Process for the preparation of trans-(R,R)-actinol

Details Process for the preparation of trans-(R,R)-actinol Process for the preparation of trans-(R,R)-actinol

1998-10-20

2001-02-13

Padmanabhan, Sreeni (Department: 1621)

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

Organic compounds

Oxygen containing

C568S343000, C556S137000

Reexamination Certificate

active

06187961

ABSTRACT:

FIELD OF THE INVENTION
The present invention is concerned with a process for the manufacture of trans-(R,R)-actinol by diastereoselective transfer hydrogenation in the presence of an amino-amide-ruthenium complex as the catalyst.
BACKGROUND OF THE INVENTION
Optically active actinol is known inter alia as an important building block for the synthesis of carotenoids such as zeaxanthin [Pure & Appl. Chem. 51, 535-564 (1979)]. In known processes actinol is manufactured from the trimethylcyclo-hexadione levodione. One such process is based, for example, on the catalytic hydrogenation of levodione in the presence of Raney nickel with a low base content [Helv. Chim. Acta 59, 1832 (1976)]. The poor diastereoselectivity of the heterogeneous hydrogenation, which leads to a 3-4:1 mixture of trans-and cis-actinol, results, however, in a loss in yield by virtue of the complicated purification; moreover there is a danger of a racemization of the levodione under the reaction conditions used in the heterogeneous catalysis. An alternative purification using a suitable distillation column is described in EP-A 0 775 685, but the yields are modest. The interest in manufacturing methods which yield actinol with high enantiomeric and diastereomeric purity is as great now as it always has been.
Processes for the manufacture of alcohols from ketones by transfer hydrogenation are known. Thus, for example, R. Noyori et al. [Acc. Chem. Res. 30, 97-102 (1997)] have investigated the asymmetric transfer hydrogenation of aryl alkyl ketones, such as, for example, acetophenone, which can be hydrogenated with high optical and chemical yield in the presence of a hydrogen donor, e.g. isopropanol/potassium hydroxide or acetic acid/triethylamine, and a ruthenium complex. However, not only the chemical yields, but also the optical yields diminish considerable when, for example, dialkyl ketones are used as substrates.
Surprisingly, it has now been found that (R)-levodione can be converted into (R,R)-actinol in good chemical yield and in high optical yield by transfer hydrogenation in the presence of an amino-amide-ruthenium complex.
SUMMARY OF THE INVENTION
The invention is accordingly concerned with a process for the manufacture of trans-(R,R)-actinol (1)
by the diastereoselective transfer hydrogenation of levodione by hydrogenating (R)-levodione (2)
in the presence of a hydrogen donor, which simultaneously can be used as the solvent, and an amino-amide-ruthenium complex.
Specifically, this invention is directed to a process for the manufacture of trans-(R,R)-actinol (1)
which process comprises hydrogenating (R)-levodione (2)
in the presence of a hydrogen donor and a solvent or in the presence of a hydrogen donor which is simultaneously used as the solvent, and an amino-amide-ruthenium complex.
A further process of this invention is the above process wherein the amino-amide-ruthenium complex has the formula
RuH(L{—H})(Y)  I
wherein
Y signifies a neutral ligand, and
L signifies a group of formula
wherein
R
1
signifies alkyl which may be substituted with one or more fluorine atoms, alkenyl, alkynyl, cycloalkyl, aryl which may be substituted, heteroaryl, or camphor-10-yl,
R
2
and R
3
each independently signify hydrogen, alkyl, cycloalkyl, or aryl which may be substituted, or R
2
and R
3
together with —CH—(CH
2
)
n
—CH— form a carbocycle with 4 to 8 carbon atoms,
R
4
signifies hydrogen or alkyl, and
n signifies 0,1,2 or 3.
The above process where R
1
is aryl or heteroaryl, and R
2
and R
3
are independently aryl, of which aryl is unsubstituted or substituted with phenyl, halogen, alkyl, or alkoxy, is also part of this invention, especially where R
1
as heteroaryl is a five- to six-membered heteroaryl with O as the heteroatom. The above process where R
1
is phenyl, tolyl, anisyl, or naphthyl is also part of this invention, as is the above process where Y is unsubstituted or substituted benzene.
DETAILED DESCRIPTION OF THE INVENTION
For the process in accordance with the invention there is preferably used an amino-amide-ruthenium complex of the general formula
RuH(L{—H})(Y)  I
wherein
Y signifies a neutral ligand,
L signifies an optionally optically active, monosulphonylated diamine of the general formula
R
1
signifies optionally mono- or multiply-fluorinated alkyl, alkenyl, alkynyl, cycloalkyl, optionally mono- or multiply-substituted aryl, heteroaryl or camphor-10-yl,
R
2
and R
3
each independently signify hydrogen, alkyl, cycloalkyl or optionally mono- or multiply-substituted aryl, or R
2
and R
3
together with the associated grouping —CH—(CH
2
)
2
—CH— form a carbocycle with 4 to 8 carbon atoms,
R
4
signifies hydrogen or alkyl, and
n signifies 0, 1, 2 or 3.
The monosulphonylated diamine is present in the complex as a monoanion and is accordingly denoted in formula I as “L{—H}”.
In the scope of the present invention the term “substituted with one or more fluorine atoms”, otherwise expressed as “mono- or multiply-fluorinated”, means having at least one fluorine substituent to as many fluorines as the alkyl group so modified is capable of accepting; however one to five fluorines is preferred.
In the scope of the present invention the term “alkyl” embraces straight-chain or branched optionally chiral alkyl groups with 1 to 8 carbon atoms, preferably with 1 to 5 carbon atoms. “Alkoxy” is an alkyl as defined above bonded by an oxygen atom. Methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl and isopentyl are examples of alkyl groups. Similarly, methoxy, ethoxy, etc. are examples of alkoxy groups. Trifluromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl are examples of mono- or multiply-fluorinated alkyl groups.
The term “alkenyl” embraces straight-chain or branched alkenyl groups with 3 to 8 carbon atoms, e.g. allyl, 2-butenyl and 3-butenyl.
The term “alkynyl” signifies a straight-chain or branched alkynyl group with one triple bond and 3 to 8 carbon atoms, e.g. propynyl and butynyl.
The term “cycloalkyl” signifies a 3- to 7-membered alicyclic group, namely cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, of which cyclopentyl and cyclohexyl are preferred.
The term “unsubstituted or substituted aryl” or equally “aryl which may be substituted” or “optionally mono- or multiply-substituted aryl” preferably embraces a phenyl or naphthyl group, which can be unsubstituted, mono-substituted or multiply-substituted. As substitutents there come into consideration e.g. phenyl, halogen and straight-chain and branched alkyl and alkoxy groups with in each case 1 to 5 carbon atoms, whereby the multiply-substituted phenyl or naphthyl groups can have the same or different substituents. Of the alkyl and alkoxy groups the methyl and, respectively, methoxy group is preferred. Examples of optionally substituted aryl groups are phenyl, chloro-, bromo- and fluorophenyl, tolyl, anisyl, 2,4-dimethylphenyl as well as naphthyl.
The term “heteroaryl” embraces 5- or 6-membered heterocyclic groups featuring O, S or N as a ring member, i.e. heteroatom, such as, for example, furyl, thienyl, benzo-furyl, dibenzofuryl, xanthenyl, pyrrolyl and pyridinyl. The heterocyclic groups featuring O as the heteroatom are especially preferred.
Under the term “neutral ligand” there is to be understood in the scope of the present invention an arene (an aromatic ring which may have an aliphatic side-chain), especially benzene, naphthalene or tetralin, which in the case of benzene is unsubstituted or substituted, in particular which can be mono- or multiply-substituted with straight-chain or branched alkyl and/or alkoxy groups with in each case 1 to 5 carbon atoms, preferably methyl or methoxy groups, and/or with cycloalkyl groups. Examples of such ligands are benzene, p-cymene, toluene, anisole, xylene, 1,3,5-trimethylbenzene, p-dicyclohexylbenzene, naphthalene and tetralin.
The (R)-levodione used as the starting material in the process in accordance with the invention can be obtained, as is known, inter alia by fermentation and is

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