Cover
Foreword by Prof. W. Hoffmann
Foreword by Prof. G. Mehta
Preface
1 Introduction
1. 1.1 Introduction, Concepts, and Brief History
2. 1.2 Need and Future Prospects of Protecting‐Group‐Free Synthesis
3. References
2 Protecting‐Group‐Free Synthesis of Natural Products and Analogs, Part I
1. 2.1 Introduction
2. 2.2 Mytilipin A
3. 2.3 Chokols
4. 2.4 (±)‐Diospongin A
5. 2.5 (−)‐Bitungolide F
6. 2.6 (+)‐Brevisamide
7. 2.7 21,22‐Diepi‐membrarolin
8. 2.8 (±)‐Pogostol and (±)‐Kessane
9. 2.9 (+)‐Allopumiliotoxin 267A
10. 2.10 (−)‐Hortonones A–C
11. 2.11 (−)‐Heliophenanthrone
12. 2.12 (−)‐Pycnanthuquinone C
13. 2.13 (+)‐Aplykurodinone‐1
14. 2.14 (±)‐Hippolachnin A
15. 2.15 (+)‐Linoxepin
16. 2.16 (+)‐Antofine and (–)‐Cryptopleurine
17. 2.17 (+)‐Tylophorine
18. 2.18 (±)‐Cruciferane
19. 2.19 (+)‐Artemisinin
20. 2.20 (±)‐Dievodiamine
21. 2.21 (−)‐Chaetominine
22. 2.22 Rubicordifolin
23. 2.23 (+)‐Caribenol A
24. 2.24 Camptothecin and 10‐Hydroxycamptothecin
25. 2.25 (+)‐Ainsliadimer A
26. 2.26 Cannabicyclol, Clusiacyclols A and B, Iso‐Eriobrucinols A and B, and Eriobrucinol
27. 2.27 (−)‐Mersicarpine, (−)‐Scholarisine G, (+)‐Melodinine, (−)‐Leuconoxine, and (−)‐Leuconolam
28. 2.28 (−)‐Lannotinidine B
29. 2.29 (−)‐Lycopodine
30. 2.30 (−)‐Lycospidine A
31. 2.31 Transtaganolides C and D
32. 2.32 (+)‐Chatancin
33. 2.33 (−)‐Jiadifenolide
34. 2.34 Pallambins C and D
35. 2.35 (+)‐Vellosimine
36. 2.36 (−)‐Pallavicinin and (+)‐Neopallavicinin
37. 2.37 Asteriscunolides A–D and Asteriscanolide
38. 2.38 (−)‐ and (+)‐Palmyrolide A
39. 2.39 (±)‐Bipinnatin J
40. 2.40 Cyanolide
41. 2.41 Conclusions
42. References
3 Protecting‐Group‐Free Synthesis of Natural Products and Analogs, Part II
1. 3.1 Introduction
2. 3.2 Hapalindole U and Ambiguine H
3. 3.3 Stenine
4. 3.4 Neostenine
5. 3.5 Englerin A
6. 3.6 Shimalactones A and B
7. 3.7 Cyanthiwigin F
8. 3.8 Sintokamides A, B, and E
9. 3.9 Ecklonialactones A and B
10. 3.10 (E)‐ and (Z)‐Alstoscholarines
11. 3.11 Berkelic Acid
12. 3.12 Myxalamide A
13. 3.13 Pipercyclobutanamide A
14. 3.14 Fusarisetin A
15. 3.15 Rhazinilam
16. 3.16 Yezo’otogirin C
17. 3.17 Clavosolide A
18. 3.18 Conclusion
19. References
4 Protecting‐Group‐Free Synthesis of Natural Products and Analogs, Part III
1. 4.1 Introduction
2. 4.2 Syntheses of Naturally Occurring Alkaloids
3. 4.3 Syntheses of Naturally Occurring Terpenoids
4. 4.4 Conclusions
5. References
5 Protecting‐Group‐Free Synthesis of Heterocycles
1. 5.1 Introduction
2. 5.2 Historical Background of Protection‐Free Strategy
3. 5.3 Protecting‐Group‐Free (PGF) Strategy for the Synthesis of N‐Heterocycles
4. 5.4 Protection‐Free Synthesis of Quinoline Derivatives
5. 5.5 Synthesis of Piperidine‐Containing Heterocycles Without Using Protecting Groups
6. 5.6 Synthesis of Quinazolines Without Using Protecting Groups
7. 5.7 Protection‐Free Synthesis of Pyrrolizine Alkaloid (−)‐Rosmarinecine
8. 5.8 Protecting‐Group‐Free Synthesis of O‐Heterocycles
9. 5.9 Protecting‐Group‐Free Synthesis of N,S‐Heterocycles
10. 5.10 Protection‐Free Synthesis of Macrocyclic Ring Heterocycles
11. 5.11 Protection‐Free Synthesis of Thiophene Polymer
12. 5.12 Protection‐Free Synthesis of Azaborine
13. 5.13 Conclusion
14. References
6 Protecting‐Group‐Free Synthesis of Drugs and Pharmaceuticals
1. 6.1 Introduction
2. 6.2 Raltegravir
3. 6.3 Levetiracetam
4. 6.4 Sitagliptin
5. 6.5 Paroxetine
6. 6.6 Synthesis of PI3K/mTOR Inhibitor Apitolisib
7. 6.7 Azepinomycin
8. 6.8 One‐Pot Synthesis of Sulfanyl‐histidine
9. 6.9 Synthesis of an Antiwrinkle Venom Analog
10. 6.10 Preparation of 5‐Arylidene Rhodanine and 2,4‐Thiazolidinediones
11. 6.11 Se‐Adenosyl‐L‐Selenomethionine and Analogs
12. 6.12 Conclusions
13. Acknowledgment
14. References
7 Protecting‐Group‐Free Synthesis in Carbohydrate Chemistry
1. 7.1 Introduction
2. 7.2 Protecting‐Group‐Free Total Synthesis (PGF‐TS)
3. 7.3 Selective PGF Functionalization at the Anomeric Position (O‐, N‐, and C‐Glycosylation)
4. 7.4 Selective PGF Functionalization at the Anomeric and Nonanomeric Positions (Oxidations)
5. 7.5 Conclusion
6. References
8 Protecting‐Group‐Free Synthesis of Glycosyl Derivatives, Glycopolymers, and Glycoconjugates
1. 8.1 Introduction
2. 8.2 Protecting‐Group‐Free Synthesis of Glycosyl Derivatives from Free Saccharides
3. 8.3 Protecting‐Group‐Free Synthesis of Glycopolymers
4. 8.4 Protecting‐Group‐Free Synthesis of Glycoconjugates
5. 8.5 Conclusions
6. References
9 Latent Functionality
1. 9.1 Introduction
2. 9.2 Latent Functionality for Direct Conversions Using Short‐Term Latent Groups
3. 9.3 Silicon‐Centered Latent Functionalities
4. 9.4 Latent Functionality in Total Synthesis (Long‐Term Latent Groups)
5. 9.5 Symmetry‐Based Latent Functionality Considerations
6. 9.6 Conclusions
7. References
Index
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List of Illustrations

Chapter 01
1. Scheme 1.1 Anderson’s synthesis of α‐cedrene (5).
2. Scheme 1.2 Corey’s synthesis of α‐cedrene (5).
3. Scheme 1.3 Robinson’s synthesis of tropinone (21) in 1917.
4. Scheme 1.4 Danishefsky’s synthesis of (±)‐patchouli alcohol.
5. Scheme 1.5 Total synthesis of (−)‐estafiatin (30).
6. Scheme 1.6 Kenney’s synthesis of (+)‐makomakine, (+)‐aristoteline, and (±)‐hobartine.
7. Scheme 1.7 Total synthesis of (±)‐cryptopleurine (48) by Weinreb et al. in 1983.
8. Scheme 1.8 Total synthesis of (±)‐fawcettimine (58) by Heathcock in 1989.
Chapter 02
1. Scheme 2.1 Total synthesis of mytilipin A (9) by Vanderwal et al.
2. Scheme 2.2 Kinetic resolution of (±)‐4 to enantio‐enriched vinyl epoxide (+)‐4.
3. Scheme 2.3 Synthesis of chokols K (14), E (15), and B (17a or 17b).
4. Scheme 2.4 Synthesis of (±)‐diospongin A (23).
5. Scheme 2.5 Total synthesis of bitungolide F (32).
6. Scheme 2.6 Zakarian’s total synthesis of (+)‐brevisamide (43).
7. Scheme 2.7 Synthesis of 21,22‐diepi‐membrarollin (53).
8. Scheme 2.8 Total synthesis of (±)‐pogostol (59) and (±)‐kessane (62).
9. Scheme 2.9 Total synthesis of (+)‐allopumiliotoxin 267A (69).
10. Scheme 2.10 Total synthesis of (−)‐hortonones A‐C (79–81).
11. Scheme 2.11 Synthesis of (−)‐heliophenanthrone (87).
12. Scheme 2.12 Total synthesis of (−)‐pycnanthuquinone C (91).
13. Scheme 2.13 Tang’s total synthesis of (+)‐aplykurodinone‐1 (99).
14. Scheme 2.14 Brown’s independent synthesis of (±)‐hippolachnin A (109).
15. Scheme 2.15 Wood’s independent synthesis of (±)‐hippolachnin A (109).
16. Scheme 2.16 Collaborative total synthesis of (±)‐hippolachnin A (109).
17. Scheme 2.17 Total synthesis of (+)‐linoxepin (125).
18. Scheme 2.18 Total synthesis of (+)‐linoxepin (125).
19. Scheme 2.19 Total synthesis of (+)‐antofine (142a).
20. Scheme 2.20 Total synthesis of (−)‐cryptopleurine (142b).
21. Scheme 2.21 Total synthesis of (S)‐tylophorine (151).
22. Scheme 2.22 Synthesis of racemic and chiral (S)‐tylophorine (151) by Opatz.
23. Scheme 2.23 The synthesis of tryptanthrin (161), (±)‐cruciferane (163), and phaitanthrins A (164) and B (162).
24. Scheme 2.24 Total synthesis of (+)‐artemisinin (170).
25. Scheme 2.25 Total synthesis of (±)‐dievodiamine (182).
26. Scheme 2.26 Total synthesis of (−)‐chaetominine (189) in a four‐step process.
27. Scheme 2.27 Synthesis of rubicordifolin (196).
28. Scheme 2.28 Total Synthesis of (+)‐caribenol A (207).
29. Scheme 2.29 Protecting‐group‐free total synthesis of camptothecin (219a) and 10‐hydroxycamptothecin (220).
30. Scheme 2.30 Total synthesis of (+)‐ainsliadimer (231).
31. Scheme 2.31 Total synthesis of cannabicyclol (235), clusiacyclols A (238) and B (239), eriobrucinol (240), and iso‐eriobrucinols A (241) and B (242).
32. Scheme 2.32 Zhu’s total synthesis of (−)‐mersicarpine (251), (−)‐scholarisine G (254), (+)‐melodinine E (255), (−)‐leuconolam (257), and (−)‐leuconoxine (258).
33. Scheme 2.33 Yao’s total synthesis of (−)‐lannotinidine B (267).
34. Scheme 2.34 Total synthesis of (−)‐lycopodine (275).
35. Scheme 2.35 Asymmetric total synthesis of (−)‐lycospidine A (284).
36. Scheme 2.36 Total synthesis of transtaganolides C (290) and D (291).
37. Scheme 2.37 Protecting‐group‐free enantioselective total synthesis of (+)‐chatancin (299).
38. Scheme 2.38 Protecting‐group‐free total synthesis of (−)‐jiadifenolide (311).
39. Scheme 2.39 Total synthesis of pallambins C (320a) and D (320b).
40. Scheme 2.40 Total syntheses of (+)‐vellosimine (329a) and analogs.
41. Scheme 2.41 Protecting‐group‐free total synthesis of (−)‐pallavicinin (340a) and (+)‐ neopallavicinin (340b).
42. Scheme 2.42 Li’s synthesis of various humulanolides.
43. Scheme 2.43 Total synthesis of (–)‐palmyrolide A (358).
44. Scheme 2.44 Total synthesis of (+)‐palmyrolide A (ent‐358) and (–)‐cis‐palmyrolide A (363).
45. Scheme 2.45 Total synthesis of (±)‐bipinnatin J (375).
46. Scheme 2.46 Total synthesis of cyanolide A (383).
Chapter 03
1. Scheme 3.1 Total synthesis of hapalindole U (5) and ambiguine H (10).
2. Scheme 3.2 (a) Total synthesis of stenine (20). (b) Transition states in the Diels–Alder reaction of 13 and cyclohexenone (14).
3. Scheme 3.3 Total synthesis of neostenine (33).
4. Scheme 3.4 Total synthesis of englerin A (48).
5. Scheme 3.5 Total synthesis of shimalactones A (66) and B (67).
6. Scheme 3.6 (a) Double asymmetric alkylation. (b) Total synthesis of cyanthiwigin F (78).
7. Scheme 3.7 (a) Synthesis of carboxylic acid 86. (b) Synthesis of amine 88a. (c) Total synthesis of sintokamides A (91), B (92), and E (93).
8. Scheme 3.8 Total synthesis of ecklonialactones A (109) and B (110).
9. Scheme 3.9 Total synthesis of (E)‐ and (Z)‐alstoscholarines (121 and 122).
10. Scheme 3.10 Total synthesis of berkelic acid (134).
11. Scheme 3.11 (a) Synthesis of vinyl iodide 139. (b) Total synthesis of myxalamide A (143).
12. Scheme 3.12 Total synthesis of the proposed structure of pipercyclobutanamide A (158).
13. Scheme 3.13 Total synthesis of fusarisetin A (173).
14. Scheme 3.14 Total synthesis of rhazinilam (191).
15. Scheme 3.15 Total synthesis of yezo’otogirin C (201).
16. Scheme 3.16 Total synthesis of clavosolide A (215).
Chapter 04
1. Figure 4.1 Tropinone and related alkaloids.
2. Scheme 4.1 Robinson’s synthesis of tropinone (1a).
3. Scheme 4.2 Protecting‐group‐free total syntheses of Aristotelia alkaloids.
4. Figure 4.2 Selected daphniphyllum alkaloids.
5. Scheme 4.3 Total synthesis of dihydroprotodaphniphylline (6a).
6. Figure 4.3 Indole monoterpene alkaloids, subincanadines A–C and F–G (9a–e).
7. Scheme 4.4 Protecting‐group‐free total synthesis of (±)‐subincanadine F (9e).
8. Scheme 4.5 Total synthesis of (±)‐subincanadine C (9c).
9. Figure 4.4 Selected benzo[c]phenanthridine alkaloids.
10. Scheme 4.6 Total syntheses of benzo[c]phenanthridine alkaloids.
11. Scheme 4.7 Synthesis of 2‐bromo‐N‐(α‐naphthyl)amines 19a–c.
12. Scheme 4.8 Syntheses of benzo[c]phenanthridine alkaloids 12 via an HAS.
13. Scheme 4.9 Proposed mechanism of benzo[c]phenanthridine synthesis.
14. Figure 4.5 Bis‐cyclotryptamine alkaloids in active form.
15. Scheme 4.10 Total synthesis of (±)‐chimonanthine (ent‐24a).
16. Scheme 4.11 Syntheses of (+)‐folicanthine (ent‐24b) and (−)‐calycanthine (ent‐24e).
17. Figure 4.6 Stereochemical rationale of catalytic enantioselective double alkylation of bis‐ester 29.
18. Scheme 4.12 Catalytic enantioselective double allylation of bis‐esters (±)‐ and meso‐29 and 35.
19. Scheme 4.13 Catalytic enantioselective total synthesis of (−)‐folicanthine (24b).
20. Figure 4.7 Representative of meso‐dimeric pyrrolidinoindoline alkaloids.
21. Scheme 4.14 Total synthesis of meso‐chimonanthine (40a) and meso‐calycanthine (40c).
22. Scheme 4.15 Sequential deacylative allylations (DaA) of bis‐esters 43a and b.
23. Scheme 4.16 Total synthesis of meso‐chimonanthine (40a) and meso‐calycanthine (40c).
24. Scheme 4.17 Proposed biosynthetic route to (+)‐versicolamide B (51) from notoamide E (54).
25. Scheme 4.18 Total synthesis of (+)‐versicolamide B (51) by Williams et al.
26. Figure 4.8 Psychotrimine (60) and plausible biogenetic pathway.
27. Scheme 4.19 Gram‐scale total synthesis of (±)‐psychotrimine (60).
28. Scheme 4.20 Synthesis of enantiopure pyrroloindoline 68 and (+)‐psychotetramine (71).
29. Scheme 4.21 Asymmetric total synthesis of (+)‐psychotrimine (60).
30. Figure 4.9 Naturally occurring triquinane natural products 73a–c.
31. Scheme 4.22 Total synthesis of (±)‐hirsutene (73a) by Mehta et al.
32. Figure 4.10 Erogorgiaene (75a) and pseudopterosin aglycon (75b).
33. Scheme 4.23 Catalytic enantioselective synthesis of (+)‐erogorgiaene (75a) by Hoveyda.
34. Scheme 4.24 Total synthesis of erogorgiaene (75a) by Davies.
35. Figure 4.11 Selected diterpenoids (82a–e) of biological relevance.
36. Scheme 4.25 Total syntheses of (±)‐nimbiol (82a), (±)‐nimbidiol (82b), and (±)‐ferruginol (82c).
37. Figure 4.12 Selected taiwaniaquinoids sharing [6,5,6]‐structural scaffolds.
38. Scheme 4.26 Total synthesis of (+)‐dichroanone (86a) by Stoltz.
39. Scheme 4.27 Collective total syntheses of taiwaniaquinoids (86a–c) by Trauner.
40. Scheme 4.28 Total syntheses of (−)‐taiwaniaquinol B (86c) by Hartwig.
41. Scheme 4.29 Hypothesis of conversion of abietane (92a) to abeo‐abietane (92d) and synthesis of (+)‐taiwaniaquinone H (86b) by Gademann.
42. Scheme 4.30 Total syntheses of (−)‐taiwaniaquinone F (86f) and (−)‐taiwaniaquinol A (86g) by Gademann.
43. Scheme 4.31 Collective total synthesis of taiwaniaquinoids by Li.
44. Scheme 4.32 Total synthesis of (±)‐taiwaniaquinone H (86b) by Hu and Yan.
45. Scheme 4.33 Total synthesis of (±)‐taiwaniaquinol F (86g) by Bisai.
46. Figure 4.13 Hongoquercins A and B (97a–b) and related meroterpenoids.
47. Scheme 4.34 Total synthesis of hongoquercin A (97a) and rhododaurichromanic acid A (97e).
48. Scheme 4.35 Proposed mechanism for the formation of (+)‐99a and 99b.
49. Scheme 4.36 Divergent synthesis of meroterpenoid natural products.
50. Scheme 4.37 Synthesis of puupehenol (110a) and (+)‐8‐epi‐puupehedione (110b).
51. Scheme 4.38 Synthesis of (−)‐pelorol (113a) and (+)‐dictyvaric acid (112).
52. Figure 4.14 Selected naturally occurring merosesquiterpenoids (113a–k).
53. Scheme 4.39 Total synthesis of pelorol (113a) by Anderson.
54. Scheme 4.40 Total synthesis of (±)‐dasyscyphin D (113f) by She.
55. Scheme 4.41 Proposed hypothesis for synthesis of merosesquiterpenoid by Bisai.
56. Scheme 4.42 Synthesis of merosesquiterpene quinol akaol A (113a).
Chapter 05
1. Scheme 5.1 General representation of protecting‐group‐free strategy.
2. Scheme 5.2 Protection‐free synthesis of flinderoles B (5a) and C (5b).
3. Scheme 5.3 Synthesis of functionalized carbazole murrayaline C (11).
4. Scheme 5.4 Synthesis of isochromene‐fused carbazole murrayamine‐O (20).
5. Scheme 5.5 Protection‐free synthesis of carbazole analog 24.
6. Scheme 5.6 Protecting‐group‐free synthesis of metatacarboline A (33).
7. Scheme 5.7 Free NH‐based synthesis of carbazoles 36.
8. Scheme 5.8 Synthesis of arcyriarubin (40) from indole.
9. Scheme 5.9 Synthesis of C3‐substituted indole compound bufopyramide (45).
10. Scheme 5.10 Synthesis of pyrrolidine 50 from unprotected carbohydrate 46.
11. Scheme 5.11 Protecting‐group‐free synthesis of marinopyrrole (58).
12. Scheme 5.12 Concise synthesis of pandamarine (67) without using protecting groups.
13. Scheme 5.13 Protection‐free synthesis of quinoline derivative 76.
14. Scheme 5.14 Synthesis of quinoline 80 using protecting group.
15. Scheme 5.15 Protection‐free approach for the synthesis of substituted quinolines 84.
16. Scheme 5.16 Protection‐free synthesis of lubeluzole (90).
17. Scheme 5.17 Protection‐free synthesis of substituted quinazolinone, asperlicin C (95).
18. Scheme 5.18 Synthesis of tetrahydroquinazolines 100.
19. Scheme 5.19 Protecting‐group‐free synthesis of (−)‐rosmarinecine (107).
20. Scheme 5.20 Protection‐free synthesis of (±)‐6‐epi‐cleistenolide (113).
21. Scheme 5.21 Protection‐free synthesis of cordiachromene (116).
22. Scheme 5.22 Protection‐free approach for the synthesis of helicascolides A (122) and C (123).
23. Scheme 5.23 Synthesis of iso‐cladospolide B (131).
24. Scheme 5.24 Synthesis of selenium‐containing heterocycle 140.
25. Scheme 5.25 Protection‐free synthesis of CCK1/CCK2 inhibitor (146).
26. Scheme 5.26 Domino approach for the synthesis of benzothiazine analogs 150.
27. Scheme 5.27 Protection‐free synthesis of macrocyclic ring 158.
28. Scheme 5.28 Protection‐free synthesis of substituted thiophene polymer 161.
29. Scheme 5.29 Synthesis of azaborine synthon 165.
Chapter 06
1. Figure 6.1 Synthesis of N‐methyl tropinone.
2. Figure 6.2 Structure of raltegravir potassium (1).
3. Scheme 6.1 First‐generation synthesis of raltegravir potassium (1).
4. Scheme 6.2 Synthesis of 12.
5. Scheme 6.3 Second‐generation synthesis of raltegravir potassium (1).
6. Scheme 6.4 Gurjar’s synthesis of raltegravir (1).
7. Figure 6.3 Structure of levetiracetam (20).
8. Figure 6.4 Novel approach to the synthesis of levetiracetam (20).
9. Scheme 6.5 Condensation reaction to obtain intermediate 23.
10. Scheme 6.6 RuO₂‐catalyzed oxidation of alcohol 23 to acid 24.
11. Scheme 6.7 Amidation to obtain levetiracetam (20).
12. Scheme 6.8 Green approach for the synthesis of levetiracetam (20).
13. Figure 6.5 Structure of sitagliptin (25).
14. Scheme 6.9 Synthesis of β‐amino acid 33.
15. Scheme 6.10 Synthesis of piperazine derivative 38.
16. Scheme 6.11 Synthesis of HCl salt of sitagliptin (25).
17. Scheme 6.12 Process chemistry route for the synthesis of sitagliptin (25).
18. Scheme 6.13 Synthesis of advanced precursor enamine 55.
19. Scheme 6.14 Greener synthesis of 25.
20. Scheme 6.15 Enzymatic synthesis of 25.
21. Figure 6.6 Structure of paroxetine (59).
22. Scheme 6.16 Medicinal chemistry route for 59.
23. Scheme 6.17 Process chemistry route for 59.
24. Scheme 6.18 Greener route for 59.
25. Scheme 6.19 First‐generation synthesis of apitolisib (86).
26. Figure 6.7 Process impurities in the final step of apitolisib synthesis.
27. Scheme 6.20 Manufacturing‐scale synthesis of apitolisib (86).
28. Scheme 6.21 Synthesis of piperazine lactamide oxalate 89.
29. Scheme 6.22 Synthesis of azepinomycin (96).
30. Scheme 6.23 Improved synthesis of azepinomycin (96).
31. Scheme 6.24 One‐pot synthesis of 5‐sulfanyl‐histidine 100.
32. Scheme 6.25 Synthesis of antiwrinkling agent Syn‐Ake (107).
33. Figure 6.8 Clinically relevant molecules of 5‐arylidene rhodanine and 2,4‐thiazolidenedione class.
34. Scheme 6.26 Synthesis of rhodanines and thiazolidinediones.
35. Scheme 6.27 Synthesis of SeAM and analogs.
Chapter 07
1. Figure 7.1 The total synthesis of cephalosporolides E and F with or without using protecting groups.
2. Scheme 7.1 PGF‐TS of hydroxypyrrolidine 4 from D‐ribose (1).
3. Scheme 7.2 Concise PGF‐TS of Hagen’s gland lactones from D‐glucono‐δ‐lactone 6.
4. Scheme 7.3 Concise PFG‐TS of cephalosporolides E and F from unnatural carbohydrate derived γ‐lactone 10.
5. Scheme 7.4 PGF‐TS of cephalosporolides H and I from D‐glucono‐δ‐lactone 6 by Du and coworkers.
6. Scheme 7.5 PGF synthesis of 3,4‐dihydroxytetrahydrofuran 22 from D‐xylose (19) and its application to an advanced intermediate of sphydrofuran.
7. Scheme 7.6 Total synthesis of Hagen’s gland lactones (5a and 5b) from D‐xylofuranose derivative 23.
8. Scheme 7.7 PGF‐TS of mixture of alkenes with eight carbons or more.
9. Scheme 7.8 PGF synthesis of thio‐sugars 1‐deoxythionojirimycin (29), 1‐deoxythiomannojirimycin, (30) and 1‐deoxythioallonojirimycin (31).
10. Scheme 7.9 Fischer O‐glycosylation.
11. Scheme 7.10 Modified PGF Fischer O‐glycosylation.
12. Scheme 7.11 Stereoselective PGF Fischer O‐glycosylation.
13. Scheme 7.12 Stereoselective PGF N‐glycosylation.
14. Scheme 7.13 Enzymatic and chemical synthesis of maradolipid (49).
15. Scheme 7.14 Total synthesis of maradolipid (49) with minimal protecting groups.
16. Scheme 7.15 Stereoselective PGF synthesis of urea‐linked glycoconjugates.
17. Scheme 7.16 Stereoselective PGF synthesis of aspartyl‐derived glycopeptide (62).
18. Scheme 7.17 PGF synthesis of triazole‐linked glycosides 66 and 70.
19. Scheme 7.18 PGF Wittig olefination.
20. Scheme 7.19 Selective PGF Wittig olefination.
21. Scheme 7.20 Selective PGF Wittig olefination for carbohydrate homologation.
22. Scheme 7.21 Selective PGF oxidation at the anomeric position.
23. Scheme 7.22 Selective PGF oxidation at primary hydroxyl group of D‐glucose derivative to 88.
24. Scheme 7.23 Selective PGF oxidation at C‐3 position of O‐ or S‐glycosides.
25. Scheme 7.24 Regioselective oxidation–reduction sequence for the synthesis of D‐allose (97) and allitol (98) from D‐glucose (41).
Chapter 08
1. Figure 8.1 Synthetic routes to glycosyl derivatives from free saccharide. (a) Direct synthesis of glycosyl derivative. (b) Protection of hydroxy groups. (c) Activation of anomeric position. (d) Substitution by a functional group at anomeric position. (e) Deprotection.
2. Scheme 8.1 Fischer glycosylation.
3. Scheme 8.2 Direct synthesis of O‐glycosides.
4. Scheme 8.3 Direct synthesis of O‐glycosides under basic conditions.
5. Scheme 8.4 Direct synthesis of O‐glycosides in ionic liquids.
6. Scheme 8.5 Direct synthesis of O‐glycosides from free furanose.
7. Scheme 8.6 Direct synthesis of O‐glycosides under the Mitsunobu reaction conditions.
8. Scheme 8.7 Direct synthesis of glycosyl derivatives via N′‐glycopyranosyl sulfonohydrazides and its utilization.
9. Scheme 8.8 Direct synthesis of N,O‐dimethylhydroxylamine‐N‐glycoside and its utilization.
10. Scheme 8.9 Direct synthesis of sugar oxazoline derivative by using dehydrative condensing agents in water.
11. Figure 8.2 Hydroxy groups on a free saccharide, GlcNAc.
12. Scheme 8.10 Chemoenzymatic synthesis of glycoprotein via sugar oxazoline derivative.
13. Scheme 8.11 Direct synthesis of (a) 1,6‐anhydro sugars, (b) glycosyl azides, and (c) thioglycosides by using DMC. (d) Direct synthesis of sugar oxazoline derivative by using CDMBI.
14. Figure 8.3 Plausible reaction mechanism of direct synthesis of glycosyl derivatives by using DMC. Nu⁻: nucleophile (N₃, RS, etc.).
15. Scheme 8.12 Synthesis of UDP‐Glc by using DMC.
16. Scheme 8.13 Synthesis of DMT‐glycosides and enzymatic transglycosylation by using DMT‐glycosides as glycosyl donors.
17. Scheme 8.14 Synthesis of nonnatural oligoxyloglucans by enzymatic polymerization using DMT‐glycosides.
18. Scheme 8.15 Direct synthesis of O‐glycosides using DMT‐ and DBT‐glycosides.
19. Scheme 8.16 Protecting‐group‐free synthesis of glycomonomers.
20. Scheme 8.17 Protecting‐group‐free synthesis of glycomonomers and glycopolymers via glycosyl azides.
21. Scheme 8.18 Synthesis of glycopolymers by post‐attachment CuAAC using glycosyl azides.
22. Scheme 8.19 Protecting‐group‐free synthesis of glycopolymers by the one‐pot glycomonomer synthesis.
23. Figure 8.4 Immobilization of glycopolymers on gold surfaces.
24. Scheme 8.20 Synthesis of (a) saccharide‐terminated PLLA by CuAAC and (b) amylose–PLLA inclusion supramolecular polymer by vine‐twining polymerization.
25. Scheme 8.21 Protecting‐group‐free synthesis of glycopeptides and glycoproteins using glycosyl azides.
26. Scheme 8.22 Protecting‐group‐free synthesis of thio‐linked glycopeptides and glycoproteins.
27. Scheme 8.23 Chemoenzymatic synthesis of artificial glycopeptides.
28. Scheme 8.24 Chemoenzymatic synthesis of N‐glycan‐bearing chitosan.
Chapter 09
1. Scheme 9.1 Synthesis of S‐(+)‐XJP (1a) and R‐(−)‐XJP (1b) with allyl alcohol as acyloin equivalent.
2. Scheme 9.2 Cyclization of fluoroalkyl pyrazolotetrahydrofluorenone 7.
3. Scheme 9.3 Latent oxazoline electrophile in pseudomonine biosynthesis.
4. Scheme 9.4 Homopropargylic ethers as latent Michael acceptors.
5. Scheme 9.5 Cyclobutene as latent functionality for cyclopentenone synthesis.
6. Scheme 9.6 Cyclobutene as latent furan moiety in the synthesis of hibiscone C (32).
7. Scheme 9.7 Dialkylsulfones as latent olefin functionality in β‐carotene (35) synthesis.
8. Scheme 9.8 Cyclic sulfones to generate strained cyclobutene.
9. Scheme 9.9 Cyclic sulfones in ring‐contracting olefination for eremantholide (45) synthesis.
10. Scheme 9.10 γ‐Silane on allylic halides as latent proton equivalent in stereospecific alkylation.
11. Scheme 9.11 (Trimethylsilyl)allyl anion 51 as latent β‐acyl anion equivalent.
12. Scheme 9.12 Vinylsilane as latent aldehyde group in the synthesis of gymnomitrol (62).
13. Scheme 9.13 Silicon‐tethered enyne metathesis for latent diene synthesis.
14. Scheme 9.14 Silicon‐tethered dienynes for latent diene synthesis.
15. Scheme 9.15 Hydrosilylation to introduce latent hydroxyl group.
16. Scheme 9.16 Tandem alkyne silylformylation/allylation.
17. Scheme 9.17 Alkyl/aryl silyl as latent hydroxyl group.
18. Scheme 9.18 Synthesis of coronafacic acid (109) using latent diene–dienophile for Diels–Alder reaction.
19. Scheme 9.19 Furan ring as latent 1,4‐diketone 113.
20. Scheme 9.20 Furan as latent ester functionality.
21. Scheme 9.21 Furan as latent 4‐oxo‐2‐alkenoic acid in total synthesis of macrosphelides A and B.
22. Scheme 9.22 Oxazole as latent carboxyl function.
23. Scheme 9.23 Methoxy phenyl group as latent p‐benzoquinone.
24. Scheme 9.24 Methoxy phenyl as latent A ring cyclohexanone in steroids.
25. Scheme 9.25 α‐Picolyl group as latent A ring cyclohexenone.
26. Scheme 9.26 Methoxy phenyl as latent β‐ketoester functionality.
27. Scheme 9.27 Nitrophenyl ketone as latent indoline or AB ring of Strychnos alkaloids.
28. Scheme 9.28 Olefin as latent keto function with no protecting groups involved.
29. Scheme 9.29 Self‐oxidizing o‐bromobenzyl protecting group for latent carbonyl functionality.
30. Scheme 9.30 Latent symmetry considerations in eburnamonine (202) synthesis.
31. Scheme 9.31 Selective generation of indoxyl in a near symmetric bis‐indole.
32. Scheme 9.32 Efficient domino processes in the synthesis of (±)‐dehaloperophoramidine (217).
33. Scheme 9.33 Synthesis of popolohuanone E core structure 223 based on inherent symmetry.
34. Scheme 9.34 Synthesis of rufescenolide (232) based on latent symmetry.
35. Scheme 9.35 Synthesis of yunnaneic acids C (239) and D (238) based on latent symmetry.
36. Scheme 9.36 Total synthesis of (−)‐angiopterlactone B (245).
37. Scheme 9.37 Synthesis of (−)‐ and (+)‐angiopterlactone B and diastereomers.

Improving Economy and Efficiency

Edited By

Rodney A. Fernandes

Indian Institute of Technology Bombay
Mumbai, India

This edition first published 2018
© 2018 John Wiley & Sons Ltd

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Library of Congress Cataloging‐in‐Publication Data

Names: Fernandes, Rodney A., 1972– editor.
Title: Protecting‐group‐free organic synthesis : improving economy and efficiency / edited by Rodney A. Fernandes.
Description: First edition. | Hoboken, NJ : John Wiley & Sons, 2018. | Includes bibliographical references and index. |
Identifiers: LCCN 2018002472 (print) | LCCN 2018010625 (ebook) | ISBN 9781119295198 (pdf) | ISBN 9781119295228 (epub) | ISBN 9781119295204 (cloth)
Subjects: LCSH: Organic compounds–Synthesis.
Classification: LCC QD262 (ebook) | LCC QD262 .P77 2018 (print) | DDC 547/.2–dc23
LC record available at https://lccn.loc.gov/2018002472

Cover Design: Wiley
Cover Image: © Aleksandr Simonov/Shutterstock

Editor Details

Rodney A. Fernandes received his PhD from National Chemical Laboratory, Pune, Maharashtra, under the tutelage of Dr. Pradeep Kumar in January 2003. Subsequently he worked with Prof. Yoshinori Yamamoto as a postdoctoral fellow at the Chemistry Department, Tohoku University, Sendai, Japan (January 2003–December 2003). He then moved to Prof. Reinhard Brückner’s laboratory at the Institute of Organic Chemistry and Biochemistry, University of Freiburg, Germany (July 2004–March 2006), as an Alexander von Humboldt fellow and then as DFG postdoctoral fellow (April 2006–June 2006). He started his independent research at the Instituto de Quimica, Universidad Nacional Autonoma de Mexico (UNAM), Mexico City (September 2006–July 2007), as assistant professor. He joined the Department of Chemistry of IIT Bombay (Mumbai, India) as assistant professor in August 2007 and became an associate professor in January 2011. He was promoted to full professor in May 2015. He has 89 publications and 8 patents to his credit and has guided 10 PhD’s at present. His area of research includes asymmetric synthesis of bioactive natural products, total synthesis, development of synthetic methodologies, and organometallic chemistry, including asymmetric catalysis. He was the recipient of the Indian National Science Academy (INSA) Young Scientist Medal Award in Chemical Sciences in 2004. He is elected fellow of Maharashtra Academy of Sciences (2015). He served as Dean Academic at IIT‐Goa on deputation from IIT‐Bombay (August 2017–July 2018).

List of Contributors

Trapti Aggarwal
Department of Chemistry
University of Delhi
India

Rakeshwar Bandichhor
API Research & Development
Integrated Product Development
Dr. Reddy’s Laboratories Ltd.,
Hyderabad, India

Alakesh Bisai
Department of Chemistry
Indian Institute of Science Education and Research Bhopal Bhauri
Bhopal, India

Vishnumaya Bisai
Department of Chemistry
Indian Institute of Science Education and Research Tirupati
India

Alejandro Cordero‐Vargas
Instituto de Química
Universidad Nacional Autónoma de México
Ciudad de México, México

Rodney A. Fernandes
Department of Chemistry
Indian Institute of Technology Bombay
Mumbai, India

Isao Kadota
Department of Chemistry
Graduate School of Natural Science and Technology
Okayama University
Japan

Remya Ramesh
Division of Organic Chemistry
CSIR‐National Chemical Laboratory
Pune, India

Fernando Sartillo‐Piscil
Centro de Investigación de la Facultad de Ciencias Químicas and Centro de Química de la Benemérita, Universidad Autónoma de Puebla
México

Swapnil Sonawane
API Research & Development
Integrated Product Development
Dr. Reddy’s Laboratories Ltd.,
HyderabadIndia

D. Srinivasa Reddy
Division of Organic Chemistry
CSIR‐National Chemical Laboratory
Pune, India

Hiroyoshi Takamura
Department of Chemistry
Graduate School of Natural Science and Technology
Okayama University
Japan

Tomonari Tanaka
Department of Biobased Materials Science
Graduate School of Science and Technology
Kyoto Institute of Technology
Japan

Akhilesh K. Verma
Department of Chemistry
University of Delhi
India

Foreword by Prof. W. Hoffmann

Protecting‐group‐free synthesis has come into focus in the twenty‐first century, as current active pharmaceutical ingredients and other targets of organic synthesis have become increasingly more complex, whereby efficiency in synthesis gets a pressing issue. Efficiency in synthesis depends critically on chemoselectivity both in skeleton‐building transformations and in refunctionalization reactions. Any lack in chemoselectivity requires protection of the affected functional groups. This and the ultimate deprotection steps decrease the efficiency of a synthesis. Accordingly, the extent of protecting‐group use in synthesis is a direct indicator for a lack of chemoselectivity in the transformations applied. While total chemoselectivity in all transformations will remain an utopic goal for long, protecting‐group‐free synthesis is within closer reach, as it depends not only on functional group‐tolerant skeleton‐building transformations, such as free radical reaction cascades, transition metal‐catalyzed sequences, or biocatalytic events, but protecting‐group‐free synthesis has in addition a strong component from strategic synthesis planning. The aim is to avoid altogether the incompatibility of vulnerable functional groups with conditions from the necessary skeleton‐building reactions. While the latter form the core of a synthesis plan, there is still the option to change the sequence of individual steps in a multistep synthesis to introduce a vulnerable functional group – not before but after the offending skeleton‐building step has been executed.

Looking at the targets of organic synthesis, it is trivial to note that protecting‐group‐free synthesis will be easier to attain with molecules that have a lower degree of functionalization. In turn, protecting‐group schemes will prevail for long, when, e.g. the synthesis of polypeptides or polysaccharides is concerned. To render their synthesis protecting‐group‐free may at present even be counterproductive when aiming for overall synthetic efficiency. That is, protecting‐group‐free synthesis has no merit in itself when it is judged by the overall economy of a synthesis.

The editor and authors have collated in this volume an impressive number of protecting‐group‐free syntheses. This number surprises in view of the limited chemoselectivity of present‐day synthetic methods. Yet, this number is at the same time encouraging, showing that protecting‐group‐free synthesis is a valuable goal that can be frequently reached with reasonable effort.

The listed beautiful syntheses in this book have reached the status of being protecting‐group‐free by significant intellectual input in synthesis planning. To extract this aspect from the individual examples will be the pleasure for the connoisseur reader.

Protecting‐group‐free synthesis is challenging the present limitations in chemoselectivity of synthetic transformations. In due time chemoselectivity should become increasingly more perfect to the point that protecting‐group‐free synthesis will in the end become accepted common practice.

Marburg, 28 November 2017

Reinhard W. Hoffmann

Fachbereich Chemie der

Philipps Universität Marburg

Foreword by Prof. G. Mehta

During the advance of synthetic organic chemistry, particularly in the second half of the last century, protecting‐group maneuvers emerged as a legitimate and often essential tactic in pursuit of multistep synthesis of complex targets. Indeed, devising new protective groups and deprotection protocols became an active area in itself, and the seminal series of Greene’s Protective Groups in Organic Synthesis (Volumes 1–4 from 1980 to 2007) with nearly 7000 references bear testimony to the activity and prevailing interest in this area. However, these worthy efforts on protection–deprotection chemistry, unavoidable at the times and contexts, also led to a quest for the avoidance of these “wasteful steps.” As green and sustainable chemistry concerns surfaced and drew traction, the assertion that “the best protecting group is one that is not required” gained momentum. In this developing scenario, tactics and strategies deployed in multistep syntheses and total syntheses of natural products that involved circumvention of protecting‐group maneuvers came to the fore. Indeed, the past couple of decades has witnessed impressive advances in protecting‐group‐free (PGF) synthesis, and there is a considerable perceived premium associated with such undertakings.

Thus, the book Protecting‐Group‐Free Organic Synthesis: Improving Economy and Efficiency edited by Rodney A. Fernandes, an active researcher himself, with contributions from many notable practitioners of organic synthesis, is a topical offering and a reminder that the days of “long” and “any how” synthesis are now passé and the need for shorter, efficient syntheses do not permit the luxury of protective group interventions. There is little doubt that in future syntheses that imbed protecting‐group operations will be discounted unless a compelling case can be brought out for their use. Such forebodings are already visible in reviewer reports and critical assessment of the quality of a synthetic effort. The strides made in PGF synthesis in recent years are indeed impressive with over 100 PGF syntheses. Many of these PGF syntheses target scarce bioactive natural products that require scale‐up and price competitiveness, and such efforts greatly enhance the centrality, utility, and potential of organic synthesis. It is hoped that PGF strategy will find increasing applications in API manufacturing and extend to carbohydrates, peptide, and nucleic acid synthesis where multiple protection–deprotection interventions are generally considered inevitable.

This book provides a diverse coverage of the nascent and emergent field of PGF syntheses of molecules of varying complexity that range from pharmaceuticals to natural products to biopolymers. The ideas based on harnessing cascade/domino processes, deployment of latent functionalities, and exploitation of hidden symmetry have been well articulated in different chapters and should be of interest to the synthetic organic chemistry community in academia as well as industry, and stimulate new directions and tactics in their synthetic efforts. It is also to be expected that PGF synthesis endeavors will lead to newer advances in reagent development and catalyst design for enhanced functional group selectivity, an operational requirement for PGF synthesis. All in all, the book Protecting‐Group‐Free Organic Synthesis: Improving Economy and Efficiency is a welcome contribution that should be of general interest to the synthetic organic chemistry community, and the editor and contributors deserve to be complemented for their efforts.

Hyderabad, 11 December 2017

Goverdhan Mehta

University Distinguished Professor &

Dr. Kallam Anji Reddy Chair

School of Chemistry

University of Hyderabad, India

Preface

Modern organic synthesis has set high standards for its practitioners today. The art of total synthesis has always inspired strong minds who ventured on the tough path of target‐oriented synthesis. The last two decades have seen tremendous growth in the complexity of natural products synthesized. I have been always inspired by the mesmerizing total synthesis work by professors – Woodward, Corey, Nicolaou, Kishi, Danheiser, Danishefsky, Paquette, Trauner, Denmark, and many more. Total synthesis has been referred to as the art of building molecules. It poses a myriad of synthetic challenges and requires unabated efforts, overcoming unforeseen hurdles that spring up between putting a proposed strategy on paper and actually executing it in the laboratory. During my days as a research scholar, I was awestruck by the articles from Nicolaou’s group on the total synthesis of CP molecules, which is compared to Theseus, a mythical king, who battled and overcame foes (Carl A. P. Ruck and Danny Staples (1994). The World of Classical Myth. ch. IX, “Theseus: Making the New Athens”, pp 203 − 222. Durham, NC: Carolina Academic Press).

Of the many challenges, chemoselectivity, which includes efficient differentiation of functional groups without masking, has been the toughest challenge imposed upon a total synthesis chemist. A target‐oriented synthesis demands that the molecule is synthesized with the correct placement of all its functionality, in addition to the correct stereochemistry in chiral molecules. This helps in validating the proposed structure. Protecting‐group‐free (PGF) synthesis is one parameter that adds to the overall efficiency and economy of a synthesis, apart from atom and redox economies. In order to achieve this, a chemist needs a clear understanding of functional group reactivity, compatibility of reagents, and reaction conditions. Even though we may be proficient in all the so‐called tactics, the ultimate target may be far from reach. Hence it is rightly said that if even the last step fails in a total synthesis, it is enough to jeopardize the whole strategy and hard work put in.

However, with the advent of powerful new reactions and compatibility of reagents and their mechanistic understanding, organic synthesis without protecting groups has now been realized. There have been tireless attempts by many synthetic chemists to design strategies either with minimal or no use of protecting groups, aiming to come closer to achieving an “ideal synthesis.” It would be next to impossible to condemn the use of protecting groups, but a sound knowledge of new chemistry, known PGF syntheses, and a desire to practice the latter will go a long way in organic synthesis. While there are a few books available on the development and use of protecting groups in detail, there are currently no books available to the best of my knowledge on practicing/practiced PGF syntheses. Details of the latter may be found as scattered occasional reviews in some forefront journals of organic chemistry. I believe this compilation is the first of its kind based on the syntheses practiced with no use of protecting groups, contributing directly to step economy and hence to the efficiency and economy of the syntheses.

This book intends to give a comprehensive account of practiced, known PGF syntheses of molecules of medium to high complexity. The introductory chapter gives a concise review of historical developments, need, the concepts, and future prospects of PGF syntheses. The next three chapters cover extensive literature on total syntheses of many molecules without protecting groups. This book includes over 100 syntheses that have been achieved without protecting groups. Some are beautifully crafted based on cascade/domino reactions, while others involve rearrangements. PGF syntheses of drugs and related pharmaceuticals with excellent examples of several molecules are discussed as a separate chapter. Synthesis of various heterocycles and carbohydrate‐based PGF syntheses will enlighten heterocyclic chemists who are majorly engaged in drug discovery. Moving ahead, more details of practicing PGF synthesis of glycoconjugates, peptides, and biopolymers constitute another relevant chapter. The book winds up with the use of latent functionality‐based approaches to target molecules and the beautiful exploration of hidden symmetry (latent symmetry considerations) to achieve the synthesis of nonsymmetric molecules.

I would like to acknowledge all the students from my research group for help in creating some of the schemes in ChemDraw. My family spared me time to work on this manuscript, and my wife, Moneesha, also a chemist, is thanked for proofreading the chapters. I am also sincerely grateful to Prof. Mahesh Lakshman for his suggestions during the proposal stage of this book. I thank my parent institute, Indian Institute of Technology Bombay, for excellent SciFinder search facility and access to other online literature. The final stages post manuscript submission including proof reading were completed at IIT‐Goa, while on deputation as Dean Academic Programme and I would like to thank the Director, IIT‐Goa for encouragement and support. I also express my gratitude to all the authors for agreeing to contribute to this book without any reservations or demands. I also thank Professor Goverdhan Mehta and Professor Reinhard W. Hoffmann for contributing the Forewords. My apologies if any known PGF synthesis was unintentionally not covered in this book by myself or any contributing author.

Rodney A. Fernandes