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Synthesis of bifunctional alkenes for nucleophile-controlled selenocyclizations

Khokhar, Shaista S. 2005. Synthesis of bifunctional alkenes for nucleophile-controlled selenocyclizations. PhD Thesis, Cardiff University.

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Synthesis of an olefin containing two functional groups, a hydroxy and an acid functionality has been successfully achieved. A methodology for highly selective cyclizations with phenylselenenyl electrophiles has been developed. The exclusive formation of substituted tetrahydrofurans can be achieved using triflate as the counterion and with the addition of acetic acid, whereas cyclizations can also be directed towards complete formation of lactones using hexafluorophosphate or sulfate as the counterion and methanol as an additive. A series of chiral diselenides were synthesized and employed in cyclization of bifunctional olefins. Highest selectivity was obtained with a chiral methoxy substituted alcohol diselenide. A comparison of endo- versus exo-cyclization was estimated using dihydroxy olefins with selenium and iodine electrophiles. The obtained results showed highest diastereomeric ratios in the endo-cyclization compared to exo-cyclization. Cyclization reactions of olefins can lead to heterocycles, which serve as essential building blocks for the synthesis of useful natural products. The most common building blocks are based on lactone and substituted tetrahydrofuran structures and are commonly obtained from individual substrates. The aim was to synthesize an olefin that contained two functional groups: a hydroxy and an acid functional group. 5-exo-cyclization via the hydroxy group of this olefin with an electrophile resulted in substituted tetrahydrofurans while the cyclization via the acid functionality resulted in the formation of lactones. A series of reactions using different additives and a variety of counterions with selenium electrophiles led to the discovery of selective cyclization conditions of each cyclized product. Using phenylselenenyl triflate in the presence of acetic acid the reaction led exclusively to the formation of substituted tetrahydrofurans while lactones could be obtained using hexafluorophosphate or sulfate as a counterion and methanol as an additive. The selective synthesis of each cyclized product indicated the influence of additives on the course of cyclization. The additives (alcohol and the acid) were than incorporated into the selenium reagents. The expected coordination of the selenium electrophile to internal heteroatoms or to the substrate led to independent cyclization and there was no influence of additives on the course of cyclization. As expected, these modified achiral selenium reagents produced a 1:1 mixture of substituted tetrahydrofurans and lactones. The enantioselectivity of known chiral selenium electrophiles containing the heteroatom in a 1,3-relation to the selenium was studied in the reaction with this olefin and the highest selectivity was found with the methoxy substituted alcohol diselenide. To increase the selectivity the synthesis of new chiral selenium reagents were attempted. The synthesis of modified sulfur selenium reagents was carried out according to the reference of Tiecco et al. but showed a lower selectivity in reaction with this substrate. To investigate the results between 5-endo and 5-exo -cyclization other bifunctional olefins containing a dihydroxy functionality were synthesized. The reaction of these olefins with selenium and iodine electrophiles gave a comparison of endo- versus exo-cyclization. The major isomer from exo-cyclization was the cis isomer while in endo-cyclization it was the trans isomer.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
ISBN: 9781303165283
Date of First Compliant Deposit: 30 March 2016
Last Modified: 10 Oct 2017 15:27

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