Development of a novel oxidatively removable and recyclable linker for combinatorial solid phase synthesis

Article abstract of DOI:10.1039/a909236f

An appropriately derivatized phenanthridine is shown to behave as a novel, reusable linker which is based on a disubstituted amide anchorage and forms an acid group on oxidative cleavage, but tolerates exposure to acidic, basic and reductive reaction cond

Full text of DOI:10.1039/a909236f

Development of a novel oxidatively removable and recyclable linker for
combinatorial solid phase synthesis
Wen-Ren Li,* Nai-Mu Hsu, Hsueh-Hsuan Chou, Sung Tsai Lin and Yu-Sheng Lin
Department of Chemistry, National Central University, Chung-Li, Taiwan 32054, ROC.
E-mail: wenrenli@rs250.ncu.edu.tw
Received (in Cambridge, UK) 23rd November 1999, Accepted 28th January 2000
An appropriately derivatized phenanthridine is shown to
behave as a novel, reusable linker which is based on a
disubstituted amide anchorage and forms an acid group on
oxidative cleavage, but tolerates exposure to acidic, basic
and reductive reaction conditions.
amide 5 in 70% yield. Oxidative cleavage of the resulting amide
5 with cerium ammonium nitrate (CAN) and subsequent
hydrolysis of the acetate with LiOH afforded the amine-masked
phenanthridine handle 1 as a crystalline compound. Of
particular note is that the synthesis of all intermediates in
Scheme 1 can be carried out on a preparative scale to afford
ample quantities of the desired compound in roughly 40%
overall yield.
Recently, a considerable amount of attention has been focused
on the use of the combinatorial library approach for the
discovery of new molecules with desired properties.1 Up to
now, syntheses of a variety of classes of chemical libraries have
been constructed employing solid phase methods.2,3 Many
linkers have, therefore, been developed for anchoring and
selectively removing the desired target molecule from polymer
supports.4–8 As far as we are aware, none of the available linkers
used for carboxylic functions survive through a series of acidic,
basic and reductive reactions and are also stable to N-alkylation
conditions.9–11 This void led us to devise a new type of
recyclable phenanthridine linker for the synthesis of acids,
which possesses greater stability under the above reaction
processes and the capability to be removed by a mild oxidative
reagent. In addition, it can be recycled.
The synthesis of an appropriately functionalized phenan-
thridine 1 is detailed in Scheme 1. The synthesis was initiated
with protection of the acid group of 4-nitrophenylacetic acid as
its methyl ester using SOCl2 and MeOH. Reduction of the nitro
group of the methyl ester was rapidly accomplished by catalytic
transfer hydrogenation with NH4HCO2 as the hydrogen donor
over a Pd/C catalyst.12 Coupling of amine 3 with 2-iodobenzoic
acid was followed by reduction using NaBH4 and BF3·OEt2 to
form the secondary amine 4 in 73% yield for four steps from
4-nitrophenylacetic acid. Attempts to perform an internal biaryl
cyclization of the aryl substituted amide, before NaBH4
reduction, gave an undesired intermolecular coupling dimer.
Acylation of the amino and hydroxy group of compound 4 with
AcBr, followed by intramolecular Heck type cyclization13
employing Pd(OAc)2, PPh3 and Ag2CO3 in MeCN led to the
The suitability for reductive processing and alkylation of the
new linker and its applicability to peptide chemistry were
demonstrated by the synthesis a trimethylated derivative of
actarit,14 an immunomodulating agent, and a N-acylated
dipeptide on the Merrifield resin as shown in Schemes 2 and 3.
The phenanthridine derivatized solid support 8 (Scheme 2) can
readily be prepared by treating chloromethylpolystyrene with
the sodium salt of phenanthridine in dry DMF at room
temperature for 16 h. In this form the phenanthridine resin is
stable and can be stored for long periods without loss of activity.
Reduction of this functionalized resin furnished the resin-bound
secondary amine, which was first derivatized with 4-nitro-
phenylacetic acid and then subjected to enolate alkylation by
employing commonly used bases such as NaH or LDA.15
Reduction of the nitro group of resin 6 with SnCl2 in DMF
afforded, after acetylation and N-alkylation, the trimethylated
acid-bound resin. Treatment of the resulting resin with 2 equiv.
of CAN in MeCN and water for 10 min resulted in complete
cleavage of the desired acid from the solid support. After
removal of the MeCN, the crude product was dissolved in
EtOAc, washed successively with water and aqueous HCl and
purified to give the trimethylated actarit derivative 7 in 57%
overall yield for eight steps. The regenerated phenanthridine
resin 8 could be reused for another synthetic sequence with only
a slight loss in activity. The yields after one and two recycles are
90 and 84%, respectively. The resin-bound amides in Scheme 2
are stable under either basic or acidic hydrolytic conditions.
Scheme 1 Reagents and conditions: (a) SOCl2, MeOH, 97%; (b) 10% Pd/C,
HCO2NH4, MeOH, 97%; (c) 2-iodobenzoic acid, DIC, MeCN, 84%; (d)
NaBH4/BF3·OEt2, THF, 93%; (e) AcBr, Et3N, MeCN, 87%; (f) PPh3,
Pd(OAc)2, Ag2CO3, MeCN, 70%; (g) CAN, MeCN, H2O, 95%; (h) LiOH,
THF, H2O, 95%.†
Scheme 2 Reagents and conditions: (a) NaH, DMF, linker 1; (b) NaBH4,
BH3·THF, EtOH, 71%; (c) 4-nitrophenylacetic acid, DIC, CH2Cl2; (d) NaH,
MeI, DMF or LDA, HMPA, THF, MeI; (e) SnCl2, DMF, 88%; (f) Ac2O,
Et3N, CH2Cl2; (g) NaH, MeI, DMF; (h) CAN, THF, H2O, 92%.†
DOI: 10.1039/a909236f
Chem. Commun., 2000, 401–402
This journal is © The Royal Society of Chemistry 2000
401

recycled through the reaction sequence. Therefore, the phenan-
thridine linker should find broad application in the field of solid
phase combinatorial synthesis where orthogonal methods of
release are required. Currently, we are investigating non-
aqueous oxidative cleavage conditions which will afford the
corresponding esters and are exploring the length and attach-
ment position of the alkoxyacyl spacer that is needed to link the
appropriate phenanthridine handle to aminated resins such as
MBHA or BHA resin through an amide bond.
The authors are grateful to the National Science Council,
ROC, for the financial support (NSC 86-2113-M-008-001) of
this work.
Notes and references
† Abbreviations used: DIC
= 1.3-diisopropylcarbodiimide, HBTU =
2-(1H-benzotriazol-l-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate,
MBHA = 4-methylbenzhydrylamine.
Scheme 3 Reagents and conditions: (a) NaBH4, BH3·THF, EtOH; (b) DIC,
Fmoc- -Ala-OH, CH2Cl2; (c) 20% piperidine, DMF, 89%; (d) HBTU,
Pri2NEt, Boc- -Phe-OH, DMF; (e) TFA, CH2Cl2, 94%; (f) BzCl, Pri2NEt,
L
L
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CH2Cl2; (g) CAN, THF, H2O, 91%.
These amides were not hydrolyzed upon treatment with 1 M
HCl or NaOH in THF–H2O solution over 24 h. The further
utility of this linker has been shown by synthesizing an N-
acylated dipeptide 11 (Scheme 3). Similar results were achieved
using a similar strategy to that employed for the previous
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L
thridine linker the resin was submitted to the peptide synthetic
sequence to provide the desired dipeptide 11 in a nonoptimized
yield of 76%, as shown in Scheme 3. At each step, the coupling
efficiency was about 86–95% yield as monitored by photo-
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not cause either any premature cleavage or damage of the
linker.
In conclusion, we have developed a new linker for solid phase
organic synthesis of carboxylic acids and have successfully
demonstrated its application. The advantages of this linker are:
(i) it is orthogonal to the Fmoc/Boc and Boc/Bn protecting
group strategies; (ii) it can be prepared in both large quantity
and high purity; (iii) its attachment to the solid support is
straightforward; (iv) it is anchored to the C-terminal residue by
a disubstituted amide and not an ester bond, ensuring stability to
N-alkylation and avoidance of diketopiperazine formation at the
dipeptide stage; (v) the linker is rapidly cleaved under mild
oxidative conditions and the reaction is very clean; (vi) the
phenanthridine resin is sufficiently robust to be recovered and
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Communication a909236f
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Chem. Commun., 2000, 401–402