Syntheses of macrocyclic bisbibenzyls on solid support

Article abstract of DOI:10.1016/j.tet.2005.09.048

We describe a route for the polymer supported total synthesis of the cyclic bisbibenzyls of the isoplagiochin type found in liverworts. TentaGel resins were used as solid support for a sequence involving Suzuki, Wittig and hydrogenation protocols. The pol

Full text of DOI:10.1016/j.tet.2005.09.048

Tetrahedron 61 (2005) 11692–11696
Syntheses of macrocyclic bisbibenzyls on solid support
*
Andreas Speicher, Timo Backes and Stefan Grosse
¨
FR 8.1 Chemie - Organische Chemie, Saarland University, D-66041 Saarbrucken, Germany
Received 25 May 2005; revised 15 September 2005; accepted 15 September 2005
Available online 3 October 2005
Abstract—We describe a route for the polymer supported total synthesis of the cyclic bisbibenzyls of the isoplagiochin type found in
liverworts. TentaGelw resins were used as solid support for a sequence involving Suzuki, Wittig and hydrogenation protocols. The polymer
linked intermediates could be characterized by HR-MAS NMR. This route is to be extended to the synthesis of small libraries of differently
halogenated derivatives.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
liverworts Bazzania trilobata,4 Lepidozia incurvata,5 Mas-
tigophora diclados, H. sakuraii,6 Plagiochila peculiaris7
and P. deflexa.8 Phenolic compounds of the bibenzyl and
bisbenzyl type exhibit remarkable antitumoural, anti-
bacterial and antimycotic activities.9,10 The isoplagiochin
framework proved to be of substantial structural interest
because of the chirality of the entire molecule.11
The cyclic bisbibenzyls isoplagiochin C (1) and D (2) were
isolated from the liverworts Plagiochila fruticosa,1 Plagio-
chila deflexa2 and Herbertus sakuraii (Fig. 1).3 Altogether,
21 chlorinated derivatives of the type 3 were detected in the
Conventional total syntheses (‘in solution’) for 1 and 212
and for three examples of 313 were described applying an
efficient and flexible unit construction system and making
extensive use of Suzuki and Wittig protocols.
Syntheses of 1 and 2 on solid support14 especially using
TentaGelw resins15 should give valuable contributions to
Suzuki and Wittig reactions on this carrier16,17 as well as
to the characterization of polymer bound intermediates by
HR-MAS NMR.18
TentaGel resins are poly(ethylene glycol) polystyrene graft
copolymers consisting of w30% polystyrene matrix (cross-
linked with w1% divinylbenzene) and of w70% poly-
(ethylene glycol). They are available in different types of
functional anchor groups (Fig. 2) chargeable up to 0.40–
0.60 mmol/g and are well capable of swelling in
Figure 1. Structures of isoplagiochins 1, 2 and halogenated derivatives 3.
Keywords: Macrocycles; Bisbibenzyls; Solid phase synthesis; TentaGel;
HR-MAS NMR.
*
Corresponding author. Tel.: C49 681 302 2749; fax: C49 681 302 2029;
e-mail: anspeich@mx.uni-saarland.de
Figure 2. Chemical constitution of TentaGel resins.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.048

A. Speicher et al. / Tetrahedron 61 (2005) 11692–11696
11693
Wittig and hydrogenation protocols should lead to an
acyclic polymer bound A–B–C–D precursor, which has to
be ring-closed after cleavage from the solid support.
Thus, starting from TentaGel–Br (4) with a coverage
density of 0.41 mmol/g resin a glycerol linker was
introduced according to the procedure of Leznoff (formerly
applied for Merrifield type resins)20 by Williamson-
coupling with the 1,3-dioxolane protected glycerol 5 (to 6)
and subsequent acidic hydrolysis to the polymer-bound 1,2-
diol 7. Coupling with the aldehyde 8 by acetal formation
yielded the TentaGel linked starting subunit 9 (fragment A).
Suzuki reaction of the polymer-bound bromoarene 9 with
the boronic acid 1012 yielded the biaryl dialdehyde 11 (A–B
fragment) on solid support, which was then reacted with the
phosphonium salt 1221 (C fragment) to the stilbene 13
according to a Wittig protocol. After coupling with the
boronic acid 14 (D fragment), the double bond in 15 (E/Z-
mixture of isomers) was hydrogenated in presence of a
homogeneous Wilkinson catalyst22 resulting in the Tenta-
Gel linked acyclic A–B–C–D precursor 16 (Scheme 2).
On acidic hydrolysis of 16 the hydroxyaldehyde 17 was
liberated from the solid support (Scheme 3). According to
the spectroscopical data the acyclic A–B–C–D fragment 17
could be clearly identified as the known precursor for the
ring-closing to 18 and completion of the syntheses of
isoplagiochins C/D 1 and 2.12
Scheme 1. Fragments and strategy for the synthesis of isoplagiochins on
solid support.
dichloromethane, chloroform, dioxane, DMF, THF, water,
methanol and pyridine (bad, however, in ethanol and
diethylether).15,19
The TentaGel coupled intermediates could be unambigu-
ously characterized by HR-MAS NMR spectroscopy as can
be demonstrated for the final polymer bound compound 16
(see Fig. 3, for all intermediates see Supporting
information).
2. Results and discussion
Our strategy of synthesis (Scheme 1) was to start with a
polymer bound aldehyde fragment A. Subsequently, Suzuki,
Scheme 2. Formation of the TentaGel linked acyclic A–B–C–D precursor 16.

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A. Speicher et al. / Tetrahedron 61 (2005) 11692–11696
The D-fragment 14 was prepared from 4-bromo-3-methox-
ybenzylalcohol 19 by regioselective bromination, (to 20),
formation of the THP ether 21 and transformation to the
corresponding boronic acid (see Scheme 4).
Scheme 4. Preparation of the D-fragment 14.
3. Conclusion
The multi-step synthesis of the target molecule could be
realized with a final charging of about 0.10 mmol/g resin
and a 25% overall-yield for 17 after cleavage from the solid
support. The intermediates could be directly characterized
by HR-MAS NMR spectroscopy. The procedure can be
extended to the synthesis of small libraries of differently
halogenated derivatives 3.
4. Experimental
4.1. General
Scheme 3. Cleavage from the solid support and completion of the synthesis
for 1 and 2. Reagents and conditions:12,13 (a) (i) Ph3PHCBrK, CH3CN,
reflux 24 h, 95%;13 (ii) NaOCH3, CH2Cl2, rt, 24 h, 82%; (b) BBr3, CH2Cl2,
K70 8C/rt, 48 h, 86%; (c) (i) H2 3 bar, 5% Pd/C, EtOAc, 88%; (ii) BBr3,
CH2Cl2, K70 8C/rt, 48 h, 82%.
TentaGelw S–Br (0.41 mmol/g) was purchased from Rapp
Polymere, Tu¨bingen, Germany. All reactions with shaking
at room temperature (rt) were performed on an IKAw
Vibrax VXR basic at 500 rpm. Reactions requiring heating
were performed in a Labnetw VorTemp 1550 at 600 rpm.
NMR spectra in solution (CDCl3, DMSO-d6) were obtained
with a Bruker DRX 500. Chemical shifts (d) are given in
ppm relative to TMS. HR-MAS NMR spectra were obtained
with a Bruker DRX 500 using a 4 mm HR-MAS probe.
1
Rotational frequency: H: 8 kHz, 13C: 8 kHz. Pulse repe-
tition time: 1H: 4 s, 13C: 2 s. Solvents were commonly dried
and purified by conventional methods prior to use. All air-
or moisture-sensitive reactions were carried out under an
argon atmosphere.
4.2. Preparation of the boronic acid 14
4.2.1. 4-Bromo-3-methoxybenzylalcohol (20). To a stirred
solution of the 3-methoxybenzylalcohol (19) (10.0 g,
72.4 mmol, 8.98 mL) in CH3CN/H2O 1:1 (500 mL) were
added NaBrO3 (19.1 g, 127 mmol) and NaHSO3 (13.2 g,
127 mmol). The reaction was stirred for 1.5 h at rt and
continuously monitored by TLC. The reaction mixture was
quenched with aqueous Na2S2O3 and extracted with Et2O
(3!200 mL). The combined organic layers were washed
with aqueous Na2CO3, H2O, dried (MgSO4) and concen-
trated in vacuo. The residue was chromatographed on silica
gel/CHCl3 to give a colourless oil; 13.9 g (88%).
Figure 3. HR-MAS 1H NMR spectrum of 16.

A. Speicher et al. / Tetrahedron 61 (2005) 11692–11696
11695
1H NMR (CDCl3) d (ppm) 7.40 (d, JZ8.8 Hz, 1H, Ar-H),
7.05 (d, JZ3.1 Hz, 1H, Ar-H), 6.70 (dd, J1Z8.8 Hz, J2Z
3.1 Hz, 1H, Ar-H), 4.69 (s, 2H, Ar-CH2O), 3.80 (s, 3H,
OCH3), 2.14 (br s, 1H, OH).
the mixture was stirred and heated to 60 8C until the sodium
had completely dissolved. The solution was cooled to rt and
TentaGel–S–Br resin 4 (2.50 g) was added. The mixture was
shaken at rt for 3 days and for additional 4 h at 80 8C. The
resin was collected by filtration and washed with 1,4-
dioxane (3!10 mL), H2O (6!10 mL), EtOH/H2O (1:1;
3!10 mL), EtOH (3!10 mL) and dry Et2O (3!10 mL) to
give the pale yellow polymer-bound dioxolane 6 (2.73 g).
13C NMR (CDCl3) d (ppm) 159.25, 140.74, 133.14, 144.77,
144.22, 112.50, 64.99, 55.52.
4.2.2. THP ether 21 of 4-bromo-3-methoxybenzyl-
alcohol. The benzyl alcohol 20 (13.9 g, 63.9 mmol) was
dissolved in anhydrous CH2Cl2 (250 mL). 3,4-Dihydro-2H-
pyrane (13.4 g, 160 mmol, 14.6 mL) and toluene-4-sulfonic
acid monohydrate (243 mg, 1.28 mmol) were added and the
mixture was stirred at rt for 16 h. The solvent was
evaporated and the residue was chromatographed on silica
gel/CH2Cl2 to give a yellowish liquid; 14.2 g (74%).
4.3.2. Hydrolysis of the polymer-bound dioxolane 6. The
polymer-bound dioxolane 6 (2.30 g) was suspended in a
mixture of 1,4-dioxane/1 M HCl (1:1, 30 mL) and the slurry
was shaken for 48 h at rt. The resin was filtered off and
washed with H2O (6!10 mL), acetone (10 mL), EtOH (3!
10 mL) and dry Et2O (3!10 mL) to give the yellow
polymer-bound diol 7 (2.30 g).
1H NMR (CDCl3) d (ppm) 7.41 (d, JZ8.5 Hz, 1H, Ar-H),
7.09 (d, JZ3.2 Hz, 1H, Ar-H), 6.70 (dd, J1Z8.5 Hz, J2Z
3.2 Hz, 1H, Ar-H), 4.78 (t, JZ3.5 Hz, 1H, O–CH–O), 4.78,
4.54 (2d, JZ13.6 Hz, 2H, Ar-CH2O), 3.96–3.89 (m, 1H,
–CH2O), 3.80 (s, 3H, OCH3), 3.60–3.55 (m, 1H, CH2O),
1.95–1.50 (m, 6H, –(CH2)3–).
4.3.3. Acetalization of the aldehyde 8 with the polymer-
bound diol 7. The diol-modified TentaGel 7 (2.13 g) was
suspended in anhydrous 1,4-dioxane (30 mL). 3-Bromo-4-
methoxybenzaldehyde 8 (1.61 g, 7.52 mmol), toluene-4-
sulfonic acid monohydrate (16.6 mg, 0.09 mmol) and
anhydrous Na2SO4 (2.00 g) were added and the mixture
was shaken at rt for 48 h with exclusion of moisture and then
shaken for additional 4 h at 80 8C. The resin was filtered off
and washed with anhydrous pyridine (2!10 mL), pyridine/
H2O (1:1; 2!10 mL), H2O (10!10 mL), EtOH (3!
10 mL) and dry Et2O (3!10 mL) to give the pale yellow
polymer-bound bromoarene 9 (2.00 g).
13C NMR (CDCl3) d (ppm) 159.06, 138.91, 133.00, 114.65,
114.23, 112.81, 98.43, 68.46, 62.22, 55.46, 30.54, 25.45,
19.36.
4.2.3. Boronic acid 14. The aryl bromide 21 (10.0 g,
33.2 mmol) was dissolved in THF (200 mL). n-Butyllithium
(16.1 mL, 40.2 mmol, 2.5 M in n-hexane) was added at
K70 8C and the reaction mixture was stirred for 30 min at
K70 8C. After addition of trimethyl borate (10.4 g,
99.6 mmol, 11.1 mL) stirring was continued for 1 h while
the reaction mixture was allowed to warm up to rt. H2O
(150 mL) was added, the aqueous layer was extracted with
Et2O (3!50 mL) and the combined organic layers were
washed with satd aqueous NaCl, dried (MgSO4) and
evaporated. For purification, the product was dissolved in
Et2O, extracted with 2 M NaOH and neutralized to pH 6–7.
The product was extracted with Et2O, dried (MgSO4) and
the solvent was evaporated to give the crude boronic acid as
a colourless solid; 8.84 g (100%).
4.3.4. Suzuki-coupling of the boronic acid 10 with the
polymer-bound bromo arene 9. The TentaGel-bound
bromo arene 9 (1.80 g) was swelled in DMF (40 mL) for
10 min. To this slurry were added the boronic acid 10
(439 mg, 2.45 mmol), Pd(PPh3)4 (36.7 mg, 24.5 mmol) and
K2CO3 (169 mg, 1.22 mmol). The mixture was shaken for
48 h at 90 8C under an argon atmosphere. The resin was
filtered and washed alternately with DMF/H2O (4:1, 3!
10 mL), followed by MeOH (3!10 mL) and CH2Cl2 (3!
10 mL). The solid was dried in vacuo at rt to give a
yellowish brown polymer-bound biarylaldehyde 11
(1.78 g).
4.3.5. Wittig-reaction between the polymer-bound alde-
hyde 11 and the phosphonium salt 12. To a solution of the
phosphonium salt 12 (3.55 g, 6.55 mmol) in anhydrous
DMF (40 mL) was added NaOCH3 (1.06 g, 19.6 mmol)
under argon atmosphere. After shaking for 5 min, the
polymer-bound aldehyde (1.77 g) was added to the orange
solution. The mixture was shaken at rt for 48 h. Then the
resin was filtered and washed alternately with DMF (3!
10 mL), DMF/H2O (1:1, 3!10 mL), H2O (3!10 mL),
followed by MeOH (3!10 mL) and CH2Cl2 (3!10 mL).
The solid was dried in vacuo at rt to give a beige polymer-
bound stilbene 13 (1.77 g).
1H NMR (d6-DMSO) d (ppm) 7.49 (d, JZ8.2 Hz, 1H, Ar-H),
6.92 (d, JZ2.5 Hz, 1H, Ar-H), 6.79 (dd, J1Z8.2 Hz, J2Z
2.5 Hz, 1H, Ar-H), 4.80, 4.61 (2d, JZ12.6 Hz, 2H, Ar-CH2O)
4.65 (t, JZ3.5 Hz, 1H, O–CH–O), 3.83–3.77 (m, 1H,
–CH2O), 3.74 (s, 3H, OCH3), 3.48–3.43 (m, 1H, –CH2O),
1.80–1.40 (comb m, 6H, –(CH2)3–).
13C NMR (d6-DMSO) d (ppm) 160.00, 144.55, 135.49,
112.83, 111.10, 97.59, 68.51, 61.21, 54.81, 30.11, 25.03,
19.02.
4.3. Preparations on solid support
4.3.6. Suzuki coupling of the boronic acid 14 with the
polymer-bound bromide 13. The polymer-bound bromide
13 (1.18 g) was swelled in EtOH (20 mL). To the mixture
was added the boronic acid 14 (606 mg, 2.10 mmol),
Pd(PPh3)4 (24.4 mg, 21.1 mmol) and Cs2CO3 (339 mg,
1.05 mmol). The mixture was shaken for 48 h at 90 8C
under an argon atmosphere. Then the resin was filtered and
For the HR-MAS NMR spectra of all polymer-bound
intermediates see Supporting information.
4.3.1. Coupling of TentaGel–S–Br 4 with the hydroxy
dioxolane 5. Sodium (236 mg, 10.3 mmol) was added to
4-hyroxymethyl-2,2-dimethyl-1,3-dioxolane 5 (20 mL) and

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A. Speicher et al. / Tetrahedron 61 (2005) 11692–11696
washed alternately with EtOH (3!10 mL), DMF/H2O (1:1,
3!10 mL), H2O (3!10 mL), followed by MeOH (3!
10 mL) and CH2Cl2 (3!10 mL). The solid was dried in
vacuo at rt to give a brown polymer-bound stilbene 15(1.20 g).
References and notes
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4.3.7. Catalytic hydrogenation of the stilbene 15. A two-
necked round bottom flask containing the polymer-bound
stilbene 15 (713 mg) was evacuated a few times and
flushed with argon. After the last evacuation, a hydrogen-
atmosphere was adjusted by a balloon. Wilkinson-catalyst
Rh(PPh3)3Cl (43.5 mg, 47 mmol) and NaOAc (40 mg) were
dissolved in MeOH (20 mL) and added by a syringe. The
mixture was shaken at rt for 24 h. The resin was filtered and
washed alternately with MeOH (3!10 mL) and CH2Cl2
(3!10 mL). The solid was dried in vacuo at rt to give a
brown polymer-bound bibenzyl 16 (700 mg).
3. Hashimoto, T.; Irita, H.; Takaoka, S.; Tanaka, T.; Asakawa, Y.
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4.3.8. Hydrolytic cleavage from the solid support. The
polymer-bound bibenzyl 16 (633 mg) was swelled in dioxane/
3 M HCl (1:1, 20 mL) and shaken at rt for 48 h. The resin was
filtered and washed alternately with H2O (6!5 mL), acetone
(1!10 mL), EtOH (3!5 mL) and Et2O (3!10 mL). The
aqueous layer was extracted with Et2O (3!40 mL), the
combined organic layers were washed with H2O (6!40 mL)
and dried (MgSO4). The solvent was evaporated to give the
crude bibenzyl (81 mg). Purification by column chromato-
graphy (SiO2/CHCl3–EtOAc 3:1) yielded pure 17 as a
colourless oil (32 mg, 25% overall for eight steps).
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The NMR-spectroscopic data were identical with those
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1H NMR (CDCl3) d (ppm) 9.92 (s, 1H, –CHO), 7.86 (dd,
J1Z8.4 Hz, J2Z2.0 Hz, 1H, Ar-H), 7.68 (d, JZ2.2 Hz, 1H,
Ar-H), 7.08 (d, JZ8.4 Hz, 1H, Ar-H), 7.05 (d, JZ8.3 Hz,
1H, Ar-H), 7.02 (d, JZ7.6 Hz, 1H, Ar-H), 6.98 (d, not
resolved, 1H, Ar-H), 6.93–6.91 (not resolved, 2H, Ar-H),
6.83 (d, JZ2.7 Hz, 1H, Ar-H), 6.80 (d, JZ8.4 Hz, 1H, Ar-H),
6.80 (dd, not resolved, 1H, Ar-H), 6.74 (d, JZ2.2 Hz, 1H,
Ar-H), 4.67 (s, 2H, Ar-CH2O), 3.84 (s, 3H, –OCH3), 3.82
(s, 3H, –OCH3), 3.75 (s, 3H, –OCH3), 3.72 (s, 3H, –OCH3),
2.69 (br s, 4H, –CH2CH2–), 1.69 (br s, 1H, –OH).
¨
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13C NMR (CDCl3) d (ppm) 191.2, 162.3, 158.9, 157.1, 155.2,
141.8, 141.7, 134.1, 132.6, 131.9, 131.6, 131.3, 131.2, 130.6,
129.6, 129.1, 128.9, 126.2, 118.6, 114.4, 111.1, 110.9, 110.7,
109.1, 65.3, 56.0, 55.8, 55.5, 55.2, 36.3, 36.1.
Acknowledgements
We thank the government of the Saarland for financial
support (project enzymes-tools, targets, therapeutics).
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.09.
048. HR-MAS NMR spectra of all polymer-bound
intermediates.