Total Synthesis of (±)-Cylindricine C Guillaume Lapointe, Kurt Schenk, and Philippe Renaud＊ Org. Lett., 2011, 13, 4774-4777 reporter: Hui-ting Chang

OUTLINE Stuctures of family Isolation and bioactivity Past synthesis Retrosynthetic analysis Synthesis Conclusion Summary

Structures of family

Isolation and bioactivity Isolated from the marine ascidian Clavelina cylindrica. Bioactivity ： against brine shrimp larvae in bioassay.

STRATEGIES FOR FORMING KEY PYRROLO-QUINOLINE RING Intramolecular Michael addition Iminium ion/diene cyclization Oxidative spirocyclization Aza〔3+3〕annulation Mannich reaction

PAST SYNTHESIS Total synthesis of (-)-Cylindricine C J. Org. Chem. 1999, 64, 5183-5187 Strategies

PAST SYNTHESIS An N-Acyliminium Cyclization Approach to a Total Synthesis of (+)-Cylindricine C J. Org. Chem. 2005, 70, 3898-3902 Strategies

PAST SYNTHESIS Fully Stereocontrolled Total Syntheses of (-)- Cylindricine C Angew. Chem. Int. Ed. 2004, 43, 4336-4338 Strategies

PAST SYNTHESIS A Concise Total synthesis of (-)- Cylindricine C through a Stereoselective Intramolecular Aza- 〔3+3〕 Annulation Strategy Org. Lett. 2006, 8, 777-780 Vinyl amide + vinyl iminium = aza-〔3+3〕 annulation Strategies

PAST SYNTHESIS Short Synthesis of (+)-Cylindricine C by Using a Catalytic Asymmetric Michael Reaction with a Two-Center Organocatalyst Angew. Chem. Int. Ed. 2006, 45, 4635 –4637 Two-center organocatalyst: TaDiAS, tartrate-derived diammonium salt that efficiently catalyzes phase-transfer alkylation

RETROSYNTHETIC ANALYSIS

Preparation of the key substrate for the carboazidation step

PREPARATION OF THE KEY SUBSTRATE OF COMPOUND 4 FOR THE CARBOAZIDATION STEP

Preparation of trans-azide Method A: (Bu3Sn)2 (1.2 equiv.), t-BuON (0.1 equiv.), 75％, (trans/cis=7:3) Method B: Et3B (4.0 equiv.), air, rt, 59 ％, (trans/cis=7:3)

Synthesis of the stereochemical tricyclic amine

SYNTHESIS OF 13-EPI-CYLINDRICINE C

Total synthesis of (±)-cylindricine C

CONCLUSION Ring formation ： A → key azaspirocenter → B and C. The concise syntheses of 13-epi-cylindricineC and cylindricine C were achieved from 1-octyne in 15% and 11% yields, respectively. The strategy involves the preparation of the tricyclic skeleton via a radical α-iodoketone carboazidation/bis-reductive amination sequence.

SUMMARY Target molecule Journal Key step Steps Yield (±)-Cylindricine C Org. Lett. 2011, 13, 4774-4777 Carbonazidation Bis-reductive amination 17 11％ (-)- Cylindricine C J. Org. Chem. 1999, 64, 5183–5187. Intramolecular Michael addition 11 12％ (+)- Cylindricine C J. Org. Chem. 2005, 70, 3898-3902. Iminium ion/diene cyclization 8 11.1％ Angew. Chem., Int. Ed. 2006, 43, 4336 –4338 Oxidative spirocyclizaation 21 14.5％ Org. Lett. 2006, 8, 777-780 Aza〔3+3〕annulation 22 4.5％ (+)-Cylindricine C Angew. Chem., Int. Ed. 2006, 45, 4635 –4637 Michael addition Mannich reaction 6 17.6％

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