Total Synthesis of Manzamine A and Related Alkaloids

Outline �Motivation �Introduction �Past work �Retrosynthesis �Synthesis �Conclusion �Summary 2

Introduction �Isolation: Alkaloids were first isolated from the marine sponge Haliclona sp. in the

Synthesis of Electrophile 6 Mechanism: 8

Stereoselective Michael Addition of Key Building Block Mechanis m: 9

Preparation of A-ring via Nitro. Mannich/lactamization cascade Mechanis m: 10

Synthesis of Key Intermediate 2 Mechanism of Nef Reaction Mechanism: 13

Completion of the Total Synthesis of Manzamine A, Ircinol A, and Ircinal A 14

Conclusion �Author and co-workers have developed a short and stereoselective synthesis of manzamine A

Summary Paper 16 Author Key Steps, yield J. Am. Chem. Soc. Winkler, J. D.

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Total Synthesis of Manzamine A and Related Alkaloids Pavol Jakubec, Alison Hawkins, Wolfgang Felzmann, and Darren J. Dixon* J. Am. Chem. Soc. , 2012, 134, 17482– 17485 1 Speaker: 王湘閔

Outline �Motivation �Introduction �Past work �Retrosynthesis �Synthesis �Conclusion �Summary 2

Motivation 3

Introduction �Isolation: Alkaloids were first isolated from the marine sponge Haliclona sp. in the Okinawa Sea by Higa et al. in 1986. �Biological activities: insecticidal, cytotoxicity, antibacterial, anti-HIV-I, anti-infective, anti. Alzheimer diseases, and anti-malarial activity. �P 388 mouse leukaemia cells (IC 50 = 0. 07 µg/m. L or 2. 4 µg/m. L) 4

Past work 5

Retrosynthetic Analysis 6

Preparation of homoallylic alcohol 10 7

Synthesis of Electrophile 6 Mechanism: 8

Stereoselective Michael Addition of Key Building Block Mechanis m: 9

Preparation of A-ring via Nitro. Mannich/lactamization cascade Mechanis m: 10

Synthesis of Intermediate 4 11

Preparation of B-ring 19 Mechanis m: 12

Synthesis of Key Intermediate 2 Mechanism of Nef Reaction Mechanism: 13

Completion of the Total Synthesis of Manzamine A, Ircinol A, and Ircinal A 14

Conclusion �Author and co-workers have developed a short and stereoselective synthesis of manzamine A (1) via 18 steps, total yield 1. 03 %. �Enol triflate 2 is a synthetically valuable late-stage intermediate. �Key steps: Stereoselective Michael addition Nitro-Mannich/Lactamization cascade Z-selective alkene RCM 15

Summary Paper 16 Author Key Steps, yield J. Am. Chem. Soc. Winkler, J. D. 1998, 120, 64256426 Pictet-Spenglar Cyclization & DDQ oxidation 22 steps, 0. 09% J. Am. Chem. Soc. 1999, 121, 866867 Stille/Diels-Alder reaction & Ring-Closing Metathesis 21 steps, 0. 17% J. Am. Chem. Soc. Fukuyama T. 2010, 132, 1023310235 Diels-Alder reaction & Ring-Closing Metathesis 27 steps, 1. 7% J. Am. Chem. Soc. 2012, 132, 1023310235 Stereoselective Michael addition Nitro. Mannich/Lactamization Z-selective alkene RCM 18 steps, 1. 03% Martin S. F. Dixon, D. J.