Adventures in Total Synthesis – The Next Chapter

Dedicated to Professor Ian Paterson and Professor K. C. Nicolaou

Abstract

This account summarizes the author’s endeavors in target-oriented synthesis at Seoul National University since 2011. A collection of the most celebrated molecules in total synthesis are revisited and the author’s solutions to these historical challenges are presented. In particular, the unique perception of their molecular frameworks and unprecedented bond-forming sequences form the basis of the newly developed strategies. Together with a ‘personal touch’ on these selected stories, the author hopes that this account will offer new insights and fresh perspectives for all levels of enthusiasts of target-oriented total synthesis.

1 Introduction

2.1 Synthesis of Strychnine

2.2 Synthesis of Actinophyllic Acid

2.3 Synthesis of Dendrobine

2.4 Synthesis of Communesin

2.5 Synthesis of Morphinans

2.6 Synthesis of Reserpine

2.7 Synthesis of Quinine and Quinidine

2.8 Synthesis of Haouamine

2.9 Future Work

3 Summary and Outlook

4 Abbreviations

Key words

molecular symmetry - natural products - synthetic strategy - target-oriented synthesis - total synthesis

Publication History

Received: 30 June 2023

Accepted after revision: 31 July 2023

Accepted Manuscript online:
31 July 2023

Article published online:
13 September 2023

• References

• 1 Chen DY.-K. Synlett 2011; 2459
• 2 Jones SB, Simmons B, Mastracchio A, MacMillan DW. C. Nature 2011; 475: 183
• 3 Martin DB. C, Vanderwal CD. Chem. Sci. 2011; 2: 649
• 4 Lee GS, Namkoong G, Park J, Chen DY.-K. Chem. Eur. J. 2017; 23: 16189
• 5 Kozmin SA, Iwama T, Huang Y, Rawal VH. J. Am. Chem. Soc. 2002; 124: 4628
• 6 Cannon JS, Overman LE. Angew. Chem. Int. Ed. 2012; 51: 4288
• 7 Ratjen L, Garcia-Garcia P, Lay F, Beck ME, List B. Angew. Chem. Int. Ed. 2011; 50: 754
• 8a Ueda H, Satoh H, Matsumoto K, Sugimoto K, Fukuyama T, Tokuyama H. Angew. Chem. Int. Ed. 2009; 48: 7600
• 8b Nicolaou KC, Dalby SM, Li S, Suzuki T, Chen DY.-K. Angew. Chem. Int. Ed. 2009; 48: 7616
• 9a Martin CL, Overman LE, Rohde JM. J. Am. Chem. Soc. 2008; 130: 7568
• 9b Martin CL, Overman LE, Rohde JM. J. Am. Chem. Soc. 2010; 132: 4894
• 10 Yoshii Y, Tokuyama H, Chen DY.-K. Angew. Chem. Int. Ed. 2017; 56: 12277
• 11 Hagedorn AA, Miller BJ, Nagy JO. Tetrahedron Lett. 1980; 21: 229
• 12 Shultz DM. Wolfe J. P. Synthesis 2012; 44: 351
• 13 Granger BA, Jewett IT, Butler JD, Hua B, Knezevic CE, Parkinson EI, Hergenrother PJ, Martin SF. J. Am. Chem. Soc. 2013; 135: 12984
• 14 Cai L, Zhang K, Kwon O. J. Am. Chem. Soc. 2016; 138: 3298
• 15 Peixoto PA, Severin R, Tseng C.-C, Chen DY.-K. Angew. Chem. Int. Ed. 2011; 50: 3013
• 16 Croatt MP, Wender PA. Eur. J. Org. Chem. 2010; 19
• 17a Li Q, Yu Z.-X. J. Am. Chem. Soc. 2010; 132: 4542
• 17b Li Q, Yu Z.-X. Angew. Chem. Int. Ed. 2011; 50: 2144
• 18 Lee Y, Rochette EM, Kim J, Chen DY.-K. Angew. Chem. Int. Ed. 2017; 56: 12250
• 19 Trost BM, Tanoury GJ, Lautens M, Chan C, MacPherson DT. J. Am. Chem. Soc. 1994; 116: 4255
• 20 Dardenne J, Desrat S, Guéritte F, Roussi F. Eur. J. Org. Chem. 2013; 2116
• 21 Kende AS, Bentley TJ, Mader RA, Ridge D. J. Am. Chem. Soc. 1974; 96: 4332
• 22 Hornillos V, Perez M, Fañanas-Mastral M, Feringa BL. Chem. Eur. J. 2013; 19: 5432
• 23 Cheng D, Ishihara Y, Tan B, Barbas CF. III. ACS Catal. 2014; 4: 743
• 24a Park J, Jean A, Chen DY.-K. Angew. Chem. Int. Ed. 2017; 56: 14237
• 24b Park J, Jean A, Chen DY.-K. J. Org. Chem. 2018; 83: 6936
• 25 Wang Q, Han J, Wang C, Zhang J, Huang Z, Shi D, Zhao Y. Chem. Sci. 2014; 5: 4962
• 26a Yang J, Wu H, Shen Y, Qin Y. J. Am. Chem. Soc. 2007; 129: 13794
• 26b Liu P, Seo JH, Weinreb SM. Angew. Chem. Int. Ed. 2010; 49: 2000
• 27 Layton ME, Morales CA, Shair MD. J. Am. Chem. Soc. 2002; 124: 773
• 28 Gu Z, Zakarian A. Org. Lett. 2010; 12: 4224
• 29 Park KH, Chen R, Chen DY.-K. Chem. Sci. 2017; 8: 7031
• 30 Dyker G. Angew. Chem. Int. Ed. 1992; 31: 1023
• 31 Chemistry of Opioids . In Topics in Current Chemistry, Vol. 299. Nagase H. Springer-Verlag; Berlin/Heidelberg: 2011: 1-312
• 32a Woodward RB, Cava MP, Ollis WD, Hunger A, Daeniker HU, Schenker K. J. Am. Chem. Soc. 1954; 76: 4749
• 32b Gilbert Stork reported a total synthesis of strychnine at the Ischia Advanced School of Organic Chemistry, Ischia Porto, Italy, September 21, 1992.
• 33a Woodward RB, Bader FE, Bickel H, Frey AJ, Kierstead RW. J. Am. Chem. Soc. 1956; 78: 2657
• 33b Stork G, Tang PC, Casey M, Goodman B, Toyota M. J. Am. Chem. Soc. 2005; 127: 16255
• 34a Woodward RB, Doering WE. J. Am. Chem. Soc. 1945; 67: 860
• 34b Stork G, Niu D, Fujimoto A, Koft ER, Balkovec JM, Tata JR, Dake GR. J. Am. Chem. Soc. 2001; 123: 3239
• 35 Chen F.-E, Huang J. Chem. Rev. 2005; 105: 4671
• 36 Park J, Chen DY.-K. Angew. Chem. Int. Ed. 2018; 57: 16152
• 37 Horwitz MA. Tetrahedron Lett. 2022; 97: 153776
• 38 Hayashi Y, Yamaguchi J, Hibino K, Sumiya T, Urushima T, Shoji M, Hashizume D, Koshino H. Adv. Synth. Catal. 2004; 346: 1435
• 39a Busca P, Piller V, Piller F, Martin OR. Bioorg. Med. Chem. Lett. 2003; 13: 1853
• 39b Altstadt TJ, Fairchild CR, Golik J, Johnston KA, Kadow JF, Lee FY, Long BH, Rose WC, Vyas DM, Wong H, Wu M.-J, Wittman MD. J. Med. Chem. 2001; 44: 4577
• 40 Uematsu N, Fujii A, Hashiguchi S, Ikariya T, Noyori R. J. Am. Chem. Soc. 1996; 118: 4916
• 41 Kallepalli V, Shi F, Paul S, Onyeozili EN, Maleczka RE. Jr, Smith MR. III. J. Org. Chem. 2009; 74: 9199
• 42 Lee J, Chen DY.-K. Angew. Chem. Int. Ed. 2019; 58: 488
• 43 Breman AC, van der Heijden G, van Maarseveen JH, Ingemann S, Hiemstra H. Chem. Eur. J. 2016; 22: 14247
• 44 Park KH, Rizzo A, Chen DY.-K. Chem. Sci. 2020; 11: 8132
• 45 Xia Y, Liu Z, Liu Z, Ge R, Ye F, Hossain M, Zhang Y, Wang J. J. Am. Chem. Soc. 2014; 136: 3013
• 46 Wehn PM, Du Bois J. Angew. Chem. Int. Ed. 2009; 48: 3802
• 47a Jeong JH, Weinreb SM. Org. Lett. 2006; 8: 2309
• 47b Cao L, Wang C, Wipf P. Org. Lett. 2019; 21: 1538
• 48 Gulder T, Baran PS. Nat. Prod. Rep. 2012; 29: 899
• 49 Trost BM, Chupak LS, Lubbers T. J. Am. Chem. Soc. 1998; 120: 1732
• 50 Chen DY.-K. Isr. J. Chem. 2018; 58: 85