C. E. Garrett et al. / Tetrahedron: Asymmetry 13 (2002) 1347–1349
1349
that the oxazaborolidine-type reduction systems are an
efficient method for generating the desired enantiomeri-
cally pure product. In this case, 3a is the simplest and
most effective catalyst. In short, we recommend the in
situ formation of the catalyst using 2 and DEANB as
the method of choice when reductions of this type are
to be employed.
ketone (1.0 equiv.) was added as a solution in tert-
BuOMe (7 mL) over 5–30 min, while maintaining the
reaction at the desired temperature.
3c: Trimethyl borate (0.09 equiv.) was mixed with (S)-2
(0.075 equiv.) in tert-BuOMe (3.5 mL). This solution was
stirred at room temperature, and DEANB (1.1–2.0
equiv.) was added after a set amount of time. The solu-
tion was warmed to the reaction temperature (20–45°C),
and the ketone (1.0 equiv.) was added as a solution in
tert-BuOMe (7 mL) over 5–30 min, while maintaining the
reaction at the desired temperature.
References
1. Nakamura, K.; Matsuda, T. J. Org. Chem. 1998, 63,
8957–8964.
2. Nozulak, J.; Oser, D. Novartis Pharmaceuticals, unpub-
lished results.
3. Of the published, non-enzymatic methods that we evalu-
ated, none generated product with ]98% ee for this
substrate.
4. (a) Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock,
T. J.; Reamer, R. A.; Mohan, J. J.; Jones, E. T. T.;
Hoogsteen, K.; Baum, M. W.; Grabowski, E. J. J. J. Org.
Chem. 1991, 56, 751–762; (b) Corey, E. J.; Bakshi, R. K.;
Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925–7926.
The progress of each reaction was followed by HPLC
after the ketone addition was complete.
15. Enantiomeric excess was determined by HPLC (Daicel
Chiralpak AD column, 0.46 cm×25 cm, 5 mL injection,
40°C, 210 nm, 99:1 hexane:ethanol, 1 mL/min, 16 min
run, (R) 10.06 min, (S) 11.04 min).
16. Cai, D.; Tschaen, D.; Shi, Y.-J.; Verhoeven, T. R.;
Reamer, R. A.; Douglas, A. W. Tetrahedron Lett. 1993,
34, 3243–3246.
17. Using catalyst (R)-3b, the reaction was performed on 150
g of 2%-fluoroacetophenone, generating 1 with 98% ee and
in 96% yield. The stereochemical assignment of this
product was confirmed by comparison of the specific
rotation with published values (Ref. 1).
18. The optimum conditions call for mixing (S)-2 (2.0 g,
0.075 equiv.), tert-BuOMe (30.3 mL), and DEANB (22.5
mL, 1.2 equiv.). This solution was warmed to 45°C, and
a solution of ketone (14.5 g, 1.0 equiv.) in tert-BuOMe
(60.6 mL) was added over 0.75 h, while maintaining the
reaction temperature at 45°C. After the ketone addition
was complete, analysis indicated complete conversion to
1 (97.8% ee).
19. Standard workup: For a 1.1 mol reaction, the reaction
solution was cooled to 0–10°C under a rapid flow of
nitrogen and methanol (702 mL) added over about 20
min while the reaction temperature was maintained at
<10°C. Caution: the quench is exothermic and generates
H2 gas, so care should be taken when performing this
operation. Once the addition was complete, the solution
was warmed to room temperature and stirred for at least
0.5 h. The solvents were removed at 65°C and 500 mbar
to azeotropically distill the methanol (and toluene if it is
present) as well as to further quench and remove the
boron-containing reagents.
5. Douglas, A. W.; Tschaen, D. M.; Reamer, R. A.; Shi,
Y.-J. Tetrahedron: Asymmetry 1996, 7, 1303–1308 and
references cited therein.
6. Salunkhe, A. M.; Burkhardt, E. R. Tetrahedron Lett.
1997, 38, 1523–1526.
7. Masui, M.; Shioiri, T. Synlett 1997, 3, 273–274.
8. Santhi, V.; Rao, J. M. Tetrahedron: Asymmetry 2000, 11,
3553–3560.
9. Stone, G. B. Tetrahedron: Asymmetry 1994, 5, 465–472.
10. Wilkinson, H. S.; Tanoury, G. J.; Walk, S. A.;
Senanayake, C. H. Org. Process Res. Dev. 2002, 6, 146–
148. The catalyst used in this study was prepared from
enantiomerically pure cis-1-amino-2-indanol, not 2.
11. Available in bulk from Aldrich Chemical Company and
Callery Chemical Company.
12. While (R)-MeCBS was readily available, (R)-2 was more
expensive than (S)-2 on a small scale. Therefore, (S)-2
was used for the in situ generation of catalysts. This leads
to (R)-1, as would be expected.
13. Surveyor is a product of Argonaut Technologies.
14. Using statistically designed experiments (DoE) these fac-
tors were evaluated in 30 runs. Typical procedures are as
follows:
The resulting residue was diluted with tert-BuOMe (935
mL) and washed with 1N aqueous HCl (935 mL). The
organic layer was removed and set aside, while the
aqueous layer was back-extracted with tert-BuOMe (935
mL). The organic layers were combined and washed with
1N HCl (935 mL), water (935 mL) and 10% brine (935
mL). The organic solution was dried over MgSO4 (70 g),
the solution was filtered, and the solvents removed result-
ing in 1 as a colorless, free-flowing oil, typically of >98%
purity.
3b: DEANB (0.66–1.1 equiv.) was mixed with 3b (1 M in
toluene, 0.02–0.15 equiv.) and solvent (3.5 mL). The
solution was warmed to the reaction temperature (20–
55°C), and the ketone solution (1.0 equiv. in 7 mL of
solvent) was added over 5–30 min while maintaining the
reaction at the desired temperature.
3a: (S)-2 (0.075 equiv.) was dissolved in tert-BuOMe (3.5
mL) and DEANB (1.1–2.0 equiv.). The solution was
warmed to the reaction temperature (20–45°C), and the