Ketyl Radical Enabled Synthesis of Oxetanes

This work is dedicated to Prof. Erick M. Carreira

Abstract

Oxetanes, 4-membered oxygen-containing heterocycles, were identified to have pharmaceutical applications after the discovery of the chemotherapeutic drug taxol (Paclitaxel) and its analogues. Furthermore, oxetanes have been identified as bioisosteres for several common functional groups and are present in a number of natural products. However, oxetanes are one of the least common oxygen-containing heterocycles in active pharmaceutical ingredients on the market, which can be attributed, in part, due to challenges with their synthesis. Previous strategies rely on nucleophilic substitutions or [2+2]-cycloadditions, but are limited by the stepwise buildup of starting material and limitations in scope resulting from requirements for activated substrates. To address these limitations, we envisioned activating simple carbonyls to their corresponding α-oxy iodides to promote ketyl radical formation. These radicals can then undergo atom-transfer radical addition with alkenes followed by one-pot nucleophilic substitution to produce oxetanes. Herein, we present a proof-of-principle of this strategy in which fluoroalkyl carbonyls are successfully converted into the corresponding fluoroalkyl oxetanes.

Key words

oxetane - ketyl radical - visible light - photochemistry - α-oxy halide - atom-transfer radical addition

Publication History

Received: 27 March 2024

Accepted after revision: 21 May 2024

Article published online:
17 June 2024

• References

• 1 Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. J. Am. Chem. Soc. 1971; 93: 2325
• 2 Delost MD, Smith DT, Anderson BJ, Njardarson JT. J. Med. Chem. 2018; 61: 10966
• 3 For select reviews of oxetanes in medicinal chemistry settings, see: Burkhard JA, Wuitschik G, Rogers-Evans M, Müller K, Carreira EM. Angew. Chem. Int. Ed. 2010; 49: 9052 ; see also refs. 4 and 5
• 4 Bull JA, Croft RA, Davis OA, Doran R, Morgan KF. Chem. Rev. 2016; 116: 12150
• 5 Rojas JJ, Bull JA. J. Med. Chem. 2023; 66: 12697
• 6 For select studies of oxetanes as bioisosteres, see: Wuitschik G, Rogers-Evans M, Müller K, Fischer H, Wagner B, Schuler F, Polonchuk L, Carreira EM. Angew. Chem. Int. Ed. 2006; 45: 7736 ; see also refs. 7-14
• 7 Wuitschik G, Rogers-Evans M, Buckl A, Bernasconi M, Märki M, Godel T, Fischer H, Wagner B, Parrilla I, Schuler F, Schneider J, Alker A, Schweizer WB, Müller K, Carreira EM. Angew. Chem. Int. Ed. 2008; 47: 4512
• 8 Wuitschik G, Carreira EM, Wagner B, Fischer H, Parrilla I, Schuler F, Rogers-Evans M, Müller K. J. Med. Chem. 2010; 53: 3227
• 9 Burkhard JA, Wuitschik G, Plancher J.-M, Rogers-Evans M, Carreira EM. Org. Lett. 2013; 15: 4312
• 10 Scott JS, Birch AM, Brocklehurst KJ, Brown HS, Goldberg K, Groombridge SD, Hudson JA, Leach AG, MacFaul PA, McKerrecher D, Poultney R, Schofield P, Svensson PH. Med. Chem. Commun. 2013; 4: 95
• 11 McLaughlin M, Yazaki R, Fessard TC, Carreira EM. Org. Lett. 2014; 16: 4070
• 12 Möller GP, Müller S, Wolfstäder BT, Wolfrum S, Schepmann D, Wünsch B, Carreira EM. Org. Lett. 2017; 19: 2510
• 13 Lassalas P, Oukoloff K, Makani V, James M, Tran V, Yao Y, Huang L, Vijayendran K, Monti L, Trojanowski JQ, Lee VM.-Y, Koslowski MC, Smith AB. III, Brunden KR, Ballatore C. ACS Med. Chem. Lett. 2017; 8: 864
• 14 For recent examples of accessing oxetanes via sulfur ylides, see: Mukherjee P, Pettersson M, Dutra JK, Xie L, am Ende CW. ChemMedChem 2017; 12: 1574 ; see also ref. 33
• 15 For a review on recent types of methods to access oxetanes, see: Malarney KP, Kc S, Schmidt VA. Org. Biomol. Chem. 2021; 19: 8425
• 16 For select initial studies of accessing oxetanes via nucleophilic substitution, see: Reboul M. Ann. Chim. (Paris) 1878; 14: 495 ; see also ref. 17
• 17 Derick CG, Bissell DW. J. Am. Chem. Soc. 1916; 38: 2478
• 18 For select initial studies of accessing oxetanes via epoxide opening, see: Murai A, Ono M, Masamune T. J. Chem. Soc., Chem. Commun. 1976; 864 ; see also refs. 19-21
• 19 Murai A, Ono M, Masamune T. Bull. Chem. Soc. Jpn. 1977; 50: 1226
• 20 Masamune T, Ono M, Sato S, Murai A. Tetrahedron Lett. 1978; 19: 371
• 21 Masamune T, Sato S, Abiko A, Ono M, Murai A. Bull. Chem. Soc. Jpn. 1980; 53: 2895
• 22 For an example of synthesizing an oxetane natural product using an epoxide opening, see: Birman VB, Danishefsky SJ. J. Am. Chem. Soc. 2002; 124: 2080
• 23 For select examples of accessing oxetanes via halocyclization, see: Diner UE, Worsley M, Lown JW. J. Chem. Soc. C 1971; 3131 ; see also refs. 24-26
• 24 Ehlinger E, Magnus P. J. Am. Chem. Soc. 1980; 102: 5004
• 25 Evans RD, Magee JW, Schauble JH. Synthesis 1988; 862
• 26 Jung ME, Nichols CJ. Tetrahedron Lett. 1996; 37: 7667
• 27 For an early example of accessing oxetanes via ring contraction of 5-membered oxygen-containing heterocycles, see: Austin GN, Fleet GW. J, Peach JM, Prout K, Son JC. Tetrahedron Lett. 1987; 28: 4741
• 28 For a review of accessing oxetanes via ring contraction of 5-membered rings see: Jenkinson SF, Fleet GW. J. Chimia 2011; 65: 71
• 29 For early studies of accessing oxetanes via sulfur ylides, see: Welch SC, Rao AS. C. P. J. Am. Chem. Soc. 1979; 101: 6135 ; see also refs. 30-32
• 30 Welch SC, Rao AS. C. P, Lyon JT, Assercq JM. J. Am. Chem. Soc. 1983; 105: 252
• 31 Okuma K, Tanaka Y, Kaji S, Ohta H. J. Org. Chem. 1983; 48: 5133
• 32 Fitton AO, Hill J, Jane DE, Millar R. Synthesis 1987; 1140
• 33 Cai Y, Liu C, Liu G, Li C, Jiang H, Zhu C. Org. Biomol. Chem. 2022; 20: 1500
• 34 Paternó E, Chieffi G. Gazz. Chim. Ital. 1909; 39: 341
• 35 Büchi G, Inman CG, Lipinsky ES. J. Am. Chem. Soc. 1954; 76: 4327
• 36 For select reviews on the Paternò–Büchi reaction, see: Bach T. Synthesis 1998; 683 ; see also refs. 37–42
• 37 Abe M. J. Chin. Chem. Soc. 2008; 55: 479
• 38 D’Auria M, Racioppi R. Molecules 2013; 18: 11384
• 39 D’Auria M. The Paternò–Büchi Reaction . In Comprehensive Organic Synthesis II, 2nd ed., Chap. 5.05. Elsevier; Amsterdam: 2014: 159-199 DOI: 10.1016/B978-0-08-097742-3.00505-X
• 40 Oelgemöller M, Hoffmann N. Org. Biomol. Chem. 2016; 14: 7392
• 41 Fréneau M, Hoffmann N. J. Photochem. Photobiol., C 2017; 33: 83
• 42 D’Auria M. Photochem. Photobiol. Sci. 2019; 18: 2297
• 43 For relevant reviews on accessing oxetanes via visible-light-mediated [2+2]-cycloadditions see: Zhang Q, Yang Y, Zhang S, Liu Q. Adv. Synth. Catal. 2023; 365: 3556 ; see also ref. 44
• 44 Franceschi P, Cuadros S, Goti G, Dell’Amico L. Angew. Chem. Int. Ed. 2023; 62: e202217210
• 45 For initial methods describing visible-light-mediated Paternó–Büchi reactions, see: Mateos J, Vega-Peñaloza A, Franceschi P, Rigodanza F, Andreetta P, Companyó X, Pelosi G, Bonchio M, Dell’Amico L. Chem. Sci. 2020; 11: 6532 ; see also refs. 46-48
• 46 Li H.-F, Cao W, Ma X, Xie X, Xia Y, Ouyang Z. J. Am. Chem. Soc. 2020; 142: 3499
• 47 Rykaczewski KA, Schindler CS. Org. Lett. 2020; 22: 6516
• 48 Zheng J, Dong X, Yoon TP. Org. Lett. 2020; 22: 6520
• 49 Flores DM, Schmidt VA. J. Am. Chem. Soc. 2019; 141: 8741
• 50 Qi D, Bai J, Zhang H, Li B, Song Z, Ma N, Guo L, Song L, Xia W. Green Chem. 2022; 24: 5046
• 51 For an alternative strategy coupling alcohol and vinyl sulfonium ion starting materials under visible light conditions followed by nucleophilic substitution, see: Paul S, Filippini D, Ficarra F, Melnychenko H, Janot C, Silvi M. J. Am. Chem. Soc. 2023; 145: 15688
• 52 For seminal works using α-acetoxy iodides as ketyl radical precursors, see: Wang L, Lear JM, Rafferty SM, Fosu SC, Nagib DA. Science 2018; 362: 225 ; see also ref. 53
• 53 Rafferty SM, Rutherford JE, Zhang L, Wang L, Nagib DA. J. Am. Chem. Soc. 2021; 143: 5622
• 54 For select recent studies using α-oxy halides as starting materials, see: Yang Z.-P, Fu GC. J. Am. Chem. Soc. 2020; 142: 5870 ; see also refs. 55–65
• 55 Zhang L, DeMuynck BM, Paneque AN, Rutherford JE, Nagib DA. Science 2022; 377: 649
• 56 Huang H.-M, Bellotti P, Kim S, Zhang X, Glorius F. Nat. Synth. 2022; 1: 464
• 57 Huang H.-M, Bellotti P, Erchinger JE, Paulisch TO, Glorius F. J. Am. Chem. Soc. 2022; 144: 1899
• 58 Bellotti P, Huang H.-M, Faber T, Laskar R, Glorius F. Chem. Sci. 2022; 13: 7855
• 59 Zhu C, Lee S.-C, Chen H, Yue H, Rueping M. Angew. Chem. Int. Ed. 2022; 61: e202204212
• 60 Ji H, Lin D, Tai L, Li X, Shi Y, Han Q, Chen L.-A. J. Am. Chem. Soc. 2022; 144: 23019
• 61 Sun D, Tao X, Ma G, Wang J, Chen Y. Chem. Sci. 2022; 13: 8365
• 62 Zhang L, Nagib DA. Nat. Chem. 2023; 16: 107
• 63 Chen J, Deng G, Wang Y, Zhu S. Chin. J. Chem. 2023; 41: 294
• 64 DeMuynck BM, Zhang L, Ralph EK, Nagib DA. Chem 2024; 10: 1015
• 65 Wen S, Bu J, Shen K. J. Org. Chem. 2024; in press, DOI: DOI: 10.1021/acs.joc.3c02293.
• 66 McAtee CC, Riehl PS, Schindler CS. J. Am. Chem. Soc. 2017; 139: 2960
• 67 For relevant reviews on halogen bonding, see: Cavallo G, Metrangolo P, Milani R, Pilati T, Priimagi A, Resnati G, Terraneo G. Chem. Rev. 2016; 116: 2478 ; see also refs. 68 and 69
• 68 Varadwaj PR, Varadwaj A, Marques HM. Inorganics 2019; 7: 40
• 69 Piedra HF, Valdés C, Plaza M. Chem. Sci. 2023; 14: 5545
• 70 For relevant studies on halogen-bonding promoted ATRA reactions, see: Yoshioka E, Kohtani S, Hashimoto T, Takebe T, Miyabe H. Chem. Pharm. Bull. 2017; 65: 33 ; see also refs 71–77
• 71 Park G.-R, Choi Y, Choi MG, Chang S.-K, Cho EJ. Asian J. Org. Chem. 2017; 6: 436
• 72 Wang Y, Wang J, Li G.-X, He G, Chen G. Org. Lett. 2017; 19: 1442
• 73 Sun X, He Y, Yu S. J. Photochem. Photobiol., A 2018; 355: 326
• 74 Matsuo K, Yamaguchi E, Itoh A. J. Org. Chem. 2020; 85: 10574
• 75 Matsuo K, Yoshitake T, Yamaguchi E, Itoh A. Molecules 2021; 26: 6781
• 76 Matsuo K, Kondo T, Yamaguchi E, Itoh A. Chem. Pharm. Bull. 2021; 69: 796
• 77 Treacy SM, Vaz DR, Noman S, Tard C, Rovis T. Chem. Sci. 2023; 14: 1569
• 78 Rolka AB, Koenig B. Org. Lett. 2020; 22: 5035
• 79 Lipshutz BH, Ghorai S, Leong WW. Y. J. Org. Chem. 2009; 74: 2854