Mono thiomalonates as thioester enolate equivalents - organocatalytic stereoselective addition reactions to different electrophiles

Clerici, Paolo. Mono thiomalonates as thioester enolate equivalents - organocatalytic stereoselective addition reactions to different electrophiles. 2013, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_10350

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Thioesters naturally occur as building blocks for the in vivo synthesis of biologically active compounds. Thioester-containing molecules are the equivalents of activated carboxylic acid and can undergo to a wide range of modifications. One of the most well known examples is the addition reaction of malonyl-S-CoA to acetyl-S-CoA to generate polyketides or fatty acids.
Synthetic chemists have ha for many years a general and broad interest in thioesters. The synthetic versatility of this functional group is one of the key features that attracted the attention of chemists and led to several methods for synthesising aldehydes ketones or amides starting from thioester that are well established and utilised on a regular basis.
The objective of this thesis is to establish efficient way to promote the addition of thioester enolates with various electrophiles under mild organocatalytic reaction conditions.
The Wennemers group, in 2007, developed organocatalysed reaction between thioester enolate equivalents and electrophiles. Inspired by nature an early example for the decarboxylative addition of malonic acid half thioesters to nitroolefins under mild organocatalytic conditions was presented.
Thioesters have typically low reactivity towards electrophiles due to the relatively low acidity of the protons in the a-position of the carbonyl group. In this thesis we want to demonstrate the utility of monothiomalonates (MTMs) as a new class of thioester enolates equivalents specifically designed to tackle the low reactivity of thioesters towards bases. We envisioned that the presence of both a thioester and a regular ester attached to the same methylidene would increase the acidity of this position.
The newly designed molecules undergo the organocatalytic 1,4-conjugate addition reaction with nitroolefins. The transformation is catalysed by as little as 1 mol % of cinchona alkaloids (thio)urea derivatives yielding the products in excellent yields and enantioselectivities (91 - >98% yield, 91 - >99% ee).
The mild organocatalytic condition and the high yields and stereoselectivity of the 1,4-addition reaction render this protocol very useful for accessing g-nitrothioesters. These compounds are densely functionalised and possess unique chemical properties. In fact, all of the obtained products are valuable building blocks for further transformations, thus making the strategies exploiting these thioester enolates very appealing for synthetic purposes.
The synthetic versatility of the 1,4-addition products is demonstrated by converting them into e.g. aldehydes, ketones, pyrrolidinones or amides.
MTMs are tested also for the organocatalytic addition reactions to other electrophiles such as diazodicarboxylaes, a,b-unsaturated sulfones or maleimides to expand the utility of this new class of nucleophiles therefore providing synthetic protocols for he synthesis of biologically active compounds or small natural compounds.
Advisors:Wennemers, Helma
Committee Members:Pfaltz, Andreas
Faculties and Departments:05 Faculty of Science > Departement Chemie > Former Organization Units Chemistry > Bioorganische Chemie (Wennemers)
UniBasel Contributors:Wennemers, Helma and Pfaltz, Andreas
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:10350
Thesis status:Complete
Number of Pages:136 S.
Identification Number:
edoc DOI:
Last Modified:22 Jan 2018 15:51
Deposited On:07 May 2013 09:19

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