[1845-25-6]  · C10H16O2  · (1S,2S,5S)-2-Hydroxypinan-3-one  · (MW 168.26) (1R,2R,5R)


(chiral auxiliary for the asymmetric synthesis of a-substituted a-amino carboxylic acids,1,2 phosphonic acids,3 and phosphinic acids,4 and of a-substituted benzylamines5 and (2-pyridyl)methylamines;6 resolution of racemic a-amino acids7)

Alternate Name: (1S,2S,5S)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one.

Physical Data: mp 36-38 °C; bp 245 °C; d 1.059 g cm-3;[a]20D -37° (c =  0.5, CHCl3).

Solubility: sol CHCl3, CCl4, ether, methanol, hot pentane.

Form Supplied in: available as the neat compound.

Analysis of Reagent Purity: NMR.

Preparative Method: prepared by oxidation of a-pinene.8

Purification: distillation, or recrystallization from pentane.

Handling, Storage, and Precautions: no reported instability or toxicity.

Asymmetric Synthesis of a-Amino Acids.

Chiral ketimines prepared from the title ketone and glycinates can be deprotonated and treated with electrophiles, such as alkyl halides (eq 1),1 or Michael acceptors,2 to give a-substituted a-amino acids with moderate to excellent levels of diastereoselectivity.

The product imine diastereomers can usually be separated by chromatography, which enables synthesis of enantiomerically pure a-amino acids even if the reaction is not completely diastereoselective, and provides an alternative to the resolution of racemic a-amino acids.7 The imine is cleaved by mild hydrolysis with aqueous citric acid or by reaction with hydroxylammonium acetate.

This method is of special value for the synthesis of a,a-disubstituted a-amino acids.1b,d Analogous chiral ketimine glycinates prepared from camphor1e,9a or a protected D-galactodialdehyde9b are also synthetically useful, and in some cases give higher diastereoselectivities; with these reagents, however, separation of the imine diastereomers by chromatography does not seem to be possible. Several other chiral glycinate enolate equivalents have been reported, many of which give excellent levels of selectivity.10 If the synthetic objective is to prepare b-hydroxy-a-amino acids by reaction of a chiral glycinate with a carbonyl compound, one of these alternative reagents should be chosen.

Asymmetric Synthesis of a-Substituted a-Amino Phosphonic and Phosphinic Acids.

The title reagent can also be used to prepare chiral Schiff bases from a-amino phosphonic3 and phosphinic4 acid esters. Deprotonation and alkylation then gives a-substituted products with good to excellent diastereoselectivity (eq 2). Chromatographic separation of the imine diastereomers is often possible, giving access to enantiomerically pure products after hydrolysis. The corresponding Schiff bases prepared from camphor sometimes give higher diastereoselectivities in reactions with activated alkyl halides.11 A useful alternative reagent based on a chiral phosphonamide has also been reported recently.12

Asymmetric Synthesis of a-Substituted Benzylamines and (2-Pyridyl)methylamines.

A strategy for the synthesis of chiral a-substituted benzylamines (eq 3)5 and (2-pyridyl)methylamines6 by alkylation of chiral ketimines has also been developed.

Ketimines derived from benzylamine and camphor can also be alkylated, but these reactions generally give lower diastereoselectivities.13 Alternative approaches based on a chiral oxazoline or chiral oxazolidinones have been reported;14 however, these reagents often give lower diastereoselectivities or problems with partial racemization during the reaction sequence required for cleaving off the chiral auxiliary.

1. (a) Oguri, T.; Kawai, N.; Shioiri, T.; Yamada, S. CPB 1978, 26, 803. (b) Bajgrowicz, J. A.; Cossec, B.; Pigiere, C.; Jacquier, R.; Viallefont, P. TL 1983, 24, 3721. (c) Bajgrowicz, J.; El Achquar, A.; Roumestant, M.-L.; Pigiere, C.; Viallefont, P. H 1986, 24, 2165. (d) Tabcheh, M.; El Achqar, A.; Pappalardo, L.; Roumestant, M.-L.; Viallefont, P. T 1991, 47, 4611. (e) Jiang, Y.; Zhou, C.; Piao, H. SC 1989, 19, 881.
2. Minowa, N.; Hirayama, M.; Fukatsu, S. BCJ 1987, 60, 1761.
3. (a) Jacquier, R.; Ouazzani, F.; Roumestant, M.-L.; Viallefont, P. PS 1988, 36, 73. (b) Ouazzani, F.; Roumestant, M.-L.; Viallefont, P.; El Hallaoui, A. TA 1991, 2, 913.
4. McCleery, P. P.; Tuck, B. JCS(P1) 1989, 1319.
5. Chen, Y.; Mi, A.; Xiao, X.; Jiang, Y. SC 1989, 19, 1423.
6. Mi, A.; Xiao, X.; Wu, L.; Jiang, Y. SC 1991, 21, 2207.
7. Bajgrowicz, J. A.; Cossec, B.; Pigiere, C.; Jacquier, R.; Viallefont, P. TL 1984, 25, 1789.
8. Carlson, R. G.; Pierce, J. K. JOC 1971, 36, 2319.
9. (a) McIntosh, J. M.; Leavitt, R. K.; Mishra, P.; Cassidy, K. C.; Drake, J. E.; Chadha, R. JOC 1988, 53, 1947. (b) Schöllkopf, U.; Tölle, R.; Egert, E.; Nieger, M. LA 1987, 399.
10. (a) Kim, B. M.; Williams, S. F.; Masamune, S. COS 1991, 2, Chapter 1.7.2. (b) Paterson, I. COS 1991, 2, Chapters 1.9.2 and 1.9.5. (c) Caine, D. COS 1991, 3, Chapter 1.1.6. (d) Fitzi, R.; Seebach, D. T 1988, 44, 5277. (e) Oppolzer, W.; Pedrosa, R.; Moretti, R. TL 1986, 27, 831.
11. Schöllkopf, U.; Schütze, R. LA 1987, 45.
12. Hanessian, S.; Bennani, Y. L. TL 1990, 31, 6465.
13. Jiang, Y.; Liu, G.; Liu, J.; Zhou, C. SC 1987, 17, 1545.
14. Gawley, R. E.; Rein, K.; Chemburkar, S. JOC 1989, 54, 3002.

Tobias Rein

The Royal Institute of Technology, Stockholm, Sweden

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