Total Synthesis of Linoxepin through a Palladium-Catalyzed Domino Reaction Lutz F. Tietze Angew. Chem. Int. Ed. 2013, 52, 3191–3194 Speaker: 王湘閔

outline  Motivation  Isolation and biological activities  Retrosynthetic analysis  Synthesis of Linoxepin  Conclusion 1

Motivation  The novel lignan is an attractive synthetic goal.  Biological profiles 2

Isolation and biological activities  In 2007, Schmidt and co-workers isolated a lignan from the aerial parts of Linum perenne L.  They have long been used as herbal remedies for pain, herbal remedies for pain, rheumatoid arthritis, and warts. rheumatoid arthritis, and warts. 3

Retrosynthetic analysis Sonogashira reaction/ Carbopalladation/Heck reaction 4

Preparation of monomer 4 & 5 Synthesis of Linoxepin 5

Preparation of domino precursor 2 Synthesis of Linoxepin 6

Domino Sonogashira/carbopalladation/ Heck reaction Synthesis of Linoxepin 7

Synthesis of linoxepin (1) Synthesis of Linoxepin 8

Conclusion  First total synthesis of (+)- and (-)-linoxepin ( 1 ) in only ten steps and an overall yield of 30% without the use of any protecting groups.  Multiple Pd-catalyzed reactions: Sonogashira reaction Sonogashira reaction Domino carbopalladation/Heck reaction Domino carbopalladation/Heck reaction 9

Total Synthesis of (+)- Linoxepin by Utilizing the Catellani Reaction Mark Lautens Angew. Chem. Int. Ed. 2013, 125, 5413–5416 Speaker: 王湘閔

Outline  Retrosynthetic analysis  Synthesis of (+)-Linoxepin  Conclusion  Summary 11

Retrosynthetic analysis Palladium-catalyzed Catellani reaction 12

Synthesis of the monomers Synthesis of Linoxepin 13

Key step: Catellani reaction Catellani reaction oxidative addition base-mediated C-H activation carbopalladation oxidative addition reductive elimination transmetalation reductive elimination retro carbopalladation Mizoroki-Heck type reaction 14

Attempted synthesis of (±)-linoxepin (1) Synthesis of Linoxepin 15

Undesired formation of (±)- iso -linoxepin (14) Synthesis of Linoxepin 16

Mechanistic rationale for the formation of (±)-1 and (±)-14 Synthesis of Linoxepin syn  -hydride elimination via Pd-enolate formal anti  -hydride elimination syn  -hydride elimination reductive elimination 17

Synthesis of (+)-linoxepin (1) Synthesis of Linoxepin 18

Conclusion  First asymmetric synthesis of (+)-1 in eight steps and an overall yield of 30% without the use of any protecting groups.  Key step: domino C-H functionalization palladium-catalyzed Catellani reaction palladium-catalyzed Catellani reaction 19

Summary [a] D (CHCl 3 ) Key steps Steps/yield Nature product +23.0; c = 0.93, Angew. Chem. Int. Ed. 2013, 52, 3191– ; c = 0.61, Sonogashira reaction and a domino carbopalladation/Heck reaction of an allylsilane 10 steps, 30 % Angew. Chem. Int. Ed. 2013, 125, 5413– ; c = 0.25, domino C-H functionalization Catellani reaction 8 steps, 30 % 20