2
5 °C, 18 h then liquid NH
3
, CH
2
Cl
2
, 6 h, 59% overall)
definitive enhancements were between C10-H and C1-H
â
15
afforded the mitosane system (9R*,9aR*)-1. The minor
diastereomer (9R*,9aS*)-1 could be separated by preparative
thin-layer chromatography.16
The relative stereochemistry of the C9 and C9a stereogenic
centers of the major diastereomer of 1 was determined to be
(4.4%) and between C9-H and C9a-H (5.7%). Notably
absent were enhancements between C9-H and either C1-H
and between the C10-H’s and C9a-H. In the minor
diastereomer [(9R*,9aS*)-1], the definitive enhancements
were between C9-H and C1-H
C9a-H and C10-H (2.7%). Completely absent were
enhancements between C10-H’s and either C1-H or C1-
. These nuclear Overhauser enhancement studies served
R
(3.4%) and between
1
13
9R*,9aR* by correlation with published H and C NMR
6
b,17
spectral data.
In addition, nuclear Overhauser enhance-
R
ment studies on both diastereomers were consistent with and
confirmed unequivocally the proposed stereochemical as-
signments. Figure 2 shows energy-minimized structures
H
â
to definitively establish the relative stereochemistry at the
C9 and C9a stereogenic centers.
A rationale for the observed diastereoselection in the
addition of enol ether 6 with the iminium ion derived from
18
8
is shown in Scheme 4. Considering the possible orienta-
Scheme 4. Origin of Diastereoselection
tions of the two reactive π-systems, the least sterically
1
crowded arrangement is the synclinal orientation sc that
leads to the desired stereochemical array in the addition
2
3
product. The alternative synclinal orientations sc , sc , and
4
sc place the pyrrolinium ring over the aromatic ring or silyl
Figure 2. Relative stereochemistry assignment by NOE.
(
13) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101. Wolfe, J. P.;
Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000,
5, 1158. Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1264.
6
Åhman, J.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6363.
(14) Not surprisingly, the dihydroindole ring system of 14 was sensitive
to air oxidation, and the modest isolated yield for the cyclization of 13 to
(
1
MMX force field) of the major and minor diastereomers of
. In the major stereoisomer [(9R*,9aR*)-1], the most
1
4 is in part due to this sensitivity.
(
15) The major stereoisomer (9R*,9aR*)-1 was characterized: 1H NMR
(
7) (a) Yamada, Y.; Matsui, M. Agr. Biol. Chem. 1971, 35, 282-284.
(CDCl3, 500 MHz) δ 7.11 (app t, 1H, J ) 8.5, 7.9 Hz), 7.07 (d, 1H, J )
7.9 Hz), 6.74 (dd, 1H, J ) 7.9, 7.3 Hz), 6.56 (d, 1H, J ) 7.9 Hz), 4.64 (br
s, 2H, NH2), 4.55 (dd, 1H, J ) 6.1, 5.5 Hz, C10-H), 4.29 (dd, 1H, J )
8.5, 5.5 Hz, C10-H), 3.96 (ddd, 1H, J ) 9.8, 8.5, 5.5 Hz, C9a-H), 3.71
(ddd, 1H, J ) 9.6, 8.5, 6.1 Hz, C9-H), 3.44 (ddd, 1H, J ) 10.7, 8.8, 3.7
Hz, C3-H), 3.12 (ddd, 1H, J ) 10.7, 8.5, 7.7 Hz, C3-H), 1.78-1.95 (m,
(
(
1
b) Takada, T.; Kosugi, Y.; Akiba, M. Tetrahedron Lett. 1974, 3283-3286.
c) Kametani, T.; Takahashi, K.; Ihara, M.; Fukumoto, K. Heterocycles
975, 3, 691-695. (d) Kametani, T.; Ohsawa, T.; Takahashi, K.; Ihara,
M.; Fukumoto, K. Heterocycles 1976, 4, 1637-1644. (e) Crump, D. R.;
Franck, R. W.; Gruska, R.; Ozorio, A. A.; Pagnotta, M.; Siuta, G. J.; White,
J. G. J. Org. Chem. 1977, 42, 105-108. (f) Kametani, T.; Takahashi, K.;
Ihara, M.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1976, 389.
13
2H, C2-H), 1.68 (m, 1H, C1-H), 1.36 (m, 1H, C1-H); C NMR (CDCl3,
125 MHz) δ 156.58, 154.81, 128.98, 128.41, 124.03, 119.35, 110.76, 68.64,
64.94, 51.80, 41.78, 26.00, 25.07; HRMS (FAB), m/e 233.1294 (calcd for
C13H16N2O2 + H, 233.1290).
(8) The mitosenes have a double bond between C9 and C9a (i.e., they
possess a dihydropyrrolo[1, 2-a]indole ring system) and thus lack these
important stereogenic centers.
(16) The minor stereoisomer (9R*,9aS*)-1 was characterized: 1H NMR
(CDCl3, 500 MHz) δ 7.12 (m, 1H, 2H), 6.75 (app t, 1H, J ) 7.3 Hz), 6.56
(d, 1H, J ) 7.9 Hz), 4.60 (br s, 2H, NH2), 4.23 (dd, 1H, J ) 10.4, 6.4 Hz,
C10-H), 4.13 (dd, 1H, J ) 11.9, 6.4 Hz, C10-H), 3.71 (ddd, 1H, J ) 9.5,
6.4, 3.1 Hz, C9a-H), 3.50 (m, 1H, C9-H), 3.40 (m, 1H, C3-H), 3.13 (m,
1H, C3-H), 1.91 (m, 1H, C1-H), 1.84 (m, 2H, C2-H), 1.35 (m, 1H, C1-
H); 13C NMR (CDCl3, 125 MHz) δ 156.65, 154.91, 129.60, 128.77, 125.25,
119.40, 111.35, 68.82, 67.82, 51.98, 46.55, 30.83, 25.68.
(
9) Duhamel, P.; Hennequin, L.; Poirier, J. M.; Tavel, G.; Vottero, C.
Tetrahedron 1986, 42, 4777.
10) Louwrier, S.; Tuynman, A.; Hiemstra, H. Tetrahedron 1996, 52,
629.
11) Fisher, M. J.; Overman, L. E. J. Org. Chem. 1990, 55, 1447. Brown,
H. C.; Krishnamurthy, S. J. Am. Chem. Soc. 1973, 95, 1669.
12) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(
2
(
(
Org. Lett., Vol. 3, No. 8, 2001
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