512
J. A. Rojas St€utz, C. Richert / Tetrahedron Letters 45 (2004) 509–513
Figure 2. Molecular ion region of the MALDI-TOF mass spectra of crude 10 and chemset 11, acquired in negative, linear mode using a matrix of
trihydroxyacetophenone and a co-matrix of diammonium citrate.
was coupled to the growing chain of oligonucleotide 8
on controlled pore glass (Scheme 2). Removal of the
MMT group with the trichloroacetic acid solution rou-
tinely used for the deblocking step of automated chain
assembly (3% in CH2Cl2) gave 9, which was either
coupled to cholic acid to give, after deprotection, 50-
capped 10, or treated with a reactivity-adjusted mix-
ture of carboxylic acids31 and deprotected to produce
chemset 11.àà The cholic acid residue has been shown to
enhance target affinity of hybridization probes and to
improve base pairing fidelity at the terminus of
duplexes.16;17 Oligonucleotides bearing this bile acid
residue have shown promise in DNA microarray
applications.18
from alcohol to MMT-protected amine, exemplified in
the conversion of 5 to 7, may prove useful in other
synthetic work. Exploratory experiments with 20-deoxy-
6-N-(dimethylformamidino) adenosine27;34 indicate that
the route to a protected 50-amino phosphoramidite
presented in Scheme 1 can also be successfully employed
for this substrate.
References and Notes
1. Lin, T. S.; Prusoff, W. H. J. Med. Chem. 1978, 21, 109–
112.
2. Lerner, C.; Masjost, B.; Ruf, A.; Gramlich, V.; Jakob-
€
Roetner, R.; Zurcher, G.; Borroni, E.; Diederich, F. Org.
Biomol. Chem. 2003, 1, 42–49.
The MALDI-TOF spectra of the crude products of the
solid phase syntheses (Fig. 2) show all the expected
products and few impurities, making chemset 11 suitable
for spectrometrically monitored selection experiments
(SMOSE).32 The use of crude chemsets of oligonucleo-
tides in SMOSE assays allows for a rapid search for new
high affinity hybridization probes,33 avoiding the time
consuming synthesis and purification of individual
compounds. Finally, the three-step/two-pot conversion
3. Shan, S.-o.; Narlikar, G. J.; Herschlag, D. Biochemistry
1999, 38, 10976–10988.
4. Pljevaljcic, G.; Pignot, M.; Weinhold, E. J. Am. Chem.
Soc. 2003, 125, 3486–3492.
5. Bergmann, F.; Bannwarth, W. Tetrahedron Lett. 1995, 36,
1839–1842.
6. Gryaznov, S. M.; Schultz, R.; Chaturvedi, S. K.; Let-
singer, R. L. Nucl. Acids Res. 1994, 22, 2366–2369.
7. Zhan, Z.-Y.; Lynn, D. G. J. Am. Chem. Soc. 1997, 119,
12420–12421.
8. Linkletter, B. A.; Szabo, I. E.; Bruice, T. C. J. Am. Chem.
Soc. 1999, 121, 3888–3896.
9. Letsinger, R. L.; Mungall, W. S. J. Org. Chem. 1970, 35,
3800–3803.
10. Letsinger, R. L.; Wilkes, J. S.; Dumas, L. B. J. Am. Chem.
Soc. 1972, 94, 292–293.
11. Letsinger, R. L.; Hapke, B.; Petersen, G. R.; Dumas, L. B.
Nucl. Acids Res. 1976, 3, 1053–1063.
12. Shchepinov, M. S.; Denissenko, M. F.; Smylie, K. J.;
A solution of cholic acid (40.9 mg, 100 lmol), HOBT (13.5 mg,
100 lmol), and HBTU (34.1 mg, 90 lmol) in DMF (600 lL) was
treated with DIEA (40 lL, 230 lmol). After 10 min, the solution was
added to support 8 (5 mg, approximately 0.19 lmol loading). After
45 min with occasional mixing, the solid support was rinsed with
DMF (2 mL) and MeCN (3 · 2 mL). After drying in vacuo, the
support was treated with ammonium hydroxide (30% aqueous NH3,
1 mL) for 14 h. MALDI-TOF MS (linear, negative mode, THAP)
calcd for [M)H]ꢀ: 2839.2, found 2838.6.
€
Worl, R. J.; Leppin, A. L.; Cantor, C. R.; Rodi, C. P.
Nucl. Acids Res. 2001, 29, 3864–3872.
àà
A mixture of hippuric acid (3.26 mg, 18.1 lmol), 3-indolepropionic
acid (3.75 mg, 19.8 lmol), Boc–Ser(Bzl)–OH (7.12 mg, 24.1 lmol),
dehydrocholic acid (11.87 mg, 29.5 lmol), and cinoxacin (2.25 mg,
8.5 lmol) in DMF (500 lL) was prepared from stock solutions and
activated with HBTU, HOBT, and DIEA in DMF (plus 100 lL) and
coupled as described for 10. MALDI-TOF MS calcd for 11-HP
([M)H]ꢀ): 2609.8, found 2610.3, calcd for 11-IP ([M)H]ꢀ): 2619.8,
found 2620.2, calcd for 11-CI ([M)H]ꢀ): 2692.8, found 2693.4, calcd
for 11-BS ([M)H]ꢀ): 2725.9, found 2726.3, calcd for 11-DH
([M)H]ꢀ): 2833.1, found 2833.
13. Wolfe, J. L.; Kawate, T.; Belenky, A.; Stanton, V. Nucl.
Acids Res. 2002, 30, 3739–3747.
14. ZagrebelÕnyi, S. N.; Zakabunin, A. I.; Melamed, N. V.;
Oreshkova, S. F.; Khripin, Y. L. Bioorg. Khim. (Russ.)
1984, 10, 1183–1189.
15. Uhlmann, E.; Peyman, A.; Breipohl, G.; Will, D. W.
Angew. Chem., Int. Ed. Engl. 1998, 37, 2796–2823.
16. Bleczinski, C. F.; Richert, C. J. Am. Chem. Soc. 1999, 121,
10889–10894.