Process for preparing (s)- and (r) -but-3-en-2-ol and the derivatives thereof from l-or d-lactic acid esters

A novel process for preparing enantiomerically pure (S)- or (R)-but-3-en-2-ol compounds includes the following reaction steps: PA1 (a) reacting an alkyl ester of D- or L-lactic acid with a hydropyran compound to obtain a lactate ester having a hydropyranyl ether group, PA1 (b) reducing the lactate ester with an aluminum hydride at a temperature below 0.degree. C. to obtain a propionaldehyde having a hydropyranyl ether group, PA1 (c) reacting the propionaldehyde with an alkyl phosphonium salt to obtain a 3-butene having a hydropyranyl ether group, and PA1 (d) cleaving the hydropyranyl ether group to prepare the enantiomerically pure (S)- or (R)- but-3-en-2-ol.

The present invention relates to a new process for preparing (S)-and 
(R)-but-3-en-2-ol (1-buten-3-ol or methylvinylcarbinol) and the 
derivatives thereof of general formula 1a and 1b, respectively, 
##STR1## 
wherein R.sub.2 may denote hydrogen and C.sub.1-6 -alkyl, starting from L- 
and D-lactic acid esters, respectively. C.sub.1-6 -alkyl generally denotes 
a branched or unbranched hydrocarbon radical having 1 to 6 carbon atoms, 
which may optionally be substituted by one or more halogen 
atoms--preferably fluorine--which may be identical to one another or 
different. The following hydrocarbon radicals are mentioned by way of 
example: methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 
1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 
2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 
2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 
3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 
1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 
3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 
1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. 
Unless otherwise specified, lower alkyl groups having 1 to 4 carbon atoms, 
such as methyl, ethyl, propyl, isopropyl, butyl and tert.-butyl are 
preferred. 
Enantiomerically pure butenols are of great importance as synthons for the 
preparation of enantiomeric secondary products--particularly for the 
synthesis of pharmaceutical active substances--of 1-buten-3-ols. 
Processes for preparing the individual stereoisomers of methylvinylcarbinol 
are known from the prior art. 
Thus, J. Kenyon et al. [J. Kenyon and D. R. Snellgrove, J. Chem. Soc., 
1926, 1169] describe a process which makes it possible to obtain 
S(+)-but-3-en-2-ol, starting from an enantiomer mixture of the 
methylvinylcarbinol, via the phthalic acid hemiesters thereof and 
subsequently subjecting them to racemate cleavage by means of brucine and 
saponification of the desired stereoisomer of the phthalic acid hemiester. 
The disadvantage of this reaction sequence consists essentially in the 
fact that numerous crystallisation steps have to be gone through. 
In addition, T. Ibrahim et al. [T. Ibrahim, T. J. Grattan and J. S. 
Whitehurst, J. Chem. Soc. Perkin Trans I, 1990, 3317] describe a process 
starting from 3-chlorobutan-2-one which is first reduced by means of yeast 
to the corresponding (2S, 3S)- and (2S,3R)-3-chlorobutan-2-ols. The 
subsequent etherification with 2-methoxypropene and dehydrohalogenation 
with potassium tert.-butoxide finally produces the desired 
(S)(+)-but-3-en-2-ol. 
A disadvantage of this reaction sequence is that the reduction with yeast 
can only be carried out in a very high dilution and consequently the 
production of a relatively small amount of the butenol requires a 
relatively large reactor volume. 
Furthermore, T. Yoshida et al. [T. Yoshida, M. Kaneoya, M. Uchida and H. 
Morita, Japanese Published Application 1-132 399 dated 24 May 1989) 
describe a process for the so-called optical cleaving of 
(R,S)-2-buten-3-ol in which, after reaction with tributyrine and 
subsequent enzymatic treatment, the two stereoisomeric butenols can be 
made available. However, this process suffers from a poor yield and 
results in products having poor characteristics. 
Moreover, G. Giacomelli et al. [G. Giacomelli, A. M. Caporusso and L. 
Lardicci, Tetrahedron Lett. 22 (1981) 3663] describe the asymmetric 
reduction of 1-buten-3-one using optically active trialkylalkanes. In the 
reaction described therein, however, the (R)-1-buten-3-ol can only be 
obtained in and enantiomeric excess (e.e.) of 7%. 
A higher enantiomeric excess is yielded by a reaction described by H. C. 
Brown et al. [H. C. Brown and G. G. Pai, J. Org. Chem. 50 (1985) 1384] in 
which 1-buten-3-one is stereoselectively reduced with so-called 
Alpine-Borane.RTM. (B-(3-pinanyl)-9-borabicyclo[3.3.1]nonane). In this 
way, (R)-1-buten-3-ol can be obtained in an enantiomeric excess (e.e.) of 
60% after a reaction time of 5 days, for example, but only in a yield of 
30%. 
The aim of the present invention is to make (R)- and 
(S)-3-buten-2-oles--and the derivatives thereof--available in high yields 
and in a high enantiomeric excess and to develop a process for preparing 
them which avoids the disadvantages of the processes known from the prior 
art. 
These objectives are achieved by means of the process described hereinafter 
and illustrated in the Examples, starting from commercially available D- 
or L-lactic acid alkylesters, the corresponding alkylesters and especially 
the ethylesters being preferred. 
The process according to the invention consists of four reaction steps: 
In the first reaction step the free hydroxyl group--for example that of the 
L-lactic acid ethylester (2)--is protected. Protection is achieved by 
means of protecting groups known from the prior art which are resistant to 
reducing agents [T. W. Greene and P. G. M. Wuts, Protective Groups in 
Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc., New York, 1991, 
p. 10 ff.]. Preferably the tetrahydropyranyl protecting group is used. The 
hydroxyl group is protected using the methods which are also known per se 
from the prior art. In a preferred embodiment the hydroxyl group of the 
ethyl lactate is etherified in bulk with 3,4-dihydro-2H-pyran in the 
presence of a catalytic quantity of an acid in a temperature range from 
-10.degree. to +50.degree. C. 
##STR2## 
However, the reaction may also be carried out in the presence of a solvent, 
the suitable solvents including all those which have no detrimental effect 
on the course of the reaction. Halogenated hydrocarbons such as 
dichloromethane may be mentioned by way of example. 
Preferably, an inorganic acid is used as the acid, hydrochloric acid being 
particularly preferred. The reaction is carried out in a temperature range 
from 0.degree. to 40.degree. C. 
Then the reaction mixture is fractionally distilled, whilst any solvent 
present is usefully distilled off beforehand and the lactic acid ester 
thus protected is isolated. 
In the second step of the reaction, reduction of the ethyl lactate prepared 
in the first reaction step is carried out to produce the corresponding 
propanal derivative (4), which can also be carried out in accordance with 
the processes known from the prior art [R. C. Larock, Comprehensive 
Organic Transformations--A Guide to Functional Group Preparations, 
VCH-Publishers, Weinheim 1989, p. 621 and loc. cit.]. Preferably the 
reduction is carried out with optionally complex aluminium hydrides, of 
which organoaluminium hydrides such as dialkylaluminium hydrides, e.g. 
diisobutylaluminium hydride (DIBAH) or alkalialkoxyaluminium hydride, and 
also complex alkali-organoaluminium hydrides such as 
lithium-tris-(tert.-butoxy)aluminium hydride or 
sodium-bis-(methoxy-ethoxy)aluminium hydride (Vitride.RTM.), are 
preferred. DIBAH is particularly preferred as reducing agent in the form 
of a 35% solution in toluene. 
##STR3## 
The reduction is preferably carried out in a solvent. Suitable reaction 
media include all the organic solvents which have no harmful effect on the 
reduction reaction. 
These include, in particular, aliphatic or aromatic hydrocarbons such as 
petroleum ether, benzene, toluene, xylene, of which toluene is 
particularly preferred. The reduction is carried out at temperatures below 
0.degree. C., preferably in the range from -50.degree. to -20.degree. C. 
and particularly preferably at -40.degree. C. particularly preferably at 
-40.degree. C. 
For working up, the reaction mixture is first subjected to hydrolysis, 
preferably using mixtures of lower aliphatic alcohols (such as methanol, 
ethanol, propanol and isopropanol) and water. It is particularly preferred 
to use a mixture of 100 parts by volume of water and about 37 parts by 
volume of methanol at a temperature of -40.degree. C. During hydrolysis, 
the temperature is also in the ranges specified above. After hydrolysis 
has ended the reaction mixture is allowed to warm up to ambient 
temperature (about 20.degree. C.), whereupon the aluminium hydroxide 
formed during hydrolysis is precipitated as a thick, liquid slurry. The 
aluminium hydroxide is separated off and the filtrate is evaporated down 
in vacuo, the residue remaining is fractionally distilled under reduced 
pressure and the resulting aldehyde (4) thus obtained is isolated. 
In the third reaction step the aldehyde (4) is converted into the desired 
alkene in a Wittig reaction [C. Ferri Reaktionen der organischen Synthese, 
Georg Thieme Verlag, Stuttgart, 1978, p. 354 and loc. cit.; J. March, 
Advanced Organic Chemistry, J. Wiley & Sons, New York, 1985, p. 845 and 
loc. cit.]. 
##STR4## 
The preparation of the desired phosphonium salts of type (5) - R.sub.2 
=C.sub.1-6 -alkyl--is also known from the prior art. When R.sub.2 is 
methyl as in the working Example, the final product is a but-3-en-2-ol, 
but when R.sub.2 is other than methyl, the final product is more 
appropriately referred to as an alk-3-en-2-ol. Preferably, 
alkyltriphenylphosphonium halides are used as so-called Wittig reagents. 
In order to prepare the alkene the aldehyde is added to a suspension of a 
solution of the phosphonium salt and a base. 
Suitable reaction media include all solvents which do not have a 
detrimental effect on the course of the reaction, including ethers such as 
di-n-butylether, glycoldimethylether, diglycoldimethylether, 
tetrahydrofuran, or sulphoxides such as dimethylsulphoxide or 
tetrahydrothiophene-1,1-dioxide (sulpholane). It is also possible to use 
mixtures of the above solvents. 
Tetrahydrofuran is particularly preferred as the reaction medium. The bases 
used are alkali organyls or alkoxyalkali compounds, of which lithium 
alkyls are preferred. It is particularly preferable to use n-butyllithium 
in the form of a 15% solution in n-hexane. 
The reaction temperature can vary within a wide range, depending on the 
particular reaction medium used, and is bounded at the bottom end of the 
range by an insufficient reaction speed and, at the top end of the range, 
by a preponderance of secondary reactions (e.g. the decomposition of the 
tetrahydrofuran by the lithium alkyls used as bases). 
It has proved advantageous to combine the phosphonium salt and the base at 
a temperature in the range from 0.degree. to 40.degree. C., the range from 
20.degree. to 25.degree. C. being particularly preferred. 
The carbonyl compound (4) can also be added within a relatively wide 
temperature range, whilst it should be mentioned that it has been found 
advantageous to cool the reaction solution during the addition. A 
temperature in the range from 0.degree. to 40.degree. C. is preferred, the 
range from 15.degree. to 20.degree. C. being particularly preferred. 
After the reaction has ended the phosphine oxide (or triphenylphosphine 
oxide) precipitated from the reaction mixture is separated off, e.g. by 
filtration, the filtrate is evaporated down under reduced pressure and the 
residue remaining is stirred with water. Then the resulting aqueous 
suspension is extracted with an organic extraction agent. Suitable 
extraction agents include solvents which are immiscible with water, of 
which, in the present case, aliphatic or aromatic hydrocarbons such as 
branched or unbranched alkanes, benzene, toluene or xylene are preferred. 
It is particularly preferred to use n-hexane as the extraction agent. 
The organic extraction solution is freed from water--optionally with the 
aid of a desiccant--and after separation of the desiccant it is evaporated 
down under reduced pressure and the residue is fractionally distilled, 
again under reduced pressure, and the resulting alkene of type (6) is 
isolated therefrom. 
Since there are a wide range of possible variants in carrying out the 
Wittig reaction, this makes it possible to choose other reaction media, 
bases and different reaction conditions, depending on the type of variant 
selected. 
In the fourth and last reaction step the protecting group is cleaved. The 
individual processes for cleaving the various protecting groups are also 
known from the prior art. [T. W. Greene and P. G. M. Wuts, Protective 
Groups in Organic Synthesis, 2nd Edition, J. Wiley & Sons, Inc. New York, 
1991, p. 10 ff]. In the process according to the invention the alkene (6) 
obtained in step 3 is dissolved in a suitable solvent. Suitable solvents, 
particularly for cleaving the tetrahydropyranyl protecting group, include 
organic acids such as acetic acid or alcohols such as methanol or ethanol, 
or polyalcohols, such as ethyleneglycol or glycerol, of which 
ethyleneglycol is particularly preferred. 
##STR5## 
The cleaving is carried out in the presence of an organic acid, organic 
sulphonic acids being preferred. It is particularly preferable to use 
p-toluenesulphonic acid. 
The reaction temperature may vary within a wide range, depending on the 
particular reaction medium used, and is bounded at the bottom end solely 
by too low a reaction speed and, at the top of the range, by the 
preponderance of secondary reactions. 
Preferably, the protecting group is cleaved at a temperature in the range 
from 0.degree. to 40.degree. C. and, particularly preferably, in the range 
from 20.degree. to 40.degree. C. and most preferably in the range from 
20.degree. to 25.degree. C. 
The isolation of the now unprotected alkenol of type (1) can be carried out 
in various ways, which are familiar to those skilled in the art. If the 
chemical and physical properties of the reaction product allow, it can be 
distilled off from the reaction mixture under reduced pressure. When 
solvents are used-which have a higher boiling point than the alkenol (1) 
it is also possible first to distil off the reaction medium and then to 
distil the reaction product, possibly fractionally. 
The process described here and in the Examples which follow yields, for 
example, the S(+)-but-3-en-2-ol in an optical purity of 98.9%. 
The objectives mentioned hereinbefore are achieved by means of the 
processes described in Examples 1-8. Various other embodiments of the 
process will be apparent from this specification to those skilled in the 
art. However, it is expressly pointed out that the Examples and the 
associated description are provided solely for the purposes of 
illustration and description and should not be regarded as restricting the 
invention. In particular, it is pointed out that the sequence of synthesis 
described in the Examples for preparing (S)-but-3-en-2-ol can be 
transferred to the preparation of the corresponding R-enantiomer. 
Similarly, any other desired L- or D-lactic acid alkylester may be used as 
the starting material.

EXAMPLE 
Preparation of S(+)-but-3-en-2-ol 
1st step: 
608.2 g (97% 5.0 mol) of ethyl L-lactate are placed in a 1.5 liter 
sulphating apparatus and within 15 minutes 433.0 g (5.0 mol) of 
3,4-dihydro-2H-pyran are added with stirring. The temperature falls from 
25.degree. C. to 20.degree. C. Then the solution is cooled to 0.degree. C. 
in a bath of ice/common salt and 4 ml of an ethereal hydrochloric acid 
solution are added dropwise in 2 minutes. The temperature slowly rises to 
12.degree. C. After 30 minutes' stirring, the cooling bath is removed, 
whereupon the temperature rises to 40.degree. C. within 30 minutes. The 
solution is stirred for 20 hours at 20.degree.-25.degree. C. Then the 
reaction solution is fractionally distilled through a column of filler 
having a mirror coating. 
Yield: 882 g of colourless oil (84% of theory) 
Bp.sub.0.4.times.10.sup.2.sub.pa : 91.degree. C. 
2nd step: 
1200 ml of absolute toluene are placed in a 4 liter sulphating apparatus 
rinsed out with nitrogen and 160 g (0.8 mol) of the tetrahydropyranylether 
prepared in reaction step 1 are added thereto with stirring. The solution 
is then cooled with a dry ice/acetone bath to a temperature of -40.degree. 
C. and within 60 minutes at -40.degree. C. 407 g (1.0 mol) of 
diisobutylaluminium hydride are added in the form of a 35% solution in 
toluene. The resulting mixture is then stirred for a further 2 hours at 
-40.degree. C. The reaction solution is hydrolysed within a period of one 
hour at a temperature of -40.degree. C. with a solution of 100 ml of 
distilled water and 36.7 ml of methanol. Then the cooling bath is removed 
and the reaction mixture is allowed to heat up to ambient temperature. 
Aluminium hydroxide is precipitated in the form of a thick slurry. It is 
stirred for 1 hour at a temperature of 25.degree. C. The precipitated 
aluminium hydroxide is suction filtered over a Seitz-K 400 filter lined 
with Celite filter clay and is then washed with 3.times.300 ml of toluene. 
The filtrate is then evaporated down at 40.degree. C under a pressure of 
53.3.times.10.sup.2 Pa and the residue is fractionally distilled in vacuo. 
Yield: 70 g of colourless oil (55.3% of theory) 
BP.sub.26.6.times.10.sup.2.sub.pa : 95.degree.-97.degree. C. 
3rd step: 
2400 ml of absolute tetrahydrofuran are placed in a 6 liter sulphating 
apparatus rinsed with N.sub.2 and 174 g (0.48 mol) of 
triphenylmethylphosphonium bromide are added with stirring. The suspension 
is mixed at ambient temperature, within one hour, with 264 ml (0.53 mol) 
of a 15% solution of butyllithium in hexane. The suspension dissolves, 
forming a yellow solution. This is then stirred for a further hour at a 
temperature of 20.degree.-25.degree. C. Then a solution of 70 g (0.44 mol) 
of the aldehyde resulting from step 2 in 600 ml of tetrahydrofuran is 
added dropwise to the Wittig reagent at a temperature in the range from 
15.degree.-20.degree. C. (ice cooling) within a period of 90 minutes. The 
solution decolorises and the resulting triphenylphosphine oxide is 
obtained in the form of colourless crystals. Stirring is continued for 2 
hours at a temperature of 20.degree.-25.degree. C. The triphenylphosphine 
oxide precipitated is filtered off through a pressure filter lined with 
Seitz-Filter K 400. The filtrate is evaporated down in vacuo and the 
residue is stirred with 1 liter of water. Then the suspension is extracted 
three times, each time with 500 ml of n-hexane. The combined extracts are 
dried with anhydrous sodium sulphate and, after the desiccant has been 
filtered off, evaporated down under a pressure of 20 kPa and at 40.degree. 
C. The residue is fractionally distilled in vacuo (temperature of 
refrigerator min. 0.degree. C.). 
Yield: 34 g of colourless oil (49.6% of theory) 
Bp.sub.26.6.times.10.sup.2.sub.pa : 70.degree.-71.degree. C. 
4th step: 
In a 250 ml three-necked flask, 34 g (0.22 mol) of the butene derivative 
isolated in reaction step 3 are dissolved in 110 ml of ethyleneglycol and 
4.2 g (22 mMol) of p-toluenesulphonic acid are added. After 2 hours 
vigorous stirring at 20.degree.-25.degree. C. the S(+)but-3-en-2-ol is 
distilled off from the reaction solution under a water jet vacuum at a 
bath temperature of 85.degree. C. and under a pressure of 35 Torr 
(46.1.times.10.sup.2 Pa). The refrigerator is loaded with coolant at 
-5.degree. C. 14 g of crude product are isolated which is distilled off 
under a water jet vacuum using a spiked tubular column. 
Yield: 10.2 g of colourless oil (64.4% of theory) 
Bp.sub.80.times.10.sup.2.sub.Pa 38.degree.-40.degree. C. 
[.alpha.]=D20+31.5.degree. pure d=0.832 
optical purity: 98.9% S(+)but-3-en-2-ol 1.1% R(-)but-3-en-2-ol