Introduction 1116 2. Carbocyclic β-Amino Acids 1118 2.1. Syntheses of Five-or Six-Membered Carbocyclic β-Amino Acids 1118 2.1.1. Carbocyclic β-Amino Acids from β-Keto Esters 1119 2.1.2. Carbocyclic β-Amino Acids by Metathesis 1119 2.1.3. Carbocyclic β-Amino Acids by Amino Group Conjugate Addition 1122 2.1.4. Carbocyclic β-Amino Acids by Cycloaddition 1124 2.1.5. Carbocyclic β-Amino Acids by Desymmetrization of meso-Anhydrides 1124 2.1.6. Carbocyclic β-Amino Acids from Natural Sources 1125 2.1.7. Miscellaneous 1127 2.2. Syntheses of Small-Ring Carbocyclic β-Amino Acids 1128 2.3. Syntheses of Carbocyclic β-Amino Acids with Larger Ring Systems 1129 2.4. Synthesis of Functionalized Carbocyclic β-Amino Acids 1131 2.4.1. Syntheses of Functionalized Cyclic β-Amino Acids by C−C Double Bond Functionalization 1131 2.4.2. Several Relevant Routes to Functionalized Cyclic β-Amino Acids Other Than Functionalization of the Ring C−C Double Bond 1137 3. Cyclic β-Amino Acids with a Heteroatom in the Ring 1137 3.1. Syntheses of Cyclic β-Amino Acids with a N Atom in the Ring 1138 3.1.1. Three-and Four-Membered N-Containing Cyclic β-Amino Acids 1138 3.1.2. Five-Membered N-Containing Cyclic β-Amino Acids 1138 3.1.3. Six-Membered N-Containing Cyclic β-Amino Acids 1145 3.1.4. N-Containing Cyclic β-Amino Acids with Larger Ring Systems 1148 3.2. Syntheses of Cyclic β-Amino Acids with an O Atom in the Ring 1148 3.2.1. Four-Membered O-Containing Cyclic β-Amino Acids 1148 3.2.2. Five-Membered O-Containing Cyclic β-Amino Acids 1149 3.2.3. Six-Membered O-Containing Cyclic β-Amino Acids 1155 3.3. Cyclic β-Amino Acids with Other Heteroatoms in the Ring 1159 4. Some Relevant Biological Properties of Cyclic β-Amino Acids 1160 4.1. Cyclic β-Amino Acids Possessing Antifungal or Antibacterial Properties 1160 4.2. Antiviral Cyclic β-Amino Acids 1162 4.3. Cyclic β-Amino Acids with Antitumoral Properties 1162 4.4. Cyclic β-Amino Acids with Cardioprotective

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].

Substituted cyclopentanes or tetrahydrofurans bearing two vinyl groups have been investigated in cross‐metathesis reactions to explore chemodiscrimination of the two olefin bonds. The syntheses consisted of ring opening of constrained unsaturated β‐lactams or bicyclic β‐amino acids, followed by cross‐metathesis to test the chemodifferentiation of the divinyl‐substituted azetidinones or β‐amino esters in the presence of various ruthenium‐based catalysts.

Conformationally restricted, orthogonally protected 2,4-diaminocarboxylates with a cyclopentane skeleton were efficiently synthesized from beta-lactam 6, the syntheses involving strategies of diastereoselective epoxidation of the beta-lactam and the corresponding monoprotected amino esters with opposite selectivities followed by regioselective opening of the oxirane ring with sodium azide. The enantiomers were also prepared. This new class of compounds can be regarded not only as conformationally constrained beta,gamma-diamino acid derivatives but also as potential functionalized carbocyclic nucleoside precursors.