K. R. Bhushan et al. / Tetrahedron Letters 44 (2003) 8585–8588
8587
Acknowledgements
12. Tsuji, Y.; Kotachi, S.; Huh, K. T.; Watanabe, Y. J. Org.
Chem. 1990, 55, 580.
13. Procedure for preparation of NPPOC chloride 3: To a
solution of 2 (6 mmol) in anhydrous THF (5 mL) at 0°C,
was added a solution of phosgene (20% in toluene, 9
mmol) over a period of 15 min with stirring under a
nitrogen atmosphere. After 45 min, the ice bath was
removed and stirring was continued at room temperature
for 2 h. A stream of N2 was then bubbled through the
solution for 1 h to remove the excess phosgene, after
which the mixture was evaporated to dryness under vac-
uum to give compound 3 (99%, brown oil). 1H NMR
(CDCl3, 400 MHz): l/ppm 7.81 (d, J=8.0 Hz, 1H,
Ar-H), 7.60 (t, J=7.4 Hz, 1H, Ar-H), 7.43 (d, J=7.6 Hz,
1H, Ar-H), 7.38 (t, J=7.6 Hz, 1H, Ar-H), 4.47 (d, J=6.4
Hz, 2H, CH2), 3.77 (m, 1H, CH), 1.39 (d, J=6.8 Hz, 3H,
CH3); MS (CI+) m/z: 243.6 (M+H+).
This work was supported by a grant from the Boston
University Community Technology Fund.
References
1. (a) Housemen, B. T.; Huh, J. H.; Kron, S. J.; Mrksich,
M. Nat. Biotechnol. 2002, 20, 270; (b) Vernet, G. Virus
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2. Fodor, S. P. A.; Read, J. L.; Pirrung, M. C.; Stryer, L.;
Lu, A. T.; Solas, D. Science 1991, 251, 767.
3. (a) Pease, A. C.; Solas, D.; Sullivan, E. J.; Cronin, M. T.;
Holmens, C. P.; Fodor, S. P. A. Proc. Natl. Acad. Sci.
(USA) 1994, 91, 5022; (b) Niemeyer, C. M.; Blohm, D.
Angew. Chem., Int. Ed. 1999, 38, 2865; (c) Singh-Gasson,
S.; Green, R. D.; Yue, Y.; Nelson, C.; Blattner, F.;
Sussman, M. R.; Cerrina, F. Nat. Biotechnol. 1999, 17,
974; (d) Frank, R. Comb. Chem. High Throughput Screen.
2002, 5, 429.
14. Typical procedure for the preparation of NPPOC protected
amino acids 4: Na2CO3 (2.2 mmol) was added to the
solution of L-amino acid (1 mmol) in 10 mL water/1,4-
dioxane (1:1) at 0°C, followed by the dropwise addition
of 3 (1 mmol, in 1 mL THF). After 20 min the ice bath
was removed and stirring was continued for 18–24 h. The
reaction mixture was evaporated to dryness, 3 mL of
water was added and the mixture was extracted with
ethyl acetate (2×5 mL) to remove 3 or its hydrolysis
product. The aqueous layer was acidified by addition of
5% HCl at 0°C and extracted with ethyl acetate (3×10
mL); the extracts were dried over Na2SO4 and concen-
trated at reduced pressure to give a glassy substance that,
in most cases was essentially pure (free of by-products),
based on spectroscopic measurements.
4. Robinson, W. H.; Steinman, L.; Utz, P. J. Arthritis &
Rheumatism 2002, 46, 885.
5. (a) Holmes, C. P.; Adams, C. L.; Kochersperger, L. M.;
Mortensen, R. B.; Aldwin, L. A. Biopolymers 1995, 37,
199; (b) Read, J. L.; Fodor, S. P. A.; Stryer, L.; Pirrung,
M. C.; Hoeprich, P. D. US Patent, 2002, 6,420,169; (c)
Pirrung, M. C.; Stryer, L.; Fodor, S. P. A.; Read, J. L.
US Patent, 2002, 6,416,952.
6. (a) Patchornik, A.; Amit, B.; Woodward, R. B. J. Am.
Chem. Soc. 1970, 92, 6333; (b) Pillai, V. N. R. Synthesis
1980, 1.
15. Spectroscopic data for selected products: 4b: 1H NMR
(CDCl3, 400 MHz): l/ppm 7.71 (d, J=8.0 Hz, 1H,
Ar-H), 7.54 (t, J=7.4 Hz, 1H, Ar-H), 7.43 (d, J=7.6 Hz,
1H, Ar-H), 7.34 (t, J=7.6 Hz, 1H, Ar-H), 5.28 (br d, 1H,
NH), 4.28 (d, J=6.4 Hz, 2H, CH2), 4.11 (m, 1H, CH),
3.67 (m, 1H, CH), 1.40 (d, J=7.6 Hz, 3H, CH3), 1.31 (d,
J=6.8 Hz, 3H, CH3); LC-MS (ESI+) m/z: 297.1 (M+H+),
319.1 (M+Na+).
7. Holmes, C. P.; Solas, D. W.; Kiangsoontra, B. PCT Int.
Appl., 1994, WO 9410128.
8. (a) Beier, M.; Hoheisel, J. D. Nucleic Acids Res. 2000, 28,
e11; (b) Beier, M.; Hoheisel, J. D. Nucleic Acids Res.
1999, 27, 1970.
9. Hasan, A.; Stengele, K.; Giegrich, H.; Cornwell, P.;
Isham, K. R.; Sachleben, R. A.; Pfleiderer, W.; Foote, R.
S. Tetrahedron 1997, 53, 4247.
10. (a) McGall, G. H.; Barone, A. D.; Diggelmann, M.;
Fodor, S. P. A.; Gentalen, E.; Ngo, N. J. Am. Chem. Soc.
1997, 119, 5081; (b) Bochet, C. G. Tetrahedron Lett.
2000, 41, 6341.
11. Procedure for preparation of 2-(2-nitrophenyl)propanol 2:
Triton B (40% in MeOH, 8 mmol) was added to 2-ethyl-
nitrobenzene (8 mmol) and paraformaldehyde (8.1
mmol), and the mixture was heated at reflux for 6 h.
After concentration under vacuum, the reaction mixture
was neutralized using 5% aqueous HCl. The mixture was
extracted with ethyl acetate (3×10 mL), dried over
Na2SO4 and concentrated at reduced pressure. The
residue was purified by flash chromatography using hex-
ane–ethyl acetate (4:1) to give compound 2 (96%, red oil).
1H NMR (CDCl3, 400 MHz): l/ppm 7.73 (d, J=8.0 Hz,
1H, Ar-H), 7.56 (t, J=7.4 Hz, 1H, Ar-H), 7.48 (d, J=7.6
Hz, 1H, Ar-H), 7.35 (t, J=7.6 Hz, 1H, Ar-H), 3.77 (d,
J=6.4 Hz, 2H, CH2), 3.51 (m, 1H, CH), 1.79 (br s, 1H,
OH), 1.32 (d, J=6.8 Hz, 3H, CH3); MS (CI+) m/z: 182.1
(M+H+).
1
4e: H NMR (CDCl3, 400 MHz): l /ppm 7.70 (d, J=8.0
Hz, 1H, Ar-H), 7.52 (t, J=7.4 Hz, 1H, Ar-H), 7.42 (d,
J=7.6 Hz, 1H, Ar-H), 7.32 (t, J=7.6 Hz, 1H, Ar-H),
5.42 (br d, 1H, NH), 4.25 (d, J=6.4 Hz, 2H, CH2), 4.09
(m, 1H, CH), 3.98 (m, 1H, CH2), 3.82 (m, 1H, CH2), 3.53
(m, 1H, CH), 1.28 (d, J=6.8 Hz, 3H, CH3), 1.10 (s, 9H,
3×CH3); LC-MS (ESI+) m/z: 369.1 (M+H+), 391.1 (M+
Na+).
1
4h: H NMR (CDCl3, 400 MHz): l /ppm 7.67 (d, J=8.0
Hz, 1H, Ar-H), 7.50 (t, J=7.4 Hz, 1H, Ar-H), 7.41 (d,
J=7.6 Hz, 1H, Ar-H), 7.30 (t, J=7.6 Hz, 1H, Ar-H),
5.48 (br d, 1H, NH), 4.23 (d, J=6.4 Hz, 2H, CH2), 4.16
(m, 1H, CH), 3.62 (m, 1H, CH), 2.28 (m, 2H, CH2), 2.09
(m, 1H, CH2), 1.90 (m, 1H, CH2), 1.37 (s, 9H, 3×CH3),
1.31 (d, J=6.8 Hz, 3H, CH3); LC-MS (ESI+) m/z: 411.1
(M+H+), 433.1 (M+Na+).
1
4j: H NMR (CDCl3, 400 MHz): l /ppm 7.70 (d, J=8.0
Hz, 1H, Ar-H), 7.51 (t, J=7.4 Hz, 1H, Ar-H), 7.40 (d,
J=7.6 Hz, 1H, Ar-H), 7.29 (t, J=7.6 Hz, 1H, Ar-H),
6.98 (d, J=8.2 Hz, 2H, Ar-H), 6.87 (d, J=8.2 Hz, 2H,
Ar-H) 5.10 (br d, 1H, NH), 4.24 (d, J=6.4 Hz, 2H, CH2),
4.16 (m, 1H, CH), 3.65 (m, 1H, CH2), 3.06 (m, 1H, CH2),