further oligomerized in rapid cycles and under mild condi-
tions.9
Scheme 2. Reduction of AzidoPNA10 a
The preparation of the four required monomers is shown
in Scheme 1. The benzyl N-(2-azidoethyl)glycinate 2 is
Scheme 1. Synthesis of AzidoPNA Monomers 510 a
a Reagents and conditions: (a) 5-C (1.0 equiv), BnNH2 (1.0
equiv), EDCl (1.0 equiv), DMF 23 °C, 30 min, 96%. (b) R3P, THF/
H2O (9:1).
We then turned our attention to the azide reduction/PNA
coupling cycle. The Staudinger14 reduction was deemed most
attractive due to its mildness; however, long reaction times
were considered to be impractical for oligomerization
purposes. To study the kinetics of aryl and alkylphosphine
addition to the azidoPNA, we converted monomer 5-C to
the corresponding benzyl amide 6 using an EDCI-mediated
coupling (Scheme 2). While the addition of triphenylphos-
phine to azidoPNA 6 did not go to completion at room
temperature after 5 h, the addition of trimethyl and tributyl
phosphine was complete within 5 min. Nevertheless, the
hydrolysis of the iminophosphorane 7 to the corresponding
amine 8 was relatively slow in both cases. Inspired by the
direct elaboration of these azaylide intermediates into amides
with carboxylic acid15 or activated esters such as succinyl
ester16 or pentofluorophenyl ester,17 we asked ourselves if
iminophosphorane 7 would react cleanly with N-hydroxy-
benzotriazole ester generated in situ. To this end, we loaded
monomer 5-T onto Rink resin (Scheme 3) to obtain polymer-
bound azido monomer 9, which was treated with a 1 M THF
a Reagents and conditions: (a) 1 (1.0 equiv), NaN3 (1.1 equiv),
DMF, 60 °C, 3 h; benzyl 2-bromoacetate (0.8 equiv), Et3N (2.0
equiv), 0 °C, 2 h, 64%. (b) 3-T (1.0 equiv), 2 (1.0 equiv), EDCl
(1.2 equiv), 4-DMAP (0.1 equiv), DMF, 23 °C, 2 h, 94%; 3-C
(1.0 equiv), NMM (2.2 equiv), Piv-Cl (1.2 equiv), 2 (1.0 equiv),
23 °C, 90 min, 50%; 3-A (1.0 equiv), NMM (2.2 equiv), Piv-Cl
(1.2 equiv), 2 (1.0 equiv), 23 °C, 90 min, 80%; 3-G (1.0 equiv),
TOTU (1.1 equiv), Et3N (1.7 equiv), 2 (1.0 equiv), 23 °C, 2h, 49%.
(c) NaOH (4.0 equiv), dioxane/H2O, 23 °C, 15 min, 77% for 4-T,
95% for 4-C, 76% for 4-A, 80% for 4-G.
prepared from 2-aminoethylbromide hydrobromide in one
pot by a displacement of the bromide with NaN3 in DMF
followed by the addition of benzyl 2-bromoacetate and Et3N
to obtain the desired amine in 64% yield. As a choice of
protecting group for the exocyclic nitrogen of the nucleo-
bases, we found N-benzhydryloxycarbonyl (Bhoc)11 to be
ideal in terms of deactivating the nucleobase toward elec-
trophiles and ease of deprotection.12 Nevertheless, more
resistant groups such as Cbz should also prove to be
compatible with this strategy. The suitably protected nucleo-
bases 3 were prepared according to minor modifications of
known procedures13 and coupled to amine 2 (Scheme 1).
While acid 3-T was coupled to amine 2 in excellent yield
under standard carbodiimide coupling conditions (EDCI,
4-DMAP), the other acids gave poor results under these
conditions. Acid 3-C and 3-A could be effectively coupled
to amine 2 via formation of the pivaloyl mixed anhydride
(50 and 80% yields, respectively), whereas TOTU15 coupling
was found to be most effective for 3-G. The hydrolyses of
the benzyl esters 4 were carried out with NaOH in H2O/
dioxane and proceeded smoothly to afford the four PNA
monomers 5 as white solids in good to excellent yields.
Scheme 3. Coupling with Iminophosphorane10 a
a Reagents and conditions: (a) 5-T (3.0 equiv), HOBt (3.0 equiv),
DIC (3.0 equiv), DMF 23 °C, 3 h. (b) R3P (1.0 M), THF, 23 °C,
5 min. (c) 5-T (3.0 equiv), HOBt (2.5 equiv), DIC (2.5 equiv),
DMF, 23 °C, 60 min. (d) DMF, 23 °C, 60 min.
(7) Will, D. W.; Breipohl, G.; Langner, D.; Knolle, J.; Uhlmann, E.
Tetrahedron 1995, 51, 12069.
(8) Planas, M.; Bardaji, E.; Jensen, K. J.; Barany, G. J. Org. Chem. 1999,
64, 7281.
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Org. Lett., Vol. 5, No. 23, 2003