(1R,2R,3S,5R), [168286-10-0]; (1S,2S,3R,5S), [69363-09-3]  · C10H19NO  · (MW 169.26)

(reagent used as a chiral source in stereoselective reactions)

Alternate Name: ATBH, 3-amino-2-hydroxypinane

Physical Data: (1R,2R,3S,5R) mp 48-49.5 °C, [a]D22 +13.1 (c 1.0, CHCl3);1 (1S,2S,3R,5S) mp 45-46.5 °C, [a]D22 -14.3 (c 1.0, CHCl3).1

Solubility: soluble in most organic solvents; e.g. THF, CH2Cl2, CHCl3, EtOAc.

Form Supplied in: colorless crystals; not commercially available.

Analysis of Reagent Purity: 1H NMR, IR, elemental analysis.

Preparative Methods: optically pure (1R,2R,3S,5R)-3-amino-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol (ATBH) can be prepared from optically impure (1R,5S)-a-pinene (1).1 Oxidation of (1R,5S)-a-pinene (81% ee) with potassium permanganate and subsequent reaction with hydroxylamine affords the a-hydroxy oxime, which is recrystallized from ethyl ether-hexane to give the enantiomerically enriched product. Reduction of the a-hydroxy oxime with lithium aluminum hydride furnishes (1R,2R,3S,5R)-ATBH in optically pure form. (1S,2S,3R,5S)-ATBH can also be prepared in the same way from (1S,5R)-a-pinene (91% ee).1

Purification: recrystallization from ethyl acetate-hexane.

Handling, Storage, and Precautions: hygroscopic crystals. Use in a fume hood.

Asymmetric Borane Reduction

The reaction of ATBH with trimethylboroxine by refluxing in toluene affords the chiral B-methyl oxazaborolidine in high yield (2).1 This oxazaborolidine can serve as an efficient catalyst for the asymmetric borane reduction of prochiral ketones (3).2 The corresponding chiral secondary alcohols are obtained in high yields with good enantioselectivities.

Reaction of ATBH with trimethyl borate in THF presumably affords the B-methoxy oxazaborolidine, which effectively catalyzes asymmetric borane reduction of prochiral ketones. Thus the borane reduction of acetophenone with the reagent prepared in situ from 0.1 equiv of ATBH and 0.12 equiv of trimethyl borate provides (S)-2-phenethyl alcohol in 93% yield with 95.5% ee (4).3 This method offers some advantages in its inexpensiveness and simplicity of the procedure.

Stereoselective Reduction of a-Oxoketoxime Ethers

The in situ generated catalyst from ATBH and trimethyl borate has also been used in the stereoselective reduction of a-oxoketoxime ethers to prepare the corresponding chiral 1,2-amino alcohols.4 Thus the asymmetric borane reduction of buta-2,3-dione monoxime ether followed by acidic work-up and subsequent reaction with benzyloxycarbonyl chloride affords a 90% yield of N-(Z)-3-aminobutan-2-ol with excellent enantioselectivities (5). A trityl group in the oxime ether is required for high enantioselectivity. This method has been successively applied to both cyclic and acyclic a-oxoketoxime ethers.

The modified procedure for asymmetric borane reduction is applicable to the stereoselective synthesis of N-benzoylsphinganine.5 Reduction of a-oxoketoxime trityl ethers 1 and 2 using catalyst prepared in situ from (1R,2R,3S,5R)-ATBH and trimethyl borate proceeds in high yields with high enantioselectivities (6). Satisfactory results are obtained by employing the borane-N,N-diethylaniline complex as a reducing agent. In the reduction of substrate 1, the predominant diastereomer is threo. On the other hand, the reduction of 2 proceeds with excellent erythro selectivity.

Stereoselective Alkylation

Chiral tricyclic lactams can be prepared from (1R,2R,3S,5R)-ATBH and g-keto acids by heating in toluene with a catalytic amount of p-toluenesulfonic acid (7).6 Enolization of the resulting lactams with sec-butyllithium, followed by trapping with methyl iodide, furnishes the methylated products in high diastereoselectivity. Subsequent enolization and alkylation with benzyl bromide affords a single diastereomer in 82% yield. Further acidic hydrolysis in butanol provides the desired ester with a quaternary asymmetric center (7).6

Related Reagents.


1. Masui, M.; Shioiri, T., Tetrahedron 1995, 51, 8363.
2. Masui, M.; Shioiri, T., Synlett 1996, 49.
3. Masui, M.; Shioiri, T., Synlett 1997, 273.
4. Masui, M.; Shioiri, T., Tetrahedron Lett. 1998, 39, 5195.
5. Masui, M.; Shioiri, T., Tetrahedron Lett. 1998, 39, 5199.
6. Roth, G. P.; Leonard, S. F.; Tong, L., J. Org. Chem. 1996, 61, 5710.

Moriyasu Masui

Aburahi Laboratories, Shionogi & Co., Ltd., Japan

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