Aryl Annulation: A Powerful Simplifying Retrosynthetic Disconnection

Abstract

Retrosynthetic deconstruction of a core aromatic ring is an especially simplifying retrosynthetic step, reducing the complexity of the precursor synthetic target. Moreover, when implemented to provide a penultimate intermediate, it enables late-stage divergent aryl introductions, permitting deep-seated core aryl modifications ordinarily accessible only by independent synthesis. Herein, we highlight the use of a ketone carbonyl group as the functionality to direct such late-stage divergent aryl introductions onto a penultimate intermediate with a projected application in the total synthesis of vinblastine and its presently inaccessible analogues containing indole replacements. Although the studies highlight this presently unconventional strategy with an especially challenging target in mind, the increase in molecular complexity (intricacy) established by the synthetic implementation of the powerful retrosynthetic disconnection, the use of a ketone as the precursor enabling functionality, and with adoption of either conventional or new wave (hetero)aromatic annulations combine to define a general and powerful strategy suited for widespread implementation with near limitless scope in target diversification.

Key words

alkaloids - annulations - arenes - cycloaddition - heterocycles - vinblastine - late-stage modification - retrosynthetic disconnection - natural products

Publication History

Received: 14 September 2022

Accepted: 12 October 2022

Accepted Manuscript online:
12 October 2022

Article published online:
21 November 2022

• References

• 1 Noble RL, Beer CT, Cutts JH. Ann. N. Y. Acad. Sci. 1958; 76: 882
• 2 Noble RL. Biochem. Cell. Biol. 1990; 68: 1344
• 3 Svoboda GH, Neuss N, Gorman M. J. Am. Pharm. Assoc. 1959; 48: 659
• 4 Neuss N, Neuss MN. Therapeutic Use of Bisindole Alkaloids from Catharanthus . In The Alkaloids: Chemistry and Pharmacology, Vol. 37. Brossi A, Suffness M. Academic Press; New York/San Diego: 1990: 229-240
• 5 Kuehne ME, Markó I. Syntheses of Vinblastine-Type Alkaloids . In The Alkaloids: Chemistry and Pharmacology, Vol. 37. Brossi A, Suffness M. Academic Press; New York/San Diego: 1990: 77-131
• 6 Pearce HL. Medicinal Chemistry of Bisindole Alkaloids from Catharanthus . In The Alkaloids: Chemistry and Pharmacology, Vol. 37. Brossi A, Suffness M. Academic Press; New York/San Diego: 1990: 145-204
• 7 Owellen RJ, Hartke CA, Dickerson RM, Hains FO. Cancer Res. 1976; 36: 1499
• 8 Jacques F. Curr. Pharm. Des. 2001; 7: 1181
• 9 Jordan MA, Wilson L. Nat. Rev. Cancer 2004; 4: 253
• 10 Boger DL. J. Org. Chem. 2017; 82: 11961
• 11 Shalinsky DR, Heath DD, Jekunen AP, Alcaraz JE, Howell SB. Br. J. Cancer 1993; 67: 471
• 12 Lampidis TJ, Kolonias D, Podona T, Israel M, Safa AR, Lothstein L, Savaraj N, Tapiero H, Priebe W. Biochemistry 1997; 36: 2679
• 13 Perego P, De Cesare M, De sabella P, Carenini N, Beggiolin G, Pezzoni G, Palumbo M, Tartaglia L, Pratesi G, Pisano C, Carminati P, Scheffer GL, Zunino FA. Cancer Res. 2001; 61: 6034
• 14 Ishikawa H, Colby DA, Boger DL. J. Am. Chem. Soc. 2008; 130: 420
• 15 Ishikawa H, Colby DA, Seto S, Va P, Tam A, Kakei H, Rayl TJ, Hwang I, Boger DL. J. Am. Chem. Soc. 2009; 131: 4904
• 16 Tam A, Gotoh H, Robertson WM, Boger DL. Bioorg. Med. Chem. Lett. 2010; 20: 6408
• 17 Va P, Campbell EL, Robertson WM, Boger DL. J. Am. Chem. Soc. 2010; 132: 8489
• 18 Sasaki Y, Kato D, Boger DL. J. Am. Chem. Soc. 2010; 132: 13533
• 19 Gotoh H, Duncan KK, Robertson WM, Boger DL. ACS Med. 2011; 2: 948
• 20 Leggans EK, Barker TJ, Duncan KK, Boger DL. Org. Lett. 2012; 14: 1428
• 21 Barker TJ, Duncan KK, Otrubova K, Boger DL. ACS Med. Chem. Lett. 2013; 4: 985
• 22 Leggans EK, Duncan KK, Barker TJ, Schleicher KD, Boger DL. J. Med. Chem. 2013; 56: 628
• 23 Campbell EL, Skepper CK, Sankar K, Duncan KK, Boger DL. Org. Lett. 2013; 15: 5306
• 24 Schleicher KD, Sasaki Y, Tam A, Kato D, Duncan KK, Boger DL. J. Med. Chem. 2013; 56: 483
• 25 Sears JE, Barker TJ, Boger DL. Org. Lett. 2015; 17: 5460
• 26 Sears JE, Boger DL. Acc. Chem. Res. 2015; 48: 653
• 27 Carney DW, Lukesh JC, Brody DM, Brütsch MM, Boger DL. Proc. Natl. Acad. Sci. U.S.A. 2016; 113: 9691
• 28 Sears JE, Boger DL. Acc. Chem. Res. 2016; 49: 241
• 29 Allemann O, Brutsch M, Lukesh JC, Brody DM, Boger DL. J. Am. Chem. Soc. 2016; 138: 8376
• 30 Allemann O, Cross RM, Brütsch MM, Radakovic A, Boger DL. Bioorg. Med. Chem. Lett. 2017; 27: 3055
• 31 Lukesh JC, Carney DW, Dong H, Cross RM, Shukla V, Duncan KK, Yang S, Brody DM, Brütsch MM, Radakovic A, Boger DL. J. Med. Chem. 2017; 60: 7591
• 32 Yang S, Sankar K, Skepper CK, Barker TJ, Iii JC. L, Brody DM, Brütsch MM, Boger DL. Chem. Sci. 2017; 8: 1560
• 33 Radakovic A, Boger DL. Bioorg. Med. Chem. Lett. 2018; 28: 863
• 34 Gigant B, Wang C, Ravelli RB. G, Roussi F, Steinmetz MO, Curmi PA, Sobel A, Knossow M. Nature 2005; 435: 519
• 35 Waight AB, Bargsten K, Doronina S, Steinmetz MO, Sussman D, Prota AE. PLoS One 2016; 11: e0160890
• 36 Hitchcock SA. J. Med. Chem. 2012; 55: 4877
• 37 Langlois N, Gueritte F, Langlois Y, Potier P. J. Am. Chem. Soc. 1976; 98: 7017
• 38 Kutney JP, Hibino T, Jahngen E, Okutani T, Ratcliffe AH, Treasurywala AM, Wunderly S. Helv. Chim. Acta 1976; 59: 2858
• 39a Kuehne ME, Matson PA, Bornmann WG. J. Org. Chem. 1991; 56: 513
• 39b Bornmann WG, Kuehne ME. A. J. Org. Chem. 1992; 57: 1752
• 40 Magnus P, Mendoza JS, Stamford A, Ladlow M, Willis P. J. Am. Chem. Soc. 1990; 112: 8210
• 41 Yokoshima S, Ueda T, Kobayashi S, Sato A, Kuboyama T, Tokuyama H, Fukuyama T. J. Am. Chem. Soc. 2002; 124: 2137
• 42 Zhang Y, Xue Y, Li G, Yuan H, Luo T. Chem. Sci. 2016; 7: 5530
• 43 Wang N, Liu J, Wang C, Bai L, Jiang X. Org. Lett. 2018; 20: 292
• 44 Boger DL, Brotherton CE. J. Org. Chem. 1984; 49: 4050
• 45 Boger DL, Mullican MD. Tetrahedron Lett. 1982; 23: 4551
• 46 Boger DL, Mullican MD. J. Org. Chem. 1984; 49: 4033
• 47 Turner TC, Shibayama K, Boger DL. Org. Lett. 2013; 15: 1100
• 48 Zhang J, Paladugu SR, Gillard RM, Sarkar A, Boger DL. J. Am. Chem. Soc. 2022; 144: 495
• 49 Boon BA, Boger DL. J. Am. Chem. Soc. 2019; 141: 14349
• 50 Corey EJ, Cheng XM. The Logic of Chemical Synthesis. Wiley; New York: 1989
• 51a Bottcher T. J. Chem. Inf. Model. 2016; 56: 462
• 51b Calculated values used herein were obtained using https://forlilab.org/services/bottcher/
• 51c See: Demoret RM, Baker MA, Ohtawa M, Chen S, Lam CC, Khom S, Roberto M, Forli S, Houk KN, Shenvi RA. J. Am. Chem. Soc. 2020; 142: 18599
• 52 Bertz SH. J. Am. Chem. Soc. 1981; 103: 3599
• 53 Bertz SH. New J. Chem. 2003; 27: 860
• 54 Bajusz D, Racz A, Heberger K. J. Cheminform. 2015; 7: 20
• 55 Fuchs P. Tetrahedron 2001; 57: 6855
• 56 Humphrey GR, Keuthe JT. Chem. Rev. 2006; 106: 2875
• 57 Jeanty M, Blu J, Suzenet F, Guillaumet G. Org. Lett. 2009; 11: 5142
• 58 Contiero F, Jones K, Matts E, Porzelle A, Tompkinson N. Synlett 2009; 3003
• 59 Iwama T, Birman VB, Kozmin SA, Rawal VH. Org. Lett. 1999; 1: 673
• 60 Gao P, Portoghese PS. J. Org. Chem. 1995; 60: 2276
• 61 Aggarwal VK, Olofsson B. Angew. Chem. Int. Ed. 2005; 44: 5516
• 62 Bielawski M, Zhu M, Olofsson B. Adv. Synth. Catal. 2007; 349: 2610
• 63 Chen C, Dormer PG. J. Org. Chem. 2005; 70: 6964
• 64 Vedejs E, Larsen S. Org. Synth. 1986; 64: 127
• 65 Chen X, Qiu S, Wang S, Wang H, Zhai H. Org. Biomol. Chem. 2017; 15: 6349
• 66 Zhang J, Shukla V, Boger DL. J. Org. Chem. 2019; 84: 9397
• 67a Anderson ED, Boger DL. J. Am. Chem. Soc. 2011; 133: 12285
• 67b Anderson ED, Boger DL. Org. Lett. 2011; 13: 2492
• 67c Anderson ED, Duerfeldt AS, Zhu K, Glinkerman CM, Boger DL. Org. Lett. 2014; 16: 5084
• 67d Glinkerman CM, Boger DL. Org. Lett. 2015; 17: 4002
• 68 Lee K, Poudel YB, Glinkerman CM, Boger DL. Tetrahedron 2015; 71: 5897
• 69 Glinkerman CM, Boger DL. J. Am. Chem. Soc. 2016; 138: 12408
• 70 Boger DL, Sakya SM. J. Org. Chem. 1988; 53: 1415
• 71 Zhu Z, Boger DL. J. Org. Chem. 2022; 87: 6288
• 72 Gotoh H, Sears JE, Eschenmoser A, Boger DL. J. Am. Chem. Soc. 2012; 134: 13240
• 73 Procedure for preparation is provided in the Supporting Information.
• 74 Bondavalle F, Schenone P, Ranise A. Synthesis 1979; 830