A latent aryl hydrazine 'safety-catch' linker compatible with N-alkylation

Article abstract of DOI:10.1016/S0040-4039(00)01108-4

The preparation and use of a latent aryl hydrazine 'safety-catch' linker for solid-phase chemistry, which is compatible with N-alkylation, is reported. Its use is exemplified by the preparation of mono-ketopiperazines, whereby release from resin is effect

Full text of DOI:10.1016/S0040-4039(00)01108-4

Tetrahedron Letters 41 (2000) 6649±6653
A latent aryl hydrazine `safety-catch' linker compatible with
N-alkylation
Frederic Berst,a Andrew B. Holmes,a Mark Ladlowb,* and Peter John Murrayb,y
aDepartment of Chemistry, University Chemical Laboratories, Lens®eld Road, Cambridge CB2 1EW, UK
bGlaxo Wellcome Cambridge Chemistry Laboratory, University Chemical Laboratories, Lens®eld Road,
Cambridge CB2 1EW, UK
Received 20 April 2000; accepted 29 June 2000
Abstract
The preparation and use of a latent aryl hydrazine `safety-catch' linker for solid-phase chemistry, which
is compatible with N-alkylation, is reported. Its use is exempli®ed by the preparation of mono-ketopiperazines,
whereby release from resin is e€ected via an intramolecular cyclitive cleavage strategy. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: solid-phase synthesis; alkylation; hydrazines; cyclisation.
As part of a program to prepare libraries of small heterocycles derived from amino acids via an
intramolecular cyclitive cleavage1 process, we required a `safety-catch'2 linker that was compatible
with both Mitsunobu N-alkylation3 and stable towards nucleophiles, but which was amenable to
activation under mild conditions towards nucleophilic cleavage. Conventional acyl-sulphonamides
would be unsuitable for this purpose, since their activation to nucleophilic attack is e€ected by
N-alkylation.4 In addition, the recently reported aryl hydrazine `safety-catch' linker5 was found to
be incompatible with Mitsunobu N-alkylation conditions in our hands, giving rise to multiple
products probably derived from alkylation of the linker itself.
However, it was anticipated that this diculty could be resolved by blocking the reactive
hydrazine functionality with a protecting group that could be easily removed prior to oxidative
cleavage from the resin (Fig. 1). Herein we report the preparation of a `latent' aryl hydrazine
`safety-catch' linker which utilises this strategy. Its utility6 was demonstrated by the preparation
of mono-ketopiperazines (MKPs)7 derived via the cyclitive cleavage of resin-bound dipeptoid
precursors which were assembled in situ using Mitsunobu N-alkylation chemistry. Notably, using
* Corresponding author. E-mail: ml9133@glaxowellcome.co.uk
y
Present address: OSI Pharmaceuticals, 10 Holt Court South, Aston Science Park, Birmingham B7 4EJ, UK.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01108-4

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Figure 1. Principle of the latent arylhydrazine `safety-catch' linker
this strategy it was possible to e€ect reductive amination of the dipeptoid N-terminus without
premature cyclitive cleavage occurring prior to the penultimate oxidative cleavage step. This
provides a synthetic route to MKPs bearing four points of diversity on a six-atom sca€old.
We chose to evaluate 2,4-dimethoxybenzyl8 (DMB) as the blocking group for the aryl hydrazine,
since this N-substituent is removable under mildly acidic conditions. Thus, N-(2,4-dimethoxy-
benzyl)-hydrazinobenzoic acid was prepared from 4-aminobenzoic acid by reductive amination
with 2,4-dimethoxybenzaldehyde, nitrosation (NaNO2, H2SO4) and subsequent zinc-mediated
reduction (Scheme 1). The linker was conveniently isolated as the Dde derivative 4.
To more easily determine its properties, the N-(2,4-dimethoxybenzyl)-arylhydrazine (DMBAH)
linker 4 was attached to ArgoGelTM amine resin preloaded with the o-nitrobenzenesulphonamide
linker9 and a diamine spacer to generate the dual linker system 5.10 Selective cleavage of the
sulphonamide (DBU, mercaptoethanol) allowed reactions at the DMBAH linker to be
conveniently studied by HPLC±MS (10±100 beads) (Scheme 2) by analysis of the products 5a±8a,
which contain an amine to enhance ionisation (ES+) and an isotopic label to aid the interpretation
of their mass spectra.
Scheme 1. Reagents and conditions: (a) 2,4-dimethoxybenzaldehyde, pTsOH, PhMe, re¯ux, 18 h; (b) NaBH(OAc)3,
AcOH, CH2Cl2, rt, 72 h; (c) NaNO2, H2SO4, EtOH, rt, 18 h; (d) Zn, H2O, AcOH, 100ꢀC, 6 h; (e) DdeOH, EtOH,
re¯ux, 0.5 h
Using this technology, optimal conditions for the removal of the Dde group from the DMBAH
linker construct 5, as well as the loading of the resin 6 with substrate and the removal of the
DMB blocking group on the N-acylated resin 7 to give 8, were readily determined. In particular,
the DMB blocking group was found to be completely removed from the acylhydrazine 7 upon
exposure to 5% TFA/CH2Cl2 at 20ꢀC for 15 min. Subsequently, treatment of 8 with n-propyl-
amine/Cu(OAc)2 e€ected complete cleavage of the deprotected DMBAH linker to a€ord amide 9

6651
.
Scheme 2. Reagents and conditions: (a) 1:5 H2NNH2 xH2O:DMF; (b) 2-naphthylacetic acid, DIC, CH2Cl2, DMF; (c)
5%TFA/CH2Cl2; (d) Cu(OAc)2, n-propylamine; (e) mercaptoethanol, DBU, MeCN
(analytical cleavage of the resulting resin showed no trace of residual 8a). Crucially, these
conditions did not a€ect the DMB-blocked resin 7, thereby demonstrating the latent `safety-catch'
principle.
To exemplify the use of the DMBAH linker 4 in solid-phase synthesis, four representative
examples of MKPs were prepared. Thus, the linker 4 was attached to ArgoGelTM amine resin,
deprotected and loaded with N-Fmoc-phenylalanine to a€ord the resin 11. The Fmoc group was
removed and the resulting amine was converted into the intermediate o-nitrobenzenesulphonamide,
which was then N-alkylated3b with N-Dde-phenylalaninol under Mitsunobu conditions in the pre-
sence of di-tert-butylazodicarboxylate to a€ord the resin-bound adduct 12 (Scheme 3 and Table 1).
At this stage, several di€erent synthetic protocols could be applied in order to provide MKPs
displaying various functionalities. For example, removal of the Dde protecting group with 20%
hydrazine hydrate/DMF a€orded an intermediate amine, which was treated with 5% TFA/
CH2Cl2 (RT, 10 min) and then with Cu(OAc)2/pyridine in MeCN to give the MKP 13 in excellent
overall yield and purity. Alternatively, the adduct 12 could ®rst be subjected to a reductive
amination with 4-methylbenzaldehyde. Deprotection and oxidation then e€ected cyclitive
cleavage to a€ord the MKP 14. In another variation the arylsulphonamide could ®rst be removed
from 12 (PhSNa, DMF) to give an intermediate secondary amine, which was then either
subjected to cyclitive cleavage to a€ord the amine 15, or derivatised further prior to cleavage.
This latter process was exempli®ed by the preparation of the carboxamide 16 using 2-naphthoyl
chloride as the acylating agent followed by deprotection/oxidation/cyclitive cleavage to a€ord the
MKP 17.
In conclusion, we have prepared and demonstrated the compatibility and utility of the latent
arylhydrazine `safety-catch' linker (DMBAH) 4 with sulphonylation and Mitsunobu chemistry.
Conditions suitable for its deprotection/cleavage have been de®ned and its use has been
exempli®ed by the preparation of MKPs. Studies to exploit this novel linker in the preparation of
other heterocycles of varying ring size and in identifying alternative hydrazine protecting groups
will be reported in due course.

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.
Scheme 3. Reagents and conditions: (a) 1:5 H2NNH2 xH2O, DMF; (b) Fmoc-Phe-OH, DIC, CH2Cl2, DMF; (c) 20%
piperidine, CH2Cl2, DMF; (d) o-nitrobenzenesulphonyl chloride, DIPEA, CH2Cl2; (e) Ph3P, TBAD, N-Dde-phenyla-
laninol, CH2Cl2; (f) 5% TFA/CH2Cl2; (g) Cu(OAc)2, pyridine, MeCN; (h) PhSNa, DMF; (i) 2-naphthoyl chloride,
DIPEA; CH2Cl2; (j) (p-Me)PhCHO, TMOF, CH2Cl2; (k) Me4NBH4, CH2Cl2
Table 1
Overall yield and purity of MKPs
Acknowledgements
We are grateful to Dr Robin Carr, Dr Albert Jaxa-Chamiec and Mr Peter Seale for their
helpful advice, and to Dr Richard Upton for help in obtaining NMR spectra.

6653
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12. Isolated yield after puri®cation by autopreparative HPLC.