Spiro Compounds E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
SPIRO COMPOUNDS A comprehensive treatment of the latest research in, and applications of, spiro compounds Spiro Compounds: Synthesis and Applications combines discussions of the latest advances in spiro compound research with the most cutting-edge, real-world applications of that knowledge. This book provides in-depth coverage of the history, significance, properties, synthetic methods, and applications of spiro compounds. As interest in spiro compounds grows due to their unique conformational features and their structural implications on biological systems, Spiro Compounds delivers fulsome treatments of advances in spiro compound synthesis (including stereoselective synthesis) methodologies. With a special focus on the mechanisms of the reactions that lead to the synthesis of spiro compounds, chapters in the book cover topics such as: * The history, significance, and unique properties of spiro compounds * The most important methodologies for their synthesis * The applications of spiro compounds in organic chemistry, biology, drug discovery * The most important syntheses of natural products bearing a spiro ring Perfect for academic and industrial chemists, this comprehensive discussion of spirocycles is an indispensable resource for those practicing in the field.
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Seitenzahl: 577
Veröffentlichungsjahr: 2022
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Table of Contents
Cover
Title Page
Copyright Page
List of Contributors
Preface
1 Spiro Compounds: A Brief History
1.1 Notes on IUPAC Rules for Spiro Compounds
References
2 Selected Applications of Spirocycles in Medicinal Chemistry
2.1 Introduction
2.2 General Features
2.3 Property Optimization in Bioactive Compounds
2.4 Four‐Membered Rings: Synthesis, Applications, and New Design Principles
2.5 Further Examples
2.6 Conclusions
References
3 Recent Advances in the Asymmetric Synthesis of Spiro Compounds Through Cycloadditions
3.1 Introduction
3.2 Organometallic Methodologies
3.3 Organocatalytic Methodologies
References
4 Design and Synthesis of Spirocycles
via
Olefin Metathesis
4.1 Introduction
4.2 Formation of Aza‐spirocycles
4.3 Formation of Oxa‐spirocycles
4.4 Miscellaneous Examples
References
5 Spirooxindoles: Synthesis
via
Organocatalytic Processes
5.1 Introduction
5.2 Enamine and Iminium Catalysis
5.3 Chiral Nucleophilic Catalysis with Tertiary Phosphines or Amines
5.4 Chiral
N
‐Heterocyclic Carbene Catalysis
5.5 Chiral Tertiary Amine‐H‐Bond Donor Bifunctional Catalysis
5.6 Chiral Hydrogen‐Bonding Catalysis
5.7 Chiral Phosphoric Acid Catalysis
5.8 Chiral Phase‐Transfer Catalysis
5.9 Chiral Organoiodine Catalysis
5.10 Conclusion
References
6 Spirooxindole Synthesis by Organometallic Processes
6.1 Introduction
6.2 Direct Construction of the Spirooxindole Unit by Cyclization Methodologies
6.3 Two‐component Annulation/Cycloaddition Methodologies
6.4 Miscellaneous Methods
6.5 Conclusions
Acknowledgements
References
7 Enantioselective Synthesis of Spiro Heterocycles
7.1 Introduction
7.2 Enantioselective Synthesis of Spiro Heterocycle with One Nitrogen Atom
7.3 Enantioselective Formation of Spirocycles Containing Heterocycle with One Oxygen Atom
7.4 Enantioselective Formation of Sulfur‐containing Spirocycles
7.5 Enantioselective Formation of Spirocycles Containing Heterocycle with More Than One Heteroatom
7.6 Enantioselective Formation of Other Spiro Heterocyclic Systems
7.7 Enantioselective Formation of Bispirocycles
7.8 Conclusion
Acknowledgements
References
8 Enantioselective Synthesis of all Carbon Spiro Compounds
8.1 Enantioselective Synthesis of All‐Carbon Spiro Compounds Based on Alkylation Methods
8.2 Enantioselective Synthesis of All‐Carbon Spirocycles by Metal‐catalyzed Methods
8.3 Enantioselective Synthesis of All‐Carbon Spirocycles by Cycloaddition Strategies
8.4 Enantioselective Synthesis of All‐Carbon Spirocycles by Radical Strategies
8.5 Enantioselective Synthesis of All‐Carbon Spirocycles by Cascade Reactions
8.6 Enantioselective Synthesis of All‐Carbon Spirocycles by Rearrangement Strategies
8.7 Conclusions
References
9 Transition‐Metal‐Catalyzed Dearomative Spiroannulation Reactions
9.1 Introduction: Discovery of Aromatic Compounds
9.2 Development of Dearomatization Reactions
9.3 Development of Dearomative Spiroannulation Reactions
9.4 Dearomative Spiroannulations of Phenols
9.5 Dearomative Spiroannulation of Indoles
9.6 Dearomative Spiroannulation of Aromatic Heterocyclic Compounds
9.7 Dearomative of Other Aromatic Compounds
9.8 Conclusion
References
10 Carbocyclic Spiro Compounds Occupying Higher Dimensions: Benzoannelated [5.5.5.5]Fenestranes and Beyond
10.1 Introduction
10.2 Selected Synthesis Strategies
10.3 Conclusions
Acknowledgements
References
11 The Synthesis of Natural Products Containing Spirocycles
11.1 Porco’s Synthesis of (+)‐Calafianin [2]
11.2 Hayashi’s Total Synthesis of Pseurotin A[6]
11.3 Trost’s Synthesis of (−)‐Ushikulide A [12]
11.4 Castle’s and Herzon’s Syntheses of (−)Acutumine
11.5 Overman’s and Carreira’s Synthesis of Spirotryprostatin B
11.6 Conclusion
References
Index
End User License Agreement
List of Tables
Chapter 2
Table 2.1 Selected examples of FDA‐ approved drugs containing spirocyclic m...
Table 2.2 Physicochemical and biochemical properties of selected oxetanes, ...
Table 2.3 Comparison of the properties of spirocyclic oxetanes with their m...
List of Illustrations
Chapter 1
Figure 1.1 Growing interest in spiro compounds in chemical literature.
Figure 1.2 Dye sensitizer 9,9‐spirobifluorene.
Figure 1.3 Donor–acceptor spiro compounds and colors displayed by them.
Figure 1.4 Examples of naturally occurring compounds containing the spiro mo...
Figure 1.5 Spiro functionality in nicotinic receptor antagonists.
Figure 1.6 Examples of marketed spiro compound drugs.
Figure 1.7 ACC inhibitors of pharmaceutical interest.
Figure 1.8 Commercial spirocyclic insecticide/acaricide products.
Figure 1.9 Recently patented spiro compound of agrochemical interest.
Figure 1.10 Example of numbering of spirocyclic compounds.
Figure 1.11 Example of naming chiral spiro compounds.
Chapter 2
Figure 2.1 X‐ray crystal structure (pdb 2gfx
12
) of Platensimycin (
2
, sticks ...
Scheme 2.1 Key enyne cycloisomerization step in Nicolaou’s total synthesis o...
Figure 2.2 Schematic comparison of substituted biaryl and spiro[3,4]octane s...
Figure 2.3 Examples of saturated spirocyclic ring systems frequently encount...
Figure 2.4 Examples of lead optimization employing spirocycles.
Scheme 2.2 Summary of common strategies for the synthesis of common four‐mem...
Figure 2.5 Comparison between carbonyl, gem‐dimethyl, and oxetane groups, hi...
Figure 2.6 (a) Spiro‐oxetane as a morpholine bioisostere. (b) comparison...
Figure 2.7 Replacement of morpholine by 2‐oxa‐6‐azaspiro[3.3]heptane in BTK ...
Figure 2.8 Top: Structure of thalidomide
34
and its oxetano analogue
35
. Bot...
Figure 2.9 Representative examples of spirocyclic bioactive lead molecules....
Figure 2.10 Additional examples further illustrating the breadth of ring typ...
Figure 2.11 Representative examples of (a) multifunctional spiro building bl...
Chapter 3
Scheme 3.1 Scandium‐catalyzed enantioselective carboannulation between alkyl...
Scheme 3.2 Copper‐catalyzed asymmetric [3+2] cycloaddition between alkyliden...
Scheme 3.3 Copper‐catalyzed asymmetric construction of dispiropyrrolidine sk...
Scheme 3.4 Magnesium‐catalyzed asymmetric [3+2] cycloaddition between methyl...
Scheme 3.5 Rhodium‐catalyzed enantioselective [3+2] annulation to form spiro...
Scheme 3.6 Palladium‐catalyzed stereoselective 1,6‐conjugate addition/annula...
Scheme 3.7 Copper‐catalyzed asymmetric synthesis of spirocyclic β‐lactams th...
Scheme 3.8 Bimetallic relay catalysis for the enantioselective synthesis of ...
Scheme 3.9 Regio‐ and enantioselective aza‐Diels–Alder reactions of 3‐vinyli...
Scheme 3.10 Ni‐catalyzed asymmetric Diels–Alder/[3,3]sigmatropic rearrangeme...
Scheme 3.11 Scandium‐catalyzed asymmetric cycloaddition between ketenes and ...
Scheme 3.12 Rhodium‐catalyzed [2+2+2] cycloadditions between alkynes and cyc...
Scheme 3.13 Synergistic palladium/chiral secondary amine‐catalyzed formal ri...
Scheme 3.14 Conjugate umpolung of β,β‐disubstituted enals and isatins promot...
Scheme 3.15 Bifunctional squaramide‐catalyzed synthesis of enantioenriched s...
Scheme 3.16 Chiral phosphoric acid‐catalyzed enantioselective 1,3‐dipolar cy...
Scheme 3.17 Stereoselective synthesis of spiroindene via trienamine catalysi...
Scheme 3.18 Organocatalytic [4+2] addition reactions
via
tetraenamine interm...
Scheme 3.19 Chiral H‐bond donor‐catalyzed asymmetric Tamura [4+2]‐cycloaddit...
Scheme 3.20 Enantioselective Diels–Alder cyclization for the synthesis of ca...
Scheme 3.21 NHC‐catalyzed [4+3] annulation of oxotryptamines with enals to a...
Scheme 3.22 Organocatalytic enamine‐activation of cyclopropanes for highly s...
Scheme 3.23 Chiral primary amine‐catalyzed regiodivergent asymmetric cycload...
Scheme 3.24 Organocatalytic asymmetric tandem Nazarov cyclization/semipinaco...
Scheme 3.25 Chiral phosphoric acid‐catalyzed asymmetric synthesis of SPINOL ...
Chapter 4
Figure 4.1 Natural and non‐natural products containing a spirocenter.
Figure 4.2 List of ruthenium catalysts used in metathesis.
Scheme 4.1 Synthesis of spirocyclic pyrazine.
Scheme 4.2 Synthesis of chiral spiro‐connected cyclopentene.
Scheme 4.3 Synthesis of spiro[4.5]–decanes.
Scheme 4.4 Synthesis of spiro‐lactam.
Scheme 4.5 Synthesis of spiro naphthalenone.
Scheme 4.6 Synthesis of spiroketal
34
.
Scheme 4.7 Synthesis of spirocycles.
Scheme 4.8 Efficient route to spiroannulated butanolide.
Scheme 4.9 Synthesis of a spirocyclic amine
53
.
Scheme 4.10 Synthesis of spiro carba‐sugar using RCM.
Scheme 4.11 Synthesis of novel spiro‐cyclohexene.
Scheme 4.12 Synthesis of spiro‐heterocycle.
Scheme 4.13 Synthesis of spiro‐center
via
an Ireland ester CR.
Scheme 4.14 Synthesis of spirocyclic compounds through RCM.
Scheme 4.15 Synthesis of spiro‐benzosultams.
Scheme 4.16 Synthesis of spiro‐azetidine
91
.
Scheme 4.17 Synthesis of spiroannulated 3‐benzofuranone.
Scheme 4.18 Asymmetric synthesis of spiroether.
Scheme 4.19 Synthesis of spiro‐Meldrum’s acid derivative.
Scheme 4.20 Synthesis of spiro‐lactone.
Scheme 4.21 Synthesis of spirocycles starting with active methylene derivati...
Scheme 4.22 Synthesis of spiro‐barbituric acid derivative.
Scheme 4.23 Synthesis of spiroindolin‐2‐one derivatives.
Scheme 4.24 Synthesis of spiro dibenzo[
a
,
d
]cycloheptene.
Scheme 4.25 Synthesis of spiro‐carbohydrate
130
.
Scheme 4.26 Synthesis of sesquiterpenoid acorenone.
Scheme 4.27 Synthesis of (+)‐spirocurcasone.
Scheme 4.28 Synthesis of spiroindenes.
Scheme 4.29 Synthesis of spiro‐bicyclo[2.2.2]octane
156
.
Scheme 4.30 Synthesis of oxaspirocyclic compound.
Scheme 4.31 Synthesis of spiro‐fused compounds
165
.
Scheme 4.32 Synthesis of
C
‐spiro‐glycoconjugate
168
.
Scheme 4.33 Synthesis of spiro‐indole derivatives.
Scheme 4.34 Synthesis of bis‐spirocycles.
Scheme 4.35 Synthesis of bis‐spiro tetralone.
Scheme 4.36 Synthesis of spiro‐bicyclic compound
189
.
Scheme 4.37 Synthesis of spirodione.
Scheme 4.38 Synthesis of spiro‐polycyclic compounds.
Scheme 4.39 Synthesis of spiro‐fluorene
204
.
Scheme 4.40 Synthesis of spiro‐truxene
208
.
Scheme 4.41 Efficient route to (+)‐perhydrohistrionicotoxin.
Scheme 4.42 Synthesis of spirocyclic compound
218
.
Scheme 4.43 Synthesis of spiropiperidine‐3,3‐oxindole.
Scheme 4.44 Construction of spiro‐mononitrogen heterocycle.
Scheme 4.45 Synthesis of natural product nankakurine.
Scheme 4.46 Synthesis of oxa‐aza spiro‐carbohydrate.
Scheme 4.47 Synthesis of carbohydrate derivative
243
.
Scheme 4.48 Synthesis of spiro‐dihydropyran.
Scheme 4.49 Synthesis of carbohydrate‐derived spiroacetal
252
.
Scheme 4.50 Synthesis of spirocyclic 3,6‐dihydro‐2
H
‐pyran
250
.
Scheme 4.51 Synthesis of spirocyclic oxindole
261
.
Scheme 4.52 Synthesis of spirocyclic ether
267
.
Scheme 4.53 Synthesis of spiroannulated carbanucleoside.
Scheme 4.54 Synthesis of spirocyclic‐2‐azetidinone.
Scheme 4.55 Synthesis of spirocyclic butenolide
280
.
Scheme 4.56 Synthesis of spiro‐2‐oxazolidinone.
Scheme 4.57 Synthetic approach to (+)‐laurencin.
Scheme 4.58 Synthesis of spiro oxacycles.
Scheme 4.59 Synthesis of ABC ring of nortriterpenoid.
Scheme 4.60 Synthesis of spiro‐
C
‐aryl glycoside.
Scheme 4.61 Synthesis of cyclic phosphazene.
Scheme 4.62 Synthesis of spiroketal
318
.
Scheme 4.63 Synthesis of anomeric spiroketal
325
.
Scheme 4.64 Synthesis of spiroketal
331
.
Scheme 4.65 RRM approach to azepine derivatives.
Scheme 4.66 Synthesis of oxa‐spirocycle.
Scheme 4.67 RCM of bisallyloxy cyclobutenone to oxa‐spirocycle.
Scheme 4.68 Synthesis of spiro‐cage derivative.
Scheme 4.69 Synthesis of bis‐oxaspirocycle.
Scheme 4.70 Synthesis of oxaspirocycles.
Scheme 4.71 Synthesis of spiro indene.
Scheme 4.72 Synthesis of spirocycle containing silicon at spioro junction....
Chapter 5
Figure 5.1 Selected natural products and bioactive molecules containing a sp...
Figure 5.2 Asymmetric synthesis of various spirooxindoles via organocatalyti...
Scheme 5.1 Double Michael cascade reaction enabled by enamine/iminium sequen...
Scheme 5.2 Asymmetric double Michael reactions involving isatylidene malonon...
Scheme 5.3 Spirocyclobutaneoxindole synthesis by a stereoselective [2+2] cyc...
Scheme 5.4 Three‐component reaction by enamine/iminium/enamine sequential ca...
Scheme 5.5 Multicomponent domino reactions by quadruple iminium/enamine/imin...
Scheme 5.6 Stereoselective Diels–Alder reaction enabled by trienamine cataly...
Scheme 5.7 Asymmetric hetero‐Diels–Alder reaction of α,β‐unsaturated ketones...
Scheme 5.8 Asymmetric Michael/Michael/aldol reaction of 3‐unsubsituted oxind...
Scheme 5.9 Asymmetric vinylogous cascade reaction of 2,4‐dienals with 3‐hydr...
Scheme 5.10 Michael/cyclization sequence of 3‐chlorooxindoles to spirocyclop...
Scheme 5.11. Synthesis of spirocyclopentaneoxindoles with 3‐alkyloxindoles
4
...
Scheme 5.12 Stereoselective Michael/cyclization sequence of 3‐propargyl oxin...
Scheme 5.13 Desymmetric intramolecular aldol condensation of 3,3′‐diacetonyl...
Scheme 5.14 Chiral phosphine‐catalyzed [3+2] cycloaddition of allene and met...
Scheme 5.15 [4+2] Annulation of isatylidene malononitriles and α‐substituted...
Scheme 5.16 Asymmetric [3+2] cycloaddition of oxindole‐derived olefins with ...
Scheme 5.17 Phosphine‐catalyzed [3+2] annulation of isatin‐derived MBH carbo...
Scheme 5.18 Chiral tertiary amines‐catalyzed [3+2] annulation of isatin‐deri...
Scheme 5.19 [4+2]‐Cycloaddition of α,β‐unsaturated acyl chlorides by nucleop...
Scheme 5.20 Asymmetric [3+2]‐cycloaddition of brominated MBH adducts and ket...
Scheme 5.21 Allylic alkylation–cyclization of 3‐hydroxyoxindoles with MBH ca...
Scheme 5.22 Chiral NHC‐catalyzed asymmetric annulation involving isatins.
Scheme 5.23 Spirooxindole‐δ‐lactones synthesis by NHC‐catalyzed formal [4+2]...
Scheme 5.24 Spirooxindole lactams synthesis by NHC‐catalyzed annulation with...
Scheme 5.25 Chiral NHC‐catalyzed annulation involving isatin‐derived enals....
Scheme 5.26 Stereoselective annulation of isatin‐derived enals with α,β‐unsa...
Scheme 5.27 Chiral NHC‐catalyzed asymmetric Michael/aldol/lactonization casc...
Scheme 5.28. NHC‐catalyzed annulation with 3‐aminooxindoles or 3‐hydroxyoxin...
Scheme 5.29. Tertiary amine‐H bond donor‐catalyzed asymmetric annulation inv...
Scheme 5.30. Asymmetric intramolecular [1,5]‐electrocyclization of functiona...
Scheme 5.31 Asymmetric annulation of isatin imine by tertiary amine‐H bondin...
Scheme 5.32 Asymmetric annulation of methyleneindolinones via double Michael...
Scheme 5.33 Asymmetric annulation of methyleneindolinones via Michael‐initia...
Scheme 5.34 Asymmetric annulation using isatylidene malononitriles as C2 syn...
Scheme 5.35 Asymmetric annulation using isatylidene malononitriles as C3 syn...
Scheme 5.36 Asymmetric annulation involving isatin‐derived β,γ‐unsaturated α...
Scheme 5.37 Asymmetric annulation involving C3 alkyl ester‐substituted oxind...
Scheme 5.38 Asymmetric annulation involving 3‐allyloxindoles.
Scheme 5.39 Asymmetric annulation involving 3‐isothiocyanato oxindoles.
Scheme 5.40 Asymmetric [4+1] cyclization of 3‐chlorooxindoles with
o
‐QMs....
Scheme 5.41 Asymmetric cyclopropanation of 3‐unsubstituted oxindoles with α‐...
Scheme 5.42 One‐pot Michael/Michael/aldol tandem reaction involving 3‐unsubs...
Scheme 5.43 Asymmetric desymmetrization of spiro cyclohexadienone oxindoles....
Scheme 5.44 Enantioselective Diels–Alder reaction of methyleneindolinones wi...
Scheme 5.45 Asymmetric [3+2] cycloaddition of methyleneindolinone and nitron...
Scheme 5.46 Asymmetric MCR of diazooxindoles, nitrosoarenes, and nitroalkene...
Scheme 5.47 Enantioselective cyclization reaction of isatin and 2‐aminobenza...
Scheme 5.48 Asymmetric three‐component 1,3‐dipolar cycloaddition by phosphor...
Scheme 5.49 Asymmetric three‐component 1,3‐dipolar cycloaddition.
Scheme 5.50 Asymmetric three‐component 1,3‐dipolar cycloaddition.
Scheme 5.51 Chiral phosphoric acid‐catalyzed cycloaddition with methyleneind...
Scheme 5.52 [3+2] Cycloaddition of isatin‐derived 3‐indolylmethanols and 2‐v...
Scheme 5.53 Chiral phosphoric acid‐catalyzed kinetic resolution of racemic s...
Scheme 5.54 Asymmetric double Michael cascade reaction of 3‐alkenyloxindoles...
Scheme 5.55 Enantioselective 1,3‐dipolar cycloaddition of 3‐alkenyloxindoles...
Scheme 5.56 Intramolecular
C
‐acylation of 3‐substituted oxindoles
320
by PTC...
Scheme 5.57 Enantioselective direct intramolecular C(sp
2
)–H/C(sp
3
)–H oxidati...
Scheme 5.58 Chiral organoiodine‐catalyzed oxidative dearomatization of pheno...
Chapter 6
Figure 6.1 Some representative examples of biologically active natural and s...
Scheme 6.1 Overman’s approach to (−)‐spirotryprostratin B.
Scheme 6.2 Catalytic asymmetric intramolecular Heck synthesis of a spirocycl...
Scheme 6.3 Takemoto’s tandem cycloamidation of 2‐(butadienyl)phenylcarbamoyl...
Scheme 6.4 Takemoto’s racemic synthesis of spirooxindole alkaloids elacomine...
Scheme 6.5 Spirocyclization of α‐substituted tosylamines and proposed mechan...
Scheme 6.6 Reductive Heck cyclization in Carreira’s synthesis of gelsemoxoni...
Scheme 6.7 Pd(0)‐catalyzed spirooxindole synthesis from isatin‐derived Morit...
Scheme 6.8 Enantioselective synthesis of 2‐oxindole spirofused lactones by a...
Scheme 6.9 Enantioselective synthesis of 2‐oxindole spirofused lactams by a ...
Scheme 6.10 Charette’s synthesis of spiro 3,3′‐cyclopropyloxindoles by silve...
Scheme 6.11 Oxidation of
N
‐aryl‐2‐oxocycloalkane‐1‐carboxamides with Mn(OAc)
Scheme 6.12 Aluminum‐promoted cyclization in Trost’s asymmetric synthesis of...
Scheme 6.13 Córdova’s asymmetric synthesis of polysubstituted spirocyclic ox...
Scheme 6.14 Proposed catalytic cycle for Córdova’s asymmetric synthesis of p...
Scheme 6.15 Iron(II)‐catalyzed asymmetric intramolecular aminohydroxylation ...
Scheme 6.16 Rhodium(II)‐catalyzed cyclopropanation of 3‐diazo‐2‐oxindole
38
....
Scheme 6.17 Rhodium(II)‐catalyzed cyclopropanation of 3‐diazo‐2‐oxindole
38
....
Scheme 6.18 Arai’s rhodium(II)‐catalyzed asymmetric cyclopropanation of 3‐di...
Scheme 6.19 Zhou’s mercury(II)‐catalyzed asymmetric cyclopropanation of 3‐di...
Scheme 6.20 Zhou’s gold(I)‐catalyzed asymmetric cyclopropanation of 3‐diazo‐...
Scheme 6.21 Feng’s magnesium(II)‐catalyzed asymmetric cyclopropanation of al...
Scheme 6.22 Feng’s scandium(III)‐catalyzed asymmetric cycloaddition of disub...
Scheme 6.23 Carreira’s MgI
2
‐catalyzed ring expansion of spiro(cyclopropane‐1...
Scheme 6.24 Proposed mechanism for the MgI
2
‐catalyzed reaction of spiro(cycl...
Scheme 6.25 Ring expansion of a spiro(cyclopropane‐1,3′‐oxindole) in the syn...
Scheme 6.26 Ring expansion of a spiro(cyclopropane‐1,3′‐oxindole) in Carreir...
Scheme 6.27 Ring expansion of a spiro(cyclopropane‐1,3′‐oxindole) in Carreir...
Scheme 6.28 Carboxylative Pd‐catalyzed TMM cycloaddition to an isopropyliden...
Scheme 6.29 Enantioselective carboxylative Pd‐catalyzed TMM cycloaddition to...
Scheme 6.30 Enantioselective Cu(I)‐catalyzed 1,3‐dipolar cycloaddition of az...
Figure 6.2 Proposed structure of the tetrahedral complex formed by coordinat...
Scheme 6.31 Enantioselective Ag(I)‐catalyzed 1,3‐dipolar cycloaddition of az...
Scheme 6.32 Franz’s titanium(IV)‐catalyzed stereoselective synthesis of spir...
Scheme 6.33 Franz’s scandium(III)‐catalyzed asymmetric [3+2] annulation of a...
Scheme 6.34 Franz’s enantioselective allylsilane annulation and C–Si oxidati...
Scheme 6.35 Franz’s titanium(IV)‐catalyzed diastereoselective synthesis of s...
Scheme 6.36 Franz’s scandium(III)‐catalyzed enantioselective synthesis of a ...
Scheme 6.37 Franz’s scandium(III)‐catalyzed enantioselective [3+2] carboannu...
Scheme 6.38 Franz’s scandium(III)‐catalyzed enantioselective [3+2] carboannu...
Scheme 6.39 Feng’s magnesium(II)‐catalyzed enantioselective [3+2] cycloaddit...
Scheme 6.40 Lu’s palladium(0)‐catalyzed enantioselective [3+2] cycloaddition...
Scheme 6.41 Proposed mechanism for the palladium(0)‐catalyzed enantioselecti...
Scheme 6.42 Mei’s palladium(0)‐catalyzed enantioselective [3+2] cycloadditio...
Scheme 6.43 Du’s rhodium(0)‐catalyzed enantioselective [3+2] cycloaddition o...
Scheme 6.44 Asymmetric one‐pot sequential organo‐ and gold(I)‐catalyzed Mann...
Scheme 6.45 Trost’s dinuclear zinc‐catalyzed asymmetric spiroannulation reac...
Scheme 6.46 Kanai–Matsunaga’s strontium‐catalyzed asymmetric synthesis of 3‐...
Scheme 6.47 Chen‐Xiao’s zinc(II)‐catalyzed enantioselective cascade Michael ...
Scheme 6.48 Yan‐Zhou’s nickel(II)‐catalyzed diastereo‐ and enantioselective ...
Scheme 6.49 Ashfeld’s rhodium‐catalyzed formal [4+1] cycloaddition route to ...
Scheme 6.50 Ashfeld’s rhodium‐catalyzed formal [4+1] cycloaddition syntheses...
Scheme 6.51 Lin‐Feng’s zinc‐catalyzed asymmetric Diels–Alder reaction of a B...
Scheme 6.52 Kumar’s dysprosium‐catalyzed asymmetric hetero‐Diels–Alder react...
Scheme 6.53 Kumar’s magnesium‐catalyzed asymmetric hetero‐Diels–Alder reacti...
Scheme 6.54 Tanaka’s enantioselective synthesis of spirocyclic benzopyranone...
Scheme 6.55 Shintani–Hayashi’s stereoselective synthesis of spirocyclic oxin...
Scheme 6.56 Proposed catalytic cycle for the palladium‐catalyzed decarboxyla...
Scheme 6.57 Liu–Feng’s nickel‐catalyzed asymmetric aza‐Diels–Alder reaction ...
Scheme 6.58 Liebeskind’s enantioselective synthesis of spirooxindoles based ...
Scheme 6.59 Feng’s cobalt‐catalyzed asymmetric Darzens reaction of phenacyl ...
Scheme 6.60 Wang’s zinc‐catalyzed enantioselective desymmetrization/cyclizat...
Scheme 6.61 Shanmugam’s copper(I)‐catalyzed one‐pot, three‐component diaster...
Scheme 6.62 A plausible mechanism of the copper(I)‐catalyzed three‐component...
Chapter 7
Scheme 7.1 Synthesis of spiropyrrolidines by Mikami.
Scheme 7.2 Asymmetric construction of a dispiropyrrolidine by Yu and Deng....
Scheme 7.3 Silver phosphate‐catalyzed asymmetric intramolecular dearomatizat...
Scheme 7.4 Enantioselective [4+1] spiroannulation catalyzed by Rh.
Scheme 7.5 Chiral phosphine‐catalyzed synthesis of spiropyrrolidines reporte...
Scheme 7.6 Organocatalyzed asymmetric formal [3+2] cycloaddition of isocyano...
Scheme 7.7 The combination photoredox and primary amine catalysis used at th...
Scheme 7.8 Enantioselective synthesis of spiroindolenines reported by You....
Scheme 7.9 Enantioselective construction of spiroindolenines catalyzed by Pd...
Scheme 7.10 Enantioselective synthesis of spiroindolines by intramolecular d...
Scheme 7.11 Enantioselective organocatalyzed cascade reactions to spiroindol...
Scheme 7.12 Application of chiral phosphoric acid for the preparation of spi...
Scheme 7.13 Oxidative
N
‐heterocyclic carbene catalyzed dearomatization of in...
Scheme 7.14 Enantioselective access to gem‐difluorinated spiroindolines.
Scheme 7.15 Enantioselective synthesis of spiroindolines via cascade reactio...
Scheme 7.16 Enantioselective synthesis of spirobilactams reported by Cai....
Scheme 7.17 Enantio‐ and diastereoselective Pd‐catalyzed carbocyclization ca...
Scheme 7.18 Pd‐catalyzed asymmetric intramolecular arylative dearomatization...
Scheme 7.19 Iridium‐catalyzed intramolecular asymmetric allylic dearomatizat...
Scheme 7.20 Enantioselective organocatalyzed formal [3+3] spiroannulation re...
Scheme 7.21 NHC‐catalyzed enantioselective synthesis of spiropiperidinones r...
Scheme 7.22 Asymmetric dearomative formal [4+2] cycloadditions published by ...
Scheme 7.23 Enantioselective ene‐type spirocyclization developed by Mikami....
Scheme 7.24 Enantioselective 1,6‐conjugate addition/annulation of para‐quino...
Scheme 7.25 Enantioselective synthesis of spirodihydrofuranes developed by S...
Scheme 7.26 The enantioselective synthesis of spirolactones reported by Gade...
Scheme 7.27 Asymmetric copper‐catalyzed preparation of spirotetrahydropyrane...
Scheme 7.28 Enantioselective dearomatization of phenols using chiral hyperva...
Scheme 7.29 Chiral hypervalent organoiodine‐catalyzed enantioselective oxida...
Scheme 7.30 Enantioselective oxidative dearomatization of arenols using chir...
Scheme 7.31 Asymmetric synthesis of spiro‐2(
3H
)‐furanones
via
phase‐transfer...
Scheme 7.32 Enantioselective construction of spirocyclic benzofuranone cyclo...
Scheme 7.33 Asymmetric tandem synthesis of spirocyclic (2H)‐dihydrobenzofura...
Scheme 7.34 The enantioselective synthesis of spirobenzofuranones reported b...
Scheme 7.35 The catalytic asymmetric one‐pot [3+2] cyclization/semipinacol r...
Scheme 7.36 Reaction mechanism.
Scheme 7.37 Organocatalytic synthesis of spirobenzofuranones via cascade Mic...
Scheme 7.38 Two approaches to chiral spirocyclic benzofuranones by using ami...
Scheme 7.39 The enantioselective approaches leading to spirocyclic compounds...
Scheme 7.40 Organocatalytic asymmetric double Michael addition and Michael/a...
Scheme 7.41 Asymmetric construction of spirocyclopentenebenzofuranone core s...
Scheme 7.42 Application of trienamine catalysis for the construction of spir...
Scheme 7.43 Asymmetric synthesis of pyrrolidine‐ and tetrahydrothiophene‐fus...
Scheme 7.44 Catalytic asymmetric brominative or chlorinative dearomatization...
Scheme 7.45 The synthesis of spiro‐heterocycles by the NHC‐catalyzed annulat...
Scheme 7.46 The enantioselective formal [2+1+3] annulation forming spirocycl...
Scheme 7.47 Enantioselective ring expansion of vinyl cyclopropanes combining...
Scheme 7.48 Catalytic enantioselective synthesis of spirocycles 13.
Scheme 7.49 Enantioselective synthesis of spirocyclic benzopyranones by rhod...
Scheme 7.50 Enantioselective organometallic approach to chiral spirobenzopyr...
Scheme 7.51 Enantioselective synthesis of a‐spirocyclopropyl lactones.
Scheme 7.52 Asymmetric synthesis of 3,4‐dihydrocoumarin motif in spirocycle ...
Scheme 7.53 Synthesis of highly substituted chiral spirodihydrocoumarins....
Scheme 7.54 Organocatalytic tandem Morita–Baylis–Hillman–Michael reaction fo...
Scheme 7.55 A chiral squaramide‐catalyzed approach constructing spiro‐3,4‐di...
Scheme 7.56 Construction of spiro‐bridged polyheterocyclic compounds.
Scheme 7.57 The synthesis of spirocycle compounds via enantioselective organ...
Scheme 7.58 Catalytic desymmetrizing dehydrogenation of 4‐substituted cycloh...
Scheme 7.59 Enantioselective synthesis of spirocyclic compounds containing b...
Scheme 7.60 Asymmetric synthesis of spirocyclic tetrahydrothiophene‐chromano...
Scheme 7.61 Enantioselective synthesis of spiro compounds containing tetrahy...
Scheme 7.62 Enantioselective construction of polyfunctionalized spiroannulat...
Scheme 7.63 A chiral fluoride‐catalyzed asymmetric cascade sulfa‐Michael/ald...
Scheme 7.64 Enantioselective synthesis of spirocyclic compounds containing b...
Scheme 7.65 Enantioselective synthesis of spirocyclic compounds containing b...
Scheme 7.66 The enantioselective approach provides chiral spiro[thiopyranoin...
Scheme 7.67 NHC‐catalyzed enantioselective dearomatizing hydroacylation of b...
Scheme 7.68 Asymmetric synthesis of spiropyrazolones by complex of rhodium‐c...
Scheme 7.69 Enantioselective vinylogous Michael/aldol reaction to synthesize...
Scheme 7.70 Highly stereoselective synthesis of spiropyrazolones reported by...
Scheme 7.71 The synthesis of unsymmetrical diaryl‐substituted spirocyclohexa...
Scheme 7.72 The synthesis of spiropyrazolones via organocatalytic Michael/Mi...
Scheme 7.73 Three‐component Michael/Michael/aldol reaction cascade
reported
...
Scheme 7.74 Asymmetric synthesis of spiropyrazolones through phosphine‐catal...
Scheme 7.75 Asymmetric, three‐component, and one‐pot synthesis of spiropyraz...
Scheme 7.76 Mechanism of asymmetric, three‐component, one‐pot synthesis of s...
Scheme 7.77 Diastereo‐ and enantioselective construction of cyclohexanone‐fu...
Scheme 7.78 Lewis‐base‐catalyzed asymmetric [3+3] annulation reaction of Mor...
Scheme 7.79 Asymmetric synthesis of spirocyclohexene pyrazolones via formal ...
Scheme 7.80 Enantioselective synthesis of pyrazolone‐fused spirocyclohexenol...
Scheme 7.81 Diastereodivergent and enantioselective access to spiroepoxides....
Scheme 7.82 Synthesis of chiral pyrazolone and spiropyrazolone derivatives t...
Scheme 7.83 NHC‐catalyzed asymmetric formal [4+2] annulation to construct sp...
Scheme 7.84 Asymmetric synthesis of spiropyrazolones by sequential organo‐ a...
Scheme 7.85 Michael/Conia‐ene cascade reaction under synergistic catalysis p...
Scheme 7.86 Diastereoselective and enantioselective synthesis of barbiturate...
Scheme 7.87 The enantioselective approaches to spirobarbiturates by using ch...
Scheme 7.88 Isothiocyanate strategy for the synthesis of spirocyclic barbitu...
Scheme 7.89 Palladium‐catalyzed enantioselective synthesis of spirocyclic az...
Scheme 7.90 Application of chiral phosphine in organocatalytic synthesis of ...
Scheme 7.91 Anderson’s synthesis of spirocyclic azlactones.
Scheme 7.92 Formal [3+2] cycloaddition of vinylcyclopropane azlactones to en...
Scheme 7.93 Enantioselective access to spirocyclic sultams by chiral Cp
x
–rho...
Scheme 7.94 The synthesis of chiral spirosultams by multi sequential reactio...
Scheme 7.95 Asymmetric construction of spirocyclic pyrrolidine‐thiazolidined...
Scheme 7.96 The enantioselective cycloaddition of cyclic enones with sultams...
Scheme 7.97 Asymmetric construction of spiro thiopyrano‐indole‐benzoisothiaz...
Scheme 7.98 Enantioselective synthesis of chiral spirocycles containing rhod...
Scheme 7.99 Asymmetric synthesis of highly functionalized spirothiazolidinon...
Scheme 7.100 Enantioselective construction of spiro chroman‐thiazolones.
Scheme 7.101 Catalytic asymmetric synthesis of aromatic spiroketals.
Scheme 7.102 Enantio‐ and diastereoselective spiroketalization catalyzed by ...
Scheme 7.103 Asymmetric synthesis of spiroketals and spiroaminals.
Scheme 7.104 Chiral phosphoric acid‐catalyzed enantioselective and diastereo...
Scheme 7.105 Organohalogenite‐catalyzed spiroketalization.
Scheme 7.106 Stereoselective three‐component reaction of salicylaldehydes, a...
Scheme 7.107 The enantioselective synthesis spiropyrrolidines containing dih...
Scheme 7.108 Asymmetric synthesis of spirocyclic β‐lactams through copper‐ca...
Scheme 7.109 Hetero‐Diels−Alder process used for the synthesis of spiropyrro...
Scheme 7.110 The enantioselective fluorocyclization catalyzed by chiral BINO...
Scheme 7.111 Enantioselective cycloaddition to trisubstituted nitroolefins t...
Scheme 7.112 Enantioselective access to dispirooxindoles from furfurylcyclob...
Scheme 7.113 The enantioselective synthesis of bis‐spiroketals.
Scheme 7.114 Highly efficient enantioselective synthesis of bispiro benzofur...
Chapter 8
Figure 8.1 Common strategies for the synthesis of spirocycles: (a) alkylatio...
Scheme 8.1 Spirocyclizations reported by Gade.
Scheme 8.2 Spirocyclization reported by Takisawa.
Scheme 8.3 Spirocyclization reported by Smith.
Scheme 8.4 Synthesis of spirocycles reported by Hashimoto et al.
Scheme 8.5 Synthesis of spirofuranes and spiropyrrolidines reported by Mikam...
Scheme 8.6 Nicolaou synthesis of platensimycin.
Figure 8.2 Proposed mechanism for the Rh‐catalyzed synthesis of spirocycles ...
Scheme 8.7 Rh–catalyzed synthesis of spirocycles reported by Shintani and Ha...
Scheme 8.8 First asymmetric palladium‐catalyzed synthesis of spirocycles.
Scheme 8.9 Pd‐catalyzed synthesis of spirocycles reported by Mikami.
Scheme 8.10 Pd‐catalyzed spirocyclization of allyl propargyl ethers.
Scheme 8.11 Pd‐catalyzed spirocyclization reported by Toste.
Scheme 8.12 Spirocyclization reported by Cai.
Scheme 8.13 Spirocyclization reported by Dixon.
Scheme 8.14 Spirocyclization reported by Luan.
Scheme 8.15 [2+2+2] Cycloaddition reported by Shibata et al.
Scheme 8.16 [2+2+2] Cycloaddition with unsymmetrical dialkynes.
Scheme 8.17 Synthesis of spirocyclanes via a [2+2+2] cycloaddition reported ...
Figure 8.3 Proposed mechanism by Tanaka.
Scheme 8.18 [2+2+2] Spirocyclization reported by Tanaka.
Scheme 8.19 Copper‐catalyzed enantioselective Diels–Alder reaction.
Scheme 8.20 [3+2] Cycloaddition reported by C.‐J. Wang.
Scheme 8.21 Spirocyclization reported by Deng.
Scheme 8.22 Spirocyclizations reported by Trost and Zhao.
Scheme 8.23 Spirocyclization reported by Liu.
Scheme 8.24 Spirocyclization reported by Rios.
Scheme 8.25 Spirocyclization reported by Liu.
Scheme 8.26 Enantioselective PET reaction developed by Bach.
Scheme 8.27 Synthesis of spirocyclic β‐lactones developed by Romo.
Scheme 8.28 Cascade reaction reported by Wang.
Scheme 8.29 Spirocyclization reported by Xie.
Scheme 8.30 Spirocyclization reported by Chen.
Scheme 8.31 Spirocyclization reported by Jørgensen.
Scheme 8.32 Spirocyclopropanation of benzofulvenes.
Scheme 8.33 Spirocyclization reported by Lin.
Scheme 8.34 Spirocyclization reported by Rodriguez and Bonne.
Scheme 8.35 Spirocyclization reported by Li.
Scheme 8.36 α‐ketol rearrangement reported by Tu.
Scheme 8.37 Ring expansion reported by Takisawa.
Scheme 8.38 Spirocyclization reported by Zhang.
Scheme 8.39 Spirocyclization reported by Zhang.
Chapter 9
Scheme 9.1 Intramolecular dearomative reaction of
para
‐substituted phenol.
Scheme 9.2 Proposed dearomative reaction pathway.
Scheme 9.3 Preliminary enantioselective construction of all‐carbon spirocent...
Scheme 9.4 Synthesis of spiro[4.5]decane core architecture via dearomative s...
Scheme 9.5 Iridium‐catalyzed asymmetric allylic dearomatization of phenols....
Scheme 9.6 C‐alkylation for
ortho
‐substituted naphthols.
Scheme 9.7 Intramolecular dearomative reaction of alkyne‐substituted phenol....
Scheme 9.8 Intermolecular dearomative spiroannulation of phenol and iodobenz...
Scheme 9.9 Strategy for dearomative arylation of phenols.
Scheme 9.10 Preliminary results of asymmetric dearomative arylation of pheno...
Figure 9.1 Natural erythrina alkaloids.
Scheme 9.11 Pd(0)‐catalyzed intramolecular arylative coupling of 5‐hydroxyl ...
Scheme 9.12 Preliminary asymmetric studies for constructing erythrinane skel...
Scheme 9.13 Proposed one‐step construction of spirocarbocycles and potential...
Scheme 9.14 A DYKAT of phenolic derivative via axial‐to‐central chirality tr...
Scheme 9.15 Palladium‐catalyzed dynamic kinetic asymmetric transformation.
Scheme 9.16 [3+2] Spiroannulation of phenol‐derived biaryls and diynes.
Scheme 9.17 Formal [2+2+1] cycloaddition routes to new tricycles.
Scheme 9.18 Ru
II
‐catalyzed dearomative spiroannulation of naphthols via C(sp
Figure 9.2 Proposed mechanism of C–H bond activation/dearomative reaction.
Scheme 9.19 Spiroannulation of 2‐arylphenols via C–H activation/dearomative ...
Scheme 9.20 Pd‐catalyzed oxidative dearomatization of free naphthols.
Scheme 9.21 [2+2+1] Spiroannulation of unsymmetrical alkynes.
Scheme 9.22 Spirocyclopentadienes of 2‐alkenylphenols and alkynes.
Scheme 9.23 Spirocyclopentadienes of 2‐alkenylphenols and conjugated enynes....
Scheme 9.24 Three‐component dearomatizing [2+2+1] spiroannulation.
Scheme 9.25 Preliminary studies on the synthetic application of dearomatizin...
Scheme 9.26 Pd/NBE‐catalyzed C–H activation/arene dearomatization reaction....
Scheme 9.27 [4+1] Spiroannulation by C(sp
3
)‐H activation and naphthol dearom...
Scheme 9.28 Ir‐catalyzed asymmetric allylic alkylation for constructing spir...
Scheme 9.29 Allylic dearomatization for the synthesis of spiro cyclopentene‐...
Figure 9.3 The energetic barrier of transition states.
Scheme 9.30 Dearomative arylation of indoles for spiroindolenine derivatives...
Scheme 9.31 Dearomatization of C2‐substitued indoles for spirooxindoles.
Scheme 9.32 Synthesis of the core structure of phalarine.
Scheme 9.33 Process of gold‐catalyzed intramolecular alkyne hydroarylation....
Scheme 9.34 Dearomatization of aromatic ynones for spirocyclic scaffolds.
Scheme 9.35 One‐pot spirocyclization/trapping to form tetracycles.
Scheme 9.36 Scaffolds for the synthesis of spirocyclic indole derivatives.
Scheme 9.37 Intermolecular spirocyclization of indoles and propargyl carbona...
Figure 9.4 Novel spiroindolenine products.
Scheme 9.38 Stepwise synthesis spirocyclic indolines of indoles with allyl a...
Scheme 9.39 Pd/NBE‐catalyzed intermolecular dearomative spiroannulation of i...
Figure 9.5 Proposed reaction mechanism for palladium‐catalyzed dearomatizati...
Scheme 9.40 Asymmetric cycloadditions of vinylcyclopropanes with indoles.
Scheme 9.41 Allylic dearomatization of pyrroles for six‐membered spiro‐2H‐py...
Scheme 9.42 Arylative dearomatization of pyrroles for six‐membered spiro‐2H‐...
Figure 9.6 Selected bioactive compounds bearing spironaphthalene‐pyrrolidine...
Scheme 9.43 Allylic dearomatization of pyrroles for five‐membered spiro‐2H‐p...
Figure 9.7 Quantitative formation of spirocycles from 3‐pyrroles.
Scheme 9.44 Intramolecular nucleophilic dearomatization of furans.
Scheme 9.45 Dearomatizing 2,5‐alkoxyarylation of furan rings for spirooxindo...
Scheme 9.46 Three possible pathways for the formation of
142a
.
Scheme 9.47 Mechanistic experiments for dearomatizing 2,5‐alkoxyarylation of...
Scheme 9.48 Further transformations of spiro π‐allyl palladium.
Scheme 9.49 Synthesis of spiroacetals from boronic acids and hydroxyalkylfur...
Scheme 9.50 Synthesis of thiophene‐containing spirocyclic products via C–H a...
Scheme 9.51 Cu(II)‐promoted transformations of α‐thienylcarbinols into spiro...
Scheme 9.52 Synthesis of halogenated spirothienooxindoles from
159a
and
158a
Scheme 9.53 Intermolecular Heck‐type dearomative [2+2+1] spiroannulation of ...
Scheme 9.54 Palladium‐catalyzed aryne insertion/arene dearomatization to spi...
Scheme 9.55 Mechanism studies for the
5‐exo‐trig
spiroannulation...
Scheme 9.56 Intramolecular asymmetric allylic dearomatization of benzene der...
Scheme 9.57 A Cu‐catalyzed Sommelet–Hauser dearomatization of dihydrophenant...
Scheme 9.58 Substituent effects.
Chapter 10
Figure 10.1 Fenestrane motifs and their multifariousness. Top: (a) A stylist...
Figure 10.2 From spiranes to fenestranes and beyond. Top: Spiro[4.4]nonane (
Scheme 10.1 Retrosynthetic approach to the [5.5.5.5]fenestrane skeleton from...
Figure 10.3 Systematic extensions of Keese’s parent all‐
cis
‐[5.5.5.5]fenestr...
Scheme 10.2 Keese’s first synthesis of all‐
cis
‐[5.5.5.5]fenestrane (
2
).
Scheme 10.3 Cook’s first‐reported synthesis of all‐
cis
‐[5.5.5.5]fenestra‐2,5...
Scheme 10.4 Three hypothetical functionalized spiro structures as starting p...
Scheme 10.5 Synthesis of 1,3‐indanediol
24
and [2,2′]spirobiindane‐1,1′‐diol...
Scheme 10.6 Attempted construction of the benzoannelated [5.6.6.6]fenestrane...
Scheme 10.7 Synthesis of the benzoannelated [5.5.5.6]fenestranes with
cis
,
ci
...
Scheme 10.8 Unsuccessful attempts to synthesize fenestrindane
7
along the fu...
Scheme 10.9 Naphthoannelated all‐
cis
‐[5.5.5.6]fenestranones
51
and
53
‐
55
acc...
Figure 10.4 The first benzoannelated [5.5.5.6]fenestranones bearing two (
56
)...
Scheme 10.10 Construction of extended benzoannelated fenestrane derivatives ...
Scheme 10.11 Top: Both the stereoisomeric tetramethyl‐substituted [5.5.5.6]f...
Scheme 10.12 Synthesis of the bis‐(pentaarylphenyl)fenestrindane
82
from the...
Scheme 10.13 Synthesis of saddle‐shaped fourfold bay‐bridged fenestrindane
9
...
Figure 10.5 The parent fenestrindane saddle
10
and its octamethoxy derivativ...
Figure 10.6 Solid‐state structure of the fourfold bay‐bridged fenestrindane
Scheme 10.14 Access to centrohexaindanes
via
the “broken fenestrane route” a...
Figure 10.7 Solid‐state molecular structure of tetramethoxycentrohexaindane
Figure 10.8 Selected derivatives of centrohexaindane (
9
) in a perspective pr...
Figure 10.9 The four constitutional isomers of hexanitrocentrohexaindane,
10
...
Figure 10.10 Dodecafunctionalized centrohexaindanes
105
–
107
, synthesized by ...
Figure 10.11 Solid‐state molecular structure of dodecaphenylcentrohexaindane...
Figure 10.12 Two hypothetical extensions of the centrohexaindane core, model...
Chapter 11
Figure 11.1 The different synthesized natural products discussed in this cha...
Figure 11.2 The structure of (+)‐calafianin.
Figure 11.3 The proposed retrosynthesis for (+)‐calafianin.
Scheme 11.1 The synthesis of exocyclic vinyl epoxide
7
.
Scheme 11.2 The 1,3 dipolar cycloaddition leading to compounds
6
and
11
.
Scheme 11.3 The synthesis of
(+)‐calafianin (1)
.
Figure 11.4 The structure of pseurotin A.
Figure 11.5 The retrosynthesis of pseurotin A.
Scheme 11.4 The synthesis of
16
.
Scheme 11.5 The synthesis of pseurotin A.
Figure 11.6 The structure of
(−)ushikulide A
.
Figure 11.7 The retrosynthesis of
(−)ushikulide A
.
Scheme 11.6 The synthesis of compounds
33
,
34
, and
35
.
Scheme 11.7 The synthesis of compound
30
.
Scheme 11.8 The synthesis of compound
31
.
Scheme 11.9 The synthesis of
(−)ushikulide A
.
Figure 11.8 The structure of
(−)‐acutamine
.
Figure 11.9 The proposed retrosynthesis procedure.
Scheme 11.10 The synthesis of compounds
60
and
61
.
Scheme 11.11 The synthesis of compound
59
.
Scheme 11.12 The synthesis of
58
.
Scheme 11.13 The synthesis of
77
.
Scheme 11.14 The synthesis of compound
80
.
Scheme 11.15 The synthesis of (−)‐acutumine.
Figure 11.10 Herzon’s retrosynthesis of (−)‐acutumine.
Scheme 11.16 The synthesis of compound
87
.
Scheme 11.17 The synthesis of compound
95
.
Scheme 11.18 The synthesis of (−)‐acutumine.
Figure 11.11 The structure of spirotryprostatin B.
Figure 11.12 The proposed retrosynthesis.
Scheme 11.19 The synthesis of compound
101
.
Scheme 11.20 The synthesis of compounds
109
and
110
.
Scheme 11.21 The synthesis of (−)‐spirotryprostatin B.
Figure 11.13 The retrosynthesis proposed by Carreira.
Scheme 11.22 The synthesis of compound
116
.
Scheme 11.23 The synthesis of compound
115
.
Scheme 11.24 The synthesis of (−)‐spirotryprostatin B.
Guide
Cover Page
Title Page
Copyright Page
List of Contributors
Preface
Table of Contents
Begin Reading
Index
Wiley End User License Agreement
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Spiro Compounds
Synthesis and Applications
Edited by
Ramon Rios Torres
University of Southampton
Southampton, United Kingdom
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Library of Congress Cataloging-in-Publication Data
Names: Riós Torres, Ramón, author.Title: Spiro compounds : synthesis and applications / Ramon Rios Torres, University of Southampton, Southhampton, United Kingdom.Description: First edition. | Hoboken, NJ : Wiley, 2022. | Includes index.Identifiers: LCCN 2021031988 (print) | LCCN 2021031989 (ebook) | ISBN 9781119567639 (hardback) | ISBN 9781119567622 (adobe pdf) | ISBN 9781119567653 (epub)Subjects: LCSH: Organic compounds–Structure.Classification: LCC QD255.4 .R56 2022 (print) | LCC QD255.4 (ebook) | DDC 547/.5–dc23LC record available at https://lccn.loc.gov/2021031988LC ebook record available at https://lccn.loc.gov/2021031989
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List of Contributors
Vikas R. AswarDepartment of Chemistry, Indian Institute of Technology Bombay, Mumbai, India
Lu Bai
Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi’an, China
Matthias BaudSchool of Chemistry and Institute for Life Sciences, University of Southampton, Southampton, UK
Hak‐Fun ChowDepartment of Chemistry, Institute of Molecular Functional Materials and The Center of Novel Functional Molecules, The Chinese University of Hong Kong, Shatin, Hong Kong
Xavier CompanyóDepartment of Chemical Sciences, University of Padova, Padova, PD, Italy
Xiao‐Yuan CuiSchool of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
Luca Dell’AmicoDepartment of Chemical Sciences, University of Padova, Padova, PD, Italy
Sambasivarao KothaDepartment of Chemistry, Indian Institute of Technology Bombay, Mumbai, India
Dietmar KuckDepartment of Chemistry and Center for Molecular Materials (CM2), Bielefeld University, Bielefeld, Germany
Jingjing LiuKey Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi’an, China
Xinjun LuanKey Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi’an, China
Marta MeazzaSchool of Chemistry, University of Southampton, Southampton, UK
Albert MoyanoSecció de Química Orgànica, Departament de Química Inorgànica i Orgànica, Facultat de Química, Universitat de Barcelona, Barcelona, Catalonia, Spain
Suva PariaDepartment of Chemical Sciences, University of Padova, Padova, PD, Italy
Ramon RiosDepartment of Organic Chemistry, University of Southampton, Southampton, UK
Yellaiah TangellaDepartment of Chemistry, Indian Institute of Technology Bombay, Mumbai, India
Alberto Vega‐PeñalozaDepartment of Chemical Sciences, University of Padova, Padova, PD, Italy
Jan VeselýDepartment of Organic Chemistry, Faculty of Science, Charles University, Prague, Czech Republic
Michal UrbanDepartment of Organic Chemistry, Faculty of Science, Charles University, Prague, Czech Republic
Peng‐Wei XuSchool of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
Jin‐Sheng YuSchool of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
Jian ZhouSchool of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
Preface
When I was a kid, I dreamt to be an engineer and build planes, cars, etc. However, in high school, I felt in love with Organic Chemistry. I changed my dreams of building things for how to assemble C, H, N, and other atoms to form molecules. I was always astonished of the inherent difficulty of organic structures, not only for their diversity and ordered assembly but also for their 3D shape. With time, I enjoyed learning Organic Chemistry: starting from my bachelor in organic chemistry, followed by a PhD in organometallic chemistry, and several postdocs in organometallic chemistry and organocatalysis. Later on, as academic, I have always tried to develop new reactions that can allow to obtain difficult structures in an enantiopure form. However, one of the greatest challenges that I faced has been the synthesis of spiro compounds. My own way to be interested in the synthesis of spiro compounds first started in the synthesis of quaternary carbons in an enantiopure fashion. Precisely, while studying how to synthesize quaternary carbons, I developed an interest in spiro compounds, how difficult it will be to join two cycles by a single atom, and do it enantioselectively. In my research group, we have been lucky enough to develop several reactions that led to spiro compounds in an enantiopure form (or almost enantiopure), but I still remember the first time that we got a spiro compound in an enantiopure form as an incredible feeling of achievement. Now, several years later, I decided to honor this type of compounds by editing a book, summarizing the achievements that Organic Chemists have been done in the last decades.
I also want to dedicate this book to Professor Dieter Enders who left us during the writing of this book. He was always a source of inspiration, since his early success with RAMP and SAMP chemistry, until the development of highly complex domino reactions, showing a commitment and brilliance to organic chemistry that inspired me in my career. I still remember his kind hospitality in The Domino cat symposium in Aachen. Professor Enders, you left a huge footprint in organic and synthetic chemistry.
Finally, I want to thanks all the authors for their work and commitment in those difficult COVID times.
1 Spiro Compounds: A Brief History
Marta Meazza
School of Chemistry, University of Southampton, Southampton, UK
Policyclic molecules containing at least two rings joined together by a single atom, mostly a carbon atom, previously named spiranes, are called spiro compounds or spirocycles, and the single central atom is referred to as the spiro atom [1]. We should mention that apart from carbon, other elements such as nitrogen, phosphorus, and arsenic may represent the spiro atom.
The term was coined by the German chemist Nobel laureate Adolf von Baeyer who created the first spirane in 1900 [2].
This peculiar structural feature is present in natural products and has long been the subject of methodological studies and synthetic efforts [3].
Several synthetic procedures for spiro compounds have been developed and will be extensively discussed in the next chapters. However, the asymmetric synthesis of spirocycles that allow the creation of stereogenic quaternary centers represent a demanding task for organic chemists. Even the concepts of spiro aromaticity and spiro antiaromaticity can be applied when spiroconjugation is possible [4].
The search for the key term “spiro” in SciFindern database, at the end of October 2019, resulted in more than 40 700 references with an exponential growth starting from the middle of the last century and an increasing attention to this subject is expected in the future (Figure 1.1).
These massive research efforts cover a wide range of fields from organic and medicinal chemistry to material sciences and engineering, to name a few.
The enormous interest in spiro compounds rely on their distinctive properties often associated with the three‐dimensional stereochemical features, reflecting on their pharmacological properties that include, among others, bactericidal, fungicidal, anticancer, cytotoxic, antidepressant, antihypertensive, insecticidal, herbicidal, and plant growth regulatory effects [5]. These properties are due to the tetrahedral nature of the spiro carbon and consequent asymmetric features associated with it.
Figure 1.1 Growing interest in spiro compounds in chemical literature.
Figure 1.2 Dye sensitizer 9,9‐spirobifluorene.
Source: Lupo et al. [7].
In addition, many other practical utilizations include optoelectronic devices, ophthalmic lenses, and solar cells [6]. Compounds like 9,9‐spirobifluorene 1 (Figure 1.2) have application in dye‐sensitized solar cells (DSCs) and represent the most efficient alternative to the current solar cell technologies [7].
Spirocyclic compounds find technological application as efficient charge‐transfer molecules due to their intramolecular donor–acceptor structural feature amplified by spiroconjugation. The desired optical properties can be achieved by careful design of the spiro donor–acceptor characteristic as illustrated in Figure 1.3[8]. When structural characteristics make it possible, spiro compounds can equilibrate with their non‐spiro analogues exhibiting photochemical phenomena like photochemical memory.
We report here some examples of carbocyclic and heterocyclic naturally occurring compounds containing the spiro moiety (Figure 1.4). One of the simplest compounds is the pheromone of the olive fly Dacus oleae5. Phelligridin G 6 from the fungus Phellinus igniarius has been long used in Traditional Chinese Medicine for the treatment of gonorrhea [9]. The antimycotic drug griseofulvin 7, isolated from a penicillium mold in 1939, found application in the treatment of fungal skin infections since 1957. Hecogenin 8, the aglycone part of a steroid saponin found in the plant Agave sisalana, is responsible for many therapeutic effects and is also used as a starting material in the synthesis of corticosteroids [10]. Horsfiline 9 is an oxindole alkaloid having analgesic effect, isolated from the plant Horsfieldia superba[11].
Figure 1.3 Donor–acceptor spiro compounds and colors displayed by them.
Source: Wössner et al. [8].
Figure 1.4 Examples of naturally occurring compounds containing the spiro moiety.
A classic example of the importance of the presence of a spiro functionality is the retention of the biological activity of perhydrohistrionicotoxin 10, the completely reduced analogue of the potent nicotinic receptor antagonist alkaloid (−)‐histrionicotoxin 11, isolated from “dart‐poison” frogs, that clearly suggests the fundamental role of the spiropiperidine moiety in determining a strong receptor binding. The massive synthetic efforts on this topic are collected in a book chapter [12] (Figure 1.5).
Figure 1.5 Spiro functionality in nicotinic receptor antagonists.
Source: Hart [12].
As stated before, spirocycles are present in successfully developed medications and represent attractive synthetic targets included in chemical libraries for diversity‐oriented synthesis within drug discovery projects. In this context, the spiro moiety has been and can be employed both as core structure and as an activity modulator, appended to decorate the peripheral part of the molecule [13].
The major advantage of spirocycles in biological applications as core structure or pharmacophores originates from their 3‐D nature and the associated conformational features that allow for a better ability to interact with the target protein enzyme. The tetrahedral feature of the spiro atom renders the two ring planes nearly perpendicular to each other with a limited number of potential conformations. When added in the periphery of the molecule, the spirocycle acts as a modulator of physicochemical properties such as log P and water solubility, as well as affecting the metabolic stability of the molecule. Not least, from an intellectual property perspective, the introduction of spirocycles offers the possibility of obtaining a free patent space in a me‐too research approach.
Prominent examples of marketed spirocompounds, illustrating these concepts, include fluspirilene 12, spiraprilat 13, and cevimeline 14, while experimental compounds in different stages of clinical development are ETX0914 15, a DNA gyrase inhibitor; tofoglifozin CSG452 16, an inhibitor of hSGLT2 for the treatment of Type 2 diabetes; AZD1979 17, an antagonist of melanin‐concentrating hormone receptor; and rolapitant 18, a neurokinine 1 receptor antagonist [13, 14] (Figure 1.6).
We wish once more to draw the attention of the readers on the potential usefulness and uniqueness of the spiro motif in the interaction with a specific biological target spanning from drugs to agrochemicals.
The enzyme Acetyl‐coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism in most living organisms, among which include humans, insects, and plants. The experimental ACC inhibitor compounds for the treatment of human metabolic disease contain a spirocyclic moiety as in Takeda compound 19[15] and in Pfizer PF‐05221304 20. The last one is currently in phase II clinical trials for the treatment of Non‐Alcoholic Steatohepatitis (NASH) [16] (Figure 1.7).
Figure 1.6 Examples of marketed spiro compound drugs.
Sources: Based on Zheng and Tice [13]; Zheng et al. [14].
Figure 1.7 ACC inhibitors of pharmaceutical interest.
Sources: Based on Bourbeau and Bartberger [16a]; Esler and Bence [16b].
The commercial insecticide/acaricide products spirotetramat 21, spiromesifen 22, and spirodiclofen 23 from Bayer CS and spiropidion 24 from Syngenta, acting as insect ACC inhibitors, all have spirocyclic structures [17] (Figure 1.8).
New spirocyclic herbicide compounds with the representative formula 25 have been recently patented [18]. It is noteworthy that compounds 21 and 24, sharing similar molecular features with 25, do not show any phytotoxic effect (Figure 1.9).
Figure 1.8 Commercial spirocyclic insecticide/acaricide products.
Source: Jeschke et al. [17].
Figure 1.9 Recently patented spiro compound of agrochemical interest.
Figure 1.10 Example of numbering of spirocyclic compounds.
As presented in this chapter, spirocyclic scaffolds find application in a large number of sectors for their own peculiar architecture characteristics, displaying valuable application properties, or simply because of the introduction of structural novelty that guarantee patentability and intellectual property rights.
1.1 Notes on IUPAC Rules for Spiro Compounds
Naming spirocycles could be quite complex. The accepted rules are collected in the IUPAC blue book [1, 19].
Simplifying with two examples, the structure 26 is numbered starting from the smallest cycle (Figure 1.10). The name comes from the prefix spiro followed by square brackets containing the number of atoms of the two cycles starting from the smallest and excluding the spirocenter. In this case, the functional group is an alkane so that the name became spiro[4,5]decane.
Figure 1.11 Example of naming chiral spiro compounds.
When the compound is chiral because it contains a chiral center, the CIP rules are followed. In the case in which the substituents on the spirocenter are the same, but the structures display an axial chirality as in Figure 1.11, we assign arbitrarily the priority to one of the cycles and then, within each cycle the order follows the CIP rules: a>a′>b>b′.
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2 Selected Applications of Spirocycles in Medicinal Chemistry
Matthias Baud
School of Chemistry and Institute for Life Sciences, University of Southampton, Southampton, UK
2.1 Introduction
Spiro compounds contain two rings, connected by a single sp3 hybridized quaternary center, the “spiroatom” [1]. The latter is often a carbon, although a number of quaternary N‐spiro ammoniums have also been reported. Trospium chloride (1) (Table 2.1) is a good example, and its spiro ammonium motif can be readily prepared by double N‐alkylation of endo‐nortropine [3]. Spirocyclic systems are found in a wide range of natural products [4], including spiro‐ketals [5, 6], lactones [7], lactams [8, 9], and oxindoles [10–12]. An early and illustrative example of spirocyclic natural product which has attracted the attention of medicinal chemists is the antibiotic platensimycin (2). It is a metabolite from Streptomyces platensis which represents a structurally unusual example of bioactive molecule containing a carbaspirocyclic scaffold. Its antibiotic activity was reported by Merck in 2006, as part of a screening campaign to identify inhibitors of beta‐ketoacyl synthases I/II (FabF/B) enzymes [13]. Inhibition of FAB enzymes by platensimycin leads to impaired biosynthesis of key fatty acids required bacterial cell membrane integrity [14]. Platensimycin displays activity against a range of Gram‐positive bacteria, including strains showing resistance to other potent antibiotics such as methicillin, vancomycin, linezolid, or macrolide. Structural studies on an Escherichia coli FabF(C163Q) in complex with platensimycin highlighted important interactions underlying complex formation. The shape complementarity and conformational restriction provided by the spiro motif are important contributors to the potency of platensimycin, allowing polar interactions and hydrophobic contacts at the binding site entrance (Figure 2.1) [13]. The first total synthesis of racemic platensimycin was reported by Nicolaou on the same year (Scheme 2.1) [15], involving a key ruthenium‐catalyzed enyne cycloisomerization [16]. Since then, stereoselective syntheses of platensimycin spirocyclic core based on rhodium‐catalyzed asymmetric cycloisomerization and hypervalent iodine‐mediated de‐aromatizing cyclization [17], decarboxylative allylation [18], and intramolecular Diels–Alder [19] have been reported.
Table 2.1 Selected examples of FDA‐ approved drugs containing spirocyclic motifs.
Source: Adapted from Knox et al. [2].
Structure
ID
Name (Trade name)
Indication
1
Trospium chloride (Flotros)
Overactive bladder
3
Spironolactone (Aldactone)
Heart failure, edema, hypertension
4
Cevimeline (Evoxac)
Dry mouth (Sjögren's Syndrome)
5
Griseofulvin (Crivicin)
Antifungal antibiotic for ringworm infections
6
Guanadrel (Hylorel)
Hypertension
7
Amcinonide (Cyclocort)
Inflammatory and pruritic manifestations
8
Ivermectin (Ascapil)
Anti‐parasitic
9
Fenspiride (Eurespal)
Antitussive
10
Rifabutin (Ansatipin)
Antibiotic, tuberculosis
11
Homo‐harringtonine (Ceflatonin)
Chronic myeloid leukemia
12
Irbesartan (Avapro)
Hypertension
13
Fluspirilene (Imap)
Schizophrenia
14
Spirapril (Renormax)
Hypertension
15
Buspirone (Buspar)
Anxiety disorders
Figure 2.1 X‐ray crystal structure (pdb 2gfx12) of Platensimycin (2, sticks representation) bound to the active site of FabF (surface representation) highlights hydrophobic contacts and hydrogen bonds in the complex.
Scheme 2.1 Key enyne cycloisomerization step in Nicolaou’s total synthesis of platensimycin.
Source:
