M. Ueno et al. / Tetrahedron Letters 42 (2001) 7863–7865
7865
O
O
MeI
Ag2O
conc. HCl aq.
MeOH, reflux
NH OH
Ph
NH OH
Ph
HO
MeO
MeO
HN
O
H
NH2 OH
Ph
HN
O
CDI
H
O
Ph
MeO
MeO
DMF
Ph
H
O
H
J = 4.8, 11.7 Hz
J = 2.2, 11.7 Hz
Scheme 4.
this synthetic scheme, we have synthesized all four
stereoisomers of HPA-12, and confirmed that only the
(1R,3R)-isomer showed high activity.4 Further investi-
gations to search for more active compounds as well as
to clarify biological aspects of the inhibition are now in
progress.
6. Compound 3c: [h]2D1 +8.26 (c 1.23, CHCl3, 80% ee); IR
(neat): 3358, 2928, 2856, 1680, 1589, 1476, 1254, 836
cm−1 1H NMR (CDCl3): l 0.00 (s, 6H), 0.85 (s, 9H),
;
1.18 (t, 3H, J=7.4 Hz), 2.18 (s, 3H), 2.66 (dd, 1H,
J=4.7, 13.9 Hz), 2.82 (q, 2H, J=7.5 Hz), 2.85 (m,
1H), 3.40 (dd, 1H, J=3.6, 8.2 Hz), 3.45–3.56 (m, 2H),
6.56 (dd, 1H, J=0.7, 7.2 Hz), 6.68 (dd, 1H, J=1.3, 7.2
Hz), 6.79 (t, 1H, J=7.7 Hz); 13C NMR (CDCl3): l
−5.6, −5.5, 14.6, 17.6, 18.3, 23.6, 25.9, 46.1, 55.7, 64.0,
113.5, 121.6, 124.8, 131.5, 132.4, 152.1, 199.7; HPLC:
Daicel Chiralpak AD, hexane/iPrOH=200/1, flow rate=
1.0 ml/min: tR=16.5 min (3R), tR=20.3 min (3S);
HRMS: calcd for C19H33NO3SSi (M+) 383.1950, found
383.1932.
Acknowledgements
This work was partially supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Japan. M.U. thanks the
JSPS fellowship for Japanese Junior Scientists.
7. Nitta, H.; Ueda, I.; Hatanaka, M. J. Chem. Soc.,
Perkin Trans. 1 1997, 1973.
8. The stereochemical assignment of the syn-adduct was
performed by 1H NMR analysis after converting to the
3,4,5,6-tetrahydro-1,3-oxazin-2-one (Scheme 4).
References
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10. HPA-12 (1): mp 75.5–77.0°C; [h]2D2 −35.1 (c 0.8, CHCl3,
96% ee); IR (neat): 3293, 2919, 2849, 1643, 1551, 1493,
1
1054, 746 cm−1; H NMR (CDCl3): l 0.88 (t, 3H, J=6.8
Hz), 1.26 (bs, 16H), 1.59 (bt, 2H, J=7.2 Hz), 1.92 (ddd,
1H, J=6.6, 8.5, 15.1 Hz), 2.03 (ddd, 1H, J=3.6, 5.7, 14.6
Hz), 2.15 (t, 2H, J=7.7 Hz), 3.65 (ddd, 1H, J=4.1, 11.3,
15.5 Hz), 4.01–4.08 (m, 1H), 4.79 (dd, 1H, J=3.4, 8.8
Hz), 6.48 (d, 1H, J=6.8 Hz), 7.23–7.36 (m, 5H); 13C
NMR (CDCl3): l 14.1, 22.7, 25.7, 29.3, 29.3, 29.3, 29.5,
29.6, 29.6, 31.9, 36.8, 40.7, 50.4, 65.5, 71.8, 125.5, 127.7,
128.5, 144.2, 174.3; HPLC: Daicel Chiralpak AD, hex-
t
ane/iPrOH=19/1, flow rate=1.0 ml/min: R=11.4 min
5. (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem.
Soc. 1997, 119, 7153; (b) Ishitani, H.; Ueno, M.;
Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180.
(1S,3S), tR=15.0 min (1R,3R); HRMS: calcd for
C22H37NO3 (M+) 363.2273, found 363.2279.