Synthesis and application of the first planar chiral strong bronsted acid organocatalysts

Article abstract of DOI:10.1002/chir.21985

The synthesis of planar chiral strong Bronsted acid organocatalysts derived from [2.2]paracyclophane is described. Resolution was accomplished according to a modified protocol involving pseudo-ortho-substituted [2.2]paracyclophane-based sulfoxides for the synthesis of three new sulfonic acids. The first planar chiral phosphoric acid diester was obtained from the corresponding phenyl-substituted diol derived from enantiopure 4-bromo-12-hydroxy [2.2]paracyclophane. These new classes of catalysts were tested in an enantioselective Friedel-Crafts reaction as well as in a direct asymmetric Mannich reaction and gave yields of up to 93% and ee-values of up to 38%. Copyright

Full text of DOI:10.1002/chir.21985

CHIRALITY 24:215–222 (2012)
Synthesis and Application of the First Planar Chiral Strong
Brønsted Acid Organocatalysts
*
DIETER ENDERS, MONIKA LUDWIG, AND GERHARD RAABE
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
ABSTRACT
The synthesis of planar chiral strong Brønsted acid organocatalysts derived
from [2.2]paracyclophane is described. Resolution was accomplished according to a modified
protocol involving pseudo-ortho-substituted [2.2]paracyclophane-based sulfoxides for the synthe-
sis of three new sulfonic acids. The first planar chiral phosphoric acid diester was obtained
from the corresponding phenyl-substituted diol derived from enantiopure 4-bromo-12-hydroxy
[2.2]paracyclophane. These new classes of catalysts were tested in an enantioselective Friedel–
Crafts reaction as well as in a direct asymmetric Mannich reaction and gave yields of up to 93%
C
VV
and ee-values of up to 38%. Chirality 24:215–222, 2012.
2012 Wiley Periodicals, Inc.
KEY WORDS: paracyclophane; Brønsted acid; organocatalysis; planar chirality; Friedel–Crafts;
Mannich
INTRODUCTION
also in accordance with previously published results.9,11,12,17
We decided to add a sterically demanding group in pseudo-
ortho position to the acid moiety. We assumed that especially
in the case of sulfonic acids, steric hindrance to avoid free
rotation of the acid is very important.
Enantiopure catalysts (RP)-1, 2, and 3 and (SP)-4 were
obtained in several steps starting from commercially avail-
able [2.2]paracyclophane (5) and applied in asymmetric
organocatalytic transformation.
The first synthesis of a planar chiral derivative of [2.2]para-
cyclophane was described in 1955 by Cram and Allinger.1
However, it took 40 years to realize the potential of these
structural elements in stereoselective synthesis,2 but then
resulting in numerous reports on applications of [2.2]paracy-
clophanes as chiral inducers such as ligands3–5 and auxilia-
ries.6,7
The use of [2.2]paracyclophanes in catalysis was first
reported in 2003 by Braddock et al., who utilized PHANOL
(4,12-dihydroxy[2.2]paracyclophanediol) as a double hydro-
gen bond donor organocatalyst, but unfortunately no noticea-
ble enantioselectivities were observed.8,9
EXPERIMENTAL
General Remarks
All reactions in which moisture-sensitive reagents were used were per-
formed in oven-dried glassware under a slightly positive pressure of ar-
gon. Starting materials and reagents were purchased from commercial
suppliers and used without further purification unless otherwise stated.
rac-4,12-Dibromo[2.2]paracyclophane (7), (RP)-4-bromo-12-hydroxy[2.2]-
paracyclophane ((RP)-21), and (SS)-(2)-tert-butyl-tert-butanethiosulfinate
(8) were synthesized according to literature procedures (see text). All
solvents were dried by conventional methods. Preparative column chro-
matography: Merck silica gel 60, particle size 0.040–0.063 mm (230–240
mesh, flash). Analytical thin layer chromatography (TLC): silica gel 60
F254 plates from Merck, Darmstadt. Visualization of the developed TLC
plates was performed with ultraviolet irradiation (254 nm) or by staining
with a solution of phosphomolybdic acid in EtOH or potassium perman-
In 2007, Kunz and coworkers10 used enantiopure N-galac-
tosyl[2.2]paracyclophane carbaldimines as organocatalysts in
asymmetric Strecker reactions and obtained excellent enan-
tiomeric excesses.
Recently, the application of a planar chiral thiourea hydro-
gen-bond catalyst11 giving moderate enantioselectivities was
described by Paradies and coworkers. Rowlands and co-
workers reported on paracyclophane-derived N-oxides as
Lewis base catalysts in enantioselective allylations giving
likewise moderate enantioselectivities.12 Besides these few
examples, the application of [2.2]paracyclophanes in asym-
metric organocatalysis has scarcely been investigated. To
the best of our knowledge, synthesis or application of paracy-
clophane-derived stronger Brønsted acid organocatalysts has
not been reported until now.
In the field of Brønsted acid organocatalysis, most of the
utilized stronger acids such as phosphoric13,14 and sulfonic
acids15 as well as N-triflyl phosphoramides16 are derived
from BINOL. Herein we report on the synthesis and first
applications of three new sulfonic acids 1, 2, and 3 and one
new phosphoric acid diester 4 (Fig. 1) derived from [2.2]par-
acyclophane as the first planar chiral strong Brønsted acid
organocatalysts.
1
ganate. H- and 13C-NMR spectra were recorded at ambient temperature
on a Varian Mercury 300 instrument with tetramethylsilane as internal
standard. Chemical shifts for 1H-NMR and 13C-NMR are reported in
parts per million (ppm), with coupling constants reported in Hertz (Hz).
The following abbreviations are used for spin multiplicity: s 5 singlet, d
5 doublet, dd 5 doublet of doublet, ddd 5 doublet of doublet of dou-
blet, t 5 triplet, dt 5 doublet of triplet, q 5 quartet, qd 5 quartet of dou-
blet, and m 5 multiplet. Mass spectra were acquired on a Finnigan
SSQ7000 (EI 70 eV) spectrometer, electrospray ionization (ESI) spectra
on a ThermoFinnigan LCQ Deca XP plus, and high resolution ESI spec-
tra on a ThermoFisher Scientific LTQ-Orbitrap XL. IR spectra were
taken on a PerkinElmer Spectrum 100 FTIR Spectrometer. The following
*Correspondence to: Dieter Enders, Institute of Organic Chemistry, RWTH
Aachen University, Landoltweg 1, 52074 Aachen, Germany.
E-mail: enders@rwth-aachen.de
Received for publication 6 June 2011; Accepted 2 November 2011
DOI: 10.1002/chir.21985
Because in binaphthol-derived catalysts sterically demand-
ing substituents in 3- and 30-position are crucial for a high
stereocontrol in asymmetric transformations,13 it was pre-
sumable that the [2.2]paracyclophane-backbone alone would
not provide a suitable chiral environment. This assumption is
Published online 25 January 2012 in Wiley Online Library
(wileyonlinelibrary.com).
C
VV
2012 Wiley Periodicals, Inc.

216
ENDERS ET AL.
added triethylamine (1.42 ml, 10.2 mmol, 10 eq.) and the resulting yel-
low suspension stirred at reflux for 18 h. After cooling to 08C, 2 N aque-
ous NaOH was added dropwise (Caution! Strong exothermic reaction
occurs!) until the pH is below 7. After addition of MTBE (10 ml), the
phases were separated and the aqueous phase extracted with MTBE (3
3 30 ml). The combined organic phases were dried over MgSO4 and
concentrated. The crude product was purified by column chromatogra-
phy (n-pentane:MTBE 20:1) to yield (RP)-10 (99%) as a colorless pow-
der. m.p. 888C; [a]2D0 5 –140 (c 1.0, CHCl3); FTIR 2959 (vs), 2929 (vs),
2855 (s), 2323 (w), 2107 (w), 1899 (w), 1729 (w), 1582 (s), 1539 (m),
1470 (s), 1451 (s), 1390 (s), 1360 (s), 1320 (w), 1269 (w), 1162 (vs), 1031
(vs), 953 (vs), 907 (s), 864 (s), 816 (s), 787 (s), 708 (vs), 669 (m) cm21
;
1H-NMR (300 MHz, CDCl3) d: 7.31 (d, J 5 1.9 Hz, 1H), 6.67 (d, J 5 1.7
Hz, 1H), 6.63 (d, J 5 7.8 Hz, 1H), 6.55–6.49 (m, 2H), 6.47 (d, J 5 7.8 Hz,
1H), 3.84–3.74 (m, 1H), 3.45 (ddd, J 5 13.1 Hz, Jcis 5 9.7 Hz, Jtrans 5 1.9
Hz, 1H), 3.19–3.08 (m, 1H), 3.08–2.97 (m, 3H), 2.86–2.73 (m, 2H), 1.18
(s, 9H) ppm; 13C-NMR (75 MHz, CDCl3) d: 145.4, 141.9, 139.7, 139.1,
138.7, 135.2, 134.9, 134.2, 133.8, 132.9, 131.3, 126.7, 46.5, 35.8, 35.5, 33.8,
32.4, 30.9 (3C); Analysis calculated for C20H23BrS: C, 63.99; H, 6.18;
Found: C, 63.69; H, 6.22.
Fig. 1. New planar chiral Brønsted acids.
abbreviations are used: w 5 weak, m 5 medium, s 5 strong, and vs 5
very strong. Microanalyses were performed with a Vario EL element an-
alyzer. Analytical high pressure liquid chromatography (HPLC) was car-
ried out on a Hewlett-Packard 1050 Series instrument and Agilent 1100
Series instrument using chiral stationary phases. Optical rotation values
were measured on a Perkin–Elmer 241 polarimeter.
Sulfides (RP)-14, (RP)-15, and (RP)-16
General method for the Suzuki cross-coupling. Method A:
(RP)-4-(2-Naphthyl)-12-tert-butylsulfanyl[2.2]paracyclophane ((RP)-
14). To a solution of (Rp)-4-bromo-12-tert-butylsulfanyl[2.2]paracyclo-
phane ((RP)-10) (850 mg, 2.26 mmol, 1 eq.), 2-naphthylboronic acid
(11) (776 mg, 4.36 mmol, 1.9 eq) and tetrakis(triphenylphosphine)palla-
dium(0) (270 mg, 0.23 mmol, 0.1 eq) in DMF (21 ml) was added 2 M
aqueous Na2CO3 and the suspension was degased using the freeze-
pump-thaw method and then heated to 1008C for 48 h. After cooling to
room temperature, MTBE (100 ml) and saturated aqueous NaHCO3 (100
ml) were added, the phases were separated and the aqueous phase
extracted with MTBE (5 3 100 ml). The combined organic phases were
dried over MgSO4 and concentrated. The crude product was purified by
column chromatography (n-pentane:DCM 50:1) to yield (RP)-14 (58%) as
a colorless powder. M.p. 1758C; ee 5 98% (determined by chiral HPLC
(Merck (s,s)-Whelk O1, 250 mm 3 4.6 mm), n-heptane:isopropanol 98:2,
0.5 ml/min, tR 5 7.56 min (major), tR 5 8.23 (minor)); [a]2D0 5 –20 (c
0.5, CHCl3); FTIR 3035 (m), 2958 (s), 2926 (vs), 2855 (s), 2327 (m), 2205
(w), 1930 (w), 1896 (w), 1745 (w), 1625 (w), 1584 (s), 1501 (m), 1455 (s),
1389 (s), 1361 (s), 1261 (m), 1196 (m), 1162 (s), 1094 (w), 1049 (m),
1020 (m), 1020 (s), 949 (s), 907 (s), 863 (s), 824 (s), 801 (s), 751 (vs),
(SP,SS)- and (RP,SS)-4-Bromo-12-tert-butylsulfinyl[2.2]paracy-
clophane ((RP,SS)-9 and (SP,SS)-9). To a solution of 4,12-dibro-
mo[2.2]paracyclophane (7) (1.00 g, 2.73 mmol, 1 eq.) in anhydrous tetra-
hydrofuran (THF) (20 ml) at 2788C, n-BuLi (1.88 ml (1.6 M in n-hex-
ane), 3.00 mmol, 1.1 eq.) was added dropwise via syringe pump. After
stirring for 1 h at 2788C, the reaction mixture was transferred to a pre-
cooled (-788C) solution of (SS)-(2)-tert-butyl-tert-butanethiosulfinate (8)
(800 mg, 4.09 mmol, 1.5 eq.) in anhydrous THF (2 ml) with a metal
cannula and the resulting suspension was warmed to room temperature
overnight. After addition of saturated aqueous NH4Cl (10 ml) and methyl
tert-butyl ether (MTBE) (10 ml) the phases were separated and the
aqueous phase extracted with MTBE (3 3 20 ml). The combined or-
ganic phases were dried over MgSO4 and concentrated. The crude prod-
uct was purified by column chromatography (n-pentane:ethyl acetate
4:1) with (RP,SS)-9 being eluted first to obtain (RP,SS)-9 (20%) and
(SP,SS)-9 (18%) as colorless crystals. (RP,SS)-9: m.p. 1758C; de > 99%
(determined by NMR); [a]D20 5 –199 (c 1.0, CHCl3); FTIR 2967 (m),
2934 (m), 2858 (m), 2297 (w), 2114 (w), 1585 (w), 1542 (w), 1453 (m),
1391 (m), 1390 (m), 1169 (s), 1133 (w), 1038 (vs), 955 (w), 909 (s), 864
723 (vs), 682 (m) cm21 1H-NMR (300 MHz, CDCl3) d: 8.36 (d, J 5 1.0
;
Hz, 1H), 8.03 (dd, J 5 7.7 Hz, J 5 1.0 Hz, 1H), 7.94–7.88 (m, 2H), 7.76
(dd, J 5 8.5, J 5 1.7, 1H), 7.57–7.48 (m, 2H), 6.88 (d, J 5 1.8 Hz, 1H),
6.80 (d, J 5 1.8 Hz, 1H), 6.72 (d, J 5 7.7 Hz, 1H), 6.66 (d, J 5 7.7 Hz,
1H), 6.60 (dd, J 5 7.7 Hz, J 5 1.8 Hz, 1H), 6.57 (dd, J 5 7.7 Hz, J 5 1.7
Hz, 1H), 3.89 (ddd, J 5 12.4 Hz, Jcis 5 9.3 Hz, Jtrans 5 2.1 Hz, 1H), 3.66–
3.55 (m, 1H), 3.23–3.06 (m, 2H), 2.93–2.78 (m, 3H), 2.40–2.31 (m, 1H),
1.24 (s, 9H); 13C-NMR (75 MHz, CDCl3) d: 145.5, 141.2, 140.5, 140.1,
139.3, 138.7, 136.8, 135.9, 133.9, 133.8, 133.3, 132.4, 132.3, 131.8, 131.0,
128.6, 128.4, 128.3, 127.6, 127.5, 125.8, 125.7, 46.8, 35.9, 34.9, 34.0, 33.5,
31.1 (3C); HRMS calculated for C30H31S: 423.2141, Found: 423.2142.
(m), 820 (m), 794 (m), 711 (s), 676 (w) cm21 1H-NMR (300 MHz,
;
CDCl3) d: 7.16 (d, J 5 1.6 Hz, 1H.), 6.95 (d, J 5 1.6 Hz, 1H), 6.62–6.54
(m, 3H), 6.50 (d, J 5 7.8 Hz, 1H), 4.29 (ddd, J 5 12.1 Hz, Jcis 5 10.4 Hz,
Jtrans 5 1.5 Hz, 1H), 3.50 (ddd, J 5 13.1 Hz, Jcis 5 9.8 Hz, Jtrans 5 1.8 Hz,
1H), 3.31–3.13 (m, 2H), 3.13–2.95 (m, 2H), 2.89–2.71 (m, 2H), 1.08 (s,
9H); 13C-NMR (75 MHz, CDCl3) d: 142.7, 142.3, 138.9, 138.5, 137.4,
137.2, 135.9, 134.9, 134.6, 130.9, 129.8, 127.1, 56.6, 35.6, 35.2, 34.4, 32.4,
23.1(3C); Analysis calculated for C20H23BrOS: C, 61.38; H, 5.92. Found:
C, 61.12; H, 6.00.
(SP,SS)-9: m.p. 1688C; de > 99% (determined by NMR); [a]2D0 5 151
(c 1.0, CHCl3); FTIR 3015 (w), 2930 (s), 2858 (m), 2315 (w), 1586 (w),
1543 (w), 1474 (m), 1454 (s), 1389 (m), 1362 (m), 1168 (s), 1137 (m),
1054 (s), 1023 (vs), 959 (w), 910 (s), 863 (m), 826 (s), 791 (m), 712 (s),
(Rp)-4-(2-Phenanthryl)-12-tert-butylsulfanyl[2.2]paracyclophane
((RP)-15). Compound (RP)-15 was prepared following method A
using 9-phenanthrylboronic acid (12) (95%, colorless solid). M.p. 1698C;
[a]2D0 5 1217 (c 0.5, CHCl3); FTIR 3303 (w), 3200 (w), 3064 (w), 2958
(s), 2924 (s), 2857 (m), 2327 (w), 2109 (w), 1580 (m), 1516 (w), 1439 (s),
1305 (s), 1206 (vs), 1158 (vs), 1054 (s), 950 (w), 906 (m), 867 (m), 731
670 (m) cm21 1H-NMR (300 MHz, CDCl3) d: 7.59 (d, J 5 1.8 Hz, 1H),
;
6.85 (d, J 5 1.7 Hz, 1H), 6.64–6.42 (m, 4H), 3.56–3.43 (m, 2H), 3.32–3.19
(m, 1H), 3.15–3.03 (m, 3H), 2.89–2.72 (m, 2H), 1.04 (s, 9H); 13C-NMR
(75 MHz, CDCl3) d: 140.8, 140.3, 138.9, 138.6, 138.5, 136.2 (2C), 134.8,
134.7, 131.0, 126.8, 126.6, 56.9, 35.9, 34.2, 33.5, 32.5, 22.6 (3C); Analysis
calculated for C20H23BrOS: C, 61.38; H, 5.92; Found.: C, 61.48; H, 6.20.
(vs) cm21 1H-NMR (300 MHz, CDCl3) d: 8.78–8.71 (m, 2H), 8.70 (s,
;
1H), 8.26–8.19 (m, 1H), 7.95 (dd, J 5 8.3 Hz, J 5 1.2 Hz, 1H), 7.74–7.68
(m, 2H), 7.62 (ddd, J 5 8.3 Hz, J 5 6.9 Hz, J 5 1.4 Hz, 1H), 7.45 (ddd, J
5 8.2 Hz, J 5 6.9 Hz, J 5 1.3 Hz, 1H), 7.05 (d, J 5 1.9, 1H), 6.88–6.85
(m, 1H), 6.81 (d, J 5 7.7 Hz, 1H), 6.68–6.64 (m, 3H), 3.93 (ddd, J 5 12.6
Hz, Jcis 5 9.6 Hz, Jtrans 5 1.7 Hz, 1H), 3.29–3.08 (m, 2H), 2.91 (ddd, J 5
12.7 Hz, Jcis 5 10.3 Hz, Jtrans 5 6.9 Hz, 1H), 2.85–2.71 (m, 3H), 2.48–2.34
(m, 1H), 1.29 (s, 9H) ppm; 13C-NMR (75 MHz, CDCl3) d: 145.9, 140.4,
139.9, 139.7, 139.4, 137.5, 134.8, 134.0, 133.6, 132.7, 132.4 (2C), 132.3,
(RP)-4-Bromo-12-tert-butylsulfanyl[2.2]paracyclophane
((RP)-
10). To a solution of (RP,SS)-4-bromo-12-tert-butylsulfinyl[2.2]paracy-
clophane ((RP,SS)-9) (400 mg, 1.02 mmol, 1 eq.) and trichlorosilane
(1.55 ml, 15.3 mmol, 15 eq.) in anhydrous toluene (6 ml) was slowly
Chirality DOI 10.1002/chir

PLANAR CHIRAL STRONG BRØNSTED ACID ORGANOCATALYSTS
217
131.8, 131.0, 130.3, 129.9, 128.9, 128.6, 126.6, 126.5, 126.4, 126.3, 126.1,
122.7, 122.5, 46.8, 35.8, 34.8, 34.0, 33.7, 31.2 (3C); analysis calculated for
C34H32BS: C, 86.39; H, 6.82; Found: C, 86.54; H, 7.16.
(RP)-4-(2,4,6-Triisopropylphenyl)-12-acetylmercapto[2.2]para-
cyclophane ((RP)-19). Compound (RP)-19 was prepared following
method
B
using (RP)-4-(2,4,6-triisopropylphenyl)-12-tert-butylsulfa-
nyl[2.2]paracyclophane ((RP)-16) (77%, pale yellow solid). M.p. 1708C;
[a]2D0 5 135 (c 0.5, CHCl3); FTIR 3396 (w), 2957 (vs), 2866 (s), 2083
(w), 1889 (w), 1706 (vs), 1606 (m), 1579 (m), 1458 (s), 1380 (m), 1357
(s), 1313 (w), 1253 (w), 1199 (w), 1163 (w), 1105 (vs), 1051 (m), 1019
(s), 941 (s), 865 (s), 811 (m), 722 (s), 655 (w) cm21; 1H-NMR (300 MHz,
CDCl3) d: 7.14 (d, J 5 1.6 Hz, 1H), 7.02 (d, J 5 7.7 Hz, 1H), 6.93–6.88
(m, 2H), 6.58 (d, J 5 1.2 Hz, 1H), 6.52–6.42 (m, 3H), 3.63–3.50 (m, 1H),
3.50–3.38 (m, 1H), 3.38–3.24 (m, 1H), 3.05–2.80 (m, 6H), 2.80–2.66 (m,
1H), 2.37 (s, 3H), 2.12–1.96 (m, 1H), 1.53 (d, J 5 6.8 Hz, 3H), 1.43 (d, J
5 6.8 Hz, 3H), 1.31 (d, J 5 6.9 Hz, 6H), 0.99 (d, J 5 6.8 Hz, 3H), 0.54 (d,
J 5 6.8 Hz, 3H); 13C-NMR (75 MHz, CDCl3) d: 193.6, 148.5, 147.4, 146.0,
143.6, 140.2, 138.9, 136.9, 136.7, 136.1, 134.6, 134.5, 134.3, 134.2, 132.6,
128.9, 128.1, 121.3, 121.0, 77.0, 35.3, 34.4, 33.9, 33.6, 33.1, 30.3, 30.2,
29.6, 26.4, 25.5, 24.1, 24.0 (2C), 23.6; HRMS calculated for C33H40OKS:
523.24315, Found: 523.2424.
(Rp)-4-(2,4,6-Triisopropylphenyl)-12-tert-butylsulfanyl[2.2]para-
cyclophane ((RP)-16). Compound (RP)-16 was prepared following
method A using 2,4,6-triisopropylboronic acid (13) (16%). M.p. 1388C;
[a]2D0 5 19 (c 0.5, CHCl3); FTIR 3298 (w), 3193 (w), 2960 (m), 2873 (w),
2711 (w), 1575 (m), 1517 (w), 1434 (s), 1308 (vs), 1217 (vs), 1159 (s),
1057 (vs), 868 (m), 805 (m), 727 (m) cm21 1H-NMR (300 MHz, CDCl3)
;
d: 7.13 (d, J 5 1.9 Hz, 1H), 6.94 (d, J 5 7.6 Hz, 1H), 6.88 (d, J 5 1.9 Hz,
1H), 6.81 (dd, J 5 7.6 Hz, J 5 1.9 Hz, 1H), 6.66 (d, J 5 1.9 Hz, 1H),
6.47–6.40 (m, 3H), 3.92–3.70 (m, 2H), 3.30–3.21 (m, 1H), 3.02–2.65 (m,
7H), 2.16–2.01 (m, 1H), 1.46 (d, J 5 6.6 Hz, 3H), 1.43 (d, J 5 6.6 Hz,
3H), 1.29 (d, J 5 6.9 Hz, 6H), 1.12 (s, 9H), 0.99 (d, J 5 6.9 Hz, 3H), 0.51
(d, J 5 6.9 Hz, 3H) ppm; 13C-NMR (75 MHz, CDCl3) d: 148.4, 147.2,
146.6, 146.4, 141.0, 139.2, 138.7, 137.5, 136.6, 134.4, 134.1, 133.7, 133.3,
132.5, 132.4, 129.5, 121.6, 120.7, 46.1, 36.2, 34.4, 34.0, 33.9, 33.2, 30.8
(3C), 29.7, 29.6, 26.6, 25.5, 24.2, 24.1, 24.0, 23.6; HRMS calculated for
C35H47S: 499.3393, Found: 499.3398.
Sulfonic Acids (RP)-1, (RP)-2, and (RP)-3
Thioacetates (RP)-17, (RP)-18, and (RP)-19
General method for the deprotection of thioacetates and oxida-
tion to sulfonic acids. Method C: (RP)-4-(2-Naphthyl)[2.2]paracy-
clophane-12-sulfonic acid ((RP)-1). (RP)-4-(2-Naphthyl)-12-acetyl-
mercapto[2.2]paracyclophane ((RP)-17) (1.00 g, 2.45 mmol, 1 eq.) and
freshly powdered KOH (2.00 g, 35.6 mmol, 14.5 eq.) were dissolved in
MeOH (100 ml) and O2 was bubbled through the solution for 72 h.
The solvent was evaporated in vacuo, the residue dissolved in MTBE
and 2 N aqueous HCl (50 ml) was added. The phases were separated
and the aqueous phase extracted with MTBE (3 3 100 ml) and DCM
(2 3 100 mL). The combined organic phases were dried over MgSO4
and concentrated. The crude product was purified by column chroma-
tography (DCM:MeOH 9:1) to yield (RP)-1 (69%) as a yellow solid. To
remove a possible contamination with alkali metals from the column,
the product was dissolved in DCM, washed with 2 N aqueous HCl,
and evaporated to give the free acid as a yellow-green foam. M.p.
1428C (decomposition); [a]D22 5 179 (c 0.5, MeOH); FTIR 3407 (m),
2925 (vs), 2855 (s), 2090 (w), 1735 (vs), 1661 (w), 1589 (m), 1459 (s),
1370 (s), 1213 (vs), 1078 (s), 1021 (vs), 951 (m), 903 (m), 861 (m), 821
General method for the acetylation. Method B: (RP)-4-(2-Naph-
thyl)-12-acetylmercapto[2.2]paracyclophane ((RP)-17). To a solu-
tion of (RP)-4-(2-naphthyl)-12-tert-butylsulfanyl[2.2]paracyclophane ((RP)-
14) (300 mg, 0.71 mmol, 1 eq.) and acetyl chloride (0.36 ml, 4.97 mmol,
7 eq.) in anhydrous toluene (8 ml) was slowly added boron tribromide
(0.852 ml (1 M in DCM), 0.85 mmol, 1.2 eq.). After stirring at room tem-
perature overnight, saturated aqueous NH4Cl (20 ml) and MTBE (50
ml) were added. The phases were separated and the aqueous phase
extracted with MTBE (3 3 20 ml) and DCM (2 3 20 ml). The combined
organic phases were dried over MgSO4 and concentrated. The crude
product was purified by column chromatography (n-pentane:ethyl ace-
tate 9:1) to yield (RP)-17 (99 %) as a colorless solid. M.p. 1128C; ee >
99% (determined by chiral HPLC (Chiralcel OD 10 l (250 mm 3 4.6
mm), n-heptane/isopropanol 95:5, 0.7 ml/min, tR 5 14.53 min (major), tR
5 20.80 min (minor)); [a]2D2 5 153 (c 0.5, CHCl3); FTIR 3386 (w), 3059
(m), 2933 (m), 2852 (w), 2322 (m), 2084 (s), 1903 (w), 1701 (s), 1586
(m), 1476 (m), 1434 (m), 1347 (w), 1261 (m), 1198 (w), 1102 (s), 1053
(s), 749 (s), 726 (s), 694 (m), 665 (w) cm21 1H-NMR (300 MHz,
;
(s), 947 (s), 898 (w), 862 (m), 814 (s), 728 (s), 669 (w), 608 (vs) cm21
;
CDCl3) d 8.33 (d, J 5 1.3 Hz, 1H), 8.12 (dd, J 5 6.7 Hz, J 5 2.3 Hz,
1H), 7.90–7.86 (m, 1H), 7.88 (d, J 5 8.5 Hz, 1H), 7.72 (dd, J 5 8.5 Hz,
J 5 1.7 Hz, 1H), 7.50–7.42 (m, 2H), 7.25 (d, J 5 1.4 Hz, 1H), 7.11 (d,
J 5 1.7 Hz, 1H), 6.73 (d, J 5 7.7 Hz, 1H), 6.63 (dd, J 5 7.7 Hz, J 5 1.7
Hz, 1H), 6.61–6.55 (m, 2H), 4.05–3.97 (m, 1H), 3.69–3.61 (m, 1H),
3.40–3.31 (m, 1H), 3.10–2.99 (m, 1H), 2.99–2.88 (m, 1H), 2.87–2.69
(m, 2H), 2.13–2.05 (m, 1H); 13C-NMR (300 MHz, CDCl3) d: 142.5,
141.8, 141.2, 140.9, 139.9, 138.9, 138.1, 137.1, 136.6, 136.3, 135.4, 133.7,
132.8, 132.5, 129.7, 129.6, 129.5, 128.7, 128.6, 128.3, 126.7, 126.6, 36.3,
35.7, 34.9, 34.2; HRMS calculated for C26H21O3S: 413.1206, Found:
413.1209.
1H-NMR (300 MHz, CDCl3) d: 8.06 (d, J 5 1.1 Hz, 1H), 8.04–7.89 (m,
3H), 7.67 (dd, J 5 8.5 Hz, J 5 1.8 Hz, 1H), 7.61–7.51 (m, 2H), 6.85 (d, J
5 1.9 Hz, 1H), 6.79 (d, J 5 7.8 Hz, 1H), 6.75 (d, J 5 1.8 Hz, 1H), 6.73–
6.67 (m, 2H), 6.59 (dd, J 5 7.8, J 5 1.9, 1H), 3.67–3.59 (m, 1H), 3.50
(ddd, J 5 13.1 Hz, Jcis 5 9.6 Hz, Jtrans 5 1.4 Hz, 1H), 3.29–3.18 (m, 1H),
3.16–3.03 (m, 1H), 3.02–2.79 (m, 3H), 2.48 (s, 3H), 2.44–2.32 (m, 1H);
13C-NMR (75 MHz, CDCl3) d: 193.6, 143.2, 141.3, 140.5, 139.7, 138.4,
137.2, 136.3, 136.0, 134.9, 134.7, 133.8, 132.4, 132.2, 130.3, 128.4, 128.3,
128.2, 128.1 (2C), 127.6, 126.1, 125.9, 35.0, 34.8, 33.7, 33.6, 30.4; HRMS
calculated for C28H24ONaS: 431.1440, Found: 431.1435.
(RP)-4-(2-Phenanthryl)-12-acetylmercapto[2.2]paracyclophane
((RP)-18). Compound (RP)-18 was prepared following method B
(Rp)-4-(2-Phenanthryl)[2.2]paracyclophane-12-sulfonic
acid
using
(RP)-4-(2-phenanthryl)-12-tert-butylsulfanyl[2.2]paracyclophane
((RP)-2). Compound (RP)-2 was prepared following method C using
(Rp)-4-(2-phenanthryl)-12-acetylmercapto[2.2]paracyclophane ((RP)-18)
(80%, yellow solid). M.p. 688C (decomposition); [a]2D0 5 1195 (c 0.5,
CHCl3); FTIR 3838 (w), 3384 (m), 3069 (w), 2927 (s), 2859 (s), 2310 (w),
2166 (w), 2086 (m), 1995 (w), 1929 (w), 1715 (s), 1589 (m), 1451 (s),
1367 (w), 1260 (m), 1122 (s), 1075 (s), 1009 (s), 954 (w), 897 (s), 870
(s), 804 (m), 729 (vs) cm21; 1H-NMR (300 MHz, CDCl3) d: 8.68–8.58 (m,
2H), 8.44 (s, 1H), 8.30 (dd, J 5 7.1 Hz, J 5 2.0 Hz, 1H), 7.84 (dd, J 5 8.3
Hz, J 5 1.0 Hz, 1H), 7.61–7.47 (m, 3H), 7.38–7.29 (m, 2H), 7.05 (d, J 5
0.9 Hz, 1H), 6.71–6.64 (m, 2H), 6.64–6.54 (m, 2H), 3.95–3.62 (m, 1H),
3.36–3.18 (m, 2H), 3.14–2.98 (m, 1H), 2.96–2.81 (m, 1H), 2.81–2.59 (m,
2H), 2.32–2.10 (m, 1H); 13C-NMR (75 MHz, CDCl3) d: 140.2, 140.0,
139.5, 139.4, 137.6, 137.5, 137.3, 135.7, 135.4, 133.9, 132.5, 132.3, 132.0,
130.6, 130.1, 129.6, 129.3, 128.4, 126.9, 126.2, 126.1, 126.1, 125.9, 125.8,
122.5, 121.9, 35.1, 34.4, 33.8, 33.3; HRMS calculated for C30H23O3S:
463.1362, Found: 463.1367.
((RP)-18) (99%, yellow solid); m.p. 1518C; [a]2D0 5 1270 (c 0.5, CHCl3);
FTIR 3067 (w), 2926 (m), 2852 (w), 2317 (w), 2186 (w), 2161 (w), 2110
(w), 2058 (w), 2005 (m), 1930 (w), 1897 (w), 1702 (vs), 1583 (w), 1478
(m), 1447 (m), 1428 (m), 1351 (m), 1240 (w), 1202 (w), 1108 (s), 1047
(m), 948 (s), 899 (s), 866 (m), 813 (w), 726 (vs) cm21 1H-NMR (300
;
MHz, CDCl3) d: 8.80–8.71 (m, 2H), 8.17 (s, 1H), 8.17–8.12 (m, 1H), 7.89
(dd, J 5 8.3 Hz, J 5 1.0 Hz, 1H), 7.76–7.68 (m, 2H), 7.64 (ddd, J 5 8.3, J
5 6.9, J 5 1.3, 1H), 7.46 (ddd, J 5 8.2, J 5 6.9, J 5 1.2, 1H), 6.93 (d, J 5
1.6 Hz, 1H), 6.90–6.85 (m, 2H), 6.74 (dd, J 5 7.8 Hz, J 5 1.7 Hz, 1H),
6.72–6.65 (m, 2H), 3.57–3.45 (m, 1H), 3.34–3.22 (m, 1H), 3.16–2.89 (m,
2H), 2.88–2.68 (m, 3H), 2.51 (s, 3H), 2.47–2.34 (m, 1H); 13C-NMR (75
MHz, CDCl3) d: 193.5, 143.3, 140.7, 139.9, 139.7, 138.1, 137.5, 135.4,
135.0, 134.9, 134.7, 133.0, 131.9 (2C), 131.1, 130.4, 130.0 (2C), 128.9,
127.8, 126.8, 126.7, 126.6, 126.4, 126.3, 122.8, 122.5, 35.0, 34.7, 33.8, 33.7,
30.5; HRMS calculated for C32H26ONaS: 481.1597, Found: 481.1595.
Chirality DOI 10.1002/chir

218
ENDERS ET AL.
(Rp)-4-(2,4,6-Triisopropylphenyl)[2.2]paracyclophane-12-sul-
General Procedure for the Catalytic Asymmetric
Friedel–Crafts Reaction
fonic acid ((RP)-3). Compound (RP)-3 was prepared following
method C using (Rp)-4-(2,4,6-triisopropylphenyl)-12-acetylmercapto[2.2]-
paracyclophane ((RP)-19) (66 %, yellow solid). M.p: 1398C (decomposi-
tion); [a]2D0 5 132 (c 0.5, CHCl3); FTIR 2961 (s), 2927 (m), 2866 (m),
1722 (w), 1460 (m), 1382 (w), 1360 (w), 1259 (s), 1077 (vs), 1015 (vs),
868 (m), 796 (vs), 689 (m), 657 (w) cm21; 1H-NMR (300 MHz, CDCl3) d:
7.13–7.04 (m, 2H), 6.95–6.87 (m, 2H), 6.87–6.62 (m, 1H), 6.62–6.49 (m,
3H), 3.92–3.33 (m, 3H), 3.26–2.63 (m, 7H), 1.92–1.72 (m, 1H), 1.43 (d, J
5 6.9 Hz, 3H), 1.39 (d, J 5 6.9 Hz, 3H), 1.27 (d, J 5 6.9 Hz, 6H), 0.94 (d,
J 5 7.2 Hz, 3H), 0.51 (d, J 5 7.2 Hz, 3H); 3C-NMR (75 MHz, CDCl3) d:
148.3, 147.2, 146.9, 140.4, 139.2, 139.1, 137.4 (2C), 137.0, 136.8, 136.2,
134.1, 133.6, 132.2, 130.6, 128.8, 121.4, 120.6, 35.1, 34.5, 34.4, 33.9, 33.6,
30.2, 29.5, 26.0, 25.3, 24.1, 24.0, 24.0, 23.9; HRMS calculated for
N-Sulfonyl imine (0.1 mmol) and Brønsted acid (0.01 mmol) were
placed in a dry Schlenk tube and dissolved in dry toluene (0.2 ml) under
argon. After stirring for 15 min at room temperature the solution was
cooled to –788C and indole (0.5 mmol) was added. The reaction was
warmed to –608C for 20 min and then quenched by addition of sat. aque-
ous NaHCO3. After extraction with ethyl acetate and drying over MgSO4
the solvent was removed. The crude product was purified by column
chromatography (n-pentane:ethylacetate 4:1).
N-(Indol-3-yl-phenylmethyl)-4-methylbenzenesulfonamide
(25a). 1H-NMR (300 MHz, CDCl3) d: 8.04 (s, 1H), 7.55 (d, J 5 8.3 Hz,
2H), 7.32–7.05 (m, 8H), 7.09 (d, J 5 8.0 Hz, 2H), 6.99 (t, J 5 7.9 Hz, 1H),
6.65 (d, J 5 2.4 Hz, 1H), 5.84 (d, J 5 6.9 Hz, 1H), 5.18 (d, J 5 6.9 Hz,
1H), 2.36 (s, 3H); 13C-NMR (75 MHz, CDCl3) d: 142.9, 140.2, 137.3,
136.5, 129.2, 128.3, 127.3, 127.2, 127.1, 125.3, 123.8, 122.4, 119.9, 119.2,
116.2, 111.2, 54.9, 21.4.
C
31H37O3S: 489.2458, Found: 489.2466.
(SP)-4,12-Bis(2-hydroxyphenyl)[2.2]paracyclophane
((SP)-
22). To
a solution of (SP)-4-bromo-12-hydroxy[2.2]paracyclophane
N-(5-Methoxy-indol-3-yl-phenylmethyl)-4-methylbenzenesulfona-
mide (25b). 1H-NMR (300 MHz, CDCl3) d: 8.08 (s, 1H), 7.52 (d, J 5
8.4 Hz, 2H), 7.25–7.12 (m, 6H), 7.04 (d, J 5 7.9 Hz, 2H), 6.82–6.76 (m,
2H, 1H), 6.58 (d, J 5 2.6 Hz, 1H), 5.80 (d, J 5 7.4 Hz, 1H), 5.56 (d, J 5
7.4 Hz, 1H), 3.71 (s, 3H), 2.36 (s, 3H); 13C-NMR (75 MHz, CDCl3) d:
154.1, 142.9, 140.1, 137.4, 131.5, 129.7, 129.2, 128.3, 127.3, 127.1, 125.8,
124.5, 112.8, 111.9, 100.8, 55.7, 54.9, 21.4.
((SP)-21), 2-hydroxyphenylboronic acid (21) (245 mg, 1.78 mmol, 2.7
eq) and tetrakis(triphenylphosphine)-palladium(0) (38.8 mg, 0.034
mmol, 0.05 eq.) in DMF (7 ml) was added 2 M aqueous Na2CO3 (2.8
ml) and the suspension was degased using the freeze-pump-thaw
method and then heated to 1008C for 48 h. After cooling to room temper-
ature, MTBE (40 ml) and saturated aqueous NaHCO3 (40 ml) were
added, the phases were separated and the aqueous phase extracted with
MTBE (5 3 40 ml). The combined organic phases were dried over
MgSO4 and concentrated. The crude product was purified by column
chromatography (n-pentane:ethylacetate 10:1) to yield (SP)-22 (53%) as
a colorless powder. M.p. 588C; [a]2D2 5 2138 (c 1.0, CHCl3); FTIR 3404
(m), 2927 (m), 2854 (m), 1708 (w), 1654 (s), 1576 (s), 1485 (s), 1443 (s),
1418 (m), 1377 (w), 1339 (w), 1221 (s), 1096 (m), 1043 (m), 979 (m), 942
General Procedure for the Catalytic Asymmetric Mannich
Reaction
Aniline (36.5 ll, 0.4 mmol), 4-nitrobenzaldehyde (66.5 mg, 0.44
mmol), and Brønsted acid (0.008 mmol, 0.02 eq.) were dissolved in tolu-
ene (5 ml). After stirring for 30 min at room temperature the solution
was cooled to 08C and cyclohexanone (0.41 ml, 4 mmol) was added. The
reaction was stirred for 2–3 days (until completion, monitored by TLC)
and then quenched by addition of sat. aqueous NaHCO3. After extraction
with ethyl acetate and drying over MgSO4 the solvent was removed. The
crude product was purified by column chromatography (n-pentane:ethy-
lacetate 8:1).
(w), 903 (m), 873 (s), 807 (m), 756 (vs), 660 (m) cm21 1H-NMR (300
;
MHz, CD3OD): 7.53 (d, J 5 7.3 Hz, 1H), 7.19 (ddd, J 5 7.9 Hz, 7.4 Hz, J
5 1.8 Hz, 1H), 7.02 (ddd, J 5 7.6 Hz, 7.5 Hz, J 5 1.2 Hz, 1H), 6.96 (d, J
5 1.2 Hz, 1H), 6.87 (dd, J 5 8.0 Hz, J 5 1.2 Hz, 1H), 6.58 (d, J 5 7.7 Hz,
1H), 6.48 (d, J 5 7.7 Hz, 1H), 6.37 (dd, J 5 7.7 Hz, J 5 1.8 Hz, 1H), 6.27
(dd, J 5 7.7 Hz, J 5 1.7 Hz, 1H), 5.75 (d, J 5 7.3 Hz, 1H), 3.44 (ddd, J 5
213.2 Hz, Jcis 5 8.9 Hz, Jtrans 5 2.7 Hz, 1H), 3.17–2.97 (m, 3H), 2.97–
2.85 (m, 1H), 2.79–2.68 (m, 1H), 2.68–2.57 (m, 1H), 2.49 (ddd, J 5 13.1
Hz, Jcis 5 10.3 Hz, Jtrans 5 4.8 Hz, 1H); 13C-NMR (75 MHz, CD3OD) d:
156.1, 154.8, 143.3, 140.6, 139.5, 136.0, 135.2 (2C), 134.0, 130.2, 129.5
(2C), 125.6 (2C), 121.5 (2C), 120.3, 116.8, 35.2, 35.2, 34.4, 32.5; HRMS
calculated for C22H21O2: 317.1536, Found: 317.1531.
2-(4-Methoxyphenylamino)(4-nitrophenyl)methyl)cyclohexanone
(30). Anti-diastereomer. 1H-NMR (300 MHz, CDCl3) d: 8.18–8.12 (m,
2H), 7.61–7.54 (m, 2H), 7.13–7.04 (m, 2H), 6.70–6.64 (m, 1H), 6.53–6.47
(m, 2H), 4.88 (s, 1H), 4.71 (d, J 5 5.3, 1H), 2.92–2.79 (m, 1H), 2.47–2.25
(m, 2H), 2.10–1.86 (m, 3H), 1.86–1.65 (m, 3H); 13C-NMR (75 MHz,
CDCl3) d: 24.4, 27.7, 32.0, 42.4, 56.9, 57.7, 113.4, 118.0, 123.7, 128.2,
129.2, 146.6, 146.9, 149.8, 211.8. Syn-diastereomer. 1H-NMR (300 MHz,
CDCl3) d: 8.18–8.12 (m, 2H), 7.61–7.54 (m, 2H), 7.13–7.04 (m, 2H), 6.70–
6.64 (m, 1H), 6.53–6.47 (m, 2H), 4.85 (d, J 5 4.2, 1H), 4.59 (s, 1H), 2.92–
2.79 (m, 1H), 2.47–2.25 (m, 2H), 2.14–1.86 (m, 3H), 1.72–1.47 (m, 3H);
13C-NMR (75 MHz, CDCl3) d: 24.9, 27.0, 29.0, 42.4, 56.1, 57.2, 114.0,
118.3, 123.6, 128.5, 129.2, 146.5, 146.9, 149.5, 210.6.
(SP)-4-(Phenyl-2-yl)-[2.2]paracyclophane-12-yl-hydrogenphos-
phate ((SP)-4). To a solution of (SP)-4,12-bis(2-hydroxyphenyl)[2.2]-
paracyclophane ((SP)-22) (345 mg, 1.09 mmol, 1 eq.) in dry pyridine (35
ml), phosphoryl chloride (0.200 ml, 2.19 mmol, 2 eq.) was added slowly
at room temperature and stirred overnight. After addition of water (15
ml) stirring was continued for another 24 h. The reaction mixture was
diluted with DCM, the phases were separated and the aqueous phase
extracted with DCM several times. The combined organic phases were
thoroughly washed with 2 N aqueous HCl, dried over MgSO4, and con-
centrated to yield (SP)-4 as a light red solid (48 %). M.p. 3308C (decom-
position); [a]2D2 5 251.1 (c 1.0, MeOH); FTIR 3286 (w), 3051 (w), 2963
(w), 2925 (m), 2853 (w), 2296 (w), 2142 (w), 2112 (w), 2073 (w), 2002
(w), 1920 (w), 1725 (w), 1630 (w), 1596 (m), 1565 (w), 1493 (m), 1467
(m), 1444 (s), 1411 (s), 1324 (w), 1259 (s), 1200 (s), 1095 (s), 1020 (vs),
965 (vs), 905 (m), 867 (m), 800 (s), 767 (s), 655 (w) cm21; 1H-NMR (300
MHz, DMSO-d6) d: 7.42 (d, J 5 1.8 Hz, 1H), 7.38 (ddd, J 5 9.0 Hz, 7.4
Hz, J 5 1.8 Hz, 1H), 7.27–7.19 (m, 2H), 7.19–7.13 (m, 1H), 6.75 (d, J 5
7.9 Hz, 1H), 6.65 (dd, J 5 7.7 Hz, J 5 1.1 Hz, 1H), 6.56–6.52 (m, 1H),
6.51–6.43 (m, 2H), 3.37–3.26 (m, 1H), 3.21–3.06 (m, 2H), 3.03–2.64 (m,
5H); 13C-NMR (75 MHz, DMSO-d6) d: 150.5, 149.4, 142.5, 139.1, 138.3,
137.8, 135.3, 134.9, 134.4, 133.8, 130.5, 129.5, 129.4, 129.0, 128.3, 125.2,
124.1, 119.3, 35.1, 34.7, 32.9, 29.1; 31P-NMR (121 MHz, DMSO-d6) d:
212.05; HRMS calculated for C22H19O4P: 379.1094, Found: 379.1087.
RESULTS AND DISCUSSION
Synthesis of Sulfonic Acids
To obtain enantiopure sulfonic acids, chiral sulfoxides
seemed to be a good choice, because they offer a way for re-
solution and also provide a sulfur-containing moiety, which
then can be converted to a sulfonic acid. The successful use
of Ellman’s18 reagent (tert-butyl-tert-butanethiosulfinate (8))
as the chiral source in paracyclophanes was published
recently19 and the sulfoxide moiety was then converted into
thiols.20 Whereas the literature known synthesis used the
mono-brominated paracyclophane as the starting material,
we chose to use a dibromide for later insertion of a sterically
demanding group. The pseudo-ortho 4,12-dibromo[2.2]paracy-
clophane (7) has often been used as starting material for a
variety of substituted paracyclophane-derivatives.5,21–23
Chirality DOI 10.1002/chir

PLANAR CHIRAL STRONG BRØNSTED ACID ORGANOCATALYSTS
219
Scheme 2. Reduction of sulfoxide (RP,SS)-9 to sulfide (RP)-10. Condi-
tions: HSiCl3, Et3N, toluene, reflux, 24 h.
the desired product. By employing of an additional equiva-
lent of n-BuLi, the generated product could favor a second
lithiation thus leading to more disulfoxide. Considering the
reisolation of unreacted starting material, the total yield of
the two diasteromers was 58%. They could easily be sepa-
rated by column chromatography, crystallized, and subjected
to X-ray crystal structure analysis (Fig. 2) to determine the
absolute configuration.
Scheme 1. Synthesis of the sulfoxide-precursor. Conditions: (a) Fe/Br2,
DCM, reflux, 20 h; (b) triglyme, reflux, 6 h, (c) 1: n-BuLi, 2788C, THF, 1 h,
2: 8, 2788C ?r.t.
After the successful synthesis of the precursor (RP,SS)-9,
we planned to introduce different sterically demanding
groups by a Suzuki coupling with the corresponding boronic
acid.
Starting from [2.2]paracyclophane (5), iron-catalyzed
dibromination gave the pseudo-para isomer 6 as the main
product, which is the only isolable isomer due to its insolubil-
ity in dimethylformamide.22 After isomerization in refluxing
triglyme, the desired pseudo-ortho isomer 7 was obtained.
Lithiation with a slight excess of n-BuLi and addition of (SS)-
(2)-tert-butyl-tert-butanethiosulfinate (8) (ee > 97%) yielded
the two diasteromers (RP,SS)-9 and (SP,SS)-9 in relatively
low yields (Scheme 1). Interestingly, we were able to reiso-
late about 35% of the starting material. Conversely, using an
excess of n-BuLi, less starting material but more disulfoxide
was obtained. Since in published procedures by using mono-
brominated paracyclophane,20 the yield of the obtained prod-
uct was much higher with only one equivalent of n-BuLi, we
believe that the additional bromine atom causes sterical hin-
drance to the electrophile due to its bulky tert-butyl moieties.
The equilibrium during lithiation between n-bromobutane
and lithiated paracyclophane could thus be less favorable for
Initially, we tried to react the sulfoxide (RP,SS)-9 directly
with 2-naphthyl boronic acid (11) under standard Suzuki
conditions. Unfortunately, the sulfoxide moiety was not sta-
ble under Suzuki conditions yielding a disulfide. Even
though this observation was unprecedented, we found that
sulfoxides can be pyrrolized by strong heating,24 producing
water and sulfides. Because in the proposed mechanism the
sulfoxide-oxygen played a crucial role, we first reduced
(RP,SS)-9 to the sulfide (RP)-10 according to a known proto-
col20 employing trichlorosilane and triethylamine (Scheme
2). The sulfide (RP)-10 was obtained almost quantitatively
(99%).
Fig. 2. ORTEP plot of (RP,SS)-9. The compound crystallizes with two sym-
metrically independent species in the asymmetric unit. Crystal data for
(RP,SS)-9: Sum formula (C20H23BrOS)2, Mr 5 782.75, space group P212121
˚
˚
˚
(19), Z 5 4, a 5 10.9767 (4) A, b 5 11.8188 (4) A, c 5 28.3255 (10) A. Crystal-
lographic data for the structure of (RP,SS)-9 have been deposited with the
Cambridge Crystallographic Data Centre (CCDC 824753). Copies can be
obtained, free of charge, on application to the Director, CCDC, 12 Union
Road, Cambridge CB12 1EZ, United Kingdom (Fax: 44-1223-336033 or email:
deposit@ccdc.cam.ac.uk). [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
Scheme 3. Suzuki-coupling of (RP)-10 with different boronic acids. Con-
ditions: Pd(PPh3)4, Na2CO3(aq.), DMF, 1008C, 48 h.
Chirality DOI 10.1002/chir

220
ENDERS ET AL.
Scheme 4. Synthesis of new sulfonic acids (RP)-1, (RP)-2, and (RP)-3. Con-
ditions: (a) AcCl, BBr3, toluene, r.t., 12 h; (b) KOH, O2, #MeOH, r.t., 72 h.
We then tried the Suzuki coupling again, which this time
was successful (Scheme 3). The 2-naphthyl-substituted deriv-
ative (RP)-14 was isolated in 58% yield and the 9-phenan-
thryl-substituted derivative (RP)-15 was obtained almost
quantitatively (95%).
Scheme 6. Synthesis of enantiopure phosphoric acid diester (SP)-4. Con-
ditions: (a) Pd(PPh3)4, Na2CO3(aq.), DMF, 1008C, 48 h; (b) 1: POCl3, pyri-
dine, r.t., 24 h; 2: H2O, r.t., 24 h.
Unfortunately, the reaction of sulfide (RP)-10 with 2,4,6-
triisopropylphenyl boronic acid (13) was challenging. De-
spite employing a large excess of boronic acid (13) and vari-
ation of solvents, we were not able to obtain more than 16%
of the product (RP)-16, which is most likely due to the steric
hindrance of the triisopropyl groups.
The following conversion to the thioacetates proceeded
smoothly by reaction of a mixture of the corresponding sul-
fides with acetyl chloride in toluene with boron tribromide,20
producing quantitative yields for (RP)-17 (99%), (RP)-18
(99%) as well as 77% yield for the more sterically hindered
(RP)-19 (Scheme 4).
fides, sulfones and sulfonic acids under the influence of
strong bases in polar solvents was previously published with
the thiolate anion RS2 being the active species.25,26 Carrying
out the transformation with potassium hydroxide in metha-
nol, we were able to deprotect the thioacetate and oxidize it
to the corresponding sulfonic acid in one step. In this way,
we obtained the target sulfonic acids (RP)-1, (RP)-2, and
(RP)-3 with 69%, 80%, and 66% yield, respectively (Scheme 4).
Synthesis of the Phosphoric Acid Diester
For the synthesis of the phosphoric acid diester, we
started from enantiopure (SP)-4-bromo-12-hydroxy[2.2]para-
cyclophane ((SP)-20) which can be synthesized in five steps
from [2.2]paracyclophane (5), involving a resolution employ-
ing the diastereomeric ester with (1S)-(2)-camphanic acid
(Scheme 5). The resolution has been described previously
by Rozenberg and coworkers.27
In the next step, we tried the deprotection of the thioace-
tates (RP)-17, (RP)-18, and (RP)-19 by using potassium car-
bonate in methanol to obtain the corresponding thiols which
could then be oxidized to the sulfonic acids. Interestingly,
we noticed that the use of technical grade methanol pro-
duced 10–20% sulfonic acid along with the thiol and disulfide.
We assume that traces of water could lead to the formation
of potassium hydroxide from potassium carbonate which
starts an autoxidation. The autoxidation of thiols to disul-
A Suzuki coupling of enantiopure (SP)-20 with 2-hydroxy-
phenyl boronic acid (21) gave the diol (SP)-22 in 70% yield
Scheme 5. Synthesis of resolved 4-bromo-12-hydroxy[2.2]-paracyclophanes
((SP)- and (RP)-20). Conditions: (a) see Scheme 1 condition (a) 1 (b); (b) 1: n-
BuLi, 2788C, THF, 1 h; 2: B(OCH3)3, 2788C?r.t.; 3: H2O2, NaOH, r.t.; (c) 1:
(S)-(2)-camphanic chloride, pyridine, r.t., 6 h; 2: separation by column chroma-
tography of diastereomeric esters; 3: KOH, MeOH, r.t., 2 h.
Scheme 7. Asymmetric Friedel–Crafts reaction of indole 23 with N-tosyli-
mine 24. Conditions: (1) 0.1 mmol N-sulfonyl imine, 0.01 mmol Brønsted
acid, 0.2 ml toluene, r.t., 15 min; (2) 2788C, 0.5 mmol indole,
2788C?2608C, 20 min.
Chirality DOI 10.1002/chir

PLANAR CHIRAL STRONG BRØNSTED ACID ORGANOCATALYSTS
TABLE 1. Results of the Friedel-Crafts reactions TABLE 2. Results of the Mannich reactions
221
Entry
1
Catalyst
R
Yield (%)
56
ee (%)
Yield
(%)
de
(%)
ee %
(anti)
ee %
(syn)
Entry
1
Catalyst
H
6
93
23
2
6
2
H
H
31
75
3
2
93
30
15
5
3
4
14
3
4
92
62
39
12
20
7
2
7
H
80
86
34
38
OMe
acids, which is possibly due to reduced rotation of the acid
caused by the triisopropyl substituents.
(Scheme 6). This compound has been mentioned in the liter-
ature several times,27–29 but no characterization has been
published so far.
We also employed the new catalysts in a direct asymmetric
Mannich reaction31 (Scheme 8).
As shown in Table 2, the reaction proceeded with good to
excellent yields, moderate diastereoselectivities of 23–39%
(anti) and enantiomeric excesses of 2-20%. It is noticeable
that in this asymmetric transformation the sulfonic acid (RP)-
3 shows the best enantioselectivity whereas the phosphoric
acid (SP)-4 gives only a poor asymmetric induction.
In summary, the promising results of the initial test reac-
tions clearly show the stereoselective activity of this new
class of catalysts in asymmetric transformations.
Reacting the diol (SP)-22 with phosphoryl chloride gave
enantiopure acid (SP)-4 in 48% yield.
Applications in Asymmetric Transformations
The new enantiopure planar chiral Brønsted acids were
then employed in asymmetric transformations. For our initial
test reactions the known asymmetric Friedel–Crafts reaction
of indoles 23 with N-tosylimine 24 was chosen (Scheme 7).30
The results are summarized in Table 1. As shown, all cata-
lysts were able to catalyze the reaction in moderate to good
yields with promising enantiomeric excesses of 3-38% with
the phosphoric acid diester (SP)-4 showing the best result in
both categories.
We assume that the sulfonic acids promote the formation
of the bisindole sideproduct 26 thus leading to lower yields
of 25. In addition, the free rotation of the sulfonic acid in
contrast to the strained phosphoric acid could explain the
lower asymmetric induction, even though we constructed
the sulfonic acids with bulkier groups. This assumption is in
accordance to entry 3 (Table 1) of compound (RP)-3 achiev-
ing the highest enantiomeric excess within the sulfonic
CONCLUSION
In conclusion, we synthesized the first planar chiral strong
Brønsted acid organocatalysts. Employing a modified proto-
col for the resolution of pseudo-ortho-substituted [2.2]paracy-
clophane-based sulfoxides, we obtained three sulfonic acids
with different sterically demanding groups.
Starting from enantiopure (SP)-4-hydroxy-12-bromo[2.2]-
paracyclophane, the first planar chiral phosphoric acid die-
ster was synthesized in only two steps. The results of the ini-
tial test reactions indicate that in principle asymmetric induc-
tions can be obtained with these new classes of catalysts.
Further investigations of the effect of different sterically
demanding groups in pseudo-ortho position as well as the ac-
tivity of the new catalysts in other asymmetric organocata-
lytic reactions are currently underway in our laboratories.
LITERATURE CITED
1. Cram DJ, Allinger NL. Macro rings. XII. Stereochemical consequences of
steric compression in the smallest paracyclophane. J Am Chem Soc
1955;77:6289–6294.
2. Rozenberg V, Sergeeva E, Hopf H. Cyclophanes as templates in stereose-
lective synthesis. In: Gleiter R, Hopf H, editors. Modern cyclophane
chemistry. Weinheim: Wiley-VCH; 2004. p 435–462.
Scheme 8. Asymmetric direct Mannich reaction. Conditions: 0.4 mmol
aniline, 0.44 mmol 4-nitrobenzaldehyde, 0.008 mmol Brønsted acid, 5 ml tolu-
ene, 4 mmol cyclohexanone, r.t., 2–3 days.
Chirality DOI 10.1002/chir

222
ENDERS ET AL.
3. Gibson SE, Knight JD. [2.2]Paracyclophane derivatives in asymmetric ca-
18. Cogan DA, Liu G, Kim K, Backes BJ, Ellman JA. Catalytic asymmetric
talysis. Org Biomol Chem 2003;1:1256–1269.
oxidation of tert-butyl disulfide. Synthesis of tert-butanesulfinamides,
tert-butyl sulfoxides, and tert-butanesulfinimines.
1998;120:8011–8019.
J Am Chem Soc
4. Hou X-L, Wu X-W, Dai L-X, Cao B-X, Sun J. Novel N,S- and N,Se-planar
chiral [2,2]paracyclophane ligands: synthesis and application in Pd-cata-
lyzed allylic alkylation. Chem Commun 2000:1195–1196.
19. Hitchcock PB, Rowlands GJ, Seacome RJ. The synthesis and directed
ortho-lithiation of 4-tert-butylsulfinyl[2.2]paracyclophane. Org Biomol
Chem 2005;3:3873–3876.
5. Pye PJ, Rossen K, Reamer RA, Tsou NN, Volante RP, Reider PJ. A new
planar chiral bisphosphine ligand for asymmetric catalysis: highly enan-
tioselective hydrogenations under mild conditions. J Am Chem Soc
1997;119:6207–6208.
20. Rowlands GJ, Seacome RJ. Enantiospecific synthesis of [2.2]paracy-
clophane-4-thiol and derivatives. Beilstein J Org Chem 2009;5:9.
6. Rozenberg V, Kharitonov V, Antonov D, Sergeeva E, Aleshkin A, Ikonni-
kov N, Orlova S, Belokon Y. Scalemic 2-formyl-3-hydroxy[2.2]paracyclo-
phane: a new auxiliary for asymmetric synthesis. Angew Chem Int Ed
Engl 1994;33:91–92.
21. Rossen K, Pye PJ, Maliakal A, Volante RP. Kinetic resolution of rac-4,12-
dibromo[2.2]paracyclophane in a palladium [2.2]PHANEPHOS catalyzed
amination. J Org Chem 1997;62:6462–6463.
22. Braddock DC, MacGilp ID, Perry BG. Improved synthesis of (6)-4,12-
7. Antonov DY, Belokon YN, Ikonnikov NS, Orlova SA, Pisarevsky AP,
Raevski NI, Rozenberg VI, Sergeeva EV, Struchkov YT, Tararov VI, et al.
Synthesis, resolution and absolute configuration determination of (S)-
and (R)-4-formyl-5-hydroxy [2.2]paracyclophane and its application in the
asymmetric synthesis of a-amino acids. J Chem Soc Perkin Trans 1
1995:1873–1879.
dihydroxy[2.2]paracyclophane and its enantiomeric resolution by enzy-
matic methods: planar chiral (R)- and (S)-phanol.
J Org Chem
2002;67:8679–8681.
23. Focken T, Rudolph J, Bolm C. Planar chiral imidazolium salts in the
asymmetric Rhodium-catalyzed 1,2-addition of arylboronic acids to alde-
hydes. Synthesis 2005:429–436.
8. Braddock DC, MacGilp ID, Perry BG. Planar chiral PHANOLs as organo-
catalysts for the Diels-Alder reaction via double hydrogen-bonding to a
carbonyl group. Synlett 2003:1121–1124.
24. Davis FA, Yocklovich SG, Baker GS. Synthesis of sulfenic acids: flash
vacuum pyrolysis of aryl and alkyl t-butyl sulfoxides. Tetrahedron Lett
1978;19:97–100.
9. Braddock DC, MacGilp ID, Perry BG. Planar chiral PHANOLs as double
hydrogen bonding donor organocatalysts: synthesis and catalysis. Adv
Synth Catal 2004;346:1117–1130.
25. Wallace TJ, Schriesheim A. Solvent effects in the oxidation of thiols. IV.
Base catalyzed oxidation of thiols and disulfides to sulfonic acids. Tetra-
hedron Lett 1963;4:1131–1136.
10. Negru M, Schollmeyer D, Kunz H. Enantioselective Strecker reaction
catalyzed by an organocatalyst lacking a hydrogen-bond-donor function.
Angew Chem Int Ed Engl 2007;46:9339–9341.
26. Wallace TJ, Schriesheim A. The base-catalysed oxidation of aliphatic and
aromatic thiols and disulphides to sulphonic acids. Tetrahedron
1965;21:2271–2280.
11. Schneider JF, Falk FC, Fro¨hlich R, Paradies J. Planar-chiral thioureas as
hydrogen-bond catalysts. Eur J Org Chem 2010:2265–2269.
27. Zhuravsky R, Starikova Z, Vorontsov E, Rozenberg V. Novel strategy for
the synthesis of chiral pseudo-ortho-substituted hydroxy[2.2]paracyclo-
phane-based ligands from the resolved 4-bromo-12-hydroxy[2.2]paracyclo-
phane as a parent compound. Tetrahedron: Asymmetry 2008;19:216–222.
12. Fulton JR, Glover JE, Kamara L, Rowlands GJ. Facile synthesis of planar
chiral N-oxides and their use in Lewis base catalysis. Chem Commun
2011;47:433–435.
28. Vorontsova N, Zhuravsky R, Sergeeva E, Vorontsov E, Starikova Z,
Rozenberg V. Planar chiral hydroxy derivatives of [2.2]paracyclophane as
auxiliaries for asymmetric allylboration. Russ Chem Bull 2007;56:2225–
2231.
13. Akiyama T. Stronger Brønsted acids. Chem Rev 2007;107:5744–5758.
14. Terada M. Chiral phosphoric acids as versatile catalysts for enantioselec-
tive transformations. Synthesis 2010:1929–1982.
15. Hatano M, Maki T, Moriyama K, Arinobe M, Ishihara K. Pyridinium 1,10-
binaphthyl-2,20-disulfonates as highly effective chiral Brønsted acid–base
combined salt catalysts for enantioselective Mannich-type reaction. J Am
Chem Soc 2008;130:16858–16860.
29. Rozenberg V, Zhuravsky R, Sergeeva E. Design, classification, and strat-
egies of synthesis of modular bidentate ligands based on aryl[2.2]paracy-
clophane backbone. Chirality 2006;18:95–102.
30. Kang Q, Zhao Z-A, You S-L. Highly enantioselective Friedel–Crafts reac-
tion of indoles with imines by a chiral phosphoric acid. J Am Chem Soc
2007;129:1484–1485.
16. Nakashima D, Yamamoto H. Design of chiral N-triflyl phosphoramide as
a strong chiral Brønsted acid and its application to asymmetric Diels–
Alder reaction. J Am Chem Soc 2006;128:9626–9627.
31. Guo Q-X, Liu H, Guo C, Luo S-W, Gu Y, Gong L-Z. Chiral Brønsted acid-
17. Schneider JF, Fro¨hlich R, Paradies J. Synthesis of enantiopure planar-
chiral thiourea derivatives. Synthesis 2010:3486–3492.
catalyzed direct asymmetric Mannich reaction.
2007;129:3790–3791.
J Am Chem Soc
Chirality DOI 10.1002/chir