Classics in Total Synthesis IV E-Book

K. C. Nicolaou

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1032

Veröffentlichungsjahr: 2024

Beschreibung

Fourth volume of a classic in the field of organic synthesis, describing retrosynthetic analysis and total synthesis of important molecules

Classics in Total Synthesis IV is a compilation of highly important synthetic methods which lead to complex molecules with valuable properties. From the complex architectures of natural products to the streamlined synthesis of functional molecules, each chapter in Classics in Total Synthesis IV unfolds a unique story. The interplay of mechanisms, reactivity, selectivity, and stereochemical aspects is thoroughly examined, echoing the pedagogical format that has become synonymous with this series. Well-designed graphics are included throughout, and all important parts of the reaction sequences are highlighted.

This volume encapsulates the culmination of new methodologies, emerging trends, and a selection of significant total syntheses undertaken from 2009 to 2022 while additionally including two earlier syntheses from 1979 and 1992 for comparison and to highlight the development of organic synthesis over the past decades. The careful balance between historical context, comments on the molecules’ impact to humankind, and the design and execution aspects of each synthesis creates a narrative that is not only clear but also intellectually stimulating.

Written by K. C. Nicolaou, Ruocheng Yu and Stephan Rigol, Classics in Total Synthesis IV includes 16 chapters covering:

• Coupling and rearrangement reactions
• Recent advances in nonenzymatic enantioselective cyclization
• Cycloaddition and annulation reactions
• C−H functionalization and transition metal-mediated C−H activation
• Electroorganic chemistry and visible-light photoredox catalysis
• HAT-initiated olefin hydrogenation, isomerization, and hydrofunctionalization

Joining its predecessors in weaving together the threads of scientific discovery, challenge, and intellectual pursuit and establishing strong connections with biology and medicine, Classics in Total Synthesis IV is an essential reference for all future and present synthetic organic chemists.

Leseprobe

Table of Contents

Cover

Table of Contents

Title Page

Copyright

Foreword

Preface

About the Authors

Abbreviations

1

Introduction: Total Synthesis Marching on with New Methods and Strategies and with Molecules for Biology and Medicine

1.1 Targets

1.2 Methods and Strategies

1.3 Classics in Total Synthesis IV

2

Halichondrin B and Norhalichondrin B

2.1 Introduction

2.2 Kishi’s Retrosynthetic Analysis and Strategy

2.3 Kishi’s Total Syntheses of Halichondrin B and Norhalichondrin B

2.4 Phillips’ Retrosynthetic Analysis and Strategy

2.5 Phillips’ Total Synthesis of Norhalichondrin B

2.6 Nicolaou’s Retrosynthetic Analyses and Strategies

2.7 Nicolaou’s Total Synthesis of Halichondrin B

2.8 Nicolaou’s Total Synthesis of Norhalichondrin B

2.9 … and the Sky’s the Limit

References

3

Daphmanidin E

3.1 Introduction

3.2 Retrosynthetic Analysis and Strategy

3.3 Total Synthesis

3.4 Conclusion

References

4

Epicoccin G and (−)-Acetylaranotin

4.1 Introduction

4.2 Nicolaou’s Retrosynthetic Analysis of Epicoccin G

4.3 Nicolaou’s Total Synthesis of Epicoccin G

4.4 Reisman’s Retrosynthetic Analysis of (−)-Acetylaranotin

4.5 Reisman’s Total Synthesis of (−)-Acetylaranotin

4.6 Tokuyama’s Retrosynthetic Analysis of (−)-Acetylaranotin

4.7 Tokuyama’s Total Synthesis of (−)-Acetylaranotin

4.8 Conclusion

References

5

Taiwaniadducts B, C, and D

5.1 Introduction

5.2 Retrosynthetic Analysis and Strategy

5.3 Total Synthesis

5.4 Conclusion

References

6

Schindilactone A

6.1 Introduction

6.2 Retrosynthetic Analysis and Strategy

6.3 Total Synthesis

6.4 The After Story

References

Note

7

Welwitindolinones

7.1 Introduction

7.2 Rawal’s Retrosynthetic Analysis of Oxidized Welwitindolinones

7.3 Rawal’s Total Synthesis of Oxidized Welwitindolinones

7.4 Garg’s Retrosynthetic Analysis of Oxidized Welwitindolinones

7.5 Garg’s Total Synthesis of Oxidized Welwitindolinones

7.6 Total Syntheses of

N

-Methylwelwitindolinone B Isothiocyanate

7.7 Conclusion

References

8

Ryanodine and Ryanodol

8.1 Introduction

8.2 Deslongchamps’ Retrosynthetic Analysis and Strategy

8.3 Deslongchamps’ Total Synthesis of Ryanodol

8.4 Inoue’s Retrosynthetic Analysis and Strategy

8.5 Inoue’s Total Synthesis of Ryanodol

8.6 Reisman’s Retrosynthetic Analysis and Strategy

8.7 Reisman’s Total Synthesis of Ryanodol

8.8 Inoue’s and Reisman’s Total Syntheses of Ryanodine

8.9 Conclusion

References

9

Gedunin, Mitrephorone A, and Antiretroviral Agent Islatravir

9.1 Introduction

9.2 Renata’s Retrosynthetic Analysis of Gedunin

9.3 Renata’s Chemoenzymatic Synthesis of Gedunin

9.4 Renata’s Retrosynthetic Analysis of Mitrephorone A

9.5 Renata’s Formal Total Synthesis of Mitrephorone A

9.6 Huffman and Fryszkowska’s Retrosynthetic Analysis of Islatravir

9.7 Huffman and Fryszkowska’s Total Synthesis of Islatravir

9.8 Conclusion

References

10

Trioxacarcins

10.1 Introduction

10.2 Myers’ Retrosynthetic Analysis and Strategy

10.3 Myers’ Total Synthesis of Trioxacarcins

10.4 Nicolaou’s Retrosynthetic Analysis and Strategy

10.5 Nicolaou’s Total Synthesis of Trioxacarcins

10.6 Synthesis and Biological Evaluation of Trioxacarcin Analogues

10.7 Conclusion

References

11

Aplyviolene

11.1 Introduction

11.2 Overman’s Retrosynthetic Analysis of Aplyviolene

11.3 Overman’s Total Synthesis of Aplyviolene

11.4 Visible-Light Photoredox Catalysis

11.5 Conclusion

References

12

Dixiamycin B

12.1 Introduction

12.2 Retrosynthetic Analysis and Strategy

12.3 Total Synthesis

12.4 Electroorganic Chemistry

12.5 Conclusion

References

Note

13

Ingenol

13.1 Introduction

13.2 Retrosynthetic Analysis and Strategy

13.3 Total Synthesis

13.4 Synthesis and Biological Evaluation of Ingenol Analogues

13.5 Conclusion

References

14

Cardamom Peroxide, Nodulisporic Acid C, and Bilobalide

14.1 Introduction

14.2 Maimone’s Retrosynthetic Analysis of Cardamom Peroxide

14.3 Maimone’s Total Synthesis of Cardamom Peroxide

14.4 2nd Movement: HAT-Initiated Olefin Hydrogenation and Isomerization

14.5 Shenvi’s Retrosynthetic Analysis of Bilobalide

14.6 Shenvi’s Total Synthesis of Bilobalide

14.7 3rd Movement: HAT-Initiated Olefin Hydrofunctionalizations

14.8 Pronin’s Retrosynthesis Analysis of Nodulisporic Acid C

14.9 Pronin’s Total Synthesis of Nodulisporic Acid C

14.10 To Be Continued…

14.11 Conclusion

References

Notes

15

Batrachotoxin and Conidiogenones

15.1 Introduction

15.2 Snyder’s Retrosynthetic Analysis of Conidiogenones

15.3 Snyder’s Total Synthesis of Conidiogenones

15.4 More Methods and Strategies

15.5 Du Bois’ Retrosynthetic Analysis of Batrachotoxin

15.6 Du Bois’ Total Synthesis of Batrachotoxin

15.7 Conclusion

References

16

Gukulenin B and C—H Functionalization

16.1 Introduction

16.2 Retrosynthetic Analysis and Strategy

16.3 Total Synthesis

16.4 Conclusion

References

Image / Photo Credits

Author Index

Subject Index

End User License Agreement

List of Illustrations

Chapter 1

Figure 1. Molecular structures of selected natural products featured.

Scheme 1. Representative examples of selected methodologies featured.

Chapter 2

Figure 1. Molecular structures of halichondrins A, B and C (

1

–

3

), norhalicho...

Figure 2. Important stages of the history and development of organochromium ...

Figure 3. (A) Catalytic cycle of the classic Nozaki–Hiyama–Kishi reaction; (...

Figure 4. (A) Catalytic, asymmetric Nozaki–Hiyama–Kishi reaction employing s...

Figure 5. Catalytic cycle of the electrochemical Nozaki–Hiyama–Kishi reactio...

Figure 6. (A) Mechanism of the Achmatowicz rearrangement; (B) mechanism of L...

Figure 7. Kishi’s retrosynthetic analysis of halichondrin B (

2

).

Scheme 1. Synthesis of alkyl bromide fragment

80

.

Scheme 2. Synthesis of vinyl iodide building block

77

.

Scheme 3. Synthesis of aldehyde building block

81

.

Scheme 4. Synthesis of vinyl iodide building block

83

.

Scheme 5. Synthesis of

β

-ketophosphonate building block

122

.

Scheme 6. Synthesis of vinyl iodide building block

82

and its elaboration to...

Scheme 7. Synthesis of advanced macrolactone intermediate

133

.

Scheme 8. Synthesis of advanced aldehyde fragment

137

.

Scheme 9. Final stages and completion of Kishi’s total synthesis of halichon...

Figure 8. Rationale for the formation of halichondrin B (

2

) from cyclization...

Scheme 10. Synthesis of vinyl iodide building block

145

.

Scheme 11. Final stages and completion of Kishi’s total synthesis of norhali...

Figure 9. (A) Molecular structures of eribulin (

149

) and eribulin mesylate (...

Figure 10. Phillips’ retrosynthetic analysis of norhalichondrin B (

5

).

Scheme 12. Synthesis of aldehyde building blocks

81

and

151

.

Scheme 13. Synthesis of vinyl iodide building block

82

.

Scheme 14. Synthesis of allyl alcohol building block

153

.

Scheme 15. Synthesis of advanced intermediate

190

.

Scheme 16. Final stages and completion of Phillips’ total synthesis of norha...

Figure 11. Nicolaou’s retrosynthetic analysis of halichondrin B (

2

).

Figure 12. Nicolaou’s retrosynthetic analysis of norhalichondrin B (

5

).

Scheme 17. Synthesis of tetrahydrofuran ketoaldehyde fragment

195

.

Scheme 18. Synthesis of tricyclic aldehyde fragment

196

.

Scheme 19. Synthesis of

β

-ketophosphonate fragment

197

.

Scheme 20. Synthesis of tricyclic aldehyde ester fragment

198

.

Scheme 21. Synthesis of macrolactonization precursor hydroxy ester

248

.

Scheme 22. Synthesis of macrolactone fragment

250

.

Scheme 23. Final stages and completion of Nicolaou’s total synthesis of hali...

Scheme 24. Synthesis of ketoaldehyde building block

258

.

Scheme 25. Synthesis of octacyclic hydroxy aldehyde C38-

epi

-

199

.

Scheme 26. Final stages and completion of Nicolaou’s total synthesis of norh...

Chapter 3

Figure 1. Molecular structures of selected

daphniphyllum

alkaloids.

Figure 2. Proposed biosynthetic pathways of (A)

proto

-daphniphylline (

14

) an...

Figure 3. Retrosynthetic analysis of (+)-daphmanidin E (

5

).

Scheme 1. (A) Synthesis and resolution of

C

2

-symmetric diketone

23

; (B) dete...

Scheme 2. Synthesis of trisubstituted alkene

35

.

Scheme 3. (A) Synthesis of Claisen rearrangement precursor

41

; (B) synthesis...

Scheme 4. Claisen rearrangements of (A) enol ether

41

and (B) the C10-epimer...

Scheme 5. Second Claisen rearrangement and synthesis of aldehyde

56

.

Scheme 6. Synthesis of primary alkyl iodide

60

.

Scheme 7. (A) Radical cyclization of model compound

61

employing

n

-Bu

3

SnH an...

Figure 4. Proposed mechanism of the cobaloxime

65

-catalyzed alkyl-Heck-type ...

Scheme 8. Synthesis of unsaturated aldehyde

74

via an intramolecular aldol r...

Scheme 9. Completion of the total synthesis of (+)-daphmanidin E (

5

).

Scheme 10. Highlights of Smith’s total synthesis of calyciphylline N (2014)....

Scheme 11. (A–F) Highlights of recent total syntheses of daphenylline.

Scheme 12. (A–D) Highlights of recent total syntheses of himalensine A.

Scheme 13. Highlights of the total syntheses of (A) C5-

epi

-daphlongamine H (...

Scheme 14. (A–D) Highlights of selected total syntheses of other

daphniphyll

...

Chapter 4

Figure 1. Molecular structures of selected epipolythiodiketopiperazines and ...

Scheme 1. Selected early methods for the construction of dihydrooxepine stru...

Scheme 2. Previous methods for diketopiperazine sulfenylation: (A) nucleophi...

Figure 2. Nicolaou’s retrosynthetic analysis of epicoccin G (

3

).

Scheme 3. Nicolaou’s synthesis of bicycle

38

.

Scheme 4. Nicolaou’s synthesis of diketopiperazine

30

.

Scheme 5. (A) Mechanistic rationale for the formation of sulfenylation reage...

Scheme 6. Final stages and completion of Nicolaou’s total syntheses of epico...

Scheme 7. (A) Application of the enolate sulfenylation method to gliotoxin (

Scheme 8. Example of tetrahydrooxepine synthesis via a tungsten vinylidene i...

Figure 3. (A) Reisman’s retrosynthetic analysis of (−)-acetylaranotin (

7

); (...

Scheme 9. Reisman’s synthesis of enantioenriched pyrrolidine

80

.

Scheme 10. Reisman’s synthesis of aldehyde

67

.

Scheme 11. Reisman’s synthesis of chlorotetrahydrooxepine

98

.

Scheme 12. Reisman’s synthesis of diketopiperazine

65

.

Scheme 13. Final stages and completion of Reisman’s synthesis of (−)-acetyla...

Figure 4. Tokuyama’s retrosynthetic analysis of (−)-acetylaranotin (

7

).

Scheme 14. Tokuyama’s synthesis of enone

119

.

Scheme 15. Tokuyama’s synthesis of dihydrooxepine

122

via a Baeyer–Villiger ...

Scheme 16. Final stages and completion of Tokuyama’s synthesis of (−)-acetyl...

Chapter 5

Figure 1. Molecular structures of taiwaniadducts A–E and their putative bios...

Scheme 1. Highlights of Majetich’s biomimetic synthesis of perovskone (

9

).

Figure 2. (A,B) Synthetic challenges and (C) biosynthetic proposal for taiwa...

Scheme 2. Highlights of Johnson’s synthesis of (±)-progesterone (1971).

Scheme 3. Chiral-LBA-based enantioselective polyene cyclization. (A) Yamamot...

Scheme 4. Transition-metal-catalyzed enantioselective polyene cyclization. (...

Scheme 5. Enantioselective polyene cyclization promoted by small organic mol...

Figure 3. Retrosynthetic analysis of taiwaniadducts B–D (

2

,

3

,

4

).

Scheme 6. Syntheses of (A) vinyl iodide

62

and (B) styrene derivative

74

.

Scheme 7. Li’s synthesis of tricyclic intermediate

79

through polyene cycliz...

Scheme 8. Li’s synthesis of taiwaniaquinones A (

6

) and F (

86

) (atom numberin...

Scheme 9. Li’s synthesis of oxatricycle

58

through enantioselective polyene ...

Scheme 10. Li’s synthesis of tricyclic intermediate

97

.

Scheme 11. Li’s synthesis of

trans

-ozic acid (

8

) and its methyl ester

103

.

Scheme 12. (A) Attempted and (B) successful intermolecular Diels–Alder cyclo...

Scheme 13. Final stages and completion of Li’s total synthesis of taiwaniadd...

Figure 4. (A) Proposed biogenesis and (B) synthetic construction of the 6/5/...

Chapter 6

Figure 1. Molecular structures of representative schinortriterpenoids

1

–

7

an...

Scheme 1. Yang and Chen’s synthesis of model bicycle

13

via a Claisen rearra...

Scheme 2. Paquette’s synthesis of model tricycle

21

via a pinacol coupling r...

Scheme 3. Anderson’s synthesis of model tricycle

27

via a cascade of cycliza...

Figure 2. Yang and Chen’s synthetic blueprint for the

AB

ring system of schi...

Figure 3. General reaction equation for the Pauson–Khand reaction.

Figure 4. (A) Currently accepted mechanism for the Co

2

(CO)

8

-mediated Pauson–...

Figure 5. Intramolecular variant of the Pauson–Khand reaction.

Scheme 4. Application of an intramolecular Pauson–Khand reaction in Schreibe...

Scheme 5. Co

2

(CO)

8

/TMTU-catalyzed Pauson–Khand reaction (Yang, Chen

et al

., ...

Figure 6. Pd-mediated carbonylative annulation for the synthesis of

cis

-fuse...

Scheme 6. Application of Pd-catalyzed carbonylative annulation in the total ...

Figure 7. (A) Yang and Chen’s retrosynthetic analysis of the

FGH

ring system...

Figure 8. Yang and Chen’s retrosynthetic analysis of schindilactone A (

1

).

Scheme 7. Importance of templating effect in the construction of eight-membe...

Scheme 8. (A) Racemic and (B) enantioselective versions of the Diels–Alder r...

Scheme 9. Yang, Chen, and Tang’s synthesis of bicyclic bromide

78

.

Scheme 10. Yang, Chen, and Tang’s synthesis of tetracyclic intermediate

76

....

Scheme 11. Yang, Chen, and Tang’s synthesis of pentacyclic intermediate

102

....

Scheme 12. Yang, Chen, and Tang’s synthesis of heptacyclic intermediate

108

....

Scheme 13. Final stages and completion of the Yang/Chen/Tang total synthesis...

Figure 9. Summary of the Yang/Chen/Tang total synthesis of schindilactone A ...

Figure 10. Yang and Chen’s branching-oriented strategy for the divergent tot...

Figure 11. Select schinortriterpenoid natural products succumbed to chemical...

Chapter 7

Figure 1. Molecular structures of representative welwitindolinones

1

–

5

.

Figure 2. Current hypothesis for the biosynthesis of welwitindolinones (part...

Figure 3. Current hypothesis for the biosynthesis of welwitindolinones (part...

Figure 4. Select synthetic approaches toward bicyclo[4.3.1]decane-containing...

Figure 5. Rawal’s retrosynthetic analysis of oxidized welwitindolinones

3a

,

Scheme 1. (A) Catalytic cycle of a typical Pd-catalyzed enolate arylation re...

Scheme 2. Rawal’s model study on the Pd-catalyzed enolate arylation and subs...

Scheme 3. Rawal’s synthesis of vinylogous ester

44

. [The first step followed...

Scheme 4. Rawal’s synthesis of tetracycle

51

.

Scheme 5. Final stages and completion of Rawal’s total synthesis of

N

-methyl...

Scheme 6. Rawal’s collective total synthesis of oxidized welwitindolinones

3

...

Figure 6. (A) First proposal of an aryne intermediate (1902) and a later cha...

Figure 7. Studies on (A) the generation of indolynes, and (B) the nucleophil...

Scheme 7. Overturning the intrinsic regioselectivity in nucleophilic additio...

Figure 8. Garg’s retrosynthetic analysis of oxidized welwitindolinones

3a

,

3

...

Scheme 8. Garg’s synthesis of tetracycle

103

through an intramolecular indol...

Scheme 9. Failed substrates for the intramolecular indolyne cyclization. (A)...

Scheme 10. Garg’s synthesis of oxindole intermediate

117

.

Scheme 11. Garg’s synthesis of bridgehead amine

123

via intramolecular C—H a...

Scheme 12. Final stages and completion of Garg’s total synthesis of oxidized...

Figure 9. Failed attempts to install the C13

α

-chloride functionality....

Scheme 13. Garg’s total synthesis of

N

-methylwelwitindolinone B isothiocyana...

Scheme 14. Rawal’s total synthesis of

N

-methylwelwitindolinone B isothiocyan...

Chapter 8

Scheme 1. (A) Molecular structures of ryanodine (

1

), ryanodol (

2

), and relat...

Figure 1. Semisynthetic [

3

H]-labeled ryanodine analogues.

Figure 2. Schematic representation of a striated muscle cell.

Figure 3. Deslongchamps’ retrosynthetic analysis of ryanodol (

2

).

Scheme 2. Deslongchamps’ synthesis of dienone

26

.

Scheme 3. (A) Deslongchamps’ model study of the Diels–Alder reaction; (B) ad...

Scheme 4. Deslongchamps’ synthesis of dienophile (

S

)-

40

and its conversion t...

Scheme 5. (A) Deslongchamps’ synthesis of aldol products

53

and

55

; (B) dias...

Scheme 6. Study on the reactions between acetals

59a,b

and ozone.

Scheme 7. Deslongchamps’ synthesis of intermediate

68

via

C

-ring decoration ...

Scheme 8. Deslongchamps’ synthesis of anhydroryanodol (

4

).

Scheme 9. Final stages and completion of Deslongchamps’ total synthesis of (...

Figure 4. Inoue’s retrosynthetic analysis of ryanodol (

2

).

Scheme 10. (A) Inoue’s synthesis of

C

2

-symmetric diketone (+)-

84

; (B) Song a...

Scheme 11. Inoue’s synthesis of

C

2

-symmetric diketone

82

.

Scheme 12. (A) Inoue’s proposed desymmetrization of diketone

82

; (B) success...

Scheme 13. Inoue’s synthesis of intermediate

111

via bridgehead radical

110

....

Scheme 14. Inoue’s synthesis of advanced intermediate

116

via

C

-ring formati...

Scheme 15. Final stages and completion of Inoue’s total synthesis of (+)-rya...

Figure 5. Reisman’s retrosynthetic analysis of ryanodol (

2

).

Scheme 16. (A) Reisman’s exploratory hydroxylation studies; (B) a one-pot do...

Scheme 17. Reisman’s synthesis of tetracycle 122 using an intramolecular Pau...

Scheme 18. Reisman’s synthesis of enone

142

via

A

-ring oxidation/functionali...

Scheme 19. Final stages and completion of Reisman’s total synthesis of (+)-r...

Scheme 20. Deslongchamps’ and Inoue’s initial acylation studies.

Scheme 21. Inoue’s total synthesis of (+)-ryanodine (

1

).

Scheme 22. Reisman’s synthesis of (+)-anhydroryanodine (

3

).

Scheme 23. Reisman’s synthesis of (+)-ryanodine (

1

).

Scheme 24. Comparison of the orders of ring formation in the three syntheses...

Chapter 9

Figure 1. Symbolic illustrations demonstrating Fischer’s lock and key model ...

Figure 2. Historic milestone achievements toward chiral resolution: (A) manu...

Figure 3. (A) Structure of the enzyme commission (EC) number for the classif...

Figure 4. Schematic overview over the individual steps of the iterative cycl...

Figure 5. Requirement (left) and general course (right) of directed evolutio...

Figure 6. Renata’s retrosynthetic analysis of gedunin (

26

).

Scheme 1. Synthesis of alkyl iodide lactone

32

.

Scheme 2. Synthesis of bicyclic hydroxy ketone

33

.

Scheme 3. Final stages and completion of Renata’s synthesis of gedunin (

26

)....

Figure 7. Renata’s retrosynthetic analysis of mitrephorone A (

27

).

Scheme 4. Synthesis of

ent

-trachylobane carboxylic acid fragment

50

.

Scheme 5. Final stages and completion of Renata’s formal total synthesis of ...

Figure 8. Huffman and Fryszkowska’s retrosynthetic analysis of islatravir (

3

...

Scheme 6. Huffman and Fryszkowska’s chemoenzymatic total synthesis of islatr...

Chapter 10

Figure 1. Molecular structures of representative trioxacarcins

1

–

8

and their...

Figure 2. Preparation and characterization of DNA–trioxacarcin A complex

10

...

Figure 3. Representation of a partial X-ray crystallographic structure of DN...

Scheme 1. Structural specificity in the binding of trioxacarcin A (

3

) with D...

Figure 4. Tang’s proposed biosynthesis of trioxacarcins (2015).

Scheme 2. Hauser’s and Kraus’ original reports on the annulation reactions b...

Figure 5. (A) Mechanism and (B,C) selected substrate scopes of the Hauser–Kr...

Scheme 3. Switch of strategy from Hauser–Kraus annulation to Diels–Alder rea...

Scheme 4. Hauser–Kraus annulations in Nicolaou’s (A) first-generation, and (...

Figure 6. Myers’ retrosynthetic analysis of DC-45-A2 (

1

), DC-45-A1 (

2

), and ...

Scheme 5. Myers’ synthesis of cyanophthalide

76

.

Scheme 6. Myers’ synthesis of cyclohexenone derivative

77

via a diastereosel...

Scheme 7. (A) Baylis–Hillman reaction generating dioxane product

95

; (B) its...

Scheme 8. Myers’ synthesis of diazo compound

75

.

Scheme 9. Fragment coupling and completion of Myers’ total synthesis of DC-4...

Scheme 10. Myers’ synthesis of trioxacarcinoside A glycosyl donors

109

and

1

...

Scheme 11. (A) Final stages and completion of Myers’ total synthesis of DC-4...

Scheme 12. Myers’ synthesis of trioxacarcinose B bis-acetate (

120

).

Scheme 13. Final stages and completion of Myers’ total synthesis of trioxaca...

Figure 7. Naturally occurring trioxacarcins synthesized in the Nicolaou grou...

Figure 8. Nicolaou’s retrosynthetic analysis of advanced intermediate

71

.

Scheme 14. Nicolaou’s synthesis of tricyclic intermediate

138

.

Scheme 15. Nicolaou’s synthesis of intermediate

147

via sequential functiona...

Scheme 16. Nicolaou’s synthesis of epoxyketone

154

.

Scheme 17. Lewis acid-induced stereodivergent rearrangement of epoxyketone

1

...

Scheme 18. Final stages and completion of Nicolaou’s total synthesis of DC-4...

Scheme 19. Nicolaou’s synthesis of glycosyl donors

162

and

163

.

Scheme 20. Nicolaou’s synthesis of glycosyl donors

166

,

167a

, and

167b

.

Scheme 21. Final stages and completion of Nicolaou’s total synthesis of trio...

Scheme 22. Nicolaou’s total synthesis and full structural elucidation of tri...

Scheme 23. (A) Nicolaou’s syntheses of designed analogues

183

and

191

; (B) c...

Scheme 24. Myers’ synthesis and biological evaluation of iso-DC-45-A2 (

192

)....

Scheme 25. (A) Myers’ synthesis of antibody–drug conjugate

198

; (B) proposed...

Chapter 11

Figure 1. Biosynthetic hypothesis for aplyviolene (

1

) and the related natura...

Figure 2. (A) Feasibility interrogation of the assembly of the bis-acetal un...

Scheme 1. Overman’s synthesis of silyl enol ether

24

.

Scheme 2. Final stages and completion of Overman’s first-generation synthesi...

Scheme 3. Overman’s synthesis of enone intermediate

33

(the first two steps ...

Scheme 4. Overman’s studies on the preparation and conjugate addition of org...

Figure 3. Potential precursors of a

cis

-perhydroazulene coupling partner bea...

Figure 4. Electronic configurations of the ground,

1

MLCT and

3

MLCT states of...

Scheme 5. (A) Photocatalytic reduction of phenacyl bromide (

50

) to acetophen...

Scheme 6. (A) Okada and Oda’s radical conjugate addition enabled by visible-...

Scheme 7. Overman’s streamlined synthesis of aplyviolene (

1

) featuring a pho...

Scheme 8. Examples of photochemical [2+2] cycloadditions.

Scheme 9. (A) Stephenson’s dehalogenation reaction enabled by visible-light ...

Scheme 10. Selected total syntheses featuring radical addition reactions ena...

Scheme 11. (A) Visible-light-driven [2+2] cycloaddition of bis-enones; (B) r...

Scheme 12. Visible-light-driven [4+2] cycloaddition in the total synthesis o...

Scheme 13. Photochemical functionalizations of alkenes and electron-rich are...

Scheme 14. (A) Asymmetric

α

-alkylation of aldehydes via cooperative vis...

Scheme 15. Visible-light photoredox catalysis merged with HAT catalysis [(A)...

Scheme 16. Room temperature C—H arylation enabled by visible-light metallaph...

Scheme 17. Merging visible-light photoredox catalysis with nickel catalysis ...

Figure 5. Comparison of the ground and excited state electronic configuratio...

Scheme 18. Photoinduced, copper-catalyzed enantioconvergent C—N coupling (Fu...

Scheme 19. An example of near-infrared (NIR)-light photoredox catalysis (Cam...

Chapter 12

Figure 1. Molecular structures of representative oligomeric indole alkaloids...

Scheme 1. (A) Current understanding of the biosynthesis of ditryptophenaline...

Scheme 2. (A) Retrosynthetic analysis of communesin F (

18

); (B) Movassaghi’s...

Figure 2. (A) Li’s rationale on the biosynthesis of naseseazine B (

2

); (B) t...

Scheme 3. Different strategies toward the C5—C5′ linkage construction in the...

Scheme 4. Baran’s synthesis of (±)-psychotrimine [(±)-

5

] featuring the const...

Figure 3. Oligomeric indole alkaloids with N—N linkages.

Figure 4. Baran’s retrosynthetic analysis of dixiamycin A/B (

49a/b

).

Scheme 5. Baran’s synthesis of diene fragment

55

(the first five steps follo...

Scheme 6. Baran’s synthesis of xiamycin A (

50

).

Figure 5. Cyclic voltammetry of adsorbed (A) and dissolved (B) analyte: sche...

Figure 6. Cyclic voltammogram of carbazole (

64

) and chemical interpretation ...

Scheme 7. Baran’s electrochemical oxidative dimerization of (A) carbazole (

6

...

Scheme 8. Reaction course and synthetic applications of Kolbe and non-Kolbe ...

Scheme 9. Shono oxidation and the “cation pool” method.

Scheme 10. Comparison of electrochemical and PhI(OAc)

2

-mediated oxidative ma...

Scheme 11. TEMPO-mediated electrochemical oxidation of alcohols (Semmelhack

Scheme 12. Mediated electrochemical oxidation of C—H bonds (Baran

et al

., 20...

Scheme 13. Pd-Catalyzed electrochemical C—H acetoxylation (Mei

et al

., 2017)...

Scheme 14. Mn-catalyzed electrochemical olefin difunctionalization reactions...

Scheme 15. Electrophotocatalysis for the generation of extremely strong oxid...

Chapter 13

Figure 1.

In

,

out

-bridgehead stereochemistry and its embodiment in the struct...

Scheme 1. Synthesis of model tricycle

10

via a de Mayo-type [2+2] cycloaddit...

Scheme 2. Winkler’s total synthesis of (±)-ingenol [(±)-

4

] (2002).

Scheme 3. Tanino and Kuwajima’s total synthesis of (±)-ingenol [(±)-

4

] (2003...

Scheme 4. Wood’s total synthesis of (−)-ingenol [(−)-

4

] (2004).

Scheme 5. Improved isolation protocol of ingenol (

4

) and its semisynthetic c...

Figure 2. Biosynthetic pathway of jolkinol C (

54

), a possible key intermedia...

Figure 3. (A) Mapping isoprene units onto the skeletons of jolkinol C and in...

Figure 4. Baran’s retrosynthetic analysis of (−)-ingenol [(−)-

4

].

Scheme 6. Baran’s synthesis of aldehyde (

R

)-

66

(the first three steps follow...

Scheme 7. Baran’s synthesis of methyl-ketone building block

65

.

Scheme 8. Baran’s synthesis of tetracycle

62

via fragment coupling and an al...

Scheme 9. Failed attempts to perform a vinylogous pinacol rearrangement on a...

Scheme 10. Baran’s synthesis of carbonate intermediate

82

.

Scheme 11. (A) Successful vinylogous pinacol rearrangement of carbonate subs...

Scheme 12. Undesired retro-pinacol pathways from intermediate

85

.

Scheme 13. Final stages and completion of Baran’s total synthesis of (−)-ing...

Figure 5. Comparison of two synthetic routes from ethyl-arene

96

to diol

97

...

Figure 6. Summary of Baran’s two-phase redox-economic total synthesis of ing...

Figure 7. Synthesis and biological evaluation of diversely oxygenated ingeno...

Chapter 14

Scheme 1. (A) Co-catalyzed Markovnikov hydration of unactivated olefins (Muk...

Figure 1. Currently accepted mechanism of the Mukaiyama hydration and relate...

Scheme 2. Nojima’s study of the Co-catalyzed hydrosilylperoxidation reaction...

Figure 2. (A) Representative endoperoxide natural products with antimalarial...

Scheme 3. Maimone’s synthesis of key intermediate

31

.

Scheme 4. Study and optimization of the radical peroxidation cascade leading...

Figure 3. Summary of Maimone’s four-step total synthesis of cardamom peroxid...

Scheme 5. (A) Mn-catalyzed hydrogenation of electron-neutral olefins with th...

Scheme 6. Selective reduction of C=C bonds in the presence of other competin...

Scheme 7. Co-catalyzed isomerization of terminal alkenes (Shenvi

et al

., 201...

Scheme 8. Application of HAT hydrogenation in Zhang’s total synthesis of apl...

Figure 4. Molecular structures of ginkgolide B (

69

) and bilobalide (

70

).

Figure 5. Prior total syntheses of bilobalide by Corey

et al

. (1987, 1988) a...

Figure 6. Shenvi’s retrosynthetic analysis of bilobalide (

70

).

Scheme 9. Shenvi’s synthesis of cyclopentene intermediate

79

.

Scheme 10. (A) Diastereoselective Mukaiyama-type hydration of olefin

79

; (B)...

Scheme 11. (A) Failed attempts toward diastereoselective bond formation at C...

Scheme 12. Advancement of alkyne intermediate

95

to bilobalide (

70

).

Scheme 13. Hydroxylation of intermediate

77

at the undesired C1 position.

Scheme 14. Successful and reproducible C10-hydroxylation to provide bilobali...

Figure 7. Co- or Mn-catalyzed olefin hydrofunctionalizations (Carreira

et al

Scheme 15. Boger’s synthesis of vinblastine (

120

) and analogues thereof usin...

Scheme 16. Baran’s olefin hydroamination with nitroarenes (2015).

Figure 8. Baran’s HAT-initiated olefin cross-coupling (2014, 2017).

Figure 9. Molecular structures of nodulisporic acids A–F (

136

–

141

) and Smith...

Figure 10. Pronin’s retrosynthetic analysis of nodulisporic acid C (

138

).

Scheme 17. Pronin’s first-generation synthesis of tricyclic fragment

150

.

Scheme 18. Pronin’s second-generation synthesis of tricyclic fragment

150

an...

Scheme 19. Pronin’s synthesis of aryl chloride fragment

145

.

Scheme 20. Final stages and completion of Pronin’s total synthesis of noduli...

Figure 11. Co-catalyzed asymmetric olefin hydrofunctionalization (Pronin

et

...

Figure 12. Co/Ni-dual catalyzed olefin hydroarylation (Shenvi

et al

., 2016, ...

Figure 13. Biosynthetic machineries which likely provided inspiration for th...

Chapter 15

Scheme 1. Construction of an all-carbon quaternary stereocenter via asymmetr...

Scheme 2. (A) Possible biosynthetic pathway of a family of nonclassical taxa...

Scheme 3. Application of Claisen rearrangement for the construction of an al...

Scheme 4. Examples of transition metal-catalyzed allylic substitution reacti...

Scheme 5. Examples of transition metal-catalyzed conjugate addition reaction...

Scheme 6. Application of asymmetric intramolecular Heck reaction in Overman’...

Figure 1. Snyder’s retrosynthetic analysis of conidiogenone (

52

) and its sib...

Scheme 7. Snyder’s synthesis of bicyclic ketone

60

.

Scheme 8. Snyder’s attempted synthesis of intermediate

73

.

Scheme 9. Snyder’s synthesis of tricyclic iodide

56

via a modified intramole...

Figure 2. Currently understood mechanism of the Cr/Co-catalyzed NHK-type rea...

Scheme 10. Comparison of the performances of substrates

56

and C1-

epi

-

56

in ...

Scheme 11. Final stages and completion of Snyder’s synthesis of conidiogenon...

Scheme 12. (A) Failed and (B) successful endeavours for casting the C5 all-c...

Scheme 13. Enantioselective pinacol rearrangement for the construction of al...

Scheme 14. Total synthesis of (

S

)-sporochnol (

116

) via successive rearrangem...

Scheme 15. Total synthesis of (±)-herbertenolide [(±)-

117

] via photolytic ge...

Figure 3. Construction of all-carbon quaternary stereocenter(s) via addition...

Figure 4. Molecular structures of batrachotoxin (

130

) and its parent alcohol...

Scheme 16. Highlights of Kishi’s total synthesis of (±)-batrachotoxinin A [(...

Figure 5. Du Bois’ retrosynthetic analysis of batrachotoxin (

130

) and batrac...

Scheme 17. Du Bois’ synthesis of methylene-cyclopentanone fragment

141

(the ...

Scheme 18. Du Bois’ synthesis of terminal alkyne intermediate

139

.

Figure 6. Du Bois’ preliminary explorations of the radical cyclization.

Scheme 19. (A) Failed and (B) successful endeavours from the Du Bois team fo...

Scheme 20. Du Bois’ synthesis of hexacyclic lactam

173

.

Scheme 21. Du Bois’ synthesis of advanced intermediate

137

.

Scheme 22. Final stages and completion of Du Bois’ total synthesis of batrac...

Chapter 16

Scheme 1. C(sp

2

)—H functionalization via electrophilic aromatic substitution...

Scheme 2. C(sp

2

)—H functionalization via nucleophilic aromatic substitution ...

Scheme 3. C4-selective functionalization of pyridine derivatives (McNally

et

...

Scheme 4. Minisci-type reactions: (A) initial discovery by Minisci

et al

. (1...

Scheme 5. Siegel’s radical-mediated C(sp

2

)—H oxidation (2013).

Scheme 6. (A) Knochel’s regiodivergent C—H deprotonation/functionalization (...

Scheme 7. C—H activation mediated by stoichiometric amounts of Pd(OAc)

2

(Rya...

Scheme 8. Sanford’s Pd-catalyzed C—H acetoxylation directed by (A) a 2-pyrid...

Scheme 9. Application of C—H oxidation reactions in the total syntheses of (...

Scheme 10. Yu’s Pd-catalyzed C—H methylation directed by a carboxylate group...

Scheme 11. (A,B) Acceleration effects of MPAA ligands on Pd-catalyzed direct...

Scheme 12. Application of ligand-accelerated C—H olefination in the total sy...

Scheme 13. Desymmetrization of achiral aromatic compounds via (A) enantiosel...

Scheme 14. Applications of Pd-catalyzed asymmetric C—H functionalizations in...

Scheme 15. (A) The Catellani reaction and its proposed mechanism; (B) applic...

Scheme 16. Adaptations of the Catellani reaction for

meta

-C—H functionalizat...

Scheme 17. Pd-catalyzed directed functionalizations of (A)

meta

-C—H bonds (Y...

Scheme 18. Examples of Rh-catalyzed aromatic C—H functionalization [(A) Cram...

Scheme 19. Ir-catalyzed C—H borylation of (hetero)aromatic compounds [(A) Sm...

Scheme 20. Effect of ligand structure on the regiochemical outcome of Ir-cat...

Scheme 21. Aromatic C—H functionalization via formal carbene/nitrene inserti...

Figure 1. Site-selective C—H functionalization of quinoline—a case study.

Scheme 22. (A) Sanford’s directed C(sp

3

)—H acetoxylation and (B,C) its appli...

Scheme 23. Dong’s oxime-directed C(sp

3

)—H acetoxylation (2012).

Scheme 24. (A) Auxiliary-assisted arylation of secondary C—H bonds (Daugulis...

Scheme 25. (A) Yu’s ligand-enabled secondary C—H arylation (2012) and (B) it...

Scheme 26. C(sp

3

)—H functionalization via “nonstandard” palladacycle interme...

Scheme 27.

γ

-Selective C—H functionalization via the participation of a...

Scheme 28. Hydroxy group-directed Ir-catalyzed functionalization of (A) prim...

Scheme 29. Ir-catalyzed nondirected C—H functionalization on saturated heter...

Figure 2. Two common mechanisms for C(sp

3

)—H insertion by an [M]=X complex (...

Figure 3. Intramolecular and intermolecular C—H insertions of metal carbenoi...

Scheme 30. Rh-catalyzed site-selective C—H carbene insertions (Davies

et al

....

Scheme 31. Macrocycle formation via C—H carbene insertion (Davies

et al

., 20...

Scheme 32. Examples of Rh-catalyzed intermolecular C—H amination (Du Bois

et

...

Scheme 33. Examples of Fe-catalyzed intermolecular C—H amination (Che

et al

....

Scheme 34. Fe-catalyzed oxidation of unactivated tertiary C—H bonds (White

e

...

Scheme 35. (A) Catalyst-governed site-selective oxidation of secondary C—H b...

Scheme 36. C—H functionalization of ethane and methane mediated by a polyoxo...

Scheme 37. C(sp

3

)—H functionalization mediated by oxygen radicals. [(A) Bart...

Scheme 38. C(sp

3

)—H functionalization via (A) classical and (B) modified Hof...

Scheme 39. Intermolecular amidylradical-mediated C(sp

3

)—H functionalization ...

Figure 4. Tabulated summary of aromatic and aliphatic C—H functionalizations...

Figure 5. Molecular structures of gukulenins B (

290

) and A (

291

) and their s...

Figure 6. Molecular structures of tropolone (

292

), its methyl ether (

294

), a...

Scheme 40. Formulation of a “sequential tropolone functionalizations” strate...

Figure 7. Nicolaou’s forward synthetic plan toward gukulenin B (

290

).

Scheme 41. Nicolaou’s synthesis of tropolone intermediate

309

.

Scheme 42. Nicolaou’s synthesis of intermediate

326

through successive olefi...

Scheme 43. Nicolaou’s regio- and atroposelective functionalization of the tr...

Scheme 44. Nicolaou’s synthesis of the right-hand fragment

338

via Ir-cataly...

Scheme 45. Nicolaou’s synthesis of tricycle

342

via S

E

Ar-type C

γ

—H func...

Scheme 46. (A,B) Failed attempts toward the synthesis of an

α

,

β

,

γ

...

Scheme 47. Nicolaou’s synthesis of the left-hand monomeric fragment

351

via ...

Scheme 48. Nicolaou’s synthesis of pseudodimer

355

via two consecutive cross...

Scheme 49. Final stages and completion of Nicolaou’s total synthesis of guku...

Figure 8. Speculated biosynthesis of gukulenin B (

290

).

Guide

Cover

Table of Contents

Title Page

Copyright

Foreword

Preface

About the Authors

Abbreviations

Begin Reading

Image / Photo Credits

Author Index

Subject Index

End User License Agreement

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Further Reading from Wiley-VCH

Nicolaou, K. C. / Sorensen, E. J.

Classics in Total Synthesis – Targets, Strategies, Methods

1996

ISBN 978-3-527-29231-8 (Softcover)

Nicolaou, K. C. / Snyder, S. A.

Classics in Total Synthesis II – More Targets, Strategies, Methods

2003

ISBN 978-3-527-30684-8 (Softcover)

Nicolaou, K. C. / Chen, J. S.

Classics in Total Synthesis III – Further Targets, Strategies, Methods

2011

ISBN 978-3-527-32958-8 (Hardcover)

ISBN 978-3-527-32957-1 (Softcover)

Carreira, E. M. / Kvaerno, L.

Classics in Stereoselective Synthesis

2009

ISBN 978-3-527-32452-1 (Hardcover)

ISBN 978-3-527-29966-9 (Softcover)

Corey, E. J. / Cheng, X.-M.

The Logic of Chemical Synthesis

1995

ISBN 978-0-471-11594-6 (Softcover)

Corey, E. J. / Wu, Y.-J.

Molecules Engineered Against Oncogenic Proteins and Cancer

2023

ISBN 978-1-394-20708-4 (Hardcover)

Classics in Total Synthesis IV

New Targets, Strategies, Methods

K. C. Nicolaou

Ruocheng Yu

Stephan Rigol

With a Foreword by

E. J. Corey

Authors

Prof. Dr. K. C. NicolaouRice University6100 Main StreetHouston, TX 77005USA

Dr. Ruocheng YuRice University6100 Main StreetHouston, TX 77005USA

Dr. Stephan RigolRice University6100 Main StreetHouston, TX 77005USA

Cover Design: Wiley

Cover Image: © Black sponge Halichondria okadai, Courtesy of Dr. Norihito Maru

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Print ISBN: 978-3-527-34877-0ePDF ISBN: 978-3-527-83148-7ePub ISBN: 978-3-527-83149-4

Foreword

It is both an honor and a pleasure to pen the foreword for the fourth volume of Classics in Total Synthesis, as I did for the three previous volumes. This series has emerged as a guiding light in the ever-expansive realm of total synthesis. As we embark on this intellectual journey, it is essential to reflect on the profound impact that the preceding volumes have had on our understanding of the total synthesis of complex molecules.

Classics IV seamlessly joins its predecessors, weaving together the threads of scientific discovery, challenge, and intellectual pursuit. This series has proven to be not only a chronicle of synthetic triumphs but also a celebration of the inherent complexity and beauty, which are inherent to total synthesis endeavours.

As I delve into the prepublication draft of this volume, I find the presented synthetic research remarkably clear and vivid and find each of the chapters exerting a captive force. The collection of synthetic triumphs within these pages invites readers to traverse the great complexity and variety that is characteristic for total synthesis journeys. The challenges presented verge on the impossible, demanding not only mental and practical rigor but also unwavering dedication, persistence, and hard work.

One of the remarkable aspects of the Classics in Total Synthesis series has been its ability to transcend disciplinary boundaries. While rooted in chemistry, the series establishes strong connections with biology and medicine. This interdisciplinary approach highlights the relevance of synthetic chemistry at a fundamental level to human well-being, health, and education.

The educational approach employed by the authors is enormously valuable and effective. The careful balance between historical context, comments on the molecules’ impact to humankind, and the design and execution aspects of each synthesis creates a narrative that is not only clear but also intellectually stimulating. It is a sheer delight to revisit each synthetic success guided by the insightful analyses found throughout Classics IV.

As mentioned in the Forewords of the earlier volumes, the enormous number of achievements in total synthesis is so large that capturing them all in a single collection is an impossible task. However, Classics in Total Synthesis has risen to this challenge with grace, presenting a carefully made selection that not only represents outstanding achievements, namely the construction of highly complex natural products, but also covers a diverse set of synthetic methodologies.

The question arises: Have we reached a plateau in scientific or intellectual discovery within the field of synthetic organic chemistry? The answer, as echoed by the authors, is a resounding no. The opportunities for new developments and discoveries are as vast as the synthetic targets that remain to be uncovered, chased, and conquered. Today’s total synthesis is not a culmination but a prelude to a future that promises continued dynamic development, relentlessly pushing the boundaries of what we perceive as possible.

In crafting this Foreword, I thank K. C. Nicolaou, Ruocheng Yu, and Stephan Rigol for their work in sustaining the heritage of Classics in Total Synthesis. May the publication of Classics IV be met with the same enthusiasm and admiration as it was rightly the case with its predecessors. I am confident that studying the Classics will empower upcoming generations of chemists, fostering a profound comprehension and appreciation for the significance of total synthesis. This endeavour will instill in them a deep understanding of the value and importance of natural products through showcasing the appealing beauty inherent to their molecular architectures and such insights will serve as catalyst, inspiring these aspiring chemists to embark on their own transformative journeys of exploration, discovery, and innovation.

E. J. CoreyHarvard University23 January 2024

Preface

As we embark on the journey into the pages of this fourth volume in the Classics in Total Synthesis series, we find ourselves standing at the precipice of a new chapter in the evolving narrative of organic synthesis. This series, conceived with the dual purpose of documenting historical milestones and serving as an educational beacon, has traversed through the annals of synthetic chemistry, illuminating the paths carved by the practitioners of our field.

In the preceding volumes (Classics I, Classics II, and Classics III), we witnessed the meticulous unraveling of nature’s complexity through ingenious synthetic strategies. Classics I laid the groundwork, introducing us to the profound philosophy and purpose of total synthesis. Building upon these foundational principles, Classics II expanded our horizons with a focused exploration of the transformative potential that the 21st century holds for synthetic chemistry. Classics III brought us up to speed with the rapid advancements of the recent era, showcasing the elegance, brevity, and environmental consciousness that characterize the latest synthetic frontiers.

As we delve into the rich tapestry of Classics IV, our aim remains steadfast—to chronicle the evolving landscape of total synthesis. This volume encapsulates the culmination of new methodologies, emerging trends, and a selection of significant total syntheses undertaken from 2009 to 2022 while additionally including two earlier syntheses from 1979 and 1992 for comparison and to highlight the development of organic synthesis over the past decades. In the spirit of its predecessors, Classics IV seeks to inspire and educate, weaving together the historical context, the intricacies of retrosynthetic analysis, and the tactical brilliance in execution.

From the complex architectures of natural products to the streamlined synthesis of functional molecules, each Chapter in Classics IV unfolds a unique story. The interplay of mechanisms, reactivity, selectivity, and stereochemical aspects is thoroughly examined, echoing the pedagogical format that has become synonymous with this series. Clear Schemes and Figures accompany the text, providing a visual guide to the sophisticated dance of atoms that is initiated by organic chemists, breaking bonds between some of them and forming new ones between others to build the molecules of Nature and their designed analogues in the laboratory.

The creation of Classics IV has been a collaborative endeavour, made possible by the dedication and insights of numerous individuals. Besides all scientists involved in the presented synthetic journeys, we extend our deepest gratitude to Janise L. Petrey for her careful editing, ensuring a seamless reading experience and bringing clarity to complex concepts; Jenna L. Kripal for her valuable assistance in creating stimulating and engaging frontispieces for each Chapter; and the Editorial staff from Wiley-VCH for their professional and straightforward handling of our manuscript and its translation to the finished book that you are holding in your hands now.

We dedicate Classics IV to the continued legacy of organic synthesis and recognize the responsibility that lies ahead. To the students, researchers, and practitioners who hold these pages, we impart the torch of innovation and the quest for knowledge. May this volume inspire the next generation of synthetic organic chemists, just as its predecessors have done, to further sharpen the art and science of organic synthesis in general and total synthesis in particular for the betterment of humankind.

Houston, TXSeptember 2024                                                 

K. C. NicolaouRuocheng YuStephan Rigol

About the Authors

K. C. Nicolaou was born in Cyprus and educated in the United Kingdom and United States. He currently holds the Harry C. and Olga K. Wiess Chair in Natural Sciences at Rice University. His previous appointments include positions at the University of Pennsylvania and joint positions as the Darlene Shiley Chair in Chemistry and the Aline W. and L. S. Skaggs Chair in Chemical Biology at The Scripps Research Institute and as Distinguished Professor of Chemistry at the University of California, San Diego. The impact of his work in chemistry, biology, and medicine flows from his contributions to chemical synthesis as described in over 800 publications. He is the recipient of numerous Prizes, Awards, and Honors (e.g., Nemitsas Prize, Wolf Prize, and the Robert Koch Gold Medal) and has been elected to several Academies, such as the New York Academy of Sciences; the American Academy of Arts and Sciences; the American Philosophical Society; the Royal Society of London; the National Academy of Sciences (USA); the Royal Society of Chemistry (UK); the Cyprus Academy of Sciences, Letters and Arts; and the German Academy of Sciences Leopoldina.

Ruocheng Yu studied chemistry at Peking University, China, as an undergraduate student under the supervision of Zhen Yang and Jiahua Chen. After receiving his bachelor’s degree in 2012, he went on to pursue his doctoral studies under the guidance of K. C. Nicolaou at The Scripps Research Institute and later Rice University. In the Nicolaou lab, he completed the total syntheses of several natural and designed molecules, including gukulenin B. He is currently a postdoctoral fellow in the laboratory of Emily Balskus.

Stephan Rigol received his higher education at Leipzig University, Germany, where he obtained his undergraduate degrees, and received his doctorate in 2013 after carrying out research in the fields of synthetic organic and medicinal chemistry under the guidance of Athanassios Giannis. He then moved to the United States to join the group of K. C. Nicolaou at Rice University where he is currently conducting research in the field of natural products chemistry with a particular focus on molecules with antibacterial and anticancer activities.

Abbreviations

18-crown-6

1,4,7,10,13,16-hexaoxacyclooctadecane

4CzIPN

1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene

9-BBN

9-borabicyclo[3.3.1]nonane

A

adenine

Ac

acetyl

acac

acetoacetate

Ad

adamantane

AD

asymmetric dihydroxylation

ADC

antibody–drug conjugate

ADP

adenosine diphosphate

AIBN

2,2′-azobisisobutyronitrile

AIDS

acquired immunodeficiency syndrome

α

KG

α

-ketoglutaric acid disodium salt dihydrate

AK

actinic keratosis

Alloc

allyloxycarbonyl

amphos

di-

tert

-butyl(4-dimethylaminophenyl)phosphine

aq.

aqueous

AQN

anthraquinone

ar

or

Ar

aryl

ATP

adenosine triphosphate

ATCC

American Type Culture Collection

ax

axial

AZADO

2-azaadamantane-

N

-oxyl

BAIB

bis(acetoxy)iodobenzene

BAr

F

tetrakis[3,5-bis(trifluoromethyl)-phenyl]borate

BDE

bond dissociation energy

BHT

2,6-di-

tert

-butyl-4-methylphenol

BINAP

([1,1′-binaphthalene]-2,2′-diyl)bis-(diphenylphosphane)

BINOL

2,2′-dihydroxy-1,1′-binaphthyl

BIPHEP

2,2′-bis(diphenylphosphino)-1,1′-biphenyl

Bn

benzyl

BNAH

1-benzyl-1,4-dihydronicotinamide

Boc

tert

-butoxycarbonyl

BOM

benzyloxymethyl

BOP

bis(2-oxo-3-oxazolidinyl)phosphinic

bpy

2,2′-bipyridine

bpz

2,2′-bipyrazine

brsm

based on recovered starting material

Bu

butyl

Bz

benzoyl

C

cytosine

CAN

ceric ammonium nitrate

Cap

caproyl

Cas9

CRISPR associated protein 9

cat.

catalytic

or

catalyst

Cbz

benzyloxycarbonyl

CD

cluster of differentiation

CDI

1,1′-carbonyldiimidazole

CFL

compact fluorescent light

CIPE

complex-induced proximity effect

Cit

L

-citrulline

Cl

4

NHPI

tetrachloro-

N

-hydroxyphthalimide

CMD

concerted metalation–deprotonation

CNS

central nervous system

CoA

coenzyme A

cod

1,5-cyclooctadiene

coe

cyclooctene

Cp

cyclopentadienyl

CRISPR

clustered regularly interspaced short palindromic repeats

CSA

10-camphorsulfonic acid

CV

cyclic voltammetry

cy

or

Cy

cyclohexyl

Δ

heat

dab

2,9-bis(

p

-anisyl)-1,10-phenanthroline

DABCO

1,4-diazabicyclo[2.2.2]octane

DAST

(diethylamino)sulfur trifluoride

dba

(

E

,

E

)-dibenzylideneacetone

DBB

di-

tert

-butylbiphenylide

DBN

1,5-diazabicyclo[4.3.0]non-5-ene

DBU

1,8-diazabicyclo[5.4.0]undec-7-ene

DCC

1,3-dicyclohexylcarbodiimide

DDQ

2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DDT

dichlorodiphenyltrichloroethane

DEAD

diethyl azodicarboxylate

DERA

2-deoxy-

D

-ribose-5-phosphate aldolase

dF(CF

3

)ppy

2-(2,4-difluorophenyl)-5-trifluoromethylpyridine

DG

directing group

DHPR

dihydropyridine receptor

DHQ

dihydroquinine

DIAD

diisopropyl azodicarboxylate

DIANANE

endo

,

endo

-2,5-diaminonorbornane

DIBAL-H

diisobutylaluminium hydride

dibm

diisobutyrylmethane

DMAP

4-dimethylaminopyridine

DMDO

3,3-dimethyldioxirane

DME

ethylene glycol dimethyl ether

DMF

N

,

N

-dimethylformamide

DMP

Dess–Martin periodinane

DMPU

1,3-dimethyl-3,4,5,6-tetrahydro-2(1

H

)-pyrimidinone

DMSO

dimethyl sulfoxide

DNA

deoxyribonucleic acid

DoM

directed

ortho

-metalation

DPBS

Dulbecco’s phosphate-buffered saline

dpm

dipivaloylmethanato

DPPA

diphenylphosphoryl azide

dppb

1,4-bis(diphenylphosphino)butane

dppf

diphenylphosphinoferrocene

dppp

1,3-bis(diphenylphosphino)propane

dr

diastereomeric ratio

dtbbpy

4,4′-di-

tert

-butyl-2,2′-bipyridine

DTBM

di-

tert

-butyl-4-methoxyphenyl

dtbpy

4,4′-di-

tert

-butyl-2,2′-bipyridine

EBX

ethynylbenziodoxolone

EC

50

half maximal effective concentration

ECC

excitation–contraction coupling

EDCI

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

ee

enantiomeric excess

ep

error-prone

eq

equatorial

equiv

equivalent(s)

esp

α

,

α

,

α

′,

α

′-tetramethyl-1,3-benzenedipropionic acid

ETP

epipolythiodiketopiperazine

EWG

electron-withdrawing group

Fc

ferrocenyl

FDPP

furanyldiketopyrrolopyrrole

FMO

frontier molecular orbital

fod

1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-4,6-octanedionate

G

guanine

G2

gap 2

gen.

generation

Glc

glucose

GlyR

glycine receptors

GOase

galactose oxidase

HAT

hydrogen atom transfer

hfacac

hexafluoroacetylacetonate

HFIP

hexafluoroisopropanol

HIV

human immunodeficiency virus

HLF

Hofmann–Löffler–Freytag

HMDS

hexamethyldisilazane

HMG

3-hydroxy-3-methylglutaryl

HMPA

hexamethylphosphoramide

HOBt

1-hydroxybenzotriazole

HPLC

high-performance liquid chromatography

HRMS

high-resolution mass spectrometry

Hsp

heat shock protein

HWE

Horner–Wadsworth–Emmons

hν

light

IBX

o

-iodoxybenzoic acid

IC

50

50% inhibitory concentration

IC

70

70% inhibitory concentration

imid.

imidazole

Ipc

isopinocampheyl

i

-Pr

isopropyl

IR

infrared

ISC

intersystem crossing

k

reaction rate constant

KHMDS

potassium hexamethyldisilazide

LA

Lewis acid

LBA

Lewis acid-assisted chiral Brønsted acid

LD

50

50% lethal dose

LDA

lithium diisopropylamide

LED

light-emitting diode

LG

leaving group

LiHMDS

lithium hexamethyldisilazide

liq.

liquid

LLG-5

Linckia laevigata

ganglioside 5

LLS

longest linear sequence

LSF

late-stage functionalization

M

molar

M

mitosis

Mal

maleimido

MC

metal-centered

m

-CPBA

m

-chloroperoxybenzoic acid

MDR

multi-drug resistance

MeOH

methanol

MES

mesityl (2,4,6-trimethylphenyl)

MIC

minimum inhibitory concentration

MLCT

metal-to-ligand charge transfer

MMPP

magnesium monoperoxyphthalate hexahydrate

MMTrCl

4-methoxytriphenylmethyl

MNBA

2-methyl-6-nitrobenzoic anhydride

modp

bis(1-morpholinocarbamoyl-4,4-dimethyl-1,3-pentanedionato) [i.e., 4-[5,5-dimethyl-2,4-di(oxo-κ

O

)-1-oxohexyl]morpholinato]

mol.

molecular

MOM

methoxymethyl

MoOPH

oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide)

MPAA

mono-

N

-protected amino acid

MPO

4-methylpyridine

N

-oxide

Ms

methanesulfonyl

MS

molecular sieves

MVK

methyl vinyl ketone (butenone)

MW

microwave

N

normal (equivalent concentration)

NAD

+

nicotinamide adenine dinucleotide (oxidized form)

NADH

nicotinamide adenine dinucleotide (reduced form)

NADP

+

nicotinamide adenine dinucleotide phosphate (oxidized form)

NADPH

nicotinamide adenine dinucleotide phosphate (reduced form)

NaHMDS

sodium hexamethyldisilazide

Nap

naphthalenide

or

naphthalenyl

NBS

N

-bromosuccinimide

NCIMB

National Collection of Industrial, Food and Marine Bacteria

NCS

N

-chlorosuccinimide

Nf

nonafluorobutanesulfonyl

NHC

N

-heterocyclic carbene

NHK

Nozaki–Hiyama–Kishi

NIR

near-infrared

NIS

N

-iodosuccinimide

NMM

N

-methylmorpholine

NMO

4-methylmorpholine

N

-oxide

NMP

N

-methylpyrrolidone

NMR

nuclear magnetic resonance

NOE

nuclear Overhauser effect

Ns

nitrobenzenesulfonyl

Nu

nucleophile

ox

oxalate

PABC

p

-aminobenzyloxycarbonyl

PAF

platelet-activating factor

PAFR

platelet-activating factor receptor

PanK

pantothenate kinase

PBR

peripheral benzodiazepine receptor

Pc

phthalocyanine

PCC

pyridinium chlorochromate

PCR

polymerase chain reaction

PDC

pyridinium dichromate

PDP

2-({(

S

)-2-[(

S

)-1-(pyridin-2-ylmethyl)pyrrolidin-2-yl]pyrrolidin-1-yl}methyl)pyridine

PdPc

palladium(II) octabutoxyphthalocyanine

PET

positron emission tomography

or

photoinduced electron transfer

PG

protecting group

Ph

phenyl

phen

1,10-phenanthroline

PHOX

2-[2-(diphenylphosphino)phenyl]-2-oxazoline

pin

pinacolato

PIPES

piperazine-

N

,

N

′-bis(2-ethanesulfonic acid)

Piv

pivaloyl

PKC

protein kinase C

PKS

polyketide synthase

PMB

4-methoxybenzyl

PMP

4-methoxyphenyl

or

1,2,2,6,6-pentamethylpiperidine

PNP

p

-nitrophenol

or

purine nucleoside phosphorylase

PPM

phosphopentomutase

PPO

pyrophosphate

PPTS

pyridinium 4-toluenesulfonate

ppy

2-phenylpyridine

PS-BEMP

polystyrene-bound 2-

tert

-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine

py

pyridine

PyOX

2-(pyridin-2-yl)-4,5-dihydrooxazole

quant.

quantitative

RCM

ring-closing metathesis

Red-Al

sodium bis(2-methoxyethoxy)aluminium hydride

RHF

restricted Hartree–Fock model

RNA

ribonucleic acid

rsm

recovered starting material

RyR

ryanodine receptor

Sal

salen

SAR

structure–activity relationship

SCE

saturated calomel electrode

SET

single-electron transfer

Sia

siamyl

SP

sucrose phosphorylase

sp.

species

T

thymine

TAS-F

tris(dimethylamino)sulfonium difluorotrimethylsilicate

TBADT

tetra-

n

-butylammonium decatungstate

TBAF

tetra-

n

-butylammonium fluoride

TBAI

tetra-

n

-butylammonium iodide

TBD

triazabicyclodecene

TBDPS

tert

-butyldiphenylsilyl

TBDPSCl

tert

-butyldiphenylchlorosilane

TBHP

tert

-butyl hydroperoxide

TBOx

tethered bis(8-quinolinolato)

TBS

tert

-butyldimethylsilyl

TCAI

trichloroacetimidate

TCPTAD

adamantan-1-yl-(4,5,6,7-tetrachloro-1,3-dioxo-1,3-dihydroisoindol-2-yl)acetate

TDAE

tetrakis(dimethylamino)ethylene

TEMPO

2,2,6,6-tetramethyl-1-piperidinyloxy, free radical

Teoc

2-(trimethylsilyl)ethoxycarbonyl

TES

triethylsilyl

Tf

trifluoromethanesulfonyl

TFA

trifluoroacetic acid

TFAA

trifluoroacetic anhydride

tfb*

tetrafluorobenzobarrelene

TFMS

zinc trifluoromethanesulfinate

THF

tetrahydrofuran

THP

tetrahydropyranyl

TIPS

triisopropylsilyl

Tle

tert

-leucine

TMEDA

N

,

N

,

N

′,

N

′-tetramethylethylenediamine

TMP

2,2,6,6-tetramethylpiperidide

tmphen

3,4,7,8-tetramethyl-1,10-phenanthroline

TMS

trimethylsilyl

TMTU

tetramethylthiourea

tol

or

Tol

tolyl

TPAP

tetra-

n

-propylammonium perruthenate

TPCP

1,2,2-triphenylcyclopropanecarboxylate

TPP

tetraphenylporphyrin

Tris

2,4,6-triisopropylbenzenesulfonyl

Ts

4-toluenesulfonyl

TS

transition state

Txn

trioxacarcin

UHP

urea hydrogen peroxide complex

USSR

Union of Soviet Socialist Republics

UV

ultraviolet

vs.

versus