The Problem with Problems: Fundamental to Applied Research Using Palladium

Dedicated to our co-workers and collaborators, past, present, and future

Abstract

This Account describes the development of our cross-coupling and medicinal chemistry research from its origins at the outset of my independent career through to the present day. Throughout, the decisions and motivations as well as the mistakes and pitfalls are discussed.

1 Introduction

2 Hobbies and Interests

3 Scooped before Starting

4 Opportunity from Collaboration

5 Chemoselective Suzuki–Miyaura Cross-Coupling

6 Applications to the Medicinal Chemistry Campaign

7 Autotaxin and Heterocycle Synthesis

8 ATX Hybrids and Pd(II) Speciation

9 Conclusions

Key words

boron - cross-coupling - medicinal chemistry - palladium - speciation

• References

• 1 Burns AR, Kerr JH, Kerr WJ, Passmore J, Paterson LC, Watson AJ. B. Org. Biomol. Chem. 2010; 8: 2777

For reviews, see:
• 2a Hayashi T, Yamasaki K. Chem. Rev. 2003; 103: 2829
• 2b Jean M, Casanova B, Gnoatto S, van de Weghe P. Org. Biomol. Chem. 2015; 13: 9168
• 3 For some of our collaborative medicinal chemistry work in Rh-catalyzed 1,4-addition, see: Anderson NA, Fallon BJ, Valverde E, MacDonald SJ. F, Pritchard JM, Suckling CJ, Watson AJ. B. Synlett 2012; 23: 2817
• 4 Rupnicki L, Saxena A, Lam HW. J. Am. Chem. Soc. 2009; 131: 10386
• 5 For a review, see: Best D, Lam HW. J. Org. Chem. 2014; 79: 831
• 6 Xu C, Muir CW, Leach AG, Kennedy AR, Watson AJ. B. Angew. Chem. Int. Ed. 2018; 57: 11374

For a selection of this work, see:
• 7a MacMillan DS, Murray J, Sneddon HF, Jamieson C, Watson AJ. B. Green Chem. 2012; 14: 3016
• 7b MacMillan DS, Murray J, Sneddon HF, Jamieson C, Watson AJ. B. Green Chem. 2013; 15: 596
• 7c Caldwell N, Jamieson C, Simpson I, Watson AJ. B. ACS Sustain. Chem. Eng. 2013; 1: 1339
• 7d McGonagle FI, MacMillan DS, Murray J, Sneddon HF, Jamieson C, Watson AJ. B. Green Chem. 2013; 15: 1159
• 7e McGonagle FI, Sneddon HF, Jamieson C, Watson AJ. B. ACS Sustain. Chem. Eng. 2014; 2: 523
• 7f Caldwell N, Campbell PS, Jamieson C, Potjewyd F, Simpson I, Watson AJ. B. J. Org. Chem. 2014; 79: 9347
• 7g Caldwell N, Jamieson C, Simpson I, Watson AJ. B. Chem. Commun. 2015; 51: 9495
• 7h Eastman HE, Jamieson C, Watson AJ. B. Aldrichimica Acta 2015; 48: 51
• 7i Wilson KL, Kennedy AR, Murray J, Greatrex B, Jamieson C, Watson AJ. B. Beilstein J. Org. Chem. 2016; 12: 2005
• 7j McPherson CG, Caldwell N, Jamieson C, Simpson I, Watson AJ. B. Org. Biomol. Chem. 2017; 15: 3507
• 7k Wilson KL, Murray J, Sneddon HF, Wheelhouse KM. P, Watson AJ. B. Chem 2017; 3: 365
• 7l Wilson KL, Murray J, Jamieson C, Watson AJ. B. Synlett 2018; 29: 650
• 7m McPherson CG, Cooper AK, Bubliauskas A, Mulrainey P, Jamieson C, Watson AJ. B. Org. Lett. 2017; 19: 6736
• 7n Wilson L, Murray J, Jamieson C, Watson AJ. B. Org. Biomol. Chem. 2018; 16: 2851
• 7o Wilson KL, Murray J, Sneddon HF, Jamieson C, Watson AJ. B. Synlett 2018; 29: 2293

For reviews, see:
• 8a Barbayianni E, Magrioti V, Moutevelis-Minakakis GP, Kokotos G. Expert Opin. Ther. Pat. 2013; 23: 1123
• 8b Castagna D, Budd DC, Macdonald SJ. F, Jamieson C, Watson AJ. B. J. Med. Chem. 2016; 59: 5604
• 9a Swaney JS, Chapman C, Correa LD, Stebbins KJ, Bundey RA, Prodanovich PC, Fagan P, Baccei CS, Santini AM, Hutchinson JH, Seiders TJ, Parr TA, Prasit P, Evans JF, Lorrain DS. Br. J. Pharmacol. 2010; 160: 1699
• 9b Swaney JS, Chapman C, Correa LD, Stebbins KJ, Broadhead AR, Bain G, Santini AM, Darlington J, King CD, Baccei CS, Lee C, Parr TA, Roppe JR, Seiders TJ, Ziff J, Prasit P, Hutchinson JH, Evans JF, Lorrain DS. J. Pharmacol. Exp. Ther. 2011; 336: 693
• 10 Sinclair DJ, Sherburn MS. J. Org. Chem. 2005; 70: 3730
• 11 Dong C.-G, Hu Q.-S. J. Am. Chem. Soc. 2005; 127: 10006
• 12 Groombridge BJ, Goldup SM, Larrosa I. Chem. Commun. 2015; 51: 3832
• 13 Littke AF, Dai C, Fu GC. J. Am. Chem. Soc. 2000; 122: 4020
• 14 Almond-Thynne J, Blakemore DC, Prydeb DC, Spivey AC. Chem. Sci. 2017; 8: 40
• 15a Gillis EP, Burke MD. Aldrichimica Acta 2009; 42: 17
• 15b Li J, Grillo AS, Burke MD. Acc. Chem. Res. 2015; 48: 2297
• 16 Lee SJ, Gray KC, Paek JS, Burke MD. J. Am. Chem. Soc. 2008; 130: 466
• 17 Mancilla T, Contreras R, Wrackmeyer B. J. Organomet. Chem. 1986; 307: 1
• 18 Noguchi H, Hojo K, Suginome M. J. Am. Chem. Soc. 2007; 129: 758

For examples, see:
• 19a Noguchi H, Shioda T, Chou C.-M, Suginome M. Org. Lett. 2008; 10: 377
• 19b Iwadate N, Suginome M. Org. Lett. 2009; 11: 1899
• 19c Iwadate N, Suginome M. Chem. Lett. 2010; 39: 558
• 19d Iwadate N, Suginome M. J. Am. Chem. Soc. 2010; 132: 2548
• 19e Ihara H, Koyanagi M, Suginome M. Org. Lett. 2011; 13: 2662
• 19f Feng X, Jeon H, Yun J. Angew. Chem. Int. Ed. 2013; 52: 3989
• 19g Yoshida H, Takemoto Y, Takaki K. Chem. Commun. 2015; 51: 6297
• 20 Endo K, Ohkubo T, Hirokami M, Shibata T. J. Am. Chem. Soc. 2010; 132: 11033

For examples, see:
• 21a Mlynarski SN, Schuster CH, Morken JP. Nature 2014; 505: 386
• 21b Sun C, Potter B, Morken JP. J. Am. Chem. Soc. 2014; 136: 6534
• 21c Potter B, Szymaniak AA, Edelstein EK, Morken JP. J. Am. Chem. Soc. 2014; 136: 17918

For examples, see:
• 22a Lee JC. H, McDonald R, Hall DG. Nature Chem. 2011; 3: 894
• 22b Sun H.-Y, Kubota K, Hall DG. Chem. Eur. J. 2015; 21: 19186
• 23a Crudden CM, Ziebenhaus C, Rygus JP. G, Ghozati K, Unsworth PJ, Nambo M, Both S, Hutchinson M, Laberge VS, Maekawa Y, Imao D. Nat. Commun. 2016; 7: 11065
• 23b Glasspoole BW, Oderinde MS, Moore BD, Antoft-Finch A, Crudden CM. Synthesis 2013; 45: 1759
• 24 Rygus JP. G, Crudden CM. J. Am. Chem. Soc. 2017; 139: 18124
• 25a Fyfe JW. B, Watson AJ. B. Synlett 2015; 26: 1139
• 25b Fyfe JW. B, Watson AJ. B. Chem 2017; 3: 31
• 26 Carrow BP, Hartwig JF. J. Am. Chem. Soc. 2011; 133: 2116
• 27 Fyfe JW. B, Valverde E, Seath CP, Kennedy AR, Redmond JM, Anderson NA, Watson AJ. B. Chem. Eur. J. 2015; 24: 8951
• 28 Knapp DM, Gillis EP, Burke MD. J. Am. Chem. Soc. 2009; 131: 6961

For informative studies on the esterification of boronic acids, see:
• 29a Babcock L, Pizer R. Inorg. Chem. 1980; 19: 56
• 29b Pizer R, Tihal CA. Polyhedron 1996; 15: 3411
• 29c Springsteen G, Wang B. Tetrahedron 2002; 58: 5291
• 29d Bosch LI, Fyles TM, James TD. Tetrahedron 2004; 60: 11175
• 29e Yan J, Springsteen G, Deeter S, Wang B. Tetrahedron 2004; 60: 11205
• 29f Iwatsuki S, Nakajima S, Inamo M, Takagi HD, Ishihara K. Inorg. Chem. 2007; 46: 354
• 29g Miyamoto C, Suzuki K, Iwatsuki S, Inamo M, Takagi HD, Ishihara K. Inorg. Chem. 2008; 47: 1417
• 29h Martínez-Aguirre MA, Villamil-Ramos R, Guerrero-Alvarez JA, Yatsmirsky AK. J. Org. Chem. 2013; 78: 4674
• 29i Watanabe E, Miyamoto C, Tanaka A, Iizuka K, Iwatsuki S, Inamo M, Takagi HD, Ishihara K. Dalton Trans. 2013; 42: 8446
• 29j Okamoto T, Tanaka A, Watanabe E, Miyazaki T, Sugaya T, Iwatsuki S, Inamo M, Takagi HD, Odani A, Ishihara K. Eur. J. Inorg. Chem. 2014; 2389
• 29k Furikado Y, Nagahata T, Okamoto T, Sugaya T, Iwatsuki S, Inamo M, Takagi HD, Odani A, Ishihara K. Chem. Eur. J. 2014; 20: 13194
• 30 Gonzalez JA, Maduka Ogba O, Morehouse GF, Rosson N, Houk KN, Leach AG, Cheong PH. Y, Burke MD, Lloyd-Jones GC. Nat. Chem. 2016; 8: 1067
• 31a Fyfe JW. B, Seath CP, Watson AJ. B. Angew. Chem. Int. Ed. 2014; 53: 12077
• 31b Molloy JJ, Law RP, Fyfe JW. B, Seath CP, Hirst DJ, Watson AJ. B. Org. Biomol. Chem. 2015; 13: 3093
• 32 The formal homologation also operates well for arylboronic acids, see: Muir CW, Vantourout JC, Isidro-Llobet A, Macdonald SJ. F, Watson AJ. B. Org. Lett. 2015; 17: 6030
• 33 Seath CP, Fyfe JW. B, Molloy JJ, Watson AJ. B. Angew. Chem. Int. Ed. 2015; 54: 9976
• 34 Fyfe JW. B, Fazakerley NJ, Watson AJ. B. Angew. Chem. Int. Ed. 2017; 56: 1249
• 35 Law RP, Atkinson SJ, Bamborough P, Chung C, Demont EH, Gordon LJ, Lindon M, Prinjha RK, Watson AJ. B, Hirst DJ. J. Med. Chem. 2018; 61: 4317
• 36 Castagna D, Duffy EL, Semann D, Young LC, Pritchard JM, MacDonald SJ. F, Budd DC, Jamieson C, Watson AJ. B. Med. Chem. Commun. 2015; 6: 1149
• 37a Hausmann J, Kamtekar S, Christodoulou E, Day JE, Wu T, Fulkerson Z, Albers HM. H. G, van Meeteren LA, Houben AJ. S, van Zeijl L, Jansen S, Andries M, Hall T, Pegg LE, Benson TE, Kasiem M, Harlos K, Kooi CW. V, Smyth SS, Ovaa H, Bollen M, Morris AJ, Moolenaar WH, Perrakis A. Nat. Struct. Mol. Biol. 2011; 18: 198
• 37b Nishimasu H, Okudaira S, Hama K, Mihara E, Dohmae N, Inoue A, Ishitani R, Takagi J, Aoki J, Nureki O. Nat. Struct. Mol. Biol. 2011; 18: 205
• 37c Stein AJ, Bain G, Prodanovich P, Santini AM, Darlington J, Stelzer NM. P, Sidhu RS, Schaub J, Goulet L, Lonergan D, Calderon I, Evans JF, Hutchinson JH. Mol. Pharmacol. 2015; 88: 982
• 38a Roppe JR, Parr TA, Hutchinson JH. US 20130029948 A1, 2013
• 38b Hutchinson JH, Parr TA, Roppe JF, Stock NS, Volkots D. WO 2012024620 A2, 2012
• 38c Roppe JR, Parr TA, Hutchinson JH. WO 2012166415, 2012 .
• 39 Gierse J, Thorarensen A, Beltey K, Bradshaw-Pierce E, Cortes-Burgos L, Hall T, Johnston A, Murphy M, Nemirovskiy O, Ogawa S, Pegg L, Pelc M, Prinsen M, Schnute M, Wendling J, Wene S, Weinberg R, Wittwer A, Zweifel B, Masferrer J. J. Pharmacol. Exp. Ther. 2010; 334: 310
• 40 Miller LM, Keune W.-J, Castagna D, Young L, Duffy E, Potjewyd F, Salgado-Polo F, Engel García P, Semaan D, Pritchard J, Perrakis A, Macdonald SJ. F, Jamieson C, Watson AJ. B. J. Med. Chem. 2017; 60: 722
• 41a Hutchinson JH, Parr TA, Bunker KD, Lonergan D. WO 2015042053 A1, 2015
• 41b Hutchinson JH, Lonergan D. WO 2015077502 A1, 2015
• 41c Hutchinson JH, Parr TA, Bunker KD, Lonergan D. WO 2015042052 A1, 2015
• 41d Hutchinson JH, Lonergan D, Huang F, Rowbottom M, Calderon I. WO 2015048301 A1, 2015
• 41e Hutchinson JE, Lonegan D. WO 2015077503 A1, 2015
• 41f Stein AJ, Bain G, Prodanovich P, Santini AM, Darlington J, Stelzer NM. P, Sidhu RS, Schaub J, Goulet L, Lonergan D, Calderon I, Evans JF, Hutchinson JH. Mol. Pharmacol. 2015; 88: 982
• 42 Shah P, Cheasty A, Foxton C, Raynham T, Farooq M, Gutierrez IF, Lejeune A, Pritchard M, Turnbull A, Pang L, Owen P, Boyd S, Stowell A, Jordan A, Hamilton NM, Hitchin JR, Stockley M, MacDonald E, Quesada MJ, Trivier E, Skeete J, Ovaa H, Moolenaar WH, Ryder H. Bioorg. Med. Chem. Lett. 2016; 15: 5403

For initial reports, see:
• 43a Castro CE, Gaughan EJ, Owsley DC. J. Org. Chem. 1966; 31: 4071
• 43b Sakamoto T, Kondo Y, Iwashita S, Nagano T, Yamanaka H. Chem. Pharm. Bull. 1988; 36: 1305

For selected reviews, see:
• 44a Humphrey GR, Kuethe JT. Chem. Rev. 2006; 106: 2875
• 44b Cacchi S, Fabrizi G. Chem. Rev. 2011; 111: PR215
• 45 Seath CP, Wilson KL, Campbell A, Mowat JM, Watson AJ. B. Chem. Commun. 2016; 52: 8703
• 46 Seath CP, Fyfe JW. B, Molloy JJ, Watson AJ. B. Synthesis 2017; 49: 891
• 47 Keune W.-J, Potjewyd F, Hediebrecht T, Salgado-Polo F, Macdonald SJ. F, Chelvarajan L, Latif AA, Soman S, Morris AJ, Watson AJ. B, Jamieson C, Perrakis A. J. Med. Chem. 2017; 60: 2006
• 48 Molloy JJ, Seath CP, West MJ, McLaughlin C, Fazakerley NJ, Kennedy AR, Nelson DJ, Watson AJ. B. J. Am. Chem. Soc. 2018; 140: 126
• 49 For some related work, see: Xu C, Fyfe JW. B, Seath CP, Bennett SH, Watson AJ. B. Chem. Commun. 2017; 53: 9139

For selected examples, see:
• 50a Hunt AR, Stewart SK, Whiting A. Tetrahedron Lett. 1993; 34: 3599
• 50b Itami K, Tonogaki K, Nokami T, Ohashi Y, Yoshida J. Angew. Chem. Int. Ed. 2006; 45: 2404
• 50c Batsanov AS, Knowles JP, Whiting A. J. Org. Chem. 2007; 72: 2525
• 51a Amatore C, Jutand A, Le Duc G. Chem. Eur. J. 2011; 17: 2492
• 51b Amatore C, Jutand A, Le Duc G. Chem. Eur. J. 2012; 18: 6616
• 52a Thomas AA, Denmark SE. Science 2016; 352: 329
• 52b Thomas AA, Wang H, Zahrt AF, Denmark SE. J. Am. Chem. Soc. 2017; 139: 3805
• 53 For a review, see: Lennox AJ. J, Lloyd-Jones GC. Angew. Chem. Int. Ed. 2013; 52: 7362
• 54 Butters M, Harvey JN, Jover J, Lennox AJ. J, Lloyd-Jones GC, Murray PM. Angew. Chem. Int. Ed. 2010; 49: 5156
• 55 Cain DL, McLaughlin C, Molloy JJ, Carpenter-Warren C, Anderson NA, Watson AJ. B. Synlett 2019; 30: 787