Diastereoselective hydrogenation of 1,3-hydroxyketones

Details Diastereoselective hydrogenation of 1,3-hydroxyketones Diastereoselective hydrogenation of 1,3-hydroxyketones

2003-07-02

2004-11-02

Shippen, Michael L. (Department: 1621)

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

Organic compounds

Oxygen containing

C549S313000, C560S060000, C560S186000, C564S201000

Reexamination Certificate

active

06812368

ABSTRACT:

This invention relates to a novel process of diastereoselective hydrogenation of 1,3-hydroxyketones.
Stereoselective preparation of the 1,3-diol function has great utility in organic chemistry due to the occurrence of such a group in natural products. Besides enzymatic routes, there are also transition-metal-catalysed hydrogenation reactions described. For example, in
Eur. J. Org. Chem
. 1999, 1787-1793, the enantioselective homogeneous catalysis using rhodium- or ruthenium-bisphosphane complexes are described. However, the different proposed routes are not fully satisfactory.
It is therefore an object of the instant invention to provide for a hydrogenation process using a simple, commercially available heterogeneous catalyst which can be filtered off after the reaction. It is a further object that the process has a good selectivity and that the hydrogenation proceeds fast. It is also an object to provide for a process not using expensive compounds. A further object is a process which does not necessarily require low temperature thus avoiding cooling equipment. An even further object is a process whereby the waste problems are minimised.
Surprisingly, it has now been found that the addition of magnesium salts to a heterogeneous catalytic system based on platinum catalysts significantlyimproves the diastereoselective hydrogenation of 1,3-hydroxyketones. A further surprising improvement, especially with regard to the overall conversion and the diastereomeric ratio is observed when a catalytic amount of an oxidant such as H
2
O
2
is added to the reaction mixture.
In general, the beneficial effects of the inventive reaction are observed for a large structural variety of 1,3-hydroxyketones and in general at least an increase in the conversion is observed by the addition of a magnesium salt and the optional addition of a catalytic amount of an oxidant. Such increase is in particular also observed for acyl derivatives of 1,3-hydroxyketones and 1,3-hydroxyketones which are twice substituted in the 2-position.
The invention especially relates to a process, wherein a compound of formula (I)
wherein R, R′ and R″ are independently of each other a radical being compatible with the reaction conditions,
except compounds wherein
a) one R is H and the other R is —CH
2
CN, R″ is H and R′ is —C(═O)OR
b
and R
b
is a H or a carboxy-protecting group;
b) one R is H and the other R is —CH
2
C(═O)NR*R**, R″ is H and R′ is —C(═O)OR
b
and R* and R** are independently of each other H or an amide-protecting group and R
b
is H or a carboxy-protecting group;
c) one R is H and the other R is —CH
2
C(═O)OR
b
, R″ is H and R′ is —CH
2
—N
3
and R
b
is H or a carboxy-protecting group; and
d) one R is H and the other R is —CH
2
C(═O)OR
b
, R″ is H and R′ is —CH
2
—R
d
and R
b
is H or a carboxy-protecting group and R
d
is halogen;
is reduced with hydrogen to the corresponding diol, which is predominantly in the form of the syn-diol, in the presence of a magnesium salt and a heterogeneous platinum catalyst in a solvent.
Unless otherwise indicated, halogen is preferably fluorine, chlorine, bromine or iodine.
Suitable compatible radicals R, whereby the two radicals R must be different from each other, are for example H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkyl-alkyl, cycloalkylalkoxy, aryl, aryloxy, aralkyl, aralkoxy, —CH
2
CO
2
R
4
, —CHR
4
CO
2
R
5
, —CO
2
R
4
, —CH
2
C(O)NH
2
, —CH
2
C(O)NHR
4
, —CH
2
C(O)NR
4
R
5
, —CHR
4
C(O)NH
2
, —CHR
4
C(O)NHR
5
, —CHR
4
C(O)NR
5
R
6
, —C(O)—NH
2
, —C(O)—NHR
4
and —C(O)—NR
4
R
5
, wherein R
4
, R
5
and R
6
are independently from each other alkyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl; to the extent possible said radicals may be branched or unbranched and may be unsubstituted or substituted. Preferred radicals R are H, alkyl (most preferred C
1
-C
12
-alkyl), aryl (most preferred phenyl or naphthyl), —CH
2
CO
2
R
4
, —CHR
4
CO
2
R
5
, —CO
2
R
4
, —CH
2
C(O)NH
2
, —CH
2
C(O)NHR
4
, —CH
2
C(O)NR
4
R
5
, —CHR
4
C(O)NH
2
, —CHR
4
C(O)NHR
5
, —CHR
4
C(O)NR
5
R
6
, —C(O)—NH
2
, —C(O)—NHR and —C(O)—NR
4
R
5
which independently of each other may be unsubstituted or substituted. Also preferred are compounds where at least one radical R is H or lower alkyl, whereby H is particularly preferred. Suitable substituents are apparent from the given lists of compatible radicals and protecting groups. Preferred substituents are halogen, oxygen, nitrogen, hydroxy and lower alkoxy.
Suitable compatible radicals R′ or R″ are for example H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkyl-alkyl, cycloalkylalkoxy, aryl, aryloxy, aralkyl, aralkoxy, halogen, —OH, —OR
4
, —OC(O)R
4
, —NH—C(O)—R
4
, —NR
4
—C(O)—R
4
, —CO
2
R
4
, —C(O)—NH
2
, —C(O)—NHR
4
, and —C(O)—NR
4
R
5
, wherein R
4
and R
5
are independently from each other alkyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl; to the extent possible said radicals may be branched or unbranched and may be unsubstituted or substituted. Preferred radicals R′ are H, alkyl (most preferred C
1
-C
12
-alkyl), aryl (most preferred phenyl or naphthyl), —CO
2
R
4
, —C(O)—NH
2
, —C(O)—NHR
4
, and —C(O)—NR
4
R
5
which may be unsubstituted or substituted. Preferred radicals R″ are H, alkyl (most preferred C
1
-C
12
-alkyl), cycloalkyl and aryl (most preferred phenyl or naphthyl) which independently of each other may be unsubstituted or substituted. Suitable substituents are apparent from the given lists of compatible radicals and protecting groups. Preferred substituents are halogen, oxygen, nitrogen, hydroxy and lower alkoxy.
The prefix “lower-” or “lower” indicates that the radical in question contains preferably up to 7 carbon atoms, especially up to 4 carbon atoms. Lower alkyl is therefore preferably C
1
-C
7
-alkyl, especially C
1
-C
4
-alkyl, and may be unbranched or branched one or more times, insofar as possible. Cyclic radicals, such as cycloalkyl, have at least 3 carbon atoms, especially from 3 to 7.
Carboxy-protecting groups are especially ester-forming, enzymatically and/or chemically removable protecting groups, preferably enzymatically and/or chemically removable protecting groups, such as heptyl, 2-N-(morpholino)ethyl, cholinyl, methoxyethoxyethyl or methoxyethyl; or those which are primarily chemically removable, e.g. alkyl, such as lower alkyl, especially methyl, ethyl, substituted lower alkyl (except for benzyl and substituted benzyl), such as substituted methyl, especially 9-fluorenylmethyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, pivaloyloxymethyl, phenylacetoxymethyl, triisopropylsilylmethyl, 1-3-dithianyl-2-methyl, dicyclopropylmethyl, acetonyl, phenacyl, p-bromophenacyl, &agr;-methylphenacyl, p-methoxyphenacyl, desyl, carbamidomethyl, p-azobenzenecarboxamidomethyl, N-phthalimidomethyl or 4-picolyl, 2-substituted ethyl, especially 2-iodo-, 2-bromo- or 2-chloro-ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2′-pyridyl)ethyl, 2-(p-methoxyphenyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, 2-(4-acetyl-2-nitrophenyl)ethyl or 2-cyanoethyl, tert-butyl, 3-methyl-3-pentyl, 2,4-dimentyl-3-pentyl or &ohgr;-chloro-lower alkyl, especially 4-chlorobutyl or 5-choropentyl, cyclopentyl, cyclohexyl, lower alkenyl, especially allyl, methallyl, 2-methylbut-3-en-2-yl, 3-methylbut-2-enyl or 3-buten-1-yl, substituted lower alkenyl, especially 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl or &agr;-methylcinnamyl, lower alkynyl, such as prop-2-ynyl, phenyl, substituted phenyl, especially 2,6-dialkylphenyl, such as 2,6-dimethylphenyl, 2,6-diisoproylphenyl, 2,6-di-tert-butyl-4-methylphenyl, 2,6-di-tert-butyl-4-methoxyphenyl, p-(methylthio)phenyl or pentafluorophenyl, benzyl, substituted benzyl, especially triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-

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