Asymmetric synthesis using branched selective hydroformylation

  • Rachael Pittaway

Student thesis: Doctoral Thesis (PhD)

Abstract

This thesis investigates the application of branched selective hydroformylation for the asymmetric synthesis of natural products and pharmaceutical intermediates. This includes the development of a CO-free asymmetric transfer hydroformylation (ATHF) reaction to deliver aldehydes in high enantiomeric excess from challenging 1,2- disubstituted unsymmetrical cis-stilbenes. Good yields and selectivities were found using a [Rh]/Ph-BPE catalyst and paraformaldehyde as the syngas surrogate. A weak trend in regioselectivity is reported, whereby the formyl group forms either proximal to the electron-withdrawing group or distal to a sterically hindering group. This chemistry was used for the synthesis of a precursor to the isoflavandiol, (S)-equol.

This thesis also explores the hydroformylation of allylglycine derivatives using the [Rh]/BOBPHOS catalyst to give high yields of amino-aldehydes, with >75% branched selectivity and high diastereoselectivity. The reaction synthesised an amino diol that is a precursor in a synthesis of the antibiotic, Nemonoxacin. This was improved upon by utilising a tandem hydroformylation-cyclisation reaction for the synthesis of the amino diol, via the hemiacetal intermediate. The tandem reaction was extended to the synthesis of hemiaminals, which upon reduction, were converted to a single piperidine diastereomer en route to the antibiotic, Nemonoxacin.

Tandem hydroformylation-cyclisation reactions were investigated further using the [Rh]/BOBPHOS catalyst for the hydroformylation of (R)-1-phenylpent-4-en-1-ol. This homoallylic alcohol was synthesised using a sequential manganese asymmetric hydrogenation and an isothiourea catalysed kinetic resolution to upgrade the enantioselectivity. The subsequent hydroformylation gave high branched selectivity and excellent diastereoselectivity (b:l = 3.5:1, d.r = 97:3). This was also achieved in a dual catalyst asymmetric transfer hydroformylation reaction, with only a small decrease in selectivity. A dual catalyst ATHF protocol was explored with other ligands, including Kelliphite, giving comparable results to AHF. The conclusions found here are hopefully the beginning of the application of a versatile catalyst ([Rh]/BOBPHOS) and methodology (AHF/ATHF) for the synthesis of important chiral molecules.
Date of Award6 Dec 2018
Original languageEnglish
Awarding Institution
  • University of St Andrews
SupervisorMatt Clarke (Supervisor)

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