Preparation of chiral cycloalkanols such as endo-5-norbornen-2-o

Details Preparation of chiral cycloalkanols such as endo-5-norbornen-2-o Preparation of chiral cycloalkanols such as endo-5-norbornen-2-o

1997-12-23

2000-06-13

Carr, Deborah D.

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

Organic compounds

Fatty compounds having an acid moiety which contains the...

568820, C07C 6700

Patent

active

060751568

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to a process for the manufacture of endo-5-norbornen-2-ol or related cycloalkanols as their racemates or as their enantiomers.


BACKGROUND OF THE INVENTION

Racemic endo-5-norbornen-2-ol can be obtained by heating dicyclopentadiene with vinyl acetate. The reaction requires a high temperature (typically >160.degree. C.) at which the dicyclopentadiene is in equilibrium with the monomer cyclopentadiene that then undergoes Diels-Alder cycloaddition with the vinyl acetate. Pre-cracked cyclopentadiene cannot be used, as it dimerises faster than it reacts with the vinyl acetate. A consequence of the use of vinyl acetate is that, at the temperature of the reaction, it generates a significant pressure and specialised reactors are needed to contain this. The use of such specialised equipment adds markedly to the process cost.
The enantiomers of the 5-norbornen-2-ol which are of value as intermediates for pharmaceutical agents can be obtained by biocatalytic resolution, typically by treatment of an ester such as the acetate in a water-containing system with a lipase where one enantiomer is hydrolysed preferentially; see Eichberger et al, Tetrahedron Lett. (1986) 27:2843; and Oberhauser et al, Tetrahedron (1987) 43:3931. Alternatively, they can be obtained by biocatalyst-mediated esterification of the racemic alcohol with an acyl donor such as vinyl acetate in an organic solvent.
An issue following such a biotransformation is separation of the products. When these are the norbornenol and its acetate, the separation is difficult owing to the similarity of their physical properties; their boiling points are too similar for separation by distillation. While chromatographic separation is effective, that is not amenable to large-scale operation.


SUMMARY OF THE INVENTION

This invention is based in part on the realisation that an easier separation of the products from a biocatalytic resolution of endo-5-norbornen-2-ol should result if the ester is derived from a higher molecular weight carboxylic acid than is the acetate. Where the feedstock is derived from the vinyl acetate cycloaddition, then either the ester has to be exchanged for another, or the acetate has to be hydrolysed to the alcohol and that esterified under biocatalysis with a donor such as vinyl butyrate. The norbornenol and esters such as the butyrate thus derived were separable readily by either distillation or partitioning between water and a hydrophobic organic solvent such as heptane. In principle, the appropriate substrates for the hydrolytic mode of biotransformation could be obtained by carrying out the cycloaddition with a higher vinyl ester such as vinyl butyrate, vinyl hexanoate, or vinyl laurate. Such higher vinyl esters are readily available as a result of their use as monomers in the polymer industry.
It has been discovered that these higher vinyl esters were effective in the cycloaddition reaction with cyclopentadiene, surprisingly forming the required product as cleanly as did the vinyl acetate, despite the addition of the extra carbons which might have been thought to reduce reactivity and give more opportunities for unwanted reactions. Moreover, when the vinyl ester was vinyl hexanoate or a higher ester, the cycloaddition reaction could be performed without a pressure vessel, simply by heating a mixture of cyclopentadiene and the vinyl ester at reflux. The product, e.g. 5-norbornen-2-yl hexanoate, was then available directly as a substrate for the biotransformation; the product (R)-endo-norbornenol from that biotransformation, using an enzyme such as Candida cylindracea lipase (CCL), was easily separable from the residual ester by distillation.
As a further feature of this invention, it has been discovered that the higher vinyl esters transformed with the CCL biocatalyst at a greater rate than the acetate for a given amount of enzyme. This in turn results in improved process cost through the saving in time or saving in enzyme (less enzyme used for the same time period).
Therefore, according

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