Review

. 2018 Apr 11;118(7):3887-3964.

doi: 10.1021/acs.chemrev.7b00778. Epub 2018 Apr 2.

Modern Approaches for Asymmetric Construction of Carbon-Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs

Yi Zhu¹, Jianlin Han¹, Jiandong Wang², Norio Shibata², Mikiko Sodeoka³, Vadim A Soloshonok^{4

5}, Jaime A S Coelho⁶, F Dean Toste⁶

Affiliations

¹ School of Chemistry and Chemical Engineering, State Key laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials , Nanjing University , 210093 Nanjing , China.
² Department of Nanopharmaceutical Sciences & Department of Frontier Materials , Nagoya Institute of Technology , Gokiso, Showa-ku , Nagoya 466-8555 , Japan.
³ Synthetic Organic Chemistry Laboratory , RIKEN, and RIKEN Center for Sustainable Resourse Science , 2-1 Hirosawa , Wako 351-0198 , Japan.
⁴ Department of Organic Chemistry I, Faculty of Chemistry , University of the Basque Country UPV/EHU , 20018 San Sebastian , Spain.
⁵ IKERBASQUE, Basque Foundation for Science , 48011 Bilbao , Spain.
⁶ Department of Chemistry , University of California , Berkeley , California 94720 , United States.

PMID: 29608052
PMCID: PMC6497456
DOI: 10.1021/acs.chemrev.7b00778

Review

Modern Approaches for Asymmetric Construction of Carbon-Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs

Yi Zhu et al. Chem Rev. 2018.

. 2018 Apr 11;118(7):3887-3964.

doi: 10.1021/acs.chemrev.7b00778. Epub 2018 Apr 2.

Authors

Yi Zhu¹, Jianlin Han¹, Jiandong Wang², Norio Shibata², Mikiko Sodeoka³, Vadim A Soloshonok^{4

5}, Jaime A S Coelho⁶, F Dean Toste⁶

Affiliations

¹ School of Chemistry and Chemical Engineering, State Key laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials , Nanjing University , 210093 Nanjing , China.
² Department of Nanopharmaceutical Sciences & Department of Frontier Materials , Nagoya Institute of Technology , Gokiso, Showa-ku , Nagoya 466-8555 , Japan.
³ Synthetic Organic Chemistry Laboratory , RIKEN, and RIKEN Center for Sustainable Resourse Science , 2-1 Hirosawa , Wako 351-0198 , Japan.
⁴ Department of Organic Chemistry I, Faculty of Chemistry , University of the Basque Country UPV/EHU , 20018 San Sebastian , Spain.
⁵ IKERBASQUE, Basque Foundation for Science , 48011 Bilbao , Spain.
⁶ Department of Chemistry , University of California , Berkeley , California 94720 , United States.

PMID: 29608052
PMCID: PMC6497456
DOI: 10.1021/acs.chemrev.7b00778

Abstract

New methods for preparation of tailor-made fluorine-containing compounds are in extremely high demand in nearly every sector of chemical industry. The asymmetric construction of quaternary C-F stereogenic centers is the most synthetically challenging and, consequently, the least developed area of research. As a reflection of this apparent methodological deficit, pharmaceutical drugs featuring C-F stereogenic centers constitute less than 1% of all fluorine-containing medicines currently on the market or in clinical development. Here we provide a comprehensive review of current research activity in this area, including such general directions as asymmetric electrophilic fluorination via organocatalytic and transition-metal catalyzed reactions, asymmetric elaboration of fluorine-containing substrates via alkylations, Mannich, Michael, and aldol additions, cross-coupling reactions, and biocatalytic approaches.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

**Figure 1**
Structures of fluticasone propionate 4 and salmeterol 5.

**Figure 2**
A plausible catalytic cycle for cinchona alkaloids catalyzed enantioselective fluorodesilylation.

**Figure 3**
Enamine transition-state geometries to rationalize the enantioselectivity.

**Figure 4**
Possible enamine intermediate showing a proposed intramolecular hydrogen bond.

**Figure 5**
Proposed transition states (I and II) for the two enantioselectivity switch fluorination reactions.

**Figure 6**
Proposed transition model for asymmetric fluorination.

**Figure 7**
Fluorine–ammonium ion gauche effect controlling the conformation of 9-fluoro-cinchonine.

**Figure 8**
Proposed transition state structure for asymmetric fluorination of β-keto esters.

**Figure 9**
Proposed dual catalytic cycle for the enantioselective fluorination of ketones.

**Figure 10**
Proposed transition state for asymmetric fluorination catalyzed by thiourea–tertiary amine.

**Figure 11**
Proposed activation model of the urea-containing chiral quaternary ammonium salt.

**Figure 12**
Proposed mechanism for the 1,4-addition and fluorination sequence.

**Figure 13**
Proposed transition state mode for fluorination catalyzed by chiral sodium phosphate.

**Figure 14**
Possible mechanism for the **C41**-catalyzed enantioselective fluorination of ketenes.

**Figure 15**
Proposed catalytic cycle for chiral anion phase-transfer catalyst.

**Figure 16**
Proposed transition state model for asymmetric fluorination of cyclic enamides catalyzed by anionic phase-transfer catalyst.

**Figure 17**
Suggested origin of diastereo- and regioselectivity for fluoro-amination.

**Scheme 1**
Synthesis and Structure of Fludrocortisone 3

**Scheme 2**
Key Fluorination Steps in the Synthesis of Fluticasone 4 and Difluprednate 6

**Scheme 3**
Key Fluorination Step in the Synthesis of Solithromycin 13

**Scheme 4**
Key Fluorination Step in the Synthesis of Sofosbuvir 14

**Scheme 5**
Synthesis of α-Monofluorinated Compound 18 (a) and the Target Fluorinated Product 20 (b)

**Scheme 6**
Intramolecular Michael Addition Sequence Leading to Fluorinated Product 22 (a) and α-Fluorination Leading to Compound 24 (b)

**Scheme 7**
Asymmetric Electrophilic Fluorination Affording Compounds 26 (a), 28 (b), 31 (c), and 33 (d)

**Scheme 8**
Chiral N–F Reagents for Enantioselective Fluorination

**Scheme 9**
Substrate Types for Enantioselective Fluorination Using N–F Reagents: Silyl Enol Ethers (a), Allylsilanes (b), 1,3- Dicarbonyl Compounds (c), Oxindoles (d), Dipeptides (e), and Enolates (f)

**Scheme 10**
Enantioselective Fluorination Using Cinchona Alkaloid Derived Reagents: Structural Types 65 (a) and 68 (b)

**Scheme 11**
Preparation of Enantiomers of 3-Fluorothalidomide 74

**Scheme 12**
Preparation of α-Fluorinated Ketones 76 Bearing a C–F Quaternary Carbon Center

**Scheme 13**
Preparation of α-Fluorinated Ketones 78 Bearing a C–F Quaternary Carbon Center

**Scheme 14**
Enantioselective Fluorination of Oxindoles

**Scheme 15**
Enantioselective Fluorodesilylation Reactions of Silyl Enol Ethers

**Scheme 16**
Enantioselective Fluorination of 3-Aryl-oxindoles

**Scheme 17**
Enantioselective Fluorination of 3-Aryl-oxindoles Using Selectfluor

**Scheme 18**
Enantioselective Fluorination–Cyclization of Indoles 92 with a Pendant Heteronucleophile Tethered at C3 Position

**Scheme 19**
Asymmetric Electrophilic Fluorination of 4-Substituted Isoxazolinones 94

**Scheme 20**
Asymmetric Fluorination of 4-Substituted Pyrazolones 96

**Scheme 21**
Asymmetric α-Fluorination of Linear Aldehydes 98

**Scheme 22**
Asymmetric α-Fluorination of Branched Aldehydes 101

**Scheme 23**
Asymmetric α-Fluorination of α-Chloroaldehydes 103

**Scheme 24**
Asymmetric α-Fluorination of α-Alkyl-α-chloroaldehydes 107

**Scheme 25**
Enantioselective Preparation of *gem*-Chlorofluoro Compounds from Unfunctionalized Aldehydes

**Scheme 26**
Asymmetric Synthesis of Fluorinated β-Prolinol Analogues

**Scheme 27**
Enantioselective Fluorination of Cyclic α-Branched Aldehydes

**Scheme 28**
Enantioselective Fluorination of α,α-Dialkyl Aldehydes

**Scheme 29**
Enantioselective Fluorination of α,α-Dialkyl Aldehydes Followed by the Reduction to the Corresponding Alcohols

**Scheme 30**
Enantioselective Fluorination of α,α-Dialkyl Aldehydes via Enamine Intermediates

**Scheme 31**
Enantioselective Fluorination of α-Aryl-α-alkyl aldehydes

**Scheme 32**
Enantioselective Fluorination of β-Ketoesters 126

**Scheme 33**
Asymmetric Fluorination of β-Ketoesters 128

**Scheme 34**
Enantioselective Electrophilic Fluorination of β-Keto Esters 130

**Scheme 35**
Asymmetric Fluorination of α-Cyano Acetates 134

**Scheme 36**
Asymmetric Fluorination of Indane Carboxylates 136

**Scheme 37**
Asymmetric Electrophilic Fluorination of β-Ketoesters 138

**Scheme 38**
Asymmetric α-Fluorination of t-Butyl Indane Carboxylates and Their Analogues 140

**Scheme 39**
Asymmetric Electrophilic Fluorination of 3-Substituted Benzofuran-2(3H)-ones 142

**Scheme 40**
Enantioselective Fluorination of Cyclohexanones 146

**Scheme 41**
Enantioselective Fluorination of β-Keto Esters 148

**Scheme 42**
Asymmetric Fluorination of β-Keto Esters 150

**Scheme 43**
Asymmetric Fluorination of Pyrazolone Derivatives 152

**Scheme 44**
Conjugate Addition/Dearomatizative Fluorination of Isoxazol-5(4H)-ones 155

**Scheme 45**
oxa-Michael Addition/Electrophilic Fluorination Transformations

**Scheme 46**
Tandem Friedel–Crafts/Fluorination Process: Structural Generality (1), Large-Scale Synthesis (2), and Elucidation of the Stereochemical Outcome (3)

**Scheme 47**
Preparation of α-Fluoro-ester 163

**Scheme 48**
Enantioselective Fluorination of 1,3-Dicarbonyl and α-Cyano Carbonyl Compounds 164

**Scheme 49**
Enantioselective Fluorination of β-Keto Esters 166

**Scheme 50**
Enantioselective Coupling of Aryl Alkyl Ketenes 168

**Scheme 51**
Phosphono-fluorination of Unactivated Alkenes 170

**Scheme 52**
Electrophilic Fluoro-cyclization of Indenes 172

**Scheme 53**
Preparation of Fluorotetrahydro-5H-indeno-[2,1-c]quinolones 176

**Scheme 54**
Enantioselective Tandem Nazarov Cyclization/Electrophilic Fluorination Sequence

**Scheme 55**
Tandem 1,4-Addition/Fluorination Sequence of Acyclic Alkylidene β-Keto Esters 179

**Scheme 56**
Asymmetric Fluorination of Alkylidene β-Keto Esters

**Scheme 57**
Enantioselective Fluoro-cyclization of Alkenes 181

**Scheme 58**
Preparation of α-Fluorinated Benzoyl-imines 184

**Scheme 59**
Tandem Oxyfluorination Transformations of Acyclic Aldehyde-Derived Enamides

**Scheme 60**
Enantioselective 1,4-Aminofluorocyclization of Conjugated 1,3-Dienes

**Scheme 61**
Preparation of Octahydro-isoquinoline Compounds with a C–F Quaternary Carbon Center

**Scheme 62**
Enantioselective Electrophilic Fluorination of Alkenes 189

**Scheme 63**
Asymmetric Fluorination of 2,3-Disubstituted Phenols 191

**Scheme 64**
Tandem Fluorination-[4 + 2] Cycloaddition

**Scheme 65**
Preparation of Fluorinated Analogue of Natural Product (–)-Grandifloracin

**Scheme 66**
Asymmetric Fluorinative Dearomatization of Tryptamide Derivatives

**Scheme 67**
Asymmetric Fluorinative Dearomatization of 3,5-Dimethyl Substituted Substrate

**Scheme 68**
Intermediate Transition Metal Bidentate Enolate Complexes

**Scheme 69**
Asymmetric Fluorination of Acyclic (a) and Cyclic β-Keto Esters (b)

**Scheme 70**
Enolate Re-Face (a) and Si-Face (b) Shielding Considerations

**Scheme 71**
Enantioselective Sequential Fluoro-chlorination and Chloro-fluorination of β-Keto Esters

**Scheme 72**
Enantioselective Fluorination Reactions Catalyzed by Palladium Complex (a) and Its Application for Acyclic and Cyclic Substrates (b)

**Scheme 73**
Pd-Catalyzed Fluorination of β-Keto Esters

**Scheme 74**
Pd-Catalyzed Fluorination of β-Keto Amides (a) and Their Heterocyclic Analogues (b)

**Scheme 75**
Large-Scale Preparation of Commercial SYK Inhibitor

**Scheme 76**
Asymmetric Fluorination of β-Keto Phosphonate Esters (a) and α-Aryl-α-cyanophosphate Esters (b)

**Scheme 77**
Enantioselective Fluorination of Oxindole Derivatives; 3-Substituted N-Boc Oxindoles (a), 3-Unsubstituted N-Boc Oxindoles (b), and Conditions Using only 0.5 mol % of the Catalysts (c)

**Scheme 78**
Asymmetric Fluorination of α-Ketoester 216

**Scheme 79**
Ni- and Cu-Catalyzed Fluorination Using (*S,S*)-Box-Ph Ligand (a) and (*R,R*)-DBFOX-Ph Ligand (b)

**Scheme 80**
Asymmetric Ni-Catalyzed Fluorination of β-Keto Esters

**Scheme 81**
Ni-Catalyzed Asymmetric Fluorination Using (R)-BINAP (a) and (*R,R*)-DBFOX (b) Ligands

**Scheme 82**
Cu-Catalyzed Enantioselective Fluorination of β-Keto Esters Using (*R,R*)-Box-Ph (a), Chiral Sulfoximine, Nap-(*R,R*)-Box, Chiral Spiro Oxazoline, Diphenylamine-Linked Bis(thiazoline), Ph-BINMOL-Derived Salan Ligands (b), and DNA as a Catalyst (c)

**Scheme 83**
Asymmetric Fluorination of 1,3-Dicarbonyl Compounds 206 Catalyzed by Chiral Dicationic Ruthenium PNNP Complex

**Scheme 84**
Asymmetric Fluorination of β-Keto Phosphonates (a) and Alkyl *tert*-Butyl Malonate Esters (b)

**Scheme 85**
Rare Earth Metal Complex-Catalyzed Asymmetric Fluorination

**Scheme 86**
Enantioselective Fluorination of β-Keto Esters Using Chiral Cobalt–Salen Complex (a) and Iron(III)–Salan Complex (b)

**Scheme 87**
Asymmetric Catalytic Alkylation of Cyclic α-Fluoro Ketones

**Scheme 88**
Phase-Transfer Catalyzed Asymmetric Alkylations

**Scheme 89**
Pd-Catalyzed Asymmetric Arylation of α-Fluoroketones

**Scheme 90**
Asymmetric Pd-Catalyzed Arylation Reaction with Aryl Triflates

**Scheme 91**
Pd-Catalyzed Asymmetric Allylation Reaction of Silyl Protected Enolates

**Scheme 92**
Asymmetric Allylic Alkylation Reaction of Linear α-Fluoro-β-keto Esters

**Scheme 93**
Pd-Catalyzed Asymmetric Allylic Alkylation α-Fluoro Ketones

**Scheme 94**
Asymmetric Allylic Alkylation of Tertiary Fluorinated Enolates Generated from C3-Fluorinated Oxindoles

**Scheme 95**
Pd-Catalyzed Enantioselective Decarboxylative Allylation of α-Fluorinated Ketoesters

**Scheme 96**
Pd-Catalyzed Allylation Reaction Using (S)-t-Bu-PHOX Ligand

**Scheme 97**
Ni/bis(oxazoline)-Catalyzed Asymmetric Alkylation of Racemic α-Halo-α-fluoroketones

**Scheme 98**
Mannich Reactions of Detrifluoroacetylatively in Situ Generated Fluorinated Enolates

**Scheme 99**
Mannich Reactions of Detrifluoroacetylatively in Situ Generated Enolates Derived from 3-Fluoroindolin-2-ones

**Scheme 100**
Asymmetric Detrifluoroacetylative Mannich Reactions Using *N-tert*-Butylsulfinyl-(perfluoro)benzaldimine

**Scheme 101**
Detrifluoroacetylative Mannich Reactions of Indolin-2-ones with Fluorinated Aldimines

**Scheme 102**
Mannich Reactions between α-Fluoro Esters and *N-tert*-Butylsulfinyl imines

**Scheme 103**
Substrate Generality of the Mannich Reactions between α-Fluoro Esters and *N-tert*-Butylsulfinyl Imines

**Scheme 104**
Mannich Reactions of α-Fluoro Ketones with *N-tert*-Butylsulfinylimines

**Scheme 105**
Organocatalytic Mannich Reaction between α-Fluorinated Ketoesters and N-Boc-Protected Imines

**Scheme 106**
Pd-Catalyzed Asymmetric Mannich Reactions of α-Fluoro-β-ketoesters with N-Boc-aldimines

**Scheme 107**
Asymmetric Organocatalyzed Mannich Addition Reactions of α-Fluorinated Monothiomalonates with Imines

**Scheme 108**
Asymmetric Mannich Reactions of Imines with β-Keto Acetyloxazolidinone Protected β-Keto-α-fluoro Esters

**Scheme 109**
Mannich Reactions of α-Fluorinated Aromatic Cyclic Ketones with Imines Catalyzed by (*S,S*)-Bicyclic Guanidine

**Scheme 110**
Asymmetric Catalytic Mannich Reactions Catalyzed by ZnEt₂/(*R,R*)-Prophenol

**Scheme 111**
Mannich Reactions of α-Fluoro Cyclic Ketones Using Song’s Chiral oligoEGs C63 Catalyst

**Scheme 112**
Asymmetric Detrifluoroacetylative Mannich Reactions Using Chiral Anthracenyl-Substituted Cyclohexane-1,2-diamine as Organocatalyst

**Scheme 113**
Detrifluoroacetylative Aldol Reactions Using Cinchona Alkaloid Derived Thiourea Catalyst

**Scheme 114**
Detrifluoroacetylative Aldol Reactions Using Copper(II)/Chiral Bisoxazoline as a Catalyst

**Scheme 115**
Detrifluoroacetylative Aldol Reactions of Alkyl Aldehydes in the Presence of Copper(II)/Chiral Bisoxazoline as a Catalyst

**Scheme 116**
Detrifluoroacetylative Aldol Reactions of Aldehydes with Tertiary Enolates Derived from Fluoro-indolinones

**Scheme 117**
Tandem Detrifluoroacetylative Aldol-Cyclization Reactions

**Scheme 118**
Asymmetric Organocatalytic Aldol Reactions between Fluorinated Silyl Enol Ethers and Isatins

**Scheme 119**
Organocatalytic Asymmetric Aldol Reactions between Fluorinated Enolates of Fluoromalonic Acid Half-Thioesters and Aldehydes

**Scheme 120**
Asymmetric Organocatalytic Michael Reactions between Nitroolefins and Fluorinated β-Ketoesters

**Scheme 121**
Organocatalytic Asymmetric Michael Addition Reactions between α-Fluoroketoesters to Nitroolefins

**Scheme 122**
Bifunctional Thiourea–Tertiary Amine Organocatalytic Michael Reactions of β-Ketoesters

**Scheme 123**
Asymmetric Michael Reactions of α-Fluoro-β-ketoesters with Nitroolefins

**Scheme 124**
Asymmetric Michael Additions of α-Fluorinated-α-sulfonyl Ketones

**Scheme 125**
Asymmetric Michael Additions of α-Fluoro β-Ketophosphonates

**Scheme 126**
Michael Addition Reactions of 2-Fluoro-1,3-diketones with Nitroolefins

**Scheme 127**
Asymmetric Michael Additions of α-Fluorinated Carbonyl Compounds with Nitroolefins

**Scheme 128**
Asymmetric Organocatalytic Michael Addition Reactions of Fluorinated Monothiomalonates with β-Nitrostyrenes

**Scheme 129**
Organocatalytic Asymmetric Michael Reactions of α-Fluoro-β-keto Esters with N-Alkyl Maleimides

**Scheme 130**
Asymmetric Michael Addition Reactions of α-Fluorinated β-Keto Esters with di-*tert*-Butyl Azodicarboxylates

**Scheme 131**
Asymmetric Michael Reactions Using (S)-1-Phenylethylamine as the Chiral Auxiliary

**Scheme 132**
Asymmetric Michael Additions of Fluorinated Enol Silyl Ethers with Isatylidene Malononitriles

**Scheme 133**
Asymmetric Michael Addition Reactions of 2,3-Butadienoates with 3-Fluorooxindoles

**Scheme 134**
Asymmetric Michael Addition Reactions of α,β-Unsaturated Ketones with Malonates

**Scheme 135**
Asymmetric Organocatalytic Michael Reactions Vinyl Sulfones with 3-Fluorinated Oxindoles

**Scheme 136**
Cu-Catalyzed Detrifluoroacetylative Michael Addition Reactions

**Scheme 137**
Palladium-Catalyzed Sonogashira Coupling Reactions of 2-Fluoro-9-oxime Ketolides

**Scheme 138**
Sonogashira Coupling of 2-Fluoro-6-O-Propargyl Diazalides with Two Different Heteroaryl Bromide Reagents

**Scheme 139**
Palladium-Catalyzed Sonogashira Cross-Coupling under Copper-Free Conditions

**Scheme 140**
Palladium-Catalyzed Heck (A) and Sonogashira (B) Coupling Reactions

**Scheme 141**
Palladium-Catalyzed Cyanation: Suzuki (A) and Stille (B) Coupling Reactions

**Scheme 142**
Cross-Coupling Reactions Using Stille, Suzuki, Sonogashira, or Heck Conditions

**Scheme 143**
Kumada Coupling Reactions

**Scheme 144**
Nickel-Catalyzed Suzuki Coupling Reactions

**Scheme 145**
Cross-Coupling Approach for the Formation of α-Alkyl-α-fluoro-β-lactams

**Scheme 146**
Palladium-Catalyzed Suzuki Coupling Reactions

**Scheme 147**
Suzuki Coupling Reactions of Iodo-sulfonamide with 4-Carboxylphenylboronic Acid Using Palladium Black as the Catalyst

**Scheme 148**
Lipase-Catalyzed Transesterification Reactions

**Scheme 149**
Lipase-Catalyzed Hydrolysis Reactions

**Scheme 150**
Biocatalytic Oxidation Reactions

**Scheme 151**
Enzymatic Kinetic Resolution of 1-Acetoxy-2-aryl-2-fluoroalkanes by Hydrolysis (A) and Transesterification (B)

**Scheme 152**
Desymmetrization of Glycol Systems by Biocatalytic Hydrolysis (A) and Esterification (B)

**Scheme 153**
Desymmetrization of Fluorinated Polyfunctionalized Synthons by Lipase Mediated Asymmetric Hydrolysis (A) and Esterification (B)

**Scheme 154**
Kinetic Resolution of Racemic 2-Fluoro-2-phenylcyclopropyl Derivatives by Lipase-Catalyzed Transesterification or Hydrolysis

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Modern Approaches for Asymmetric Construction of Carbon-Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs

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Modern Approaches for Asymmetric Construction of Carbon-Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs

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