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Total Syntheses of (–)-Kopsifoline

D and (–)-Deoxoapodine:

Divergent Total Synthesis via Late-

Stage Key Strategic Bond

Formation

Kiyoun Lee and Dale L. Boger The Scripps Research Institute

La Jolla, Ca J. Am. Chem. Soc. 2014, 136, 3312.

Joseph Salamoun Current Lit. 3/15/14

Wipf Group Joe Salamoun @ Wipf Group Page 1 of 10 4/12/2014

Kopsifolines and Related Compounds

• Common pentacyclic core structure.

• Allows for a common intermediate.

• Same synthetic strategy provides access to a number of natural products.

Joe Salamoun @ Wipf Group Page 2 of 10 4/12/2014

Synthesis of the Common Intermediate

J. Am. Chem. Soc., 2010, 132, 3009.

Indole

Ester

OTBS

O-Bridge

Simplified representation of A.

Joe Salamoun @ Wipf Group Page 3 of 10 4/12/2014

J. Am. Chem. Soc., 2010, 132, 3009. Org. Lett., 2013, 15, 868.

Synthesis of (+)-Fendleridine and Kopsinine

Joe Salamoun @ Wipf Group Page 4 of 10 4/12/2014

MacMillan’s Enantioselective Synthesis of (–)-Kopsinine

Nature, 2011, 475, 183. Joe Salamoun @ Wipf Group Page 5 of 10 4/12/2014

Synthesis of Kopsifoline H and Dihydrokopsifoline D

J. Am. Chem. Soc., 2014, 136, 3312. Joe Salamoun @ Wipf Group Page 6 of 10 4/12/2014

Synthesis of Kopsifoline D and Deoxoapodine

J. Am. Chem. Soc., 2014, 136, 3312. Joe Salamoun @ Wipf Group Page 7 of 10 4/12/2014

Overman Racemic Synthesis of Deoxoapodine

J. Am. Chem. Soc., 1991, 113, 2598. Joe Salamoun @ Wipf Group Page 8 of 10 4/12/2014

Key Step from Overman Synthesis

J. Am. Chem. Soc., 1991, 113, 2598. Joe Salamoun @ Wipf Group Page 9 of 10 4/12/2014

Conclusions

• Practical use of the same intermediate for the synthesis of a variety of natural products with the same core structure.

• The synthetic routes utilize similar chemistry

displaying reproducibility/usefulness of the reactions.

• Key steps are diastereoselective but not

enantioselective. It is a racemic synthesis with chiral separation of key intermediates. This invites questions about the true yields of the reactions when accounting for enantiomers.

Joe Salamoun @ Wipf Group Page 10 of 10 4/12/2014