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Application of iminium activation technologies to natural product synthesis: Total syntheses of the spiculisporic acids, progress towards the total synthesis of cylindrocyclophane F, and a formal synthesis of cylindrocyclophane A

Citation

Goodwin, Nicole C (2007) Application of iminium activation technologies to natural product synthesis: Total syntheses of the spiculisporic acids, progress towards the total synthesis of cylindrocyclophane F, and a formal synthesis of cylindrocyclophane A. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechETD:etd-07242006-134454

Abstract

The first enantioselective, catalytic vinylogous Mukaiyama-Michael reaction of siloxyfurans with simple alpha,beta-unsaturated aldehydes has been reported using chiral imidazolidinones. This methodology provides access to enantioenriched gamma-butenolides, a privileged motif in organic synthesis. The utility of this organocatalytic Mukaiyama-Michael reaction was highlighted by the total syntheses of (--)-spiculisporic acid and (--)-5-epi-spiculisporic acid.

Investigations into the total syntheses of cylindrocyclophanes A and F necessitated the development of a novel B-alkyl Suzuki cross-coupling of trimethylanilinium salts using a nickel(0) catalyst and bulky phosphine ligand. This methodology study revealed a very competitive nickel-catalyzed demethylation pathway, which produced dimethylaniline byproducts. A possible explanation for this side reaction is discussed. This technology was applied to a dimerization strategy for the C2-symmetric cylindrocyclophane F. Synthesis of a dimerization precursor included an enantioselective organocatalytic 1,4-addition of 3,5-dimethoxy-N,N-dimethylaniline into an alpha,beta-unsaturated aldehyde. However, the B-alkyl Suzuki cross-coupling was unsuccessful in promoting a dimerization.

Next, the synthesis of cylindrocyclophane A was explored using an alternative ring-closing metathesis dimerization strategy. A dimerization precursor was to be assembled via the cross-coupling of trimethylanilinium salts with potassium (vinyl)trifluoroborate salts, whose syntheses featured an organocatalytic 1,4-conjugate reduction of a beta,beta-disubstituted enal. This cross-coupling strategy revealed olefin isomerization as a major side-reaction in the nickel-catalyzed Suzuki dimerization, making this route a non-productive approach to the natural product.

Lastly, formal synthesis of cylindrocyclophane A was accomplished using (i) a nickel-catalyzed Stille cross-coupling of an activated vinyl stannane with a judiciously chosen trimethylanilinium salt and (ii) an asymmetric palladium-catalyzed allylic alkylation of an acyclic ketone. The latter represents the first example of application of the Pd2(dba)3/t-Bu-PHOX catalyst system to effect an asymmetric allylic alkylation on an acyclic system with good stereoselectivity. This route constituted a formal synthesis of cyclindrocyclophane A in eight linear steps, making it more efficient than the published route to the same advanced intermediate reported by Smith, which was synthesized in eleven steps.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:asymmetric allylic alkylation; cylindrocyclophane; organocatalysis; spiculisporic acid; trimethylanilnium salt; vinylogous Mukaiyama-Michael
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • MacMillan, David W. C.
Thesis Committee:
  • Barton, Jacqueline K. (chair)
  • MacMillan, David W. C.
  • Dougherty, Dennis A.
  • Hsieh-Wilson, Linda C.
Defense Date:17 July 2006
Record Number:CaltechETD:etd-07242006-134454
Persistent URL:http://resolver.caltech.edu/CaltechETD:etd-07242006-134454
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:2974
Collection:CaltechTHESIS
Deposited By: Imported from ETD-db
Deposited On:24 Jul 2006
Last Modified:26 Dec 2012 02:55

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