated in
cold diethyl ether to give a white solid. The suspension was filtered,
and the filtrate was concentrated under reduced pressure. The resi-
due was placed on a column of silica gel and eluted with ethyl
acetate/hexane (5:95) to give 3 as a colourless oil (12.0 g, 50%).
[α]D = –34.9 (c = 0.93, CHCl3). HRMS: calcd. for C9H13O2+ [M +
Conclusions
The results of the investigation of tetraalkoxyresorcin-
[4]arene formation from optically pure (–)-3-[(2R)-2-meth-
oxy-2-phenylethoxy]phenol (5) using boron trifluoride H]+ 287.1283; found 287.1281. IR (CH2Cl2): ν˜max = 2933, 1764,
1605, 1591, 1487, 1208, 1140, 1111 cm–1. 1H NMR (400 MHz,
catalysis, indicate that diastereoselective ring closure of
linear tetrameric intermediates is controlled by the steric
demand of the alkyl group in the precursor 3-alkoxyphenol.
CDCl3): δ = 2.27 (s, 3 H, CH3), 3.35 (s, 3 H, OCH3), 3.97 (dd, J =
10.4, 3.6 Hz, 1 H, CH2OAr), 4.14 (dd, J = 10.4, 7.8 Hz, 1 H,
CH2OAr), 4.57 (dd, J = 7.8, 3.6 Hz, 1 H, CHOMe), 6.64 (s, 1 H,
ArH), 6.66 (m, 1 H, ArH), 6.78 (m, 1 H, ArH), 7.24 (m, 1 H, ArH),
7.26–7.37 (m, 5 H, PhH) ppm. 13C NMR (100 MHz, CDCl3): δ =
21.1 (CH3), 57.2 (OCH3), 72.5 (CH2OAr), 81.9 (CHOMe), 108.5
Experimental Section
(CArH), 112.4 (CArH), 114.0 (CArH), 127.0 (CArH), 128.3 (CArH),
128.5 (CArH), 129.8 (CArH), 138.4 (CAr), 151.6 (CAr), 159.9 (CAr),
169.3 (C=O) ppm.
General: Commercially available reagents were used as supplied,
unless stated otherwise, and stored according to the manufacturer’s
recommendations. Flash chromatography was carried out using
glass columns packed with Merck Kieselgel 60–45. Thin layer
chromatography was carried out on aluminium-backed plates
coated with Merck Kieselgel 60 GF254. Plates were viewed under
UV light and developed by staining using aqueous potassium per-
manganate or ethanolic phosphomolybdic acid, followed by heat-
ing. All infrared spectra were obtained with a Perkin–Elmer Para-
gon 2000 FTIR spectrophotometer; thin-film spectra were acquired
using sodium chloride plates. All 1H and 13C NMR spectra were
measured at 400 and 100 MHz with a Bruker DPX 400 spectrome-
ter; samples were dissolved in deuteriochloroform solution unless
otherwise stated, using TMS (tetramethylsilane) as the internal ref-
erence. Mass spectra were recorded by the EPSRC national mass
spectrometry service at the University of Wales, Swansea; measure-
ments were performed utilising electrospray (ES) and MALDI-
TOF and using a Jeol-SX102 instrument with electron-impact (EI)
and fast atom bombardment (FAB). Optical rotations were mea-
sured with a B&S ADP-440 spectrometer.
3-[(2R)-2-Methoxy-2-phenylethoxy]phenyl Benzoate (4): (2R)-2-
Methoxy-2-phenylethanol (2; 8.0 g, 52.6 mmol, 1.0 equiv.), resor-
cinol monobenzoate (13.5 g, 63.1 mmol, 1.2 equiv.) and tri-
phenylphosphane (20.7 g, 78.8 mmol, 1.5 equiv.) were dissolved in
anhydrous THF (150 mL) in a 500 mL oven-dried round-bottomed
flask under nitrogen, and the mixture was cooled to 0 °C. Diisopro-
pyl azodicarboxylate (13.4 mL, 68.3 mmol, 1.3 equiv.) was then
added dropwise over 30 min, after which time the mixture was
warmed to room temperature and stirred for 12 h. The solvent was
then removed under reduced pressure, and the residue was tritu-
rated with cold diethyl ether to give a white solid. The suspension
was filtered, and the filtrate was concentrated under reduced pres-
sure. The residue was placed on a column of silica gel and eluted
with ethyl acetate/hexane (3:97) to give 4 as a colourless oil (14.3 g,
78%). [α]D = –30.0 (c = 0.85, CHCl3). HRMS: Calcd. for
+
C22H20O4 [M]+ 348.1362; found 348.1360. IR (CH Cl ): ν
=
˜
2
2
max
3062, 3030, 2982, 2931, 2874, 2824, 1733, 1606, 1488, 1450, 1259,
1
(2R)-2-Methoxy-2-phenylethanol (2):[24] Methyl (2R)-2-methoxy-2- 936 cm–1. H NMR (400 MHz, CDCl3): δ = 3.27 (s, 3 H, OCH3),
phenylacetate (8.4 g, 46.7 mmol, 1 equiv.) was dissolved in anhy-
drous diethyl ether (150 mL) in an oven-dried 500 mL round-bot-
3.92 (dd, J = 10.4, 3.6 Hz, 1 H, CH2OAr), 4.07 (dd, J = 10.4,
8.0 Hz, 1 H, CH2OAr), 4.65 (dd, J = 8.0, 3.6 Hz, 1 H, CHOMe),
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The Diastereoselective Formation of Calixarenes
6.69–6.74 (m, 3 H, ArH), 7.15–7.31 (m, 6 H, ArH), 7.39–7.43 (m,
2 H, ArH), 7.49–7.53 (m, 1 H, ArH), 8.08–8.11 (m, 2 H, ArH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 57.6 (OCH3), 72.9
(CH2OAr), 82.5 (CHOMe), 108.9 (CArH), 113.0 (CArH), 114.6
(CArH), 127.4 (CArH), 128.7 (CArH), 129.0 (CArH), 129.1 (CArH),
130.3 (CArH), 130.58 (CArH), 130.60 (CAr), 134.0 (CArH), 138.7
(CAr), 152.2 (CAr), 160.0 (CAr), 165.5 (C=O) ppm.
as brown foams after chromatography on silica gel with hexane/
ethyl acetate (85:15) as eluent.
Using Hexanal: 3-[(2R)-2-Methoxy-2-phenylethoxy]phenol (5;
2.0 g, 8.2 mmol, 1 equiv.), hexanal (1.0 mL, 8.2 mmol, 1 equiv.) and
boron trifluoride–diethyl ether (2.0 mL, 16.4 mmol, 2 equiv.) were
used to give diastereoisomer 6a (first eluting; 0.55 g, 21%) and 6b
(second eluting; 1.05 g, 39%) as brown foams after chromatography
on silica gel with hexane/ethyl acetate (85:15) as eluent.
3-[(2R)-2-Methoxy-2-phenylethoxy]phenol (5)
First Eluting Diastereoisomer 6a: [α]D = +3.2 (c = 1.1, CHCl3).
First Method: 3-[(2R)-2-Methoxy-2-phenylethoxy]phenyl acetate (3;
11.3 g, 36 mmol, 1 equiv.) was dissolved in methanol (200 mL) and
water (2 mL) in a 500 mL round-bottomed flask. A solution of
saturated sodium hydrogen carbonate (15 mL) was then added, and
the mixture was stirred at room temperature for 1 d. Water
(200 mL) and CH2Cl2 (200 mL) were added, and the phases were
separated. The aqueous phase was extracted with CH2Cl2
(3ϫ50 mL) and the combined organic phases were washed with
brine, dried with anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was placed on a column of silica gel
and eluted with ethyl acetate/hexane (1:9) to give 5 as a yellow oil
(7.1 g, 81%).
HRMS: Calcd. for C84H105O12 [M + H]+ 1305.7610; found
+
1305.7606. IR (CH Cl ): νmax = 3447, 2927, 2858, 1623, 1617, 1587,
˜
2
2
1506, 1496, 1462, 1330, 1291, 1174, 1115, 1026, 908, 838, 761,
701 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.84 [t, J = 6.8 Hz, 12
H, (CH2)3CH3], 1.19–1.30 [m, 24 H, (CH2)3CH3], 2.05 (m, 8 H,
Ar2CHCH2), 3.28 (s, 12 H, OCH3), 3.92 (dd, J = 10.1, 8.8 Hz, 4
H, CH2OAr), 3.99 (dd, J = 10.1, 2.9 Hz, 4 H, CH2OAr), 4.25 (t, J
= 7.0 Hz, 4 H, Ar2CHCH2), 4.52 (dd, J = 8.8, 2.9 Hz, 4 H,
CHOMe), 6.23 (s, 4 H, ArH), 7.13 (s, 4 H, ArH), 7.21–7.30 (m, 24
H, ArH and ArOH) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.2
[(CH2)3CH3], 22.8 (CH2CH3), 27.7 (CHCH2CH2), 32.0
(CH2CH2CH3), 33.2 (Ar2CHCH2), 34.5 (Ar2CHCH2), 57.0
(OCH3), 73.2 (CH2OAr), 82.0 (CHOMe), 101.5 (CArH), 124.1
(CArH), 125.0 (CAr), 125.2 (CAr), 127.0 (CArH), 128.2 (CArH), 128.5
(CArH), 137.7 (CAr), 153.0 (CAr), 153.4 (CAr) ppm.
Second Method: 3-[(2R)-2-Methoxy-2-phenylethoxy]phenyl benzo-
ate (4; 14.0 g, 40.2 mmol, 1 equiv.) was added to a solution of po-
tassium hydroxide (1 m) in ethanol (50 mL) in a 250 mL round-
bottomed flask. The mixture was stirred at room temperature for
15 h, then hydrochloric acid (3.5 m) was added to bring the pH
below 3. The aqueous phase was extracted with diethyl ether
(3ϫ50 mL), and the combined organic phases were washed with
brine, dried with anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was placed on a column of silica gel
and eluted with ethyl acetate/hexane (1:9) to give 5 as a colourless
Second Eluting Diastereoisomer 6b: [α]D = –44.3 (c = 4.5, CHCl3).
+
HRMS: Calcd. for C84H104O12 [M]+ 1304.7528; found 1304.7509.
IR (CH Cl ): ν = 3441, 2927, 2857, 1615, 1586, 1494, 1454,
˜
max
2
2
1
1292, 1233, 1174, 1116, 1026, 761, 701 cm–1. H NMR (400 MHz,
CDCl3): δ = 0.88 [t, J = 6.8 Hz, 12 H, (CH2)3CH3], 1.24–1.33 [m,
24 H, (CH2)3CH3], 2.01–2.22 (m, 8 H, Ar2CHCH2), 3.33 (s, 12 H,
OCH3), 3.97 (dd, J = 10.1, 4.2 Hz, 4 H, CH2OAr), 4.10 (dd, J =
10.1, 8.6 Hz, 4 H, CH2OAr), 4.23 (t, J = 7.0 Hz, 4 H, Ar2CHCH2),
4.57 (dd, J = 8.6, 4.2 Hz, 4 H, CHOMe), 6.35 (s, 4 H, ArH), 7.21
(s, 4 H, ArH), 7.21–7.34 (m, 24 H, ArH and ArOH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 14.2 [(CH2)3CH3], 22.8 (CH2CH3),
27.7 (CHCH2CH2), 32.0 (CH2CH2CH3), 33.2 (Ar2CHCH2), 34.6
(Ar2CHCH2), 56.9 (OCH3), 72.8 (CH2OAr), 82.0 (CHOMe), 101.8
(CArH), 124.0 (CArH), 125.0 (CAr), 125.3 (CAr), 127.2 (CArH), 128.5
(CArH), 128.7 (CArH), 137.7 (CAr), 153.0 (CAr) ppm.
oil (9.6 g, 93%). [α]D = –35.4 (c = 1.89, CHCl3). HRMS: Calcd.
+
for C15H16O3 [M]+ 244.1100; found 244.1102. IR (CH Cl ): ν
˜
2
2
max
= 3354, 2931, 2874, 1597, 1492, 1454, 1287, 1175, 1117, 1086, 1064,
1
841 cm–1. H NMR (400 MHz, CDCl3): δ = 3.39 (s, 3 H, OCH3),
4.00 (dd, J = 10.6, 3.2 Hz, 1 H, CH2OAr), 4.16 (dd, J = 10.6,
8.2 Hz, 1 H, CH2OAr), 4.65 (dd, J = 8.2, 3.2 Hz, 1 H, CHOMe),
6.19 (s, 1 H, ArOH), 6.46 (m, 2 H, ArH), 6.52 (m, 1 H, ArH), 7.09
(m, 1 H, ArH), 7.27–7.38 (m, 5 H, PhH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 57.5 (OCH3), 72.6 (CH2OAr), 82.6
(CHOMe), 103.7 (CArH), 106.8 (CArH), 108.7 (CArH), 127.4
(CArH), 128.8 (CArH), 129.0 (CArH), 130.4 (CArH), 138.6 (CAr),
157.5 (CAr), 160.3 (CAr) ppm.
Resorcinarenes 7a and 7b
Using 1,1-Dimethoxy-3-phenylpropane: 3-[(2R)-2-Methoxy-2-phen-
ylethoxy]phenol (5; 700 mg, 2.88 mmol, 1 equiv.), 1,1-dimethoxy-3-
phenylpropane (520 mg, 2.88 mmol, 1 equiv.) and boron trifluo-
ride–diethyl ether (700 μL, 5.76 mmol, 2 equiv.) were used to give
diastereoisomer 7a (first eluting; 134 mg, 13%) and 7b (second elut-
ing; 134 mg, 13%) as pale-red foams after chromatography on silica
gel with hexane/ethyl acetate (4:1) as eluent.
General Procedure for the Preparation of the Tetraalkoxyresorcin-
arenes: 3-[(2R)-2-Methoxy-2-phenylethoxy]phenol (5; 1 equiv.) and
the dimethoxyalkane (1 equiv.) or the aldehyde (1 equiv.) were dis-
solved in anhydrous CH2Cl2 under nitrogen. The reaction mixture
was cooled to 0 °C, and boron trifluoride–diethyl ether (2 equiv.)
was added dropwise. The reaction mixture was then warmed to
room temperature and stirred for 6 h. Water was then added to the
reaction mixture, and the phases were separated. The aqueous layer
was extracted with CH2Cl2, and the combined organic phases were
washed with brine, dried with anhydrous sodium sulfate and con-
centrated under reduced pressure. The residue was placed on a col-
umn of silica gel and eluted with ethyl acetate/hexane to give the
pure product.
Using 3-Phenylpropanal: 3-[(2R)-2-Methoxy-2-phenylethoxy]phen-
ol (5; 700 mg, 2.88 mmol, 1 equiv.), 3-phenylpropanal (380 μL,
2.88 mmol, 1 equiv.) and boron trifluoride–diethyl ether (700 μL,
5.76 mmol, 2 equiv.) were used to give diastereoisomer 7a (first
eluting; 83 mg, 8%) and 7b (second eluting; 176 mg, 17%) as pale-
red foams after chromatography on silica gel with hexane/ethyl
acetate (4:1) as eluent.
First Eluting Diastereoisomer 7a: [α]D = –20.3 (c = 0.9, CHCl3).
Resorcinarenes 6a and 6b
+
HRMS: Calcd. for C96H97O12 [M + H]+ 1441.6980; found 1441.7
Using 1,1-Dimethoxyhexane: 3-[(2R)-2-Methoxy-2-phenylethoxy]-
phenol (5; 500 mg, 2.05 mmol, 1 equiv.), 1,1-dimethoxyhexane
(250 μL, 2.05 mmol, 1 equiv.) and boron trifluoride–diethyl ether
(500 μL, 4.1 mmol, 2 equiv.) were used to give diastereoisomer 6a
(first eluting; 107 mg, 16%) and 6b (second eluting; 334 mg, 50%)
(the isotopic distribution of the observed data matched the theoret-
ical [M]+ and [M + Na]+ isotopic distributions). IR (CH Cl ): ν
˜
2
2
max
= 3442, 3112, 2923, 2859, 1631, 1624, 1583, 1539, 1506, 1496, 1461,
1334, 1285, 1049, 1026, 907, 841, 759, 701 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 2.33–2.47 (m, 16 H, CH2CH2Ph), 3.27 (s,
Eur. J. Org. Chem. 2011, 5347–5354
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5351

H. Heaney et al.
FULL PAPER
12 H, OCH3), 3.93 (dd, J = 8.5, 10.2 Hz, 4 H, CH2OAr), 4.02 (dd,
J = 10.2, 3.0 Hz, 4 H, CH2OAr), 4.33 (t, J = 7.5 Hz, 4 H,
CH2CHAr2), 4.53 (dd, J = 8.5, 3.0 Hz, 4 H, CHOMe), 6.28 (s, 4
7.73 (d, J = 6.4 Hz, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3):
δ
=
21.6 (C6H4CH3), 57.1 (OCH3), 72.9 (CH2OSO2), 81.3
(CHOMe), 127.0 (CArH), 127.9 (CArH), 128.6 (CArH), 128.7
H, ArH), 7.02–7.04 (m, 8 H, ArH), 7.11–7.18 (m, 24 H, ArH), (CArH), 129.8 (CArH), 133.1 (CAr), 136.9 (CAr), 144.7 (CAr) ppm.
7.25–7.38 (m, 16 H, ArH and ArOH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 33.3 (CH2CHAr2), 34.5 (CH2Ph), 36.9 (CH2CH2Ph),
4,10,16,22-Tetramethoxy-6,12,18,24-tetrakis[(2R)-2-methoxy-2-
phenylethoxy]-2,8,14,20-tetrapentylresorcinarene (11)
56.9 (OCH3), 73.1 (CH2OAr), 81.6 (CHOMe), 101.6 (CArH), 123.9
First Method: Tetramethoxyresorcinarene (–)-8 (100 mg, 0.1 mmol,
(CArH), 124.6 (CAr), 124.9 (CAr), 125.8 (CArH), 127.0 (CArH), 128.5
1 equiv.), (2R)-2-methoxy-2-phenylethyl toluenesulfonate (10;
(CArH), 128.6 (CArH), 128.7 (CArH), 137.7 (CAr), 142.1 (CAr), 153.2
310 mg, 1.0 mmol, 10 equiv.) and cesium carbonate (500 mg,
1.5 mmol, 15 equiv.) were dissolved in anhydrous acetonitrile
(CAr), 153.4 (CAr) ppm.
Second Eluting Diastereoisomer 7b: [α]D = –26.7 (c = 1.2, CHCl3).
HRMS: Calcd. for C96H100O12N+ [M + NH4]+ 1458.7245; found
1458.7 (the isotopic distribution of the observed data matched the
(10 mL) in a 50 mL oven-dried round-bottomed flask under nitro-
gen. The reaction mixture was heated to reflux for 10 d, then water
(10 mL) was added, and the phases were separated. The aqueous
layer was extracted with diethyl ether (3ϫ10 mL), and the organic
phases were combined, washed with brine, dried with anhydrous
theoretical [M]+ isotopic distributions). IR (CH Cl ): ν
= 3445,
˜
max
2
2
2927, 2852, 1619, 1588, 1495, 1450, 1291, 1229, 1176, 1033, 755.
1H NMR (400 MHz, CDCl3):
CH2CH2Ph), 3.11 (s, 12 H, OCH3), 3.72 (dd, J = 9.5, 3.6 Hz, 4 H, due was placed on a column of silica gel and eluted with ethyl
δ
= 2.39–2.46 (m, 16 H, sodium sulfate, and concentrated under reduced pressure. The resi-
CH2OAr), 3.95 (t, J = 9.5 Hz, 4 H, CH2OAr), 4.22 (t, J = 7 Hz, 4
H, CH2CHAr2), 4.28 (dd, J = 9.5, 3.6 Hz, 4 H, CHOMe), 6.18 (s,
4 H, ArH), 6.75–7.20 (m, 48 H, ArH and ArOH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 32.7 (CH2CHAr2), 34.4 (CH2Ph), 36.7
(CH2CH2Ph), 56.9 (OCH3), 72.8 (CH2OAr), 81.9 (CHOMe), 102.0
(CArH), 123.8 (CArH), 124.5 (CAr), 125.0 (CAr), 125.9 (CArH), 127.1
(CArH), 128.5 (CArH), 128.6 (CArH), 128.7 (CArH), 128.8 (CArH),
137.7 (CAr), 142.0 (CAr), 153.3 (CAr) ppm.
acetate/hexane (1:9) to give 11 (81 mg, 49%) as a yellow oil.
Second Method: Resorcinarene (6a; 200 mg, 0.15 mmol, 1 equiv.)
was dissolved in acetonitrile (30 mL) in a 50 mL round-bottomed
flask under nitrogen, and potassium carbonate (348 mg,
1.84 mmol, 12 equiv.) and methyl tosylate (342 mg, 1.84 mmol,
12 equiv.) were slowly added to the solution at room temp. The
solution was heated to reflux overnight, then brine (100 mL) was
added, and the mixture was extracted with CH2Cl2 (3ϫ20 mL).
The organic phases were combined, dried with anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
placed on a column of silica gel and eluted with hexane/ethyl acet-
ate (85:15) to give 11 (113 mg, 55%) as a yellow oil.
(2R)-2-Methoxy-2-phenylethyl Methanesulfonate (9): (2R)-2-Meth-
oxy-2-phenylethanol (2; 1.0 g, 6.6 mmol, 1 equiv.), triethylamine
(1.3 g, 13.2 mmol, 2 equiv.) and a catalytic amount of DMAP were
dissolved in CH2Cl2 (40 mL) in a 100 mL round-bottomed flask.
Methanesulfonyl chloride (764 μL, 9.1 mmol, 1.4 equiv.) was then
added, and the reaction mixture was stirred at room temperature
for 2 h. Brine (20 mL) was added to the mixture, and the two
phases were separated. The organic phase was dried with anhy-
drous sodium sulfate and concentrated under reduced pressure. The
residue was placed on a column of silica gel and eluted with ethyl
[α]D = –32.7 (c = 1.2, CHCl3). HRMS: Calcd. for C88H112O12Na+
[M + Na]+ 1383.8051; found 1383.8 (the isotopic distribution of
the observed data matched the theoretical [M + Na]+ isotopic dis-
tributions). IR (CH Cl ): ν = 3027, 2926, 2856, 1731, 1609,
˜
max
2
2
1582, 1497, 1452, 1296, 1194, 1117, 1039, 913 cm–1. 1H NMR
(400 MHz, [D6]DMSO, 100 °C): δ = 0.75 [m, 12 H, (CH2)3CH3],
1.09–1.24 [m, 24 H, (CH2)3CH3], 1.56–1.71 (m, 8 H, Ar2CHCH2),
3.28 (s, 12 H, OCH3), 3.38 (s, 12 H, ArOCH3), 3.86 (dd, J = 10.1,
3.9 Hz, 4 H, CH2OAr), 3.97 (dd, J = 10.1, 7.0 Hz, 4 H, CH2OAr),
4.35 (dd, J = 7.0, 3.9 Hz, 4 H, CHOMe), 4.70 (t, J = 7.2 Hz, 4 H,
Ar2CHCH2), 6.37 (s, 4 H, ArH), 6.51 (s, 4 H, ArH), 7.26–7.34 (m,
20 H, C6H5) ppm. 13C NMR (100 MHz, [D6]DMSO, 100 °C): δ =
13.0 [(CH2)3CH3], 21.3 (CH2CH3), 26.6 (CHCH2CH2), 30.9
acetate/hexane (3:7) to give 9 as a yellow oil (1.3 g, 87%). [α]D
–71.1 (c = 1.8, CHCl3). HRMS: Calcd. for C10H15O4S+ [M + H]+
231.0691; found 231.0694. IR (CH Cl ): ν = 3404, 3086, 3016,
=
˜
max
2
2
2938, 2891, 2831, 1450, 1336, 1172, 1121, 970, 763, 701 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 3.00 (s, 3 H, SO2CH3), 3.31 (s, 3 H,
OCH3), 4.21–4.25 (m, 1 H, CH2OSO2), 4.29–4.34 (m, 1 H,
CH2OSO2), 4.50 (dd, J = 8.0, 3.6 Hz, 1 H, CHOMe), 7.32–7.35
(m, 5 H, PhH) ppm. 13C NMR (100 MHz, CDCl3): δ = 37.7 (CH2CH2CH3), 34.0 (Ar2CHCH2), 34.3 (Ar2CHCH2), 55.0 (Ar-
(SO2CH3), 57.0 (OCH3), 72.8 (CH2OSO2), 81.5 (CHOMe), 126.0 OCH3), 56.0 (OCH3), 72.8 (CH2OAr), 81.7 (CHOMe), 98.5
(CArH), 128.9 (CArH), 135.5 (CAr) ppm.
(CArH), 125.13 (CArH), 125.32 (CAr), 125.88 (CAr), 126.26 (CArH),
126.97 (CArH), 127.51 (CArH), 138.68 (CAr), 154.37 (CAr), 155.09
(CAr) ppm.
(2R)-2-Methoxy-2-phenylethyl p-Toluenesulfonate (10):[23] (2R)-2-
Methoxy-2-phenylethanol (45; 1 g, 6.6 mmol, 1 equiv.), triethyl-
amine (1.3 g, 13.2 mmol, 2 equiv.) and a catalytic amount of
DMAP were dissolved in CH2Cl2 (40 mL) in a 100 mL round-bot-
tomed flask. Toluenesulfonyl chloride (1.5 g, 7.8 mmol, 1.2 equiv.)
was then added, and the reaction mixture was stirred at room tem-
perature for 6 h. Brine (20 mL) was added, the phases were sepa-
rated, and the organic phase was dried with anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
placed on a column of silica gel and eluted with ethyl acetate/hex-
4,10,16,22-Tetramethoxy-6,12,18,24-tetrakis[(2R)-2-methoxy-2-
phenylethoxy]-2,8,14,20-tetrapentylresorcinarene (12)
First Method: Tetramethoxyresorcinarene (+)-8 (70 mg, 0.1 mmol,
1 equiv.), (2R)-2-methoxy-2-phenylethyl methanesulfonate (9;
230 mg, 1.0 mmol, 10 equiv.) and potassium carbonate (140 mg,
1.0 mmol, 10 equiv.) were dissolved in anhydrous acetonitrile
(10 mL) in a 50 mL oven-dried round-bottomed flask under nitro-
gen. The reaction mixture was heated to reflux for 10 d, then water
ane (1:4) to give 10 as a yellow oil (1.5 g, 75%). [α]D = –93.8 (c = (10 mL) was added, and the two phases were separated. The aque-
1.6, CHCl3) {ref.[23] (for enantiomer): [α]D = +92.6 (c = 3.0, C6H6)}. ous layer was extracted with diethyl ether (3ϫ10 mL), and the or-
HRMS: Calcd. for C16H19O4S+ [M + H]+ 307.1004; found ganic phases were combined, washed with brine, dried with anhy-
307.1002. IR (CH Cl ): νmax = 3378, 2935, 2826, 1358, 1189, 1176, drous sodium sulfate, and concentrated under reduced pressure.
˜
2
2
1
1121, 975, 666 cm–1. H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3
H, C6H4CH3), 3.23 (s, 3 H, OCH3), 4.02–4.11 (m, 2 H, CH2OSO2), ethyl acetate/hexane (15:85) to give 12 (92 mg, 56%) as a yellow
4.41 (dd, J = 7.6, 4.4 Hz, 1 H, CHOMe), 7.23–7.34 (m, 7 H, ArH). oil.
The residue was placed on a column of silica gel and eluted with
5352
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5347–5354

The Diastereoselective Formation of Calixarenes
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and methyl tosylate (1.84 mmol, 12 equiv.) were slowly added to
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of silica gel and eluted with hexane/ethyl acetate (85:15) to give 12
(144 mg, 70%) as a yellow oil.
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˜
max
2
2
1582, 1497, 1452, 1296, 1194, 1117, 1039, 913 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.84 [m, 12 H, (CH2)3CH3], 1.19–1.31 [m,
24 H, (CH2)3CH3], 1.71–1.80 (m, 8 H, Ar2CHCH2), 3.26 (s, 12 H,
OCH3), 3.48 (s, 12 H, ArOCH3), 3.86 (d, J = 6 Hz, 8 H, CH2OAr),
4.34 (t, J = 6 Hz, 4 H, CHOMe), 4.46 (t, J = 7.4 Hz, 4 H,
Ar2CHCH2), 6.22 (s, 4 H, ArH), 6.56 (s, 4 H, ArH), 7.27–7.41 (m,
20 H, PhH) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.2
[(CH2)3CH3], 22.7 (CH2CH3), 28.1 (CHCH2CH2), 32.3
(CH2CH2CH3), 34.50 (Ar2CHCH2), 35.8 (Ar2CHCH2), 55.7 (Ar-
OCH3), 57.3 (OCH3), 73.6 (CH2OAr), 82.3 (CHOMe), 98.15
(CArH), 126.29 (CArH), 126.97 (CArH), 127.85 (CArH), 128.36
(CArH), 139.7 (CAr), 154.9 (CAr), 155.7 (CAr) ppm.
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Acknowledgment
This work has enjoyed the support of EPSRC, Loughborough Uni-
versity and a Royal Society Industrial Fellowship. We are also in-
debted to the EPSRC Mass Spectrometry Unit, Swansea and the
Secretaria de Estado de Educacion y Universidades y Fondo Social
Europeo.
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