Asymmetric Dearomatization Reactions E-Book
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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
The first comprehensive account of the rapidly growing field of asymmetric dearomatization reactions with a focus on catalytic methods. It introduces the concept of dearomatization and describes recent progress in asymmetric reaction procedures with different catalyst systems, such as organocatalysts, transition metal catalysts, and enzymes. Chapters on dearomatizations of electron-deficient aromatic rings, dearomatization reactions via transition metal-catalyzed cross-couplings as well as dearomatization strategies in the synthesis of complex natural products are also included. Written by pioneers in the field, this is a highly valuable source of information not only for professional synthetic chemists in academia and industry but also for all those are interested in asymmetric methodologies and organic synthesis in general.
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Seitenzahl: 547
Veröffentlichungsjahr: 2016
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Table of Contents
Cover
Title Page
Copyright
List of Contributors
Preface
Chapter 1: Introduction
1.1 Why Asymmetric Dearomatization Reactions?
1.2 Discovery of Aromatic Compounds and Dearomatization Reactions
1.3 Development of Dearomatization Reactions
1.4 Asymmetric Dearomatization Reactions
References
Chapter 2: Asymmetric Dearomatization with Chiral Auxiliaries and Reagents
2.1 Introduction
2.2 Chiral σ-Bound Auxiliaries
2.3 Diastereospecific Anionic Cyclizations
2.4 Use of Chiral Reagents
2.5 Chiral π-Complexes
2.6 Conclusion
References
Chapter 3: Organocatalytic Asymmetric Transfer Hydrogenation of (Hetero)Arenes
3.1 Introduction
3.2 Organocatalytic Asymmetric Transfer Hydrogenation of Heteroaromatics
3.3 Organocatalytic Asymmetric Transfer Hydrogenation in Aqueous Solution
3.4 Cascade Reactions
3.5 Cooperative and Relay Catalysis: Combining Brønsted Acid- and Metal-Catalysis
3.6 Summary and Conclusion
References
Chapter 4: Transition-Metal-Catalyzed Asymmetric Hydrogenation of Aromatics
4.1 Introduction
4.2 Catalytic Asymmetric Hydrogenation of Five-Membered Heteroarenes
4.3 Catalytic Asymmetric Hydrogenation of Six-Membered Heteroarenes
4.4 Catalytic Asymmetric Hydrogenation of Carbocyclic Arenes
4.5 Summary and Conclusion
References
Chapter 5: Stepwise Asymmetric Dearomatization of Phenols
5.1 Introduction
5.2 Stepwise Asymmetric Dearomatization of Phenols
5.3 Conclusion and Perspective
References
Chapter 6: Asymmetric Oxidative Dearomatization Reaction
6.1 Introduction
6.2 Diastereoselective Oxidative Dearomatization using Chiral Auxiliaries
6.3 Enantioselective Oxidative Dearomatization using Chiral Reagents or Catalysts
6.4 Conclusions and Perspectives
References
Chapter 7: Asymmetric Dearomatization via Cycloaddition Reaction
7.1 Introduction
7.2 [2 + 1] Cycloaddition
7.3 [3 + 2] Cycloaddition
7.4 [3 + 3] Cycloaddition
7.5 [4 + 2] Cycloaddition
7.6 [4 + 3] Cycloaddition
7.7 Conclusion
References
Chapter 8: Organocatalytic Asymmetric Dearomatization Reactions
8.1 Introduction
8.2 Diels–Alder
8.3 Oxidative Dearomatization
8.4 Cascade Reactions
8.5 Stepwise
8.6 Nucleophilic Dearomatization
8.7 Summary and Conclusion
References
Chapter 9: Dearomatization via Transition-Metal-Catalyzed Allylic Substitution Reactions
9.1 Introduction
9.2 Dearomatization of Indoles and Pyrroles via Transition-Metal-Catalyzed Allylic Substitution Reactions
9.3 Dearomatization of Phenols via Transition-Metal-Catalyzed Allylic Substitution Reactions
9.4 Dearomatization of Phenols and Indoles via Activation of Propargyl Carbonates with Pd Catalyst
9.5 Conclusion
References
Chapter 10: Dearomatization via Transition-Metal-Catalyzed Cross-Coupling Reactions
10.1 Introduction: From Cross-Coupling to Catalytic Dearomatization
10.2 Dearomatization of Phenolic Substrates
10.3 Dearomatization of Nitrogen-Containing Substrates
10.4 Conclusion and Outlook
References
Chapter 11: Dearomatization Reactions of Electron-Deficient Aromatic Rings
11.1 Introduction
11.2 Dearomatization of Activated Pyridines and Other Electron-Deficient Heterocycles
11.3 Summary and Conclusion
References
Chapter 12: Asymmetric Dearomatization Under Enzymatic Conditions
12.1 Introduction
12.2 Dearomatizing Arene
cis
-Dihydroxylation
12.3 Dearomatizing Arene Epoxidation
12.4 Dearomatizing Arene Reduction
12.5 Summary and Conclusion
List of Abbreviations
References
Chapter 13: Total Synthesis of Complex Natural Products via Dearomatization
13.1 Introduction
13.2 Natural Products Synthesis via Oxidative Dearomatization
13.3 Dearomatization via Cycloaddition in Synthesis of Natural Products
13.4 Dearomatization via Nucleophilic Addition in Synthesis of Natural Products
13.5 Reductive Dearomatization in Synthesis of Natural Products
13.6 Dearomatization via Electrophilic Addition in Synthesis of Natural Products
13.7 Dearomatization via Intramolecular Arylation in Natural Products Synthesis
13.8 Summary and Perspective
References
Chapter 14: Miscellaneous Asymmetric Dearomatization Reactions
14.1 Introduction
14.2 Miscellaneous Asymmetric Dearomatization Reactions
14.3 Conclusions and Perspectives
References
Index
End User License Agreement
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Guide
Cover
Table of Contents
Preface
Begin Reading
List of Illustrations
Chapter 1: Introduction
Figure 1.1 The representative arenes and heteroarenes and their discovery years.
Scheme 1.1 Buchner ring expansion reaction (first reported in 1885).
Scheme 1.2 Birch reaction (first reported in 1944).
Scheme 1.3 Reimer–Tiemann reaction.
Scheme 1.4 Dearomatization reactions via photochemical process.
Scheme 1.5 Dearomatization through arene metal complexes.
Scheme 1.6 Alternative strategy for dearomatization processes.
Scheme 1.7 Dearomatization step in the total synthesis of strychnine .
Scheme 1.8 Dearomatization step in the total synthesis of griseofulvin.
Chapter 2: Asymmetric Dearomatization with Chiral Auxiliaries and Reagents
Scheme 2.1 Meyers use of chiral 2-oxazolines in the diastereoselective dearomatization of naphthalenes.
Scheme 2.2 Highly diastereoselective tandem dearomatization.
Scheme 2.3 Meyers syntheses of (+)-phyltetralin (top) and of (−)-podophyllotoxin (bottom).
Scheme 2.4 Silyl as oxygen and nitrogen surrogates in the asymmetric synthesis of fused tetralines.
Scheme 2.5 Clayden's diastereoselective dearomatization of benzenoid aromatics.
Scheme 2.6 Cooperative action of chiral oxazolines and arene π-activation.
Scheme 2.7 Rapid access to highly enantiomerically enriched
cis
-fused alicyclic compounds.
Scheme 2.8 Dearomatization with a valinol-derived chiral imine.
Scheme 2.9 Pridgen's use of chiral oxazolidine auxiliaries.
Scheme 2.10 Meyers' extension to 3-methoxy-2-naphthaldehydes.
Scheme 2.11 Asymmetric dearomatization of a chiral benzaldimine complex.
Scheme 2.12 SAMP- and RAMP-directed dearomatization.
Scheme 2.13 Semmelhack's synthesis of nonracemic cyclohexenones.
Scheme 2.14 Pearson's synthesis of nonracemic cyclohexadienes.
Scheme 2.15 Diastereoselective dearomatization of a chiral arene osmium pentamine complex.
Scheme 2.16 Stereospecific dearomatizing anionic cyclizations.
Scheme 2.17 Mechanism of Clayden's stereospecific dearomatizing anionic cyclization.
Scheme 2.18 Stereospecific lithiation/dearomatizing cyclization: synthesis of α-methyl kainic acid.
Scheme 2.19 Stereospecific lithiation/dearomatizing cyclization of
N
-(α-methylbenzyl)phosphinamides.
Scheme 2.20 Dearomatizing cyclization via enantioselective deprotonation.
Scheme 2.21 Stereospecific rearrangements of enantioenriched enolates of pyrrolidinone products.
Scheme 2.22 Miles approach to (+)-juvabione.
Scheme 2.23 Dearomatizing conjugate addition/electrophile trapping with chiral diether ligands.
Scheme 2.24 Sequential asymmetric nucleophile/electrophile addition to a Cr(CO)
3
phenyloxazoline complex in the presence of a chiral ligand.
Scheme 2.25 Sequential asymmetric nucleophile/electrophile addition to a Cr(CO)
3
benzaldehyde imine complex in the presence of a chiral ligand.
Scheme 2.26 A chiral organolithium approach to the synthesis of (−)-15-acetoxytubipofuran.
Scheme 2.27 (+)-Ptilocaulin synthesis via a planar chiral Cr(arene)(CO)
3
complex.
Scheme 2.28 Diastereoselective propargylation/allylation/Pauson–Khand reaction with a planar chiral anisole complex.
Scheme 2.29 Sequential double nucleophile addition to a planar chiral cationic arene manganese complex.
Scheme 2.30 Asymmetric induction of a cyclohexadienyl Cr(CO)
3
complex.
Scheme 2.31 Asymmetric dearomatization via a chiral at metal rhenium complex.
Chapter 3: Organocatalytic Asymmetric Transfer Hydrogenation of (Hetero)Arenes
Scheme 3.1
Scheme 3.2
Figure 3.1
Scheme 3.3
Scheme 3.4
Scheme 3.5
Scheme 3.6
Scheme 3.7
Scheme 3.8
Figure 3.2
Scheme 3.9
Scheme 3.10
Scheme 3.11
Scheme 3.12
Scheme 3.13
Scheme 3.14
Scheme 3.15
Scheme 3.16
Scheme 3.17
Scheme 3.18
Scheme 3.19
Scheme 3.20
Scheme 3.21
Scheme 3.22
Scheme 3.23
Scheme 3.24
Scheme 3.25
Scheme 3.26
Scheme 3.27
Scheme 3.28
Scheme 3.29
Scheme 3.30
Scheme 3.31
Scheme 3.32
Scheme 3.33
Scheme 3.34
Scheme 3.35
Scheme 3.36
Scheme 3.37
Scheme 3.38
Scheme 3.39
Scheme 3.40
Scheme 3.41
Scheme 3.42
Scheme 3.43
Chapter 4: Transition-Metal-Catalyzed Asymmetric Hydrogenation of Aromatics
Figure 4.1 Resonance energies (kJ mol
−1
) of aromatic compounds from literatures [6].
Scheme 4.1 Three possible pathways for the hydrogenation of N-protected pyrroles.
Figure 4.2 Structures and numbers of the chiral ligands in this chapter.
Scheme 4.2 Pathway of the ruthenium-catalyzed hydrogenation of
N
-Boc-pyrroles.
Scheme 4.3 Ruthenium-catalyzed asymmetric hydrogenation of imidazoles.
Scheme 4.4 Ruthenium-catalyzed asymmetric hydrogenation of oxazoles. TMG = 1,1,3,3-tetramethylquanidine.
Scheme 4.5 Pathway of the palladium-catalyzed hydrogenation of indoles.
Scheme 4.6 Palladium-catalyzed asymmetric hydrogenation of pyrroles.
Scheme 4.7 Pathway of the palladium-catalyzed hydrogenation of pyrroles.
Scheme 4.8 Iridium-catalyzed asymmetric hydrogenation of
N
-iminopyridinium ylides.
Scheme 4.9 Pathway of the iridium-catalyzed asymmetric hydrogenation of pyrimidines. [Yb] = Yb(OTf)
3
. [Ir] =
L16
IrX
2
(X = I or Cl).
Figure 4.3 Tetrahydroquinoline alkaloids synthesized through the iridium-catalyzed asymmetric hydrogenation of quinolines.
Scheme 4.10 Pathway of the iridium-catalyzed asymmetric hydrogenation of quinolines. [Ir] =
L
IrX
2
(
L
= chiral bisphosphine, X = I or Cl).
Scheme 4.11 Pathway of the ruthenium-catalyzed asymmetric hydrogenation of quinolines. [Ru] = [(η
6
-arene)Ru(
L25
)]
+
.
Scheme 4.12 Catalytic asymmetric synthesis of (+)-solifenacin.
Scheme 4.13 Pathway of the ruthenium-catalyzed asymmetric hydrogenation of isoquinolines.
Scheme 4.14 Pathway of the iridium-catalyzed asymmetric hydrogenation of quinoxalines. R'
2
NH =
N
-methyl-4-methoxyaniline. [Ir] = [(
S
)-
L7
]IrCl (
L7
= BINAP).
Figure 4.4 Structure of RUCY
70
(R = 3,5-Me
2
C
6
H
3
).
Scheme 4.15 Asymmetric hydrogenation of quinoxalines through ruthenium–Brønsted acid catalyst system.
Scheme 4.16 Asymmetric hydrogenation of quinoxalines through iron–Brønsted acid catalyst system.
Scheme 4.17 Ruthenium-catalyzed asymmetric hydrogenation of phenanthrolines.
Scheme 4.18 Iridium-catalyzed asymmetric hydrogenation of quinazolines.
Scheme 4.19 Ruthenium-catalyzed asymmetric hydrogenation of indolidines.
Chapter 5: Stepwise Asymmetric Dearomatization of Phenols
Scheme 5.1 Stepwise asymmetric dearomatization of phenols.
Scheme 5.2 Oxidative dearomatization of phenols/asymmetric Diels-Alder reactions.
Scheme 5.3 One-pot oxidative dearomatization of hydroquinone/amine-catalyzed Diels-Alder/Michael reaction.
Scheme 5.4 Intramolecular [4+2] cycloaddition reaction of cyclohexadienone.
Scheme 5.5 Oxidative dearomatization of phenol 8 and asymmetric Heck reaction.
Scheme 5.6 One-pot oxidative deraromatization of aldehyde tethered phenol/amine-catalyzed Michael reaction.
Scheme 5.7 Electrophile-triggered dearomatization/amine-catalyzed Michael reaction.
Scheme 5.8 Oxidative dearomatization of phenol and cinchonine derived urea catalyzed Michael reaction.
Scheme 5.9 Desymmetric Michael reaction by cinchona alkaloid based phase transfer catalyst.
Scheme 5.10 Oxidative dearomatization of phenol and chiral phosphoric acid catalyzed oxo-Michael reaction.
Scheme 5.11 Syntheses of Cleroindicins.
Scheme 5.12 Dearomatization of phenol and cinchonine derived-thiourea catalyzed aza-Michael reaction.
Scheme 5.13 Synthesis of (-)-Mesembrine reported by You.
Scheme 5.14 Intermolecular sulfa-Michael reaction catalyzed by chiral bifunctional thiourea.
Scheme 5.15 Brønsted acid catalyzed enantioselective acetalization/oxo-Michael cascade reaction.
Scheme 5.16 Oxidative dearomatization of phenol and oxo-Michael/Michael cascade reaction.
Scheme 5.17 Oxidative dearomatization of phenol and aza-Michael/Michael cascade reaction.
Scheme 5.18 Oxidative dearomatization of phenol and
N
-heterocyclic carbene catalyzed Stetter reaction.
Scheme 5.19
ipso
-Iodocyclization dearomatization/asymmetric Stetter reaction.
Scheme 5.20 Oxidative dearomatization of phenol and CamphNHC catalyzed Stetter reaction.
Scheme 5.21 Oxidative dearomatization of phenol and phosphino-amide catalyzed Rauhut-Currier reaction.
Scheme 5.22 Rhodium-catalyzed arylation of alkyne/conjugate addition reaction.
Scheme 5.23 Rh/diene-catalyzed arylation of alkyne/conjugate addition reaction.
Scheme 5.24 Cu-catalyzed borylative cyclization of 1,6-enynyl cyclohexadienone.
Scheme 5.25 Pd-catalyzed cyclization of alkyne-tethered 2,5-cyclohexadienone.
Scheme 5.26 Pd-catalyzed diacetoxylation of alkynyl 2,5-cyclohexadienone.
Chapter 6: Asymmetric Oxidative Dearomatization Reaction
Scheme 6.1
Scheme 6.2
Scheme 6.3
Scheme 6.4
Scheme 6.5
Scheme 6.6
Scheme 6.7
Scheme 6.8
Scheme 6.9
Scheme 6.10
Scheme 6.11
Scheme 6.12
Scheme 6.13
Scheme 6.14
Scheme 6.15
Scheme 6.16
Scheme 6.17
Scheme 6.18
Scheme 6.19
Scheme 6.20
Scheme 6.21
Scheme 6.22
Scheme 6.23
Scheme 6.24
Scheme 6.25
Scheme 6.26
Scheme 6.27
Chapter 7: Asymmetric Dearomatization via Cycloaddition Reaction
Scheme 7.1 Early investigations of the asymmetric Büchner reaction.
Scheme 7.2 Asymmetric Büchner reactions in naphthyl and diaryl systems.
Scheme 7.3 Copper-catalyzed asymmetric cyclopropanation of heteroarenes with acceptor-substituted carbenoids.
Scheme 7.4 Rhodium-catalyzed asymmetric cyclopropanation of heteroarenes with donor–acceptor-substituted carbenoids.
Scheme 7.5 Rhodium-catalyzed enantioselective functionalization of indoles.
Scheme 7.6 Rhodium-catalyzed [3 + 2] cycloaddition between indoles and diazodiketoesters.
Scheme 7.7 Asymmetric [3 + 2] cycloaddition of indoles and donor–acceptor cyclopropanes.
Scheme 7.8 Formal enantioselective [3 + 2] cycloadditions of indoles.
Scheme 7.9 Formal enantioselective [3 + 2] cycloadditions between 3-nitroindoles and iminoesters.
Scheme 7.10 Catalytic, asymmetric [3 + 3] dearomatizing cycloaddition reactions.
Scheme 7.11 Organocatalytic asymmetric Diels–Alder reactions of 3-vinyl indoles.
Scheme 7.12 Organocatalytic asymmetric Diels–Alder reactions of 3-vinyl indoles.
Scheme 7.13 Organocatalytic asymmetric Diels–Alder/cyclization cascade reaction.
Scheme 7.14 Organocatalytic asymmetric Diels–Alder/elimination/conjugate addition cascade reaction.
Scheme 7.15 Organocatalytic asymmetric Michael addition/Mannich cyclization cascade reactions.
Scheme 7.16 Organocatalytic asymmetric intermolecular Diels–Alder reactions of heteroaryl enones.
Scheme 7.17 Organocatalytic dearomative Diels–Alder reactions with anthracenylacetaldehydes.
Scheme 7.18 Holmium(III)-catalyzed enantioselective Diels–Alder reactions.
Scheme 7.19 Gold-catalyzed intramolecular formal [4 + 2] cycloaddition reactions.
Scheme 7.20 Asymmetric Diels–Alder cycloaddition reactions of furans and β-trifluoromethylacrylates.
Scheme 7.21 Enantioselective [4 + 2] cycloaddition reactions of indoles and nitrosoalkenes.
Scheme 7.22 Enantioselective [4 + 2] cycloaddition reactions of indoles and α-halogenated hydrazones.
Scheme 7.23 Preliminary studies of asymmetric rhodium-catalyzed [4 + 3] cycloaddition reactions of heteroarenes and vinyldiazoesters.
Scheme 7.24 Asymmetric Rh-catalyzed [4 + 3] cycloaddition reactions of pyrroles and siloxyvinyldiazoacetates.
Scheme 7.25 Organocatalytic [4 + 3] cycloaddition reactions of furans.
Scheme 7.26 Copper-catalyzed asymmetric [4 + 3] cycloaddition reactions of furans.
Chapter 8: Organocatalytic Asymmetric Dearomatization Reactions
Scheme 8.1 Enantioselective Diels–Alder reaction of anthracene.
Scheme 8.2 [4 + 3] asymmetric cycloaddition reaction of furan and silyloxypentadienals.
Scheme 8.3 Total synthesis of englerin A.
Figure 8.1 Bifunctional Brønsted base/Lewis acid organocatalyst.
Scheme 8.4 Organocatalytic asymmetric Diels–Alder reactions of 3-vinylindoles.
Scheme 8.5 Bisthiourea-catalyzed synthesis of carbazolespirooxindole.
Scheme 8.6 Proposed activation of unreactive vinyl heteroarenes.
Scheme 8.7 Product of Diels–Alder dearomatization reaction.
Scheme 8.8 Synthesis of hypervalent iodine(III) catalyst.
Scheme 8.9 Oxidative dearomatization of α-naphthols to
o
-spirolactones.
Scheme 8.10 Enantioselective synthesis of 2-(o-iodoxyphenyl)-oxazolines.
Scheme 8.11 Asymmetric oxidation of dimethylphenols with (
S
)-9 CIPO.
Scheme 8.12 Enantioselective hydroxylative dearomatization of 2-methylnaphthol.
Scheme 8.13 Oxidation of indoles to hydroxyl-indolenines.
Scheme 8.14 Total synthesis of (−)-trigonoliimines A, B, and C.
Scheme 8.15 Dearomatizing redox cross-coupling reaction of ketones with aryl hydrazines.
Scheme 8.16 Stereoselective synthesis of spiro-tetrahydroquinolines.
Scheme 8.17 Epimerization of dearomatization product in the presence of acid.
Scheme 8.18 Formation of chiral organoiodine(III) catalyst and Diels–Alder reaction.
Scheme 8.19 Reaction scope of enantioselective dearomatization and Diels–Alder reactions.
Scheme 8.20 An asymmetric dearomatization amination of naphthols.
Scheme 8.21 Total synthesis of (+)-minfiensine.
Scheme 8.22 Total synthesis of (−)-flustramine B.
Scheme 8.23 Total synthesis of (−)-hyperibone K via alkylative dearomatization–annulation reaction.
Scheme 8.24 [4 + 2] Cycloaddition of 2,3-disubstituted indoles with vinyl methyl ketone.
Scheme 8.25 Asymmetric dearomatization of indoles via a fluorocyclization cascade reaction.
Scheme 8.26 Asymmetric Michael/Mannich cascade dearomatization of 3-indolyl enone..
Scheme 8.27 Enantioselective cascade Michael addition–cyclization reaction of tryptamines.
Scheme 8.28 Enantioselective synthesis of tricyclic derivatives.
Scheme 8.29 (DHQD)
2
PHAL-catalyzed chiral indoline skeletons via chlorocyclization of indoles.
Scheme 8.30 (DHQD)
2
PHAL-catalyzed chlorocyclization of benzamides.
Scheme 8.31 Chiral phosphoric acid-catalyzed synthesis of enantioenriched piperidines.
Scheme 8.32 Proposed mechanism of cascade reaction.
Scheme 8.33 Chiral phosphoric acid-catalyzed 1,4 addition/elimination cascade reaction.
Scheme 8.34 Synthesis of hydrobenzofuranones via desymmetrization of cyclohexadienones.
Scheme 8.35 Enantioselective organocatalytic oxidative dearomatization of
p
-substituted phenols.
Scheme 8.36 Asymmetric oxo-Michael reaction.
Scheme 8.37 Asymmetric synthesis of cleroindicines.
Scheme 8.38 Asymmetric aza-Michael reaction.
Scheme 8.39 Asymmetric Michael reaction.
Scheme 8.40 Catalytic enantioselective assembly of complex molecules.
Scheme 8.41 Oxidative dearomatization of phenols followed by Rauhut–Currier reaction.
Scheme 8.42 Proposed mechanism of the Rauhut–Currier reaction.
Scheme 8.43 Dearomatization/intramolecular Stetter reaction.
Scheme 8.44 Amino indanol-derived triazolium salt-catalyzed intramolecular Stetter reaction.
Scheme 8.45 Fluorinative phenol dearomatization.
Scheme 8.46 Enantioselective fluorination/[4 + 2]-phenol dimerization.
Scheme 8.47 Synthesis of chiral spirocyclopropane compounds via dearomatization of indoles.
Scheme 8.48 Asymmetric organocatalytic annulation reaction.
Scheme 8.49 Enantioselective acyl-Mannich reaction of substituted isoquinolines.
Scheme 8.50 Thiourea-catalyzed Petasis-type reaction of quinolines.
Scheme 8.51 Total synthesis of (−)-debromoflustramine B.
Scheme 8.52 Diarylprolinol silyl ether catalyzed 1, 4-addition of aldehydes to acridiniums.
Scheme 8.53 Asymmetric conjugate addition of indoloazepines to propargyl aldehydes.
Scheme 8.54 Stereoselective dearomatization of indoles via activation of allenamides.
Scheme 8.55 Asymmetric intermolecular oxygenative phenol dearomatization reaction.
Scheme 8.56 Asymmetric dearomatization of electron-deficient
N
-heteroarenes.
Chapter 9: Dearomatization via Transition-Metal-Catalyzed Allylic Substitution Reactions
Scheme 9.1
Scheme 9.2
Scheme 9.3
Scheme 9.4
Scheme 9.5
Scheme 9.6
Scheme 9.7
Scheme 9.8
Scheme 9.9
Scheme 9.10
Scheme 9.11
Scheme 9.12
Scheme 9.13
Scheme 9.14
Scheme 9.15
Scheme 9.16
Scheme 9.17
Scheme 9.18
Scheme 9.19
Scheme 9.20
Scheme 9.21
Scheme 9.22
Scheme 9.23
Scheme 9.24
Scheme 9.25
Scheme 9.26
Chapter 10: Dearomatization via Transition-Metal-Catalyzed Cross-Coupling Reactions
Scheme 10.1 Generalized biaryl cross-coupling reactions.
Scheme 10.2 Generalized catalytic dearomatization leading to increased topological complexity.
Scheme 10.3 General aromatic C–H functionalization.
Scheme 10.4 Palladium-catalyzed aromatic arylation with a tethered aryl halide.
Scheme 10.5 Illustrative palladium-catalyzed dearomatization of a tethered substrate.
Scheme 10.6 Dearomatizing cross-coupling at the
para
-position of phenolic substrates.
Scheme 10.7 Synthesis of a salutaridine derivative (
10
) by catalytic dearomatization.
Scheme 10.8 Proposed catalytic cycle for the dearomatization/cross-coupling of aryl bromides tethered to the
para
-position of phenols.
Scheme 10.9 Competitive intramolecular etherification of an
ortho
-tethered phenol.
Scheme 10.10 Rh-catalyzed spirocyclization at
para
-position of phenolic substrates.
Scheme 10.11 Palladium-catalyzed route to the erythrinane skeleton.
Scheme 10.12 Synthesis of steroidal intermediates by catalytic dearomatization.
Scheme 10.13 Alkyne insertion followed by dearomatization.
Scheme 10.14 Asymmetric alkyne insertion/spirocyclization of phenolic substrates.
Scheme 10.15 Proposed catalytic cycle for alkyne insertion/spirocyclization of phenolic substrates.
Scheme 10.16 General oxidative alkyne insertion/spirocyclization.
Scheme 10.17 Proposed catalytic cycle for ruthenium-catalyzed oxidative alkyne insertion/spirocyclization of 2-arylnaphthol substrates.
Scheme 10.18 Rhodium-catalyzed spirocyclization versus benzoxepine formation.
Scheme 10.19 Double alkyne insertion/spirocyclization of naphthol.
Scheme 10.20 Enantioselective oxidative alkyne insertion/spirocyclization.
Scheme 10.21 Asymmetric dearomatization of naphthalene derivatives.
Scheme 10.22 Derivatization of a representative carbazole.
Scheme 10.23 Formation of highly reactive 4a-alkyl-4aH-carbazoles by palladium-catalyzed dearomatization.
Scheme 10.24 Formation of highly reactive indoloindoles by palladium-catalyzed dearomatization.
Scheme 10.25 Electrophilic dearomatization versus a Heck-like pathway.
Scheme 10.26 Palladium-catalyzed formation of spiroindoles.
Scheme 10.27 Spirocyclization of an indole with a five-membered ring at C-3.
Scheme 10.28 Catalytic spirocyclization at C-2 of pyrroles.
Scheme 10.29 Reductive dearomatization of indole-based substrates.
Chapter 11: Dearomatization Reactions of Electron-Deficient Aromatic Rings
Figure 11.1 Pyridinium salt (
1
).
Scheme 11.1 Total syntheses of verticine (
10
) and septicine (
13
) via reductive dearomatization.
Figure 11.2 (±)-Cylindricine C (
34
).
Scheme 11.2 Comins' total synthesis of (±)-lasubine II (
76
).
Figure 11.3 Piperidine alkaloids synthesized by Yamaguchi and coworkers.
Scheme 11.3 Comins' enantioselective total synthesis of (+)-elaeokanine A and C.
Figure 11.4 Piperidine alkaloids synthesized by Comins and coworkers.
Figure 11.5 Emetine (
117
).
Scheme 11.4 Total synthesis of quinolizidine 207I.
Figure 11.6 Piperidine alkaloids synthesized by Charette and coworkers.
Chapter 12: Asymmetric Dearomatization Under Enzymatic Conditions
Scheme 12.1
Scheme 12.2
Scheme 12.3
Scheme 12.6
Scheme 12.4
Scheme 12.5
Scheme 12.7
Scheme 12.8
Scheme 12.9
Scheme 12.10
Scheme 12.11
Scheme 12.12
Scheme 12.13
Scheme 12.14
Scheme 12.15
Scheme 12.16
Scheme 12.17
Scheme 12.18
Scheme 12.19
Scheme 12.20
Scheme 12.21
Scheme 12.22
Scheme 12.23
Scheme 12.24
Scheme 12.25
Figure 12.1 Two views of the X-ray structure of the metal–organic framework having the formula [Zn
2
(fumarate)
2
268
]
n
.
Scheme 12.26
Scheme 12.27
Scheme 12.28
Scheme 12.29
Scheme 12.30
Scheme 12.31
Chapter 13: Total Synthesis of Complex Natural Products via Dearomatization
Scheme 13.1 Hudlicky's synthesis of
ent
-hydromorphone.
Scheme 13.2 Li and Yang's total synthesis of maoecrystal V using an oxidative dearomatization of phenol/intramolecular Diels–Alder reaction process.
Scheme 13.3 Zakarian's total synthesis of (−)-maoecrystal V employing oxidative dearomatization of phenol.
Scheme 13.4 Fukuyama's total synthesis of lepenine via a cascade oxidative dearomatization/intermolecular Diels–Alder reaction process.
Scheme 13.5 Njardarson's total synthesis of vinigrol via rearrangement of bicyclo[2.2.2]octane.
Scheme 13.6 Trauner's biomimetic total synthesis of epicolactone via an oxidative dearomatization/heterodimerization process.
Scheme 13.7 Thomas' total synthesis of (−)-maoecrystal V.
Scheme 13.8 Oxidative cycloisomerization of phenol enables collective synthesis of cortistatin A, J, K, L.
Scheme 13.9 George's total synthesis of merochlorin A via oxidative dearomatization/[5 + 2] cycloaddition.
Scheme 13.10 Ma's total synthesis of (−)-Communesin F and A, B relying on intramolecular oxidative coupling of indole.
Scheme 13.11 Synthesis of (−)-vincorine and aspidophylline via type II intramolecular oxidative coupling.
Scheme 13.12 Synthesis of (+)-methyl
N
-decarbomethoxychanofruticosinate via type III intramolecular oxidative coupling.
Scheme 13.13 Reisman's synthesis of (+)-salvileucalin B by intramolecular cyclopropanation of benzene.
Scheme 13.14 MacMillan's total synthesis of (−)-strychnine and (−)-akuammicine.
Scheme 13.15 Divergent total synthesis of kopsia and aspidosperma alkaloids by taking advantage of an intramolecular [4 + 2]/[3 + 2] cycloaddition tandem reaction.
Scheme 13.16 Intramolecular [4 + 3] cycloaddition of furan en route to (−)-cortistatin J.
Scheme 13.17 Herzon's total synthesis of (−)-batzelladine based on dearomatization of pyrrole.
Scheme 13.18 Martin's total synthesis of citrinadin A and B via nucleophilic dearomatization of pyridium.
Scheme 13.19 Reduction of pyridium led to expedient synthesis of (±)-corynoxine and B.
Scheme 13.20 Construction of core structure of chartelline C by intramolecular alkylation of indole.
Scheme 13.21 Porco's enantioselective synthesis of (−)-clusianone by dearomatization of phenol via intermolecular alkylation reaction.
Scheme 13.22 Randrade's total synthesis of (−)-melotenine A by means of alkylative dearomatization of indole.
Scheme 13.23 You's synthesis of erythrina alkaloids demethoxyerytratidinone via Pd-catalyzed intramolecular dearomatization of dearomatization of
para
-amino phenol.
Scheme 13.24 Tang's asymmetric synthesis of (−)-totaradiol by enantioselective palladium-catalyzed dearomatization.
Chapter 14: Miscellaneous Asymmetric Dearomatization Reactions
Scheme 14.1 Enantioselective dearomatization cascade of indoles employing chiral Au catalysts by Bandini and coworkers.
Scheme 14.2 An unexpected dearomatization of benzene ring in Au(I)-catalyzed asymmetric cyclopropanation of internal alkynes by Davies and coworkers.
Scheme 14.3 Asymmetric dearomatization of 1-aminonaphthalene derivatives via Au catalysis by Tanaka and coworkers.
Scheme 14.4 Au-catalyzed asymmetric intermolecular [2 + 2]-cycloaddition between indoles and allenamides by Bandini and coworkers.
Scheme 14.5 Au-catalyzed asymmetric dearomative Rautenstrauch rearrangement of indoles by Toste and coworkers.
Scheme 14.6 Stereoselective alkylative dearomatization of phenols and naphthols in the presence of a chiral base by Fráter and coworkers.
Scheme 14.7 Asymmetric alkylative dearomatization of indoles with chiral Ni catalyst by Wang and coworkers.
Scheme 14.8 Intermolecular asymmetric dearomatization of indoles via Cu-catalyzed propargylic substitution by You and coworkers.
Scheme 14.9 Mg-catalyzed intermolecular asymmetric dearomatization of β-naphthols with
meso
-aziridines by Wang and coworkers.
Scheme 14.10 Mg-catalyzed intermolecular cascade asymmetric dearomatization of indoles with
meso
-aziridines by Wang and coworkers.
Scheme 14.11 Asymmetric dearomatization of indoles via Pd-catalyzed cycloadditions .of vinyl cyclopropanes and
in situ
formed unsaturated imines by Liu and coworkers.
Scheme 14.12 Asymmetric dearomatization of naphthols and phenol via scandium-catalyzed electrophilic amination by Luan and coworkers.
Scheme 14.13 Asymmetric dearomatization of indoles via Mg-catalyzed cascade reactions by Feng and coworkers.
Scheme 14.14 Organocatalytic asymmetric cascade dearomatization of 3-nitroindoles by Yuan and coworkers.
List of Tables
Chapter 4: Transition-Metal-Catalyzed Asymmetric Hydrogenation of Aromatics
Table 4.1 Iridium-catalyzed asymmetric hydrogenation of
41a
with various chiral ligands
Chapter 11: Dearomatization Reactions of Electron-Deficient Aromatic Rings
Table 11.1 Regioselective reduction of alkoxycarbonyl pyridinium salt (
49
)
Table 11.2 1,4-Reduction of acyl pyridinium salts (
151
)
Chapter 12: Asymmetric Dearomatization Under Enzymatic Conditions
Table 12.1 Arene dioxygenase strains used to produce
cis
-dihydrodiols for synthesis, and reported producing organisms
Table 12.2 Reported monocyclic substituted benzene substrates for
cis
-dihydroxylation
Table 12.3 Reported biaryl substrates for
cis
-dihydroxylation
Table 12.4 Reported substituted naphthalene substrates for
cis
-dihydroxylation
Table 12.5 Reported monocyclic substituted benzene substrates for
cis
-dihydroxylation
Table 12.6 Reported mono- and bicyclic heterocycle substrates for
cis
-dihydroxylation
Table 12.7 Reported bicyclic carbocyclic substrates (other than naphthalenes) for
cis
-dihydroxylation
Table 12.8 Reported tricyclic substrates for
cis
-dihydroxylation
Edited by Shu-Li You
Asymmetric Dearomatization Reactions
Editor
Prof. Shu-Li You
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
State Key Laboratory of Organometallic Chemistry
345 Lingling Lu
Shanghai 200032
China
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List of Contributors
Jon C. Antilla
University of South Florida
Department of Chemistry
4202 East Fowler Avenue
Tampa, FL 33620
USA
Robin B. Bedford
University of Bristol
School of Chemistry
Cantock's Close
Bristol BS8 1TS
UK
Qing Gu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu
Shanghai 200032
China
Yasumasa Hamada
Chiba University
Graduate School of Pharmaceutical Sciences
1-8-1 Inohana
Chuo-ku
Chiba 260-8675
Japan
Kazuaki Ishihara
Nagoya University
Graduate School of Engineering
Furo-cho
Chikusa
Nagoya 464-8603
Japan
Madeleine E. Kieffer
California Institute of Technology
Division of Chemistry and
Chemical Engineering
1200 E. California Blvd.
MC 101-20
Pasadena, CA 91125
USA
E. Peter Kündig
University of Geneva
Department of Organic Chemistry
30 Quai Ernest Ansermet
1211 Geneva 4
Switzerland
Ryoichi Kuwano
Kyushu University
Faculty of Science
Department of Chemistry
744 Motooka
Nishi-ku
Fukuoka 819-0395
Japan
Simon E. Lewis
University of Bath
Department of Chemistry
Bath BA2 7AY
UK
Susana S. Lopez
University of South Florida
Department of Chemistry
4202 East Fowler Avenue
Tampa, FL 33620
USA
Dawei Ma
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
State Key
Laboratory of Bioorganic & Natural Products Chemistry
345 Lingling Lu
Shanghai 200032
China
Gaëlle Mingat
RWTH Aachen University
Department of Chemistry
Institute of Organic Chemistry
Landoltweg 1
52074 Aachen
Germany
Tetsuhiro Nemoto
Chiba University
Graduate School of Pharmaceutical Sciences
1-8-1 Inohana
Chuo-ku
Chiba 260-8675
Japan
Sri K. Nimmagadda
University of South Florida
Department of Chemistry
4202 East Fowler Avenue
Tampa, FL 33620
USA
Sarah E. Reisman
California Institute of Technology
Division of Chemistry and Chemical Engineering
1200 E. California Blvd.
MC 101-20
Pasadena, CA 91125
USA
Magnus Rueping
King Abdullah University of Science and Technology (KAUST)
KAUST Catalysis Center (KCC)
Thuwal 23955-6900
Saudi Arabia
Yoshiji Takemoto
Kyoto University
Graduate School of Pharmaceutical Sciences
Department of Organic Chemistry
Yoshida
Sakyo-ku
Kyoto 606-8501
Japan
Chihiro Tsukano
Kyoto University
Graduate School of Pharmaceutical Sciences
Department of Organic Chemistry
Yoshida
Sakyo-ku
Kyoto 606-8501
Japan
Muhammet Uyanik
Nagoya University
Graduate School of Engineering
Furo-cho
Chikusa
Nagoya 464-8603
Japan
Haoxuan Wang
California Institute of Technology
Division of Chemistry and Chemical Engineering
1200 E. California Blvd.
MC 101-20
Pasadena, CA 91125
USA
Weiqing Xie
Northwest A&F University
Shaanxi Key Laboratory of Natural Products & Chemical Biology
College of Science
Department of Chemistry
22 Xinong Road
Yangling 712100
Shaanxi
China
Shu-Li You
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
State Key Laboratory of Organometallic Chemistry
345 Lingling Lu
Shanghai 200032
China
Wei Zhang
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
State Key Laboratory of Organometallic Chemistry
345 Lingling Lu
Shanghai 200032
China
Preface
Aromatic compounds are widely distributed in nature. They serve as extremely important synthetic materials in both academia and industry. Significant efforts have been devoted to the transformations of aromatic compounds, which now mainly focus on the introduction of substituents onto aromatic rings via nucleophilic, electrophilic, radical, and metal-mediated substitution reactions. In addition, dearomatization reactions, another important type of transformations of aromatic compounds, have recently witnessed significant development due to their unique potentials to convert relatively simple molecules into much more complicated structures. The existed rings of aromatic compounds provide carbocyclic or heterocyclic frameworks in a very straightforward manner during the dearomatization reaction. Moreover, the advantage of building quaternary carbon centers makes the dearomatization reactions straightforward protocols to construct spiro or bridged compounds via intramolecular dearomatization reactions. As attractive strategies, dearomatization reactions have a long history in the synthesis of natural products, pharmaceuticals, and other functional molecules. The earliest dearomatization reaction could be dated back to 1885 when the Buchner ring expansion reaction was discovered. Although many dearomatization protocols have been either explored as new methodologies or applied as the key steps during the synthesis of functional molecules, they have been rather limited within racemic studies for a long time. Asymmetric dearomatization reactions, especially catalytic asymmetric dearomatization (CADA) reactions, are relatively rare. The vast majority of dearomatization reactions constructing chiral molecules rely on the chiral substrate-controlled strategy and the utilization of chiral auxiliaries or reagents. The high energy barrier encountered during the process of dearomatization generally requires harsh reaction conditions, which undoubtedly pose challenges for the control of regioselectivity and stereoselectivity. As powerful tools in synthetic chemistry, dearomatization reactions have recently received their renaissance with the emerging of newly designed dearomative protocols and efficient stereoselective control of these processes. Delightfully, asymmetric dearomatization reactions, especially those by catalytic methods, have gained rapid progress in the past few years.
Numerous elegant books have been contributed to the topics on aromatic compounds. However, few of them describe dearomatization reactions, and none of them introduces the achievement in the area of asymmetric dearomatization reactions. In contrast, several comprehensive reviews have introduced either the application of dearomatization strategies in the total synthesis of natural products or the development of various CADA methodologies for the construction of complex chiral molecules. Given the dramatic progress and increasing interest in the area of asymmetric dearomatization reactions, a comprehensive book detailing the state-of-the-art in this area should be timely and necessary. This book is aiming to provide readers the historical respect, recent development, and future perspectives in the field of asymmetric dearomatization reactions.
There are 14 chapters in this book. In Chapter 1, an introduction on asymmetric dearomatization reactions has been provided, with an emphasis on the historical retrospect of the reaction development of aromatic compounds and early contributions toward the dearomatization reactions. The following chapter is focused on the asymmetric dearomatization reactions of substituted benzenes and naphthalenes with chiral auxiliaries and chiral reagents by Peter Kündig, one of the pioneering contributors in the area of diastereoselective dearomatization reactions. Chapter 3 by Gaëlle Mingat and Magnus Rueping covers the development of asymmetric transfer hydrogenation reactions of aromatic compounds using organocatalysts as well as the relay catalysis combining metal and chiral organocatalysts. This chapter is followed by transition-metal-catalyzed asymmetric hydrogenation of aromatic compounds in Chapter 4 by Ryoichi Kuwano. In Chapter 5, by summarizing the asymmetric reactions of dearomatized intermediates, Qing Gu introduces a stepwise strategy combining dearomatization reaction (achiral in general) and asymmetric catalysis with the dearomatized intermediates. In Chapter 6, the asymmetric oxidative dearomatization reactions of electron-rich arenes are introduced by Muhammet Uyanik and Kazuaki Ishihara, major contributors in this area. The following chapter by Sarah E. Reisman thoroughly summarizes the asymmetric dearomatization via cycloaddition reactions including the Diels–Alder reaction, [4 + 3] or [3 + 2] cycloaddition reaction, cyclopropanation reaction, and rearrangement reaction. In Chapter 8, Susana S. Lopez, Sri Krishna Nimmagadda, and Jon C. Antilla discuss the organocatalytic asymmetric dearomatization reactions enabled by iminium catalysis, iminium–enamine catalysis cascade, hydrogen-bonding catalysis, and so on. In Chapter 9, dearomatization reactions of various arenes via transition-metal-catalyzed allylic substitutions have been introduced by Tetsuhiro Nemoto and Yasumasa Hamada, who have contributed significantly in this area. The dearomatization via transition-metal-catalyzed cross-coupling reactions is introduced by Robin B. Bedford. Although the existed examples are limited at this stage, this is a promising area as the fast pace of the development of cross-coupling reactions together with the availability of vast potentially suitable chiral ligands. Next, Chihiro Tsukano and Yoshiji Takemoto provide a summary on the dearomatization reactions of electron-deficient aromatic rings such as pyridines, quinolines, and isoquinolines. These reactions generally proceed by N-acylation or alkylation and then a subsequent nucleophilic attack to break the aromaticity of rings. As an important branch of dearomatization reactions, the asymmetric dearomatization reactions under enzymatic conditions are introduced by Simon E. Lewis in Chapter 12. Chapter 13 is devoted to the dearomatization strategies in the synthesis of complex natural products by Weiqing Xie and Dawei Ma, who have made significant contributions in this area. Finally, miscellaneous asymmetric dearomatization reactions, which cannot be covered in the previous chapters, are introduced in Chapter 14.
It is a great fortune for me to work with the above-mentioned fantastic groups of prominent scientists who have made this book project very successful one. All the invited authors are the leading experts in the field and have made significant contributions in the area covered in their chapters. I would also like to express my great gratitude to Professor Wei Zhang (SIOC) who has assisted me greatly in the preparation of the whole book. Drs Anne Brennführer and Stefanie Volk from Wiley-VCH are highly appreciated for their kind assistance and great patience. I hope all the 14 chapters from these leading experts will promote the development of this fast growing field and benefit the professional synthetic and medicinal chemists who are interested in dearomatization reactions.
Our works appeared in this book are supported by the National Basic Research Program of China (973 Program 2015CB856600) and the National Natural Science Foundation of China (21332009).
Shu-Li You
Shanghai, October 2015
Chapter 1Introduction
Wei Zhang and Shu-Li You
1.1 Why Asymmetric Dearomatization Reactions?
Arenes and heteroarenes are widely distributed in nature, and some simple arenes are produced multimillion metric tons annually. They are recognized as fundamental synthetic materials in both academia and industry. The chemistry involving aromatic compounds is thus rich and of prime importance. Tremendous efforts have been devoted to various substitution reactions of aromatic compounds, and many name reactions such as Friedel–Crafts reaction and Sandmeyer reaction have become elementary contents of organic chemistry textbooks. These fully developed processes are undoubtedly essential tools for the total synthesis of natural products. Moreover, they provide chemists with the access to a huge library of aromatic compounds, which are extremely important in the discovery of pharmaceuticals, materials, and other functional molecules. In contrast, dearomatization reactions, another important branch of transformations of aromatic compounds, have been undervalued for a long time despite their potentials to convert simple molecules into complex structures. The specific feature of building quaternary carbon centers and interesting structures makes them straightforward protocols to construct spiro or bridged compounds. In spite of a long history of application in the total synthesis of natural products, only recently the systematic methodology exploration of dearomatization reactions has received huge interest. In this area, asymmetric dearomatization reactions are of particular importance due to the great demand of highly efficient strategies toward the construction of complex chiral molecules.
1.2 Discovery of Aromatic Compounds and Dearomatization Reactions
Although aromatic compounds exist widely in nature, it was only in 1825 that benzene was first isolated by Michael Faraday. Several years later, Eilhard Mitscherlich also obtained this substance and identified its molecular formula as C6H6. He gave it the name “benzin.” The highly unsaturated structure of benzene remained controversial for a long time, and various proposed structures were full of imagination. In 1865, Friedrich A. Kekulé postulated that benzene contains a six-membered ring of carbon atoms with alternating single and double bonds. Today, the famous Kekulé formula is still widely used. In 1931, by quantum mechanical calculations, Erich Hückel explained the unique stability of benzene different from other unsaturated hydrocarbons, namely, aromaticity. He differentiated the bonding electrons as π electrons and σ electrons, and the Hückel “4n + 2” rule becomes a basis for estimation of aromatic compounds. Around the same time with or after the discovery of benzene, several other aromatic compounds have been discovered, and today, most of them have become extremely important industrial chemical starting materials (Figure 1.1).
Figure 1.1 The representative arenes and heteroarenes and their discovery years.
Great demand on diverse arenes and heteroarenes has stimulated the related synthetic chemistry. Besides some very simple ones coming from petrochemicals (e.g., benzene, toluene, xylene, phenol), the vast majority of aromatic compounds need to be synthesized. Fundamental electrophilic aromatic substitution reactions including nitration, sulfonation, halogenation, Friedel–Crafts alkylation, and Friedel–Crafts acylation are frequently used synthetic tools, and the nucleophilic aromatic substitution reactions via diazonium ions also provide reliable routes to complicated aryl compounds. Moreover, recent development of transition-metal-catalyzed cross-coupling reactions between aryl halides (or equivalent) and organometallic compounds has enriched the transformations of aromatic compounds, and the direct use of aryl compounds through C–H functionalization is an alternative straightforward method. Meanwhile, the chemistry of heteroarene synthesis has also gained significant progress.
Compared with the chemistry to synthesize aromatic compounds, dearomatization reactions also have a long history. In 1885, the Buchner ring expansion of benzene with ethyl diazoacetate was reported to provide cycloheptatriene under thermal or photochemical conditions, and this methodology was further improved by the introduction of transition metal catalysts (Scheme 1.1) [1, 2]. The Birch reduction was first reported in 1944 to partially hydrogenate benzene to 1,4-cyclohexadiene (Scheme 1.2) [3]. The Reimer–Tiemann reaction discovered in 1876 was originally used for the ortho-formylation of phenols, and an interesting phenomenon was observed later that a dearomative by-product was generated when para-methyl phenol reacted with dichlorocarbene (Scheme 1.3) [4].
Scheme 1.1 Buchner ring expansion reaction (first reported in 1885).
Scheme 1.2 Birch reaction (first reported in 1944).
Scheme 1.3 Reimer–Tiemann reaction.
1.3 Development of Dearomatization Reactions
The history of dearomatization reactions can be dated back to the nineteenth century. Early studies on dearomatization reactions include photochemical processes, transition-metal-mediated processes, hydrogenation processes, enzyme-catalyzed processes, and so on.
In 1957, Blair and Bryce-Smith discovered that fulvene was generated by subjecting pure benzene under the irradiation conditions (Scheme 1.4, eq 1) [5]. Although the conversion of this dearomatization reaction was low, it was believed to be the “first example of the direct isomerization of an aromatic to a nonaromatic hydrocarbon” [5]. Soon after, many related studies emerged, such as the irradiation of substituted benzenes (Scheme 1.4, eq 2) [6]. Meanwhile, the photochemical reaction between benzene and alkene was also investigated (Scheme 1.4, eq 3) [7]. However, this type of dearomatization reaction was not developed into an applicable level due to the multiple reaction pathways to deliver complicated mixtures of dearomatized products.
Scheme 1.4 Dearomatization reactions via photochemical process.
Early studies of transition metal–arene complexes in the 1950s were emphasized on their preparation, as exemplified by the synthesis of C6H5Cr(CO)3 by Fischer in 1957 [8]. Activation of the aromatic ligands by transition metal centers toward nucleophiles was then discovered and explored [9]. Among the versatile transformations of the nucleophilic addition intermediates (Scheme 1.5, A), protonation and other electrophilic trapping generally deliver dearomatized products [10]. However, this type of dearomatization reaction is mediated by stoichiometric amount of transition metal complexes, and recent rapid growth is focused on transition-metal-catalyzed dearomatization processes. Chapters 4, 6, 7, and 9–11 elucidate the detailed development of transition-metal-catalyzed asymmetric dearomatization reactions.
Scheme 1.5 Dearomatization through arene metal complexes.
Dearomatization reactions of aromatic compounds by hydrogenation process (Scheme 1.2) and enzymatic process also have a long history. Chapters 3 and 4 introduce organocatalytic and transition-metal-catalyzed asymmetric dearomatization reactions by hydrogenation process, respectively. Chapter 12 is devoted to the development of enzymatic dearomatization reactions including the details on both history of discovery and current status.
Meanwhile, some interesting approaches taking advantage of the steric effect provide alternative strategies for dearomatization. For instance, Yamamoto and coworkers designed the bulky Lewis acid ATPH that enabled the addition of tBuLi to phenyl methyl ketone occurring at the para position of the phenyl ring, delivering dearomatized product in excellent yield (Scheme 1.6) [11].
Scheme 1.6 Alternative strategy for dearomatization processes.
As attractive strategies, dearomatization reactions are frequently applied to the total synthesis of natural products, providing more efficient synthetic routes, in many cases biomimetic synthesis as a result of inspiration by nature. In 1954, Woodward and coworkers first reported an elegant total synthesis of strychnine, in which the Pictet–Spengler-type dearomatization of indole core was employed as one key step to construct the complex polycyclic framework (Scheme 1.7) [12]. In 1960, Day and coworkers first completed the total synthesis of racemic griseofulvin, in which the dearomatization step was inspired by its biosynthetic pathway (Scheme 1.8) [13]. Numerous fabulous total syntheses were then reported with the application of dearomatization strategy, and Chapter 13 introduces this topic in detail.
Scheme 1.7 Dearomatization step in the total synthesis of strychnine .
Scheme 1.8 Dearomatization step in the total synthesis of griseofulvin.
Despite the wide utilization of dearomatization reactions in total synthesis of natural products, the systematic studies to develop practical dearomatization methodologies are still rare. Many of the known dearomatization methods are limited with scope and selectivity, and difficult to be practically used. For instance, the photochemical processes of arenes generally deliver a complicated mixture of dearomative products due to the poor selectivity (Scheme 1.4). The transition-metal-mediated processes require stoichiometric metal sources and the subsequent removal of metal is also needed to make it less appealing (Scheme 1.5). Various hydrogenation processes could only generate simple skeletons from the corresponding aromatic compounds, as the hydrogenation reaction generally forms C(X)–H bonds only (Scheme 1.2). For the enzyme-catalyzed processes, only specific substrates could be used. As said, the great potentials of dearomatization reactions, especially in an enantioselective manner, have been much more underdeveloped. On the other hand, dearomatization reactions are such powerful tools to provide various ring systems including heterocyclic skeletons directly from relatively simple planar aromatic rings. The advantage to build quaternary carbon centers makes them extremely straightforward routes to construct spiro or bridged compounds via intramolecular dearomatization reactions. Due to these features and great demand on chiral molecules, dearomatization reactions, particularly asymmetric ones, have received the renaissance recently.
1.4 Asymmetric Dearomatization Reactions
We have briefly introduced the history and early development of dearomatization reactions, and have shown their application in the total synthesis of natural products. Although quite a number of dearomatization protocols have been reported either in the methodology development or during the synthesis of functional molecules, the vast majority of them are limited within racemic studies. The enantioselective versions of dearomatization reactions are rather rare, especially those employing catalytic methods. The known asymmetric dearomatization reactions rely heavily on the chiral substrate–controlled strategy. The challenging of high energy barrier encountered during the process of dearomatization generally requires harsh reaction conditions, which pose formidable challenges in the control of regioselectivity and stereoselectivity. Delightfully, both asymmetric dearomatization reactions by chiral reagents and catalytic asymmetric dearomatization (CADA) reactions have received great attention and gained fruitful progress in the past few years. With the worldwide increased efforts in this field, we believe that every single type of asymmetric reaction would eventually become compatible with dearomatization process. In addition, more and more types of aromatic compounds can undergo the CADA reactions sooner or later.
There are many books focusing on the topic of aromatic compounds, but few of them describe dearomatization reactions. Given the dramatic progress in the field of asymmetric dearomatization reactions, this book is aiming to provide readers very detailed information about recent developments of asymmetric dearomatization reactions, especially the CADA approaches.
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Chapter 2Asymmetric Dearomatization with Chiral Auxiliaries and Reagents
E. Peter Kündig
2.1 Introduction
This chapter reviews dearomatization reactions of benzene as well as substituted and fused analogs with chiral auxiliaries and chiral reagents. Excluded are dearomatizations via oxidative and via cycloaddition reactions, as well as dearomatizations of heteroaromatics and of electron-deficient arenes as these are discussed in Chapters 6, 7, and 11, respectively. The chapter is organized according to the source of chiral information leading to enantiomerically or diastereomerically enriched alicyclic products.
2.2 Chiral σ-Bound Auxiliaries
2.2.1 Oxazolines
In the course of the pioneering work of Meyers and coworkers in developing oxazolines as auxiliaries [1], the directing power of this heterocycle was probed in the ortho-lithiation/ortho-substitution of phenyl oxazolines and ortho-chloro and methoxy analogs, respectively [1b]. Extending these investigations to 1-naphthyloxazolines, it was found that RLi reagents react not by ortho-lithiation but by conjugate addition. Trapping of the intermediate with electrophiles afforded 1,1,2-trisubstituted dihydronaphthalenes. In 1984, Barner and Meyers reported the first highly diastereoselective dearomatization of a chiral 1-naphthyloxazoline [2]. It was shown that the nature of the group at the stereogenic center adjacent to O had little influence on the course of the reaction–diastereoselectivity being controlled by the stereogenic center adjacent to the oxazoline-N. Chelation of the incoming organolithium reagent was initially thought to be essential in the control of facial selectivity. Subsequently, it was found that (S)-valinol- and (S)-t-leucinol-derived oxazolines led to even higher diastereoselectivities (Scheme 2.1). Coordination of the incoming organolithium compound to the Lewis-basic chiral oxazoline nitrogen directs addition to the naphthalene β-face. Methyl iodide then enters from the more accessible α-face. This trans-addition across a naphthalene double bond occurs with very high diastereoselectivity, producing two new stereogenic centers, one of them being tertiary. Removal of the auxiliary by reduction followed by hydrogenolysis afforded the corresponding enantioenriched dihydronaphthylaldehydes [3, 4]. Oxazolines in the naphthalene 2-position direct the nucleophile to C(1) [2, 5].
Scheme 2.1 Meyers use of chiral 2-oxazolines in the diastereoselective dearomatization of naphthalenes.
The scope of the reaction with 1- and 2-naphthyloxazolines includes the reactive RLi nucleophiles with R = Me, Et, n-Bu, s-Bu, t-Bu, vinyl, 2-propenyl, 1-cyclopentenyl, pent-4-en-1-yl, 4-methylpent-3-en-1-yl, and Ph. Electrophiles used successfully were H+ (i-PrOH), MeI, ClCO2Me, and (PhS)2 [5, 6]. An annelleted tricyclic product is accessible via reaction with 1-lithio-4-chlorobutane (Scheme 2.2) [7].
Scheme 2.2 Highly diastereoselective tandem dearomatization.
The asymmetric tandem addition sequence was successfully applied to the synthesis of a large number of natural products and analogs, principally by the Meyers group [1b, c] but also by others [8, 9]. Two examples, the aryllignan (+)-phyltetralin [5] and the aryltetralin lactone (−)-podophyllotoxin are shown in Scheme 2.3 [10].
Scheme 2.3 Meyers syntheses of (+)-phyltetralin (top) and of (−)-podophyllotoxin (bottom).
Oxygen nucleophiles do not undergo addition reactions to naphthyloxazolines but secondary lithiumamides [11] and dimethylphenylsilyllithium [12] do. The latter proved particularly useful as it adds with complete diastereoselectivity. Silicon can then serve as surrogate for oxygen and, via reductive amination of intermediate ketones, for nitrogen. This provided access to a range of highly enantioenriched fused tetralin systems containing a quaternary center (Scheme 2.4) [13].
Scheme 2.4 Silyl as oxygen and nitrogen surrogates in the asymmetric synthesis of fused tetralines.
Oxazolines are readily accessible, stable, and powerful directing groups in lithiations, nucleophilic aromatic substitutions, and conjugate additions without competing 1,2 addition. They are easily converted into other functional groups, and they are therefore a powerful synthetic tool. Dearomatizations with chiral oxazolines were long limited to naphthalenes. Despite this limitation, oxazolines are the most popular and arguably the most efficient chiral auxiliaries used to bring about the dearomatization of an arene.
Clayden reported the first dearomatizations of phenyloxazolines providing single diastereoisomers. To date, successful nucleophiles are limited to sec-RLi compounds (i-Pr, s-Bu), electrophiles used are MeI and H+, and the reaction medium requires addition of 6–10 equiv. of DMPU (Scheme 2.5) [14].
Scheme 2.5 Clayden's diastereoselective dearomatization of benzenoid aromatics.
A larger scope is on hand when combining the chiral oxazoline methodology with a temporary activation of the benzenoid aromatic by π-complexation to the Cr(CO)3 fragment (Scheme 2.6). Valinol- and t-Bu-glycinol-derived chiral oxazolines are excellent directing groups as had already been established by Meyers et al. [1c, d]. π-Complexation of an arene by a suitable Cr(CO)3 precursor [Cr(CO)6, Cr(CO)3L3 (L = CH3CN, NH3 or L3 = naphthalene) can be carried out with high yields and leads to air-stable, crystalline arene complexes with the arene activated for nucleophilic addition [15, 16]. Nucleophilic additions to Cr(arene)(CO)3 complexes afford anionic cyclohexadienyl complexes that can be isolated or, more convenient for organic transformations, be converted in situ into cyclohexadienes via reaction with electrophiles. Stabilized nucleophiles such as α-nitrile carbanions and enolates add reversibly and only trapping with strong acid is faster than the reverse reaction leading to the starting arene complex. However, alkyl- and aryl-lithium reagents as well as sulfur-stabilized carbanions react irreversibly and can be trapped by acid as well as a range of carbon electrophiles. Electrophile addition occurs at the Cr center and is followed by either direct reductive elimination/decomplexation to give A or CO insertion/reductive elimination/decomplexation to give B. When carrying out the reaction under a CO atmosphere, Cr(CO)6 can be recycled if desired. Propargyl halides always provide selectively A, whereas alkyl halides lead selectively to B. Allyl and benzyl halides give either A or B depending on the substitution pattern in the starting arene (Scheme 2.6). This matches the inclination of metal-σ-C fragments to undergo carbonylation versus direct reductive elimination. Enolate formation from B and alkylation/allylation leads to C. The initially formed diene complex is labile and decomplexation is taking place readily when a ligand L is present (CO, RCN, PR3, P(OR)3). Nucleophiles R′Li include R′ = alkyl, vinyl, allyl, aryl, propargyl, CH2SAr, dithianes [16]. Complexation also lifts the equivalence of the two ortho-positions. Product yields in the range of 50–90 % are achieved and diastereomeric ratios are typically around 95 : 5 with the valinol-derived oxazoline and >97 : 3 with the t-Bu-glycinol-derived oxazoline [16, 17]. Li+/n-Bu4N+
