1,2-bis(2-hydroxylphenyl)-1,2-diaminoethane 8 with methyl
2-formylbenzoate at room temperature in EtOH and via
enantioselective diaza-Cope rearrangement reaction gave the
corresponding key diimine 7 in 86% yield with completely
inversion of stereochemistry to give the (S,S)-enantiomer.
The key ester-containing diimine 7 was then treated with
water in the presence of Brønsted acid leading to intramo-
lecular hydrolysis cyclization, which afforded the lactams 5
and 6. As indicated in Table 1, the regioselectivity of
Figure 1. Design of the rigid chiral amines 1 and 2.
Table 1. Reactions of 7 under Various Conditionsa
entry
conditions
5 (%) 6 (%)
and -NH2, two kinds of cyclic diamines would be con-
structed, namely biisoindoline 1 and hexahydrodibenzo[c,h]-
[1,5]naphthyridine 2 (Figure 1). The two additional cyclic
rings in their backbones might improve the conformational
rigidity by restraining the free rotation of the phenyl group.
The chiral amines 1 and 2, possessing bipyrrolidine3 and
diaza-cis-decalin4 backbones, respectively, are expected to
be more conformationally rigid due to the fused benzene
rings on their scaffolds. The conformational rigidity of a
chiral ligand has been demonstrated to be an important factor
for high enantioselectivity in asymmetric catalysis.5 In
addition, the chiral amine 1 containing the isoindoline
backbone,could be regarded as biisoindoline. The isoindoline
backbone is a common structure in various natural products
and pharmaceuticals.6 In this context, these two chiral amines
are expected to be key platform molecules not only for
synthesis of chiral ligands but also for chiral drugs. Herein
we report the design and synthesis of the novel optically
pure biisoindoline 1 and its isomer 2 as well as their
applications as chiral ligands in metal-catalyzed asymmetric
reactions.
1
2
3
4
5
6
7
H2O, 70 °C, 24 h
TFA (2 equiv), H2O, 70 °C, 2 h
0
0
0
0
84.5
92.8
66.2
33.2
TFA (2 equiv), t-BuOH/H2O, 70 °C, 2 h
H2O (30 equiv), TFA, 70 °C, 24 h
AcOH (2 equiv), H2O, 70 °C, 24 h
AcOH (2 equiv), t-BuOH/H2O, 70 °C, 2 h 64.3
H2O (30 equiv), AcOH, 70 °C, 2 h 58.2
0
5.7
19.2
25.7
a All reactions were performed on a 0.5 mmol scale, and the yield shown
is the isolated yield.
cyclization was strongly dependent on the Brønsted acid and
reaction conditions. The ester-containing diimine 7 was stable
and remained intact after heating 24 h in H2O (entry 1), but
in the presence of acetic acid or trifluoroacetic acid (TFA),
7 underwent hydrolysis cyclization to form products 5 and
6. In the presence of TFA, only the five-membered lactam 5
could be observed (entries 2-4). Remarkably, heating of 7
in t-BuOH and water in the presence of TFA led to the
exclusive formation of the biisoindolinone 5 in excellent yield
(entry 3). On the other hand, with AcOH as promoter, both
the five-membered and six-membered lactams could be
formed, and the five-membered biisoindolinone 5 was always
the major product regardless of changing the reaction
As shown in Scheme 1, the synthesis of the chiral amines
1 and 2 was quite straightforward, the basic strategy of which
(3) (a) Hirama, M.; Oishi, T.; Ito, S. J. Chem. Soc., Chem. Commun.
1989, 665. (b) Oishi, T.; Hirama, M. J. Org. Chem. 1989, 54, 5834. (c)
Kotsuki, H.; Kuzume, H.; Ghoda, T.; Fukuhara, M.; Ochi, M.; Oishi, T.;
Hirama, M.; Shiro, M. Tetrahedron: Asymmetry 1995, 6, 2227. (d) Oishi,
T.; Hirama, M.; Sita, L. R.; Masamune, S. Synthesis 1991, 789. (e) Alexakis,
A.; Tomassini, A.; Chouillet, C.; Roland, S.; Mangeney, P.; Bernardinelli,
G. Angew. Chem., Int. Ed. 2000, 39, 4093. (f) Alexakis, A.; Andrey, O.
Org. Lett. 2002, 4, 3611. (g) Andrey, O.; Alexakis, A.; Bernardinelli, G.
Org. Lett. 2003, 5, 2559. (h) Andrey, O.; Vidonne, A.; Alexakis, A.
Tetrahedron Lett. 2003, 44, 7901. (i) Andrey, O.; Alexakis, A.; Tomassini,
A.; Bernardinelli, G. AdV. Synth. Catal. 2004, 346, 1147. (j) Mosse´, S.;
Alexakis, A. Org. Lett. 2005, 7, 4361. (k) Denmark, S. E.; Fu, J.; Lawler,
M. J. J. Org. Chem. 2006, 71, 1523. For a review, see: Mosse´, S.; Alexakis,
A. Chem. Commun. 2007, 3123.
Scheme 1. Synthesis of the Rigid Chiral Amines 1 and 2
(4) (a) Li, X.; Schenkel, L. B.; Kozlowski, M. C. Org. Lett. 2000, 2,
875. (b) Li, X.; Yang, J.; Kozlowski, M. C. Org. Lett. 2001, 3, 1137. (c)
Xu, Z.; Kozlowski, M. C. J. Org. Chem. 2002, 67, 3072.
(5) (a) Zhang, X. Enantiomer 1999, 4, 541. (b) Blaser, H.-U.; Malan,
C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. AdV. Synth. Catal. 2003,
345, 103.
(6) (a) Cornish, E. J.; Lee, G. E.; Wragg, W. R. Nature 1963, 197, 1296.
(b) Gilchrist, T. L. Heterocyclic Chemistry; Addison Wesley: Esses,
England, 1997; Vol. 3. (c) Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo,
V. Tetrahedron Lett. 1984, 25, 599. (d) Protevin, B.; Tordjman, C.;
Pastoureau, P.; Bonnet, J.; De Nanteuil, G. J. Med. Chem. 2000, 43, 4582.
(e) Stuk, T. L.; Assink, B. K.; Bates, R. C.; Erdman, D. T.; Fedij, V. S.;
Jennings, M.; Lassig, J. A.; Smith, R. J.; Smith, T. L. Org. Process Res.
DeV. 2003, 7, 851.
involved the stereoselective diaza-Cope rearrangement pro-
cedure.7 As the first step, simple condensation of (1R,2R)-
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