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Synlett 2011(8): 1052-1072  
DOI: 10.1055/s-0030-1259947
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© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Trifluoromethylated and gem-Difluoromethylenated Biologically Interesting Compounds from Fluorine-Containing Synthons

Feng-Ling Qing*, Feng Zheng
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. of China
Fax: +86(21)64166128; e-Mail: flq@mail.sioc.ac.cn;
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Received 8 December 2010
Publikationsdatum:
07. April 2011 (online)

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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 SN2 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 FSO2CF2CO2Me/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 CF2H 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