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Title: Enantioselective syntheses of pharmaceutically important molecules using lithiation/borylation methodology
Author: Roesner , Stefan Kurt
ISNI:       0000 0004 5915 3060
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2014
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The application of lithiationiborylation of benzylic carbamates and subsequent protodeboronation methodology for the syntheses of the antidepressant drug (+ )-seltraline, the monoamine reuptake inhibitor (+ )-indatraline, the muscarine receptor anatagonist (R)-tolterodine, the antiandrogen bifluranol and the potential oestrogen receptor-based imaging agent fluorohexestrol is reported. In addition, a strategy towards the synthesis of the antituberculosis drug bedaquiline is discussed. However, some modifications of the standard conditions in the lithiationlborylation reaction were found to be necessary. In the syntheses of (+)-sertraline and (+)-indatraline involving homoallylic carbamate 1, it was necessary to add a crown ether or to carry out a solvent exchange from diethyl ether to CHCb to achieve efficient 1,2-metallate rearrangement of the intermediate boron-ate complex. For the synthesis of (R)-tolterodine the addition of MgBr2 in MeOH was needed. Thus, tertiary boronic esters 2 were obtained in high yield and with high enantioselectivity with retention of the stereo centre. After protodeboronation to provide gel11- diarylalkyls 3, the intermediates were converted to provide (+)-serh'aline, (+)-indatraline and (R)-tolterodine. Our lithiationlborylation methodology has also been applied to the syntheses of bifluranol and fluorohexestrol. By using a convergent synthetic strategy both stereo genic centres were generated by two subsequent lithiationibOlylation reactions followed by protodeboronation. Bifluranol was obtained after further elaboration of tertiary boronic ester 4. For the synthesis of fluorohexestrol employing sterically more hindered coupling partners, the use of a more of a more electrophilic borane species was necessalY to afford intermediate tertiaty borane 5.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available