Access to the Akuammiline Family of Alkaloids : Total Synthesis of (+)-Scholarisine A Speaker ： Yi-Chih Lu Date ： 2013/4/20 Gregory L. Adams, Patrick J.

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

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

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

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

Family Structure of akuammiline alkaloids 5

Past synthesis of (±) vincorine J. Am. Chem. Soc. 2009, 16,

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

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

Isolation and Bioactivity of Scholarisine A 9 Derivatives of picraline (3) are reported to be selective inhibitors of the receptor SGLT2, 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.

10 Tetrahedron, 1965, 21, Open form view of akummiline alkaloids

11 Open form view of akummiline alkaloids

12 Fragmentation approach to the akuammiline core

13 Fragmentation approach to the akuammiline core

Retrosynthetic analysis of Scholarisine A 14

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

16 Synthesis of epoxide (-)-33 by mCPBA + 3:1

17 Construction of ketone (+)-44

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

Synthesis of phenylhydrazono Fischer Indole Synthesis

20 Construction of indole (-)-50

21 + Construction of indole (-)-49

22 + Construction of indole (-)-52

23 Lactone ring-opening and hydroxyl protection

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

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 34 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.

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