[78603-95-9]  · C17H21NO  · 2-Amino-3-methyl-1,1-diphenyl-1-butanol  · (MW 255.36) (.HCl)

[130432-39-2] (R)

[86695-06-9] (.HCl)


(precursor to Itsuno's reagent, a chiral oxazaborolidine catalyst1 used for the enantioselective reduction of prochiral ketones,2 oxime O-ethers,2c,d,3 and imines4)

Alternate Name: 1,1-diphenylvalinol.

Physical Data: mp 94-95 °C; [a]589 -127.7° (c 0.693, CHCl3) for the (S) enantiomer.

Solubility: very sol THF, CH2Cl2, MeOH; not very sol water.

Preparative Method: from valine methyl ester hydrochloride and excess Phenylmagnesium Bromide in 56% yield.2

Purification: recrystallization from ethanol-water (10:1).

Handling, Storage, and Precautions: no special information available. In general, however, it is advisable that all reactions with this reagent be conducted in a well ventilated fume hood. Care should be exercised to avoid contact of this reagent and the derived oxazaborolidine catalyst with the eyes and skin.

Stoichiometric Enantioselective Ketone Reduction.

The oxazaborolidine-borane complex (3) prepared in situ from diphenylvalinol (1) and Borane-Tetrahydrofuran (2 mol equiv) (eq 1) will enantioselectively reduce a variety of prochiral ketones (eq 2, Table 1).2 Free oxazaborolidine (2) is ineffective stoichiometrically as an enantioselective reducing agent. The asymmetric catalyst (3) works best for the reduction of aryl alkyl ketones, providing very high levels of enantioselectivity (94-100% ee). In the case of dialkyl ketones, the best enantioselectivity (78% ee) is obtained for the reduction of t-butyl methyl ketone. Reduction of acylsilanes affords the corresponding carbinols in moderate to high enantioselectivity (50-94% ee).5

Reduction of a-chloroacetophenone using the catalyst prepared from the related (S)-diphenylisoleucinol (4) and borane gives (S)-chlorohydrin (5), which is readily transformed to (S)-styrene oxide (eq 3).3a The reduction affords the (S) enantiomer of (5) due to chlorine having a higher priority in nomenclature, not a change in the enantiofacial selectivity of the asymmetric catalyst.

Catalytic Enantioselective Ketone Reduction.

Although free oxazaborolidine (2) is ineffective by itself as an enantioselective reducing agent, Corey demonstrated that it can be used catalytically (0.025-0.5 equiv) with excess borane (0.6 mol equiv) for the enantioselective reduction of acetophenone (eq 4).6 A mechanism was proposed to explain the behavior of the catalyst. Initial coordination between the Lewis acidic ring boron and the ketonic oxygen activates the ketone towards reduction. Intramolecular hydride transfer from the BH3 coordinated to the ring nitrogen then occurs via a six-membered ring cyclic transition state. In addition, oxazaborolidine (6) prepared from a,a-diphenyl-2-pyrrolidinemethanol (eq 5) was reported to be an even better catalyst for the reduction of ketones. For a more detailed discussion, see the entries for a,a-Diphenyl-2-pyrrolidinemethanol and Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole.

Recently, Katz employed oxazaborolidine (2) to catalyze the enantioselective reduction of ketone (7) (eq 6). The resultant carbinol was used for the synthesis of optically active helical metallocene oligimers.7

Enantioselective Reduction of Oxime O-Ethers.

In addition to the reduction of prochiral ketones, oxazaborolidine (3) has been used (both stoichiometrically and catalytically with borane-THF) to catalyze the enantioselective reduction of prochiral ketoxime O-ethers to the corresponding amine (eq 7).2c-d,3 Unlike the ketone reduction described above, the (S)-oxazaborolidine catalyst gives (S)-amines. The best enantioselectivity is obtained for the case where R = Me (Table 2). Addition of a Lewis acid, such as Aluminum Chloride, to the oxime increases the rate of reduction (complete reaction in 3 h vs. 24 h).

Enantioselective Reduction of Imines.

Oxazaborolidine (3) also enantioselectively reduces N-substituted ketimines to the corresponding N-substituted amine in low to moderate ee (eq 8, Table 3).4a In this case the enantioselectivity is the same as the reduction of ketones; thus the (S)-oxazaborolidine catalyst gives (R)-amines. Oxazaborolidine (3) is reported to provide higher enantioselectivity than oxazaborolidine (6). An interesting application of this reaction is the preparation of a (aRS,S) diastereomerically enriched (63% de) sample of the more active atropisomers of the herbicide Metalochlor (eq 9).4b

Related Reagents.

a,a-Diphenyl-2-pyrrolidinemethanol; Ephedrine-borane; Norephedrine-Borane; Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole.

1. (a) Wallbaum S.; Martens, J. TA 1992, 3, 1475. (b) Singh, V. K. S 1992, 605.
2. (a) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. CC 1983, 469. (b) Itsuno, S.; Hirao, A.; Nakahama, S.; Yamazaki, N. JCS(P1) 1983, 1673. (c) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. JOC 1984, 49, 555. (d) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.; Ito, K.; Hirao, A.; Nakahama, S. JCS(P1) 1985, 2039. (e) Itsuno, S.; Nakano, M.; Ito, K.; Hirao, A.; Owa, M.; Kanda, N.; Nakahama, S. JCS(P1) 1985, 2615.
3. (a) Itsuno, S.; Sakurai, Y.; Ito, K.; Hirao, A.; Nakahama, S. BCJ 1987, 60, 395. (b) Itsuno, S.; Sakurai, Y.; Shimizu, K.; Ito, K. JCS(P1) 1989, 1548. (c) Itsuno, S.; Sakurai, Y.; Shimizu, K.; Ito, K. JCS(P1) 1990, 1859.
4. (a) Cho, B. T.; Chun, Y. S. JCS(P1) 1990, 3200. (b) Cho, B. T.; Chun, Y. S. TA 1992, 3, 337.
5. Buynak, J. D.; Strickland, J. B.; Hurd, T.; Phan, A. CC 1989, 89.
6. Corey, E. J.; Bakshi, R. K.; Shibata, S. JACS 1987, 109, 5551.
7. Katz, T. J.; Sudhakar, A.; Teasley, M. F.; Gilbert, A. M.; Geiger, W. E.; Robben, M. P.; Wuensch, M.; Ward, M. D. JACS 1993, 115, 3182.

David J. Mathre & Ichiro Shinkai

Merck Research Laboratories, Rahway, NJ, USA

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