Abstract
A number of fluorinated versatile building blocks (synthons)
were developed for the synthesis of trifluoromethylated and gem -difluoromethylenated biologically
interesting compounds. Extensive studies have demonstrated that
fluorine atoms have profound stereoelectronic effects on neighboring
groups, leading to special performance of the fluorine-containing
compounds in reactions. It was found that, in comparison with their
nonfluorinated counterparts, a C-O bond adjacent to a CF2 group
was more stabilized which made it hard to be substituted in a SN 2
way; double bond next to fluorinated groups was too electron deficient
to participate in ring-closing-metathesis (RCM) reactions, and the
carbocation that was strongly destabilized by neighboring CF2 group
reacted immediately with nucleophilic molecules to produce unexpected
product and so on. Thus improved methodologies were developed to achieve
the desired transformations. The conformational analysis of difluorothiouridine
suggested that the gem -difluoro atoms
governed the overall conformation of the sugar ring and nucleobase.
The biological evaluation of the synthetic difluoromethylenated
azasugars towards eight glycosidases showed that the CF2 group
decreased the pK
a of azasugars
which enhanced their binding affinity and selectivity to glycosidases.
1 Introduction
2 Synthesis of Trifluoromethylated Building Blocks and their Application
for the Preparation of Biologically Interesting Molecules
2.1 Improved FSO2 CF2 CO2 Me/CuI
Method for the Synthesis of Trifluoromethylated Retinoid
2.2 Preparation of α-Trifluoromethyl-α,β-Unsaturated
Esters for the Synthesis of Trifluoromethylated Nucleosides and Prolines
2.3 Development of Trifluoropropenyl-Containing Synthons for
the Preparation of Trifluoromethylated Analogues of Amino Acids,
Sugars, and Macrolactones
3 Preparation of Difluoromethylenated Building Blocks and their
Application for the Synthesis of Difluoromethylenated Nucleosides, α,β-Uunsaturated-β-lactones
and Azasugars
3.1 Novel Route to Difluorohomoallyl Alcohol and its Wide Utility
in the Synthesis of Difluoromethylenated Nucleosides
3.2 Construction of Difluoromethylenated Synthons via Silicon-Induced
Reformatskii-Claisen Rearrangement and their Application
for the Preparation of Difluoromethylenated Nucleosides
3.3 Synthesis of Azanucleosides Bearing Exocyclic CF2 H Group
Using a Wittig-Type Olefination Approach
3.4 Conformational Analysis of d -2′-Deoxy-2′,2′-difluoro-4′-dihydro-4′-thiouridine
3.5 Synthesis of Difluoromethylenated Six-Membered α,β-Unsaturated-β-lactones
and other Related Compounds
3.6 Synthesis and Biological Evaluation of Difluoromethylenated
Azasugars
4 Conclusion
Key words
fluorinated molecules - building blocks - biologically interesting
compounds
