Synthesis 2021; 53(08): 1396-1408
DOI: 10.1055/a-1340-3423
short review

Synthesis and Reactivity of Uhle’s Ketone and Its Derivatives

Francesca Bartoccini
,


Abstract

Uhle’s ketone and its derivatives are highly versatile intermediates for the synthesis of a variety of 3,4-fused tricyclic indole frameworks, i.e. indole alkaloids of the ergot family, that are found in various bioactive natural products and pharmaceuticals. Therefore, the development of a convenient preparative method for this structural motif as well as its opportune/useful derivatization have been the subject of longstanding interest in the fields of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent and less recent methods for the preparation of Uhle’s ketone and its derivatives as well as its main reactivity towards the synthesis of bioactive substances. Regarding the preparation, it can be roughly classified into two categories: (a) using 4-unfunctionalized and 4-functionalized indole derivatives as starting materials to construct a fused six-member ring, and (b) constructing the indole ring through intramolecular cycloaddition. Principally, the reactivity of the cyclic Uhle’s ketone shown here is derived from the classical electrophilicity of the carbonyl carbon or the acidity of the α-hydrogen and, though less intensively investigated, chemical reactions that induce ring expansion to form novel ring skeletons.

1 Introduction

2 Synthesis

2.1 Disconnection A: Cyclization Reaction of the Opportune 3,4-Disubstituted Indole

2.2 Disconnection B: Intramolecular Friedel–Crafts Cyclization

2.3 Disconnection B: Intramolecular Cyclization via Metal–Halogen Exchange

2.4 Disconnection C: Intramolecular Diels–Alder Furan Cycloaddition

2.5 Disconnection D: Intramolecular Dearomatizing [3 + 2] Annulation

3 Reactivity

3.1 Use of Uhle’s Ketone for Lysergic Acid

3.2 Use of Uhle’s Ketone for Rearranged Clavines

3.3 Use of Uhle’s Ketone for Medicinal Chemistry

4 Conclusion and Outlook



Publication History

Received: 05 November 2020

Accepted after revision: 18 December 2020

Publication Date:
18 December 2020 (online)

© 2020. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Uhle FC. J. Am. Chem. Soc. 1949; 71: 761
    • 2a Schiff P. Am. J. Pharm. Educ. 2006; 70: 1
    • 2b Řeháček Z, Sajdl P. Ergot Alkaloids . Elsevier Science; New York: 1990: 28
    • 2c Panaccione DG. Ergot Alkaloids . In The Mycota, Industrial Applications, 2nd ed., Vol. X. Hofrichter M. Springer; Berlin: 2010: 195
    • 2d Somei M, Yokoyama Y, Murakami Y, Ninomiya I, Kiguchi T, Naito T. Recent Synthetic Studies on the Ergot Alkaloids and Related Compounds . In The Alkaloids, Vol. 54. Cordell GA. Academic Press; San Diego: 2000: 191
    • 2e Krogsgaard-Larsen N, Jensen AA, Schrøder TJ, Christoffersen CT, Kehler J. J. Med. Chem. 2014; 57: 5823
    • 2f Sinz A. Pharm. Unserer Zeit 2008; 37: 306
    • 2g Mantegani S, Brambilla E, Varasi M. Farmaco 1999; 54: 288
    • 3a Liu H, Jia Y. Nat. Prod. Rep. 2017; 34: 411
    • 3b McCabe SR, Wipf P. Org. Biomol. Chem. 2016; 14: 5894
    • 4a Nemoto T, Harada S, Nakajima M. Asian J. Org. Chem. 2018; 7: 1730
    • 4b Connon R, Guiry PJ. Tetrahedron Lett. 2020; 61: 151696
    • 4c Nemoto T. Chem. Rec. 2019; 19: 320
    • 4d Kuo Y, Yanxing J. Chin. J. Org. Chem. 2018; 38: 2386

      The greater stability of the naphthalenoid isomers was based on the fact that the resonance energy of naphthalene is much greater than that of indole, see:
    • 5a Grob CA, Voltz J. Helv. Chim. Acta 1950; 33: 1796
    • 5b Grob CA, Hofer B. Helv. Chim. Acta 1952; 35: 2095
    • 5c Grob C, Payot P. Helv. Chim. Acta 1953; 36: 839
    • 6a Kornfeld EC, Fornefeld EJ, Kline GB, Mann MJ, Jones RG, Woodward RB. J. Am. Chem. Soc. 1954; 76: 5256
    • 6b Kornfeld EC, Fornefeld EJ, Kline GB, Mann MJ, Morrison DE, Jones RG, Woodward RB. J. Am. Chem. Soc. 1956; 78: 3087
    • 7a Rebek JJr, Tai DF, Shue YK. J. Am. Chem. Soc. 1984; 106: 1813
    • 7b Kruse LI, Meyer MD. J. Org. Chem. 1984; 49: 4761
    • 7c Lee K, Poudel YB, Glinkerman CM, Boger DL. Tetrahedron 2015; 71: 5897
  • 8 Tasker NR, Wipf P. Biosynthesis, Total Synthesis, and Biological Profiles of Ergot Alkaloids. In The Alkaloids. Knölker H.-J. Elsevier; San Diego: 2020. DOI: 10.1016/bs.alkal.2020.08.001
  • 9 Caruana L, Fochi MF, Bernardi L. Synlett 2017; 28: 1530
  • 10 Uhle FC, McEwen CM. Jr, Schröter H, Yuan C, Baker BW. J. Am. Chem. Soc. 1960; 82: 1200
  • 11 Harris LS, Uhle FC. J. Pharmacol. Exp. Ther. 1960; 128: 358
  • 12 Bowman RE, Goodburn TG, Reynolds AA. J. Chem. Soc., Perkin Trans. 1 1972; 1121
  • 13 Ponticello GS, Baldwin JJ, Lumma PK, McClure DE. J. Org. Chem. 1980; 45: 4236
  • 14 Danishefsky SJ, Phillips GB. Tetrahedron Lett. 1984; 25: 3159
  • 15 Chen J.-Q, Mi Y, Shi Z.-F, Cao X.-P. Org. Biomol. Chem. 2018; 16: 3801
  • 16 Romanini S, Galletti E, Caruana L, Mazzanti A, Himo F, Santoro S, Fochi MF, Bernardi L. Chem. Eur. J. 2015; 21: 17582
  • 17 Szmuszkovicz J. J. Org. Chem. 1964; 29: 843
  • 18 Bedini A, Di Giacomo B, Gatti G, Spadoni G. Bioorg. Med. Chem. 2005; 13: 4651
  • 19 Nagasaka T, Ohki S. Chem. Pharm. Bull. 1977; 25: 3023
  • 20 Meyer MD, Kruse LI. J. Org. Chem. 1984; 49: 3195
    • 21a Teranishi K, Hayashi S, Nakatsuka S, Goto T. Tetrahedron Lett. 1994; 35: 8173
    • 21b Teranishi K, Hayashi S, Nakatsuka S, Goto T. Synthesis 1995; 506
  • 22 Alluri SR, Riss PJ. ACS Chem. Neurosci. 2018; 9: 1259
  • 23 Kalepu J, Gandeepan P, Ackermann L, Pilarski LT. Chem. Sci. 2018; 9: 4203
  • 24 Hurt CR, Lin R, Rapoport H. J. Org. Chem. 1999; 64: 225
  • 25 Zhang Y.-A, Liu Q, Wang C, Jia Y. Org. Lett. 2013; 15: 3662
    • 26a Jia Y, Zhu J. J. Org. Chem. 2006; 71: 7826
    • 26b Xu Z, Hu W, Liu Q, Zhang L, Jia Y. J. Org. Chem. 2010; 75: 7626
  • 27 Balasubramaniam S, Aidhen IS. Synthesis 2008; 3707
    • 28a Bur SK, Padwa A. Org. Lett. 2002; 4: 4135
    • 28b Padwa A, Bur SK, Zhang H. J. Org. Chem. 2005; 70: 6833
  • 29 Miura T, Funakoshi Y, Murakami M. J. Am. Chem. Soc. 2014; 136: 2272
  • 30 Liu Q, Zhang Y.-A, Xu P, Jia Y. J. Org. Chem. 2013; 78: 10885
  • 31 Moldvai I, Temesvári-Major E, Gács-Baitz E, Egyed O, Gömöry A, Nyulászi L, Szántay C. Heterocycles 1999; 51: 2321
  • 32 Moldvai I, Temesvári-Major E, Balázs M, Gács-Baitz E, Egyed O, Szántay C. J. Chem. Res., Miniprint 1999; 3018
  • 33 Bowman RE, Evans DD, Guyett J, Nagy H, Weale J, Weyell DJ, White AC. J. Chem. Soc., Perkin Trans. 1 1972; 1926
  • 34 Incze M, Moldvai I, Temesvari-Major E, Dornyei G, Kajtar-Peredy M, Szántay C. Tetrahedron 2003; 59: 4281
  • 35 Moldvai I, Temesvári-Major E, Incze M, Szentirmay E, Gács-Baitz E, Szántay C. J. Org. Chem. 2004; 69: 5993
  • 36 Incze M, Dörnyei G, Moldvai I, Temesvári-Major E, Egyed O, Szántay C. Tetrahedron 2008; 64: 2924
  • 37 Jabre ND, Watanabe T, Brewer M. Tetrahedron Lett. 2014; 55: 197
    • 38a Mukherjee J, Menge M. Adv. Biochem. Eng./Biotechnol. 2000; 68: 1
    • 38b Abe M, Ohmono S, Ohashi T, Tabuchi T. Agric. Biol. Chem. 1969; 33: 469
    • 38c Cole RJ, Kirksey JW, Cutler HG, Wilson DM, Morgan-Jones G. Can. J. Microbiol. 1976; 22: 741
    • 38d Cole RJ, Kirksey JW, Clardy J, Eickman N, Weinreb SM, Singh P, Kim D. Tetrahedron Lett. 1976; 17: 3849
    • 39a Rebek J, Shue YK. J. Am. Chem. Soc. 1980; 102: 5426
    • 39b Rebek J, Shue Y.-K, Tai DF. J. Org. Chem. 1984; 49: 3540
    • 40a Martin SF, Liras S. J. Am. Chem. Soc. 1993; 115: 10450
    • 40b Liras S, Lynch CL, Fryer AM, Vu BT, Martin SF. J. Am. Chem. Soc. 2001; 123: 5918
  • 41 Taylor EW. Synth. Commun. 1989; 19: 369
  • 42 Taylor EW, Nikam S, Weck B, Martin AR, Nelson DL. Life Sci. 1987; 41: 1961
  • 43 Russell MG. N, Baker RJ, Barden L, Beer MS, Bristow L, Broughton HB, Knowles M, McAllister G, Patel S, Castro JL. J. Med. Chem. 2001; 44: 3881
  • 44 Bowman RE, Evans DD, Guyett J, Nagy H, Weale J, Weyell DJ. J. Chem. Soc., Perkin Trans. 1 1973; 438
  • 45 PARP Inhibitors for Cancer Therapy . In Cancer Drug Discovery and Development, Vol. 83. Curtin NJ, Sharma R. Springer International; Switzerland: 2015
  • 46 For another interesting regioselective ring expansion of Uhle’s ketone see: Ruiz M, López-Alvarado P, Menéndez JC. Org. Biomol. Chem. 2010; 8: 4521
  • 47 McCabe SR, Wipf P. Synthesis 2019; 51: 213