T. Onishi et al. / Tetrahedron Letters 42 (2001) 5887–5890
5889
by HPLC using a Crownpak CR(+) column. [h]2D5=
+30.2 (c=0.5, H2O); 1H NMR (DMSO-d6) l 3.04 (dd,
J=7.1, 15.2 Hz, 1H), 3.22 (dd, J=7.1, 15.2 Hz, 1H),
4.54 (t, J=7.1 Hz, 1H), 4.58 (d, J=17.3 Hz, 1H), 4.70
(d, J=17.3 Hz, 1H), 7.28–7.41 (m. 5H), 8.37 (bs, 3H);
ESI MASS m/z 198 (MH+).
10. Dondoni, A.; Perrone, D. Tetrahedron Lett. 1992, 33,
7259.
Scheme 4.
11. Bocoum, A.; Boga, C.; Savoia, D.; Umani-Ronchi, A.
Tetrahedron Lett. 1991, 32, 1367.
12. Alonso, E.; Alonso, E.; Solis, A.; del Pozo, C. Synlett
2000, 5, 698.
13. Yamada, S.; Hongo, C.; Yoshioka, R.; Chibata, I. J.
Org. Chem. 1983, 48, 843.
14. A solution of ester 4 and bromochloromethane (1.3
equiv.) in anhydrous THF–toluene was cooled to
−78°C, and n-butyllithium (1.3 equiv.) in hexane was
added dropwise. After stirring for 30 min at −78°C, the
reaction mixture was poured into a solution of 35%
HCl in MeOH. After stirring for 1 h at rt, heptane was
added and the methanolic layer was separated. After
the addition of MTBE, the mixture was cooled to
−10°C to afford 3 as a white solid.
ation of N-imine-protected amino acid esters were
achieved. Chloromethylation and successive acid
hydrolysis afforded a-aminoalkyl-a%-chloromethylke-
tone as a salt form in good yield without racemization.
The amino group can be conveniently protected with
carbamate protecting reagents to give various useful
intermediates leading to the known protease inhibitors.
Acknowledgements
We thank Messrs. Yasuyuki Otake, Shinji Kuroda,
Takayoshi Torii, Daigaku Hideura and Yutaka Honda
for their helpful discussion and technical assistance. We
are grateful to Professor Jose Barluenga of Universidad
de Oviedo for his helpful discussion.
15. Fittkau, S. J. Prakt. Chem. 1973, 315, 1037.
16. Rich, D. H.; Green, J.; Toth, M. V.; Marshall, G. R.;
Kent, S. B. H. J. Med. Chem. 1990, 33, 1285.
17. Sonntag, N. O. V. Chem. Rev. 1953, 52, 237.
18. A solution of methyl chloroformate (1.3 equiv.) in tolu-
ene was added to a solution of 3 in H2O. An aqueous
NaHCO3 solution (2 equiv.) was added dropwise with
good stirring. After stirring for 1 h at rt, the product
was extracted and recrystallized from 2-propanol and
hexane to afford 5 as a white solid. 1H NMR (CDCl3)
l 2.97–3.14 (m, 2H), 3.66 (s, 3H), 3.98 (d, J=16.0 Hz,
1H), 4.15 (d, J=16.0 Hz, 1H), 4.75 (q, J=7.2 Hz, 1H),
5.21 (bd, 1H), 7.12–7.18 (m. 2H), 7.23–7.37 (m, 3H).
19. A solution of benzyl chloroformate (1.3 equiv.) in tolu-
ene was added to a solution of 3 in H2O. An aqueous
NaHCO3 solution (2 equiv.) was added dropwise with
good stirring. After stirring for 1 h at rt, the product
was extracted and purified by silica gel chromatography
to give 6 as a white solid. 1H NMR (CDCl3) l 3.00
(dd, J=7.0, 13.9 Hz, 1H), 3.09 (dd, J=6.9, 13.9 Hz),
3.97 (d, J=16.2 Hz), 4.14 (d, J=16.2 Hz), 4.75 (bq,
J=7.0 Hz, 1H), 5.06 (s, 2H), 5.38 (bd, J=7.6 Hz, 1H),
7.12–7.35 (m, 10H); ESI MASS m/z 332 (MH+).
20. 8 (a pale orange solid); 1H NMR (CDCl3) l 2.50 (s,
3H), 4.17 (s, 2H), 4.29 (s, 2H), 4.62 (s, 2H), 7.15–7.32
(m. 10H); ESI MASS m/z 323 (MH+).
21. A solution of di-tert-butyl dicarbonate (1.1 equiv.) in
dichloromethane was added to an aqueous Na2CO3
solution (1.5 equiv.). Compound 3 was slowly added to
the mixture at rt with good stirring. After stirring for 1
h at 35°C, the product was extracted and recrystallized
from 2-propanol and hexane to afford 7 as a white
solid. [h]2D5=−55.7 (c=1, EtOH); 1H NMR (CDCl3) l
1.41 (s, 9H), 3.00 (dd, J=6.9, 13.8 Hz), 3.08 (dd, J=
6.9, 13.8 Hz, 1H), 3.98 (d, J=16.2 Hz, 1H), 4.17 (d,
J=16.2 Hz, 1H), 4.68 (q, J=6.9 Hz, 1H), 5.02 (bd,
J=6.9 Hz, 1H), 7.16 (m, 2H), 7.26–7.36 (m, 3H); ESI
MASS m/z 296 (M−H+).
References
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8. A solution of ester 1 and bromochloromethane (1.3
equiv.) in anhydrous THF was cooled to −78°C, and
n-butyllithium (1.3 equiv.) in hexane was added drop-
wise. After stirring for 30 min at −78°C, a saturated
NH4Cl aqueous solution was added. The product was
extracted to give 2 as a pale yellow oil. [h]2D5=+8.5
(c=1, EtOH); 1H NMR (CDCl3) l 3.07 (dd, J=8.8,
13.8 Hz, 1H), 3.15 (dd, J=4.2, 13.8 Hz, 1H), 4.31 (dd,
J=4.2, 8.8 Hz, 1H), 4.38 (d, J=17.1 Hz, 1H), 4.58 (d,
J=17.1 Hz, 1H), 6.43 (d, J=9.9 Hz, 2H), 6.99–7.04
(m, 2H), 7.18–7.40 (m, 9H), 7.60 (d, J=9.1 Hz).
9. A solution of chloromethylketone
2 in THF was
treated with an excess of 2 mol/l HCl at rt for 11 h.
After concentration, the resultant slurry was washed
with MeOH–MTBE to give 3 as a white solid. The
reaction yield was determined by HPLC using an Inert-
sil ODS-2 column. Enantiomer purity was determined