The invention relates to a method of producing optically active, 4-substituted (S)-2-Oxazolidinones, novel (S)-2-oxazolidinones, novel, optically active (S)-amino alcohols and the use of these compounds.

The invention is relative to a method of producing optically active, 
4-substituted (S)-2-oxazolidinones of general formula IV 
##STR1## 
in which R stands for a space-filling, branched alkyl group with 5-10 C 
atoms which contains at least one tertiary C atom, as well as novel, 
optically active (S)-2-oxazolidinones of general formula IV, novel, 
optically active (S)-amino alcohols of general formula III 
##STR2## 
in which R stands for a space-filling, branched alkyl group with 5-10 C 
atoms which contains at least one tertiary C atom, which compounds of 
formula III are interesting as intermediates for the production of the 
compounds of formula IV. The invention also describes the use of the novel 
compounds. Optically active (S)-2-oxazolidinones and the corresponding, 
optically active amino alcohols which appear in their synthesis as 
intermediate (product) are extremely important substance classes in 
organic chemistry. They find broad application in asymmetric synthesis, in 
the production of pharmaceutical active substances such as e.g. peptides, 
in the synthesis of insecticides, the splitting of racemic mixtures and in 
other areas (see for further literature on these topics, among others, J. 
Org. Chem. 1993, 58, 3568). 
The use of optically active amino alcohols of the general formula III in 
asymmetric synthesis is very frequently based on the fact that amino 
alcohols with sterically demanding side groups are inserted into suitable 
derivatives with which an asymmetric catalysis or asymmetric induction is 
possible in the synthesis of daughter products. Examples for such amino 
alcohols are, among others, phenylglycinol (R=Ph), phenylalaninol 
(R=CH.sub.2 Ph), valinol (R=CHMe.sub.2) and tert.-leucinol (R=CMe.sub.3). 
These substances can be derivatized e.g. to optically active oxazolines 
and similar compounds which for their part can be used as ligands for 
highly active (potent) catalysts, e.g. in the asymmetric cyclopropanation 
and reduction of olefines, the hydrosilylation and reduction of ketones, 
in Diels-Alder reactions and nucleophilic substitutions (further 
literature e.g. in: Angew. Chem. 1991, 103, 556). 4-substituted 
2-oxazolidinones (Org. Synth. 1989, 68, 77 and lit. cited there), bicyclic 
lactams (Tetrahedron 1991, 47, 9503 and lit. cited there) and formamidines 
(Tetrahedron 1992, 48, 2589 and lit. cited there) are named as examples 
for daughter products of optically active amino alcohols which can be used 
in many ways in asymmetric synthesis. 
In the instances cited and in many others the side groups of the inserted, 
optically active amino alcohols of general formula III exert a directing 
influence for steric or stereoelectronic reasons on the reactions taking 
place on and with these molecules, from which the partially (at times) 
extremely high enantio- or diastereoselectivities of such subsequent 
reactions result. This directing influence is in many instances all the 
greater, the more space-filling the cited R side groups are (Angew. Chem. 
1991, 103, 556). Thus, the e.e. or d.e. obtained is frequently greater if 
the side group is a tert.-butyl group (R=CMe.sub.3) instead of an 
isopropyl group (R=CHMe.sub.2) (for examples, see among others: 
Tetrahedron Lett. 1990, 31, 6005; Tetrahedron 1992, 48, 2589; Angew. Chem. 
1987, 99, 1197; J. Am. Chem. Soc. 1988, 110, 1238). 
In view of these facts, the present invention has the problem of indicating 
a method of producing oxazolidinones which makes accessible in particular 
those derivatives with space-filling side chains which exceed, if 
possible, the steric demand of a tert.-butyl group in order to exert an 
even greater directing influence in asymmetric syntheses in this manner 
and therewith improve the enantio- and diastereoselectivity in these 
reactions even more. The invention also has the problem of indicating the 
preparation of novel oxazolidinone compounds as well as of novel, 
optically active (S)-amino alcohols and their use. 
These and other problems not explained in detail are solved by a method 
with the features of the characterizing part of claim 1. Advantageous 
method modifications are placed under protection in the method claims 
dependent on claim 1. Novel compounds constitute subject matter of claims 
17 and 18. 
The fact that an optically active (S)-amino alcohol of general formula III 
##STR3## 
in which R stands for a space-filling, branched alkyl group with 5-10 C 
atoms which contains at least one tertiary C atom, is converted in 
accordance with the invention into the corresponding, optically active 
4-substituted (S)-2-oxazolidinone of general formula IV 
##STR4## 
in which R has the significance indicated at III, in that the amino 
alcohol is acylated by reaction (conversion) with a chloroformic acid 
ester under pH control on the nitrogen and the intermediately formed, 
N-protected amino alcohol is then cyclized base-catalyzed to the 
(S)-2-oxazolidinones of general formula IV makes it possible under mild 
reaction conditions to prepare the sterically especially demanding 
compounds of formula IV striven for in a good yield. 
The acylation is carried out in the neutral to slightly basic range in a 
2-phase system of water and an organic solvent, preferably in a range of 
pH 6-10, especially preferably pH 7-8.5. Chloroformic acid methyl- and 
ethyl ester are especially preferred as chloroformic acid ester. The 
organic solvent must dissolve the reaction partners sufficiently well and 
be inert under the reaction conditions but can in principle be selected 
almost freely. Solvents with ether structure or hydrocarbons are 
preferred. It is especially preferable to use solvents which can be 
simultaneously used for the extraction of the amino alcohol of general 
formula III from aqueous phase, (for) the acylation with chloroformic acid 
ester, the following basic cyclization to the oxazolidinone of general 
formula IV and its crystallization since complicated and expensive solvent 
changes are then eliminated. According to the invention toluene and 
xylenes are quite particularly preferred for this purpose. 
The cyclization can be carried out with a plurality of bases; however, 
according to the present invention the simplest and most economical bases, 
namely alkali metal hydroxides, proved to be the most suited. Sodium 
hydroxide is quite particularly preferred, which is again preferably used 
in a finely granulated or powdered form. In addition, an elevated 
temperature of advantageously at least 50.degree. C. to the boiling point 
of the solvent used is favorable for achieving a complete cyclization. The 
alcohol released during the cyclization is distilled out of the reaction 
mixture if the reaction temperature is selected to be sufficiently high. 
When the reaction is over the base is advantageously neutralized by the 
addition of an equivalent amount of acid, the salt washed out with water 
and the oxazolidinone of general formula IV isolated and purified by 
cooling off, evaporation to low bulk and optional recrystallization. 
The optically active (S)-amino alcohols of formula III can basically be 
obtained from optically active L-amino acids of general formula II 
Compounds of formula II are preferably reduced 
##STR5## 
with hydridic reagents to the (S)-amino alcohols of general formula III. 
Reagents such as lithium aluminum hydride or especially alkali boron 
hydrides activated with an activator can be considered as reducing agents 
thereby. In the case of the alkali boron hydrides, lithium- and sodium 
boron hydride are preferred, of which the latter is especially preferred 
on account of its favorable price. 1.5-4, preferably 2-2.5 moles of the 
hydridic reducing agent, relative to 1 moles amino acid, are used for the 
reduction. 
Various reagents can be considered as activators, e.g. boron trifluoride 
etherate, trimethylchlorosilane, iodine, chlorine, hydrogen chloride or 
sulfuric acid (for further literature on such reduction systems for amino 
acids in general: J. Org. Chem. 1993, 58, 3568), of which iodine and 
sulfuric acid are especially preferable. Preferably, 1/2 mole odine or 
sulfuric acid relative to 1 mole alkali boron hydride is used thereby for 
the activation. 
Solvents with ether structure, especially 1,2-dimethoxyethane (DME) and 
tetrahydrofurane (THF), are particularly advantageous; however, in 
principle even other solvents such as alcohols or acetals can be 
considered for the reduction. The reduction can be carried out within a 
broad temperature range (approximately -20.degree. C.--boiling temperature 
of the solvent used); however, it is advantageous to proceed in such a 
manner that a solution of the activator is added dropwise to a suspension 
of sodium boron hydride and the amino acid of general formula II in a 
suitable solvent at 0.degree.-30.degree. C., which activator solution is 
in this solvent or another suitable solvent, and thereafter the mixture is 
heated several hours for completion of the reaction up to a maximum of the 
boiling temperature of the solvent used. After the mixture has cooled off, 
it is made acidic by adding alcohol, then water, then acid, preferably 
hydrochloric acid, then alkalized, preferably with sodium hydroxide 
solution, and the optically active amino alcohol of general formula III 
extracted with a suitable organic solvent under heating, if required. It 
can then, if desired, be distilled for further purification, crystallized, 
chromatographed or converted into a crystalline salt, e.g. a 
hydrochloride. 
On the other hand, the optically active L-amino acids of general formula II 
can be obtained in accordance with the invention from .alpha.-keto 
carboxylic acids of general formula I 
##STR6## 
in which R stands for a space-filling, branched alkyl group with 5-10 C 
atoms which contains at least one tertiary C atom. This preferably takes 
place by means of co-factor-dependent, enzymatic, reductive amination 
using dehydrogenases. 
It was especially surprising thereby, in no way foreseeable and especially 
advantageous in accordance with the invention that the enzymes used also 
accept .alpha.-keto acids of general formula I with their particularly 
space-filling R groups as substrates for the conversion into the L-amino 
acids of general formula II and that the products are also obtained with a 
high chemical and enantiomeric purity in good to very good yield. 
The compounds of general formulas III and IV are novel. 
Compounds of general formula II are novel if R is not neopentyl (R=CH.sub.2 
CMe.sub.3). 
The production of the compounds described in this invention is 
recapitulated in the following formula scheme: 
##STR7## 
In all, novel, optically active L-amino acids of general formula II, 
(S)-amino alcohols of general formula III and 4-substituted 
(S)-2-oxazolidinones of general formula IV as well as methods are made 
available by the present invention, according to which these compounds can 
be produced in a ready and reliable manner in good to very good yield and 
in very high chemical and especially enantiomeric purity. The compounds 
produced in this manner are used, among other areas, in the synthesis of 
pharmaceutical active substances and in asymmetric synthesis.

The compounds of the invention and the method of their production are 
explained in detail by the following examples: 
EXAMPLE 1 
(S)-neopentylglycinol 
50.8 g (0.35 mole) L-neopentylglycine were added to a suspension of 30.4 g 
(0.805 mole) sodium boron hydride in 250 ml DME. Then a solution of 21.5 
ml (0.4025 mole) sulfuric acid in 75 ml DME was added dropwise at a 
maximum of 10.degree. C. within 2.5 h and the mixture then heated 3 h to 
70.degree. C. After the mixture cooled off, 60 ml MeOH were added. The 
mixture was then rotated in, the residue taken up in 250 ml water and 45 
ml conc. hydrochloric acid and agitated for a while. After the addition of 
300 ml toluene the mixture was made basic with 65 ml 50% sodium hydroxide 
solution, heated to 70.degree. C., the organic phase separated off, 
filtered, evaporated to low bulk (90 g) and cooled to approximately 
5.degree. C. After filtration, washing with toluene and drying in a vacuum 
drying oven 40.0 g (87.1%) (S)-neopentylglycinol were obtained in the form 
of colorless crystals. 
The structure was corroborated by an NMR spectrum. 
______________________________________ 
.alpha.!D20: +5.9.degree. (c = 1, EtOH) Content (titration): 
&gt;99% 
______________________________________ 
C7H17NO 
Calc. C 64.07 H 13.06 N 10.67 
131.22 Obs. C 64.01 H 13.13 N 10.90 
______________________________________ 
EXAMPLE 2 
(S)-4-neopentyl-2-oxazolidinone 
130 g (0.99 mole) (S)-neopentylglycinol were suspended in 700 ml toluene 
and 100 ml water. 99 ml (1.03 mole) chloroformic acid ethyl ester were 
added dropwise at 20.degree.-25.degree. C. within 1 h, during which the pH 
was maintained with 30% sodium hydroxide solution at approximately 8. 
After 30 min subsequent agitation the mixture was heated to 70.degree. C. 
and the aqueous phase separated off. The organic phase was filtered and 
freed of residual water by azeotropic distillation. After the addition of 
2 g granulated sodium hydroxide the mixture was slowly heated. EtOH began 
to distill off at 95.degree. C., which was ended at 111.degree. C. bottom 
temperature. After the mixture had cooled off to 85.degree. C. and 3 g 
glacial acetic acid in 40 ml water were added, it was briefly agitated, 
the aqueous phase separated off and the organic phase washed again with 30 
ml water. After evaporation to low bulk to 300 g and cooling overnight to 
approximately 5.degree. C., 102.8 g (66.1%) 
(S)-4-neopentyl-2-oxazolidinone in the form of colorless crystals were 
obtained after removal filtration! by suction, washing and drying. The 
structure was corroborated by an NMR spectrum. 
______________________________________ 
.alpha.!D20: +9.3.degree. (c = 1, EtOH) 
Melt point: 94-95.degree. C. 
______________________________________ 
C8H15NO2 Calc. C 61.12 H 9.62 N 8.91 
131.22 Obs. C 61.25 H 10.02 N 8.99 
______________________________________ 
The mother liquor was evaporated and the residue recrystallized out of 200 
ml hexane, which yielded a further 28.3 g (18.2 %) product (total yield 
84.3%). 
EXAMPLE 3 
Synthesis of (S)-neopentylglycine 
31.53 g (0.5 mole) ammonium formate and 20.89 g (125 nmole) 2 keto 4,4 
dimethyl-pentanoic acid sodium salt are suspended in 400 ml of water, the 
pH value is adjusted with ammonia to pH 8.5 so that we have a solution and 
the volume is adjusted to 500 ml. Subsequently, 71.7 mg (0.1 mmole) 
NAD.sup.+.H.sub.2 O cofactor as well as 2000 U of leucine dehydrogenase 
(LeuDH) and 2500 U of formate dehydrogenase (FDH) are added. The 
temperature is set to 28.degree. C. The reaction is gently stirred and the 
pH value is adjusted to 8.2 during the reactin by a pH stat unit. As 
demonstrated by determining degree of conversion with HPLC, the reaction 
is finished after 48 h. The enzymes are separated via an ultra filter of 
pore size 10000 kDA and a solution is adjusted with ammonium to pH 9.5. 
Subsequently, the solution is clarified with 2% active charcoal and the 
almost colourless solution is concentrated at the rotary evaporator, the 
amino acid is crystallized, is separated via a funnel, is washed three 
times with small amounts of ethanol and is dried overnight in vacuum at 
50.degree. C. 
Yield: 15.4 g (84.9% of theoretical yield) 
Proof of identity: NMR spectrum 
Enantiomeric purity: &gt;99.8% e.e., as measured by chiral gas chromatography 
on chirasil-val. 
EXAMPLE 4 
Synthesis of (S)-3-methyl-isoleucine ((S)-3,3-dimethyl-norvalin) 
6.3 g (0.1 mole) ammonium formate and 1.67 g (10 mmoles) 
2-keto-3,3-dimethyl pentanoic acid sodium salt are suspended in 80 ml of 
water, the pH value is adjusted with ammonia to 8.2, so that the solids 
dissolve and the volume is adjusted to 100 ml. Subsequently, 14.34 mg 
(0.02 mmole) NAD.sup.+.3H.sub.2 O cofactor as well as 800 U of leucine 
dehydrogenase (LeuDH) and 500 U of formate dehydrogenase (FDH) are added. 
The temperature is set to 32.degree. C. During the reaction the system is 
gently stirred and the pH value is adjusted to 8.2 via a pH stat unit. 
After at most 72 h it is demonstrated via determination of degree of 
conversion by HPLC that the reaction is finished. The reaction solution is 
adjusted to pH 9.5 with ammonia and subsequently clarified with 2% active 
charcoal. The almost colourless solution is concentrated at a rotary 
evaporator, the amino acid is crystallized, is separated via a funnel, is 
washed three times with little ethanol and is dried overnight under vacuum 
at 50.degree. C. 
Yield: 1.17 g (80.6% of theoretical yield) 
Proof of identity: NMR spectrum 
Enantiomeric purity: &gt;99.9% e.e., as measured by chiral gas chromatography 
on chirasil-val. 
EXAMPLE 5 
Synthesis of (S)-homoneopentylglycine ((S)-5,5-dimethyl norleucin) 
Reaction and isolation were carried out analogously to example 4 with the 
exception that the reaction system was a suspension during the whole time 
of reaction and that the reaction was finished only after 96 h. 
Substrate charged: 1.81 g (10 mmole) of 2-keto-5,5-dimethyl-hexanoic acid 
sodium salt 
Yield: 1.08 g (67.9% of theoretical yield) 
Proof of identity: NMR spectrum 
Enantiomeric purity: &gt;99.9% e.e., as measured by chiral HPLC on 
Crownpak-CR+ column.