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Synlett 2014; 25(18): 2536-2557
DOI: 10.1055/s-0034-1378529
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© Georg Thieme Verlag Stuttgart · New York

2,3-Dihydropyridin-4(1H)-ones and 3-Aminocyclohex-2-enones: Synthesis, Functionalization, and Applications to Alkaloid Synthesis

Hajime Seki
Departments of Chemistry and Medicinal Chemistry, and the Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55414, USA   Fax: +1(612)6266318   Email: georg@umn.edu
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Gunda I. Georg*
Departments of Chemistry and Medicinal Chemistry, and the Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55414, USA   Fax: +1(612)6266318   Email: georg@umn.edu
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Publication History

Received: 13 March 2014

Accepted after revision: 23 June 2014

Publication Date:
24 September 2014 (online)

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Abstract

This account summarizes our recent investigations into the chemistry of 2,3-dihydropyridin-4(1H)-ones and 3-aminocyclohex-2-enones (enaminones). These enaminones are exceptionally versatile chemical scaffolds that serve as valuable intermediates in the synthesis of indolizidine and quinolizidine alkaloids and other bioactive compounds. Since we reported our first method for constructing enaminones in 2006, we have developed a number of additional approaches to the synthesis and derivatization of enaminones and we have explored their applications in natural product synthesis.

1 Background

2 Ynone Cyclization

2.1 Initial Discovery

2.2 Optimization of Reaction Conditions

2.3 Scope and Limitations

2.4 Mechanistic Studies

2.4 Application to Quinolone Synthesis

2.6 N-Butoxycarbonyl β-Lactam Approach

2.7 Synthesis of 3,4-Dihydro-1,2-oxazepin-5(2H)-ones and Their Conversion into Enaminones

3 Ketene Cyclization

3.1 Chiral-Pool Approach

3.2 Three-Component Synthesis

4 C5 Functionalization

4.1 Suzuki Coupling of Iodoenaminones

4.2 Suzuki-Type Direct Cross-Coupling

4.3 Suzuki-Type Direct Cross-Coupling with Arylboronic ­Acids

4.4 Hiyama-Type Direct Cross-Coupling

4.5 Direct Coupling with Aryl Iodides

4.6 Alkenylation by the Fujiwara–Moritani Reaction

4.7 Alkenylation of Uracils

4.8 Aerobic Alkenylation and its Application to the Synthesis of 1,3,5-Trisubstituted Benzenes

4.9 Lithium Perchlorate-Catalyzed Alkylation

5 Applications to Total Synthesis

5.1 Total Synthesis of (+)-Ipalbidine and (+)-Antofine

5.2 Total Synthesis of (R)- and (S)-Boehmeriasin A

5.3 Total Synthesis of Tylocrebrine and Related Phenanthropiperidines

6 Summary and Outlook

Key words

heterocycles - enaminones - alkaloids - natural product synthesis