Synthetic studies towards a novel, chemical stable, abasic site analogue of DNA

Article abstract of DOI:10.1081/NCN-120022836

We synthesized the phosphinate 7 via photoaddition of methanol to the α,β unsaturated deoxyribono lactone as the key step, followed by an Arbusov reaction for the introduction of phosphorous. Precursor 7 serves for the synthesis and incorporation into DNA

Full text of DOI:10.1081/NCN-120022836

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Synthetic Studies Towards a Novel, Chemical Stable,
Abasic Site Analogue of DNA
Caroline Hirtz a & Christian J. Leumann a b
a Department of Chemistry and Biochemistry , University of Bern , Bern, Switzerland
b Department of Chemistry and Biochemistry , University of Bern , Freiestrasse 3, 3012,
Bern, Switzerland
Published online: 31 Aug 2006.
To cite this article: Caroline Hirtz & Christian J. Leumann (2003) Synthetic Studies Towards a Novel, Chemical Stable, Abasic
Site Analogue of DNA, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 1203-1206, DOI: 10.1081/NCN-120022836
To link to this article: http://dx.doi.org/10.1081/NCN-120022836
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1203–1206, 2003
Synthetic Studies Towards a Novel, Chemical Stable,
Abasic Site Analogue of DNA
*
Caroline Hirtz and Christian J. Leumann
Department of Chemistry and Biochemistry, University of Bern,
Bern, Switzerland
ABSTRACT
We synthesized the phosphinate 7 via photoaddition of methanol to the a, b
unsaturated deoxyribono lactone as the key step, followed by an Arbusov reac-
tion for the introduction of phosphorous. Precursor 7 serves for the synthesis
and incorporation into DNA of a novel chemically stable abasic site analogue
that might act as an inhibitor for DNA glycosylases.
Formation of an abasic site in DNA, leaving a deoxyribose residue behind, is a
frequent lesion that occurs spontaneously or by enzymatic cleavage of the N-glyco-
sidic bond in the DNA repair process. The abasic site exists as an equilibrium mix-
ture of the a- and b-hemiacetal and the open chain aldehyde form of the ribose unit.
Under basic conditions, b-elimination, and thus strand cleavage occurs.
We are interested in developing a new stable abasic site analogue, in which the
usual 30-phosphodiester linkage is replaced by a phosphonate linkage. Incorporated
into an oligonucleotide, we expect increased chemical stability of the oligonucleotide
*Correspondence: Christian J. Leumann, Department of Chemistry and Biochemistry,
University of Bern, Freiestrasse 3, 3012 Bern, Switzerland; E-mail: leumann@ioc.unibe.ch.
1203
DOI: 10.1081/NCN-120022836
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

1204
Hirtz and Leumann
Figure 1.
at the abasic site, as well as inhibitory activity in the context of DNA glycosylases
(Fig. 1).
In our synthetic strategy, we envisaged to introduce the 30-C-methylene group
stereoselectively into the ribose skeleton via a photochemical addition reaction devel-
oped by Mann and co-workers.[1,2] Starting from 2, photochemical addition of
methanol leads to 3 in acceptable yields of 48–53% (Sch. 1).
In order to introduce the phosphonate function, the hydroxymethyl derivative 3
was converted into a precursor suitable for subsequent Arbusov reaction with BTSP
(bis-(trimethylsilyl) -hypophosphite) as the nucleophile.[3] As leaving groups, we
decided to explore the iodide (as in 4, 6a, and 6b) as well as sulfonates such as the
trifluoromethylsulfonate (triflate) (as in 8a and 11) and the 4-methylbenzenesulfo-
nate (tosylate) (as in 8b).[4] These compounds were treated with BTSP in order to
Scheme 1. a) 1.2 eq. DMT-Cl=Pyridine=3 h=92%; b) hv 350 nm=1 eq Benzophenone=
MeOH=8 h=48–53%; c) 1,2 eq. MePþ(OPh)3 Iꢀ=2 eq. Lutidine=DMF=4 h=58% or 1 eq. I2=1 eq.
1.
2.
PPh3=2 eq. Im=THF=2 h=86%; d) 12 eq. BTSP=CH3CN=Hunig’s base=ꢀ42ꢁC; Triethyl-
ammonium hydrogen carbonate (aq.)=8 h=32%; e) 1.2 eq. Dibal=CH2Cl2=ꢀ78ꢁC=2 h=quant;
f) for 6a, 1.2 eq. Anhydride acetic=0.2 eq. DMAP=Pyridine=overnight=91%; for 6b, 2q.
1.
TBDMS-Cl=2 eq. Im.=0.2 eq. DMAP=DMF=overnight=78%; g)
2.
10 eq. BTSP=CH3CN=
Hunig’s base; Triethylammonium hydrogen carbonate (aq.)=22–31% for 7a; 20% for 7b.

Abasic Site Analogue of DNA
1205
Scheme 2. a) for 8a, 2,5 eq. 2,6-di-ter-butylpyridine=1,2 eq. Tf2O=CH2Cl2=ꢀ78ꢁC=3 h=78%;
for 8b, 1.2 eq. TosCl=Pyridine= overnight=rt=76%; b) 1.6 eq. TBDMS-Cl=2 eq Im.=DMF=
overnight=77%; c) 1.6 eq Dibal=CH2Cl2=ꢀ78ꢁC=2 h=quant; d) 2 eq. Anhydride acetic=0.2 eq.
DMAP=Pyridine=overnight=86%; e) 1.5 eq. Acetic acid=1.5 eq. TBAF=THF=0ꢁC to rt=
overnight=74%; f) 2,5 eq. 2,6-di-ter-butylpyridine=1,2 eq. Tf2O=CH2Cl2=ꢀ78ꢁC=3 h=52%;
1.
2.
g) 150 eq. BTSP=CH3CN=Hunig’s base= 0ꢁC= 8 h; Triethylammonium hydrogen carbo-
nate (aq.)=22%.
introduce the C-P bond in form of a 30-C-methylphosphonate linkage in the presence
of base (EtNiPr2, or 2,6-di-ter-butylpyridine) to avoid loss of the DMT group. At r.t.
and in CH2Cl2, we observed in all cases that carry the iodide as leaving group (4, 6a
and 6b) mostly products of reduction and incomplete consumption of the halides
with less than 5% of the desired phosphonate salts. The reduction as a competition
reaction by BTSP has been reported previously.[5] For 6a and 6b, the best results
were obtained by using CH3CN at r.t. with 10 eq. of BTSP for 48 hours. Thus, we
observed the formation of the desired phosphinate derivatives 7a (22–31%) and 7b
(20%), together with the corresponding reduced compounds (ca. 55%). Decreasing
the temperature to ꢀ42ꢁC, did not lead to improved product formation.
In order to favor substitution over reduction, the triflates 8a and 11 and tosylate
8b were tested, too.[4] However, only the triflate 8a was stable enough. The phosphi-
nate derivative 9 was obtained in 22% yield, by treatment of 150 eq. BTSP in CH3CN
at 0ꢁC during 8 h. The other compounds 11 and 8b were not stable at r.t. and under
neutral conditions, and rapidly decomposed.
With phosphinate 7a in hands we now approach the synthesis of the correspond-
ing building block for oligonucleotide synthesis.
REFERENCES
1. Mann, J.; Weymouth-Wilson, A.C. J. Chem. Soc. Perkin. Trans.1 1994,
3141–3147.
2. Gilbert, A.; Baggott, J. ch. 5. In Essential of Molecular Photochemistry; Black-
well, 1991.

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Hirtz and Leumann
3. a) Boyd, E.A.; Regan, A.C. Tetrahedron Lett. 1992, 33, 813–816; b) Boyd, E.A.;
Regan, A.C. Tetrahedron Lett. 1994, 35, 4223–4226.
4. Winqvist, A.; Stro¨mberg, R. Eur. J. Org. Chem. 2002, 1509–1515.
5. An, H.; Wang, T.; Maier, M.; Manoharan, M.; Ross, B.S.; Cook, P.D. J. Org.
Chem. 2001, 66, 2789–2801.