Year

2010

Degree Name

Doctor of Philosophy

Department

School of Chemistry

Abstract

An investigation into the design and synthesis of helical chiral ligands for atropoenantioselective Suzuki reactions was undertaken. The chiral synthesis of 2,2'- bipyrrolidine was the subject of primary investigations which focused on methods to prepare the key intermediate alkene - (4E)-1,8-di(benzyloxy)-4-octene - in high geometrical purity. The trans selective Wittig reaction provided the optimum stereoselectivity (E:Z, 97:3), albeit with a low chemical yield (30%). Subsequent Sharpless asymmetric dihydroxylation afforded (4R,5R)-1,8-di(benzyloxy)-4,5- octanediol (73%, 97% ee) and separately, its S,S-enantiomer (77%, 87% ee). These diols can be easily elaborated to the target enantiomers of 2,2'-bipyrrolidine with preservation of stereochemical integrity.

The first two stereoselective syntheses of (2S,2'S)-2,2'-biindoline were concurrently performed using (2R,2'R)-2,2'-bioxirane and (2S,2'S)-N,N'-di-tert-butoxycarbonyl-2,2'- biaziridine as chiral precursors. The copper catalysed ring opening of each heterocycle with 2-bromophenylmagnesium chloride provided two pathways to (2S,3S)-1,4-di(2- bromophenyl)-2,3-butanediamine, which was regioselectively cyclised under microwave assisted palladium catalysis. The synthesis of (2S,2'S)-2,2'-biindoline was thus achieved in five-steps with an overall yield of 5% (>99% ee) from the bioxirane and in three-steps with in an overall yield of 15% from the biazidirine (>99% ee). Crystallographic analysis of the biindoline and its corresponding palladium(II) dichloride complex unequivocally confirmed the structure, enantiomeric purity and absolute stereochemistry of the molecule.

The chiral bioxirane was also used in a highly stereoselective four-step synthesis of (2S,2'S)-N,N'-di-tert-butoxycarbonyl-2,2'-bipyrrolidine using acetonitrile as the carbanion source for the ring opening reaction. A chiral copper(II) complex was subsequently prepared from the parent compound for application in oxidative aryl homo-coupling reactions, however its precise structure is yet to be determined.

The preparation of the analogous phospholane and arsolane monomers was investigated using a one-pot diGrignard cyclisation strategy. The reaction of 1,4-di(bromomagnesio)butane at 0 oC with PhPOCl2 and separately, PhAsO, provided 1- phenylphospholane 1-oxide and 1-phenylarsolane in unoptimised yields of 23% and 12% respectively. The same electrophiles in combination with 1-bromomagnesio-2-(2- (chloromagnesio)ethyl)benzene at -78 oC afforded racemic mixtures of 1- phenylbenzophospholane 1-oxide (46%) and 1-phenylbenzoarsolane (20%). The labile dimethylamino moiety was also accommodated as a P-substituent in the cyclisation of the latter diGrignard, providing racemic dimethylaminobenzophospholane 1-oxide in 60% yield.

Share

COinS