Approaches to Obtaining Fluorinated Î±-Amino Acids | Chemical Reviews

Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

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Approaches to Obtaining Fluorinated α‑Amino Acids Johann Moschner, Valentina Stulberg, Rita Fernandes, Susanne Huhmann, Jakob Leppkes, and Beate Koksch*

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Department of Biology, Chemistry and Pharmacy, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany ABSTRACT: Fluorine does not belong to the pool of chemical elements that nature uses to build organic matter. However, chemists have exploited the unique properties of fluorine and produced countless fluoro-organic compounds without which our everyday lives would be unimaginable. The incorporation of fluorine into amino acids established a completely new class of amino acids and their properties, and those of the biopolymers constructed from them are extremely interesting. Increasing interest in this class of amino acids caused the demand for robust and stereoselective synthetic protocols that enable straightforward access to these building blocks. Herein, we present a comprehensive account of the literature in this field going back to 1995. We place special emphasis on a particular fluorination strategy. The four main sections describe fluorinated versions of alkyl, cyclic, aromatic amino acids, and also nickel-complexes to access them. We progress by one carbon unit increments. Special cases of amino acids for which there is no natural counterpart are described at the end of each section. Synthetic access to each of the amino acids is summarized in form of a table at the end of this article with the aim to make the information easily accessible to the reader.

CONTENTS 1. Introduction 2. Synthesis of Side Chain Fluorinated α-Amino Acids 3. Fluorinated Alkyl α-Amino Acids 3.1. Synthesis of Amino Acids Bearing One Carbon Atom in the Aliphatic Side Chain 3.1.1. 2-Amino-3-fluoropropanoic Acid (3-Fluoroalanine) 3.1.2. 2-Amino-3,3-difluoropropanoic Acid (3,3-Difluoroalanine) 3.1.3. 2-Amino-3,3,3-trifluoropropanoic Acid (3,3,3-Trifluoroalanine) 3.1.4. General Entry for C3-Fluorinated 2Amino-propanoic Acids 3.2. Synthesis of Amino Acids Bearing One Carbon Atom in the Polar Side Chain 3.2.1. Fluoroalkyl Thioethers of L-Cysteine and L-Homocysteine 3.2.2. 3-(Benzylsulfonyl)-2-amino-3-fluoropropanoic Acid 3.3. Synthesis of Amino Acids Bearing Two Carbon Atoms in the Aliphatic Side Chain 3.3.1. 2-Amino-4-fluorobutanoic Acid (Monofluoro-ethyl Glycine, MfeGly) 3.3.2. 2-Amino-4,4-difluorobutanoic Acid (Difluoro-ethyl Glycine, DfeGly) 3.3.3. 2-Amino-4,4,4-trifluorobutanoic Acid (Trifluoro-ethyl Glycine, TfeGly) 3.3.4. 2-Amino-3-fluorobutanoate

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3.4. Synthesis of Amino Acids Bearing Two Carbon Atoms in the Polar Side Chain 3.4.1. O-(Trifluoromethyl)homoserine 3.4.2. 2-Amino-4-fluoro-3-hydroxybutanoic Acid (4-Fluorothreonine) 3.4.3. 2-Amino-4,4-difluoro-3-hydroxybutanoic Acid (4,4-Difluorothreonine) 3.4.4. 2-Amino-4,4,4-trifluoro-3-hydroxybutanoic Acid (4,4,4-Trifluorothreonine) 3.4.5. 2-((Fmoc)Amino)-4-(diethoxyphosphoryl)-4,4-difluorobutanoic Acid 3.4.6. 3,3-Difluoro-4-hydroxybutanoate (Homoserine), 3,3-Difluoro-4-mercaptobutanoate (Homocysteine), and 3,3-Difluoro-4-(methylthio)butanoate (Methionine) 3.4.7. 3-(Acetylthio)-2-(1,3-dioxoisoindolin-2yl)-4,4,4-trifluorobutanoic Acid 3.5. Synthesis of Amino Acids Bearing Three Carbon Atoms in the Aliphatic Side Chain 3.5.1. 2-Amino-4,4-difluoropentanoic Acid (Difluoropropyl Glycine, DfpGly) and 2Amino-5-bromo-4,4-difluoropentanoic Acid (5-Bromo-4,4-difluoronorvaline) 3.5.2. tert-Butyl 2-(1,3-Dioxoisoindolin-2-yl)5,5-difluoropentanoate (5,5-Difluoronorvaline)

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DOI: 10.1021/acs.chemrev.9b00024 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 3.5.3. Methyl 2-((Boc)Amino-5,5,5-trifluoropentanoate (5,5,5-Trifluoronorvaline) 3.5.4. 2-Amino-4-fluoropent-4-enoic Acid 3.5.5. (E)-2-Amino-5-fluoropent-3-enoic Acid (Fluoroallylglycine) 3.5.6. Methyl 2-Amino-3-fluoro-3-methylbutanoate (3-Fluorovaline) 3.5.7. 2-Amino-4-fluoro-3-methylbutanoic Acid (4-Fluorovaline) 3.5.8. 2-((Boc)Amino)-4,4,4-trifluoro-3-methylbutanoic Acid (4,4,4-Trifluorovaline) 3.5.9. 2-Amino-4,4,4-trifluoro-3(trifluoromethyl)butanoic Acid (4,4,4,4′,4′,4′-Hexafluorovaline) 3.6. Synthesis of Amino Acids Bearing Three Carbon Atoms in the Polar Side Chain 3.6.1. 2-Amino-4-fluoropentanedioic Acid (4Fluoroglutamic Acid) 3.6.2. Dibenzyl 2-((Cbz)Amino)-3,3-difluoropentanedioate (3,3-Difluoroglutamic Acid) 3.6.3. 4-Amino-2,2-difluoropentanedioic Acid (4,4-Difluoroglutamic Acid) 3.6.4. 5-Amino-2-((Cbz)amino)-4,4-difluoro-5oxopentanoic Acid (4,4-Difluoroglutamine) 3.6.5. 2-Amino-4,4-difluoro-5-guanidinopentanoic Acid (4,4-Difluoroarginine) and 2((Boc)Amino)-4,4-difluoro-5-(2hydroxyguanidino)pentanoic Acid (NGHydroxy-4,4-difluoroarginine Derivative) 3.7. Synthesis of Amino Acids Bearing Four Carbon Atoms in the Aliphatic Side Chain 3.7.1. Methyl 2-((Boc)Amino)-5-fluorohex-5enoate 3.7.2. 2-Amino-3-fluoro-4-methylpentanoic Acid (3-Fluoroleucine) 3.7.3. Ethyl 2-(Benzylamino)-4-fluoro-4-methylpentanoate (4-Fluoroleucine) 3.7.4. tert-Butyl 2-((di-Boc)Amino)-5-fluoro-4methylpentanoate (5-Fluoroleucine) 3.7.5. Benzyl 2-((Boc)Amino)-5,5,5-trifluoro-4methylpentanoate (5,5,5-Trifluoroleucine) 3.7.6. 2-Amino-4-(difluoromethyl)-5,5-difluoropentanoic Acid (5,5,5′,5′-Tetrafluoroleucine) and 2-Amino-5,5,5-trifluoro-4(trifluoromethyl)pentanoic Acid (5,5,5,5′,5′,5′-Hexafluoroleucine) 3.7.7. 2-Amino-3-(fluoromethyl)pentanoic Acid (4′-Fluoroisoleucine) 3.7.8. 2-Amino-3-(trifluoromethyl)pentanoic Acid (4′,4′,4′-Trifluoroisoleucine) 3.7.9. 2-Amino-5,5,5-trifluoro-3-methylpentanoic Acid (5,5,5-Trifluoroisoleucine) 3.8. Synthesis of Amino Acids Bearing Four Carbon Atoms in the Polar Side Chain 3.8.1. 6-((Cbz))Amino)-2-((Boc)amino)-4-fluorohexanoic Acid (Nα-Boc-Nε-Cbz-4-Fluorolysine) and 6-Acetimidamido-2-((Boc)amino)-4-fluorohexanoic Acid (N-Boc-4Fluoro-(iminoethyl)lysine)

Review

3.8.2. 6-((Cbz)Amino)-2-((Boc)amino)-4,4-difluorohexanoic Acid (Nα-Boc-Nε-Cbz4,4-Difluorolysine) and 6-Acetimidamido-2-((Boc)amino)-4,4-difluorohexanoic Acid (N-Boc-4,4-Difluoro-(iminoethyl)lysine) 3.8.3. 6-Acetimidamido-2-amino-5,5-difluorohexanoic Acid (5,5-Difluoro(iminoethyl)lysine) 3.9. Synthesis of Amino Acids Bearing Five or More Carbon Atoms in the Aliphatic Side Chain 3.9.1. tert-Butyl 2-((Boc)Amino)-6-fluoroheptanoate 3.9.2. 2-(1,3-Dioxoisoindolin-2-yl)-3-fluoroundecanoic Acid 3.10. Miscellaneous Fluorinated Amino Acids 3.10.1. 4-Alkenyl Glutamic Acid Derivatives 3.10.2. Synthesis of Perfluoroalkyl Amino Acids 3.10.3. Catalytical Hydrogenation of Aliphatic Imines and Enamides 3.10.4. Photoinduced Trifluoromethylation and Perfluoroalkylation of Cysteine Derivatives in Batch and Continuous Flow 4. Synthesis of Cyclic Side Chain Fluorinated Amino Acids 4.1. Three-Membered Rings 4.1.1. Synthesis of 3-(Trifluoromethyl)aziridine-2-carboxylates 4.2. Four-Membered Rings 4.2.1. 1-Benzyl-3-fluoro-4-(hydroxymethyl)azetidine-2-carboxylic Acid 4.3. Five-Membered Rings 4.3.1. 1-(Boc)-3-Fluoropyrrolidine-2-carboxylic Acid (3-Fluoroproline) 4.3.2. Dibenzyl 3,3-Difluoropyrrolidine-1,2-dicarboxylate (3,3-Difluoroproline) 4.3.3. 1-(tert-Butyl)-2-methyl-4-fluoropyrrolidine-1,2-dicarboxylate (4-Fluoroproline Derivative) 4.3.4. 4,4-Difluoropyrrolidine-2-carboxylic Acid (4,4-Difluoroproline) 4.3.5. Methyl 4,4-Difluoro-5-oxopyrrolidine-2carboxylate (4,4-Difluoropyroglutamate) 4.3.6. 3-Substituted Prolines 4.3.7. 1-(Boc)-4-(Trifluoromethyl)pyrrolidine2-carboxylic Acid (4-Trifluoromethylproline) 4.3.8. 4-Fluoromethyl-prolines and -pyroglutamates 4.3.9. 5-(Trifluoromethyl)pyrrolidine-2-carboxylic Acid (5-Trifluoromethyl-proline) 4.3.10. 1-(Boc)-3,4-Difluoropyrrolidine-2-carboxylic Acid (3,4-Difluoroproline) 4.3.11. 1-Benzyl-4,4-difluoro-3,3-dimethylpyrrolidine-2-carboxylic Acid (4,4-Difluoro-3,3-dimethylproline) 4.3.12. Fluorinated Kainic Acid Derivatives

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Chemical Reviews 4.3.13. Methyl-4-amino-5-(m-tolyl)-3(trifluoromethyl)pyrrolidine-2-carboxylate 4.3.14. 1-(tert-Butyl)-2-methyl-4-((1,1,1,3,3,3hexafluoro-2-(trifluoromethyl)propan2-yl)oxy)pyrrolidine-1,2-dicarboxylate (Perfluoro-tert-butyl-4-hydroxyproline) 4.3.15. Methyl 2-(Trifluoromethyl)oxazolidine4-carboxylate (Trifluoromethyl Pseudoproline) 4.4. Five- and Six-Membered Rings 4.5. Six-Membered Rings 4.5.1. 5,5-Difluoropiperidine-2-carboxylic Acid (5,5-Difluoropipecolic Acid) 4.5.2. Methyl 6-(Trifluoromethyl)piperidine-2carboxylate (Methyl 6-Trifluoromethylpipecolate) 4.6. Polycyclic Derivatives 4.6.1. 5-(Boc)-Difluoro-5-Azaspiro[2.4]heptane-6-carboxylic Acid 4.6.2. Fluorinated Methyl Azabicyclo[2.1.1]hexane-3-carboxylates (Methano-fluoroprolines) 4.6.3. 2-Amino-2-(4-fluorobicyclo[2.2.2]octan1-yl)acetic Acid 4.6.4. 6-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic Acid and 6-(Trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic Acid 4.6.5. 4-Fluorooctahydrocyclopenta[c]pyrrole-1-carboxylic Acid 5. Synthesis of Side Chain Fluorinated Aromatic Amino Acids 5.1. Histidine Derivatives 5.1.1. 2-Amino-3-(5-fluoro-1H-imidazol-4-yl)propanoic Acid (4-Fluorohistidine) 5.1.2. Methyl 2-Acetamido-3-(1-benzyl-5((trifluoromethyl)phenyl)-1H-imidazol4-yl)propanoate (4-(Trifluoromethyl)phenyl-histidine) 5.2. Phenylalanine and Tyrosine Derivatives 5.2.1. 2-Amino-3-(fluoro-4-hydroxyphenyl)propanoic Acid (Fluorotyrosine) 5.2.2. 2-Amino-3-(4-fluorophenyl)propanoic Acid (4-Fluorophenylalanine) 5.2.3. Benzyl 2-((Boc)Amino)-3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)propanoate and Benzyl 2-((Boc)Amino)-3-(3-(pentafluoro-λ6-sulfaneyl)phenyl)propanoate 5.2.4. Methyl 2-Amino-3-(3,5-difluorophenyl)propanoate (3,5-Difluorophenylalanine, Dfp) 5.2.5. Methyl 2-Amino-3-(4-fluoro-3nitrophenyl)propanoate 5.2.6. 4-Substituted tert-Butyl 2-((Fmoc)Amino)-3-(2,3,5,6-tetrafluorophenyl)propanoates (4-Substituted Tetrafluorophenylalanines)

Review

5.2.7. 2-Acetamido-3-(4-hydroxy-3(trifluoromethyl)phenyl)-N-methylpropanamide and 2-Acetamido-3-(4hydroxy-3,5-bis(trifluoromethyl)phenyl)-N-methylpropanamide 5.2.8. Palladium-Catalyzed Arylation of C(sp3)H Bonds to Synthesize 2-(1,3-Dioxoisoindolin-2-yl)-3-fluoroaryl-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)propanamide (Fluorophenylalanine) and 2-(1,3-Dioxoisoindolin-2-yl)-3-(4fluoroaryl)-3-phenyl-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (β-Fluoroaryl-phenylalanine) 5.2.9. 2-((Fmoc)Amino)-3-(tetrafluorophenyl)propanoic Acid (Tetrafluorophenylalanines) 5.2.10. Fluoroaryl-phenylalanines 5.2.11. Benzyl 2-((Fmoc)Amino)-3-(2-(3-((Boc)amino)propyl)-6-(trifluoromethyl)phenyl)propanoate 5.3. β-Fluorination of Aromatic Amino Acids 5.3.1. β-Fluorination of C(sp3-H) Bonds Using Selectfluor 5.3.2. Synthesis of β-Fluorophenylalanine Derivatives Using XtalFluor-E 5.3.3. 2-Amino-3-fluoro-3-phenylpropanoic Acid (β-Fluorophenylalanine) 5.3.4. Methyl 2-Amino-3-(fluoro-3,4-dihydroxyphenyl)-3-hydroxypropanoate 5.4. Synthesis of Tryptophan Derivatives 5.4.1. 2-((Fmoc)Amino)-3-(2-(fluoroaryl)-1Hindol-3-yl)propanoic Acid (2-Fluoroaryltryptophan) 5.5. Synthesis of Homo-Phenylalanine Derivatives 5.5.1. tert-Butyl 2-((Boc)Amino)-3-fluoro-4phenylbutanoate 5.6. Miscellaneous Fluorinated Aromatic Amino Acids 5.6.1. 5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl-2-(dimethylamino)-2-(2methyl-(trifluoromethyl)phenyl)acetate (2-Fluororyl-glycine Derivative) 5.6.2. tert-Butyl (R)-2-((Diphenylmethylene)amino)-2-(4-fluorophenyl)-acetate 541 6. Synthesis of Side-Chain Fluorinated Amino Acids Using Nickel-Complexes 6.1. Reaction with Alkyl Halides 6.1.1. Linear Trifluoroalkyl Containing Amino Acids 6.2. Reaction with Alcohols 6.3. Reaction with Benzyl Halides 6.3.1. Photoreactive Fluorophenylalanine Derivatives 6.3.2. Fluorophenylalanines 6.4. Reaction with Alkyl- and Benzyl Halides 6.5. Reaction with Biaryl Chlorides 6.6. Mannich-type Additions 6.6.1. Reaction with Aldimines 6.6.2. Reaction with Sulfones 6.6.3. Reaction with Sulfimines

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Chemical Reviews 6.7. Additions of Ni(II)-Complexes to Michael Acceptors 6.7.1. Reaction with Crotonates 6.7.2. Reaction with Acrylates 6.7.3. Reaction with But-2-enoyl-oxazolidinone 6.8. Perfluoroalkyl Ketones 6.9. Oxidative Dehydrogenative Cross-Coupling 6.10. Deracemization and (S) to (R) Interconversion of α-Amino Acids 7. Perspective 8. Fluorinated Amino Acid Table Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

Review

blood pressure control, allergies, and tumor growth.28−32 Incorporation of FAAs is one of the most utilized strategies in peptide and protein science. In fact, the effects of incorporation of fluorinated α-amino acids into peptides and proteins on the primary and secondary structure and proteolytic stability have been widely reviewed including by Koksch et al.31,33,34 Moreover, the incorporation of unnatural amino acids per se into peptides and proteins is generally closely associated with effects on antimicrobial,35−37 antiviral,38 and metal chelating properties39 as well as thrombin, trypsin, and factor VIIa inhibitory activity.40 In this review, we will focus on the synthesis of enantio- or diastereo- pure mono-substituted α-amino acids that bear at least one fluorine atom in their side chain. We will present the different fluorination strategies employed in the literature to form fluorine bonds in the carbon backbone. Overall, we aim to give a general update on this topic, and our starting point is the well-received book by Kukhar and Soloshonok in 1995.41 One synthetic entry to each presented amino acid will be discussed in detail, and further access to the same amino acid will be mentioned and discussed in brevity. We will not distinguish between unprotected or protected amino acids, as the removal or the change of protecting groups can be considered as a standard operation. Enzymatic incorporation of fluorine and the broad field of PET-probes are beyond the scope of this review, as these topics have been extensively reviewed recently elsewhere.42−44

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1. INTRODUCTION Organic fluorine chemistry was pioneered by the Belgian chemist Frédéric Swarts in 1890,1 and since then, numerous aliphatic and aromatic fluorine-containing molecules were synthesized. However, it took the field another 50 years to connect with medicinal chemistry thanks to the discovery of the toxic fluoroacetate in the late 1940s.2 Nowadays, fluorination is a standard modification to favorably tailor molecules’ properties, and it is widely established in the field of medicinal and agricultural chemistry. In medicinal chemistry, approximately 20% of all approved pharmaceuticals have at least one fluorine atom present with an increasing tendency up to 30% since numerous fluorinated compounds are in Phase II−III clinical trials.3−8 In the agrochemical field, approximately 30% of approved chemicals contain fluorine.9,10 Thus, selective fluorination of bioactive molecules is a well-established strategy in the design of drugs to increase pharmaceutical effectiveness, biological half-life, and bioabsorption.3,11−14 Additionally, fluorine is widely employed in the field of photovoltaics15−17 or as a diagnostic tool in positron emission tomography (PET) that employs radiotracers labeled with 18 F nuclei.18,19 Furthermore, 19F magnetic resonance imaging (MRI)20 relies on the design and synthesis of polyfluorinated (fluorous) molecules.21 The high sensitivity of the 19F isotope in nuclear magnetic resonance (NMR) experiments and the nonexisting background make fluorinated molecules ideal for biological studies.22,23 Apart from the above-mentioned, fluorous reagents, catalysts, and solid-supported reagents/catalysts also enable the application of synthetic methodologies in a more efficient manner that allows for the recovering and recycling of valuable materials.24−26 The diversity of fluorine-containing compounds and their applications raised the need for reliable synthetic transformations and means to precisely incorporate fluorine substituents into organic molecules. Also, the incorporation of fluorine into biomolecules such as fluorinated amino acids (FAAs), fluorinated nucleosides, and fluorinated steroids raised considerable interest in recent years.27 FAAs and their biopolymers, as well as peptides containing them, are of particular interest since they find widespread bio-organic applications as biological tracers, mechanistic probes, and enzyme inhibitors as well as medical applications including

2. SYNTHESIS OF SIDE CHAIN FLUORINATED α-AMINO ACIDS The synthesis of fluorine-containing amino acids can be generally achieved following the strategies shown in Scheme 1. As the stereochemistry of the FAAs is of paramount importance on the folding and function properties of peptides and proteins, the synthetic entry should allow the generation of enantio- or diastereo- pure amino acids. Fluorination of the side chain of amino acids heavily relies on suitable fluorine-introducing reagents. All reagents used in this review are shown in Scheme 2. Apart from using fluorinecontaining building blocks, introduction of fluorine is usually performed by nucleophilic (Scheme 2A) or electrophilic (Scheme 2B) reagents, as well as radical mediated introduction of fluorine (Scheme 2 C), since the use of the toxic and corrosive hydrogen fluoride or fluorine gas requires special equipment and techniques. Another often employed strategy is trifluoromethylation, which can be achieved using the reagents shown in Scheme 2D. One more reagent reported in this review is fluorodecarboxylation using XeF2 in hexafluorobenzene. For an in-depth discussion and detailed application of fluorinating reagents, see these excellent reviews: Liang et al.,45 Alonso et al.,46 Kirk et al.,47 Barata-Vallejo et al.,48 and Bi et al.49. 3. FLUORINATED ALKYL α-AMINO ACIDS This section will be divided based on the number of side chain carbon atoms the amino acid is bearing. As soon as the carbon chain is interrupted, the counting stops to prevent complicated captions. We will present fluorinated derivatives of the hydrophobic amino acids: alanine, aminobutanoic acid, valine, norvaline, leucine, norleucine, methionine, isoleucine, and allylglycine. Furthermore, we will present synthetic entries for the polar FAAs: serine, threonine, aspartic acid, cysteine, glutamic acid, homoserine, homocysteine, lysine, arginine, and D


Chemical Reviews

Review

Scheme 1. General Entries for Synthesis of Fluorinated α-Amino Acids

Scheme 2. Common Fluorinating Reagents to Generate Side-Chain Fluorinated α-Amino Acids

Scheme 3. Synthesis of N-Cbz Protected (2S)- and (2R)-3Fluoroalanines (S)-1 and (R)-1

glutamic acid. In the end of the section, we will present more general entries to synthesize FAAs. 3.1. Synthesis of Amino Acids Bearing One Carbon Atom in the Aliphatic Side Chain

3.1.1. 2-Amino-3-fluoropropanoic Acid (3-Fluoroalanine). An important criterion for accessing fluorinated alanine derivatives is the degree of fluorination as higher fluorinated variants easily eliminate hydrogen fluoride under Ti-catalyzed glyoxylate-ene reaction ambient conditions. Utilizing a chiral pool strategy, Hoveyda et al. reported the synthesis of N-Cbz protected (2S)- and (2R)-3-fluoroalanine ((S)- and (R)-1) starting from the corresponding N-Cbz protected serine ((S)and (R)-2). TBS protection of the alcohol moiety of (S)- and (R)-2 was followed by formation of the corresponding oxazolidinone (S)-3 and (R)-3 in the presence of paraformaldehyde. The one pot TBS deprotection and deoxyfluorination using Deoxo-Fluor50 furnished the fluorinated oxazolidinones (S)-4 and (R)-4. Subsequent acidic hydrolysis gave the N-Cbz protected (2S)- and (2R)-3-fluoroalanines (S)-1 and (R)-1 with excellent enantiomeric excess (Scheme 3).51 A conceptually different approach to synthesize N-Cbz-(2S)3-fluoroalanine (S)-1 was reported by Bravo et al. By reacting a chiral α-lithiosulfinyl carbanion with lithium fluoroacetate, they were able to access the chiral 3-fluorinated 2-oxopropyl sulfoxide, which was then diastereoselectively reduced to the α-sulfinyl alcohol using diisobutylaluminium hydride (DIBALH) through substrate-controlled attack of the hydride in ≥95% de. The Cbz-protected amine was installed in a three-step protocol involving a Mitsunobu reaction variant using CBr4 and

PPh3 to introduce an azide, which was subsequently reduced using propane-1,3-dithiol and triethylamine (TEA), and the soobtained free amine was reacted with benzyl chloroformate. Removal of the chiral auxiliary and oxidation of alcohol to the corresponding carboxylic acid resulted in the generation of NCbz-(S)-3-fluoroalanine (S)-1 (Scheme 3).52 Additionally, the presented entry was modified by Carpentier et al.53 3.1.2. 2-Amino-3,3-difluoropropanoic Acid (3,3-Difluoroalanine). In general, difluorination is performed with diethylaminosulfur trifluoride (DAST) or its variants on ketones and aldehydes. Li et al. reported the synthesis of 3,3difluoroalanine, which starts with the commercially available and optically pure substrate (2S)-2,3-O-isopropylideneglyceraldehyde 5. Reaction of the aldehyde 5 with DAST to introduce the difluoro moiety produced the dioxolane 6. Acidic hydrolysis of 6 and chemoselective protection of the primary hydroxyl E


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group with TBSCl gave the secondary alcohol 7. The secondary alcohol was then reacted with triflic anhydride to generate a good leaving group, which was displaced using sodium azide to generate the azide 8. Reduction of the latter and treatment of the so-obtained free amine with FmocCl afforded the N-Fmoc protected alcohol 9. Removal of the TBS group with HF in pyridine and oxidation using Jones reagent yielded (2R)-NFmoc-3,3-difluoroalanine 10 (Scheme 4) without loss of

Scheme 5. Synthesis of (2S)-3,3,3-Trifluoroalanine 13

Scheme 4. Synthesis of (R)-N-Fmoc-3,3-difluoroalanine 10

3.1.4. General Entry for C3-Fluorinated 2-Aminopropanoic Acids. The entry presented by Fustero et al. involved the generation of fluoroalkyl imidoyl halides, which were accessible by reaction of fluoroalkyl carboxylic acids and primary amines.57 The starting lithiated sulfinimine 16 was reacted with the fluoroalkyl imidoyl halides 17a−c to afford the β-iminosulfinimines 18a−c. Reduction of the imine was achieved employing nBu4NBH4 to obtain the corresponding syn-diastereomers. Change of the N-protection group was performed to give the secondary amines 19a−c. Interestingly, the authors investigated the effect of the aromatic moiety of the sulfinimine on the diastereoselectivity of imine reduction and found that the 1-naphthyl moiety outperformed the other substituents (1-naph > 2-naph > p-tolyl ≫ cyclohexyl). Next, a “non-oxidative” Pummerer reaction was conducted to generate the corresponding aminols 20a−c, which were oxidized to give the (2S)-N-Cbz-protected amino acids 21a−c (Scheme 6).63,64

stereochemical purity.54 The same methodology was employed to generate 4,4-difluorothreonine (Section 3.4.3). The diastereoselective hydrogenation of α-fluorinated iminoesters was reported by Abe et al. The iminoesters were synthesized according to a known procedure55 and then hydrogenated using palladium(II) trifluoroacetate and 2,2′bis(diphenylphosphino)-1,1′-binaphthyl in trifluoroethanol (TFE). This approach also facilitates the synthesis of 3,3,3trifluoroalanine and 2-chloro-2,2-difluoro alanine (the synthesis of N-Cbz-2-chloro-2,2-difluoroalanine 21b will be presented in Section 3.1.4).56 3.1.3. 2-Amino-3,3,3-trifluoropropanoic Acid (3,3,3Trifluoroalanine). Tamura et al. reported the one-pot synthesis of trifluoroacetimidoyl iodide 11 (accessible by reacting TFA 12 with 4-methoxyaniline and tetrachloromethane in the presence of triphenylphosphine, and a subsequent treatment with sodium iodide57) that can be used to furnish (2S)-3,3,3-trifluoroalanine 13. Palladium catalyzed carbonylation afforded the corresponding benzyl ester 14. Careful investigations of the stereoselective reduction of the imine of 14 performed by Sakai et al. showed that the best conversion and stereoinduction was achieved using the CBS catalyst in combination with catecholborane to give 15 (Scheme 5, red.). Oxidative removal of the p-methoxy phenyl moiety using cerium(IV) ammonium nitrate and reductive removal of the benzyl moiety yielded the unprotected (2S)-3,3,3-trifluoroalanine 13 (Scheme 5).58 Demir et al. started with the literature known 2,2,2-trifluoro1-furan-2-yl-ethanone,59,60 which they converted into the chromatographic separable (E)- and (Z)-oximes. Oxazaborolidine-catalyzed stereoselective reduction of the corresponding O-benzyl oxime ethers afforded the (R)- and (S)-enantiomer of 2,2,2-trifluoro-1-furan-2-yl-ethylamine with 88% ee. Furan ring oxidation using ozone gave both enantiomers of 3,3,3trifluoroalanine 13.61 Kawano et al. reported the enantioselective trifluoromethylation using N-(tolylsulfinyl)imines with (trifluoromethyl)trimethylsilane in the presence of Lewis bases with >99% ee.62

3.2. Synthesis of Amino Acids Bearing One Carbon Atom in the Polar Side Chain

3.2.1. Fluoroalkyl Thioethers of L-Cysteine and LHomocysteine. Yasui et al. reported a reductive trifluoromethylation of cysteine to obtain the corresponding trifluoromethyl thioethers by employing a Birch reduction with CF3I and full retention of stereochemistry. By subjecting cystine 22 to these conditions, the corresponding (S)-trifluoromethyl thioether 23 was obtained. This method also allows the generation of (S)trifluoromethylmethionine 24 and (S)-pentafluoroethylmethionine 25 starting from homocysteine dimer 26 (Scheme 7).65 Soloshonok et al. used CF3I to construct a thiotrifluoromethyl moiety in the presence of liquid ammonia and UV-irradiation.66 Kieltsch et al. utilized hypervalent iodine(III) trifluoromethylating reagents to synthesize trifluorinated cysteine derivatives.67 3.2.2. 3-(Benzylsulfonyl)-2-amino-3-fluoropropanoic Acid. Wei et al. investigated the synthesis of 3-benzylsulfonyl2-amino-3-fluoropropanoic acid by starting with (S)- and (R)-4(hydroxymethyl)-2,2-dimethyloxazolidine (S)- and (R)-26, which can be accessed from the corresponding Garner’s aldehyde or serine precursor. Treatment of the oxazolidines (S)- and (R)-26 with benzo[d]thiazole-2-thiol under Mitsunobu conditions furnished the thioethers (S)- and (R)-27, which were oxidized using ammonium molybdate and hydrogen peroxide to yield the corresponding sulfones (S)- and (R)-28. Following a protocol established by Zajc et al.,68 electrophilic fluorination of the sulfones with NFSI afforded the enantiomeric α-fluoro pairs F


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Scheme 6. Synthesis of (2S)-N-Cbz-Protected Amino Acids 21a−c

3.3. Synthesis of Amino Acids Bearing Two Carbon Atoms in the Aliphatic Side Chain

Scheme 7. Synthesis of Fluoroalkyl Thioethers of Cysteine and Homocysteine 23−25

3.3.1. 2-Amino-4-fluorobutanoic Acid (Monofluoroethyl Glycine, MfeGly). A substantial body of literature deals with the synthesis of fluorinated derivatives of amino butyric acids (Abu) as they are widely employed in peptide and protein science. The nomenclature of these analogues is derived from the glycine carbon skeleton, which is alkylated with an ethyl moiety. Thus, the first derivative monofluoroethyl glycine 33 was stereoselectively synthesized by employing chiral Schiff bases. Laue et al. used the (−)-α-pinene derived (1R,2R,5R)-

(R,R)- and (R,S)-29 starting with (R)-28 and (S,S)- and (S,R)29 starting with (S)-28, both in ≥ 97:3 d.r. (only the major products (R,R)-29 and (S,S)-29 are shown). With (S,S)-29 in hand, the authors demonstrate an epimerization reaction to access the (S,R)-29 derivative in 98:2 d.r. Since all synthetic transformations are the same, only the (S,S)-29 derivative will be discussed. Cleavage of the benzo[d]thiazole moiety using NaBH4 and reaction with benzyl bromide gave the benzylsulfonyl derivative (S,S)-30. The oxazolidine moiety of (S,S)-30 was hydrolyzed, and the simultaneous cleaved Boc group was reattached to yield the N-Boc amino alcohol (S,S)-31. Oxidation of the primary alcohol generated (2S,3S)-3-benzylsulfonyl-2((Boc)amino)-3-fluoropropanoic acid (S,S)-32 ( Scheme 8, (S,R)-32 not shown).69

Scheme 9. Synthesis of (S)-MfeGly 33

(+)-2-hydroxy-3-pinanone 34,70,71 which was coupled to glycine tert-butyl ester. The so-obtained Schiff base 35 was deprotonated and stereoselectively alkylated with 1-bromo-2-fluoro-

Scheme 8. Synthesis of 3-Benzylsulfonyl-2-amino-3-fluoropropanoic Acid (S,S)-32

G


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and was followed by acid hydrolysis of the sulfate generating the secondary alcohol 47. To only reduce the azido group, the azide moiety of 47 was hydrogenated using Pd/C. The so-obtained amine was protected, and the secondary alcohol was removed in a radical-mediated deoxygenation to give 48. Removal of the benzyl group, oxidation of the primary alcohol, and hydrolysis of the N-Boc group furnished (S)-2-amino-4,4,4-trifluorobutanoic acid 42 (Scheme 11). The above-mentioned N-Boc protected (2R,3R)-3-amino-4-(benzyloxy)-1,1,1-trifluorobutan-2-ol 47 was also used to synthesize 4,4,4-trifluorothreonine, which will be discussed later (Section3.4.4).78 The earlier described method established by Winkler et al. (Scheme 10, Section 3.3.2) was further investigated by Schedel et al. to synthesize TfeGly 42 and methylene homologues thereof. Simultaneous protection of the C1 hydroxy- and carboxy function using HFA yielded the corresponding 1,3dioxolan-4-one, which was further treated with gaseous sulfur tetrafluoride in an autoclave to generate the trifluoromethyl group. Hydrolysis of the 1,3-dioxolan-4-one, activation of the hydroxyl group using triflic anhydride, and nucleophilic substitution with benzylamine gave the desired (2R)-N-BnTfeGly methyl ester.79 3.3.4. 2-Amino-3-fluorobutanoate. Introduction of a fluorine atom into the β-position of Abu was reported by Kalow et al., as they investigated the asymmetric ring-opening reaction of an unsymmetrically-substituted aziridine using a fluoride species. The aziridine of choice was accessible through a two-step protocol starting with crotonaldehyde 49, which was reacted with tert-butyl (tosyloxy)carbamate 50, as a source of nitrogen, in the presence of (S)-diphenylprolinol triethylsilyl ether 51 to give the aldehyde 52 in 97% ee, as an inseparable trans/cis mixture of 91:9. Oxidation of 52 with activated manganese dioxide in the presence of sodium cyanide directly gave the methyl ester 53.80 The hydrofluorination mixture using 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in combination with benzoyl fluoride and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) serves as a synthetically useful latent source of HF, which proceeds with excellent diastereoselectivity and no erosion of ee. The fluorination occurred at the carbon that best stabilizes a positive charge giving methyl (2R,3S)-2-((Boc)amino)-3fluorobutanoate 54 in 98% ee and 10:1 d.r. (Scheme 12).81

ethane to give 36 in 98% d.r. Deprotection of the acid moiety and acidic hydrolysis gave (S)-MfeGly 33 (Scheme 9).72,73 Wang et al. used a chiral aspartic acid derivative for their synthesis of (S)-MfeGly 33. The free acid moiety of (S)-4(benzyloxy)-2-((Boc)amino)-4-oxobutanoic acid was protected as the corresponding tert-butyl ester, and the benzyl protecting group was chemoselectively hydrogenated. The so-obtained free acid was reduced, and the resulting hydroxyl group was activated as a tosylate to set stage for a nucleophilic substitution using “neutralized” TASF and TREAT-HF to give N-Boc-O-tBuMfeGly.74 3.3.2. 2-Amino-4,4-difluorobutanoic Acid (Difluoroethyl Glycine, DfeGly). The synthesis of the next homologue difluoroethyl glycine 37 was reported by Winkler et al. They employed hexafluoroacetone (HFA) to cyclize aspartic acid 38, which simultaneously protected the amino and C1-carboxy functionality without affecting the ω-carboxylic acid, giving the Scheme 10. Synthesis of (S)-DfeGly 37

oxazolidine 39.75 Conversion of the acid to the corresponding acid chloride using thionyl chloride and hydrogenation using the Rosemund catalyst gave the β-semialdehyde 40. Difluorination of the aldehyde using DAST yielded the difluorinated oxazolidine 41, which then was hydrolyzed using a water/iPrOH mixture to generate (S)-DfeGly 37 (Scheme 10).76 3.3.3. 2-Amino-4,4,4-trifluorobutanoic Acid (Trifluoroethyl Glycine, TfeGly). Jiang et al. reported the preparation of enantiomeric pure (S)-TfeGly 42 employing the Sharpless asymmetric dihydroxylation (AD) of trifluoromethylated transdisubstituted alkene 43. The key intermediate was prepared starting from propargylic alcohol 44 (following the entry of Chen et al.77). Sharpless AD was carried out in the presence of AD-mix-β and methanesulfonamide providing the vicinal diol 45, which was converted to the corresponding cyclic sulfite and immediately oxidized giving the cyclic sulfate 46. Ring opening of 46 with NaN3 occurred exclusively at C2 with chiral inversion

3.4. Synthesis of Amino Acids Bearing Two Carbon Atoms in the Polar Side Chain

3.4.1. O-(Trifluoromethyl)homoserine. Kondratov et al. published an asymmetric synthetic approach to obtain enantiomerically pure (2R)- and (2S)-O-(trifluoromethyl)-

Scheme 11. Synthesis of (S)-TfeGly 42

H


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Scheme 12. Synthesis of Methyl (2R,3S)-2-((Boc)Amino)-3fluorobutanoate 54

Scheme 14. Synthesis of (2S,3S)-4-Fluorothreonine 62

the preparation of difluorothreonine using L-ascorbic acid as starting material. In a three-step synthesis, 63 was generated88 and the free hydroxyl group was protected. Next, the ester moiety was reduced with DIBALH, followed by difluorination with DAST to yield the difluoro dioxolane 64. After acidic hydrolysis of the dioxolane 64, the resulting primary alcohol was chemoselectively protected, and the secondary alcohol was in situ activated with triflic anhydride and immediately reacted with NaN3 to give the azide 65. The latter was hydrogenated to give the corresponding amino alcohol, which was N-protected with Fmoc to give the secondary alcohol 66. The hydroxyl group was protected as a tert-butyl ether, the TBS group was cleaved using HF·py, and the so-obtained primary alcohol was oxidized using Jones reagent to yield the desired N-Fmoc-O-tBu-(2S,3S)-4,4difluorothreonine 67 (Scheme 15). The same methodology was employed to synthesize difluoroalanine (Section 3.1.2).54 The synthesis of (2S,3R)-difluoro-threonine 68 published by Prakash et al. used an earlier established general procedure for the preparation of anti-α-(difluoromethyl)-β-amino alcohols.89 This three-component reaction methodology was extended to generate the corresponding amino acids. Thus, diallylamine 69, (R)-3,3-difluoro-2-hydroxypropanal 70, and furan-2-ylboronic acid 71 were reacted to give the 3,3-difluoro propanol 72. (R)3,3-Difluoro-2-hydroxypropanal 70 is accessible by a four-step protocol starting from 1,1-difluoroacetic acid ethyl ester 73. Deallylation with a phosphino palladium catalyst and N,N′dimethylbarbituric acid gave the free amine 74, which was subjected to a reaction sequence consisting of N-protection and treatment with sodium hydride to generate the chiral 2oxazolidinone 75. The furyl moiety of 75 was ozonolytically oxidized to the acid, after which, the compound was hydrolyzed under acidic conditions giving the desired (2S,3R)-antidifluorothreonine (2S,3R)-68 (Scheme 16).90 3.4.4. 2-Amino-4,4,4-trifluoro-3-hydroxybutanoic Acid (4,4,4-Trifluorothreonine). Cho et al. described the

homoserine 55 using the earlier described (+)- and (−)-2hydroxy-3-pinanones (+)- and (−)-34 as chiral auxiliaries (Section 3.3.1). The key step is the alkylation of imino tertbutylesters (+)- and (−)-35 with the triflate 56, which was synthesized starting from diethylene glycol 57 following a threestep procedure reported by Wakselman et al.82 to generate the trifluoromethyl ethers (+)- and (−)-58. In this procedure, fluorine was introduced following a fluorodesulfurization reaction by treatment of 59 with 1,3-dibromo-5,5-dimethylhydantoin (DBH) in a HF-pyridine medium to give the triflate 56. This transformation may be interpreted as involving successive bromonium formation with sulfur atoms followed by nucleophilic introduction of fluorine substituents. Acidic hydrolysis of the chiral auxiliary of (+)- and (−)-58 afforded the desired O-(trifluoromethyl)homoserines (R)- and (S)-55 with an enantiomeric purity of > 95% ee (Scheme 13).83 3.4.2. 2-Amino-4-fluoro-3-hydroxybutanoic Acid (4Fluorothreonine). Amin et al. modified Seebach’s imidazolidinone methodology for the synthesis of α-amino-β-hydroxy acids.84,85 The imidazolidinone 60 was treated with fluoroacetyl chloride86 to generate the resulting β-ketone, which formed the corresponding benzoate ester 61 upon treatment with NaBH4. After acetic hydrolysis, (2S,3S)-4-fluorothreonine 62 was formed (Scheme 14).87 3.4.3. 2-Amino-4,4-difluoro-3-hydroxybutanoic Acid (4,4-Difluorothreonine). Li et al. presented an approach for Scheme 13. Synthesis of O-(Trifluoromethyl)homoserine (R)-55

I


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Scheme 15. Synthesis of (2S,3S)-N-Fmoc-O-tBu-4,4-Difluorothreonine 67

Scheme 16. Synthesis of (2S,3R)-Difluorothreonine (2S,3R)-68

Scheme 17. Synthesis of (2R,3S)-4,4,4-Trifluorothreonine (2R,3S)-76

synthesis of enantiopure (2R,3S)-4,4,4-trifluorothreonine (2R,3S)-76. In the first step, an esterification of the chiral oxazolidinone 77 using ethylbromoacetate was performed. This was followed by hydrolysis of the ester moiety and subsequent acid chloride formation to give 78. A three component annulation reaction of trifluoroacetic anhydride, acetone, and an in situ generated ketene (from acyl chloride 78), formed the α,β-unsaturated lactone 79 in one step (the authors show the use of difluoroacetic- and pentafluoro propionic acid anhydride in the three component reaction as well). In the following asymmetric hydride reduction, two consecutive asymmetric transformations are involved: a hydride is added to the α,βunsaturated lactone and the resulting enolate is protonated. Excellent diastereo- and enantioselectivity was achieved by performing the reaction in methanol and subsequent treatment with aqueous NH4Cl to obtain (2R,3S)-80 in 99% d.r. In a twostep deprotection sequence, the acetal moiety was removed and then the oxazolidinone fragment was hydrogenated, which gave the desired (2R,3S)-4,4,4-trifluorothreonine (2R,3S)-76 (Scheme 17).91 Jiang et al. reported the preparation of enantiomeric pure (2S,3R)-4,4,4-trifluorothreonine (2S,3R)-76 (and TfeGly 42, Section 3.3.3). The Pd(OH)2 catalyzed hydrogenation of the earlier described secondary alcohol 47 led to the reduction of the azido group and to the removal of the benzyl group generating

Scheme 18. Synthesis of (2S,3R)-4,4,4-Trifluorothreonine (2S,3R)-76

the amino alcohol, which was immediately protected to give NBoc amino alcohol 81. Oxidation of the primary alcohol and removal of the N-Boc protecting group generated the desired (2S,3R)-4,4,4-trifluorothreonine (2S,3R)-76 (Scheme 18).78 3.4.5. 2-((Fmoc)Amino)-4-(diethoxyphosphoryl)-4,4difluorobutanoic Acid. Protein phosphorylation is one of the most common modes in protein function regulation. Peptides containing nonhydrolyzable phosphoamino acids have been described as tools for studying the roles of phosphorylation in cellular signaling.92 Moreover, attributed to the tetrahedral configuration of the phosphorus group, these types of amino acid derivatives serve as analogues of the tetrahedral carbon intermediates formed during enzymatic reactions, and thus can act as enzyme inhibitors.93 An entry to fluorinated aminophosphonates reported by Arrendale et al. used the chiral (2S)-O-TBS-tosylaziridine 82 as starting material, which was reacted with the in situ generated J


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Scheme 19. Synthesis of (S)-2-((Fmoc)Amino)-4-(diethoxyphosphoryl)-4,4-difluorobutanoic Acid 86

Scheme 20. Synthesis of 3,3-Difluoro-homoserine, -methionine, and -homocysteine Derivatives 93, 95, and 96

primary alcohol was TBS protected giving the secondary alcohol 90. Upon activation of the secondary alcohol, a substitution with sodium azide was performed and the TBS group was removed to give the primary alcohol 91. The latter was oxidized to the corresponding acid and protected to obtain the tert-butyl ester 92. Reduction of the azido moiety, hydrogenolysis of the benzyl group and protection of the amino group furnished tert-butyl (R)-2-((Boc)amino)-3,3-difluoro-4-hydroxybutanoate 93. With 93 in hand, they were able to introduce a sulfur moiety by activating the hydroxyl group as a triflate and substitution with potassium thioacetate to yield the thioester 94. Basic hydrolysis of the thioester 94 gave tert-butyl (R)-2-((Boc)amino)-3,3difluoro-4-mercaptobutanoate 95 and methylation afforded tertbutyl (R)-2-((Boc)amino)-3,3-difluoro-4-(methylthio)butanoate 96. The final amino acid derivatives 93, 95, and 96 were hydrolyzed using TFA to produce the corresponding free amino acids (not shown, Scheme 20).101 3.4.7. 3-(Acetylthio)-2-(1,3-dioxoisoindolin-2-yl)4,4,4-trifluorobutanoic Acid. The previously described building block 46 (Scheme 11) was employed for the synthesis of syn(3-trifluoromethyl)-cysteine derivatives by Jing et al. Starting from the enantiomeric cyclic sulfates (2S,3S)-46 and (2R,3R)-46 (the latter is accessible by using Ad-mix-α; only (2S,3S)-46 will be shown; all synthetic transformations remain the same to generate the (2S,3R)-derivative) the ring opening reaction was conducted using potassium phthalimide to generate the corresponding sulfate, which was hydrolyzed under acidic conditions to give the secondary alcohol 97. Activation of the secondary alcohol and nucleophilic displacement of the triflate with thioacetic acid furnished the thioester 98. Lewis acid-mediated deprotection of the alcohol and oxidation using Jones reagent gave the syn-(3-trifluoromethyl)cysteine derivative (2R,3S)-99 (Scheme 21).102

((diethoxyphosphoryl)difluoromethyl)lithium to undergo a ring opening at the terminal carbon giving protected amino alcohol 83. Conversion of the N-protecting group to Boc giving N-Boc amino alcohol 84 set stage for the concomitant removal of all protecting groups and subsequent N-Fmoc protection to yield the primary alcohol 85. Jones oxidation of the alcohol furnished (S)-2-((Fmoc)amino)-4-(diethoxyphosphoryl)-4,4difluorobutanoic acid 86 (Scheme 19).94 Otaka et al. investigated the use of Garner’s aldehyde as starting material to synthesize 86. The key steps involved the addition of ((diethoxyphosphoryl)difluoromethyl)lithium to the Garner’s aldehyde and the radical mediated deoxygenation of the generated secondary alcohol.95 An enzymatic desymmetrization approach to access 86 was conducted by Yokomatsu et al. They started with (2,2-dimethyl-1,3-dioxan-5-yl)methanol, which was converted into the corresponding triflate and reacted with the earlier described ((diethoxyphosphoryl)difluoromethyl)lithium reagent. The so-obtained diethyl (1,1-difluoro3-hydroxy-2-(hydroxymethyl)propyl)phosphonate was subjected to lipase PS-30 and vinyl acetate that only converted the (R)-derivative into the corresponding acetate. Subsequent oxidation and Curtius rearrangement furnished 86 as a single diastereomer.96 3.4.6. 3,3-Difluoro-4-hydroxybutanoate (Homoserine), 3,3-Difluoro-4-mercaptobutanoate (Homocysteine), and 3,3-Difluoro-4-(methylthio)butanoate (Methionine). In early works, several methods for the incorporation of fluorine in the side chain of cysteine derivatives have been reported using fluorination reagents such as XeF2,97 DAST,98 chlorodifluoromethane,99 and CF3I.66 A multistep strategy for the synthesis of 3,3-difluorohomoserine, -homocysteine and -methionine starting from isoascorbic acid 87 was reported by Keqiang et al. The key intermediate 1,3-dioxolane 88100 was difluorinated using DAST, giving the difluoro 1,3-dioxolane 89, which was hydrolyzed in acidic environment and the resulting K


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Scheme 23. Synthesis of N-Phth-5,5-Difluoronorvaline Derivative 108

Scheme 21. Synthesis of (2R,3S)-3-(Acetylthio)-2-(1,3dioxoisoindolin-2-yl)-4,4,4-trifluorobutanoic Acid

3.5. Synthesis of Amino Acids Bearing Three Carbon Atoms in the Aliphatic Side Chain

3.5.1. 2-Amino-4,4-difluoropentanoic Acid (Difluoropropyl Glycine, DfpGly) and 2-Amino-5-bromo-4,4difluoropentanoic Acid (5-Bromo-4,4-difluoronorvaline). The amino acid difluoropropyl glycine (DfpGly, following the nomenclature for the C2 derivative DfeGly) attracted considerable synthetic interest. Osipov et al. employed the earlier described HFA chemistry developed in the Burger lab (Section 3.3.2). Starting from the acid 39 (Scheme 10), a C1 elongation protocol using thionyl chloride and diazomethane

with Deoxo-Fluor giving N-Phth-5,5-difluoronorvaline derivative 108 as the major product (Scheme 23). During the fluorination reaction, the authors also observed an occurring cyclization reaction.104 Scheme 24. Synthesis of 5,5,5-Trifluoronorvaline 109

Scheme 22. Synthesis of 5-Bromo-4,4-difluoropentanoic Acid and Difluoropropyl Glycine 104

3.5.3. Methyl 2-((Boc)Amino-5,5,5-trifluoropentanoate (5,5,5-Trifluoronorvaline). The synthesis of 5,5,5trifluoronorvaline 109 was reported by Li et al. starting from the vinyl glycine 110, which is accessible by a four-step procedure from L-methionine 111.105 Addition of the vinyl glycine 110 to the xanthate 112 afforded the 3-substituted trifluoronorvaline 113. Reductive dexanthylation was achieved using Barton’s hypophosphorous acid based method yielding 5,5,5-trifluoronorvaline 109 (Scheme 24).106 The xanthate 112 was made accessible following the protocol of Bertrand et al. starting with the corresponding sodium salt.107 This entry also enables the synthesis of 6-trifluoromethylpipecolate (Section 4.5.2). Ojima et al. reported the synthesis of (S)- and (R)-5,5,5trifluoronorvaline 109 as well as (S)- and (R)-5,5,5-trifluoronorleucine. They synthesized a racemic mixture of the amino acid, acetylated the amine functionality and were able to separate the enantiomers through enzymatic resolution.108 3.5.4. 2-Amino-4-fluoropent-4-enoic Acid. The already described 2-hydroxy-3-pinanone chemistry (Sections 3.3.1 and 3.4.1) was utilized by Laue et al. to synthesize (S)-2-amino-4fluoropent-4-enoic acid 114. The glycine ester enolate (+)-35 (Scheme 9 and 13) was alkylated using 3-bromo-2-fluoropropene affording the fluoro alkene 115. Removal of the chiral auxiliary, hydrolysis of the ester and stirring in propene oxide generated (S)-2-amino-4-fluoropent-4-enoic acid 114 in 88% ee (Scheme 25).109 Alternatively, Shenage et al. established a synthetic approach for the asymmetric synthesis of 114 starting from enantiopure (S)-Boc-BMI84,85 as a chiral glycine building block. The

was performed giving the ketone 100. The reaction of 100 with hydrogen bromide and DAST gave the bromo-difluoro oxazolidinone 101. Hydrolysis of the latter yielded 5-bromo4,4-difluoropentanoic acid 102. Reductive debromination of the bromo-difluoro oxazolidinone 101 using tributyltin hydride and azobis(isobutyronitril) gave the difluoro derivative 103, which was hydrolyzed affording difluoropropyl glycine 104 (Scheme 22).103 3.5.2. tert-Butyl 2-(1,3-Dioxoisoindolin-2-yl)-5,5-difluoropentanoate (5,5-Difluoronorvaline). The synthesis of (R)-2-amino-5,5-difluoropentanoic acid derivative was described by Ulbrich et al. utilizing 3-hydroxy-pinanone as a chiral auxiliary. The Schiff base (−)-35 (Scheme 9 and 13) was stereoselectively alkylated with the tosylate 105 giving the benzyl ether 106. Cleavage of the auxiliary and protection of the obtained free amine with phthalic anhydride gave the Nphthaloyl derivative 107. Hydrogenation of the benzyl group of 107 and oxidation of the resulting primary hydroxy group with DMP gave the corresponding aldehyde which was then treated L


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access (2S,3S)-4-fluorovaline 122. The starting material (2S)pyroglutamic acid derivative 123 was synthesized following the procedure of Shimamoto.113 Stereoselective addition of 2methyl-1propenyl-magnesium bromide in the presence of copper bromide-dimethyl sulfide gave the alkene 124 as a single diastereomer. Ozonolysis and subsequent reduction of the double bond led to the primary alcohol 125, which then was deoxyfluorinated with DAST giving the lactam 126. Hydrolysis of the lactam moiety produced the free acid 127, which was in turn subjected to a decarboxylation using the protocol established by Barton.114 The acid 127 was converted to the corresponding mixed anhydride with iso-butylchloroformate and reacted with N-hydroxythiopyridone furnishing the thiohydroxamic ester 128. The latter was treated with tertbutyl thiol and irradiated with light to yield the radical induced decarboxylation product 129. After removal of the TBDPS protecting group, affording the alcohol 130, and subsequent oxidation, the Boc-protecting group was removed to afford the desired (2S,3S)-4-fluorovaline 122 (Scheme 28).115 This methodology was also employed for the synthesis of 4fluoroisoleucine (Section 3.7.7). 3.5.8. 2-((Boc)Amino)-4,4,4-trifluoro-3-methylbutanoic Acid (4,4,4-Trifluorovaline). Erdbrink et al. synthesized all four diastereomers of trifluorovaline employing the Evans auxiliary strategy to induce chirality. Coupling of crotonic acid chloride to the Evans oxazolidinone (S)-131 gave the key intermediate 132, which was treated with trifluoroiodomethane, triethylborane and ytterbium triflate in an oxygen atmosphere to generate the separable trifluoromethylated products (3S)-133 and (3R)-133. The addition of iodoperfluoroalkanes utilizing triethylborane, which presumably serves as an initiator and radical terminator, occurs in a reductive fashion. Next, (3S)-133 and (3R)-133 were each subjected to an α-azidation using trisyl azide to generate the (2S)-azido oxazolidinones (2S,3S)-134 and (2S,3R)-134. Reduction of the azide and protection using Boc2O as well as hydrolysis of the auxiliary gave (2S,3S) and (2S,3R)-2-((Boc)amino)-4,4,4-trifluoro-3-methylbutanoic acids (2S,3S)-135 and (2S,3R)-135. To access the (2R) derivatives, (3S)-133 and (3R)-133 were α-brominated using N-bromosuccinimide to yield the bromides (2S,3S)-136 and (2S,3R)-136, which were reacted with N,N,N′,N′-tetramethylguanidinium azide to achieve an inversion at C2. The soobtained azides (2S,3S)-137 and (2S,3R)-137 were reduced, Nprotected and the auxiliary was hydrolyzed to give (2R,3S) and (2R,3R)-2-((Boc)amino)-4,4,4-trifluoro-3-methylbutanoic acids (2R,3S)-135 and (2R,3R)-135 (Scheme 29).116 This methodology also enables the preparation of 4′,4′,4′- and 5,5,5trifluoroisoleucine, which will be discussed later (Sections 3.7.8 and 3.7.9). Alternatively, Chen et al. started with (R)-2,3-O-isopropylideneglyceraldehyde, which was diastereoselectively allylated using indium to give (1R,2S)-N-benzyl-1-((S)-2,2-dimethyl-1,3dioxolan-4-yl)-2-(trifluoromethyl)but-3-en-1-amine. Ozonolysis of the double bond and dehydroxylation of the primary alcohol cleanly furnished (2R,3S)-135.117 Another entry was reported by Pigza et al. starting from commercially available (E)4,4,4-trifluoro-3-methylbut-2-enoic acid, which was coupled to Oppolzer’s sultam ((S)-camphorsultam) and hydrogenated to give the major (3S)-derivative (4.2:1, ((3S):(3R)). After hydrolysis of the camphor moiety and coupling to (R)phenylglycinol the chiral oxazoline was generated. SeO2promoted oxidative rearrangement afforded the dihydro-2Hoxazinone, of which the C=N bond was face-selectively

Scheme 25. Synthesis of (S)-2-Amino-4-fluoropent-4-enoic Acid 114

stereoselective alkylation of (S)-Boc-BMI with 2-fluoroallyl tosylate was performed in the presence of DMPU using LDA as a base, leading to a single diastereomer. Deprotection of the alkylation product was achieved in two steps and gave the desired product 114.110 3.5.5. (E)-2-Amino-5-fluoropent-3-enoic Acid (Fluoroallylglycine). Starting from D-Garner’s aldehyde (R)-116, Zhang et al. reported the synthesis of (S,E)-2-amino-5Scheme 26. Synthesis of N-Fmoc-Fluoroallylglycine 117

fluoropent-3-enoic acid 117. Wittig reaction between (triphenyl-phosphanylidene)-acetaldehyde and (R)-116 gave the (E)α,β-unsaturated aldehyde, that was reduced using DIBALH to afford the allylic alcohol 118. After deoxofluorination of the alcohol moiety of 118 with DAST, the isopropylidene protecting group was removed and the N-Boc protecting group was changed to N-Fmoc giving the primary alcohol 119. The latter Scheme 27. Synthesis of 3-Fluorovaline 121

was oxidized with Jones reagent to yield the desired 117 (Scheme 26).111 3.5.6. Methyl 2-Amino-3-fluoro-3-methylbutanoate (3-Fluorovaline). Halperin et al. reported the conversion of valine methylester 120 to 3-fluorovaline methyl ester 121 by direct fluorination of unactivated C(sp3)-H-bonds with tetrabutylammonium decatungstate (TBADT, Na4W10O32) as photocatalyst and NFSI as electrophilic fluorine source (Scheme 27). This methodology was carried out under mild conditions in wet solvents and with a large degree of functional group tolerance.112 This strategy also allows the generation of 4fluoroleucine (Section 3.7.3). 3.5.7. 2-Amino-4-fluoro-3-methylbutanoic Acid (4Fluorovaline). Charrier et al. established a synthetic route to M


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Scheme 28. Synthesis 4-Fluorovaline 122

3.5.9. 2-Amino-4,4,4-trifluoro-3-(trifluoromethyl)butanoic Acid (4,4,4,4′,4′,4′-Hexafluorovaline). The first approach which made enantiopure hexafluorovaline available was published by Keese et al. (R)-1-Phenethylamine was added to β,β-bis(trifluoromethyl)acrylic acid methyl ester 139 and the (S,R)- and (R,R)- adducts 140 were obtained with 4.8 and 22% de, respectively. Crystallization led to enantiomeric enrichment and gave the methyl ester (S,R)-140 in 99.8% de. The latter was hydrogenated to give (S)-hexafluorovaline methyl ester (S)-141. The remaining (R,R)-140 which can be found in the supernatant of the earlier described crystallization, was treated with BBr3 affording (R)-hexafluorovaline (R)-141 (Scheme 30).121 Since hexafluorovaline is prone to racemization at Cα, Eberle et al. improved the methodology so that the free (S)-amino acid is accessible without an acidic or basic hydrolysis step, starting with β,β-bis(trifluoromethyl)acrylic acid benzyl ester, which is accessible by a Wittig reaction between HFA and benzyl(triphenylphosphoranylidene)acetate.122

Scheme 29. Synthesis of all four Diastereomers of Trifluorovaline (2S,3S)-135, (2S,3R)-135, (2R,3S)-135, and (2R,3R)-135

3.6. Synthesis of Amino Acids Bearing Three Carbon Atoms in the Polar Side Chain

3.6.1. 2-Amino-4-fluoropentanedioic Acid (4-Fluoroglutamic Acid). The synthesis of fluorinated glutamic acid derivatives was investigated by Hart et al. Starting from the pyroglutamate derivative 142, the direct electrophilic fluorination of the corresponding enolate of 142 with NFSI gave the monofluorinated derivative 143 as a single diastereomer. Cleavage of the protecting groups and oxidation using CrO3, H5IO6 in wet acetonitrile furnished the carboxylic acid which was esterified giving 144. Acidic hydrolysis and desalting using propene oxide gave (4R,2S)-4-fluoroglutamic acid (4R,2S)-145. By slightly altering the reaction sequence, (4S,2S)-4-fluoroglutamic acid (4S,2S)-145 was made accessible. The authors described a second approach: by treating 142 with LiHMDS and subsequent electrophilic hydroxylation using MoOPH, the secondary alcohol 146 was synthesized having the already observed trans selectivity. Activation of the hydroxyl group using triflic anhydride and reaction with TBAF and methyl iodide gave the (4S)-lactam 147, which was subjected to the earlier described reactions to give (4S,2S)-4-fluoroglutamic acid (4S,2S)-145 (Scheme 31).123 3.6.2. Dibenzyl 2-((Cbz)Amino)-3,3-difluoropentanedioate (3,3-Difluoroglutamic Acid). Suzuki et al. described a synthetic route to afford 3,3-difluorinated glutamic acid derivatives starting from the easily accessible (R)-trifluoromethyl iminoester 148. First the difluoroenamine 149 was generated

hydrogenated. That was followed by a hydrogenolysishydrolysis reaction cascade to give (2S,3S)-135. In this publication, the synthesis of 4,4,4- trifloroisoleucine (Section 3.7.8) is also reported.118 Alternatively, Benhaim et al. used 1,1,1-trifluoroacetone which was reacted with cyanoacetate, to provide the prochiral methyl (Z)-4,4,4-trifluoro-2-formamido3-methylbut-2-enoate, which was then hydrogenated using [((R)-TCFP)Rh(cod)]BF4 138 (Scheme 29) to furnish methyl (2R,3R)-4,4,4-trifluoro-2-formamido-3-methylbutanoate (NAc-(2S,3S)-4,4,4-trifluorovaline).119 Using racemic 4,4,4-trifluorovalines, Xing et al. employed a derivatization/enzymatic resolution approach to separate all four possible diastereomers.120 N


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Scheme 30. Synthesis of (S)- and (R)-4,4,4,4′,4′,4′-Hexafluorovaline (S)-141 and (R)-141

Scheme 31. Synthesis of (4R,2S)- and (4S,2S)-4-Fluoroglutamic Acid (4R,2S)-145 and (4S,2S)-145

Scheme 32. Synthesis of Dibenzyl (2S)-N-Cbz-3,3-Difluoroglutamate 154

3.6.3. 4-Amino-2,2-difluoropentanedioic Acid (4,4Difluoroglutamic Acid). All efforts to synthesize 4,4-difluoro glutamic acid variants by treating the earlier described pyroglutamic acid derivatives 143 or 147 with a base followed by the reaction with an electrophilic fluorine source were met with failure (Scheme 31). This was overcome by Konas et al. by transforming the pyroglutamic acid derivative 142 into the corresponding bicycle 155. Subjecting 155 to the electrophilic fluorination conditions twice, the difluorinated bicycle 156 was generated. Acidic hydrolysis, oxidation of the hydroxyl group and ring opening gave (2S)-4,4-difluoroglutamic acid 157 (Scheme 33).125,126

by Mg(0)-promoted defluorination, followed by bromination to give the bromodifluoromethyl iminoester 150. Asymmetric hydrogenation of the latter with Pd(OCOCF3)2 and (R)BINAP and allylation with allyltributylstannane led to the desired alkene 151. Change of the N-protection from PMP to Boc generated 152, that was in turn subjected to oxidative conditions to obtain the acid which was then benzyl protected to yield the ester 153. Next, the protection groups were again modified to allow the generation of (2S)-N-Cbz-3,3-difluoroglutamicacid dibenzyl ester 154 in 88% ee (Scheme 32). The same methodology was employed for the synthesis of 3,3difluoroproline (Scheme 60, Section 4.3.2).124 O


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then deoxygenated to give the ethyl ester 161 (Scheme 34, Section 3.6.4). The ester was converted to the corresponding free amine and reduced using Red-Al giving the primary amine 166. The amine was then reacted with 2-N,N′-di-Cbz-N′trifylguanidine to give 167. Hydrolysis of the oxazolidine and oxidation of the primary alcohol furnished the acid 168, which in turn was hydrogenated to give (2S)-4,4-difluoro arginine 164. To access 165, the synthesis was altered and the N-Boc protected Garner’s aldehyde (R)-169 was used. The first five steps to produce 165 remained the same and the primary amine 170 was synthesized. The amine moiety of 170 was reacted with CbzCl and the oxazolidine was hydrolyzed giving the primary alcohol 171. The latter was oxidized and protected as tert-butyl ester giving the ester 172. Hydrogenation of the Cbz-group and reaction with O-benzyl carbonisothiocyanatidate gave the thiourea derivative 173. Reaction of 173 with O-(oxan-2yl)hydroxylamine and concomitant hydrolysis of the THPmoiety and the tert-butyl ester, without cleaving the Boc-group, gave the (2S)-NG-hydroxy-4,4-difluoroarginine 165 (Scheme 35).132,133

Scheme 33. Synthesis of 4,4-Difluoroglutamic Acid 157

Another entry to 157 was presented by Ding et al. starting from L-serine. Conversion of L-serine into the corresponding chiral aldehyde 158 followed by addition of an in situ generated Reformatsky reagent, prepared by mixing zinc and ethyl bromodifluoroacetate, gave the corresponding secondary alcohol in a 7:1 diastereomeric mixture. Deoxygenation and cleavage of the protecting groups gave 157.127 A similar approach was published by Meffre et al. using N-Boc-Garner’s aldehyde to synthesize 157.128 3.6.4. 5-Amino-2-((Cbz)amino)-4,4-difluoro-5-oxopentanoic Acid (4,4-Difluoroglutamine). A convenient diastereoselective synthesis was reported by Konas et al. employing fluoro-Reformatsky chemistry. Reaction of the NCbz protected Garner’s Aldehyde (R)-159 with the earlier mentioned Reformatsky reagent gave the secondary alcohol 160 as a mixture of diastereomers. The hydroxy group was reacted with 1,1′-thiocarbonyldiimidazole and the so-obtained thiocarbonyl derivative was deoxygenated using the triethyl silane/ benzoyl peroxide system to give the difluoro ester 161. Acidic hydrolysis and subsequent oxidation of the free primary alcohol moiety to the corresponding acid gave 162. It should be noted that the glutamic acid derivative is also accessible by hydrolysis of the ester. Nevertheless, the authors chose to hydrolyze the ester by aminolysis to give (S)-4,4-difluoroglutamine 163 (Scheme 34).129 Some of the earlier reported glutamic acids were converted into the corresponding glutamine derivatives without affecting the stereochemistry, reported by Tolman et al.130 3.6.5. 2-Amino-4,4-difluoro-5-guanidinopentanoic Acid (4,4-Difluoroarginine) and 2-((Boc)Amino)-4,4-difluoro-5-(2-hydroxyguanidino)pentanoic Acid (NG-Hydroxy-4,4-difluoroarginine Derivative). The N-Cbz protected Garner’s aldehyde (R)-159 was employed by Martin et al. in the synthesis of (2S)-4,4-difluoroarginine 164 and (2S)-NGhydroxy-4,4-difluoroarginine 165 using an earlier entry, which was reported by Kim et al.,131 omitting the use of toxic mercury salts. Reformatsky reaction between ethyl 2-bromo-2,2-difluoroacetate and (R)-159 gave the secondary alcohol which was

3.7. Synthesis of Amino Acids Bearing Four Carbon Atoms in the Aliphatic Side Chain

3.7.1. Methyl 2-((Boc)Amino)-5-fluorohex-5-enoate. Lübke et al. synthesized a norleucine derivative starting from (S)-N-Boc-3-iodo-L-alanine methyl ester 174, which was reacted with 3-fluorobut-3-enyl tosylate 175 in the presence of activated zinc134,135 affording the targeted methyl 2-((Boc)amino)-5fluorohex-5-enoate 176. The tosylate 175 was accessible starting from but-3-en-1-ol 177 by conducting a reaction sequence consisting of concomitant fluorination and bromination of the double bond in the presence of NBS and triethylamine trihydrofluoride as well as benzoyl protection of the primary alcohol to generate the 4-bromo-3-fluorobutyl benzoate 178. Elimination of the bromine of 178 and cleavage of the benzoyl group to activate the hydroxy group as a tosylate gave 3-fluorbut3-enyl tosylate 175 (Scheme 36).136 3.7.2. 2-Amino-3-fluoro-4-methylpentanoic Acid (3Fluoroleucine). 3-Monofluoroinated derivatives of leucine were reported by Davis et al. employing oxazolidone chemistry. The sodium enolate of 179 (see also the synthesis of βmonofluorinated phenylalanine, Section 5.3) was subjected to an electrophilic fluorination with NFSI to give the oxazolidone α-fluoro amide 180. Reductive removal of the auxiliary afforded the 2-fluorohydrin, which was oxidized using DMP to give the aldehyde 181 in > 95% ee. The latter was coupled with the chiral sulfinamide (S)-182, which yielded the corresponding sulfinimine 183. The following sulfinimine-mediated asymmetric Strecker synthesis using the in situ generated ethylammonium cyanoisopropoxide gave the β-fluoro-α-amino nitrile in > 96% de, which was hydrolyzed under acidic conditions and stirred in

Scheme 34. Synthesis of (S)-4,4-Difluoroglutamine 163

P


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Scheme 35. Synthesis of (S)-4,4-Difluoroarginine 164 and (2S)-NG-Hydroxy-4,4-difluoroarginine 165

Scheme 36. Synthesis of Methyl 2-((Boc)Amino)-5-fluorohex-5-enoate 175

3.7.3. Ethyl 2-(Benzylamino)-4-fluoro-4-methylpentanoate (4-Fluoroleucine). The synthesis of 4-fluoroleucine was reported by Nadeau et al. Ethyl glyoxylate 185 was treated with 5 mol % of ZnCl2 to induce depolymerization and to set stage for the enantioselective ene-reaction using TiCl2(OiPr)2, (R)-BINOL and isobutylene giving the hydroxy ester 186 in > 95% ee. Hydrofluorination was achieved using HF·py and afforded the (R)-4-fluoroleucic acid ethyl ester 187. Activation of the hydroxy group as the corresponding triflate and nucleophilic substitution with benzyl amine resulted in an inversion at C2 and gave (2S)-N-Bn-4-fluoroleucine 188 in >95% ee (Scheme 38).138 Other approaches to synthesize (2S)-4-fluoroleucine used an enzyme-catalyzed dynamic kinetic ring-opening of an azlactone139 and a multistep transformation of L-aspartic acid where a tertiary alcohol was deoxyfluorinated using DAST.140 Another entry reported the use of side-chain bromination of leucine and

Scheme 37. Synthesis of 3-Fluoroleucine 184

propylene oxide to give (2S,3S)-3-fluoroleucine 184 (Scheme 37). Since the nitrile addition is governed by the chiral sulfinimine, the corresponding anti β-fluoro-α-amino acid is accessible by starting with the enantiomeric fluoro aldehyde of 181 or (R)-sulfonamide (R)-182.137 Scheme 38. Synthesis of 4-Fluoroleucine 188

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Scheme 39. Synthesis of (2S,4S)- and (2S,4R)-5-Fluoroleucine (2S,4S)-191 and (2S,4R)-191

AgF as fluorinating reagent.141 The earlier described photocatalyst promoted C(sp3)-H-bond fluorination with NFSI (Section 3.5.6) was employed to synthesize 188.142 Lygo et al. used the Corey-Lygo catalyst143 to synthesize a (2S)-amino methylpent-4-enoate derivative and subjected it to a Fe(III)/ NaBH4 mediated free radical hydrofluorination to synthesize 188.144 3.7.4. tert-Butyl 2-((di-Boc)Amino)-5-fluoro-4-methylpentanoate (5-Fluoroleucine). A synthetic entry to enantiopure 5-fluoroleucine was reported by Charrier et al. using 4-methyl pyroglutamate as starting material.145−147 Hydrolysis of the lactam 189 and formation of a mixed anhydride followed by reduction with NaBH4 gave the alcohol, which was activated using methansulfonyl chloride to give the mesylate 190. To avoid the concurring cyclization reaction to the prolinate, bis-protection of the nitrogen was required using Boc2O. The bisprotected mesylate was reacted with TBAF and 2-mesitylenesulfonic acid to give N-Bis-Boc-(2S,4S)-5-fluoroleucine tert-butyl ester (2S,4S)-191 in 94% ee. (2S,4R)-191 was accessible by refluxing 189 with TBAF in THF to achieve stereoinversion at C-4 (compound 192, 62% ee, the resulting isomers were separated by column chromatography) and then by conducting the same described transformations (Scheme 39).148 3.7.5. Benzyl 2-((Boc)Amino)-5,5,5-trifluoro-4-methylpentanoate (5,5,5-Trifluoroleucine). Two diastereomers of 5,5,5-trifluoroleucine were synthesized by Biava et al. by conducting Wittig chemistry using 1,1,1-trifluoro acetone. The latter was reacted with ethyl (triphenylphosphoranylidene)pyruvate 193 and the resulting alkene was hydrogenated to yield ethyl pyruvate 194. After hydrolysis of the ester the α-keto acid was converted to the (2S)-amino acid by transamination using a

system of phenylalanine dehydrogenase, formate dehydrogenase, NADH and ammonium formate at pH = 8.5 to give (2S)5,5,5-trifluoromethyl leucine 195.149 Derivatization by protection of the amino and carboxy moiety gave the separable diastereomeric pairs (2S,4R)-196 and (2S,4S)-196 (Scheme 40).150 Racemic 5,5,5-trifluoroleucine was separated into its diastereomers by a derivatization approach, which involved Nprotection, reduction of the carboxylic acid, change of Nprotection and oxidation to reobtain the acid moiety.120 3.7.6. 2-Amino-4-(difluoromethyl)-5,5-difluoropentanoic Acid (5,5,5′,5′-Tetrafluoroleucine) and 2-Amino5,5,5-trifluoro-4-(trifluoromethyl)pentanoic Acid (5,5,5,5′,5′,5′-Hexafluoroleucine). The synthesis of 5,5,5′,5′-tetrafluoroleucine 197 and 5,5,5,5′,5′,5′-hexafluoroleucine 198 was reported by Chiu et al. employing the same entry as discussed in Scheme 40. In this case, ethyl (triphenylphosphoranylidene)pyruvate 193 was reacted with 1,1,3,3-tetrafluoroacetone or 1,1,1,3,3,3-hexafluoroacetone, respectively, to give the corresponding alkenes 199 and 200, which were converted to the amino acids 197 and 198 using the transamination system described in Section 3.7.5 (Scheme 41).151 Other approaches to synthesize 198 were employing chiral starting materials like the Garner’s aldehyde (Xing et al.152), Lserine (Anderson et al.153) or conducted a stereoselective reduction of a fluoro-α-keto ester (Zhang et al.154). 3.7.7. 2-Amino-3-(fluoromethyl)pentanoic Acid (4′Fluoroisoleucine). The earlier discussed synthesis of 4fluorovaline described by Charrier et al. was employed to generate 4-fluoroisoleucine 201. The acid 127 (Scheme 28, Section 3.5.7) was converted to the corresponding mixed anhydride and then reduced yielding the primary alcohol 202. A Barton McCombie radical deoxygenation gave the fluoromethyl derivative 203. Hydrolysis of the silyl ether and oxidation of the so-obtained primary alcohol afforded 4′-fluoroisoleucine 201 (Scheme 42).155 3.7.8. 2-Amino-3-(trifluoromethyl)pentanoic Acid (4′,4′,4′-Trifluoroisoleucine). The synthesis of 4′,4′,4′trifluoroisoleucine reported by Erdbrink et al. utilized the same approach as for the fluorinated valines described earlier (Scheme 29, Section 3.5.8). Addition of (E)-pent-2-enoyl chloride to the Evans oxazilidinone (S)-131 gave the corresponding alkene 204 which was converted to the (2S,3S)-N-Boc-4′,4′,4′-trifluorosisoleucine (2S,3S)-205 (Scheme 43).116 The earlier described diastereoselective allylation reported by Chen et al. can be employed to synthesize trifluoroisoleucine. Starting from (R)-2,3-O-isopropylidene glyceraldehyde (R)-206, the corresponding imine was generated

Scheme 40. Synthesis of (2S,4R)- and (2S,4S)-5,5,5Trifluoroleucine (2S,4R)-196 and (2S,4S)-196

R


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Scheme 41. Synthesis of 5,5,5′,5′-Tetrafluoroleucine 197 and 5,5,5,5′,5′,5′-Hexafluoroleucine 198

Scheme 42. Synthesis of 4′-Fluoroisoleucine 201

Scheme 44. Synthesis of 5,5,5-Trifluoroisoleucine Derivative (2S,3R)-214 and N-Boc-5,5,5-Trifluoroisoleucines (2S,3S)and (2R,3S)-210

using benzylamine. Diastereoselective allylation of the imine using (E)-4-bromo-1,1,1-trifluorobut-2-ene and indium gave the dioxolane 207. Protection of the amine and oxidative glycol cleavage furnished (2R,3S)-4′,4′,4′-trifluoroisoleucine (2R,3S)208 (Scheme 43). Starting from (S)-206 the diastereomeric (2S,3R)-208 was accessible using the same synthetic transformations.117 3.7.9. 2-Amino-5,5,5-trifluoro-3-methylpentanoic Acid (5,5,5-Trifluoroisoleucine). 5,5,5-Trifluoroisoleucine was synthesized applying Evans chemistry. In this context, Erdbrink et al. coupled (R)-5,5,5-trifluoro-3-methylpentanoic acid (starting from (R)-5,5,5-trifluoro-pentanoic acid156) to the chiral auxiliary to give the oxazolidinone 209, which was converted to the corresponding N-Boc-5,5,5-trifluoroisoleucines (2S,3S)- and (2R,3S)-210 using earlier described transformations (Scheme 29, Section 3.5.8).157 The method published by Wang et al. used (R)-4,4,4-trifluoro-butanoic acid as starting material. However, in this case, they stereoselectively introduced the methyl group at C2 of 211 employing Evans chemistry. Reductive cleavage of the auxiliary gave the chiral alcohol 212, which was oxidized using DMP and coupled with (R)-toluenesulfinamide (R)-182 to yield the chiral imine 213. Diastereoselective Strecker158−160 reaction and concomitant hydrolysis of both the chiral auxiliary and the nitrile furnished (2S,3R)-5,5,5-trifluoroisoleucine derivative (2S,3R)214 (Scheme 44).154 Biava et al. reported the synthesis of (2S,3S)-214 and (2S,3R)-214 using enzymatic resolution of N-Ac-5,5,5-trifluoroisoleucine employing Aspergillus melleus acylase I and Porcine kidney acylase I.161 It should be noted that a great effort to synthesize numerous fluorinated leucine and isoleucine analogues was successfully conducted and filed in patents. The

authors reported different methods to generate the racemic amino acid of choice and purified the final compounds by chiral column chromatography.162,163 3.8. Synthesis of Amino Acids Bearing Four Carbon Atoms in the Polar Side Chain

3.8.1. 6-((Cbz))Amino)-2-((Boc)amino)-4-fluorohexanoic Acid (Nα-Boc-Nε-Cbz-4-Fluorolysine) and 6-Acetimidamido-2-((Boc)amino)-4-fluorohexanoic Acid (N-Boc4-Fluoro-(iminoethyl)lysine). Hallinan et al. synthesized 4fluorinated lysine derivatives by utilizing the Garner’s aldehyde as the chiral starting material. The latter was subjected to a Horner−Wadsworth−Emmons (HWE) reaction with triethyl 2-fluoro-2-phosphonoacetate giving the fluoro alkene 215, followed by hydrogenation of the double bond furnishing 216 as the major isomer. Reduction of the ester moiety followed by a Henry reaction using nitromethane gave the nitro alcohol 217. Reaction of the secondary alcohol with MsCl resulted in the elimination of the mesiylate to generate the conjugated nitro alkene 218. Sequential reduction of the double bond with

Scheme 43. Synthesis of 4′,4′,4′-Trifluoroisoleucine (2R,3S)-208 and N-Boc Protected (2S,3S)-205

S


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Scheme 45. Synthesis of Nα-Boc-Nε-Cbz-4-Fluorolysine 220 and N-Boc-4-Fluoro-(iminoethyl)lysine 221

Scheme 46. Synthesis of Nα-Boc-Nε-Cbz-4,4-Difluorolysine 225 and N-Boc-4,4-Difluoro-(iminoethyl)lysine 226

Scheme 47. Synthesis of 5,5-Difluoro-(iminoethyl)lysine 230

the Cbz-group and reaction with ethyl acetimidate hydrochloride to obtain N-Boc-4,4-difluoro-(iminoethyl)lysine 226 (Scheme 46).162 3.8.3. 6-Acetimidamido-2-amino-5,5-difluorohexanoic Acid (5,5-Difluoro-(iminoethyl)lysine). 5,5-Difluoroiminethyl-lysine was synthesized using an electron-transfer reaction between L-vinylglycine 227 and ethyl difluoroiodoacetate to generate the ester 228.165,166 Regioselective reduction of the ethyl ester and activation of the resulting primary alcohol as a triflate set stage for a nucleophilic substitution with the potassium salt of 3-methyl-[1,2,4]oxadiazol-5-one to generate 229. Hydrogenation of the Cbz moiety and acidic hydrolysis gave 5,5-difluoro-(iminoethyl)lysine 230 (Scheme 47).167

sodium hydride and hydrogenation of the nitro group gave the primary amine 219. Hydrolysis of the oxazolidine, protection of the amino group, and oxidation of the primary alcohol gave NαBoc-Nε-Cbz-4-fluorolysine 220. To generate the iminoethyl analogue, the Cbz-group was reductively cleaved, and the free amine was reacted with ethyl acetimidate hydrochloride to give N-Boc-4-fluoro-(iminoethyl)lysine 221 (Scheme 45).164 3.8.2. 6-((Cbz)Amino)-2-((Boc)amino)-4,4-difluorohexanoic Acid (Nα-Boc-Nε-Cbz-4,4-Difluorolysine) and 6-Acetimidamido-2-((Boc)amino)-4,4-difluorohexanoic Acid (N-Boc-4,4-Difluoro-(iminoethyl)lysine). 4,4-Difluorinated variants of lysine were made accessible by homologization of the difluoro oxazolidine 222 (synthesis analogous to 161, Scheme 35, Section 3.6.5). Reduction of the ester moiety and Henry reaction with nitromethane gave the secondary alcohol 223. Reduction of the nitro group and protection of the soobtained amine gave N-Cbz protected secondary alcohol 224. Deoxygenation, hydrolysis of the oxazolidine, and oxidation of the primary alcohol gave Nα-Boc-Nε-Cbz-4,4-difluorolysine 225. Similarly, the imineoethyl moiety was introduced by cleavage of

3.9. Synthesis of Amino Acids Bearing Five or More Carbon Atoms in the Aliphatic Side Chain

3.9.1. tert-Butyl 2-((Boc)Amino)-6-fluoroheptanoate. Fanelli et al. described the electrophilic fluorination using Fe(III)/NaBH4 mediated free radical hydrofluorination of unsaturated α-amino acids to synthesize an (2S)-amino 6T


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Scheme 48. Synthesis of tert-Butyl (2S)-2-((Boc)amino)-6fluoroheptanoate 232

3.10.2. Synthesis of Perfluoroalkyl Amino Acids. The photoinduced radical hydroperfluoroalkylation of unsaturated carboxylic acids using TTMSS as an H-donor was successfully developed by Yajima et al. The stereoselective induction was achieved using Oppolzer’s camphorsultam 244 as a chiral auxiliary. Preparation of the starting material was achieved with reaction of the lithium salt of the chiral auxiliary 244 and propiolic acid, which was in situ activated by the generation of the tert-butyl mixed anhydride, giving the alkyne 245.172 Next, an α-addition of phthalimide to the alkyne 245 was conducted to produce the dehydroamino acid 246, which was subjected to the hydroperfluoroalkylation conditions generating the perfluoro products 247a−e. Removal of the chiral auxiliary and Ndeprotection cleanly furnished the corresponding perfluoro alkyl amino acids 248a and (R)-42 (deprotection was conducted for two derivatives, Scheme 51).173 3.10.3. Catalytical Hydrogenation of Aliphatic Imines and Enamides. A synthetically versatile approach to synthesize fluorinated aliphatic amino acids is the hydrogenation of suitable substituted imines or enamides. These approaches are robust and generate the corresponding amino acids with high enantiomeric excess. Burk et al. employed (S,S)-[Pr-DuPHOS-Rh]+ to hydrogenate the enamide 249 giving the corresponding (2S)-N-Cbz fluoro alkyl amino acid 250 in ≥ 98% ee (using (R,R)-[Pr-DuPHOS-Rh]+ led to the generation of the (R)-derivative with ≥ 98% ee).174,175 For imines, Abe et al. utilized Pd-BINAP as the catalyst system and achieved enantioselectivities of up to 91% ee when nBu4NHSO4 was added (reported for entry 252a, not shown). In the case of iminoesters176,177 251a−f, the corresponding fluorinated amino acid derivatives 252a−f were synthesized (Scheme 52).56 3.10.4. Photoinduced Trifluoromethylation and Perfluoroalkylation of Cysteine Derivatives in Batch and Continuous Flow. Bottecchie et al. described a visible lightinduced trifluoromethylation and perfluoroalkylation of cysteine derivative 253. In their studies, Ru(Bpy)32+ was used as photocatalyst and the commercially available perfluoroalkylated iodides 254a−h were coupled to the cysteine 253 in the presence of TMEDA generating the thioethers 255a−h. In this approach, it was feasible to use ethyl 2,2-difluoro-2-iodoacetate to generate the cysteine derivative 256. The authors demonstrated the use of continuous-flow setup to improve the reaction and the handling of gaseous reactants as well (e.g., CF3I, Scheme 53).178

fluoroheptanoate derivative. The unsaturated α-amino acid 231 was accessible through a strategy described by Lygo et al.142 With the amino acid 231 in hand, the electrophilic fluorination was employed using Selectfluor as fluorine source yielding tertbutyl (2S)-2-((Boc)amino)-6-fluoroheptanoate 232 (Scheme 48).168 3.9.2. 2-(1,3-Dioxoisoindolin-2-yl)-3-fluoroundecanoic Acid. Starting from (R)-2,3-O-isopropylideneglyceraldehyde (R)-206, the synthesis of (2S,3R)-2-(1,3-dioxoisoindolin2-yl)-3-fluoroundecanoic acid (2S,3R)-233 was described by Fokina et al. Addition of n-octyl magnesium bromide to the aldehyde (R)-206 furnished a mixture of the diastereomeric alcohols 234a and 234b (in a ratio of 2.5:1, (2R,3S)/(2R,3R)). Conversion of the secondary alcohol to the corresponding trimethylsilyl ether and fluorination using Morpho-DAST gave the diastereomeric fluorides 235a and 235b (in a ratio of 5.7:1, (2R,3R)/(2R,3S)). Hydrolysis of the dioxolane and protection of the primary hydroxyl group using TBSCl gave the chromatographic separable secondary alcohols 236a and 236b (of which only 236a will be further discussed). Mitsunobu reaction of the secondary alcohol with phthalimide and TBS deprotection produced the primary alcohol, which was then oxidized to generate (2S,3R)-2-(1,3-dioxoisoindolin-2-yl)-3fluoroundecanoic acid (2S,3R)-233 (Scheme 49).169 3.10. Miscellaneous Fluorinated Amino Acids

3.10.1. 4-Alkenyl Glutamic Acid Derivatives. Ramachandran et al. reported the synthesis of 4-(fluoroalkylidenyl) and 4(fluorobenzylidenyl)-glutamic acid derivatives. Enantioselective addition of the Schiff base of glycine tert-butyl ester 237 with fluorinated allylic acetates 238a−c was achieved by phasetransfer catalysis with O-allyl-N-(9-anthracenylmethyl)cinchonidium bromide 239 to generate the (2S)-4-(fluoroalkylidenyl) and 4-(fluorobenzylidenyl)-glutamic acid derivatives 240a−c. The fluorinated allylic acetates 238a−c were synthesized by reaction of the corresponding fluorinated aldehydes 241a−c with di-isobutyl(3-methoxy-3-oxoprop-1en-2-yl)aluminum 242. The latter was obtained by vinylalumination of methyl propiolate 243 (Scheme 50).170,171

Scheme 49. Synthesis of (2S,3R)-2-(1,3-Dioxoisoindolin-2-yl)-3-fluoroundecanoic Acid (2S,3R)-233

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Scheme 50. Synthesis of 4-(Fluoroalkylidenyl) and 4-(Fluorobenzylidenyl) Glutamic Acid Derivatives 240a−c

Scheme 51. Radical Hydroperfluoroalkylation of Unsaturated Carboxylic Acids 248a and (R)-42

Scheme 52. Catalytic Hydrogenation of Imines 251a−f and Enamide 249

Scheme 53. Perfluoroalkylation of Cysteine Derivatives

4. SYNTHESIS OF CYCLIC SIDE CHAIN FLUORINATED AMINO ACIDS In the following section, the synthesis of fluorinated cyclic amino acids will be presented. This section is subdivided according to the ring size of the corresponding FAAs. We will present entries to fluorinated aziridines, azetidines, pyrrolidines, 5-oxopyrrolidines, kainic acids, oxazolidines, and piperidines. This section finishes with synthetic entries toward fluorinated bicyclic amino acids.

and ethyl diazoacetate. The best performing Lewis acid was BF3· Et2O, and the cyclic amino acid derivatives were obtained with a cis/trans ratio of 95:5.179 Further improvements of the entry by De Kimpe et al. led to a higher diastereoselectivity (d.r. > 99:1) again favoring the cis isomer (Scheme 54).180 Akiyama et al. investigated the Lewis acid-mediated aziridination of diazoacetates with N,O-hemiacetals, which are obtained by reaction of trifluoroacetaldehyde ethyl hemiacetal

4.1. Three-Membered Rings

4.1.1. Synthesis of 3-(Trifluoromethyl)aziridine-2carboxylates. Crousse et al. established a Lewis acid catalyzed pathway for the synthesis of trifluoromethylated aziridine-2carboxylates 257a and 257b. They studied various conditions of the reaction between trifluoroaldimines 258, which are generated by the reaction of fluoral with the respective amines V


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Scheme 54. Lewis Acid Catalyzed Synthesis of Ethyl 3(Trifluoromethyl)aziridine-2-carboxylates 257a and 257b

Scheme 56. Synthesis of Methyl (2S,3S)-3(Trifluoromethyl)aziridine-2-carboxylate 266

259 with the corresponding aniline. Initially, the reaction of N,O-hemiacetal 260 with various diazoacetates to give the (4methoxyphenyl)-3-(trifluoromethyl)aziridines 261a−g was examined. In almost all cases, the cis isomer was predominantly formed except for the aziridination involving 2,6-di-tert-butyl-4methyl-phenyl diazoacetate and tin tetrachloride, where a trans selectivity (cis/trans, 10:90) could be observed. Additionally, a diastereoselective synthesis was achieved by using the (R)pantolactone-containing diazo ester and N,O-hemiacetal 262a and 262b to yield the (4-methoxyphenyl)-3-(trifluoromethyl)aziridines 263a and 263b with both high cis stereoselectivity (cis/trans, 99:1) and diastereoselectivity 94% de (Scheme 55).181 Another approach to obtain 3-(trifluoromethyl)aziridines was established by Prati et al., starting from the 4,4,4-trifluorocrotonate 264. By bromination of 264 and subsequent treatment with benzylamine, the trans-aziridine 265 was synthesized. Hydrogenolysis of the benzyl moiety led to the formation of methyl (2S,3S)-3-(trifluoromethyl)aziridine-2-carboxylate 266 (Scheme 56).182

a sequential reduction that formed azetidine 271. Periodate cleavage of the 1,2-diol of 271 and immediate oxidation gave the methyl ester. Hydrolysis of the ester with potassium carbonate afforded the N-benzyl hydroxyazetidine carboxylic acid, from which the benzyl group was removed, which generated the unprotected fluoro-D-hydroxyazetidine carboxylic acid 272 (Scheme 57).183 To generate the L-diastereomer, diacetone 3-fluoroglucose 268 was hydrolyzed under mild conditions to generate the monoacetonide. Subsequent oxidation of the diol followed by reduction of the resulting aldehyde led to the formation of the alcohol 273. Afterward, hydrolysis of the acetonide with Dowex afforded an anomeric mixture of 3-fluoroxylose. The so-obtained hydroxyl functionalities were acetylated, and the anomeric bromide was generated and converted to the diacetate 274. The acetate protecting groups were removed by treatment with sodium methoxide, the obtained β-methyl xylopyranoside was reacted with triflic anhydride to generate the ditriflate, and treatment with benzylamine furnished the bicyclic azetidine 275. The acetal moiety was hydrolyzed to yield the lactol, which was transformed into the methyl ester. The latter was hydrolyzed and hydrogenolysis of the N-protection furnished (2R,3S,4S)-3fluoro-4-(hydroxymethyl)azetidine-2-carboxylic acid 276 (Scheme 58).181

4.2. Four-Membered Rings

4.3. Five-Membered Rings

4.2.1. 1-Benzyl-3-fluoro-4-(hydroxymethyl)azetidine2-carboxylic Acid. Lui et al. reported a synthetic pathway to generate 4-(hydroxymethyl)azetidine-2-carboxylic acid starting from diacetone allose 267. Activation of the hydroxy group and nucleophilic displacement of the triflate with CsF gave the diacetone 3-fluoroglucose 268. Hydrolysis of the diacetone moieties of 268 and peracylation of the resulting hydroxy groups generated the corresponding tetraacetate. Upon treatment of the tetraacetate with hydrobromic acid, a bromide was introduced, which was then converted to yield the β-methyl pyranoside 269. Chemoselective protection of the primary hydroxyl group of 269 as a silyl ether, activation of the secondary alcohols as triflates and reaction with benzylamine afforded the bicyclic azetide 270. Acetolysis of 270 in the presence of boron trifluoride etherate gave the mixed acetal, which was exposed to

4.3.1. 1-(Boc)-3-Fluoropyrrolidine-2-carboxylic Acid (3-Fluoroproline). Starting from (2S,3S)-3-hydroxyproline 277, Demenge et al. described the synthetic route to obtain (2R,3R)- and (2R,3S)-3-fluoroprolines (2R,3R)- and (2R,3S)278. First, the amino group of 277 was N-Boc-protected and the carboxylic group was converted into the corresponding benzyl ester 279. Then the obtained benzyl ester 279 was fluorinated using DAST and the benzyl group was removed by hydrogenolysis, which led to the corresponding (2R,3R)-3-fluoroproline (2R,3R)-278. The N-Boc-protecting group was exchanged to a N-Trt group, which afforded the hydroxyproline derivative 280 to enable the inversion of configuration of the alcohol group of 278. Consequently, the Mitsunobu reaction was performed affording the inversion of the hydroxyl function giving the hydroxyproline derivative 281. Before the fluorination was

Scheme 55. Synthesis of cis-(4-Methoxyphenyl)-3-(trifluoromethyl)aziridines 261a−g, 263a, and 263b Using N,O-Hemiacetals

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Scheme 57. Synthesis of (2S,3R,4R)-1-Benzyl-3-fluoro-4-(hydroxymethyl)azetidine-2-carboxylic Acid 272

4.3.2. Dibenzyl 3,3-Difluoropyrrolidine-1,2-dicarboxylate (3,3-Difluoroproline). Starting from the earlier described alkene 151 (Scheme 32, Section 3.6.2), Suzuki et al. reported the synthesis of a 3,3-difluoroproline derivative. The protection groups of the alkene were changed to generate the NCbz protected benzyl ester 283, which set the stage for an ozonolysis to obtain dibenzyl (2R)-3,3-difluoro-5-hydroxypyrrolidine-1,2-dicarboxylate 284. Elimination of the secondary

Scheme 58. Synthesis of (2R,3S,4S)-3-Fluoro-4(hydroxymethyl)azetidine-2-carboxylic Acid 276

Scheme 61. Synthesis of (2S,4R)-4-Fluoroproline Derivative (2S,4R)-286 Scheme 59. Synthesis of (2R,3R)- and (2R,3S)-3Fluoroproline Derivatives (2R,3R)-278 and (2R,3S)-278 alcohol using dichlorotriphenylphosphorane and hydrogenation of the resulting alkene using Wilkinson catalyst gave dibenzyl (R)-3,3-difluoropyrrolidine-1,2-dicarboxylate 285 (Scheme 60).124 4.3.3. 1-(tert-Butyl)-2-methyl-4-fluoropyrrolidine-1,2dicarboxylate (4-Fluoroproline Derivative). Kim et al. described a synthetic approach to obtain the 1-(tert-butyl) 2methyl (2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate 286. trans-4-Hydroxy-L-proline 287 was converted to the corresponding methyl ester under Fisher esterification conditions, and then the amino group was protected using Boc2O to give the N-Boc proline methyl ester 288. Fluorination with DAST furnished the desired 4-fluoroproline derivative (2S,4S)-286. This approach allowed the generation of the (2S,4R)-4fluoroproline derivative (2S,4R)-286, starting from cis-4hydroxy-L-proline ((2S,4R)-286 not shown, Scheme 61).185 Another approach reported by Hamacher et al. involved the generation of unprotected (2S,4S)-4-fluoroproline also starting with 4-hydroxy-L-prolines. Treatment of the (2S,4R) or (2S,4S)isomer of hydroxyproline with HFA led to the conversion to the corresponding 1,3-oxazolidinones. Treatment of the latter with DAST gave the fluorinated compounds with inversed configuration. Subsequent hydrolysis of the fluorinated oxazolodinones afforded the desired 4-fluoroprolines.186 In a similar strategy, Doi et al. reported the synthesis of N-Boc- and N-Fmoc-4-fluoroproline starting with trans-4-hydroxyproline and employing Morpho-DAST as fluorinating agent.187 4.3.4. 4,4-Difluoropyrrolidine-2-carboxylic Acid (4,4Difluoroproline). Burger et al. reported the synthesis of (2S)4,4-difluoroproline (S)-289 starting from diazoketone 290 (accessible by a three-step procedure starting with aspartic acid 38188). Treatment of 290 with dirhodium tetraacetate gave the bicyclic ketone 291. Difluorination was performed by

conducted, the protecting group of the amino group was changed to N-Boc, which yielded the hydroxyproline derivative 282. Deoxyfluorination with DAST and hydrogenolysis of the ester afforded the desired (2R,3S)-3-fluoroproline derivative (2R,3S)-278 (Scheme 59).184 Scheme 60. Synthesis of 3,3-Difluoroproline Derivative 285

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and 7:93 in EtOAc or THF) and 297b (syn/anti, 1:2). Ozonolysis of syn-297a or anti-297a followed by saponification with LiOH gave exclusively (2S,3S)-5-oxo-3-(trifluoromethyl)pyrrolidine-2-carboxylic acid trans-298a. The cis-isomer is unstable and immediately isomerizes into the trans-isomer. Esterification, N-Boc protection, and reduction of lactam moiety gave trans-N-Boc-3-trifluoromethylproline trans-299a, which was hydrolyzed giving 3-trifluoromethylproline trans-300a. To obtain the cis-isomers, the synthesis was optimized. Syn-297a or

Scheme 62. Synthesis of (2S,4R)-4-Fluoroproline Derivative (2S,4R)-286 and (2S,4R)-4-Fluoroproline (2S,4R)-292

Scheme 64. 3-Substituted Prolines trans- or cis-300a, trans- or cis-300b, (2S,3S)-301a, and (2R,3R)-301a as well as Pyroglutamic Acid trans-298a

reaction with DAST, and subsequent hydrolysis led to the desired (2S)-4,4-difluoroproline (S)-289. Reduction of the ketone 291 with Na[BH3CN], subsequent fluorination with DAST, and hydrolysis generated (2S,4R)-4-fluoroproline (2S,4R)-292 (Scheme 62).189 Demange et al. reported the synthesis of mono- and difluoro prolines starting with trans-hydroxyproline. Oxidation of Scheme 63. Synthesis of (2S)-4,4-Difluoropyroglutamate Derivative 295

hydroxyproline led to the generation of 4-oxo proline, which was difluorinated using DAST.190 4.3.5. Methyl 4,4-Difluoro-5-oxopyrrolidine-2-carboxylate (4,4-Difluoropyroglutamate). The previously described entry by Konas et al. to synthesize 4,4-difluoroglutamate 155125 (Scheme 33, Section 3.6.3) was modified by Doyle et al. in their synthesis of 4,4-difluoropyroglutamate. Starting with the pyroglutaminol 293, the bicycle 155 was generated by usage of 2,2-dimethoxypropane. Subjecting 155 twice, first to LDA followed by electrophilic fluorination employing NFSI, led to the difluorinated product 156, which yielded the monofluorinated variant as an intermediate. Acidic hydrolysis of the oxazolidine gave the corresponding difluoro pyroglutaminol 294. Oxidation of the primary alcohol with Jones reagent and formation of the methyl ester using diazomethane yielded the desired (2S)-4,4-difluoropyroglutamate derivative 295 (Scheme 63).191 4.3.6. 3-Substituted Prolines. Tolmachova et al. developed a synthetic approach to synthesize fluorinated proline derivatives starting from fluorinated ketoacetals, which were prepared according to Kondratov et al.192,193 Reaction of two different ketoacetals 296a and 296b with ethyl isocyanoacetate under Schöllkopfś conditions and subsequent hydrogenation gave the syn- and anti-butanoates 297a (syn/anti, 1:3 in EtOH

anti-297a, as well as syn-297b or anti-297b, was subjected to acidic conditions and hydrogenated to give the four possible products trans- or cis-3-fluoroalkylprolines 300a and 300b. Hydrolysis of the ethyl ester and N-Boc protection gave trans301a or cis-301a (trans/cis, 1:1) and trans-301b or cis-301b (trans/cis, 1:1). The stereogenic pairs trans-301a or cis-301a Y


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Scheme 65. Synthesis of N-Boc Protected 4-Trifluoromethyl-proline (4S,2R)-309 and (4R,2R)-309

Scheme 66. Synthesis of N-Boc Protected 4-Trifluoromethyl-proline (4R,2S)-309 and (4S,2S)-309

Scheme 67. Synthesis of 4-Difluoromethyl-proline 317 and (4S,2S)-4-Trifluoromethyl-proline Derivative 319

between Garner’s aldehyde (S)-169 and bromo phosphorene giving the α-bromo-α,β-unsaturated ester 304. Subsequent trifluoromethylation with methyl fluorosulfonyldifluoroacetate in the presence of CuI195 gave the trifluoromethyl alkene 305. Hydrogenation with Raney-Ni followed by a reduction gave the primary alcohol 306. The latter was benzylated and the oxazolidine moiety was hydrolyzed and the primary alcohol was protected using TBSCl giving the chromatographic separable diastereomeric silyl ethers (4S,2R)-307 and (4R,2R)-307. The benzyl group was removed, and the hydroxyl group was converted into a mesylate, which then was treated with KHMDS to afford the desired cyclic intermediates (4S,2R)308 or (4R,2R)-308. Removal of TBS-protecting group gave the corresponding prolinols, which were oxidized with Jones reagent

were subjected to a classical chemical resolution using (S)phenylethylamine and then were separated using column chromatography giving the trans-isomers (2S,3S)-302a and (2R,3R)-302a and the cis-isomers (2S,3R)- and (2R,3S)-302a (only the trans-isomers are shown). Hydrolysis and N-Boc protection were only successful for the trans-isomers and gave the pure (2S,3S)- and (2R,3R)-3-trifluoromethylprolines (2S,3S)-301a and (2R,3R)-301a. Additionally, the authors used CF2Br- and CF2Cl-derivatives of 296 to generate the trans-3-fluoroalkyl-3-hydroxyproline derivative 303 (Scheme 64).194 4.3.7. 1-(Boc)-4-(Trifluoromethyl)pyrrolidine-2-carboxylic Acid (4-Trifluoromethyl-proline). The synthesis of (4R,2R)- and (4S,2R)-4-trifluoromethyl-proline derivatives reported by Qiu et al. commenced with a Wittig reaction Z


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resulting in the generation of N-Boc protected 4-trifluoromethyl-proline (4S,2R)-309 and (4R,2R)-309 (Scheme 65).196 Del Valle et al. used the methyl ester of trans-4-hydroxyproline 310 as starting material in their synthetic strategy to obtain NBoc protected (2S)-4-trifluoromethyl-proline derivatives. After Boc-protection of the amino function of 310, oxidation (with trichloroisocyanuric acid, TEMPO) of the hydroxyl function was conducted to synthesize the corresponding ketone 311. The latter was treated with Ruppert-Prakash’s reagent, in the presence of a fluoride initiator, to give the tertiary alcohol 312. Reduction of the methyl ester moiety and protection of the so-obtained primary alcohol gave the corresponding silylether 313. Tosylation of the tertiary alcohol of 313 set stage for an elimination using tert-butoxide giving 314. Desilylation, asymmetric hydrogenation employing [Ir(cod)(py)PCy3]+ as catalyst, and oxidation gave N-Boc protected 4-trifluoromethylproline (4R,2S)-309. To obtain the enantiomeric (4S,2S)derivative (4S,2S)-309, a heterogeneous hydrogenation was performed that also removed the TBS-protecting group, and the resulting primary alcohol was oxidized (Scheme 66).197 4.3.8. 4-Fluoromethyl-prolines and -pyroglutamates. Qui et al. described the first synthetic route to obtain (2S,4S)-1(Boc)-4-(difluoromethyl)pyrrolidine-2-carboxylic acid starting from commercially available trans-4-hydroxy-L-proline conducting a dehydrofluorination approach. After the protection of both the amino and the carboxylic functions of trans-4-hydroxy-Lproline 287, an oxidation was carried out to give the ketone 315. Treatment of 315 with dibromodifluoro-methane and zinc led

(4S,2S)-4-trifluoromethyl-proline derivative 319 (Scheme 67).198 To synthesize the pyroglutamate derivatives of 317 and 319, the carboxylic function was protected with a tert-butyl group and then oxidized with RuO2·xH2O/NaIO4 to afford the lactams 320 and 321. The protecting groups were removed, which generated (2S,4S)-4-(difluoromethyl)-5-oxopyrrolidine-2-carboxylic acid 322 and (2S,4S)-5-oxo-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid 323 (Scheme 68).199 To generate di-tert-butyl (2S,4S)-4-(fluoromethyl)-5-oxopyrrolidine-1,2-dicarboxylate, a dehydrofluorination reaction of compound 320 with TEA in a THF/water mixture gave 4monofluoromethylenyl-pyroglutamic acid 324 as described by Qui et al. With 324 in hand, the hydrogenation was carried out using Pd-BaSO4 as the catalyst in dioxane or EtOAc to synthesize N-protected 4-fluoromethyl pyroglutamate derivative 325 (Scheme 69).200 4.3.9. 5-(Trifluoromethyl)pyrrolidine-2-carboxylic Acid (5-Trifluoromethyl-proline). To synthesize 5-trifluoromethyl-proline, Lubin et al. first developed a route to obtain fluorinated oxazolopyrrolidines as precursors through condensation of fluoral with (R)-phenylglycinol 326 under acidic conditions giving the oxazolidine 327. Then a γ-addition with (1-methoxyallyl)lithium was performed (by an oxazolidine imine-type cyclic transition state involving chelation of the lithium metal by both the imine and the phenylglycinol residue), and the so-obtained vinylethers (4R)-328 and (4S)-328 were cyclized under acidic conditions generating the bicycles (5R)329 and (5S)-329 ((5R)-329 being the major product, 84:16 d.r.).201 Treatment of the mixture of bicycles (4R)-329 and (4S)-329 with PhMgBr resulted in the reaction of only the (4S) enantiomer to the primary alcohols (S)-330 and (R)-330, thus yielding (4R)-329 in > 98:2 d.r. In a Strecker-type reaction, (4R)-329 was reacted with TMSCN affording the chromatographic separable diastereomeric nitriles (5R,2S)-331 and (5R,2R)-331. Next, the nitrile (5R,2S)-331 was subjected to acidic conditions, the so-obtained methyl ester was hydrolyzed, and hydrogenation of the phenylethanol moiety gave (2S,5R)-5trifluoromethyl-proline (2S,5R)-332. To obtain the transconfiguration, (5R,2R)-331 was treated with methanol under acidic conditions producing a bicyclic lactone, which was hydrogenated and hydrolyzed, again under acidic conditions, to afford (5R,2R)-5-trifluoromethyl-proline (5R,2R)-332 (Scheme 70).202 Starting from commercially available L-glutamic acid, Ortial et al. established a synthetic route to obtain 332 through a trifluoromethylation of an aldehyde using Ruppert Prakash’s reagent.203 4.3.10. 1-(Boc)-3,4-Difluoropyrrolidine-2-carboxylic Acid (3,4-Difluoroproline). Hofman et al. described the synthesis of a vicinal difluorinated proline analogue starting from N-Boc-trans-4-hydroxy-L-proline benzyl ester 333. Elimination

Scheme 68. Synthesis of (2S,4S)-4-(Difluoromethyl)-5oxopyrrolidine-2-carboxylic Acid 322 and (2S,4S)-5-Oxo-4(trifluoromethyl)pyrrolidine-2-carboxylic Acid 323

to the formation of the difluoroalkene 316, which was hydrogenated to yield the N-protected 4-difluoromethyl-proline 317. The authors also report the synthesis of the 4trifluoromethyl-proline derivative by reaction of the ketone 315 with Ruppert-Prakash’s reagent and cleavage of the silylether to yield the tertiary alcohol 318. The latter was dehydroxylated giving the corresponding alkene and concomitant hydrogenation of the alkene and the benzyl moiety gave

Scheme 69. Synthesis of N-Protected 4-Fluoromethyl pyroglutamic Acid Derivative 325

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Scheme 70. Synthesis of 5-Trifluoromethyl-prolines (2S,5R)-332 and (5R,2R)-332

Scheme 71. Synthesis of 3,4-Difluoroproline 338

Scheme 72. Synthesis of N-Boc-4,4-Difluoro-3,3-dimethylproline (2S)-346

of the hydroxy function gave the 3,4-dehydroproline 334 in a two-step procedure by employing a protocol described by

Grieco et al., which led to a high selectivity for the 3,4-alkene (10:1; 3,4-alkene/4,5-alkene).204 Oxidation with potassium AB


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Scheme 73. Synthesis of Kainic Acid Derivatives 347 and 351

Scheme 74. Synthesis of Methyl-(2R,3S,4S,5R)-4-amino-5-(m-tolyl)-3-(trifluoromethyl)pyrrolidine-2-carboxylate 357

Scheme 75. Synthesis of Perfluoro-tert-butyl-4-hydroxyproline Derivatives (2S,4S)- and (2S,4R)-358

consisting of reduction of the amide, dehydroxylation to generate the pyrrolidine, hydroxylation of the double bond and a change of N-protection to Boc yielded the difluoro pyrrolidine 344. The latter was oxidized to give the carboxylic acid 345, which was subjected to (1R,2S)-2-amino-1,2diphenylethanol to crystallize the enantiopure N-Boc-4,4difluoro-3,3-dimethylproline (2S)-346. The diastereomer (2R)-346 (86% ee) was found in the supernatant of (2S)-346 (Scheme 72).206 4.3.12. Fluorinated Kainic Acid Derivatives. Starting from trans-4-hydroxy-L-proline 287, Zanato et al. developed a synthetic strategy to obtain fluorinated (−)-kainic acid derivate 347. Fisher esterification, N-Pf (9-phenylfluoren-9-yl) protection, and Swern-oxidation afforded the ketone 348. Subsequent alkylation led to the generation of the ketones 349a and 349b, which were separated by silica gel chromatography. Trifluoromethylation of 349a with Ruppert−Prakash’s reagent gave 350 as a single diastereomer, which upon removal of the protecting

osmate led to the desired diol 335, which was treated with nonafluorobutanesulfonyl fluoride (NfF) and TBAT giving the enol sulfonate 336 and the desired difluoroproline 337. The enol sulfonate 337 was isolated in equal amounts, presumably through fluoride mediated E2 elimination of the corresponding bis-nonaflate intermediate. Palladium catalyzed hydrogenation yielded N-Boc-3,4-difluoroproline 338 (Scheme 71).205 4.3.11. 1-Benzyl-4,4-difluoro-3,3-dimethylpyrrolidine-2-carboxylic Acid (4,4-Difluoro-3,3-dimethylproline). Chen et al. described a synthetic route to obtain 4,4difluoro-3,3-dimethylproline variants using 3,3-dimethylallyl bromide 339 as starting material. Treatment of 339 with trifluoroacetaldehyde methyl hemiacetal gave acetal 340, which then reacted with nBuLi to form vinyl ether 341. Upon Claisen rearrangement and reaction with benzylamine, the difluoro amide 342 was obtained. Iodolactamization of the in situ generated difluoro silyl ether and treatment of the resulting lactam with DBU gave the enamide 343. A reaction sequence AC


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published a strategy to access chiral oxazolidines by a condensation reaction of trifluoroacetaldehyde ethyl hemiacetal with the serine esters 361a−c to give methyl 2(trifluoromethyl)oxazolidine-4-carboxylates 362a−c. Additionally, the authors demonstrated an epimerization by treatment of (2S,4S)-362a with BF3·Et2O to give (2R,4S)-362a. The epimers (2S,4S)- and (2R,4S)-362a were hydrolyzed to give the free acids (2S,4S)-363a and (2R,4S)-363a (Scheme 76). The condensation reaction of serine methyl ester with trifluoroacetone leads to a disubstituted oxazolidine. The same strategy was applied for the condensation of cysteine methyl ester with trifluoroacetaldehyde ethyl hemiacetal, and the corresponding thiazolidine was obtained together with a bicyclic byproduct. In both cases, the absolute configuration could not be assigned (Scheme 76).211

groups led to the generation of the kainic acid derivate 347 (Scheme 73).207 Kondratov et al. established a copper-mediated Michael addition of ethyl bromodifluoroacetate to an N-protected α,βunsaturated proline derivative for the synthesis of trans-Kainic acid derivative 351.208 4.3.13. Methyl-4-amino-5-(m-tolyl)-3-(trifluoromethyl)pyrrolidine-2-carboxylate. Ling et al. developed a synthetic approach to access optically active exo- and endo-3(fluoromethyl)-4-nitroproline derivatives 352 through a catalytic asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides (353a−g) with fluoromethyl-substituted nitroalkenes 354a−d. The reaction was carried out using a copper(I)catalyst derived from copper(I) perchlorate and the chiral Walphos ligand 355. Depending on Ar and RF, the exo selectivity varies from 2:1 to 27:1 (exo/endo) and the enantioselectivities were higher than 82% ee. Further, the authors demonstrated that the cycloaddition products exo-356 can be easily converted into the corresponding methyl (2R,3S,4S,5R)-4-amino-5-(m-tolyl)3-(trifluoromethyl)pyrrolidine-2-carboxylate 357 by reduction with NaBH4 (Scheme 74).209 4.3.14. 1-(tert-Butyl)-2-methyl-4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)pyrrolidine1,2-dicarboxylate (Perfluoro-tert-butyl-4-hydroxyproline). Tressler et al. described the synthesis of the perfluorotert-butyl-4-hydroxyproline derivatives (2S,4S)- and (2S,4R)358 starting from N-Boc-(2S,4R)-4-hydroxyproline methyl ester (2S,4R)-359. The incorporation of the perfluoro-tert-butyl moiety was achieved in a Mitsunobu reaction with perfluorotert-butanol to yield the perfluoro-tert-butyl-4-hydroxyproline (2S,4S)-358. To access the (4R)-substituted derivative (2S,4R)358, a Mitsunobu reaction with 4-nitrobenzoic acid was conducted to generate the corresponding nitrobenzoate, which was removed by treatment with sodium azide to furnish

4.4. Five- and Six-Membered Rings

Mykhailiuk et al. described a strategy to obtain cyclic fluorinated amino acids. The starting materials were synthesized following a two-step literature protocol generating the pyrrolidine-2,5dicarboxylates (2S,5S)- and (2R,5S)-364.212 Hydrolysis of (2S,5S)-364 with NaOH led to the trans-monoacid (2S,5S)365, which upon treatment with ethyl chloroformate and subsequent reduction with NaBH4 provided the corresponding trans-alcohol 366. Fluorination with Morpho-DAST afforded two cyclic compounds, which could be separated by flash column chromatography. The authors proposed the obtention of the fluoropiperidine through the formation of a cationic aziridine intermediate, which underwent a ring-opening by a fluorine-anion attack. Acidic hydrolysis and hydrogenation of the trans-alcohols (2S,5S)-367 and (2S,5R)-368 provided (2S,5S)-5-(fluoromethyl)pyrrolidine-2-carboxylic acid (2S,5S)369 and (2S,5R)-5-fluoropiperidine-2-carboxylic acid (2S,5R)370 in a relative trans-conformation (Scheme 77). The synthesis was altered to access the cis-derivatives. Starting with (2R,5S)-364, the bisacid 371 was generated by saponification. Next, the acid moieties were converted to the anhydride 372, which was hydrolyzed giving the cis-monoacid (2S,5R)-365. Subjecting (2S,5R)-365 to the earlier described transformations led to the generation of (2S,5R)-5(fluoromethyl)pyrrolidine-2-carboxylic acid (2S,5R)-369 and (2S,5S)-5-fluoropiperidine-2-carboxylic acid (2S,5S)-370 (Scheme 78).213 Alternatively, Golubev et al. utilized the earlier described HFA chemistry to synthesize the 5-fluorinated pipecolic acid derivative (2S,5R)-370 (and 5,5-fluoropipecolic acid, Scheme 79, Section 4.5.1). The introduction of fluorine was achieved by a nucleophilic displacement reaction of a triflate with TREATHF.214

Scheme 76. Synthesis of Trifluoromethyl Pseudoprolines (2S,4S)-363a and (2R,4S)-363a

4.5. Six-Membered Rings

4.5.1. 5,5-Difluoropiperidine-2-carboxylic Acid (5,5Difluoropipecolic Acid). Golubev et al. reported the synthesis of cyclic amino acids using the earlier described concomitant protection of the amino- and C1-carboxy functionality (Scheme 10, Section 3.3.2). Starting from glutamic acid 373, the cyclic acid 374 was formed using HFA. Next, the cyclic acid 374 was treated with isobutyl chloroformate to generate the corresponding mixed anhydride, which then was reacted with diazomethane to yield the diazoketone 375. Reaction with dirhodium tetraacetate produced the corresponding metal carbenoid that reacted in an intramolecular NH insertion to give the bicycle 376. The reaction proceeds by an electrophilic Fisher-type carbene complex that suppresses the possible Wolf-type

(2S,4S)-4-hydroxyproline methyl ester (2S,4S)-360. In a second Mitsunobu reaction with perfluoro-tert-butanol, the desired perfluoro-tert-butyl-4-hydroxyproline (2S,4R)-358 was generated (Scheme 75). With (2S,4S)- and (2S,4R)-358 in hand, the authors demonstrated the generation of the corresponding NFmoc protected, N-Boc protected, or free amino acid derivatives (not shown).210 4.3.15. Methyl 2-(Trifluoromethyl)oxazolidine-4-carboxylate (Trifluoromethyl Pseudoproline). Chaume et al. AD


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Scheme 77. Synthesis of (2S,5S)-5-(Fluoromethyl)pyrrolidine-2-carboxylic Acid (2S,5S)-369 and (2S,5R)-5-Fluoropiperidine-2carboxylic Acid (2S,5R)-370

Scheme 78. Synthesis of (2S,5R)-5-(Fluoromethyl)pyrrolidine-2-carboxylic Acid (2S,5R)-369 and (2S,5S)-5-Fluoropiperidine2-carboxylic Acid (2S,5S)-370

Scheme 79. Synthesis of 5,5-Difluoropipecolic Acid 377

reaction was carried out between 110 and the xanthate 378, which was prepared according to the protocol established by Danieul et al.215 The resulting 3-substituted 7,7,7-trifluoroheptanoate 379 was dexanthylated and deprotected giving methyl 6trifluoromethylpipecolate 380 (Scheme 80).106 De Matteis et al. described a synthetic route to obtain racemic fluorine-containing piperidines starting from commercially available fluorinated allyl glycines. The key step was the application of ring-closing metathesis (RCM) to obtain the pipecolic acid derivatives with a wide variety of N-protecting groups and esters tolerated in the ring forming reaction.216−218

rearrangement. The ketone moiety of the bicycle 376 was bisfluorinated using DAST, acidic hydrolysis, and refluxing in propene oxide yielded the 5,5-difluoropipecolic acid 377 (Scheme 79).212 This entry also allows the synthesis of (2S,5R)-5-fluoropipecolic acid (2S,5R)-370 (Scheme 77, Section 4.4). 4.5.2. Methyl 6-(Trifluoromethyl)piperidine-2-carboxylate (Methyl 6-Trifluoromethylpipecolate). The synthesis of 6-trifluoromethyl-substituted piperidine-2-carboxylate was described by Li et al. employing the earlier described vinyl glycine 110 (the authors also report the synthesis of 5,5,5trifluoronorvaline; Scheme 24, Section 3.5.3). The addition AE


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by an oxidation of the hydroxyl group to the carboxyl group, which then underwent an esterification with trimethylsilyldiazomethane to give the methyl ester 388. Hydrogenolysis of the Cbz-group and acetylation with acetyl chloride led to silyl ether 389. The silyl moiety was cleaved and deoxofluorination using Deoxo-Fluor gave methyl 2-acetyl-5-fluoro-2-azabicyclo[2.1.1]hexane-3-carboxylate 384 (Scheme 82).222 Another entry to [2.1.1]-bicyclic amino acid was again developed by Krow et al. Starting from pyridine, the [2.2.0]azabicyclic derivative 390 was synthesized.223,224 Exposure to iodine and mercury fluoride gave the iodofluoride 391, which was reacted with a fresh batch of mercury fluoride in nitromethane to yield the rearranged [2.1.1]-azabicyclo fluorohydrin 392. Dehydroxylation by generation of the corresponding carbonothioate and radical induced substitution gave the corresponding N-benzyloxycarbonyl fluoride 393. Change of protection group from N-benzyl to N-Boc gave the methanopyrrolidine 394. The ex-MetFlp derivative 395 was synthesized by directed α-metalation using sBuLi and treatment of the anion with either CO2, acidification, and then esterification with TMS-diazomethane (method A gave 395 in 27% yield and 396 in 17%) or treatment with methyl chloroformate (method B afforded 395 in 24% and 396 in 26%). After deprotection and acetylation, the desired methyl (1S,3S,4S,5R)-2-acetyl-5-fluoro-2-azabicyclo[2.1.1]hexane-3carboxylate 397 was obtained in 1.1:1 ratio, together with methyl (1R,4S,5R)-2-acetyl-5-fluoro-2-azabicyclo[2.1.1]hexane-1-carboxylate 398. Additionally, the en-MetFlp derivative was synthesized starting from 5-syn-carboxy methano proline 399.225 Treatment of 399 with a mixture of PhI(OAc)2/I2/CCl4 while irradiating with a 50W tungsten lamp and heating gave the desired anti-iodide 400. Exposure of the iodide 400 to silver fluoride resulted in the formation of the antifluoride 401, with stereochemical retention due to neighboring groups’ participation. With the anti-fluoride 401 in hand, an αmetalation using sBuLi, treatment of the anion with CO2, acidification, and then esterification with TMS-diazomethane produced 2-(tert-butyl) 3-methyl (1R,3S,4R,5R)-5-fluoro-2azabicyclo[2.1.1]hexane-2,3-dicarboxylate 402, 2-(tert-butyl) 3-methyl (1R,3R,4R,5R)-5-fluoro-2-azabicyclo[2.1.1]hexane2,3-dicarboxylate 403, and 2-(tert-butyl) 1-methyl (1S,4R,5R)5-fluoro-2-azabicyclo[2.1.1]hexane-1,2-dicarboxylate 404 (Scheme 83).226 Although 398 and 404 are technically no α-amino acids, we decided to include them to present the entry entirely. 4.6.3. 2-Amino-2-(4-fluorobicyclo[2.2.2]octan-1-yl)acetic Acid. Bandak et al. demonstrated the synthesis of tricyclic amino acid 405 starting from commercially available

Scheme 80. Synthesis of Methyl 6-Trifluoromethylpipecolate 380

Scheme 81. Synthesis of (3R,6S)-5-(Boc)-1,1-Difluoro-5azaspiro[2.4]heptane-6-carboxylic Acid 382 and (3S,6S)-5(Boc)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic Acid 383

4.6. Polycyclic Derivatives

4.6.1. 5-(Boc)-Difluoro-5-Azaspiro[2.4]heptane-6-carboxylic Acid. Bychek et al. performed a difluorocyclopropanation of nonactivated alkenes using the Ruppert-Prakash’s reagent. By employing the 4-methyleneproline derivative 381 as starting material, the difluorocyclopropanation yielded the spiro-connected (3R,6S)-5-(Boc)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid 382 and (3S,6S)-5-(Boc)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid 383, which were separated by standard column chromatography (Scheme 81).219,220 4.6.2. Fluorinated Methyl Azabicyclo[2.1.1]hexane-3carboxylates (Methano-fluoroprolines). The synthesis of [2.1.1]-azabicyclic amino acid 384 was reported by Jenkins et al. and started with the conversion of pyridine to the corresponding [2.2.0]-azabicycle 385 following the procedure established by Krow et al.221 The [2.2.0]-azabicycle 385 was treated with NBS to rearrange the carbon skeleton to give the corresponding [2.1.1]-azabicycle 386. TBS-protection of the alcohol moiety of 386, change of O-protection from p-nitrobenzenesulfonyl to acetyl, and bromine removal gave the ester 387. Subsequently, the ester was hydrolyzed under mild basic conditions, followed Scheme 82. Synthesis of Methano-fluoroproline Derivative 384

AF


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Scheme 83. Synthesis of Methano-fluoroprolines 402−404

acidic hydrolysis gave nitrile 412. The hydrolysis of the nitrile 412 to the corresponding (S)-2-amino-2-(4-fluorobicyclo[2.2.2]octan-1-yl)acetic acid 405 only occurred after Nacylation and acidic hydrolysis (Scheme 84).228 4.6.4. 6-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane2-carboxylic Acid and 6-(Trifluoromethyl)-2azabicyclo[3.1.0]hexane-3-carboxylic Acid. Mykhailiuk et al. described the synthesis of trifluormethyl-substituted bicyclic proline analogues. Starting from optically pure 3,4-dehydroproline derivative 413 (prepared according to Schumacher et al.229 and Dormoy et al.230), they performed a copper-catalyzed cyclopropanation of the double bond with 2,2,2-trifluoromethyldiazomethane to generate the [3.1.0]-bicycles 414a and 414b. After treatment of 414a and 414b with HBr, (1R,2S,5S)-6(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid 415a and (1S,2S,5R)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid 415b were obtained. The reaction of 416 with 2,2,2-trifluoromethyl-diazomethane in the presence of catalytic amounts of CuCl gave trifluoromethyl-substituted proline analogues 417a−c (a/b/c, 1.0:0.9:0.7). The corresponding free amino acids were synthesized by standard deprotection conditions to give (1S,3S,5R)-6-(trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid 418a, (1R,3S,5S)-6-(trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3carboxylic acid 418b, and (1R,3S,5S)-6-(trifluoromethyl)-2azabicyclo[3.1.0]hexane-3-carboxylic acid 418c (Scheme 85).231 4.6.5. 4-Fluorooctahydrocyclopenta[c]pyrrole-1-carboxylic Acid. The bicyclic proline analogue 419 was synthesized by Johnson et al. by tandem cycloadditioncyclization of thiazolium ylide 420 (prepared in situ from the corresponding thiazolium bromide 421 and triethyl-amine) with 2-cyclopentenone, which yielded the separable tetracycles 422a and 422b. Reductive cleavage of the C−S-bond, in situ hydrolysis of the resulting hemiaminal and protection of

diester 406. First, a double alkylation following the procedure of Baker and co-workers with LDA/HMPA and BrCH2CH2Cl227 Scheme 84. Synthesis of (S)-2-Amino-2-(4fluorobicyclo[2.2.2]octan-1-yl)acetic Acid 405

yielded bisester 407, which then underwent monohydrolysis of the methyl ester giving the monoacid 408. The key step to access the fluoroester 409 was the decarboxylative fluorination with XeF2 in C6F6. For the planned Strecker synthesis, the fluoroester 409 was reduced with LiAlH4 affording the corresponding alcohol, which was oxidized by using py-SO3 complex to generate the aldehyde 410. The obtained aldehyde was used in the Strecker reaction with (R)-α-phenylglycinol giving the separable alcohols 411a and 411b. Upon refluxing in MeOH, an isomerization occurred that shifted the ratio of 411a/411b to 90:10. Oxidative cleavage of the phenylglycinol moiety and AG


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Scheme 85. Synthesis of Trifluoromethyl-Substituted 2-Azabicyclo[3.1.0]hexane-3-carboxylic Acids 415a and b and 418a−c

Scheme 86. Synthesis of (1S,3aR,4S,6aS)-4-Fluorooctahydrocyclopenta[c]pyrrole-1-carboxylic Acid 419

synthetic entries of fluorinated histidine, phenylalanine, and tyrosine. Special emphasis will be laid on the β-fluorination of aromatic amino acid precursors. Afterward, synthetic entries to fluorinated tryptophan, homophenylalanine, and arylglycine derivatives are presented. We will also include the generation of nonaromatic products, if they are reported in the method, to communicate the entire scope of the presented entry.

nitrogen as its benzyl carbamate afforded the ketone 423. Reduction of the ketone gave the alcohol 424, which was subjected to fluorination conditions using DAST resulted in the generation of the fluoride 425 and an inseparable alkene, which was removed by oxidation with potassium osmate (structure not shown). Removal of the protection groups gave (1S,3aR,4S,6aS)-4-fluorooctahydrocyclopenta[c]pyrrole-1-carboxylic acid 419 (Scheme 86).232

5.1. Histidine Derivatives

5. SYNTHESIS OF SIDE CHAIN FLUORINATED AROMATIC AMINO ACIDS In this section, the synthesis of side-chain fluorinated aromatic amino acids will be presented. This section commences with the

5.1.1. 2-Amino-3-(5-fluoro-1H-imidazol-4-yl)propanoic Acid (4-Fluorohistidine). Hajduch et al. reported an asymmetric synthesis approach of 4-fluorohistidine starting with an acid-catalyzed ethanolysis of commercially available 5AH


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Scheme 87. Synthesis of 4-Fluorohistidine 432

aminoimidazole-4-carboxamide hydrochloride 426 under microwave irradiation giving the ethyl ester 427. The diazotization of the amino moiety of ester 427 and subsequent photochemical Baltz-Schiemann reaction with fluoroboric acid led to the generation of fluoroimidazole 428.233 Protection with MOMCl and reduction with LiAlH4 afforded the alcohol 429, which was then treated with CaH2, PBr3, and the lithiated Schölkopf bislactim ether 430234 to give the dihydropyrazine 431 in a onepot procedure. The cleavage of the dihydropyrazine ring and removal of the MOM protecting group was achieved by treatment with aqueous HCl. The resulting mixture of (S)-4fluorohisitidine 432 and valine 433 was converted to the corresponding N-trifluoroacetyl methyl ester derivatives by

Scheme 89. Synthesis of Fluorotyrosines 439a−h

plethora of various methods have been described to access fluoroaryl and β-fluorinated amino acids and will be discussed herein. It is important to note that some derivatives reappear in several methods. This is intended to show the various routes for similar products and provide the versatility of each presented approach. 5.2.1. 2-Amino-3-(fluoro-4-hydroxyphenyl)propanoic Acid (Fluorotyrosine). A biosynthetic approach was proposed by Cole et al. using the recombinant enzyme tyrosine phenollyase (TPL), which led to enantiopure fluorinated tyrosine derivatives. The reaction between pyruvic acid 438 and the corresponding fluorophenol in the presence of TPL led to the generation of fluorotyrosines 439a−h (Scheme 89). Gramquantities of mono-, di-, and trifluorotyrosine were obtained with this method. However, the tetrafluorinated derivative 439h was proven to be a poor substrate for this enzyme, leading to a long synthesis time and to the use of high enzyme concentrations.237 The previously described complications with the synthesis of tetrafluorotyrosine encouraged Wang et al. to establish a novel synthesis strategy involving a nucleophilic aromatic substitution reaction as a key step. Treatment of N-Boc pentafluorophenylalanine 440 with sodium allyloxide led to the O-allyl tetrafluorinated tyrosine 441. Conversion of the N-protecting group was followed by the cleavage of the O-allyl group with Pd(PPh3)4 in the presence of phenylsilane to give the desired NFmoc protected tetrafluorotyrosine 442 (Scheme 90).237,238 5.2.2. 2-Amino-3-(4-fluorophenyl)propanoic Acid (4Fluorophenylalanine). Okuro et al. developed an approach relying on a novel chiral glycine template, the chiral 4imidazolidinone 443, as a precursor for accessing a wide range of α-amino acids. The 4-imidazolidinone 443 is a new generation of the chiral glycine equivalent (S)-Boc-BMI, pioneered by Seebach et al.84,85 The reaction of the 4-

Scheme 88. C-4 Arylation of Protected Histidine 435

sequential treatment with methanolic HCl and trifluoroacetic anhydride to facilitate their separation. Consequently, Ntrifluoroacetyl-4-fluorohistidine 434 was saponified, and the desired (S)-4-fluorohistidine 432 was isolated (Scheme 87).235 5.1.2. Methyl 2-Acetamido-3-(1-benzyl-5-((trifluoromethyl)phenyl)-1H-imidazol-4-yl)propanoate (4(Trifluoromethyl)phenyl-histidine). Mahindra et al. described the regioselective C−H arylation of protected histidine 435 with substituted aryl iodides 436a−c. An extensive conditions screening allowed the identification of the Pd(CH3CN)2-PCy3 catalytic system, mild basic environment and MW radiation, as ideal for the selective C-5 arylation of the protected histidine 435 with three aryl iodides bearing trifluoromethyl groups in different positions to give the 4-arylhistidines 437a−c (Scheme 88).236 5.2. Phenylalanine and Tyrosine Derivatives

In this section, the synthesis of fluorinated phenylalanine and tyrosine derivatives will be presented. Both amino acids will be discussed parallel as they are commonly synthesized together. A AI


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Scheme 90. Synthesis of N-Fmoc Protected Tetrafluorotyrosine 442

5.2.3. Benzyl 2-((Boc)Amino)-3-(4-(pentafluoro-λ6sulfaneyl)phenyl)propanoate and Benzyl 2-((Boc)Amino)-3-(3-(pentafluoro-λ 6 -sulfaneyl)phenyl)propanoate. The synthesis of pentafluorosulfanyl containing phenylalanines was reported by Grigolato et al. The Negishi cross-coupling between iodo-alanines (S)- and (R)-446240 and commercially available pentafluorosulfanyl-benzenes 447a and b gave the targeted benzyl 2-((Boc)amino)-3-(4-(pentafluoroλ6-sulfaneyl)phenyl)propanoate (S)- and (R)-448a as well as (S)- and (R)-448b (Scheme 92). Initially, the reaction was carried out using zinc, Pd(dba)2, and P(o-tol)3 as ligand to yield the pentafluorosulfanyl derivatives in poor yield. This yield was significantly improved when the ligand was switched to SPhos.241 A first synthesis of a racemic pentafluorosulfanyl containing allyl glycine derivative was reported by Lim et al.242 5.2.4. Methyl 2-Amino-3-(3,5-difluorophenyl)́ propanoate (3,5-Difluorophenylalanine, Dfp). MartinGago et al. reported a synthetic approach of difluorophenylalanine starting from commercially available 3,5-difluorobenzaldehyde 449. Treatment of 449 with N-acetylglycine gave the corresponding oxazole 450, which in a subsequent ring-opening reaction with sodium methoxide generated (Z)-methyl-2acetamido-3-(3′,5′-difluorophenyl)acrylate 451. Asymmetric hydrogenation using the [Rh(S-MaxPHOS)(cod)]BF4-catalyst 452243,244 afforded the (S)-acetamido ester, which was hydrolyzed under acidic conditions producing the desired (S)-3,5difluorophenylalanine 453 with 99% ee (Scheme 93).245 5.2.5. Methyl 2-Amino-3-(4-fluoro-3-nitrophenyl)propanoate. Two papers described the use of the Schöllkopf bislactim ether (S)-454 and (R)-454 as a chiral template for accessing fluorinated phenylalanine derivatives. The highly diastereoselective alkylation proceeded by reaction between the organocuprate of the bislactim ethers (S)-454 and (R)-454, and 4-fluoro-3-nitro-benzyl bromide, giving the coupling products (S)-455 and (R)-455. The authors suggested that considering the organocuprate a soft nucleophile, by the HSAB-principle the displacement of bromide (SN2), is favored over the displacement of fluoride (SNAr). Acidic hydrolysis gave access to the

Scheme 91. Synthesis of 4-Fluorophenylalanine (2S)-445

imidazolidinone 443 with 4-fluorobenzyl bromide or 4fluorobenzyl chloride afforded the alkylated compound 444. Scheme 92. Synthesis of Benzyl 2-((Boc)Amino)-3-(4(pentafluoro-λ6-sulfaneyl)phenyl)propanoate 448a and Benzyl 2-((Boc)Amino)-3-(3-(pentafluoro-λ6sulfaneyl)phenyl)propanoate 448b

Removal of the N-protecting group by exposure of 444 to acidic conditions followed by hydrolysis allowed the full conversion to the desired 4-fluorophenylalanine (2S)-445 in high selectivity (Scheme 91).239 Scheme 93. Synthesis of 3,5-Difluorophenylalanine 453

AJ


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Scheme 94. Synthesis of 2-Amino-3-(4-fluoro-3-nitrophenyl)propanoate (R)-456 and (S)-456

Scheme 95. Synthesis of 4-Substituted Tetrafluorophenylalanines 459, 461, and 467−469

the desired 4-mercapto derivative 459. The same SNAr strategy allowed the access of para-amine-substituted derivative. A fourstep synthetic sequence involving the protection of the carbonyl moiety as an ester, formation of the azide 460 by treatment with n Bu4NN3/NaN3, N-protecting group conversion, and azide reduction afforded the desired 4-amino derivative 461. Access to para-halogenated derivatives was accomplished by using diazonium chemistry. To avoid possible side reactions, a change of protecting groups was performed on azide 460 to give the trifluoroacetyl protected derivative 462. Reduction of the azide moiety of 462 gave the amine 463, which set stage for diazonium chemistry using CuX2/ CuX (with X = Cl or Br) affording 464 and 465, respectively. The product 466 was generated using

desired methyl 2-amino-3-(4-fluoro-3-nitrophenyl)propanoate (R)-456 and (S)-456 (Scheme 94).246,247 5.2.6. 4-Substituted tert-Butyl 2-((Fmoc)Amino)-3(2,3,5,6-tetrafluorophenyl)propanoates (4-Substituted Tetrafluorophenylalanines). Qin et al. explored a nucleophilic aromatic substitution (SNAr) strategy for the incorporation of different functionalities in the 4-position of N-Boc protected pentafluorophenylalanine 457 by defluorination. Incorporation of a thiol functionality in the para position of the fluorinated phenyl ring was achieved using 4methoxybenzenemethanethiol (PMBSH) as a nucleophile to give the protected thioether 458. Conversion of the Nprotecting group and mild deprotection conditions afforded AK


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Scheme 96. Synthesis of (S)-2-Acetamido-3-(4-hydroxy-3-(trifluoromethyl)phenyl)-N-methylpropanamide 471 and (S)-2Acetamido-3-(4-hydroxy-3,5-bis(trifluoromethyl)phenyl)-N-methylpropanamide 472

́ aryl−α-amino acids derived from N-Phth protected alanine derivative 473 and N-Phth protected phenylalanine derivative 474, using Pd(TFA)2 as the catalyst and achiral ligands to control selectivity. To achieve the desired diarylation of C(sp3)H bonds, they started to investigate the selective monoarylation of primary C(sp3)-H bonds. By conducting the arylation using fluorinated iodo benzenes 475a−f on alanine derivative 473 with the monodentate pyridine-derived ligand 476 in the presence of Pd(TFA)2, an array of different fluorinated phenylalanines 477a−e was synthesized. Remarkably, by switching the ligand to 478 and employing the previously described conditions on phenylalanine derivative 474, β-

iodine. Conversion of the N-protecting groups afforded the NFmoc protected fluorinated amino acids 467−469 (Scheme 95).248 Bergamaschi et al. optimized the synthesis of the iododerivative 469.249 5.2.7. 2-Acetamido-3-(4-hydroxy-3-(trifluoromethyl)phenyl)-N-methylpropanamide and 2-Acetamido-3-(4hydroxy-3,5-bis(trifluoromethyl)phenyl)-N-methylpropanamide. Ichiishi et al. elaborated a radical-based aromatic trifluoromethylation of N-Boc-tyrosine derivative 470 using trifluoromethyl sulfonate salts. Synthesis of (S)-2-acetamido-3(4-hydroxy-3-(trifluoromethyl)phenyl)-N-methylpropanamide 471 and (S)-2-acetamido-3-(4-hydroxy-3,5-bis(trifluoromethyl)phenyl)-N-methylpropanamide 472 was accomplished by using stoichiometric amounts of oxidants (not shown) or visible light photoredox catalysis (Scheme 96).250 5.2.8. Palladium-Catalyzed Arylation of C(sp3)-H Bonds to Synthesize 2-(1,3-Dioxoisoindolin-2-yl)-3-fluoroaryl-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)propanamide (Fluorophenylalanine) and 2-(1,3-Dioxoisoindolin-2-yl)-3-(4-fluoroaryl)-3-phenyl-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (βFluoroaryl-phenylalanine). He et al. developed a versatile method for synthesizing β-aryl-α-amino acids and β-ayl-β-

Scheme 98. Synthesis of Tetrafluorophenylalanines 483a−c

Scheme 97. Palladium-Catalyzed Arylation of C(sp3)-H Bonds to Synthesize Fluorophenylalanines 477a−e and βFluoroaryl-phenylalanine Derivative 479

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Scheme 99. Synthesis of Fluoroaryl-substituted Phenylalanines 491−493

Scheme 100. Synthesis of Benzyl (R)-2-((Fmoc)Amino)-3-(2-(3-((Boc)amino)propyl)-6-(trifluoromethyl)phenyl)propanoate 499

Scheme 101. Fluorine Incorporation of Benzylic and Aliphatic Methylene C(sp3)-H of α-Amino Acids Using Pd(TFA)2

fluoroaryl-phenylalanine derivative 479 was synthesized with 20:1 > d.r. (Scheme 97).251 5.2.9. 2-((Fmoc)Amino)-3-(tetrafluorophenyl)propanoic Acid (Tetrafluorophenylalanines). Zheng et al. and Pace et al. reported the synthesis of tetrafluorinated phenylalanines starting from either (S)-Boc-BMI (S)-480 or bislactim ether (R)-454 (Scheme 94, Section 5.2.6). The reaction between (S)-480 and the tetrafluorinated benzyl bromides 481a and 481b furnished the imidazolidines 482a and 482b. Cleavage of the protecting groups and N-Fmoc protection gave the desired tetrafluorophenylalanines 483a and 483b; accordingly, the reaction between (R)-454 and the fluorinated benzyl bromide 481c yielded the dihydropyrazine 484c. Cleavage of the protecting groups and N-Fmoc protection gave the desired tetrafluorophenylalanine derivative 483c (Scheme 98).252,253

5.2.10. Fluoroaryl-phenylalanines. Qiao et al. reported a one-step nonaqueous Pd(OAc)2 and DtBuPF 485 catalyzed Suzuki-Miyaura cross-coupling to synthesize fluoroaryl-substituted phenylalanines. The direct cross-coupling of Fmocprotected amino acids poses a valuable tool to directly access the privileged biaryl substructure. Starting with the Fmoc-protected halogenated Phe derivatives 486 and 487, the boronic acids 488−490 were coupled yielding the fluoroaryl-substituted phenylalanines derivatives 491−493 with no enantiomeric erosion (Scheme 99).254 5.2.11. Benzyl 2-((Fmoc)Amino)-3-(2-(3-((Boc)amino)propyl)-6-(trifluoromethyl)phenyl)propanoate. Substituted phenylalanine derivatives were accessed by Stark et al. in a palladium-catalyzed domino reaction to attach two substituents on an ortho-substituted aryl iodide (Catellani reaction). First, 1-iodo-2-(trifluoromethyl)-benzene 494 was alkylated at AM


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Scheme 102. Fluorine Incorporation of Benzylic and Aliphatic Methylene C(sp3)-H of α-Amino Acids Using Pd(OAc)2 or Pd(OPiv)2

Scheme 103. Fluorine Incorporation of Benzylic and Aliphatic Methylene C(sp3)-H of α-Amino Acids Using Pd(OAc)2 and Fe(OAc)2

5.3. β-Fluorination of Aromatic Amino Acids

the ortho position that was followed by a Heck reaction with methyl acrylate at the ipso-position that terminated the reaction sequence, yielding the desired bisalkylated derivative 495. Substitution of the terminal bromide with di-tert butyl imino dicarboxylate gave the bis-N-Boc cinnamyl ester. This reaction was followed by reduction of the benzylic double bond, saponification of the methyl ester, and removal of one Boc protecting group to yield the acid 496. Activation of the resulting carboxylic acid of 496 as a mixed anhydride and coupling of the Evans auxiliary (R)-131 gave the oxazolidinone 497. Introduction of the stereocenter was done by employing Evans chemistry and trisyl azide as N-source to yield the (2R)-azide 498 (>95:5 d.r.). Cleavage of the auxiliary, generation of the amine by hydrogenation, and protection of both the amine and carboxy moieties afforded benzyl (R)-2-((Fmoc)amino)-3-(2-(3((Boc)amino)propyl)-6-(trifluoromethyl)phenyl)propanoate 499 (Scheme 100).255

Palladium-catalyzed fluorination of α-amino acids using Selectfluor and XtalFluor-E as the fluoro-containing electrophilic reagent was investigated by various groups. A great variety of aromatic substrates are tolerated, and even aliphatic acids can be converted to their β-fluorinated counterpart, although with decreased yields. As these methods are typically established for aromatic moieties in the starting material, while the aliphatic counterparts are used to show the possible substrate variety, we decided to present the aliphatic ones in this section to underline the robustness of the established methods. In the end of the section, we will present entries to β-fluorinated amino acids that not involve a CH-activation. 5.3.1. β-Fluorination of C(sp3-H) Bonds Using Selectfluor. Zhu et al. described the synthesis of a wide array of βfluorinated derivatives 500a−r starting from the respective unfluorinated derivatives 501a−r, by using the quinoline ligands 502 or 503, in the presence of palladium(II) trifluoroacetate, Selectfluor, and Ag2CO3. The optical purity was typically >20:1 AN


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Scheme 104. Synthesis of β-Fluorophenylalanine Derivatives Using XtalFluor-E

d.r. Among a variety of aromatic rings, there are also aliphatic amino acids employed as starting materials. The authors propose that the transformation is performed by a Pd(II/IV) catalytic cycle, in which the Pd(TFA)2 is coordinated by the quinoline derivative to form the active catalytic species. A final step consisting of a C−F reductive elimination on the Pd(IV) species led to the desired β-fluorinated products 500a−r (Scheme 101).256 On the basis of the work of Daugulis using N,N-bidentate groups,257 Zhang et al. reported the use of 2-(pyridine-2-yl)isopropylamine (PIP) for the Pd-catalyzed functionalization of benzylic and aliphatic methylene C(sp3)-H bonds. Employing a palladium catalyst and Selectfluor as fluorine source, a wide series of substituted N-phthaloyl protected phenylalanine derivatives 504a−v was converted to their β-fluorinated analogues 505a−k. Furthermore, for the fluorination of aliphatic secondary C(sp3)-H derivatives 504a′−n′, the addition of 2methylbenzoic anhydride (2-Me-BAH) proved to be ideal for accessing the desired products 506a′−n′ in moderate yields and without any observable epimerization. This strategy was also suitable for direct fluorination of amino acids conjugates, namely by the fluorination of glyco-amino acids and of α-amino acids bearing “clickable” functional groups (derivatives 505v and 506l′−n′, Scheme 102). The authors state that the successful application of this methodology relies on the fact that the conversion of the secondary amides 505a−k and 506a′−n′ to the corresponding anti-β-fluoro-α-amino acid methyl ester can be easily achieved in a two-step, one-pot reaction with an in situ esterification of a highly electrophilic pyridinium triflate intermediate (not shown).258 Similarly, Miao et al. reported the direct fluorination of aromatic and aliphatic precursors using Pd(OAc)2, Selectfluor, Fe(OAc)2, and Ag2CO3 for the synthesis of a vast array of βfluorinated acid derivatives with high diastereoselectivities. Consequently, starting from the N-Phth protected chiral precursors (504a, g, j, l, and o; 504b′ and f′; 507a′′−c′′; and 508), the β-fluorinated derivatives (505a, g, j, l, and o; 506b′ and f′; 509a′′−c′′; and 510) were synthesized (Scheme 103).259 5.3.2. Synthesis of β-Fluorophenylalanine Derivatives Using XtalFluor-E. Davies et al. reported the synthesis of fluorinated phenylalanine derivatives using XtalFluor-E in combination with TREAT-HF as the deoxofluorinating agent. During the key step of this synthesis, the enantiopure starting material 511, which is accessible by aminohydroxylation of α,βunsaturated esters,260 was converted to its fluorinated analogue 512a−e by XtalFluor-E promoted formation of the corresponding aziridinium ion followed by site-specific ring-opening by fluoride at C3. The fluorinated phenylalanine derivatives were deprotected to yield the free acids 513a, b, d, and f. Interestingly,

Scheme 105. Synthesis of (2R,3R)-2-Amino-3-fluoro-3phenylpropanoic Acid 514

the phenylalanine derivative 512e could not be deprotected, and only the corresponding 1,2,3,4-tetrahydroisoquinoline was isolated. Additionally, while deprotection of derivative 512c was performed, bromination of the position six of the aromatic ring occurred and 513f was obtained (Scheme 104).261 5.3.3. 2-Amino-3-fluoro-3-phenylpropanoic Acid (βFluorophenylalanine). Okuda et al. synthesized β-fluorophenylalanine 514 in a six-step procedure. The synthesis commenced with the protection of the amino and the primary hydroxyl function of commercially available (1R,2R)-2-amino1-phenylpropane-1,3-diol 515. After the secondary alcohol 516 was generated, the fluorination was achieved by treatment with DAST, which afforded the fluoropropane 517. Removal of the Alloc-protection group, oxidation of the so-obtained primary alcohol, and amine deprotection gave the targeted βfluorophenylalanine 514 (Scheme 105).262 It is noteworthy to mention that Luo et al. reported the use of chiral tricycloiminolactones derived from natural (+)-camphor Scheme 106. Synthesis of Methyl (2S,3R)-2-Amino-3(fluoro-3,4-dihydroxyphenyl)-3-hydroxypropanoate 521a and 521b

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to access fluorinated 3-hydroxy phenylalanine derivatives with full stereocontrol of C-2, but with virtually no stereocontrol at C3.263 5.3.4. Methyl 2-Amino-3-(fluoro-3,4-dihydroxyphenyl)-3-hydroxypropanoate. Kim et al. described the synthesis of fluorinated phenyl-serine derivatives by Sharpless asymmetric aminohydroxylation reaction of cinnamates 518a and 518b with anthraquinone ligands (DHQD)2AQN. The regioisomers 519a and 519b, as well as 520a and 520b, were separated (ratio 519a/ 520a is 4.4:1 and 519b/520b is 4.8:1) and recrystallized to

5.4. Synthesis of Tryptophan Derivatives

5.4.1. 2-((Fmoc)Amino)-3-(2-(fluoroaryl)-1H-indol-3yl)propanoic Acid (2-Fluoroaryl-tryptophan). Preciado et al. reported the palladium-catalyzed C-2 arylation of N-Fmoctryptophan 522. The reaction of the commercially available Fmoc-Trp-OH 522 with the aryl iodides 446b and 446d (see also Scheme 88), in the presence of Pd(OAc)2, AgBF4, and under MW irradiation, furnished the fluorinated tryptophan derivatives 523a and 523b with retention of stereochemistry (Scheme 107).266 Complementarily, Williams et al. proposed the C−H functionalization of N-acetyl tryptophan derivative 524 by reaction with different substituted boronic acids 525a and 525b under mild conditions to generate the C-2 fluoroarylated tryptophans 526a and 526b. The method allowed the preparation of a wide range of aryl-substituted tryptophan derivatives. It is noteworthy that Cu(OAc)2 is reoxidizing Pd0 with the help of O2. By conducting the same experiment in an argon atmosphere, significantly lower yields were obtained (Scheme 108).267 Alternatively, Chiotellis et al. reported the C-2 and C-5 alkylation of the indole moiety starting from tryptophan. The synthesized racemic 2-(3-fluoropropyl)-tryptophan and 5-(3fluoropropyl)-tryptophan were widely employed in the field of radiochemistry.268

Scheme 107. C-2 Fluoroarylation of N-Fmoc-Tryptophan with Aryl Iodides

increase the enantiomeric purity (519a and 520a, 93% ee; 519b and 520b, 95% ee). The desired methyl (2S,3R)-2-amino-3(fluoro-3,4-dihydroxyphenyl)-3-hydroxypropanoates 521a and 521b were obtained after the removal of the protecting groups (Scheme 106).264 Kim et al. described a multistep synthesis of β-hydroxyfluorophenylalanines 521a and 521b based on an initial aldol condensation using a chiral glycine synthon.265

5.5. Synthesis of Homo-Phenylalanine Derivatives

5.5.1. tert-Butyl 2-((Boc)Amino)-3-fluoro-4-phenylbutanoate. Suzuki et al. established an electrophilic fluorination protocol to synthesize syn- and anti-β-fluoro-α-amino acid derivatives using α-keto esters as nucleophiles. Starting with the reaction of the α-keto ester 527 with NFSI in the presence of the chiral palladium (R)-DM-Segphos-catalyst 528, the desired fluorinated keto ester 529 was obtained. The keto group of 529 was reduced to obtain the chiral β-fluoro-α-hydroxy esters anti530a and 530b with 94% ee. After the conversion of the diastereomeric alcohols anti-530a and syn-530b into their corresponding triflates, a three-step reaction sequence was performed. Nucleophilic substitution with NaN3, followed by palladium-catalyzed reduction and in situ protection, allowed the preparation of tert-butyl (2S,3R)-2-((Boc)amino)-3-fluoro-4phenylbutanoate syn-531a and anti-531b (Scheme 109).269

Scheme 108. C-2 Arylation of N-Fmoc-Tryptophan with Aryl Boronates

Scheme 109. Synthesis of tert-Butyl (2S,3R)-2-((Boc)Amino)-3-fluoro-4-phenylbutanoate syn-531a and anti-531b

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led to the synthesis of various p-substituted α-aryl amino stannanes. After the carboxylation of N-Boc-α-amido stannanes was established, the one-pot synthesis of α-amino acid derivatives from α-amino sulfones was reported.273−275 Another interesting approach was reported by Zhu et al. They investigated the synthesis of racemic β-quinolinyl α-amino acid esters and α-aryl α-amino acid esters through dehydrogenative cross-coupling (DCC) reactions. To access β-quinolinyl αamino acid esters, several substituted 2-methylquinolines were examined for a one-step DCC reaction with N-aryl glycine ester. They reported the optimal conditions with the use of Cu(OAc)2 in the presence of PivOH as a BrØnsted acid and O2 as the oxidant, with lower to zero yields when other oxidants were used.276 Further investigations revealed that in the presence of

Scheme 110. Asymmetric Sommelet-Hauser Rearrangement for Synthesis of 5-Methyl-2-(2-phenylpropan-2yl)cyclohexyl-2-(dimethylamino)-2-(2-methyl(trifluoromethyl)phenyl)acetates 535−537

5.6. Miscellaneous Fluorinated Aromatic Amino Acids

5.6.1. 5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl-2(dimethylamino)-2-(2-methyl-(trifluoromethyl)phenyl)acetate (2-Fluororyl-glycine Derivative). The asymmetric Sommelet-Hauser rearrangement of trifluoromethylated Nbenzylic ammonium ylides was reported by Tayama et al. The ylides 532−534 (accessible by reacting (−)-8-phenylmenthol with bromoacetic acid, and the so-obtained bromo ester was treated with the corresponding N,N-dimethylbenzylic amine) were subjected to basic conditions using tert-butoxide to induce the concerted [2,3]-sigmatropic rearrangement, which provided the corresponding α-aryl amino acid derivatives 535−537 with high levels of diastereoselectivities (>98:2 d.r., Scheme 110).270 It is noteworthy to mention that Teegardin et al. reported the polyfluoroarylation of oxazolones using tetramethylguanidine and were able to access an impressive amount of racemic arylated glycine derivatives.271 5.6.2. tert-Butyl (R)-2-((Diphenylmethylene)amino)-2(4-fluorophenyl)-acetate 541. The catalytic asymmetric synthesis of phenyl glycine derivatives using a C2-symmetric chiral phase transfer catalyst (S,S)-538 was proposed by Maruoka et al. The tert-butyl glycinate 539 underwent asymmetric alkylation with 1-(bromomethyl)-4-fluoro-benzene 540 in the presence of (S,S)-538 to give the (4-fluorophenyl)glycine derivative 541 in 99% ee (Scheme 111).272 The racemic one-pot synthesis of substituted amino acids using CO2 was thoroughly explored by Mita et al. to access FAAs. Although nonstereoselective, the approach appeared to us as being conceptually different for accessing fluorinated amino acids as an alternative for the Strecker synthesis. Carboxylation of N-Boc-α-amido stannanes or N-Boc-imines, using CO2 and mild activators such as fluoride, led to a wide range of aryl or alkenyl glycine derivatives. For the carboxylation of N-Boc-αamido stannanes, the use of a mild base such as a fluoride anion from CsF that selectively activates the tin atom, in the presence of CO2 and trimethylsilyldiazomethane as a methylating agent,

Scheme 112. General Synthetic Pathway

di-tert-butyl peroxide (DTBP) as oxidant, differently substituted α-aryl α-amino acid esters were obtained.277

6. SYNTHESIS OF SIDE-CHAIN FLUORINATED AMINO ACIDS USING NICKEL-COMPLEXES Nickel-complex mediated stereoselective synthesis of amino acids was pioneered by the Belokon group in the late 80s and early 90s.278 Since then, this versatile methodology was employed for the synthesis of a wide range of different substituted aliphatic and aromatic amino acids. The key step is the reaction of the carbanion of a prochiral glycine equivalent with suitably substituted acceptors. After addition of the acceptor, the Nickel-complex is hydrolyzed, affording a free amino acid and a reusable ligand. Although the decomposition step is not shown in some cases, we decided to imply the hydrolysis step since literature precedence clearly states that the

Scheme 111. Asymmetric Synthesis of tert-Butyl (R)-2-((Diphenylmethylene)amino)-2-(4-fluorophenyl)-acetate 541

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Scheme 113. Synthesis of Linear Trifluoroalkyl Containing Amino Acid (S)-545

Scheme 114. Mitsunobu−Tsunoda Alkylation of Chiral Glycine Equivalent (S)-542 with Fluorinated Alcohols 547a− n and 548

acidic hydrolysis is feasible (Scheme 112). The following section will be divided depending on the acceptor type used. 6.1. Reaction with Alkyl Halides

6.1.1. Linear Trifluoroalkyl Containing Amino Acids. Enantiopure linear trifluoromethyl-containing amino acids were accessed by an asymmetric alkylation reaction between the glycine equivalent (S)-542 and the corresponding trifluoromethyl-alkyl-iodides 543a−c (n = 1: TfeGly 42, Scheme 11, Section 3.3.3). The alkylation step was performed in the presence of NaOH to afford the corresponding Ni(II)-complex adducts (S)(2S)-544a−c with high diastereoselectivities. Acidic hydrolysis afforded (2S)-amino-6,6,6-trifluorohexanoic acid (S)-545 and the chiral ligand (S)-546, which could be separated and reused (Scheme 113).279

exemplified by the acidic cleavage of 549d to the corresponding HCl salt of (S)-2-amino-3-(3,4,5-trifluorophenyl)propanoic acid 550d with 95% ee (Scheme 114).280,281 6.3. Reaction with Benzyl Halides

6.3.1. Photoreactive Fluorophenylalanine Derivatives. Alkylation of the chiral glycine equivalent (S)-542 with (3-trifluoromethyl)phenyldiazirinyl iodide 551a or bromides 551c−d yields photoreactive (3-trifluoromethyl)phenyldiaziridine based L-phenylalanine derivatives. The Ni(II)complexes (S)(2S)-552a−i were obtained in the presence of powdered NaOH with virtually complete diastereoselectivity. Acidic hydrolysis occurred rapidly to give the free amino acids (S)-553 without destruction of the diazirine ring. The N-Boc group of Ni(II)-complexes (S)(2S)-552c and (S)(2S)-552g was selectively cleaved to give rise to Fmoc-protected and biotinylated photoreactive phenylalanine derivatives (S)(2S)552e and (S)(2S)-552f,i, respectively. Acidic hydrolysis gave the phenylalanine derivatives 553a,b and 553d−i (Scheme 115).282,283 6.3.2. Fluorophenylalanines. The synthesis of 3-fluorophenylalanine (R)-554 was reported by Belokon et al. Alkylation of the Ni(II)−PBP complex 555 with the alkyl bromide 556 was catalyzed by (R)-2-amino-2′-hydroxy-1,10-binaphthyl 557 (NOBIN) to give the alkylated Ni(II)-complex (2R)-558 under phase transfer catalysis (PTC) conditions. Subsequent hydrolysis of the alkylation product gave the free amino acid (R)-554 in 94% ee and free N-(2-benzoylphenyl)pyridine-2carbamide 559, which was reused for the synthesis of 555 (Scheme 116).284,285 Houck et al. investigated the alkylation reaction of Ni(II)complex (S)-542 with fluorinated benzyl halides 560a−c under heterogeneous PTC conditions. It was found that alkylation of (S)-542 in the presence of nBu4I yielded mixtures of diastereomeric phenylalanine-derived complexes (S)(2S)561a−c and (S)(2R)-561a−c in 68−82% de without any trace of double alkylation products. Epimerization of the minor

6.2. Reaction with Alcohols

The synthesis of fluorinated phenylalanines, heteroaryl alanines, and aliphatic FAAs was described by Drouet et al. The Mitsunobu−Tsunoda alkylation of the chiral nucleophilic glycine equivalent (S)-542 with readily available fluorinated alcohols 547a−n in the presence of cyanomethylene-tributylphosphorane (CMBP) 548 gave the corresponding chiral complexes 549a−d, f−i, and l−n. The reaction with mono-, di-, or trifluorinated benzyl alcohols 547a−d proceeded in high yields and with good diastereoselectivities. However, the conversion of pentafluorobenzyl alcohol 547e was met with failure since only CMBP 548 and alcohol 547e were consumed, and the Ni(II)-complex (S)-542 was completely recovered. Generation of the mono- or bis(trifluoromethyl)benzylsubstituted glycine derivatives 549f−g and (trifluoromethyl)pyridinyl derivative 549h was accomplished in high diastereoisomeric purity using the fluorinated derivatives 547f−h. Interestingly, the reaction also proceeded when using various aliphatic linear fluorinated alcohols 547i and 547l−n, and the complexes (S)(2S)-549i and 549l−n were generated, but in lower yields and selectivity. The Mitsunobu−Tsunoda alkylation using 2,2,2-trifluoroethanol 547j and 3,3,3-trifluoropropan1-ol 547k did not result in the formation of targeted compounds 549j and k. It appears that, when the strongly electronwithdrawing fluorinated group is too close to the alcohol functionality, the reaction cannot proceed. The chiral auxiliary can be cleaved in mild acidic conditions affording the FAAs as HCl salts in good yields and with little to no racemization, as AR


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Scheme 115. Synthesis of Photoreactive Phenylalanine Derivatives 553a,b and 553d−i

Scheme 116. Asymmetric Alkylation under PTC Conditions Using (R)-NOBIN and Benzyl Halide 556

Scheme 118. Asymmetric Alkylation under PTC Conditions Using (R)-BIMBOL and Benzyl Halide 560a

isomers (S)(2R)-561a−c with NaOMe (>95% de) afforded the single isomers (S)(2S)-561a−c without purification of the initial mixture due to the unfavorable interaction of the amino acid side-chain with the phenyl group at the C=N bond. In this manner, virtually single isomers (S)(2S)-561a−c were obtained in good overall yields and diastereoselectivities after NaOMe-

mediated diastereomeric enrichment. A putative hydrolysis step may lead to the corresponding amino acids (S)-445 and 562b,c (Scheme 117).286

Scheme 117. Asymmetric Alkylation under PTC Conditions Using nBu4NI and Benzyl Halides 560a−c

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decomposition of the complexes and subsequent cationexchange chromatography allowed the isolation of the fluorinated phenylalanine derivative (S)-445 and (S)-567a,b in >99.5% enantiomeric purity (Scheme 119).288,289 The synthesis of indolines was reported by Chen et al. Reaction between the Ni(II)-complex (S)-542 and benzyl bromides 571a−e gave the corresponding complexes (S)(2S)572a−e with high diastereoselectivity. The position of the fluorine substituent on the aromatic ring had no significant impact on the diastereoselectivity of the reaction. Disassembly of enantiopure complex (S)(2S)-572c under acidic conditions afforded the targeted (S)-2-amino-3-(2-bromo-5-fluorophenyl)propanoic acid 573c in excellent enantioselectivity of 97% ee. Copper-catalyzed intramolecular ring closure of (S)573c amino acid gave (S)-5-fluoroindoline-2-carboxylic acid (S)-574c in >99% ee. Subjecting (S)(2S)-573a, b, d, and e to the same conditions might provide access to fluorinated chiral heterocyclic amino acids with a different substitution pattern (Scheme 120).290

Another entry employing the achiral glycine Schiff base 555 to generate 4-fluorophenylalanine (S)-445 was reported by Belokon et al. Here, the Ni-complex 555 was alkylated with benzyl bromide 560a under asymmetric PTC conditions using the (R)-BIMBOL 563. Subsequent decomposition of the resulting complex (2S)-564a and separation using a cation exchange resin may afford the corresponding α-amino acid. Usage of (R)-BIMBOL furnished the (S) configurated product, whereas an (R) product might be formed using (S)-BIMBOL (Scheme 118).287 Scheme 119. Alkylation of Ni(II)-Complexes (S)-565 and (S)-566 with Benzyl Halides 560a, 560c, and 568a

6.4. Reaction with Alkyl- and Benzyl Halides

De Meijere et al. described an efficient scalable syntheses of enantiomerically pure 2-amino-3-(2-(fluoromethyl)cyclopropyl)propanoic acid derivatives 575a−c as well as a possible approach to (2S,3R)-β-methyl(p-fluorophenyl)alanine 576. Reaction of (S)- or (R)-542 with racemic mixtures of different fluorine containing iodides 577a−c and 578 (whose synthesis is also reported in their study) gave the corresponding complex pairs (S)(2S,1′S,2′R)-579a−c and (S)(2S,1′R,2′S)579a−c in a 1:1 ratio (same ratio was found for the (R)(2R,1′S,2′R)-579a−c and (R)(2R,1′R,2′S)-579a−c pair). The reaction of (S)-542 with 578 afforded the (S)(2S,3R)-580 and (S)(2S,3S)-580 pair, which can be converted to the corresponding (2S,3R)-2-amino-3-(4-fluorophenyl)butanoic acid 576 (Scheme 121).291

Saghiyan et al. reported new Ni(II)-complexes of glycine Schiff bases with modified chiral auxiliaries. They employed (S)2-N-[(N′-2-chlorobenzylprolyl)-amino]benzophenone (S)-565 and (S)-2-N-[N′-(3,4-dimethylbenzylprolyl)-amino]benzophenone (S)-566 for an efficient asymmetric synthesis of fluorophenylalanines (S)-445 and 567b,c. Alkylation of (S)565 and (S)-566 with fluorine-substituted benzyl halides 560a, 560c, and 568a gave predominantly the (S)(2S) diastereomers 569a−c and 570a−c. The meta- and para-fluorine-substituted variants showed high ee values, with complex (S)-565 working the best. In the case of nonfluorinated benzyl bromide alkylation, the authors showed that the novel Ni(II)-complex (S)-565 provided better asymmetric induction than the original (S)-542 (96% ee vs 90% ee). For the fluorine-substituted benzyl halides, this was only observed for 568a and 560c. Acidic

6.5. Reaction with Biaryl Chlorides

Deng et al. investigated the alkylation of glycine equivalent (S)542 or (R)-542 for the synthesis of (S)- or (R)-2-amino-3,3bis(4-fluorophenyl)propanoic acids (S)- or (R)-581. Reaction of (S)-542 with 4,4′-difluorobenzhydryl chloride 582 yielded the respective Ni-complex (S)(2S)- or (S)(2R)-583 in excellent diastereoselectivity. Hydrolysis by standard procedures and purification by reversed phase chromatography was utilized to obtain (S)- and (R)-2-amino-3,3-bis(4-fluorophenyl)propanoic acid (S)- and (R)-581 (Scheme 122).292

Scheme 120. Alkylation of Ni(II)-Complex (S)-542 with Fluorinated Benzyl Bromides 571a−e

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Scheme 121. Alkylation of Ni(II)-Complex (S)-542 with Fluorinated Alkyl Iodides 577a−c and Aryl Iodide 578

Scheme 122. Alkylation of Ni(II)-Complex (S)- and (R)-542 with Fluorinated Bisaryl Chloride 582

Scheme 123. Mannich-type Reaction with Aldimine 584

6.6. Mannich-type Additions

6.6.1. Reaction with Aldimines. The Mannich-type addition reaction of Ni(II)-complex (S)-542 and N-pmethoxyphenyl (PMP) protected aldimine of trifluoroacetaldehyde 584 gave access to the diastereomerically pure βperfluoroalkyl-α,β-diamino carboxylic acid 585. Addition of LiCl to the reaction mixture enhanced the rate of the reaction and resulted in high stereoselectivity and chemical yield of (S)(2S,3S)-586 (without LiCl: 32% de). Decomposition with hydrochloric acid and ion exchange chromatography gave the NPMP protected 4,4,4-trifluoro-2,3-diaminobutanoic acid (2S,3S)-585 (Scheme 123).294 6.6.2. Reaction with Sulfones. A practical and highly efficient enantio- and diastereoselective route to syn-configured aromatic α,β-diamino acids using a direct asymmetric Mannich reaction between the Ni(II)-complex 542 and the fluorinated α-

Soloshonok et al. also investigated the alkylation of the chiral glycine Schiff base (S)-542 with 4,4′-difluorobenzhydryl chloride 582 using potassium tert-butoxide as base.293 AU


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Scheme 124. Mannich-type Reaction with Fluorinated αAminosulfone 587

with high enantio- and diastereoselectivity, thus significantly expanding the scope of the reactions.295 6.6.3. Reaction with Sulfimines. Kawamura et al. reported the synthesis of (2S,3S)-2,3-diamino-4,4,4-trifluorobutanoic acid 590 using the N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines (SS)- and (RS)-591.296 While the Mannich reaction between (S)-542 and (SS)-592 afforded only one diastereomer (S)(2S,3S)(SS)-593, the same reaction using the enantiomeric (RS)-592 produced a mixture of the two separable major diastereomers (S)(2R,3R)(RS)-593 and (S)(2S,3R)(RS)-593. The latter reaction seems to be the mismatched case since both epimers were observed. The reaction was also tested using the achiral Ni(II)-complex 592 due to its enhanced chemical reactivity compared to complex (S)-542 as well as its easier synthetic access.297,298 Ni(II)-complex 592 reacted with chiral sulfinimine (SS)-591 to give a mixture of diastereomers (2S,3S)(SS)-594 and (2R,3S)(SS)-594 in excellent selectivity (94:6). Finally, disassembly of the Ni(II)-complex (2S,3S)(SS)594 followed by cation exchange chromatography with a DIAION SK1B resin afforded the free (2S,3S)-2,3-diamino4,4,4-trifluorobutanoic acid 590 (Scheme 125).299

amino sulfone 587 was reported by Wang et al. The reaction involves the creation of a carbon−carbon bond and two stereogenic centers in a single operation giving the complexes (S)- and (R)-588 and represents an attractive route to the synthesis 2,3-diamino-3-(4-fluorophenyl)propanoic acids (2S)589 and (2R)-589 (Scheme 124). A broad range of robust and readily available aryl-, heteroaryl-, and alkyl-N-Boc-α-amino sulfones (not shown) can efficiently be employed in the process

6.7. Additions of Ni(II)-Complexes to Michael Acceptors

6.7.1. Reaction with Crotonates. Soloshonok et al. investigated the addition of Ni(II)-complexes to Michael acceptors. The reaction of the Ni(II)-complex (S)-542 and ethyl 4,4,4-trifluorocrotonate 595 led to the corresponding pair of diastereomers (S)(2S,3S)-596 and (S)(2S,3R)-596 in a 5.6:1

Scheme 125. Mannich-type Reaction with Fluorinated Sulfimines (SS)- and (RS)-591

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Scheme 126. Michael Addition with Fluorinated Crotonates 595, 598, and 600

ratio. Hydrolysis and subsequent cyclization of the resultant glutamic acid under basic conditions afforded (2S,3S)- and (2S,3R)-5-oxo-3-(trifluoromethyl)pyrrolidine-2-carboxylic acid (2S,3S)-597 and (2S,3R)-597. The sterically more demanding ethyl 3-(trifluoromethyl) crotonate 598 reacted with complex (S)-542 to give the Michael adduct (S)(2S,3S)-599. The addition to ethyl 2-methyl-4,4,4-trifluorocrotonate 600 afforded the two diastereomers (S)(2S,3S,4R)-601 and (S)(2S,3S,4S)601 in a good diastereomeric ratio of 17:1 and created three stereogenic centers in the final pyroglutamic acid. The authors suggest that the high diastereoselectivities upon insertion of a trifluoromethyl group at the β-position of 598 and 600 are due to the electrostatic attractive interactions between the CF3 moiety and the Ni(II) atom in the most energetically favorable transition states leading to the major diastereomers. Using the same hydrolytic conditions as before, (2S,3S)-3-methyl-5-oxo3-(trifluoromethyl)pyrrolidine-2-carboxylic acid (2S,3S)-602 and (2S,3S,4R)-4-methyl-5-oxo-3-(trifluoromethyl)pyrrolidine-2-carboxylic acid (2S,3S,4R)-603 were prepared from complexes (S)(2S,3S)-599 and (S)(2S,3S,4R)-601, respectively (Scheme 126).300−303 6.7.2. Reaction with Acrylates. Belokon et al. elaborated the Micheal addition of Ni(II)-complex (S)-542 to methyl αfluoroacrylate 604 to give a mixture of (S)(2S,4R)-605 and

Scheme 127. Michael Addition with Fluorinated Acrylate 604

(S)(2S,4S)-605 with low diastereoselectivity (1.5:1). Acidic hydrolysis followed by ion exchange chromatography afforded the corresponding 4-fluoroglutamic acids (2S,4R)-145 and (2S,4S)-145 with high enantiomeric excess. The resulting amino acid solutions consisted of both open and closed forms of fluoroglutamic acid (Section 3.6.1). An additional hydrolysis under acidic conditions was applied to give the hydrochlorides AW


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Scheme 128. Conjugate Addition/Elimination Reaction with Fluorinated Acrylates 608a and b

Scheme 129. Michael Addition with trans-N-(Enoyl)-1,3-oxazolidine-2-ones 609a−h

Scheme 130. Michael Addition with trans-N-(Enoyl)-1,3oxazolidine-2-ones 609c and 609d

of the targeted (2S,4R)- and (2S,4S)-4-fluoroglutamic acids (2S,4R)-145 and (2S,4S)-145 (Scheme 127).304 The Michael reaction between 4-fluoroaryl-acrylates 606a and b, and (S)-542 was reported by Wang et al. Conjugate addition of the Ni(II)-complex (S)-542 to these acrylates was followed by the in situ elimination of the OAc moiety, leading to the corresponding adducts (S)(2R)-607a and (S)(2R)-607b in high diastereoselectivity.305 This strategy might be an attractive route to synthesize (R,E)-2-amino-4-(ethoxycarbonyl)-5-(4fluorophenyl)pent-4-enoic acid derivatives 608a and b, which should be obtained after acidic decomposition of the addition products (Scheme 128). 6.7.3. Reaction with But-2-enoyl-oxazolidinone. Cai and Soloshonok established trans-N-(enoyl)-1,3-oxazolidine-2ones as Michael acceptors for the synthesis of optically pure pyroglutamic acids. Reaction of (S)-542 and oxazolidinones 609a−h (prepared according to Soloshonok et al.306) furnished the complexes (S)(2S,3R)-610a−h. Addition of oxazolidines 609a−h occurred with low to moderate de values; only addition of the pentafluorophenyl derivative 609d gave (S)(2S,3R)-610d in 92% de. All addition products (S)(2S,3R)-610a−g were obtained in excellent yields, and (S)(2S,3R)-610g was readily hydrolyzed giving pure (2S,3R)-3-(4-fluorophenyl)-5-oxopyrrolidine-2-carboxylic acid (2S,3R)-611g.307 The electrondeficient aromatic ring on the starting Michael acceptors 609 favored an (S)(2S,3R) absolute configuration of the major

diastereomeric product 610. Thus, it was assumed that the ketimine phenyl of complex (S)-542 might be involved in the corresponding electron donor−acceptor attractive interactions. To prove this, Cai et al. investigated the reaction of glycine complex (S)-612 in which the ketimine phenyl is substituted by a methyl residue. Since the methyl group in this complex cannot be involved in electron donor−acceptor attractive interaction, the reaction between complex (S)-612 and pentafluorophenylAX


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Scheme 131. Michael Addition with 4-Phenyloxazolidin-2-ones (S)-616a−e and 616i

Scheme 132. Michael Addition with 4-Phenyloxazolidin-2-one 616c

tives (2S,3R)-611c and 611i. These pyroglutamic acids were further converted using standard procedures to give the Nprotected, 1-(Boc)-3-(4-fluorophenyl)pyrrolidine-2-carboxylic acids (2S,3R)-618c and (2S,3R)-618i (Scheme 131).312−314 Another approach to synthesize pyroglutamic acids was the use of Ni(II)-complex (S)-542 and N-enoyloxazolidinones (S)616c and (R)-616c, both containing chiral centers. The glycine enolate facial selectivity in the Ni(II)-complex (S)-542 was found to be controlled by the stereochemical preference of the Michael acceptors (S)-616c and (R)-616c. Thus, the addition of (S)-542 to trifluorophenyl oxazolidinone (S)-616c311 afforded the complex (S)(2S,3R)(S)-619c, whereas the same reaction with the (R) configured oxazolidinone 616c led to the adduct (S)(2R,3S)(R)-619c. Both reactions proceeded with complete diastereoselectivity. This method was used to access enantiopure (2S,3R)- and (2R,3S)-5-oxo-3-(4-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylic acid (2S,3R)-611c and (2R,3S)-611c from a single enantiomer of the initial chiral Ni(II)-complex (Scheme 132).315,316 Although usage of N-(E-enoyl)-oxazolidinones like 616 as chiral auxiliaries in various Michael addition reactions offers great efficiency, their relatively high cost led to a search for alternatives. For instance, methyl N-(E-enoyl)pyroglutamates

containing 609d resulted in a lower diastereoselectivity, as compared with the addition reaction of complex (S)-542 with 609d ((S)(2S,3R)-613 and (S)(2R,3S)-613 diastereomeric products in a ratio of 3:1; Scheme 129).308 The Michael addition of a new Ni(II)-complex of glycine’s Schiff base with o-[N-α-picolylamino] acetophenone 614 and N-(trans-enoyl)oxazolidon-2-ones 609c−d as suitable Micheal acceptors proceeded with great efficiency, affording the corresponding addition products (S)(2R,3S)-615c and (S)(2R,3S)-615d in complete diastereoselectivity (Scheme 129). Formal hydrolysis of the products followed by treatment of the reaction mixture with ammonium hydroxide afforded the corresponding 3-(fluoroary)-5-oxopyrrolidine-2-carboxylic acid derivatives (2R,3S)-611c,d (Scheme 130).309,310 An alternative route to give optically pure 3-substituted pyroglutamic acid derivatives uses oxazolidine-derived acrylamides, which contain a stereo controlling element. 4-Phenyloxazolidin-2-ones (S)-616a−e and 616i311 were used as chiral Michael acceptors in the reaction with the achiral Ni(II)complex 614. Herein, the adduct complexes 617a−e and 617i were obtained primarily as the (S)(2S,3R)-diastereomers. Decomposition of the addition products allowed the isolation of the 3-(fluoroaryl)-5-oxopyrrolidine-2-carboxylic acid derivaAY


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Scheme 133. Michael Addition with Methyl N-(EEnoyl)pyroglutamates (S)-620c and (S)-620d

Ni(II)-complex 614. The addition occurred with high diastereoselectivity giving rise to the sole reaction product (2R,3S,5′S)-621c and 621d. Hydrolysis under standard conditions of these addition products might present an efficient practical asymmetric synthesis of (2R,3S)-3-(fluoroaryl)-5oxopyrrolidine-2-carboxylic acid derivatives (2R,3S)-611c and (2R,3S)-611d (Scheme 133).317 The new generation of Ni(II)-complexes 622 and 623 has been employed in diastereoselective Michael addition reactions with fluorinated 4-phenyl-1,3-oxazolidin-2-ones (R)-616a, b, d, and e to give access to β-substituted pyroglutamic acids. The addition reaction generated the complexes 624a,d and 625a,b,e, which occurred with high diastereoselectivity (>98% de), and thus, no further purification was needed. Acidic hydrolysis followed by treatment with aqueous ammonium hydroxide led to the formation of the corresponding (2R,3S)-3-(fluoroaryl)-5oxopyrrolidine-2-carboxylic acid (2R,3S)-611a and (2R,3S)611d. The other fluorinated amino acid derivatives might be obtained following the same procedure (Scheme 134).318,319 The Ni(II)-complex 622 was used to synthesize (2R,3R)-3trifluoromethyl pyroglutamic acid 597 and (2R,3R)-3-trifluoromethyl glutamic acid 623. The reaction of the glycine Schiff base 619 with the oxazolidinone (R)-627320 gave the complex (2R,3R,4′R)-628 as a single diastereomer (compared to a dr of 5.6:1 of (2R,3R) and (2R,3S) using (S)-542)). Disassembly of the complex under standard conditions afforded the enantioand diastereomerically pure (2R,3R)-5-oxo-3-(trifluoromethyl)pyrrolidine-2-carboxylic acid (2R,3R)-597. The transformation of the pyroglutamic acid derivative (2R,3R)-597 to the free glutamic acid by hydrolysis with HCl and subsequent treatment with propylene oxide gave the targeted open form (2R,3R)-626 along with the ring-closed form (2R,3R)-599 in a 1:4 ratio. This was overcome by generating the N-Boc protected pyroglutamate (2R,3R)-629, which was saponified to generate the (2R,3R)-2((Boc)amino)-3-(trifluoromethyl)pentanedioic acid (2R,3R)630. Hydrolysis of the latter gave (2R,3R)-2-amino-3-

Scheme 134. Michael Addition with 4-Phenyloxazolidin-2ones 616a, b, d, and e

(S)-620c and (S)-620d were one-hundred-times cheaper and were successfully used as Michael acceptors in the reaction with the achiral picolinic acid/o-(amino)acetophenone derived

Scheme 135. Michael Addition with But-2-enoyl-oxazolidinone (R)-627

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Scheme 136. Michael Addition with 4-Phenyloxazolidin-2-ones (S)-616c and (R)-616c

6.8. Perfluoroalkyl Ketones

(trifluoromethyl)pentanedioic acid (2R,3R)-626 in a 3:1 ratio with the pyroglutamic acid (2R,3R)-597 (Scheme 135).321 Another type of Ni(II)-complexes 631 and 632 was used to synthesize (2R,3S)-5-oxo-3-(4-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylic acid 611c. These new Ni(II)-complexes 631 and 632 of glycine Schiff bases are referred to as NHtype and show superior features and reactivity over the previously used secondary amine derived complexes; in particular, they are readily available, very inexpensive, shelfstable, and can be easily synthesized. The N−H stereogenic center in these compounds is relatively configurationally

Soloshonok et al. investigated the reaction of alkyl trifluoromethyl ketones 635a−f with Ni(II)-complex (S)-542 to yield the complex (S)(2S,3S)-636a−f using DBU in high diastereomeric excess (>90% de) along with the minor products (S)(2R,3R)-636a−f regardless of the length of the alkyl chain. In case of highly electrophilic phenylacetylenyl trifluoromethyl ketone 635f, the use of TEA as the base was necessary to prepare the corresponding Ni(II)-complex (S)(2S,3S)-636f. Complexes (S)(2S,3S)-636a and (S)(2S,3S)-636c−e were isolated in diastereomerically pure forms and treated with HCl to give enantiomerically pure 2-amino-3-hydroxy-3-alkyl-3-trifluoromethyl carboxylic acid derivatives (2S,3S)-637a and (2S,3S)637c−e (Scheme 137).323,324

Scheme 137. Addition of Ni-Complex (S)-542 to Trifluoromethyl Ketones 635a−f

6.9. Oxidative Dehydrogenative Cross-Coupling

An oxidative dehydrogenative cross-coupling reaction between tertiary amines and nickel(II) glycinate (S)-542 was reported by Zhou et al. The reaction between complex (S)-542 and tetrahydroisoquinoline 638 occurred with o-chloranil as oxidant to give a mixture of syn-(S)(2S,1′S)-639 and anti-(S)(2S,1′R)639. The release of the free amino acids could not be conducted under the usual acidic conditions because of iminium ion formation followed by β-elimination. Thus, an alternative route yielded the fluorinated tetrahydroisoquinolin-1-yl glycine (2S,1′S)-640 by treatment of (S)(2S,1′S)-639 with EDTA and hydrazine (Scheme 138).325 6.10. Deracemization and (S) to (R) Interconversion of α-Amino Acids

Sorochinsky et al. investigated a deracemization approach to separate enantiomeric FAAs. The reaction between the chiral ligand (S)-641 and racemic ω-CF3 containing amino acids 42 (Section 3.3.3), 642b, and 545, prepared following the procedures of Tsushima et al.,326 gives the Ni(II)-complex (S,SN)(R)-643a−c in good diastereoselectivity. When (R)-641 was used, this process furnished the corresponding complexes (S)(R,RN)-643a−c and very similar diastereoselectivity. Acidic hydrolysis afforded the enantiopure amino acids 42, 642b, and 545. Reaction of the chiral ligand (S)-641 and Ni(OAc)2 with fluorinated amino acids (R)-23 and (S)-24 (Scheme 7, Section 3.2.1) gave rise to thermodynamically controlled products (S,SN)(S)-644 and (S,SN)(R)-645. These complexes were

unstable in solution; and in the case of sterically bulky groups like tBu or 1-adamantyl attached to the NH function, Micheal addition to chiral oxazolidinones like (S)- or (R)-616c occurs with excellent diastereoselectivity (>98% de), giving a single reaction product (S)(2S,3R)(S)-633 or (R)(2R,3S)(R)-634. Decomposition of the complex (S)(2S,3R)(S)-634 and subsequent cyclization gave the targeted pyroglutamic acid (2S,3R)-611c (Scheme 136).322 BA


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Scheme 138. Addition of Ni-Complex (S)-542 to Tetrahydroisoquinolidine 638

Scheme 139. Deracemization of Fluorinated Amino Acids

diagnostic probes in 18F-PET-imaging, in the engineering of enzymes that display artificial activities, and as analytical tools in 19 F-NMR of proteins as well as to generate bioinspired materials with novel properties. Facile synthetic access in substantial quantities would be the requirement to make the expansive application of these unique building blocks in future protein engineering possible. However, the synthesis of fluorinated amino acids is a rather complex field. Because of the peculiarities of the element fluorine, there are no general procedures for the incorporation of fluorine substituents into amino acids. Instead, the appropriate synthesis route needs to be chosen based on the number of fluorine substituents, their position in the side chain, and possible further functionalities. These aspects significantly affect not only the structural properties of the resulting amino acid but also the reactivity of all functional groups, the acidities of adjacent hydrogen

disassembled to afford new D-stereoisomers of S-CF3 containing amino acid derivatives (S)-23 and (R)-24 (Scheme 139).327

7. PERSPECTIVE On the basis of fluorine’s unique properties, its introduction creates a new class of amino acids with a repertoire of functionalities that is unparalleled in the world of proteins. With numerous examples, we and others have shown that the incorporation of even one fluorine atom in the side chain of an amino acid can dramatically influence key properties of peptides and proteins such as folding, protease stability, and protein− protein interactions. Thus, in a league of its own, fluorine has the potential to enable us to engineer biopolymers and to fine-tune their properties. Fluorinated amino acids are either already being used or will soon be applied to the various fields of life science and biotechnology, for example, in medical chemistry, as BB


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Table 1. Compendium of Fluorinated Amino Acids Discussed in This Review

BC


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BD


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BG


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BH


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BI


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BJ


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BK


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BL


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BM


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BN


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BO


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BP


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BQ


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BR


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BT


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BU


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BV


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the group of Prof. Koksch with a Marie-Curie ITN “Fluor21” scholarship to pursue her Ph.D. studies. Her interests are the development of new supramolecular assemblies based on peptidic scaffolds and the use of fluorine to modulate their properties.

substituents, and, consequently, the retention of stereochemistry. The establishment of robust synthetic methods and their successful implementation in amino acid synthesis can be considered a benchmark. As the development of new fluorinating reagents progresses steadily, with many novel fluorination techniques having been published over the course of writing this review, the variety of synthetic strategies for accessing fluorinated amino acids will increase accordingly. This progress will further drive and advance the area of peptide- and protein engineering and will extend our toolkit by numerous unique fluorinated amino acid building blocks.

Susanne Huhmann studied chemistry at the Freie Universität Berlin, where she received a M.Sc. degree in 2013 under supervision of Prof. Dr. Beate Koksch. Shortly afterwards, she started her Ph.D. studies in the same group and obtained her doctoral degree in 2018. Her work focuses on peptide engineering with fluorinated amino acids for the development of fluorinated, stable peptide-based HIV-1 fusion inhibitors. Jakob Leppkes, born in Singapore, received a B.Sc. (2013) and a M.Sc. degree (2017) in chemistry at Freie Universität Berlin (Germany). Currently, he is a Ph.D. student at the Institute of Chemistry and Biochemistry at Freie Universität Berlin under the supervision of Prof. Dr. Beate Koksch. Jakob’s research interest focuses on the synthesis and site-specific incorporation of fluorinated amino acids into peptides and proteins.

8. FLUORINATED AMINO ACID TABLE The following table shows all FAAs reported in this review. Additionally, their names, abbreviations (if reported), and the corresponding references are included (Table 1). AUTHOR INFORMATION Corresponding Author

Beate Koksch received a Ph.D. degree from University Leipzig and pursued postdoctoral studies at TSRI La Jolla and postdoctoral lecture qualification at University Leipzig under the mentorship of Klaus Burger. She has been Professor of Chemistry at Freie Universität Berlin since 2004. Her group investigates fluorinated amino acids in the context of peptides and proteins, studies complex folding mechanisms in neurodegenerative diseases, and develops new multivalent scaffolds.

*E-mail: [email protected]. ORCID

Susanne Huhmann: 0000-0001-5519-3426 Beate Koksch: 0000-0002-9747-0740 Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS The authors gratefully acknowledge funding by the DFG (DFGRTG 1582 “Fluorine as Key Element”, DFG-CRC 1114 “Scaling Cascades in Complex Systems”, and DFG-CRC 1349 “FluorineSpecific Interactions: Fundamentals and Functions” - project iD 387284271) as well as by the EU-ITN “FLUOR21”. The authors thank Dr. Mohamed Hedi Karoui for proofreading the manuscript. This work is dedicated to Prof. Dr. Hans-Ulrich Reißig on the occasion of his 70th birthday.

Biographies Johann Moschner received a Ph.D. degree from University Leipzig under the supervision of Prof. Athanassios Giannis in the field of natural product chemistry. Afterwards, he joined the group of Prof. Beate Koksch as a postdoctoral researcher. His work focuses on the synthesis of fluorinated amino acids as well as their incorporation into amyloidogenic peptides. Valentina Stulberg was born in Pawlodar, Kazakhstan. She studied chemistry at Humboldt-Universität zu Berlin, where she received her diploma-degree under supervision of Prof. C. Arenz in 2013. In 2015, she joined the group of Prof. B. Koksch at Freie Universität Berlin to pursue her Ph.D. degree. Her current research interest focuses on protein engineering with fluorinated amino acids and the impact of fluorine-specific interactions on protein folding.

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