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. 2019 May 1;10(22):5686-5698.
doi: 10.1039/c9sc01507h. eCollection 2019 Jun 14.

Zn(OTf)2-mediated annulations of N-propargylated tetrahydrocarbolines: divergent synthesis of four distinct alkaloidal scaffolds

Sadaiwa Yorimoto  1 , Akira Tsubouchi  1 , Haruki Mizoguchi  2 , Hideaki Oikawa  3 , Yoshiaki Tsunekawa  3 , Tomoya Ichino  3 , Satoshi Maeda  3   4 , Hiroki Oguri  1
Affiliations

Zn(OTf)2-mediated annulations of N-propargylated tetrahydrocarbolines: divergent synthesis of four distinct alkaloidal scaffolds

Sadaiwa Yorimoto et al. Chem Sci. .

Abstract

Intramolecular hydroarylations of N-propargylated tetrahydrocarbolines were efficiently mediated using a unique combination of Zn(OTf)2 with t-BuOH under neutral conditions. Use of the artificial force induced reaction method in the global reaction route mapping strategy provided insights into the Zn(OTf)2-mediated hydroarylations and the associated intriguing solvent effects of t-BuOH facilitating a protodezincation process without a Brønsted acid activator. We systematically implemented three distinct hydroarylations as well as an unanticipated α-alkenylation of a carbonyl group to obtain the four alkaloidal scaffolds 2-4, and 18. Zn(OTf)2-mediated annulation of 1c proceeded through kinetic formation of the spiroindole 3c followed by an alkenyl shift and concomitant retro-Mannich-type fragmentation to furnish azepino[4,5-b]indole 2 framework. Substituents on substrate 1 in the vicinity of the reaction sites substantially affected the mode of the divergent annulations. Judicious choices of the substituents, solvent and reaction conditions enabled programmable divergent synthesis of the four distinct skeletons.

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Figures

Fig. 1
Fig. 1. (a) Naturally occurring alkaloids. (b) Zn(OTf)2-mediated divergent cyclizations of 1 for systematic generation of four distinct scaffolds 2–5.
Fig. 2
Fig. 2. (a) The reaction of 6/1a with methyl propiolate in the absence of metal promoter. (b) Incidental discovery of the Zn(ii)-mediated ring-expansion reactions.
Fig. 3
Fig. 3. Au(i)/Au(iii)-catalyzed intramolecular hydroarylations of alkynes with indoles.
Fig. 4
Fig. 4. Zn(OTf)2-mediated hydroarylation of 1a.
Fig. 5
Fig. 5. Two intramolecular cyclization pathways. Gibbs energies (T = 333.15 K) relative to the sum of the Gibbs energies for separately calculated 1a and Zn(OTf)2 are shown in kJ mol–1.
Fig. 6
Fig. 6. (a) Reaction mechanism for the two intramolecular cyclization pathways. (b) Energy diagrams for the two cyclization pathways. Gibbs energies (T = 333.15 K) relative to the sum of the Gibbs energies for separately calculated 1a and Zn(OTf)2 are shown in kJ mol–1.
Fig. 7
Fig. 7. Time evolution of the population of intermediates and products in 3600 s.
Fig. 8
Fig. 8. An attempt to trap the intermediate IM4 to form 2d.
Fig. 9
Fig. 9. Zn(OTf)2-mediated intramolecular hydroarylations of alkynes with indoles and structural elucidation of the spirocyclized products 3a–c.
Fig. 10
Fig. 10. Conversions of 3a–c to 2b and a mechanistic rationale.
Fig. 11
Fig. 11. Zn(OTf)2-mediated ring expansion reaction of 1d–e and subsequent acetylation to form 4d and X-ray analysis of 4d.
Fig. 12
Fig. 12. (a) A strategy for the 7-endo cyclization reaction to form 5f. (b) Zn(OTf)2-mediated cyclizations with substrate 1f.
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