Enantioselective Synthesis of (R)-Tiagabine via Asymmetric Hydrogen Atom Transfer Protocol

Abstract

An enantioselective synthesis of tiagabine has been achieved utilizing an asymmetric hydrogen atom transfer protocol to construct its essential chiral tertiary carbon center. A cyclization reaction via double N-substitution is tactically orchestrated as the other key step to install the crucial alkaloid ring. Compared with the previous synthetic strategy, which used commercially available nicotinate as the starting material to ensure a short synthetic route, this strategy uses a readily modifiable and accessible alkyl-substituted acrylate as the starting material and thus provides a scenario for the facile synthesis of analogues and derivatives of tiagabine for further biological research.

Key words

analogue synthesis - chiral tertiary center - enantioselective - hydrogen atom transfer - tiagabine - titanium catalysis

Publikationsverlauf

Eingereicht: 23. Oktober 2022

Angenommen nach Revision: 21. Februar 2023

Accepted Manuscript online:
21. Februar 2023

Artikel online veröffentlicht:
20. März 2023

• References

• 1a Luer MS, Rhoney DH. Ann. Pharmacother. 1998; 32: 1173
• 1b Andersen KE, Braestrup C, Gronwald FC, Jørgensen AS, Nielsen EB, Sonnewald U, Sørensen PO, Suzdak PD, Knutsen LJ. S. J. Med. Chem. 1993; 36: 1716
• 1c Wang H, Hussain AA, Wedlund PJ. Pharm. Res. 2005; 22: 556
• 2a Takahashi K.-I, Miyoshi S, Kaneko A, Copenhagen DR. Jpn. J. Physiol. 1995; 45: 457
• 2b Suzdak PD, Jansen JA. Epilepsia 1995; 36: 612
• 2c Fink-Jensen A, Suzdak PD, Swedberg MD, Judge ME, Hansen L, Nielsen PG. Eur. J. Pharmacol. 1992; 220: 197
• 3 Shinnar S. Semin. Pediatr. Neurol. 1997; 4: 24
• 4 Moher ED, Tripp AE, Creemer LC, Vicenzi JT. Org. Process Res. Dev. 2004; 8: 593
• 5a Song S, Zhu S.-F, Pu L.-Y, Zhou Q.-L. Angew. Chem. Int. Ed. 2013; 52: 6072
• 5b Lei A, Chen M, He M, Zhang X. Eur. J. Org. Chem. 2006; 4343
• 5c Baumann M, Baxendale IR. Beilstein J. Org. Chem. 2013; 9: 2265
• 5d Schleich S, Helmchen G. Eur. J. Org. Chem. 1999; 2515
• 6a Zdrazil B, Jurik A, Sitte HH, Ecker GF. J. Cheminf. 2013; 5 (Suppl. 01) 32
• 6b Jurik A, Reicherstorfer R, Zdrazil B, Ecker GF. Mol. Inf. 2013; 32: 415
• 6c Chorghadea MS, Ellegaard P, Lee EC, Petersen H, Sørensen PO. Heterocycles 1994; 37: 783
• 6d Chorghade MS, Petersen H, Lee EC, Bain S. Appl. Chem. 1996; 68: 761
• 7a Dangi M, Khichi A, Jakhar R, Chhillar AK. Curr. Pharm. Biotechnol. 2021; 22: 1030
• 7b Wermuth CG. Drug Discovery Today 2006; 11: 348
• 8 Xu Z, Shen J, Li L, Chen W, Li S, Jiang J, Zhang Y.-Q. Angew. Chem. Int. Ed. 2022; 61: e2022141
• 9a Clausen RP, Moltzen EK, Perregaard J, Lenz SM, Sanchez C, Falch E, Frolund B, Bolvig T, Sarup A, Larsson OM, Schousboe A, Krogsgaard-Larsen P. Bioorg. Med. Chem. 2005; 13: 895
• 9b Vogensen SB, Jorgensen L, Madsen KK, Jurik A, Borkar N, Rosatelli E, Nielsen B, Ecker GF, Schousboe A, Clausen RP. Bioorg. Med. Chem. 2015; 23: 2480
• 10a Gololobov YG, Zhmurova IN, Kasukhin LF. Tetrahedron 1981; 37: 437
• 10b Tian WQ, Wang YA. J. Org. Chem. 2004; 69: 4299
• 11 Bartoli G, Bosco M, Carlone A, Dalpozzo R, Marcantoni E, Melchiorre P, Sambria L. Synthesis 2007; 3489
• 12 Appel R. Angew. Chem. Int. Ed. 1975; 14: 801
• 13 The formation of Int-1 was detected and confirmed by crude ¹H NMR spectra, please see the experimental section for details.
• 14 Omura K, Swern D. Tetrahedron 1978; 34: 1651
• 15 Dalcanale E, Montanari F. J. Org. Chem. 1986; 51: 567