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Scheme 2. Reagents and conditions: (a) for 13!15 (i) CH3SO2Cl
2.2 equiv, pyridine, 0 ꢀC–rt, 10h; (ii) BzCl 5.0equiv, 0 ꢀC–rt, 3 h; for
14!16 CH3SO2Cl 5.0equiv, pyridine,
0 9 h; (b) LiN3
ꢀC–rt,
20.0 equiv, DMF, 80 ꢀC, 4 h; (c) 10% Pd/C, H2, EtOH, 4 h; (d)
MMTrCl 1.0equiv, TEA 2.0equiv, DCM, 2 h; (e) Fmoc-NCS
1.2 equiv, DCM, rt, 2 h.
Scheme 1. Reagents and conditions: (a) for 1!3 (i) CH3SO2Cl
1.0equiv, pyridine, 0 ꢀC–rt, 9 h; (ii) TMSCl 2.5 equiv, 0 ꢀC, 30min; (iii)
BzCl 5 equiv, 0 ꢀC–rt, 3 h; for 2!4 CH3SO2Cl 1.0equiv, pyridine,
0 ꢀC–rt, 9 h; (b) LiN3 10.0 equiv, DMF, 80 ꢀC, 4 h; (c) 10% Pd/C, H2,
EtOH, 4 h; (d) pyridine, MMTrCl 1.0equiv; (e) succinic anhydride
0.95 equiv, DMAP, pyridine, 12 h; (f) 4-nitrophenol, DCC, pyridine,
1,4-dioxane; (g) CPG, TEA, DMF, 12 h.
thymidine 8 was also synthesized via 6 as shown in
Scheme 1.7 MMTr protected 50-amino-30-OH mono-
mers, 7 and 8 were loaded on to the long chain alkyla-
mine Control Pore Glass (CPG) solid support as their
succinyl derivatives.
The 30,50-diamino protected adenyl and thymidyl
building blocks 19 and 20, required for the synthesis of
the body of the DNG oligomer, were accomplished
from 13 and 14 respectively. The 30-OH inverted 13
was conveniently prepared by a literature procedure8
starting from adenosine, whereas 14 was obtained by
trityl deprotection of commercially available 22.9 N,N-
Dibenzoyl-30,50-dimesyl derivative 15 was conveniently
synthesized from 13 in a one-pot reaction. This method is
simpler, the product easier to purify in almost quantita-
tive yield, as compared to the traditional two-step reac-
tion,6 benzoylation of 6-NH2 by transient protection and
then mesylation of 30- and 50-OH groups. Treatment of
15 with LiN3 at 80 ꢀC resulted in its N-benzoyl-30,50-dia-
zido derivative by removing one of the N-benzoyl
groups. Further reduction of 30,50-azido groups with
10% Pd/C gave 30,50-diamino-20-deoxyadenosine 17.
Selective protection of 50- and 30-amino groups of 17 with
acid-labile MMTr and base-cleavable Fmoc groups gave
19. Thymidine monomer 20 was also synthesized in a
similar way from 14 via 1810 as shown in Scheme 2.
Scheme 3. Reagents and conditions: (a) for 21!23 (i) CH3SO2Cl 1.1
equiv, pyridine, 0 ꢀC–rt, 10h, (ii) BzCl 5.0equiv, 0 ꢀC–rt, 3 h; for
22!24 CH3SO2Cl 5.0equiv, pyridine, 0 ꢀC–rt, 9 h; (b) LiN3 10.0 equiv,
DMF, 80 ꢀC, 4 h; (c) 10% Pd/C, H2, EtOH, 4 h; (d) Fmoc-NCS
1.2 equiv, DCM, rt, 2 h.
15. The 30-NH2 of 25 was then protected with Fmoc-
NCS11 to afford the desired capping building block 27.
The thymidine monomer 28 was also synthesized in a
similar way as shown in Scheme 3.
The monomers 7 and 8 were loaded on to the CPG as
their succinyl derivatives by a standard procedure12
(Scheme 1). After loading, the unreacted sites were cap-
ped with acetic anhydride/TEA, and then 50-MMTr was
deprotected with 3% DCA in DCM solution. The
loading yield, 36 mmol/g, was determined spectro-
photometricaly from the amount of MMTr cation
released. A typical solid-phase synthesis is outlined in
Scheme 4. Both DNGs, 29 and 30, which are com-
plementary to each other, were synthesized on a 5 mmol
scale.
The capping building blocks 27 and 28 were synthesized
from 21 and 22, respectively, as shown in Scheme 3. The
50-OH of 13 was protected with MMTr to give 21,
which was then converted into 25 via 23 as explained for
The coupling reaction4 of MMTr deprotected 11 or 12
with 19 or 20 (Scheme 4), for the formation of guanidi-
nium linkage, was accomplished in the presence of