Synthetic Strategies to Access Heteroatomic Spirocentres Embedded in Natural Products

Michael P. Badart; Bill C. Hawkins

doi:10.1055/a-1379-2312

Synthesis, Table of Contents

Synthesis 2021; 53(10): 1683-1705
DOI: 10.1055/a-1379-2312

review

Synthetic Strategies to Access Heteroatomic Spirocentres Embedded in Natural Products

Authors

Michael P. Badart∗
Bill C. Hawkins∗

Abstract

All articles of this category

Abstract

The spirocyclic motif is abundant in natural products and provides an ideal three-dimensional template to interact with biological targets. With significant attention historically expended on the synthesis of flat-heterocyclic compound libraries, methods to access the less-explored three-dimensional medicinal-chemical space will continue to increase in demand. Herein, we highlight by reaction class the common strategies used to construct the spirocyclic centres embedded in a series of well-studied natural products.

1 Introduction

2 Cycloadditions

3 Palladium-Catalysed Coupling Reactions

4 Conjugate Additions

5 Imines, Aminals, and Hemiaminal Ethers

6 Mannich-Type Reactions

7 Oxidative Dearomatisation

8 Alkylation

9 Organometallic Additions

10 Conclusions

Key words

spiro compounds - total synthesis - cycloaddition - Michael addition - palladium - natural products

Full Text

References

References

1a Li JW.-H, Vederas JC. Science 2009; 325: 161
1b Welsch ME, Snyder SA, Stockwell BR. Curr. Opin. Chem. Biol. 2010; 14: 347
1c Rodrigues T, Reker D, Schneider P, Schneider G. Nat. Chem. 2016; 8: 531

2a Hong J. Curr. Opin. Chem. Biol. 2011; 15: 350
2b Trauner D. Nat. Prod. Rep. 2014; 31: 411

3 Moss G. Pure Appl. Chem. 1999; 71: 531
4 Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752

5a Zheng Y, Tice CM, Singh SB. Bioorg. Med. Chem. Lett. 2014; 24: 3673
5b Zheng Y.-J, Tice CM. Expert Opin. Drug Discovery 2016; 11: 831
5c Claveria-Gimeno R, Vega S, Abian O, Velazquez-Campoy A. Expert Opin. Drug Discovery 2017; 12: 363

6 Chupakhin E, Babich O, Prosekov A, Asyakina L, Krasavin M. Molecules 2019; 24: 4165

7a Moossavi M, Bagheri B, Scher RK. Dermatol. Clin. 2001; 19: 35
7b WHO Model Lists of Essential Medicines (21st List). World Health Organization; Geneva: 2019

8a Singh GS, Desta ZY. Chem. Rev. 2012; 112: 6104
8b Hong L, Wang R. Adv. Synth. Catal. 2013; 355: 1023
8c Carreira EM, Fessard TC. Chem. Rev. 2014; 114: 8257
8d Smith LK, Baxendale IR. Org. Biomol. Chem. 2015; 13: 9907
8e Gillard RM, Brimble MA. Org. Biomol. Chem. 2019; 17: 8272
8f Zhang F.-M, Zhang S.-Y, Tu Y.-Q. Nat. Prod. Rep. 2018; 35: 75

9 Diels O, Alder K. Justus Liebigs Ann. Chem. 1928; 460: 98

10a Nicolaou KC, Snyder SA, Montagnon T, Vassilikogiannakis G. Angew. Chem. Int. Ed. 2002; 41: 1668
10b Hashimoto T, Maruoka K. Chem. Rev. 2015; 115: 5366
10c Juhl M, Tanner D. Chem. Soc. Rev. 2009; 38: 2983

11a Pellegrini C, Strässler C, Weber M, Borschberg H.-J. Tetrahedron: Asymmetry 1994; 5: 1979
11b Palmisano G, Annunziata R, Papeo G, Sisti M. Tetrahedron: Asymmetry 1996; 7: 1
11c Fischer C, Meyers C, Carreira EM. Helv. Chim. Acta 2000; 83: 1175
11d Cravotto G, Giovenzana GB, Pilati T, Sisti M, Palmisano G. J. Org. Chem. 2001; 66: 8447
11e Lizos D, Tripoli R, Murphy JA. Chem. Commun. 2001; 2732
11f Selvakumar N, Azhagan AM, Srinivas D, Krishna GG. Tetrahedron Lett. 2002; 43: 9175
11g Lizos DE, Murphy JA. Org. Biomol. Chem. 2003; 1: 117
11h Chang M.-Y, Pai C.-L, Kung Y.-H. Tetrahedron Lett. 2005; 46: 8463
11i Murphy JA, Tripoli R, Khan TA, Mali UW. Org. Lett. 2005; 7: 3287
11j Trost BM, Brennan MK. Org. Lett. 2006; 8: 2027
11k Jaegli S, Vors J.-P, Neuville L, Zhu J. Synlett 2009; 2997
11l Deppermann N, Thomanek H, Prenzel AH. G. P, Maison W. J. Org. Chem. 2010; 75: 5994
11m Kulkarni MG, Dhondge AP, Chavhan SW, Borhade AS, Shaikh YB, Birhade DR, Desai MP, Dhatrak NR. Beilstein J. Org. Chem. 2010; 6: 876
11n Thomson JE, Kyle AF, Ling KB, Smith SR, Slawin AM. Z, Smith AD. Tetrahedron 2010; 66: 3801
11o White JD, Li Y, Ihle DC. J. Org. Chem. 2010; 75: 3569
11p Hong S, Jung M, Park Y, Ha MW, Park C, Lee M, Park H.-g. Chem. Eur. J. 2013; 19: 9599
11q Mukaiyama T, Ogata K, Sato I, Hayashi Y. Chem. Eur. J. 2014; 20: 13583
11r Kim M, Kim G. Bull. Korean Chem. Soc. 2012; 33: 1821
11s Lakshmaiah G, Kawabata T, Shang M, Fuji K. J. Org. Chem. 1999; 64: 1699
11t Jossang A, Jossang P, Hadi HA, Sevenet T, Bodo B. J. Org. Chem. 1991; 56: 6527

12a Anderton N, Cockrum PA, Colegate SM, Edgar JA, Flower K, Vit I, Willing RI. Phytochemistry 1998; 48: 437
12b Colegate S, Anderton N, Edgar J, Bourke C, Oram R. Aust. Vet. J. 1999; 77: 537

13 Whitesell JK, Chen HH, Lawrence RM. J. Org. Chem. 1985; 50: 4663
14 Li C, Chan C, Heimann AC, Danishefsky SJ. Angew. Chem. Int. Ed. 2007; 46: 1444

15a Badart MP, Squires CM. L, Baird SK, Hawkins BC. Tetrahedron Lett. 2016; 57: 5108
15b Shaala LA, Youssef DT, Sulaiman M, Behery FA, Foudah AI, Sayed KA. E. Mar. Drugs 2012; 10: 2492
15c Compagnone RS, Avila R, Suárez AI, Abrams OV, Rangel HR, Arvelo F, Piña IC, Merentes E. J. Nat. Prod. 1999; 62: 1443
15d Kobayashi J. i, Tsuda M, Agemi K, Shigemori H, Ishibashi M, Sasaki T, Mikami Y. Tetrahedron 1991; 47: 6617
15e Acosta AL, Rodríguez AD. J. Nat. Prod. 1992; 55: 1007
15f Copp BR, Ireland CM, Barrows LR. J. Nat. Prod. 1992; 55: 822
15g Perry NB, Blunt JW, McCombs JD, Munro MH. G. J. Org. Chem. 1986; 51: 5476

16 Gunasekera SP, Cross SS. J. Nat. Prod. 1992; 55: 509

17a Nakamura Y, Kobayashi M, Nakamura H, Wu H, Kobayashi J. i, Ohizumi Y. Eur. J. Biochem. 1987; 167: 1
17b Nakamura H, Wu H, Kobayashi J. i, Nakamura Y, Ohizumi Y, Hirata Y. Tetrahedron Lett. 1985; 26: 4517

18 Buchanan MS, Carroll AR, Wessling D, Jobling M, Avery VM, Davis RA, Feng Y, Hooper JN. A, Quinn RJ. J. Nat. Prod. 2009; 72: 973

19a Zhu G, Yang F, Balachandran R, Höök P, Vallee RB, Curran DP, Day BW. J. Med. Chem. 2006; 49: 2063
19b Rodríguez AD, Piña IC. J. Nat. Prod. 1993; 56: 907
19c Gunasekera M, Gunasekera SP. J. Nat. Prod. 1989; 52: 753
19d Kobayashi J. i, Honma K, Sasaki T, Tsuda M. Chem. Pharm. Bull. 1995; 43: 403
19e Gopichand Y, Schmitz FJ. Tetrahedron Lett. 1979; 20: 3921
19f Das P, Hamme AT. II. Eur. J. Org. Chem. 2015; 5159
19g Kita Y, Tohma H, Inagaki M, Hatanaka K, Yakura T. J. Am. Chem. Soc. 1992; 114: 2175
19h Ogamino T, Obata R, Tomoda H, Nishiyama S. Bull. Chem. Soc. Jpn. 2006; 79: 134
19i Ogamino T, Nishiyama S. Tetrahedron Lett. 2005; 46: 1083
19j Ogamino T, Ishikawa Y, Nishiyama S. Heterocycles 2003; 61: 73

20 Iwagawa T, Miyazaki M, Okamura H, Nakatani M, Doe M, Takemura K. Tetrahedron Lett. 2003; 44: 2533
21 Dai J, Jiménez JI, Kelly M, Williams PG. J. Org. Chem. 2010; 75: 2399

22a Skiredj A, Beniddir MA, Joseph D, Leblanc K, Bernadat G, Evanno L, Poupon E. Angew. Chem. Int. Ed. 2014; 53: 6419
22b Skiredj A, Beniddir MA, Joseph D, Leblanc K, Bernadat G, Evanno L, Poupon E. Org. Lett. 2014; 16: 4980

23 Duchemin N, Skiredj A, Mansot J, Leblanc K, Vasseur J.-J, Beniddir MA, Evanno L, Poupon E, Smietana M, Arseniyadis S. Angew. Chem. Int. Ed. 2018; 57: 11786
24 Ma S.-G, Gao R.-M, Li Y.-H, Jiang J.-D, Gong N.-B, Li L, Lü Y, Tang W.-Z, Liu Y.-B, Qu J, Lü H.-N, Li Y, Yu S.-S. Org. Lett. 2013; 15: 4450

25a Wei L, Xiao M, Xie Z. Org. Lett. 2014; 16: 2784
25b Zhao N, Ren X, Ren J, Lü H, Ma S, Gao R, Li Y, Xu S, Li L, Yu S. Org. Lett. 2015; 17: 3118
25c Song L, Yao H, Tong R. Org. Lett. 2014; 16: 3740

26 Barrow CJ, Sun HH. J. Nat. Prod. 1994; 57: 471

27a Hart DJ. ARKIVOC 2010; (iv): 32
27b Larsen TO, Frydenvang K, Frisvad JC, Christophersen C. J. Nat. Prod. 1998; 61: 1154
27c Ariza MR, Larsen TO, Petersen BO, Duus J. Ø, Christophersen C, Barrero AF. J. Nat. Prod. 2001; 64: 1590
27d Larsen TO, Petersen BO, Duus J. Ø, Sørensen D, Frisvad JC, Hansen ME. J. Nat. Prod. 2005; 68: 871
27e Koyama N, Inoue Y, Sekine M, Hayakawa Y, Homma H, Omura S, Tomoda H. Org. Lett. 2008; 10: 5273
27f Proença Barros FA, Rodrigues-Filho E. Biochem. Syst. Ecol. 2005; 33: 257

28 Wu M, Ma D. Angew. Chem. Int. Ed. 2013; 52: 9759

29a Kende AS, Fan J, Chen Z. Org. Lett. 2003; 5: 3205
29b Chen Z, Fan J, Kende AS. J. Org. Chem. 2004; 69: 79

30a Ding K, Lu Y, Nikolovska-Coleska Z, Qiu S, Ding Y, Gao W, Stuckey J, Krajewski K, Roller PP, Tomita Y, Parrish DA, Deschamps JR, Wang S. J. Am. Chem. Soc. 2005; 127: 10130
30b Lo MM. C, Neumann CS, Nagayama S, Perlstein EO, Schreiber SL. J. Am. Chem. Soc. 2004; 126: 16077
30c Antonchick AP, Gerding-Reimers C, Catarinella M, Schürmann M, Preut H, Ziegler S, Rauh D, Waldmann H. Nat. Chem. 2010; 2: 735
30d Antonchick AP, Schuster H, Bruss H, Schürmann M, Preut H, Rauh D, Waldmann H. Tetrahedron 2011; 67: 10195

31 von Nussbaum F, Danishefsky SJ. Angew. Chem. Int. Ed. 2000; 39: 2175

32a Edmondson S, Danishefsky SJ, Sepp-Lorenzino L, Rosen N. J. Am. Chem. Soc. 1999; 121: 2147
32b Wang H, Ganesan A. J. Org. Chem. 2000; 65: 4685
32c Edmondson SD, Danishefsky SJ. Angew. Chem. Int. Ed. 1998; 37: 1138
32d Overman LE, Rosen MD. Angew. Chem. Int. Ed. 2000; 39: 4596 ; Angew. Chem., 2000, 112, 4768

33a Miyake FY, Yakushijin K, Horne DA. Angew. Chem. Int. Ed. 2004; 43: 5357
33b Miyake FY, Yakushijin K, Horne DA. Org. Lett. 2004; 6: 4249

34a Kitahara K, Shimokawa J, Fukuyama T. Chem. Sci. 2014; 5: 904
34b Overman LE, Rosen MD. Tetrahedron 2010; 66: 6514

35a Onishi T, Sebahar PR, Williams RM. Org. Lett. 2003; 5: 3135
35b Onishi T, Sebahar PR, Williams RM. Tetrahedron 2004; 60: 9503
35c Sebahar PR, Osada H, Usui T, Williams RM. Tetrahedron 2002; 58: 6311
35d Sebahar PR, Williams RM. J. Am. Chem. Soc. 2000; 122: 5666

36a Marti C, Carreira EM. J. Am. Chem. Soc. 2005; 127: 11505
36b Meyers C, Carreira EM. Angew. Chem. Int. Ed. 2003; 42: 694

37 Bagul TD, Lakshmaiah G, Kawabata T, Fuji K. Org. Lett. 2002; 4: 249
38 Trost BM, Stiles DT. Org. Lett. 2007; 9: 2763
39 Encarnación RD, Sandoval E, Malmstrøm J, Christophersen C. J. Nat. Prod. 2000; 63: 874
40 Bardhan S, Schmitt DC, Porco JA. Org. Lett. 2006; 8: 927
41 Kikuchi H, Miyagawa Y, Sahashi Y, Inatomi S, Haganuma A, Nakahata N, Oshima Y. J. Org. Chem. 2004; 69: 352

42a Dai M, Krauss IJ, Danishefsky SJ. J. Org. Chem. 2008; 73: 9576
42b Dai M, Danishefsky SJ. J. Am. Chem. Soc. 2007; 129: 3498

43a Gerwick WH, Fenical W. J. Org. Chem. 1981; 46: 22
43b Gerwick WH, Fenical W, Fritsch N, Clardy J. Tetrahedron Lett. 1979; 20: 145
43c O’Brien ET, Asai DJ, Jacobs RS, Wilson L. Mol. Pharmacol. 1989; 35: 635
43d White SJ, Jacobs RS. Mol. Pharmacol. 1983; 24: 500

44 Mori K, Komatsu M. Liebigs Ann. Chem. 1988; 1988: 107
45 Mori K, Koga Y. Bioorg. Med. Chem. Lett. 1992; 2: 391
46 Xing X, Demuth M. Synlett 1999; 987

47a Wolfe JP, Jack Li J. An Introduction to Palladium Catalysis . In Palladium in Heterocyclic Chemistry, A Guide for the Synthetic Chemist . Li JJ, Gribble GW. Tetrahedron Organic Chemistry Series, Vol. 26, Chap. 1; Elsevier; Amsterdam: 2007: 1-35
47b Johansson Seechurn CC. C, Kitching MO, Colacot TJ, Snieckus V. Angew. Chem. Int. Ed. 2012; 51: 5062
47c The Nobel Prize in Chemistry 2010 (Nobel Media AB 2021; accessed Feb 16, 2021), see: https://www.nobelprize.org/prizes/chemistry/2010/advanced-information

48 Heck RF. Palladium-Catalyzed Vinylation of Organic Halides . In Organic Reactions, Vol. 27. Dauben WG. John Wiley & Sons; New York: 1982: 345-390
49 Zhang W, Liu Z, Li S, Yang T, Zhang Q, Ma L, Tian X, Zhang H, Huang C, Zhang S, Ju J, Shen Y, Zhang C. Org. Lett. 2012; 14: 3364
50 Blair LM, Sperry J. Chem. Commun. 2016; 52: 800

51a Saxton JE. Alkaloids of Gelsemium Species . In The Alkaloids: Chemistry and Physiology, Chap. 6, Vol. 8. Manske RH. F. Academic Press; New York: 1965: 93-117
51b Liu Z.-J, Lu R.-R. Gelsemium Alkaloids . In The Alkaloids: Chemistry and Pharmacology, Chap. 2, Vol. 33. Brossi A. Academic Press; San Diego: 1988: 83-140
51c Takayama H, Sakai S.-i. Recent Advances in the Chemistry of Gelsemium Alkaloids. In Studies in Natural Products Chemistry, Part C, Vol. 15. Atta-ur-Rahman Elsevier; Amsterdam: 1995: 465-518

52a Shimokawa J, Harada T, Yokoshima S, Fukuyama T. J. Am. Chem. Soc. 2011; 133: 17634
52b Harada T, Shimokawa J, Fukuyama T. Org. Lett. 2016; 18: 4622
52c Newcomb ET, Knutson PC, Pedersen BA, Ferreira EM. J. Am. Chem. Soc. 2016; 138: 108
52d Baldwin SW, Doll RJ. Tetrahedron Lett. 1979; 20: 3275
52e Hamer NK. J. Chem. Soc., Chem. Commun. 1990; 102
52f Kende AS, Luzzio MJ, Mendoza JS. J. Org. Chem. 1990; 55: 918
52g Phisalaphong C, Takayama H, Sakai S.-i. Tetrahedron Lett. 1993; 34: 4035
52h Takayama H, Odaka H, Aimi N, Sakai S.-i. Tetrahedron Lett. 1990; 31: 5483
52i Takayama H, Kitajima M, Ogata K, Sakai S. J. Org. Chem. 1992; 57: 4583
52j Takayama H, Tominaga Y, Kitajima M, Aimi N, Sakai S. J. Org. Chem. 1994; 59: 4381
52k Kitajima M, Takayama H, Sakai S.-i. J. Chem. Soc., Perkin Trans. 1 1994; 1573
52l Kogure N, Ishii N, Kitajima M, Wongseripipatana S, Takayama H. Org. Lett. 2006; 8: 3085
52m Yamada Y, Kitajima M, Kogure N, Wongseripipatana S, Takayama H. Tetrahedron Lett. 2009; 50: 3341
52n Yamada Y, Kitajima M, Kogure N, Takayama H. Tetrahedron 2008; 64: 7690
52o Yamada Y, Kitajima M, Kogure N, Wongseripipatana S, Takayama H. Chem. Asian J. 2011; 6: 166
52p Beyersbergen van Henegouwen WG, Fieseler RM, Rutjes FP. J. T, Hiemstra H. Angew. Chem. Int. Ed. 1999; 38: 2214
52q Beyersbergen van Henegouwen WG, Fieseler RM, Rutjes FP. J. T, Hiemstra H. J. Org. Chem. 2000; 65: 8317
52r Shimokawa J, Harada T, Yokoshima S, Fukuyama T. Pure Appl. Chem. 2012; 84: 1643
52s Diethelm S, Carreira EM. J. Am. Chem. Soc. 2015; 137: 6084
52t Diethelm S, Carreira EM. J. Am. Chem. Soc. 2013; 135: 8500

53a Schwarz H, Marion L. Can. J. Chem. 1953; 31: 958
53b Jin H.-L, Xu R.-S. Acta Chim. Sinica 1982; 40: 1129
53c Wenkert E, Orr JC, Garratt S, Hansen JH, Wickberg B, Leicht CL. J. Org. Chem. 1962; 27: 4123
53d Przybylska M, Marion L. Can. J. Chem. 1961; 39: 2124

54 Madin A, O’Donnell CJ, Oh T, Old DW, Overman LE, Sharp MJ. J. Am. Chem. Soc. 2005; 127: 18054
55 Lin L.-Z, Cordell GA, Ni C.-Z, Clardy J. Phytochemistry 1991; 30: 1311

56a Polonsky J, Merrien M.-A, Prangé T, Pascard C, Moreau S. J. Chem. Soc., Chem. Commun. 1980; 601
56b Prangé T, Billion M.-A, Vuilhorgne M, Pascard C, Polonsky J, Moreau S. Tetrahedron Lett. 1981; 22: 1977
56c Yamazaki M, Okuyama E, Kobayashi M, Inoue H. Tetrahedron Lett. 1981; 22: 135
56d Lee BH, Clothier MF, Dutton FE, Nelson SJ, Johnson SS, Thompson DP, Geary TG, Whaley HD, Haber CL, Marshall VP, Kornis GI, McNally PL, Ciadella JI, Martin DG, Bowman JW, Baker CA, Coscarelli EM, Alexander-Bowman SJ, Davis JP, Zinser EW, Wiley V, Lipton MF, Mauragis MA. Curr. Top. Med. Chem. 2002; 2: 779

57a Wiley V, Cialdella J, Yurek D, Whaley H, Marshall V. J. Antibiot. 1996; 49: 1006
57b Sommer K, Williams RM. Tetrahedron 2009; 65: 3246
57c Williams RM, Cox RJ. Acc. Chem. Res. 2003; 36: 127
57d Williams RM, Stocking EM, Sanz-Cervera JF. Biosynthesis of Prenylated Alkaloids Derived from Tryptophan . In Biosynthesis: Aromatic Polyketides, Isoprenoids, Alkaloids . Leeper FJ, Vederas JC. Springer-Verlag; Berlin: 2000: 97-173

58 Trost BM, Cramer N, Bernsmann H. J. Am. Chem. Soc. 2007; 129: 3086
59 Trost BM, Bringley DA, Zhang T, Cramer N. J. Am. Chem. Soc. 2013; 135: 16720

60a Macías FA, Galindo JL. G, Varela RM, Torres A, Molinillo JM. G, Fronczek FR. Org. Lett. 2006; 8: 4513
60b Macías FA, Varela RM, Torres A, Molinillo JG. Tetrahedron Lett. 1998; 39: 427

61a Norcott P, McErlean CS. P. Eur. J. Org. Chem. 2014; 5056
61b Norcott P, McErlean CS. P. Aust. J. Chem. 2018; 71: 366
61c Miyawaki A, Kikuchi D, Niki M, Manabe Y, Kanematsu M, Yokoe H, Yoshida M, Shishido K. J. Org. Chem. 2012; 77: 8231
61d Huang C, Zhang W, Liu B. Sci. China Chem. 2011; 54: 43
61e Miyawaki A, Manabe Y, Yoshida M, Shishido K. Tetrahedron Lett. 2012; 53: 1236
61f Yang L, Feng J, Li J, Liu B. Tetrahedron Lett. 2015; 56: 4931
61g Bai W.-J, Green JC, Pettus TR. R. J. Org. Chem. 2012; 77: 379

62a Rapson WS. J. Chem. Soc. 1938; 282
62b Murray AW. Nature 1962; 196: 484
62c Perold GW, Pachler KG. R. J. Chem. Soc. C 1966; 1918
62d Perold GW, Carlton L, Howard AS, Michael JP. J. Chem. Soc., Perkin Trans. 1 1988; 881

63 Li X.-L, Cheng X, Yang L.-M, Wang R.-R, Zheng Y.-T, Xiao W.-L, Zhao Y, Xu G, Lu Y, Chang Y, Zheng Q.-T, Zhao Q.-S, Sun H.-D. Org. Lett. 2006; 8: 1937
64 Poss AJ, Belter RK. Tetrahedron Lett. 1987; 28: 2555
65 Wang Z, Zhao K, Fu J, Zhang J, Yin W, Tang Y. Org. Biomol. Chem. 2013; 11: 2093

66a Le Goff R, Lawson AM, Daïch A, Comesse S. Org. Biomol. Chem. 2013; 11: 1818
66b Görmen M, Le Goff R, Lawson AM, Daïch A, Comesse S. Tetrahedron Lett. 2013; 54: 2174

67a Chou T, Kuramoto M, Otani Y, Shikano M, Yazawa K, Uemura D. Tetrahedron Lett. 1996; 37: 3871
67b Clive DL. J, Yu M, Wang J, Yeh VS. C, Kang S. Chem. Rev. 2005; 105: 4483

68a Tsubosaka Y, Murata T, Kinoshita K, Yamada K, Uemura D, Hori M, Ozaki H. Eur. J. Pharmacol. 2010; 628: 128
68b Kuramoto M, Tong C, Yamada K, Chiba T, Hayashi Y, Uemura D. Tetrahedron Lett. 1996; 37: 3867

69 Wu H, Zhang H, Zhao G. Tetrahedron 2007; 63: 6454

70a Xu S, Unabara D, Uemura D, Arimoto H. Chem. Asian J. 2014; 9: 367
70b Xu S, Arimoto H, Uemura D. Angew. Chem. Int. Ed. 2007; 46: 5746

71 Christie HS, Heathcock CH. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 12079
72 Sugiyama R, Nishimura S, Ozaki T, Asamizu S, Onaka H, Kakeya H. Angew. Chem. Int. Ed. 2016; 55: 10278
73 Twiner MJ, Rehmann N, Hess P, Doucette GJ. Mar. Drugs 2008; 6: 39
74 Satake M, Ofuji K, Naoki H, James KJ, Furey A, McMahon T, Silke J, Yasumoto T. J. Am. Chem. Soc. 1998; 120: 9967
75 Furey A, Moroney C, Magdalena AB, Fidalgo Saez MJ, Lehane M, James KJ. Environ. Sci. Technol. 2003; 37: 3078

76a Jauffrais T, Marcaillou C, Herrenknecht C, Truquet P, Séchet V, Nicolau E, Tillmann U, Hess P. Toxicon 2012; 60: 582
76b Salas R, Tillmann U, John U, Kilcoyne J, Burson A, Cantwell C, Hess P, Jauffrais T, Silke J. Harmful Algae 2011; 10: 774

77 Nicolaou KC, Pihko PM, Diedrichs N, Zou N, Bernal F. Angew. Chem. Int. Ed. 2001; 40: 1262

78a Nicolaou KC, Koftis TV, Vyskocil S, Petrovic G, Tang W, Frederick MO, Chen DY. K, Li Y, Ling T, Yamada YM. A. J. Am. Chem. Soc. 2006; 128: 2859
78b Nicolaou KC, Chen DY. K, Li Y, Uesaka N, Petrovic G, Koftis TV, Bernal F, Frederick MO, Govindasamy M, Ling T, Pihko PM, Tang W, Vyskocil S. J. Am. Chem. Soc. 2006; 128: 2258
78c Nicolaou K, Pihko PM, Bernal F, Frederick MO, Qian W, Uesaka N, Diedrichs N, Hinrichs J, Koftis TV, Loizidou E. J. Am. Chem. Soc. 2006; 128: 2244
78d Nicolaou K, Frederick MO, Petrovic G, Cole KP, Loizidou EZ. Angew. Chem. Int. Ed. 2006; 45: 2609
78e Nicolaou K, Frederick MO, Loizidou EZ, Petrovic G, Cole KP, Koftis TV, Yamada YM. Chem. Asian J. 2006; 1: 245

79a Evans DA, Kværnø L, Mulder JA, Raymer B, Dunn TB, Beauchemin A, Olhava EJ, Juhl M, Kagechika K. Angew. Chem. Int. Ed. 2007; 46: 4693
79b Evans DA, Dunn TB, Kværnø L, Beauchemin A, Raymer B, Olhava EJ, Mulder JA, Juhl M, Kagechika K, Favor DA. Angew. Chem. Int. Ed. 2007; 46: 4698
79c Evans DA, Kværnø L, Dunn TB, Beauchemin A, Raymer B, Mulder JA, Olhava EJ, Juhl M, Kagechika K, Favor DA. J. Am. Chem. Soc. 2008; 130: 16295

80a Kenton NT, Adu-Ampratwum D, Okumu AA, Zhang Z, Chen Y, Nguyen S, Xu J, Ding Y, McCarron P, Kilcoyne J, Rise F, Wilkins AL, Miles CO, Forsyth CJ. Angew. Chem. Int. Ed. 2018; 57: 805
80b Kenton NT, Adu-Ampratwum D, Okumu AA, McCarron P, Kilcoyne J, Rise F, Wilkins AL, Miles CO, Forsyth CJ. Angew. Chem. Int. Ed. 2018; 57: 810

81a Wanyonyi AW, Chhabra SC, Mkoji G, Eilert U, Njue WM. Phytochemistry 2002; 59: 79
81b Mahato SB, Sahu NP, Ganguly AN, Kasai R, Tanaka O. Phytochemistry 1980; 19: 2017
81c Al Chami L, Méndez R, Chataing B, O’Callaghan J, Usubillaga A, LaCruz L. Phytother. Res. 2003; 17: 254
81d Ghosh M, Sinhababu SP, Sukul NC, Sahu NP, Mahato SB. Int. J. Pharmacogn. 1994; 32: 184

82 Kalalinia F, Karimi-Sani I. Phytother. Res. 2017; 31: 858

83a Wei G, Wang J, Du Y. Bioorg. Med. Chem. Lett. 2011; 21: 2930
83b Wei G, Wei D, Du Y. Sci. China Chem. 2012; 55: 1247

84 Nonato MG, Garson MJ, Truscott RJ, Carver JA. Phytochemistry 1993; 34: 1159
85 Seah KY, Macnaughton SJ, Dallimore JW. P, Robertson J. Org. Lett. 2014; 16: 884

86a Blicke FF. The Mannich Reaction . In Organic Reactions, Vol. 1. Adams R. John Wiley & Sons; New York: 1942: 303-341
86b Mannich C, Krösche W. Arch. Pharm. 1912; 250: 647

87 Greger H. Phytochem. Rev. 2019; 18: 463

88a Liu X.-Y, Wang F.-P. Nat. Prod. Commun. 2015; 10: 1093
88b Williams DR, Brown DL, Benbow JW. J. Am. Chem. Soc. 1989; 111: 1923
88c Martin SF, Barr KJ. J. Am. Chem. Soc. 1996; 118: 3299
88d Martin SF, Barr KJ, Smith DW, Bur SK. J. Am. Chem. Soc. 1999; 121: 6990
88e Noro T, Fukushima S, Ueno A, Miyase T, Iitaka Y, Saiki Y. Chem. Pharm. Bull. 1979; 27: 1495
88f Fu J, Shen H, Chang Y, Li C, Gong J, Yang Z. Chem. Eur. J. 2014; 20: 12881
88g Sakata K, Aoki K, Chang C.-F, Sakurai A, Tamura S, Murakoshi S. Agric. Biol. Chem. 1978; 42: 457
88h Hu J.-P, Yang D.-H, Lin W.-H, Cai S.-Q. Helv. Chim. Acta 2009; 92: 2125
88i Hitotsuyanagi Y, Fukaya H, Takeda E, Matsuda S, Saishu Y, Zhu S, Komatsu K, Takeya K. Tetrahedron 2013; 69: 6297
88j Xu R.-S. Some Bioactive Natural Products from Chinese Medicinal Plants. In Studies in Natural Products Chemistry, Part B, Vol. 21. Atta-ur-Rahman Elsevier; Amsterdam: 2000: 729-772
88k Hitotsuyanagi Y, Takeda E, Fukaya H, Takeya K. Tetrahedron Lett. 2008; 49: 7376
88l Taniguchi T, Tanabe G, Muraoka O, Ishibashi H. Org. Lett. 2008; 10: 197
88m Iizuka H, Irie H, Masaki N, Osaki K, Uyeo S. J. Chem. Soc., Chem. Commun. 1973; 125
88n Kende AS, Martin Hernando JI, Milbank JB. J. Org. Lett. 2001; 3: 2505
88o Kende AS, Martin Hernando JI, Milbank JB. J. Tetrahedron 2002; 58: 61
88p Ye Y, Qin G.-W, Xu R.-S. J. Nat. Prod. 1994; 57: 665

89a Nozoye T. Chem. Pharm. Bull. 1958; 6: 309
89b Nozoye T, Shibanuma Y, Shigehisa A. Yakugaku Zasshi 1975; 95: 758
89c Haginiwa J, Sakai S.-I, Aimi N, Yamanaka E, Shinma N. Yakugaku Zasshi 1973; 93: 448
89d Houghton PJ, Shellard EJ. Planta Med. 1974; 26: 104
89e Nozoye T. Chem. Pharm. Bull. 1958; 6: 309
89f Bindra JS. Oxindole Alkaloids . In The Alkaloids: Chemistry and Physiology, Vol. 14, Chap. 2. Manske RH. F. Academic Press; New York: 1973: 83-121

90 Wanner MJ, Ingemann S, van Maarseveen JH, Hiemstra H. Eur. J. Org. Chem. 2013; 1100
91 Roche SP, Porco JA. Jr. Angew. Chem. Int. Ed. 2011; 50: 4068

92a Baker Dockrey SA, Lukowski AL, Becker MR, Narayan AR. H. Nat. Chem. 2018; 10: 119
92b Jackson SK, Wu KL, Pettus TR. R. Sequential Reactions Initiated by Oxidative Dearomatization. Biomimicry or Artifact? In Biomimetic Organic Synthesis. Poupon E, Nay B. Wiley-VCH; Weinheim: 2011: 723-749

93a Heilmann J, Mayr S, Brun R, Rali T, Sticher O. Helv. Chim. Acta 2000; 83: 2939
93b Heilmann J, Brun R, Mayr S, Rali T, Sticher O. Phytochemistry 2001; 57: 1281
93c Salim AA, Su B.-N, Chai H.-B, Riswan S, Kardin LB. S, Ruskandi A, Farnsworth NR, Swanson SM, Kinghorn AD. Tetrahedron Lett. 2007; 48: 1849
93d Chin Y.-W, Salim AA, Su B.-N, Mi Q, Chai H.-B, Riswan S, Kardono LB. S, Ruskandi A, Farnsworth NR, Swanson SM, Kinghorn AD. J. Nat. Prod. 2008; 71: 390

94 Song L, Yao H, Dai Y, Wu M, Tong R. Tetrahedron Lett. 2016; 57: 4257 ; and references cited therein
95 Wong YS. Chem. Commun. 2002; 686
96 Ralifo P, Crews P. J. Org. Chem. 2004; 69: 9025
97 White KN, Amagata T, Oliver AG, Tenney K, Wenzel PJ, Crews P. J. Org. Chem. 2008; 73: 8719

98a Lamb RA, Aberle NS, Lucas NT, Lessene G, Hawkins BC. Angew. Chem. Int. Ed. 2017; 56: 14663
98b Lamb RA, Lucas NT, Lessene G, Hawkins BC. J. Org. Chem. 2018; 83: 10120

99 Buchanan MS, Carroll AR, Wessling D, Jobling M, Avery VM, Davis RA, Feng Y, Xue Y, Öster L, Fex T, Deinum J, Hooper JN. A, Quinn RJ. J. Med. Chem. 2008; 51: 3583
100 Li Y.-X, Cheng C, Tang L, Yang Y.-Y. Org. Biomol. Chem. 2020; 18: 4551

101a Pflieger P, Mioskowski C, Salaun JP, Weissbart D, Durst F. Tetrahedron Lett. 1989; 30: 2791
101b Falck J, Chandrasekhar S, Manna S, Chiu CC. S, Mioskowski C, Wetzel I. J. Am. Chem. Soc. 1993; 115: 11606

102 Hanson FR, Eble TE. J. Bacteriol. 1949; 58: 527

103a Molina J.-M, Tourneur M, Sarfati C, Chevret S, de Gouvello A, Gobert J.-G, Balkan S, Derouin F. New Engl. J. Med. 2002; 346: 1963
103b Killough JH, Magill GB, Smith RC. Science 1952; 115: 71

104a Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J. Nature 1990; 348: 555
104b Kwon J.-Y, Jeong H.-W, Kim H.-K, Kang K.-H, Chang Y.-H, Bae K.-S, Choi J.-D, Lee U.-C, Son K.-H, Kwon B.-M. J. Antibiot. 2000; 53: 799

105 Corey EJ, Snider BB. J. Am. Chem. Soc. 1972; 94: 2549

106a Kim D, Ahn SK, Bae H, Choi WJ, Kim HS. Tetrahedron Lett. 1997; 38: 4437
106b Vosburg DA, Weiler S, Sorensen EJ. Angew. Chem. Int. Ed. 1999; 38: 971
106c Hutchings M, Moffat D, Simpkins NS. Synlett 2001; 661
106d Taber DF, Christos TE. J. Am. Chem. Soc. 1999; 121: 5589
106e Boiteau J.-G, Van de Weghe P, Eustache J. Org. Lett. 2001; 3: 2737
106f Bedel O, Haudrechy A, Langlois Y. Eur. J. Org. Chem. 2004; 3813
106g Yamaguchi J, Toyoshima M, Shoji M, Kakeya H, Osada H, Hayashi Y. Angew. Chem. Int. Ed. 2006; 45: 789
106h Yamaguchi J, Hayashi Y. Chem. Eur. J. 2010; 16: 3884
106i Takahashi S, Hongo Y, Ye YQ, Koshino H. Tetrahedron: Asymmetry 2011; 22: 703

107 Nakamura R, Ishibashi K. J. Agric. Chem. Soc. Jpn. 1958; 32: 739
108 Nozoe S, Morisaki M, Tsuda K, Iitaka Y, Takahashi N, Tamura S, Ishibashi K, Shirasaka M. J. Am. Chem. Soc. 1965; 87: 4968

109a Leung PC, Taylor WA, Wang JH, Tipton CL. J. Biol. Chem. 1984; 259: 2742
109b Fujiwara H, Matsunaga K, Kumagai H, Ishizuka M, Ohizumi Y. Pharm. Pharmacol. Commun. 2000; 6: 427
109c Shen X, Krasnoff SB, Lu S.-W, Dunbar CD, O’Neal J, Turgeon BG, Yoder OC, Gibson DM, Hamann MT. J. Nat. Prod. 1999; 62: 895
109d Au TK, Chick WS. H, Leung PC. Life Sci. 2000; 67: 733

110a Noguchi N, Nakada M. Org. Lett. 2006; 8: 2039
110b Tsuna K, Noguchi N, Nakada M. Chem. Eur. J. 2013; 19: 5476
110c Tsuna K, Noguchi N, Nakada M. Angew. Chem. Int. Ed. 2011; 50: 9452

111a An F.-L, Luo J, Li R.-J, Luo J.-G, Wang X.-B, Yang M.-H, Yang L, Yao H.-Q, Sun H.-B, Chen Y.-J, Kong L.-Y. Org. Lett. 2016; 18: 1924
111b Zhong W, Wang J, Wei X, Chen Y, Fu T, Xiang Y, Huang X, Tian X, Xiao Z, Zhang W, Zhang S, Long L, Wang F. Org. Lett. 2018; 20: 4593