Chiral, non-racemic, distally-bridged resorcin[4]arenes as models for use in asymmetric processes

Article abstract of DOI:10.1055/s-2001-11400

The synthesis of enantiomerically pure, distally-bridged resorcinarenes 3 with various R groups (CH₃, C₅H₁₁, C₁₁H₂₃) is reported. The key step makes use of the Mannich reaction for attachment of a chiral diamine-line 2 across the cavity. Yields for this step are good to excellent. One of the bridged compounds exhibits modest activity (27percent ee) as an enantioselective catalyst in the addition of diethylzinc to benzaldehyde.

Full text of DOI:10.1055/s-2001-11400

412
LETTER
Chiral, Non-racemic, Distally-bridged Resorcin[4]arenes as Models for Use in
Asymmetric Processes
Gareth Arnott,a Philip C. Bulman Page,b Harry Heaney,b Roger Hunter,*a Edward P. Samplerb
a Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa
Fax +27(21)6897499; E-mail: Roger@psipsy.uct.ac.za
b Department of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK.
Fax +44(1509)223926; E-mail: h.heaney@lboro.ac.uk
Received 4 January 2001
conditions failed to give the desired-bridged compound
Abstract: The synthesis of enantiomerically pure, distally-bridged
and a new set of reaction conditions were developed. A
resorcinarenes 3 with various R groups (CH3, C5H11, C11H23) is re-
second crucial feature was the necessity to produce quan-
tities of an appropriate C2v-symmetric tetra-substituted re-
ported. The key step makes use of the Mannich reaction for attach-
ment of a chiral diamine-line 2 across the cavity. Yields for this step
are good to excellent. One of the bridged compounds exhibits mod- sorcinarene with distal rings available for Mannich
est activity (27% ee) as an enantioselective catalyst in the addition
of diethylzinc to benzaldehyde.
functionalisation. Tetra-tosylation of C-methyl and C-
pentyl resorcinarenes as reported in the literature10 using
Key words: bridged resorcin[4]arene, chiral resorcin[4]arene,
Mannich reaction, enantioselective catalyst, C2v-symmetric diamine
chiral auxiliary
tosyl chloride (4 eq) and triethylamine (4 eq) in acetoni-
trile, and with precipitation of the products, produced tet-
ra-tosylates 1a and 1b. By comparison, formation of the
tetra-tosylate of C-undecyl resorcinarene required chang-
ing the solvent to tetrahydrofuran and the use of column
chromatography (no precipitation) to produce 1c in 41%
yield. Protection in the undecyl series with benzyl chloro-
formate similarly required THF as solvent and column
chromatography for isolation, but the resultant tetra-car-
bonate proved to be unsuitable for further elaboration in
view of competing base-catalysed migrations around the
ring during Mannich functionalisation (Figure 1).
Recent interest in the development of resorcinarenes1 as
molecular receptors2 has focused on attachment of appro-
priate groups to the upper rim, and in this regard the Man-
nich reaction has emerged as a versatile methodology.
Use of primary amines with aqueous formaldehyde results
in benzoxazine3 formation involving participation of phe-
nolic hydroxyl groups. Interestingly, reaction to the tet-
rakis(benzoxazine) level is highly regioselective to afford
the C4v product, and completely diastereoselective4 when
using -chiral amines such as -methylbenzylamine. The
latter discovery has been used to prepare the first5 inher-
ently chiral enantiomerically pure resorcin[4]arenes as a
new class of asymmetric receptor. Extension of the benz-
oxazine approach to afford distally-bridged benzoxazine
derivatives with C2v symmetry by using primary diamines
has been reported by Böhmer.6 Our interest in distally-
bridged7 chiral resorcinarenes, centres on developing the
asymmetric environment in the line to catalytic and other
processes. In this communication, we report on the syn-
thesis of the first chiral, non-racemic, distally-bridged re-
sorcin[4]arenes based on -methylbenzylamine as the
chiral source, and the application of one of them to the
enantioselective addition of diethylzinc to benzaldehyde.
Figure 1 1a, R = CH3; 1b, R = n-C5H11; 1c, R = C11H23
Synthesis of the chiral diamine bridging group was
straightforward involving thermal amide formation using
-methylbenzylamine and dimethyl glutarate to the di-
amide followed by reduction (LiAlH4/ THF / ) and iso-
lation using salt precipitation following addition of a tri-
ethylamine / water mixture. Conventional column
chromatography furnished the pure diamine 2 in around
50% overall yield for the two steps. Compound 2gave sat-
isfactory NMR data and could be unambiguously charac-
terised as its crystalline bis-hydrochloride salt or bis-
toluene-p-sulfonamide.11 Both enantiomers of 2 were pre-
pared in identical optical purity.
In designing the target it was decided to place a chiral aux-
iliary on each nitrogen of the line bridging the cavity in or-
der to generate a C2v-symmetric target, and an
-
methylbenzyl group from -methylbenzylamine was cho-
sen for this purpose. Such a choice precluded the possibil-
ity of using a benzoxazine formation / hydrolysis
sequence as used by Böhmer.6,8 However, our choice was
felt to be justified since secondary amines had been shown
by Matsushita9 to aminomethylate the upper rim of resor-
cinarenes under standard Mannich conditions (aqueous
formaldehyde / sec amine). In the event, however, these
Heating the diamine 2 under reflux with the resor-
cin[4]arene 1c using the Matsushita conditions of aqueous
formaldehyde in ethanol with a catalytic amount of glacial
acetic acid only succeeded in substituting the non-
Synlett 2001, No. 3, 412–414 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Chiral, Non-racemic, Distally-bridged Resorcin[4]arenes
413
provided by NMR chemical shifts. Thus, in their 1H spec-
tra, upfield shifts occurred in the methylene group reso-
nances going from diamine 2 to bridged compounds 3a-c.
Such shifts increased on passing from the - to the - and
-carbons, and with increasing size of R group (Table).
Scheme (i) (R)- -methylbenzylamine (3 eq.) / ; (ii) LiAIH4 /
THF /
Table 1H NMRa shifts in lineb of compounds 3a-c
protected phenolic rings of 1c with ethoxymethyl groups.
The participation of ethanol as nucleophile under these
conditions suggested that a set of conditions needed to be
developed in which the possibility of competing nucleo-
philic interception was minimised. Gratifyingly, on heat-
ing 1c under reflux with the diamine 2 in a 1:1.2 ratio in
the presence of an excess of paraformaldehyde in 1,4-di-
oxane at moderate dilution (0.02M of tosylate) furnished
the desired bridged compound 3c in about 40% yield after
column chromatography. Repeating the same reaction in
acetonitrile at 100 ºC in a sealed tube for 30 minutes suc-
ceeded in raising the yield to a reproducible 56-67% over
several runs. Similarly, using the same conditions,
bridged compounds 3a12 (58-61% over three runs), and 3b
(75% over two runs) could also be synthesised (Figure 2).
a recorded on a 400 MHz instrument
b in ppm relative to diamine 2 and with negative values = upfield
c H on line relative to nitrogen
In conclusion, we have synthesised the first chiral, non-ra-
cemic, distally-bridged resorcinarenes as models for a
number of processes that use chiral materials. As an ex-
ample, reaction of 3c with diethylzinc13 and benzaldehyde
in THF at room temperature afforded 1-phenyl-1-pro-
panol in 27% ee.14 Further studies will focus on elaborat-
ing the bridged resorcinarenes into more effective
reagents.
Typical experimental procedure
The tetra-tosylate (0.5 mmol), paraformaldehyde (10 mmol, 10 eq),
and the diamine (2) (0.6 mmol, 1.2 eq) were heated together in dry
acetonitrile (25 ml, 0.02 M in tosylate) in a sealed tube (thick glass
wall with teflon pressure screw-tap) for 30 minutes. On cooling, the
vessel was opened, the contents filtered (to remove unreacted
paraformaldehyde) and solvent evaporated to afford a crude residue
which was subjected to column chromatography directly without
work-up. Eluent ethyl acetate: light petroleum (bp 60-80 °C) = 2:1
to 1:1 depending on the R group present in the resorcinarene; yields
60-80% of bridged compounds.
Figure 2 3a, R = CH3; 3b, R = n-C5H11; 3c, R = C11H23
Compounds 3a-c displayed extremely non-polar chro-
matographic characteristics for diamines, running on TLC
in ethyl acetate/light petroleum systems depending on the
nature of R (e.g. Rf = 0.6 for 3c in ethyl acatate:light
petroleum = 3:7). Compounds 3b and 3c with the larger R
groups proved more difficult to purify chromatographi-
cally than 3a, always eluting with traces (<5%) of a mar-
ginally less polar contaminant that prevented correct
combustion analysis and optical rotation data being ob-
tained. By comparison, the bridged compound 3a was
crystalline and returned excellent spectroscopic and mi-
croanalytical data,12 as well as parity in the specific rota-
Acknowledgement
This work was initiated at Loughborough (by R.H.) during a period
of study leave. We thank the National Research Foundation, Preto-
ria, Fine Chemicals Corporation, Cape Town, and the EPSRC (UK),
for financial support.
References and Notes
(1) (a) Timmerman, P.; Verboom, W.; Reinhoudt, D. N.
Tetrahedron 1996, 52, 2663-2704; (b) Böhmer, V. Angew.
Chem., Int. Ed. Engl. 1995, 34, 713-745; (c) Mclldowie, M.;
Mocerino, M.; Skelton, B. W.; White, A. H. Org. Lett. 2000,
2, 3869-3871.
(2) (a) Higler, I.; Boerrigter, H.; Verboom, W.; Kooijman, H.;
Spek, A. I.; Reinhoudt, D. N. Eur. J. Org. Chem. 1998, 1597-
1607; (b) Shivanyuk, A.; Spaniol, T. P.; Rissanen, K.;
Kolehmainen, W.; Böhmer, V. Angew. Chem., Int. Ed. 2000,
39, 3497-3500.
1
tions of the (R, R) and (S, S) antipodes. The H NMR
spectra of compounds 3a-c required being recorded at 50
ºC to avoid line broadening, and revealed a stoichiometric
ratio of 1:1 between the diamine-line and the resorcinare-
ne. Three singlets for two sets of aromatic rings, con-
firmed that distal aromatic substitution had taken place,
while only 3a revealed the diastereotopicity of the benzyl-
ic methylene protons as an AB pair of doublets. Evidence
that the line lies over the cavity in compounds 3a-c was
(3) Airola, K.; Böhmer, V.; Paulus, E. F.; Rissanen, K.; Schmidt,
C.; Thondorf, I.; Vogt, W. Tetrahedron 1997, 53, 10709-
10724.
Synlett 2001, No. 3, 412–414 ISSN 0936-5214 © Thieme Stuttgart · New York

414
G. Arnott et al.
LETTER
(4) (a) El Gihani, M. T.; Heaney, H. Tetrahedron Lett. 1995, 36,
4905-4909; (b) Iwanek, W.; Mattay, J. Liebigs Ann. 1995,
1463-1466; (c) Arnecke, R.; Böhmer, V.; Friebe, S.; Gebauer,
S.; Krauss, G. J.; Thondorf, I.; Vogt, W. Tetrahedron Lett.
1995, 36, 6221-6224; (d) Iwanek, W. Tetrahedron:
Asymmetry 1998, 9, 4289-4290.
0.95 (2H, m, -CH2), 1.20 (2H, m, -CH2), 1.32 (6H, d, J 7.2
Hz, CH3), 2.43 (6H, s, CH3), 2.84 (4H, m, -CH2), 5.13 (2H,
q, J 7.2 Hz, CH), 7.23 (10H, m, Ar), 7.28 (4H, m, Ar), 7.71
(4H, m, Ar); 13C (75.5 MHz, CDCl3) 16.55, 21.47, 24.14,
29.94, 43.89, 55.18, 127.09, 127.50, 127.53, 128.25, 129.60,
138.39, 140.35, 142.95
(5) Bulman Page, P. C.; Heaney, H.; Sampler, E. P. J. Am. Chem.
Soc. 1999, 121, 6751-6752.
(12) Data for 3a: mp 150-157 ºC (ether / CH2Cl2) (Found: C, 66.70;
H, 5.83; N, 1.92; S, 8.32. C83H86N2O16S4 requires C, 66.64; H,
5.79; N, 1.87; S, 8.57%); [ [D for (R,R) = +8.3 (c 1.14 in
CHCl3), for (S,S) = -8.8 (c 1.06 in CHCl3); 1H (400 MHz,
CDCl3) 0.89 (2H, m, -CH2), 1.04 (4H, m, -CH2), 1.36 (12H,
d, J 6.8 Hz, CH3), 1.42 (6H, d, J 6.8 Hz, CH3), 2.10 (2H, m, -
CH2), 2.26 (2H, m, -CH2), 2.48 (12H, s, CH3), 3.71 (2H, d,
(6) Shivanyuk, A.; Schmidt, C.; Böhmer, V.; Paulus, E. F.; Lukin,
O.; Vogt, W. J. Am. Chem. Soc. 1998, 120, 4319-4326.
(7) For cases of both upper and lower-rim, distally-bridged
calix[4]arenes: (a) Wieser- Jeunesse, C.; Matt, D.; De Cian A.
Angew. Chem., Int. Ed. 1998, 37, 2861-2864; (b) Ross, H.;
Lüning, U. Angew. Chem., Int. Ed. Engl. 1995, 34, 2555-2557;
(c) Sharma, S. K.; Gutsche, C. D. J. Org. Chem. 1999, 64,
998-1003; (d) Saiki, T.; Goto, K.; Okazaki, R. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2223-2224; (e) Morikawa, O.;
Nakanishi, K.; Miyashiro, M.; Kobayashi K.; Konishi, H.
Synthesis 2000, 233; (f) Ito, K.; Yamamori, Y.; Ohba, Y.;
Sone, T. Synth. Commun. 2000, 30, 4343-4351.
J
AB 16.4 Hz, CH2 benzylic), 3.78 (2H, d, JAB 16.4 Hz, CH2
benzylic), 3.84 (2H, q, J 6.8 Hz, CH benzylicN), 4.54 (4H, m,
CH benzylicC), 6.79 (2H, s, Ar), 6.83 (br s, Ar), 7.11 (2H, s,
Ar), 7.26 (10H, m), 7.39 (8H, m), 7.96 (8H, m); 13C (100.6
MHz, CDCl3) selected resonances: 16.96 (CH3), 21.66, 21.77
(2 CH3 of Ts), 25.28, 25.36 ( - and - CH2), 30.93, 31.04
(CH benzylicC), 49.13 (CH2 benzylicN), 51.08 ( -CH2), 61.49
(CH benzylicN), 115.18 (resorc C-H), 123.11 (resorc C-H),
127.68 (resorc C-H).
(8) Schmidt, C.; Airola, K.; Böhmer, V.; Vogt, W.; Rissanen, K.
Tetrahedron 1997, 53, 17691-17698.
(9) Matsushita, Y.; Matsui, T. Tetrahedron Lett. 1993, 34, 7433-
7436.
(10) (a) Shivanyuk, A.; Paulus, E. F.; Böhmer, V.; Vogt, W. J. Org.
Chem. 1998, 63, 6448-6449; (b) Lukin, O.; Shivanyuk, A.;
Pirozhenko, V. V.; Tsymbal, I. F.; Kalchenko, V. I. J. Org.
Chem. 1998, 63, 9510-9516.
(11) Data for the bis(p-toluenesulfonamide) of 2: mp 106-108 ºC
(ether) (Found: C, 67.92; H, 6.91; N, 4.60; S, 10.04.
C35H42N2O4S requires C, 67.93; H, 6.84; N, 4.53, S, 10.36%);
[ ]D for (R,R) = +19.4 (c 1.15 in CHCl3), for (S,S) = -19.1 (c
1.19 in CHCl3); 1H (300 MHz, CDCl3) 0.80 (2H, m, -CH2),
(13) (a) Näslund, J.; Welch, C. J. Tetrahedron: Asymmetry 1991, 2,
1123-1126; (b) Soai, K.; Hirose, Y.; Sakata, S. Bull. Chem.
Soc. Jpn. 1992, 65, 1734-1735.
(14) The reaction was carried out in toluene at RT according to
conditions described in ref. 13 (a) using 0.05 eq of catalyst.
The ee was ascertained using chiral HPLC on a Chiralcel OD
column and eluting with hexane:isopropanol = 98:2. The
major isomer had the (R)-configuration.
Article Identifier:
1437-2096,E;2001,0,03,0412,0414,ftx,en;L21900ST.pdf
Synlett 2001, No. 3, 412–414 ISSN 0936-5214 © Thieme Stuttgart · New York