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The role of organo-fluorine compounds in modern health, food and energy related 2 industries is widely-appreciated. The unique properties that fluorine imparts to organic molecules, stemming from its high electronegativity and stability when bound to carbon, finds it increasing being used in the development of new bioactivities. Around 25% of the current blockbuster drugs contain fluorine and this number is increasing to well above 30% for recent FDA approvals. In this Review we highlight a selection of the most successful organo-fluorine drugs, that have achieved blockbuster status, namely, sitagliptin (diabetes), sofosbuvir (hepatitis C), emtricitabine (HIV), glecaprevir/pibrentasvir (hepatitis C), elvitegravir (HIV), dolutegravir (HIV), bictegravir (HIV), efavirenz (HIV), enzalutamide (prostate cancer), aubagio (immunomodulatory) and paliperidone palmitate (schizophrenia). For each compound we discuss their discovery, their relevant disease state and how they are made, emphasizing the source of fluorine-containing moieties, and where known, their mode of action. Scheme 7. Synthesis of intermediate 23 for the preparation of sitagliptin (4). The synthesis of β-amino acid 28 was shown in Scheme 8. An asymmetric Ru-catalyzed reduction of the carbonyl group on β-ketoester 24 is another illustration of the contribution of Noyori's asymmetric methodology to the development of pharmaceutical processes. This asymmetric reduction is followed by ester hydrolysis to generate intermediate 25. A coupling reaction between carboxylic acid 25 and BnONH2 in the presence of EDC-HCl afforded hydroxamate 26, which was subjected to an intramolecular cyclization reaction to generate lactam 27. The treatment of lactam 27 with HCl and then a hydrolysis under basic conditions, provided the key intermediate 28. Triazole 23 was then coupled to amino acid 28 in the presence of EDC-HCl and N-methylmorpholine (NMM) to afforded intermediate 29, which was finally converted into sitagliptin ( 4) via a Pd-catalyzed hydrogenation. It should be noted that Soloshonok and co-workers applied their chiral Ni-complex approach to the synthesis of sitagliptin (4) [33].

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