A de novo nucleoside synthesis and late-stage heterobenzylic fluorination strategy

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Proline catalysis, nucleoside analogues, carbohydrate analogues, diversity-oriented synthesis, late-stage fluorination

Nucleoside analogues constitute almost half of today’s major anticancer and antiviral therapeutics. Despite this, synthetic routes to these valuable molecules have typically relied on carbohydrate starting materials, which can significantly impair efforts in medicinal chemistry. Moreover, nucleoside scaffolds with increased complexity (e.g., C2’ or C4’ substitution) often require lengthy syntheses (up to 18 steps). Toward a goal of streamlining nucleoside synthesis, we have developed a one-pot proline-catalyzed α-fluorination/aldol reaction that generates enantiomerically enriched fluorohydrins that can serve as versatile building blocks for the construction of nucleoside analogues. Most importantly, this process enables access to variously functionalized nucleoside analogues in only 3 steps from commercial starting materials. The development of this process and practical application in rapidly accessing C2’- and C4’- modified nucleoside analogues, locked nucleic acids (LNAs), and iminonucleosides should inspire future efforts in drug design. Similar challenges also obstruct the synthesis of carbohydrate analogues (CAs), another important class of molecules to drug discovery efforts. To streamline CA synthesis, we developed several new proline-catalyzed α-functionalization/aldol reactions for constructing stereochemically rich and densely functionalized aldol adducts. In only 2 steps, these aldol adducts were then readily converted into a structurally diverse collection of CAs including iminosugars, annulated furanoses, bicyclic nucleosides, and fluorinated carbacycles. Incorporation of a fluorine atom can have several profound effects on a drug’s physiochemical properties – including metabolic stability, membrane permeability, and potency. However, the introduction of fluorine into the heterobenzylic position of drug molecules has remained an unsolved synthetic challenge. Towards this goal, we describe the first unified platform for the late-stage mono- and difluorination and trifluoromethylthiolation at heterobenzylic positions. This technology should become a dynamic tool for drug-lead diversification.

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This thesis may be printed or downloaded for non-commercial research and scholarly purposes. Copyright remains with the author.
Robert Britton
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.