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Title: Coupled catalytic cycles : development of a procedure for the dynamic kinetic resolution of amines
Author: Stirling, Matthew John.
ISNI:       0000 0001 3485 9858
Awarding Body: University of Huddersfield
Current Institution: University of Huddersfield
Date of Award: 2006
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Enantiomerically pure chiral amines are particularly important to the pharmaceutical and agrochemical industries. Due to the procedural operational simplicity the most common method for their synthesis on an industrial scale is kinetic resolution. However, this methodology has the inherent disadvantage of limiting the yield to a maximum of 50%. To overcome this drawback it is possible to combine the kinetic resolution with a simultaneous racemisation to give a theoretical yield of 100% in a procedure known as dynamic kinetic resolution. The most suitable method for amine resolution is via enzymatic acylation, however most known methods for amine racemisation require harsh conditions under which enzymes would be denatured. To date only three methods for amine dynamic kinetic resolution have been reported, all of which are not industrially viable. Herein we report the development of an amine dynamic kinetic resolution system using a novel iridium-based amine racemisation catalyst. Our initial attempts to utilise CATHyTM catalysts for amine racemisation proved unsuccessful, it did however reveal an unexpected property of the iridiumcatalysed CATHyTM of 6,7-dimethoxy- I -methyl-3,4-dihydroisoquinoline. During the asymmetric reduction of this substrate the enantiomeric excess of the product was observed to decrease with time. Initially this was suspected to be due to an in-situ racemisation, however our investigation disproved this and lead to the proposed system in which two catalytic species are present, one of which is (S)-selective and the other (R)-selective. During this investigation it was discovered that the iridium catalyst, pentamethylcyclopentadienyliridium (III) chloride dimer could be used as an amine racemisation catalyst. Further work found that the in-situ generation of the analogous iodo catalyst, pentamethylcyclopentadienyliridium (III) iodide dimer, led to a racemisation catalyst that was several orders of magnitude more active than the chloride species and more active than any previously reported amine racemisation catalyst. This iridium iodide catalyst was then synthesised and isolated and a standard amine racemisation protocol developed, which was utilised in the racemisation of a range of secondary amines and a tertiary amine. The catalyst also exhibited some activity towards the racemisation of amino acid esters. The attempted racemisation of primary amines led to the formation of dimeric impurities due to the reaction of the imine intermediate with the amine starting material. The catalyst was also shown to be able to racemise alcohols in the presence of a base, although the rate of hydrogen loss from the catalyst exceeded the rate of ketone hydrogenation and the reaction led to a quantitative conversion to ketone. The amine racemisation system using the pentamethylcyclopentadienyliridium (III) iodide dimer catalyst was then combined with an enzymatic resolution resulting in the dynamic kinetic resolution of 6,7-dimethoxy-l-methyl-1,2,3,4- tetrahydroisoquinoline in which the (R)-carbamate was isolated in 82% yield with 96% ee. This result constitutes the first example of a chemo-enzymatic dynamic kinetic resolution on a secondary amine using an organometallic amine racemisation catalyst.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available