Application of Iminium Activation Technologies To Natural Product Synthesis: Total Synthesis of the Spiculisporic Acids, Progress Towards the Total Synthesis of Cylindrocyclophane F, and Formal Synthesis of Cylindrocyclophane A

Author: Goodwin, Nicole Cathleen

Year: 2007

Degree: Dissertation (Ph.D.)

Advisor: MacMillan, David W. C.

Committee Members: Barton, Jacqueline K.; MacMillan, David W. C.; Dougherty, Dennis A.; Hsieh-Wilson, Linda C.

Option: Chemistry

DOI: 10.7907/C7D7-XN63

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 α,β-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 β,β-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.

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