Conformationally%20restricted%20chiral%20peptide%20nucleic%20acids%20derived%20from%20azetidines

1
Conformationally restricted chiral peptide
nucleic acids derived from azetidines
Lajos Kovács,a, Miklós Hornyák,a Nicola M.
Howarthb aNucleic Acids Laboratory, Department of
Medicinal Chemistry, University of Szeged, H-6720
Szeged, Dóm tér 8, Hungary and bDepartment of
Chemistry, Heriot-Watt University, Edinburgh,
Riccarton, EH14 4AS, United Kingdom. E-mail
kovacs_at_ovrisc.mdche.u-szeged.hu
Introduction
Aims
The recent success of peptide nucleic acids (PNA)
1, 2 is shadowed by their poor cellular uptake,
ability to form aggregates and limited water
solubility. The advent of conformationally rigid
PNA analogues derived from pyrrolidine rings 3,
4 prompted us to embark upon the synthesis of
new PNA analogues with azetidine moieties. This
structural unit should have similar
characteristics as the pyrrolidines and has the
added advantage of being cationic due to the
slightly basic azetidine ring which should
enhance cellular uptake.

• To synthesize azetidine nucleic acid (ANA)
  monomers (ANA-1, ANA-2) based on 1,3-dipolar
  cycloaddition reaction of the appropriate
  nitrones and alkenes followed by ring
  transformations.
• To reduce the formation of isomers by employing
  chiral auxiliaries (e.g. 3,5,6-tri-O-methyl-D-gluc
  ofuranose and 2,35,6-di-O-isopropylidene-a-D-mann
  ofuranose, respectively) and/or conduct the
  reactions intramolecularly.

The key steps of the synthesis should involve the
formation of isoxazoles and their ring
transformation into the corresponding azetidines
as delineated in the retrosynthetic schemes.
Results
The synthesis of ANA-1 monomer was undertaken
using the chiral auxiliary 3,5,6-tri-O-methyl-D-gl
ucofuranose 5 available from D-glucose in
simple steps. The acryloylation of this latter
substance yielded different proportions of mono-
and bis-acylated derivatives, depending on the
amount of acylating agent applied. The
transformation of the 1,2-bis-O-acryloylated
derivative into the desired 2-O-acryloyl compound
was attempted under a variety of conditions
(Bu3Sn)2O, toluene, D Bu3SnOMe, ClCH2CH2Cl, D
6, 7 (NH4)2CO3/DMF montmorillonite K10, wet
acetonitrile, D, 8 BF3 OEt2, wet
acetonitrile, 0 C 9 but exclusively the
1-O-acryloyl derivative was obtained indicating
an unwanted acyl migration of the acrylate group
from position 2 to 1. The glycosyl halide
2-O-acryloyl-3,5,6-tri-O-methyl-D-glucofuranosyl
bromide, easily available from 1,2-bis-O-acryloyl-
3,5,6-tri-O-methyl-D-glucofuranose, was
surprisingly stable and it did not afford the
2-O-acryloyl derivative with wet silver oxide.
Direct oxime formation with hydroxylamine
hydrochloride was not successful.
The rationale behind the synthesis of
2-O-acryloyl-3,5,6-tri-O-methyl-D-glucofuranose
was its transformation into the corresponding
oxime which, in turn, with nucleobase-substituted
acetaldehydes 10, 11 should give a nitrone, the
intramolecular 1,3-dipolar cycloaddition of which
would result in the formation of the desired
isoxazole. We are currently working on these
transformations. Meanwhile, two other nitrones
have been prepared en route to ANA-1 and ANA-2
monomers, respectively. Thus, 3,5,6-tri-O-methyl-D
-glucose oxime was allowed to react with
thymin-1-ylacetaldehyde 10, while
2,35,6-di-O-isopropylidene-a-D-mannose oxime
12 with Fmoc-aminoacetaldehyde 13,
respectively. The first nitrone, to be submitted
to selective acryloylation at 2-OH, presents an
alternative approach to the above detailed route
through 2-O-acryloyl-3,5,6-tri-O-methyl-D-glucofur
anose. The second nitrone is ready for
intermolecular 1,3-dipolar cycloaddition with,
e.g. N9-allyladenine 14, 15 to yield the
corresponding isoxazole.
References
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Acknowledgement
The financial support of The Wellcome Trust
(grant no. 063879/Z/01/Z) is gratefully
acknowledged.