Asymmetric transformation of ß- and γ-functionalized alcohols : Study of combined ruthenium-catalyzed racemization and enzymatic resolution

• Main Author: Träff, Annika
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: Institutionen för organisk kemi 2011
• Subjects: Kinetic resolution; dynamic kinetic resolution; kinetic asymmetric transformation; dynamic kinetic asymmetric transformation; enzyme catalysis; racemization; asymmetric synthesis; chlorohydrin; cyano acetate; amino alcohol; metalloenzyme; bifunctional catalytic system; Organic Chemistry; Organisk kemi; Antarc*; Antarctica
• Online Access: http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-56947

The major part of this thesis describes the asymmetric synthesis of β- and γ-amino alcohols through the combination of ruthenium catalyzed racemization and enzymatic kinetic resolution. The dynamic kinetic resolution, DKR, protocol for chlorohydrins was improved by employing Bäckvall’s catalyst, which is a base activated racemization catalyst, in combination with Burkholderia cepacia lipase. These optimized conditions broadened the substrate scope and improved the yields and ee’s of the obtained chlorohydrin acetates. The utility of the method was demonstrated in the synthesis of (S)-salbutamol. In the second part of the thesis, DKR was utilized in the enantio-determining step of the total synthesis of (R)-duloxetine. Optimized DKR conditions, combining Bäckvall’s catalyst together with Candida antarctica lipase B, afforded a β-cyano acetate in high yield and ee. (R)-Duloxetine was accessible through synthetic alterations of the enantioenriched β-cyano acetate in high overall yield. A dynamic kinetic asymmetric transformation, DYKAT, protocol to obtain enantio- and diastereomerically pure γ-amino alcohols was developed. In a first step N-Boc-aminoketones were obtained in high enantiomeric purity through a proline-catalyzed Mannich reaction. Subsequent in situ reduction coupled with a highly efficient DYKAT yielded γ-amino acetates in high dr and ee. The γ-amino alcohols were available through simple hydrolysis/deprotection with retained stereochemistry. In the final part of the thesis a heterogeneous bifunctional catalytic system is reported, which combines the catalytic properties of transition metal-catalyzed racemization with enzymatic acylation. A novel ruthenium-phosphonate complex was synthesized and then covalently anchored to the active site of solid supported Candida antarctica lipase B. The partially inhibited beads proved to be catalytically active both in racemization as well as enzymatic acylation. At the time of the doctoral defense, the following papers were unpublished and had a status as ...