Access to the Akuammiline Family of Alkaloids Total

Access to the Akuammiline Family of Alkaloids : Total Synthesis of (+)-Scholarisine A Gregory L. Adams, Patrick J. Carroll, and Amos B. Smith, III* J. Am. Chem. Soc. 2013, 135, 519− 528 Speaker： Yi-Chih Lu Date ： 2013/4/20

Structure of Scholarisine A bridged lactone indole tetrahydropyridine six member ring 2

Isolation of Scholarisine A • Scholarisine A (1), an akuammiline monoterpene indole alkaloid isolated from the leaves of Alstonia scholaris by Luo and co-workers. 3

Family Structure of akuammiline alkaloids acetate hydrolysis deformylation oxidation hydrolysis Additional loss of the acetoxymethyl 4

Family Structure of akuammiline alkaloids 5

Past synthesis of (±) vincorine J. Am. Chem. Soc. 2009, 16, 6013 -6020 6

Past synthesis of (-) vincorine Micheal addition + J. Am. Chem. Soc. 2012, 134, 9126 -9129 7

Past synthesis of Aspidopline A + Late-Stage interrupted Fischer indolization Heck cyclization J. Am. Chem. Soc. 2011, 133, 8877 -8879 8

Isolation and Bioactivity of Scholarisine A • Derivatives of picraline (3) are reported to be selective inhibitors of the receptor SGLT 2, a renal cortex membrane protein recently validated as a target for type II diabetes treatment. • Aspidophylline A (9) and echitamine (14) respectively reverse drug resistance in cancer cells and display in vivo anti-tumor activity in rodents. 9

Open form view of akummiline alkaloids Tetrahedron, 1965, 21, 1717 -1734 10

Open form view of akummiline alkaloids 11

Fragmentation approach to the akuammiline core 12

Fragmentation approach to the akuammiline core 13

Retrosynthetic analysis of Scholarisine A 14

Preparation of lactone (-)-32 from anhydride 35 + 15

Synthesis of epoxide (-)-33 by m. CPBA + 3: 1 16

Construction of ketone (+)-44 17

Construction of ketone (+)-45 through Fischer indole synthesis 18

Synthesis of phenylhydrazono 46 Fischer Indole Synthesis 19

Construction of indole (-)-50 20

Construction of indole (-)-49 + 21

Construction of indole (-)-52 + 22

Lactone ring-opening and hydroxyl protection 23

Oxidation of alcohol (+)-55 to the carboxylic acid Ley oxidation + 24

Construction of indole (-)-52 25

Construction of indole (-)-52 26

A new plan forward 27

Initial oxidative lactonization 28

Initial oxidative lactonization 29

Synthesize of lactone (-)-65 through Corey-Palani oxidation 30

Total synthesis of (+)-scholarisine A 31

Total synthesis of (+)-scholarisine A 32

“Retro-biosynthetic” fragmentation of scholarisine A 33

Conclusion • The first total synthesis of (+)-scholarisine A (1) has been achieved, employing a longest linear reaction sequence of 25 steps from commercially available anhydride 35. • Key synthetic tactics include 1. a novel cyclization, comprising nitrile reduction coupled with concomitant addition of the resultant amine to an epoxide 2. a modified Fischer synthetic protocol 3. an oxidative lactonization of a diol in the presence of an indole ring 4. a late-stage cyclization to complete the caged ring scaffold of (+)scholarisine A (1). • A “retro-biosynthetic” fragmentation of totally synthetic (+)scholarisine A (1) has also been achieved. Studies are currently underway to exploit this fragmentation to gain access to related members of the akuammiline family. 34

Thanks for your attendance 35