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Arginine-PNAs
The synthesis of the PNAs required the preparation of three different modified units: a 2D-
Arg submonomer, a 2D,5L-Arg submonomer, and a 5L monomer. The 2D,5L-Arg
submonomer and the 2D-Arg submonomer were prepared, as reported in Scheme 3-1, starting
from the commercial D- and L-Boc-Arginine(Tos)-OH. Boc-L-Arg(Tos)-OH was
transformed into the corresponding Weinreb amide and then reduced to the aldehyde. Boc-D-
Arg(Tos)-OH was transformed in the methyl ester and Boc deprotected. The PNA backbone
was then synthesized by reductive amination of D-Arg(Tos)-OMe with the Boc-L-Arg(Tos)
aldehyde (for 2D,5L subomonomer) or Boc aminoacethaldehyde (in the case of 2D
submonomer). The methyl ester was hydrolyzed and the secondary amine was protected by
the introduction of a Fmoc group (Scheme 3-1).
i
ii
iii
+
iv
v
vi
Scheme 3-1: i) 0.97 eq. N-methyl-N-methoxyamine.HCl, HBTU, DIPEA, DMF η: 80%; ii) 4.6 eq.
LiAlH4 (1M in THF), THF, η: 94%; iii) SOCl 2 1M in CH 3 OH, η: 98% iv) 1 eq. D-Arg(Tos)OMe, 1
eq. NaBH 3 CN, 1.1 eq. CH 3 COOH, CH 3 OH, η: 51% (2D,5L), 48% (2D); v) 10eq. NaOH THF: H 2 O
= 1:1, η: 87% (2D,5L), 75% (2D) vi) 2eq. BSA, 1.5 eq. DIPEA, 2 eq. FmocCl, CH 2 Cl 2 η: 30%
(2D,5L), 38% (2D). R= H for 2D submonomer; R=CH 2 CH 2 CH 2 NHC(NH-Tos)NH for 2D,5L
submonomer
The Arginine modified monomer was linked to a Cytosine, obtaining a 5L-Arg-Cytosine(Z)
monomer. The molecule was prepared, as reported in scheme 3-2. The PNA backbone was
then synthesized by reductive amination of Gly-OMe (hydrochloride) with the Boc-L-
Arg(Tos) aldehyde. The methyl ester was coupled with the carboxymethyl-(Z)-cytosine by
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