Enantioselective Synthesis of Drug-like Molecules via Axially-Chiral Intermediates

The self-regeneration of stereocenters via stereolabile axially-chiral intermediates (SRSvSACI) is a synthetic strategy in which the configuration of a starting material, possessing only a single stereocenter, directs the formation of a chiral axis in an intermediate. The reaction proceeds stereospecifically, although the original stereocenter is destroyed through trigonalization. This is due to the stereochemical information encoded in the chiral axis, which is transformed into the configuration of a stereocenter in the product. In this research, we investigate the generation of axially chiral intermediates arising from both (S)-methyl lactate derivatives and 1,4-benzodiazepin-2,5-dione derivatives. For the deprotonation/alkylation of O-Bn and O-TBS substituted (S)-methyl lactate derivatives containing achiral oxazolidinones, we hypothesized that a twisted amide enolate featuring a chiral C(O-)-N axis could sufficiently impart stereochemical information and control the selectivity of the reaction. Previous work completed by Kobayashi showed in related compounds (E)- vs (Z)-enolate formation could be controlled through the identity of the 2'-oxygen substituent with –Bn affording the (E)-enolate and –TBS affording the (Z)-enolate. We investigated the utilization of achiral oxazolidinone moieties to selectively generate axial chiral intermediates that could then control the facial selectivity of sequential alkylations. Unfortunately, unforeseen synthetic difficulties prevented successful accomplishment of our project goals. We also utilized axially chiral intermediates in the generation of 3,3-disubstituted quinolone-2,4-diones. The target compounds serve as potentially useful drug scaffolds, yet synthetic access to them has remained limited due to the lack of commercial availability of the corresponding enantiopure quaternary substituted amino acids. Prior work in the Carlier group demonstrated the preferential (M)-conformer deprotonation demonstrated by 1,4-benzodiazepin-2,5-diones, and through the installation of an N4-tert-butyloxycarbonyl protecting group, we were able to take advantage of this preferential (M)-conformer deprotonation and generate 3,3-disubstituted quinolone-2,5-diones through an acyl-amino variant of the Chan rearrangement. In general, these reactions were highly enantioselective proceeding with little to no loss of enantiomeric excess. Finally, we collaborated with Professor Bloomquist to test the topical toxicity of selected ring-contracted products against adult Anopheles gambiae, the African vector of malaria.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2016

Author dc:creator

• Richoux, Gary Michael Jr.

Chair dc:contributor.committeechair

• Carlier, Paul R.

Committee members dc:contributor.committeemember

• Etzkorn, Felicia A.
• Kingston, David G. I.
• Santos, Webster L.

• Memory of Chirality
• benzodiazepine
• rearrangement
• SRSvSACI

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

vt_gsexam:8578

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/71675