synthesis of (-)-flustramine b: enantioselective ...€¦ · synthesis of (-)-flustramine b:...

21
Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon Kim, Christopher J. Sinz, Wen-Jing Xiao, and David W. C. MacMillan* Proc. Nat. Acad. Sci. USA, 101, 5482-5487 (2004) SRINIVASA RAO CHINTALA

Upload: others

Post on 13-Mar-2020

28 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction

Joel F. Austin, Sung-Gon Kim, Christopher J. Sinz, Wen-Jing Xiao, and David W. C. MacMillan*

Proc. Nat. Acad. Sci. USA, 101, 5482-5487 (2004)

SRINIVASA RAO CHINTALA

Page 2: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

David W. C. MacMillan

  1991-1996: Doctoral studies with Professor Larry E. Overman at the University of California, Irvine

  1996-1998: Postdoctoral research fellow with Professor David A. Evans at Harvard University

  1998: Dave began his independent research career at the University of California, Berkeley

  2006: Appointed as the A. Barton Hepburn Professor of Chemistry at Princeton University

  2011: Appointed as James S. McDonnell Distinguished University Professor of Chemistry at Princeton University.

  1968: Born in Scotland.   1987-1991: B.S- University of Glasgow

Page 3: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Pyrroloindoline Natural Isolates

Page 4: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

  Isolated from a widespread series of natural sources, including amphibians, plants and marine algae

  First described in the late 1930s, this alkaloid family has been found to exhibit remarkable biological properties across a broad spectrum of pharmacological screens

  exhibit potent anti-cancer activities against lymphocytic leukemia cell lines and cytotoxicity to HeLa cell lines

(-)-flustramine B

  Total synthesis has been published by Austin, Kim, Christopher, Xiao, and MacMillan

Page 5: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

  Use chiral amines as LUMO-lowering catalysts instead of Lewis acids.

Page 6: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Development of effective amine catalyst

Page 7: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

The catalyst activated iminium ion was formed with (E)-isomer selectivity to avoid nonbonding interactions between the substrate olefin and the bulky tert-butyl group

Page 8: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Pyrroloindoline Construction

Page 9: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Effect of Cocatalyst and Solvent on the Organocatalytic pyrroloindoline Construction

Page 10: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Results of various protecting groups with Acrolein

Page 11: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Results With Substituted Acroleins

Page 12: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Stereochemical Rationale For Acrolein

Equation1. Enantioselective construction of pyrroloindole core in Methanol

Equation 2. Enantioselective construction of pyrroloindole core in Toluene

Page 13: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Equation1

Page 14: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Equation 2. Enantioselective construction of pyrroloindole core in Toluene

Page 15: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Frontier Molecular Orbital Explanation for Equation 2

Page 16: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Tryptamine Facial Selectivity Due to Secondary Overlap

Page 17: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Stereochemical Rationale for β-Substituted Acroleins

Page 18: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon
Page 19: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Retrosynthetic Analysis

NNHBr N

NBOCHBr N

NBOCHBr

NNBOCHBr

OH

NBr

COBHN

+ O

Page 20: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

(-)-Flustramine B Synthesis

Page 21: Synthesis of (-)-flustramine B: Enantioselective ...€¦ · Synthesis of (-)-flustramine B: Enantioselective organocatalytic Pyrroloindoline Construction Joel F. Austin, Sung-Gon

Conclusion

  The addition cyclization of tryptamines with α,β-unsaturated aldehydes in the presence of imidazolidinone catalysts provides pyrrolidinone adducts in high yield and excellent enantioselectivities.

  Application of this pyrroloindoline-forming reaction to natural product synthesis has been accomplished in the context of the enantioselective synthesis of (-)-Flustramine B