Chemical process for preparing an optically active aminodiol

Details Chemical process for preparing an optically active aminodiol Chemical process for preparing an optically active aminodiol

1995-04-06

1997-08-19

Burn, Brian M.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

548512, 564184, 564360, 564414, 564448, C07C 5116

Patent

active

056590750

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP93/02219, filed Aug. 19, 1993.
This invention relates to a new process to an optically active aminodiol which may be used to prepare chiral carbocyclic analogues of nucleosides.
During the past two decades much attention has been given to the synthesis and biological studies of carbocyclic analogues of nucleosides. Recently, a number of approaches have appeared in the literature for the preparation of enantiomerically pure carba-2'-deoxyribonucleotides, for example chemoenzymatically, by asymmetric synthesis and by chromatographic and enzymatic resolution. A key synthetic precursor of the carbocyclic analogues of 2'-deoxyribonucleotides is [1S(1.alpha., 2.beta., 4.beta.)]-4-amino-2-hydroxymethyl-1-cyclopentanol, a compound of formula (I) below first described by L Otvos et al in Tetrahedron Letters, 28 (50), 6381-6384, 1987. ##STR1##
This paper described the preparation of the compound of formula (I) from an unsaturated bicyclic lactone, (+)-(1R,5S)-2-oxabicyclo[3.3.0]oct-6-en-3-one. The authors subsequently reported in Tetrahedron, 44(19), 6207-6216, 1988 an improved procedure from a bicyclic lactone diol.
We now describe herein a novel alternative procedure for the preparation of the compound of formula (I). Thus, according to one aspect of this invention, there is provided a multistep process for preparing the compound of formula (I) as depicted in Scheme 1 hereinafter. ##STR2## wherein R represents a suitable protecting group.
Step a for the preparation of the compound of formula (V) from the compound of formula (VI) comprises treating (VI) with a suitable base such as an organic amine [e.g. 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU)]. The reaction may conveniently be effected in an organic solvent such as a halogenated hydrocarbon (e.g. dichloromethane) at an elevated temperature (e.g. reflux).
Step b for the preparation of the compound of formula (IV) from the compound of formula (V) comprises treating (V) with a Lewis acid such as aluminium trichloride, zinc chloride, titanium tetrachloride or boron trifluoride etherate in a solvent such as a halogenated hydrocarbon (e.g. dichloromethane) conveniently in admixture with a hydrocarbon solvent (e.g. toluene) at about room temperature, followed by reduction with a suitable hydride reducing agent, for example an aluminium hydride reducing agent such as diisobutylaluminium hydride (DIBAL). The DIBAL may conveniently be added as a solution in a hydrocarbon solvent (e.g. toluene) and the reduction carried out at a reduced temperature (e.g. at about 0.degree. to 10.degree. C.). The reaction may be completed by addition of a suitable inorganic acid such as hydrochloric acid.
Step c for the preparation of compounds of formula (III) from the compound of formula (IV) comprises treating (IV) with a suitable reagent to introduce the protecting group R. The group R may, for instance, represent an aralkyl group such as benzyl which can be introduced under conventional conditions. Thus, for example, benzylation may be effected by adding a benzyl halide (e.g. benzyl bromide) to (IV) in a solvent such as a hydrocarbon (e.g. toluene), preferably in the presence of a base such as an alkali or alkaline earth metal carbonate or bicarbonate (e.g. potassium carbonate).
Step d for the preparation of compounds of formula (II) from compounds of formula (III) comprises treating (III) with a hindered hydroborating agent capable of complexing to a tertiary amide such as disiamylborane in a solvent such as an ether (e.g. tetrahydrofuran) at about room temperature, followed by peroxide oxidation, for example using hydrogen peroxide. The oxidation step may be carried out in the presence of a strong inorganic base such as sodium hydroxide and at a reduced temperature (e.g. 0.degree. to 15.degree. C.). The work-up conditions may provide a compound of formula (II) in the form of a salt (e.g. a hydrochloride salt).
Step e for the preparation of the compound of formula (I) from compounds of formula (II) comprises a conventional deprotection step. Thus, for

REFERENCES:
patent: 3474093 (1969-10-01), McCaully
patent: 3972944 (1976-08-01), Beregi et al.
M. Mahmoudian, et al., "Resolution of 4-Aminocyclopentanecarboxylic Acid Methyl Esters Using Hydrolytic Enzymes," Enzyme and Microbial Technology, 14, No. 11, pp. 911-916, Nov. 1992.
J. Beres, et al., "Stereospecific Synthesis of (+)-Carbocyclic 2'-Deoxyadenosine. An Improved Procedure for the Preparation of (+)-(1R,2S,4R)-4-Amino-2-Hydroxy-1-Hydroxy Methylcyclopentane," Tetrahedron, 44, No. 19, pp.6207-6215, 1988.
L. otvos, et al., "The First Stereospecific Synthesis of (+)-(1R,2S,4R)-4-Amino-2Hydro XY-1-Cyclopentanemethanol and (+)-Carbocyclic Thymidine," Tetrahedron, 28, No. 50, pp. 6381-6384, 1987.
Y. Fulmer Shealy, et al., "Carbocyclic Analogs of Thymidine Nucleosides and Related 1-Substituted thymines," J. of Heterocyclic Chemistry, 18, pp. 383-389, Aug. 1980.
Y. Fulmer Shealy, et al., "Carbocyclic Analogs of 2'Deoxyadenosine and 3'-Deoxyadenosine," Tetrahedron Letters, 27, pp. 2231-2234, 1969.

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