6124
(S)-4a (E=CO2Me), and (S)-4a (E=CH2OH).5 Mesylation of 6 followed by reaction with 4-
(piperazin-1-yl)benzenesulfonamide (7)13 furnished the (R)-enantiomer of U-101387.14
ꢀ4
In summary, we have shown that the chiral bis(oxazoline)-mediated asymmetric lithiation/SE2
reactions of isochroman and phthalan aord the a-substituted derivatives with moderate-to-high
enantiopurities, which are a potentially useful class of chiral molecules. Further application of the
external chiral ligand-mediated asymmetric lithiation protocol to other SE2 reactions is in
progress.
Acknowledgements
This work was supported by the JSPS Research for the Future Program.
References
1. Recent reviews: (a) Beak, P.; Basu, A.; Gallageher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996,
29, 552±560. (b) Hoppe, D.; Hense, T. Angew. Chem. Int. Ed. Engl. 1997, 36, 2283±2316.
2. (a) Komine, N.; Wang, L.-F.; Tomooka, K.; Nakai, T. Tetrahedron Lett. 1999, 40, 6809±6812. (b) Tomooka, K.;
Wang, L.-F.; Komine, N.; Nakai, T. Tetrahedron Lett. 1999, 40, 6813±6816.
3. Tomooka, K.; Yamamoto, K.; Nakai, T. Angew. Chem., Int. Ed. Engl. 1999, 111, 3955±3957.
4. Tomooka, K.; Komine, N.; Nakai, T. Tetrahedron Lett. 1998, 39, 5513±5516.
5. ꢀ2D9=^41.7ꢁ (c 0.76, CHCl3). The (R)-con®guration was assigned by comparison of the optical rotation with that
of the authentic (R)-(^)-isomer which was prepared from the known10 (R)-(+)-a-(b-hydroxyethyl)isochroman 6
[=4a (E=CH2CH2OH)] obtained as depicted in Eq. (4). The preparation scheme involves tosylation of (R)-6
followed by treatment with DBN to give 4a (E=CHCH2), then ozonolysis followed by reduction with NaBH4 to
yield (^)-4a (E=CH2OH), and tosylation followed by reduction with NaBH4 to aord (^)-4a (E=Me).
6. The carboxylation product 4a (E=CO2Me): ꢀD29=^15.6ꢁ (c 1.17, CHCl3). The (S)-con®guration was assigned by
converstion to (S)-(^)-4a (E=CH2OH) via reduction with LiAlH4 (cf. Ref. 5).
7. The benzaldehyde adduct 4a [E=CH(OH)Ph] was obtained as a 60:40 mixture of the two diastereomers which
were distinguishable, e.g. by the two sets of doublet due to the a-methine protons in 1H NMR spectrum (CDCl3): ꢁ
5.22 (major) and 4.95 (minor). However, the assignments of their relative and absolute con®gurations have been
unsuccessful so far.
8. The (R)-con®guration of 4b (E=Me), ꢀ2D3=+5.1ꢁ (c 0,82, CHCl3), was assigned by its conversion to the known
(R)-(+)-3-methylphthalide via oxidation with RuCl3/NaIO4: Ewin, R. A.; MacLeod, A. M.; Price, D. A.;
Simpkins, N. S.; Watt, A. P. J. Chem. Soc., Perkin Trans. 1, 1997, 401±415. The (S)-con®guration of 4b
(E=CO2Me), ꢀ2D7=^12.7ꢁ (c 0.82, CHCl3), was assigned by conversion to (R)-(+)-4b (E=Me) via reduction
with LiAlH4 followed by tosylation and reduction with NaBH4. However, the relative and absolute con®gurations
of the benzaldehyde adducts have not been determined.
9. Refers to the % ee of the major diastereomer.