D. Krishnamurthy et al. / Tetrahedron Letters 43 (2002) 2331–2333
2333
Thus, the optimum conditions for the addition of iBuLi
to imine 3 involves the use of 20 mol% of 8 in toluene
at –78 to –60°C, and provides 40% ee with 95% yield.11
Although the asymmetric addition of iBuLi to imine 8
gave only 40% ee, it is important to note that the % ee
can be enriched to >99% ee with >90% recovery by a
single crystallization with (R)-mandelic acid ([h]2D0=
+5.3° (c 5.8, CH3OH)). Utilizing this asymmetric syn-
thesis (Scheme 2), the overall yield for (R)-DMS can be
increased to 48%, compared to 20–25% for the resolu-
tion process.
6. For a recent review, see: (a) Enders, D.; Reinhold, U.
Tetrahedron: Asymmetry, 1997, 8, 1895; (b) Kobayashi,
S.; Ishitani. H. Chem. Rev. 1999, 99, 1069.
7. Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper,
M. L. J. Am. Chem. Soc. 2001, 123, 10409.
8. For Grignard addition to methylimines, see: (a) Emling,
B. L.; Horvath, R. J.; Saraceno, E. F.; Haile, L.;
Hudac, L. D. J. Org. Chem. 1959, 24, 657; (b) Ishi-
maru, K.; Tsuru, K.; Yabuta, K.; Wada, M.;
Yamamoto, Y.; Akiba, K. Tetrahedron, 1996, 52,
13137.
9. (a) Denmark, S. E.; Stiff, C. M. J. Org. Chem. 2000,
65, 5875; (b) Denmark, S. E.; Nakajima, N.; Nicaise,
O. J.-C. J. Am. Chem. Soc. 1994, 116, 8797.
10. For the original reference of ligand 12, see: Davies, I.
W.; Gerena, L.; Castonguay, L.; Senanayake, C. H.;
Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Chem.
Commun. 1996, 1753.
11. Experimental procedure for asymmetric addition of
iBuLi to imine 3 (entry 4, Table 1) is given below. To
a −78°C cooled solution of 2 (58 mg, 0.2 mmol) in
toluene (4 mL) was added iBuLi (1.3 mL, 1.5 M in
hexane, 1.95 mmol) and stirred for 0.5 h. A solution of
imine 3 (200 mg, 0.97 mmol) in toluene (1 mL) was
added drop wise to the reaction mixture and stirred at
–78 to –60°C for 3 h. The reaction was quenched with
methanol (1 mL) and warmed to ambient temperature.
The reaction mixture was diluted with EtOAc (10 mL)
and water (5 mL). The aqueous layer was extracted
with EtOAc (2×10 mL). The combined organic layers
were dried over Na2SO4, filtered, and the filtrate was
concentrated. The product was purified by silica gel
chromatography (eluting with 1% NEt3 in EtOAc) to
give 240 mg (95%) of amine as oil. NMR (CDCl3): 1H
(l), 0.85–1.1 (m, 6H), 1.24–1.5 (b, 2H), 1.65–2.14 (b,
4H), 2.2–2.5 (b, 4H), 2.5–2.7 (m, 2H), 3.4–3.6 (b, 1H),
7.3–7.5 (m, 4H), 9.0–9.5 (b, 2H). 13C (l): 15.5, 21.4,
23.5, 24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5,
129.4, 133.0, 141.6.
In summary, we have demonstrated the first example of
an asymmetric addition of iBuLi to methyl imine, and
developed a tactile enantioselective synthesis of (R)-
DMS. Identification of new chiral ligands to improve
the enantioselectivity in the iBuLi addition to methyl
imine 3 is currently being evaluated, and will be
reported on shortly.
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