Chemical Innovation through Ligand Total Synthesis

Dedicated to Prof. Shū Kobayashi

Abstract

Natural products are an abundant source of synthetic challenges that foster crucial breakthroughs in organic chemistry. Despite the superior complexity of these targets, ligand total synthesis can inspire solutions to unsolved chemical problems and provide access to creative catalyst designs. This Synpacts article presents a comparative analysis of natural and ligand total synthesis to provide a context for our recent research and motivate the importance of future undertakings in this area.

1 Introduction

2 Ligands as Artificial Total Synthesis Targets

3 Natural Product Total Synthesis: The Inspiration of Relevant New Methods

4 Selected Syntheses of Important Ligands

5 Total Synthesis of the Ligand PiPy₆: The Invention of a New Organometallic Photoreaction

6 Conclusion

Key words

total synthesis - catalysis - ligands - cycloaddition - aluminum - photochemistry

• References

• 1 Keasling JD, Mendoza A, Baran PS. Nature (London, U.K.) 2012; 492: 188
• 2a Keding SJ, Danishefsky SJ. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 11937
• 2b Nicolaou KC, Snyder SA. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 11929
• 2c Peterson EA, Overman LE. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 11943
• 2d Nicolaou KC, Hale CR. H, Nilewski C, Ioannidou HA. Chem. Soc. Rev. 2012; 41: 5185
• 2e Ball P. Nature (London, U.K.) 2015; 528: 327
• 3a Shenvi RA, O'Malley DP, Baran PS. Acc. Chem. Res. 2009; 42: 530
• 3b Nicolaou KC, Baran PS. Angew. Chem. Int. Ed. 2002; 41: 2678
• 3c Nicolaou KC, Hale CR. H. Natl. Sci. Rev. U.S.A. 2014; 1: 233
• 4a Gaich T, Baran PS. J. Org. Chem. 2010; 75: 4657
• 4b Balieu S, Hallett GE, Burns M, Bootwicha T, Studley J, Aggarwal VK. J. Am. Chem. Soc. 2015; 137: 4398
• 5a Burns NZ, Baran PS, Hoffmann RW. Angew. Chem. Int. Ed. 2009; 48: 2854
• 5b Young IS, Baran PS. Nat. Chem. 2009; 1: 193
• 6a Tsubogo T, Oyamada H, Kobayashi S. Nature (London, U.K.) 2015; 520: 329
• 6b Li J, Ballmer SG, Gillis EP, Fujii S, Schmidt MJ, Palazzolo AM, Lehmann JW, Morehouse GF, Burke MD. Science 2015; 347: 1221
• 6c Burns M, Essafi S, Bame JR, Bull SP, Webster MP, Balieu S, Dale JW, Butts CP, Harvey JN, Aggarwal VK. Nature (London, U.K.) 2014; 513: 183
• 7a Gutekunst WR, Baran PS. Chem. Soc. Rev. 2011; 40: 1976
• 7b Davies HM. L, Manning JR. Nature (London, U.K.) 2008; 451: 417
• 7c Chen DY. K, Youn SW. Chem. Eur. J. 2012; 18: 9452
• 8a Charest MG, Lerner CD, Brubaker JD, Siegel DR, Myers AG. Science 2005; 308: 395
• 8b Shenvi RA, Guerrero CA, Shi J, Li C.-C, Baran PS. J. Am. Chem. Soc. 2008; 130: 7241
• 8c Ledford H. Nature (London, U.K.) 2010; 468: 608
• 8d Jørgensen L, McKerrall SJ, Kuttruff CA, Ungeheuer F, Felding J, Baran PS. Science 2013; 341: 878
• 9 Suárez-Pantiga S, Colas K, Johansson MJ, Mendoza A. Angew. Chem. Int. Ed. 2015; 54: 14094 ; and references cited therein
• 10a Gampe CM, Carreira EM. Angew. Chem. Int. Ed. 2011; 50: 2962
• 10b Gampe CM, Carreira EM. Chem. Eur. J. 2012; 18: 15761
• 11 Gampe CM, Boulos S, Carreira EM. Angew. Chem. Int. Ed. 2010; 49: 4092
• 12 Gampe CM, Carreira EM. Angew. Chem. Int. Ed. 2012; 51: 3766
• 13a Huters AD, Quasdorf KW, Styduhar ED, Garg NK. J. Am. Chem. Soc. 2011; 133: 15797
• 13b Huters AD, Styduhar ED, Garg NK. Angew. Chem. Int. Ed. 2012; 51: 3758
• 14a Styduhar ED, Huters AD, Weires NA, Garg NK. Angew. Chem. Int. Ed. 2013; 52: 12422
• 14b Goetz AE, Silberstein AL, Corsello MA, Garg NK. J. Am. Chem. Soc. 2014; 136: 3036
• 15 Goetz AE, Garg NK. Nat. Chem. 2013; 5: 54
• 16 Zu L, Boal BW, Garg NK. J. Am. Chem. Soc. 2011; 133: 8877
• 17a Moreno J, Picazo E, Morrill LA, Smith JM, Garg NK. J. Am. Chem. Soc. 2016; 138: 1162
• 17b Boal BW, Schammel AW, Garg NK. Org. Lett. 2009; 11: 3458
• 18 Fañanás FJ, Mendoza A, Arto T, Temelli B, Rodríguez F. Angew. Chem. Int. Ed. 2012; 51: 4930
• 19a Barluenga J, Mendoza A, Rodríguez F, Fañanás FJ. Angew. Chem. Int. Ed. 2008; 47: 7044
• 19b Barluenga J, Mendoza A, Rodríguez F, Fañanás FJ. Chem. Eur. J. 2008; 14: 10892
• 19c Barluenga J, Mendoza A, Rodríguez F, Fañanás FJ. Angew. Chem. Int. Ed. 2009; 48: 1644
• 19d Barluenga J, Calleja J, Mendoza A, Rodríguez F, Fañanás FJ. Chem. Eur. J. 2010; 16: 7110
• 20 Nilewski C, Geisser RW, Carreira EM. Nature (London, U.K.) 2009; 457: 573
• 21 Bucher C, Deans RM, Burns NZ. J. Am. Chem. Soc. 2015; 137: 12784
• 22 Hu DX, Seidl FJ, Bucher C, Burns NZ. J. Am. Chem. Soc. 2015; 137: 3795
• 23a Baran PS, Guerrero CA, Ambhaikar NB, Hafensteiner BD. Angew. Chem. Int. Ed. 2005; 44: 606
• 23b Baran PS, Hafensteiner BD, Ambhaikar NB, Guerrero CA, Gallagher JD. J. Am. Chem. Soc. 2006; 128: 8678
• 24 Baran PS, DeMartino MP. Angew. Chem. Int. Ed. 2006; 45: 7083
• 25a DeMartino MP, Chen K, Baran PS. J. Am. Chem. Soc. 2008; 130: 11546
• 25b Richter JM, Whitefield BW, Maimone TJ, Lin DW, Castroviejo MP, Baran PS. J. Am. Chem. Soc. 2007; 129: 12857
• 25c Martin CL, Overman LE, Rohde JM. J. Am. Chem. Soc. 2008; 130: 7568
• 26 Hinman A, Du Bois J. J. Am. Chem. Soc. 2003; 125: 11510
• 27 Fleming JJ, McReynolds MD, Du Bois J. J. Am. Chem. Soc. 2007; 129: 9964
• 28 Mulcahy JV, Du Bois J. J. Am. Chem. Soc. 2008; 130: 12630
• 29 Wehn PM, Du Bois J. J. Am. Chem. Soc. 2002; 124: 12950
• 30 Wehn PM, Du Bois J. Angew. Chem. Int. Ed. 2009; 48: 3802
• 31a Seiple IB, Su S, Young IS, Lewis CA, Yamaguchi J, Baran PS. Angew. Chem. Int. Ed. 2010; 49: 1095
• 31b Su S, Rodriguez RA, Baran PS. J. Am. Chem. Soc. 2011; 133: 13922
• 32 Rodriguez RA, Pan C.-M, Yabe Y, Kawamata Y, Eastgate MD, Baran PS. J. Am. Chem. Soc. 2014; 136: 6908
• 33 Su S, Seiple IB, Young IS, Baran PS. J. Am. Chem. Soc. 2008; 130: 16490
• 34 Wilde NC, Isomura M, Mendoza A, Baran PS. J. Am. Chem. Soc. 2014; 136: 4909
• 35 Levin S, Nani RR, Reisman SE. J. Am. Chem. Soc. 2011; 133: 774
• 36 Nani RR, Reisman SE. J. Am. Chem. Soc. 2013; 135: 7304
• 37a Gatineau D, Giordano L, Buono G. J. Am. Chem. Soc. 2011; 133: 10728
• 37b León T, Riera A, Verdaguer X. J. Am. Chem. Soc. 2011; 133: 5740
• 37c Huang Y, Li Y, Leung P.-H, Hayashi T. J. Am. Chem. Soc. 2014; 136: 4865
• 37d Du Z.-J, Guan J, Wu G.-J, Xu P, Gao L.-X, Han F.-S. J. Am. Chem. Soc. 2015; 137: 632
• 37e Han ZS, Zhang L, Xu Y, Sieber JD, Marsini MA, Li Z, Reeves JT, Fandrick KR, Patel ND, Desrosiers J.-N, Qu B, Chen A, Rudzinski DM, Samankumara LP, Ma S, Grinberg N, Roschangar F, Yee NK, Wang G, Song JJ, Senanayake CH. Angew. Chem. Int. Ed. 2015; 54: 5474
• 37f Chan VS, Chiu M, Bergman RG, Toste FD. J. Am. Chem. Soc. 2009; 131: 6021
• 38 Senge MO. Acc. Chem. Res. 2005; 38: 733
• 39 Lewis JE. M, Bordoli RJ, Denis M, Fletcher CJ, Galli M, Neal EA, Rochette EM, Goldup SM. Chem. Sci. 2016; 7: 3154
• 40 Gao D.-W, Gu Q, You S.-L. J. Am. Chem. Soc. 2016; 138: 2544
• 41a Martin R, Buchwald SL. Acc. Chem. Res. 2008; 41: 1461
• 41b Surry DS, Buchwald SL. Angew. Chem. Int. Ed. 2008; 47: 6338
• 42a Dorel R, Echavarren AM. Chem. Rev. 2015; 115: 9028
• 42b Jiménez-Núñez E, Echavarren AM. Chem. Rev. 2008; 108: 3326
• 43 Old DW, Wolfe JP, Buchwald SL. J. Am. Chem. Soc. 1998; 120: 9722
• 44 Tomori H, Fox JM, Buchwald SL. J. Org. Chem. 2000; 65: 5334
• 45 Hoshiya N, Buchwald SL. Adv. Synth. Catal. 2012; 354: 2031
• 46a Defieber C, Grützmacher H, Carreira EM. Angew. Chem. Int. Ed. 2008; 47: 4482
• 46b Feng C.-G, Xu M.-H, Lin G.-Q. Synlett 2011; 1345
• 46c Feng X, Du H. Asian J. Org. Chem. 2012; 1: 204
• 47a Tokunaga N, Otomaru Y, Okamoto K, Ueyama K, Shintani R, Hayashi T. J. Am. Chem. Soc. 2004; 126: 13584
• 47b Otomaru Y, Okamoto K, Shintani R, Hayashi T. J. Org. Chem. 2005; 70: 2503
• 48 Abele S, Inauen R, Spielvogel D, Moessner C. J. Org. Chem. 2012; 77: 4765
• 49 Jimenez-Gonzalez C, Ponder CS, Broxterman QB, Manley JB. Org. Process Res. Dev. 2011; 15: 912
• 50 Bao J, Wulff WD, Dominy JB, Fumo MJ, Grant EB, Rob AC, Whitcomb MC, Yeung S.-M, Ostrander RL, Rheingold AL. J. Am. Chem. Soc. 1996; 118: 3392
• 51 Ding Z, Osminski WE. G, Ren H, Wulff WD. Org. Process Res. Dev. 2011; 15: 1089
• 52 Blackman AG. Eur. J. Inorg. Chem. 2008; 2633
• 53a Mercer GJ, Sigman MS. Org. Lett. 2003; 5: 1591
• 53b Karlsson S, Lindberg J, Sörensen H. Org. Process Res. Dev. 2013; 17: 1552
• 54 Erkizia E, Aldaba E, Vara Y, Arrieta A, Gornitzka H, Cossio FP. ARKIVOC 2005; (ix): 189

This process had been documented only rarely before our work, see:
• 55a Chen Z, Wu J, Chen Y, Li L, Xia Y, Li Y, Liu W, Lei T, Yang L, Gao D, Li W. Organometallics 2012; 31: 6005
• 55b Cariou R, Gibson VC, Tomov AK, White AJ. P. J. Organomet. Chem. 2009; 694: 703
• 55c Trepanier SJ, Wang S. Can. J. Chem. 1996; 74: 2032
• 55d Westerhausen M, Bollwein T, Mayer P, Piotrowski H, Pfitzner A. Z. Anorg. Allg. Chem. 2002; 628: 1425
• 55e Pearson WH, Szura DP, Postich MJ. J. Am. Chem. Soc. 1992; 114: 1329
• 55f Huisgen R, Niklas K. Heterocycles 1984; 22: 21
• 55g Guerra PV, Yaylayan VA. Agric. Food Chem. 2010; 58: 12523
• 56a Frazier BA, Wolczanski PT, Lobkovsky EB, Cundari TR. J. Am. Chem. Soc. 2009; 131: 3428
• 56b Frazier BA, Williams VA, Wolczanski PT, Bart SC, Meyer K, Cundari TR, Lobkovsky EB. Inorg. Chem. 2013; 52: 3295
• 56c Frazier BA, Bartholomew ER, Wolczanski PT, DeBeer S, Santiago-Berrios M, Abruna HD, Lobkovsky EB, Bart SC, Mossin S, Meyer K, Cundari TR. Inorg. Chem. 2011; 50: 12414