Kiyoun Lee and Dale L. Boger* TOTAL SYNTHESES OF (−)-KOPSIFOLINE D AND (−)-DEOXOAPODINE: DIVERGENT TOTAL SYNTHESIS VIA LATE-STAGE KEY STRATEGIC BOND FORMATION Kiyoun Lee and Dale L. Boger*

Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion

Introduction -natural product (-)-kopsifoline D – 1 Structure Property term Name (-)-kopsifoline D Isolated from Kopsia fruticosa Isolated by Kam and Choo Biological actitivity Fused 6/5/5/6/6/5 ring system 6環 :indole structure. heterocyclic ring.4 chiral center.

Introduction -natural product (-)-deoxoapodine - 2 Structure Property term Name (-)-deoxoapodine Isolated from Tebernae armeniaca Isolated by Biological actitivity Fused 6/5/5/6/6/5 ring system 6環: indole structure . furan

Introduction -relative natural product 這一系列的天然物皆為6環結構，主要差別在於苯環上的取代基、double bond or hydroxyl group 及amine and imine

Introduction - the review of the nature product Dale L. Boger synthesis

Introduction -Previous reference synthesis of kopsifoline alkaloid framework Reference: Tetrahedron 63 (2007) 5962–5976

Introduction -Previous reference Total Synthesis of (+)-Fendleridine (Aspidoalbidine) and (+)-1-Acetylaspidoalbidine Reference: J. AM. CHEM. SOC. 9 VOL. 132, NO. 9, 2010

Introduction -Previous reference total Synthesis of Kopsinine Reference:Org. Lett., Vol. 15, No. 4, 2013

Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion

Retrosynthesis of monoterpen indole alkaloids

Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion

Procedure of synthesis -Synthesis of the initial material -Synthesis of the amino-1,3,4-oxadiazole (12) 4-Toluenesulfonyl chloride 1,3,4-oxadiazole

Procedure of synthesis -Synthesis of the initial material -4-(2-tert-butyldimethylsilyloxy)pent-4-enoic acid (13)

Procedure of synthesis -Synthesis of the key intermediate 15 A dipolar cycloaddition

Procedure of synthesis -synthesis of (-)-Kopsifoline D Sodium cyanoborohydride Carbonylbenzyl Selenoxide elimination

Procedure of synthesis -Total synthesis of (-)-Deoxapodine

Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion

CONCLUSION a powerful approach to synthesize the key intermediate and apply on the series of Kopsifolines. the yield of the (-)-kopsifiline D is 5.7% (13step) from the two intermediate 15 the yield of the (−)-Deoxoapodine 4.4% (12step)

CONCLUSION Publish date author step yield production Albert Padwa 7 Tetrahedron 63 (2007) 5962–5976. Albert Padwa 7 non kopsifoline alkaloid framework J. AM. CHEM. SOC. 2010, 132, 3009–3012 Dale L. Boger 16 12.2% (+)-Fendleridine J. AM. CHEM. SOC. 2010, 132, 3685–3687 22 2.1% Vindoline ORGANIC LETTERS 2013 Vol. 15, No. 4 868–870 17%from the key intermediate Kopsinine J. Am. Chem. Soc. 2014,136,3312-3317 13 5.7%from the two intermediate (−)-Kopsifoline D 12 4.4% from the two intermesiate (−)-Deoxoapodine

REFERENCE Tetrahedron 63 (2007) 5962–5976 Angew. Chem. Int. Ed. 2006 J. AM. CHEM. SOC. 2006, 128, 10596-10612 J. AM. CHEM. SOC. 2010, 132, 13533–13544 J. Am. Chem. Soc. 2012, 134, 13240−13243 J. AM. CHEM. SOC. 2009, 131, 4904–4916 J. AM. CHEM. SOC. 2010, 132, 3009–3012 J. AM. CHEM. SOC. 2010, 132, 3685–3687 J. AM. CHEM. SOC. 2010, 132, 8489–8495 J. Med. Chem. 2013, 56, 483−495 J. Org. Chem. 2002, 67, 7361-7364 J. Org. Chem., Vol. 63, No. 3, 1998 Org. Lett., Vol. 7, No. 4, 2005

THE END

PROBLEM Long strategy. The concept of the key intermediate is important.