N-Tosyl-1,2,3-triazoles as Scaffolds for Morpholines: The Total Synthesis of (–)-Chelonin A

This paper is dedicated to Professor Masahiro Murakami for his distinguished achievements in novel transition-metal-catalysed reactions and organic synthetic chemistry.

Abstract

Substituted morpholine derivatives appear frequently in biologically active compounds and thus novel routes towards such structures are of great synthetic interest. Herein, we report the total syntheses of chelonin A, a morpholine-derived marine natural product with reported antibacterial and anti-inflammatory activity. The key step in this process was a rhodium carbenoid 1,3-insertion into a bromohydrin O–H bond, followed by annulation, leading to a 2,6-disubstituted-3,4-dihydro-2H-1,4-oxazine core. This work was then extended to deliver the first asymmetric total synthesis of (–)-chelonin A using an enantioenriched bromohydrin, prepared in turn via asymmetric transfer hydrogenation of an α-bromoketone.

Key words

chelonin A - morpholine - total synthesis - rhodium catalysis - triazole - asymmetric transfer hydrogenation

Publication History

Received: 03 November 2022

Accepted after revision: 18 November 2022

Accepted Manuscript online:
18 November 2022

Article published online:
10 January 2023

• References and Notes

• 1a Delost MD, Smith DT, Anderson BJ, Njardarson JT. J. Med. Chem. 2018; 61: 10996
• 1b Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
• 1c Carlino L, Rastelli G. J. Med. Chem. 2016; 59: 9305
• 2 Tong XG, Zhou LL, Wang YH, Xia C, Wang Y, Liang M, Hou FF, Cheng YX. Org. Lett. 2010; 12: 1844
• 3 Bobzin SC, Faulkner DJ. J. Org. Chem. 1991; 56: 4403
• 4a Masanori S, Kazuko A, Yoshiyuki N, Kyoko N. Heterocycles 1995; 41: 5
• 4b Gharpure SJ, Anuradha D, Prasad JV. K, Rao PS. Eur. J. Org. Chem. 2015; 86
• 4c Borah M, Borthakur U, Saikkia AK. J. Org. Chem. 2017; 82: 1330
• 4d Wang Y, Zhang WY, You SL. J. Am. Chem. Soc. 2019; 141: 2228

For an overview of the synthesis of N-heterocycles from N-sulfonyl-1,2,3-triazoles, please see:
• 5a Miura T, Murakami M. Reactions of α-Imino Rhodium(II) Carbene Complexes Generated from N-Sulfonyl-1,2,3-Triazoles. In Rhodium Catalysis in Organic Synthesis: Methods and Reactions. Tanaka K. Wiley-VCH; Weinheim: 2019: 449
• 5b Monalisa A, Kavuri R, Pazhamalai A. Chem. Rev. 2022; 15: 13108

For some early examples N-heterocycles from N-sulfonyl-1,2,3-triazoles using dirhodium catalysis, please see:
• 5c Chattopadhyay B, Gevorgyan V. Org. Lett. 2011; 13: 3746
• 5d Miura T, Tanaka T, Hiraga K, Stewart SG, Murakami M. J. Am. Chem. Soc. 2013; 135: 13652
• 5e Zibinsky M, Fokin VV. Angew. Chem. Int. Ed. 2013; 52: 1507
• 5f Alford JS, Spangler JE, Davies HM. L. J. Am. Chem. Soc. 2013; 135: 11712
• 5g Yang Y, Zhou M.-B, Ouyang X.-H, Pi R, Song R.-J, Li J.-H. Angew. Chem. Int. Ed. 2015; 54: 6595
• 5h Shang H, Wang Y, Tian Y, Feng J, Tang Y. Angew. Chem. Int. Ed. 2014; 53: 5662
• 5i Miura T, Funakoshi Y, Murakami M. J. Am. Chem. Soc. 2014; 136: 2272
• 5j Miura T, Funakoshi Y, Fujimoto Y, Nakahashi J, Murakami M. Org. Lett. 2015; 17: 2454
• 6a Jones DK, Nutt MJ, Elena C, Sobolev AN, Moggach SA, Miura T, Murakami M, Stewart SG. Org. Lett. 2020; 22: 3490
• 6b Chuprakov S, Worrell BT, Selander N, Sit RK, Fokin VV. J. Am. Chem. Soc. 2014; 136: 195
• 6c Chuprakov S, Hwang FW, Gevorgyan V. Angew. Chem. Int. Ed. 2007; 46: 4757
• 6d Horneff T, Chuprakov S, Chernyak N, Gevorgyan V, Fokin VV. J. Am. Chem. Soc. 2008; 130: 14972
• 6e Sladojevich F, Guarna A, Trabocchi A. Org. Biomol. Chem. 2010; 8: 916
• 6f Wang L, Liu Q.-B, Wang D.-S, Li X, Han X.-W, Xiao W.-J, Zhou Y.-G. Org. Lett. 2009; 11: 1119
• 6g Zhang S, Shan C, Zhang S, Yuan L, Wang J, Tung C.-H, Xing L.-B, Xu Z. Org. Biomol. Chem. 2016; 14: 10973
• 6h Doyle MP, McOsker CC. J. Org. Chem. 1978; 43: 693
• 7 Jones BT, García-Cárceles J, Caiger L, Hazelden IR, Langer T, Bower JF. J. Am. Chem. Soc. 2021; 143: 15593
• 8 Takeda T, Harada S, Okabe A, Nishida A. J. Org. Chem. 2018; 83: 11541
• 9 Raushel J, Fokin VV. Org. Lett. 2010; 12: 4952
• 10 Yuki Y, Touge T, Nara H, Matsumura K, Fujiwhara M, Kayaki Y, Ikariya T. Adv. Synth. Catal. 2018; 360: 568
• 11 Key Rh₂Oct₄-Catalysed Synthesis of the Enantioenriched Oxazine (+)-19 In a sealed vial, under an inert atmosphere a suspension of 17 (397 mg, 0.81 mmol), (+)-18 (260 mg, 0.86 mmol, 80% ee, Table 1, entry 2), and Rh₂Oct₄ (6.7 mg, 0.0086 mmol) in CHCl₃ (2.7 mL) were stirred and maintained at 65 °C. After 3 h, the excess solvent was removed under pressure and dried under high vacuum to afford a crude enamine residue. Cs₂CO₃ (671 mg, 2.06 mmol) was then added to a magnetically stirred solution containing this residue in CH₃CN (3.8 mL) at room temperature. After 3 h, the ensuing mixture was filtered and concentrated under reduced pressure. The residue was subjected to flash column chromatography (40% ethyl acetate/hexanes) to provide previously unreported compound (+)-19 (452 mg, 0.67 mmol, 83%) as a yellow semisolid. ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 8.0 Hz, 1 H), 7.78–7.72 (m, 5 H), 7.69 (s, 1 H), 7.37–7.33 (m, 3 H), 7.30 (d, J = 7.6 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 2 H), 6.80 (s, 1 H), 6.43 (s, 2 H), 4.29 (d, J = 8.4 Hz), 4.02 (d, 1 H, J = 13.2 Hz), 3.86 (s, 3 H), 3.85 (s, 6 H), 3.13 (dd, J = 9.4 and 13.2 Hz, 1 H), 2.45 (s, 3 H), 2.35 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 153.7, 145.3, 144.6, 138.5, 136.6, 135.5, 135.2, 133.9, 132.7, 130.2, 130.1, 127.7, 127.3, 127.1, 125.2, 123.9, 123.4, 121.0, 116.7, 114.0, 103.4, 103.2, 74.8, 61.0, 56.4, 49.7, 21.8, 21.7 ppm. IR (ATR, neat): 2932, 1593, 1355, 1165, 1126 cm^–1. HRMS (ESI): m/z calcd for C₃₅H₃₅N₂O₈S₂ [M + H]⁺: 675.1835; found: 675.1835. [α]_D ²⁰ +37.7^o (c 0.0045, CHCl₃).