Novel supramolecular affinity materials based - Beilstein Journals

65 Pages·2013·6.99 MB·English

Supporting Information
for
Novel supramolecular affinity materials based on
(−)-isosteviol as molecular templates
Christina Lohoelter, Malte Brutschy, Daniel Lubczyk, and Siegfried R. Waldvogel*

Address: Institute for Organic Chemistry, Johannes Gutenberg University,
Duesbergweg 10–14, 55128 Mainz, Germany

Email: Siegfried R. Waldvogel* - [email protected]
*Corresponding author

Characterization data, spectra of synthesized compounds, QCM set up, and
QCM screening details.

A. Materials and methods S2
B. Experimental procedures and characterization S3
C. 1H and 13C NMR spectra S33
D. Evaluation of affinity S57
E. References S65

S1
A. Materials and methods
All reagents were used in analytical grades. Solvents were dried if necessary, by
standard methods. Nitrogen which was used in the QMB screening experiments was
used in a purity of 99.998%. Melting points were determined by a Melting Point
apparatus B-545 (Büchi, Flawil, Switzerland) and were uncorrected. Microanalysis
was performed with a VarioMICRO cube (Elementaranalysensysteme, Hanau,
Germany). NMR spectra were recorded with a Bruker AC 300 or AV II 400 instrument
(Bruker Analytische Messtechnik, Karlsruhe, Germany) by calibration on traces of
CHCl in the corresponding deuterated solvent with δ = 7.26 ppm for 1H NMR and δ
3
= 77.0 ppm for 13C NMR, respectively; chemical shifts are expressed in ppm. The
assignment of signals, if given, was determined via 2D NMR spectroscopy (COSY,
HSQC, HMBC) or in accordance with literature [1]. Mass spectra and high resolution
mass spectra were obtained on a QTof Ultima 3 apparatus (Waters, Milford,
Massachusetts) employing ESI or on a MAT 95 (Thermo Finnigan, Bremen,
Germany) employing FD. Optical rotations were measured using a JASCO P-2000
apparatus (Jasco Deutschland GmbH, Gross-Umstadt, Germany, path length 100
mm). All reactions were monitored by thin layer chromatography (TLC), visualization
was effected by UV and heating with a 1% aqueous solution of Ce(SO ) ·4H O
4 2 2
containing 2.5% of molybdato phosphoric acid and 6% of sulfuric acid. Column
chromatography was performed on silica gel (particle size 63–200 μm, Merck,
Darmstadt, Germany) or using a Büchi chromatography system (silica gel, particle
size 40-63 μm, Macherey-Nagel GmbH, Düren, Germany) using mixtures of
cyclohexane with ethyl acetate or dichloromethane with methanol as eluents. X-ray
analysis data were collected on a STOE IPDS-2T diffractometer (Stoe, Darmstadt,
Germany) using Incoatec microSource Cu Kα radiation (λ = 1.54186 Å). The
structures were solved by direct methods and refined anisotropically by the least-
S2
squares procedure implemented in the SHELX program system. CCDC-942549 (for
all-syn-17) contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
The experimental primary data of the QCM experiments were processed with Matlab
7.11.0 (R2010b) (The MathWorks Inc., Natick, Massachusetts, USA).
For the preparation of the diagrams OriginPro 8 SR0 (OriginLab Corporation,
Northampton, Massachusetts, USA) were used.
HFF-QCMs with a fundamental frequency of 195 MHz were used (KVG Quartz
Crystal Technology GmbH, Neckarbischofsheim, Germany. Type: XA 1600).
The QCM is excited using an aperiodic oscillator circuit and oscillates with its specific
load resonance frequency [2]. Frequency counting is performed using a FPGA (field
programmable gate array) which allows asynchronous 28-bit counting with an
accuracy of ±0.5 Hz.

B. Experimental procedures and characterization
(+)-all-syn-Trispiro[tris-ent-beyerane-16,2´;16´,7´;16´´,12´-triphenyleno-[2,3-d;6,7-
d´;10,11-d´´]tris[1,3]dioxole]-19,19´,19´´-nor-4,4´,4´´-tri-N-p-toluenesulfonamide (all-
syn-3)

To a solution of all-syn-2a [1] (153 mg, 0.13 mmol) in pyridine (10 mL), para-
toluenesulfonyl chloride (3.21 g, 16.8 mmol) was added at 25 °C. The reaction
mixture was left to stand for seven days. After that, the solution was poured on ice
S3
and left to stand for 45 minutes. 10% citric acid (10 mL) was added, the resulting
orange precipitate was filtered off and washed with cold water (5 mL). The aqueous
layer was extracted with dichloromethane (20 mL) and the organic fractions were
washed with water (2 x 20 mL) and brine (20 mL), dried (Na SO ) and concentrated
2 4
under reduced pressure. The crude product was purified by column chromatography
on silica (cyclohexane/ethyl acetate 9:1 to 75:25).

Yield: 68 mg (0.043 mmol, 32%) of a pale brown solid. R (CH:EE = 75:25): 0.39; Mp:
f
decomposition >310 °C; 1H-NMR (400 MHz, CDCl ) δ [ppm] = 0.80 – 0.83 (m, 3H),
3
0.85 (s, 9H, H-20), 0.87 – 0.94 (m, 8H), 1.08 (s, 9H, H-17), 1.11 – 1.16 (m, 3H), 1.20
(s, 9H, H-18), 1.23 – 1.28 (m, 11H), 1.31 – 1.34 (m, 5H), 1.49 (dt, J = 4.0 Hz, 13.3
Hz, 3H), 1.63 – 1.66 (m, 9H), 1.70 – 1.72 (m, 3H), 1.79 (d, J = 11.9 Hz, 3H), 1.90 (d,
J = 10.2 H, 3H), 2.01 (d, J = 15.4 Hz, 3H), 2.36 (d, 2J = 13.9 Hz, 3H, H-15 ),
15α,15β α
2.42 (s, 9H, H-25), 2.70 (d, 2J = 15.1 Hz, 3H, H-3 ), 4.30 (s, 3H, 19-NH), 7.27
3ax,3eq eq
(d, 3J = 8.8 Hz, 6H, H-23), 7.65, 7.68 (every s, every 3H, H-4’, H-15’), 7.75 (d,
22,23
3J = 8.3 Hz, 6H, H-22); 13C-NMR (100 MHz, CDCl ) δ [ppm] = 14.8 (C20), 17.1
22,23 3
(C2), 19.1 (C11), 19.4 (C17), 19.6 (C6), 21.5 (C25), 28.9 (C18), 34.8 (C12), 37.1
(C3), 37.5 (C10), 38.7 (C1), 40.6 (C7), 40.7 (C13), 46.8 (C8), 48.0 (C15), 54.2 (C14),
55.7, 56.9 (C5, C9), 58.7 (C4), 99.9, 100.0 (C4’, C15’), 124.1, 124.5 (C4a’, C14b’),
126.9 (C22), 127.8 (C16), 129.5 (C23), 140.5 (C24), 142.8 (C21), 147.4, 148.4 (C3a’,
C15a’); MS (ESI pos. mode): m/z =1623.8 [M+Na]+; HRMS (ESI, pos. mode): m/z for
C H NaN O S [M+Na]+ calc.: 1622.7692, found: 1622.7686; elem. anal.
96 117 3 12 3
C H N O S (1601.16): calc. C 72.01 H 7.37 N 2.62 S 6.01, found: C 69.78 H
96 117 3 12 3
8.63 N 2.41 S 6.12; optical rotation [α] 20 = +55.9° (c 1.00, CHCl ).
D 3
S4
Deviations in the elemental analysis are probably caused by solvent molecules within
the cavities of the molecules. The measurement of the optical rotation was therefore
carried out to determine the orientation thereof.

Methyl (+)-ent-beyeran-19-oate-[15,16-b]quinoxaline (6)

To a suspension of (+)-ent-15,16-dioxobeyeran-19-oic acid methyl ester 5b [3] (100
mg, 0.29 mmol) in glacious acetic acid (10 mL), o-phenylenediamine (31 mg, 0.29
mmol) was added. The reaction mixture was refluxed for 4 hours. After bringing to
room temperature, the mixture was fractionated between aqueous NaHCO (50 mL)
3
and tert-butyl methyl ether (TBME, 50 mL). The aqueous layer was extracted with
TBME (2 x 20 mL), the combined organic fractions were washed with water (5 x 50
mL) and brine (50 mL), dried (MgSO ), and concentrated under reduced pressure.
4
The crude product was purified by column chromatography on silica (Büchi
chromatography system, cyclohexane/ethyl acetate 98:2).

Yield: 50 mg (0.12 mmol, 41%) of a colorless solid. R (SiO , cyclohexane/ethyl
f 2
acetate, 9:1) = 0.37; Mp. = 155 °C (ethyl acetate); 1H-NMR (300 MHz, CDCl ) δ
3
[ppm] = 0.52 (s, 3H, H-20), 0.61 – 0.77 (m, 1H), 0.92 (dt, 2J = 3J = 13.1 Hz,
1ax,1eq 1ax,2ax
3J = 4.1 Hz, 1H, H-1 ), 1.05 (dt, 2J = 3J = 13.4 Hz, 3J = 4.1 Hz,
1ax,2eq ax 3ax,3eq 2ax,3ax 2eq,3ax
1H, H-3 ), 1.23 – 1.28 (m, 1H), 1.26 (s, 3H; H-17), 1.35 – 1.43 (m, 1H), 1.41 (s, 3H,
ax
H-18), 1.45 – 1.91 (m, 9H), 2.01 – 2.08 (m, 1H), 2.18 – 2.25 (m, 2H), 2.79 (dq,
S5
3J = 3.4 Hz, 2J = 3J = 3J =13.7 Hz, 1H, H-6 ), 3.72 (s, 3H, H-21),
6ax,7eq 6ax,6eq 6ax,7ax 6ax,5 ax
7.60 – 7.66 (m, 2H, H-6‘, H-7‘), 8.00 – 8.06 (m, 2H, H-5‘, H-8‘); 13C-NMR (75 MHz,
CDCl ) δ [ppm] = 11.7 (C20), 19.0 (C2), 21.2 (C6), 21.7 (C11), 22.1 (C17), 29.1
3
(C18), 36.7 (CH ), 37.9 (CH ), 38.4 (CH ), 38.9 (C10), 40.5 (CH ), 43.1, 44.1, 46.1
2 2 2 2
(C4, C8, C13), 51.3 (C21), 56.2, 57.1 (C5, C9), 58.8 (C14), 128.3, 128.6, 128.8,
129.6 (C5’ – C8’), 141.4, 141.9 (C4a’, C8a’), 165.7, 166.1 (C15, C16), 178.2 (C19);
MS (ESI, pos. mode): m/z = 441.24 [M+Na]+; 859.5 [2M+Na]+; HRMS (ESI, pos.
mode): m/z for C H N NaO [M+Na]+ calc.: 441.2518, found 441.2518; elem. anal.
27 34 2 2
C H N O (418.57): calc. C 77.48 H 8.19 N 6.69, found C 77.80 H 8.56 N 6.67;
27 34 2 2
optical rotation [α] 20 = +104.9° (c 1.00, CHCl ).
D 3

Methyl (+)-ent-beyeran-19-oate-[15,16-b]-6´,7´-dimethylquinoxaline (7)

To a suspension of (+)-ent-15,16-dioxobeyeran-19-oic acid methyl ester 5b [3] (500
mg, 1.45 mmol) in glacious acetic acid (50 mL), 4,5-dimethyl-1,2-phenylenediamine
(195 mg, 1.45 mmol) was added. The reaction mixture was refluxed for 4 hours. After
bringing to room temperature, the mixture was fractionated between aqueous
NaHCO (100 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with
3
EtOAc (2 x 50 mL), the combined organic fractions were washed with water (5 x 50
mL) and brine (50 mL), dried (MgSO ), and concentrated under reduced pressure.
4
S6
The crude product was purified by column chromatography on silica (Büchi
chromatography system, cyclohexane/ethyl acetate 99:1).
Yield: 373 mg (0.87 mmol, 60%) of a colorless foam. R (SiO , cyclohexane/ethyl
f 2
acetate, 4:1) = 0.63; 1H-NMR (400 MHz, CDCl ) δ [ppm] = 0.51 (s, 3H, H-20), 0.62 –
3
0.71 (m, 1H), 0.92 (dt, 2J = 3J = 13.3 Hz, 3J = 4.2 Hz, 1H, H-1 ), 1.05
1ax,1eq 1ax,2ax 1ax,2eq ax
(dt, 2J = 3J = 13.5 Hz, 3J = 4.1 Hz, 1H, H-3 ), 1.23 – 1.27 (m, 1H),
3ax,3eq 3ax,2ax 3ax,2eq ax
1.26 (s, 3H; H-17), 1.37 – 1.42 (m, 1H), 1.41 (s, 3H, H-18), 1.43 – 1.54 (m, 2H), 1.61
– 1.88 (m, 7H), 2.02 – 2.06 (m, 1H), 2.17 – 2.23 (m, 2H), 2.45, 2.46 (every s, every
3H, H-9‘, H-10‘), 2.77 (dq, 3J = 3.5 Hz, 2J = 3J = 3J =13.7 Hz, 1H,
6ax,7eq 6ax,6eq 6ax,7ax 6ax,5
H-6 ), 3.72 (s, 3H, H-21), 7.78, 7.83 (every s, every 1H, H-5‘, H-8‘); 13C-NMR (100
ax
MHz, CDCl ) δ [ppm] = 11.8 (C20), 19.0 (CH ), 20.06, 20.11 (C9’, C10’), 21.2 (CH ),
3 2 2
21.7 (CH ), 22.2 (C17), 28.9 (C18), 36.5 (CH ), 37.6 (CH ), 38.2 (CH ), 38.6 (C), 40.3
2 2 2 2
(CH ), 42.7 (C), 43.9 (C), 45.7 (C), 51.2 (C21), 55.9, 56.9 (C5, C9), 58.7 (C14), 128.7
2
(C5’, C8’), 138.1, 138.4 (C4a’, C8a’), 140.4 (C6’, C7’), 164.2, 164.8 (C15, C16),
178.1 (C19); MS (ESI, pos. mode): m/z = 447.32 [M+H]+; HRMS (ESI, pos. mode):
m/z for C H N O [M+H]+ calc. :447.3012, found 447.3003; elem. anal. C H N O
29 39 2 2 29 38 2 2
(446.62): calc. C 77.99 H 8.58 N 6.27, found C 77.90 H 9.06 N 6.16; optical rotation
[α] 20 = +140.0° (c 1.00, CHCl ).
D 3

S7
Methyl (+)-tris-ent-beyeran-19-oate-[16,15-e:15´,16´-e´:16´´,15´´-e´´]triptyceno*-
[2*,3*-b:6*,7*-b´:14*,15*-b´´]tripyrazine (all-syn-8)
Methyl (+)-tris-ent-beyeran-19-oate-[15,16-e:15´,16´-e´:16´´,15´´-e´´]triptyceno*-
[2*,3*-b:6*,7*-b´:14*,15*-b´´]tripyrazine (anti,anti,syn-8)

Hexaammoniumtriptycene hexachloride 4 [4] (54 mg, 0.07 mmol), (+)-ent-15,16-
dioxobeyeran-19-oic acid methyl ester 5b [3] (225 mg, 0.65 mmol), sodium acetate
(71 mg, 0.87 mmol) and THF (2 mL) were placed in a sealed tube and heated to 100
°C for 16 h. After cooling to room temperature, the reaction mixture was fractionated
between H O (50 mL) and CH Cl (50 mL). The aqueous layer was extracted with
2 2 2
CH Cl (20 mL). The combined organic fractions were washed with H O (2 x 50 mL)
2 2 2
and brine (50 mL), dried (Na SO ), and concentrated under reduced pressure. The
2 4
crude product was purified by column chromatography on silica (CH Cl /MeOH,
2 2
99.5:0.5 to 99:1).
Combined yield: 55 mg (0.042 mmol, 59% [all-syn + anti,anti,syn]) of an orange
glassy solid.
Chromatographic separation of isomers: anti,anti,syn 23 mg (25%)
all-syn 3 mg (3%)
The remaining 31% were reisolated as isomeric mixture after column
chromatography.
S8
all-syn:
R (SiO , dichloromethane/methanol, 98:2) = 0.21; 1H-NMR (600 MHz, CDCl ) δ
f 2 3
[ppm] = 0.42 (s, 9H, H-20), 0.52 – 0.59 (m, 3H), 0.85 – 0.90 (m, 5H), 1.03 (dt, 2J
3ax,3eq
= 3J = 13.5 Hz, 3J = 4.1 Hz, 3H, H-3 ), 1.22 (d, J = 12.5 Hz, 3H), 1.26 (s,
3ax,2ax 3ax,2eq ax
9H, H-17), 1.38 (s, 9H, H-18), 1.41 – 1.49 (m, 7H), 1.56 (d, J = 12.6 Hz, 3H), 1.60 –
1.63 (m, 6H), 1.68 – 1.77 (m, 9H), 1.83 – 1.84 (m, 3H), 2.00 (d, J = 12.6 Hz, 3H),
2.10 (d, J = 13.2 Hz, 3H), 2.18 (d, J = 13.9 Hz, 3H), 2.73 (dq, 3J = 3.5 Hz,
6ax,7eq
2J = 3J = 3J =13.6 Hz, 3H, H-6 ), 3.76 (s, 9H, H-21), 5.96, 5.99 (every
6ax,6eq 6ax,7ax 6ax,5 ax
s, every 1H, H-9*, H-10*), 8.11 – 8.19 (m, 6H, H-ar*); 13C-NMR (150 MHz, CDCl ) δ
3
[ppm] = 11.6 (C20), 19.0 (C2), 21.1 (C6), 21.6 (C11), 22.1 (C17), 28.9 (C18), 29.7
(CH ), 31.9 (C), 36.4 (CH ), 37.4 (CH ), 38.2 (CH ), 38.6 (C), 40.2 (CH ), 42.8 (C),
2 2 2 2 2
43.9 (C), 45.8 (C), 51.2 (C21), 52.9, 53.1, 55.8, 56.8 (C5, C9, C9*, C10*), 58.7 (C14),
123.3, 123.9 (C1*, C4*, C5*, C8*, C13*, C16*), 140.5 (C*), 143.0 (C*), 143.2 (C*),
165.0, 165.7 (C15, C16), 178.1 (C19); MS (MALDI-TOF, pos. mode): m/z = 1275.47
[M+H]+; HRMS (ESI, pos. mode): m/z for C H N O [M+H]+ calc. 1275.7626, found
83 99 6 6
1275.7592; elem. anal. C H N O (1275.70): calc. C 78.14 H 7.74 N 6.59, found C
83 98 6 6
75.42 H 8.33 N 5.48; optical rotation [α] 20 = +64.7° (c 1.00, CHCl ).
D 3
Deviations in the elemental analysis are probably caused by solvent molecules within
the cavities of the molecules. The measurement of the optical rotation was therefore
carried out to determine the orientation thereof.

anti,anti,syn
R (SiO , dichloromethane/methanol, 98:2) = 0.25; 1H-NMR (600 MHz, CDCl ) δ
f 2 3
[ppm] = 0.40, 0.41 (every s, 9H, H-20), 0.47 – 0.55 (m, 3H), 0.85 – 1.05 (m, 9H), 1.18
– 1.22 (m, 5H), 1.25 (s, 9H; H-17), 1.34 – 1.37 (m, 12H), 1.40 – 1.49 (m, 6H), 1.53 –
1.63 (m, 9H), 1.65 – 1.73 (m, 6H), 1.79 – 1.80 (m, 5H), 1.98 – 2.19 (m, 9H), 2.68 –
S9
2.77 (m, 3H, H-6 ), 3.74, 3.75, 3.77 (every s, 9H, H-21), 5.94, 5.96 (every s, every
ax
1H, H-9*, H-10*), 8.04 – 8.17 (m, 6H, H-ar*); 13C-NMR (150 MHz, CDCl ) δ [ppm] =
3
11.6, 11.7 (C20), 18.9 (CH ), 19.0 (CH ), 21.02 (CH ), 21.05 (CH ), 21.07 (CH ),
2 2 2 2 2
21.54 (CH ), 21.60 (CH ), 21.62 (CH ), 22.1 (C17), 28.87, 28.89 (C18), 36.35 (CH ),
2 2 2 2
36.42 (CH ), 37.39 (CH ), 37.47 (CH ), 37.49 (CH ), 38.1 (CH ), 38.5 (C), 40.2 (CH ),
2 2 2 2 2 2
42.71 (C), 42.75 (C), 42.76 (C), 43.8 (C), 45.72 (C), 45.74 (C), 45.76 (C), 51.18,
51.20, 51.21 (C21), 52.9, 53.0, 55.7, 55.8, 56.80, 56.83 (C5, C9, C9*, C10*), 58.64,
58.66, 58.72 (C14), 123.2, 123.3, 123.8, 123.96, 124.0 (C1*, C4*, C5*, C8*, C13*,
C16*), 140.2 (C*), 140.46 (C*), 140.48 (C*), 140.55 (C*), 142.8 (C*), 142.9 (C*),
143.0 (C*), 143.1 (C*), 143.3 (C*), 165.1, 165.4, 165.5, 165.6 (C15, C16), 178.00,
178.01 (C19); MS (MALDI-TOF, pos. mode): m/z = 1275.47 [M+H]+; HRMS (ESI,
pos. mode): m/z for C H N O [M+H]+ calc. 1275.7626, found 1275.7592; elem.
83 99 6 6
anal. C H N O (1275.70): calc. C 78.14 H 7.74 N 6.59, found C 75.49 H 9.27 N
83 98 6 6
5.69; optical rotation [α] 20 = +87.2° (c 1.00, CHCl ).
D 3
General remarks for the anti,anti,syn-isomers:
Due to isochronic effects caused by pseudo-symmetries within the anti,anti,syn-
isomers, the number of signals in the corresponding 13C NMR spectra does not
necessarily correlate with the number of C-atoms in the molecules.
Deviations in the elemental analysis are probably caused by solvent molecules within
the cavities of the molecules. The measurement of the optical rotation was therefore
carried out to determine the orientation thereof.

S10