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Type of Document	Dissertation
Author	Goodwin, Nicole C
URN	etd-07242006-134454
Persistent URL	http://resolver.caltech.edu/CaltechETD:etd-07242006-134454
Title	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
Degree	PhD
Option	Chemistry
Advisory Committee	Advisor Name Title Jacqueline K. Barton Committee Chair David W. C. MacMillan Committee Member Dennis A. Dougherty Committee Member Linda C. Hsieh-Wilson Committee Member
Keywords	trimethylanilnium salt asymmetric allylic alkylation cylindrocyclophane vinylogous Mukaiyama-Michael organocatalysis spiculisporic acid
Date of Defense	2006-07-17
Availability	unrestricted
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.
Files	Filename       Size       Approximate Download Time (Hours:Minutes:Seconds)     28.8 Modem   56K Modem   ISDN (64 Kb)   ISDN (128 Kb)   Higher-speed Access    Chapter00.pdf 558.81 Kb 00:02:35 00:01:19 00:01:09 00:00:34 00:00:02   Chapter01.pdf 654.22 Kb 00:03:01 00:01:33 00:01:21 00:00:40 00:00:03   Chapter02.pdf 2.43 Mb 00:11:14 00:05:46 00:05:03 00:02:31 00:00:12   Chapter03.pdf 3.78 Mb 00:17:30 00:09:00 00:07:52 00:03:56 00:00:20   Chapter04.pdf 3.26 Mb 00:15:06 00:07:46 00:06:47 00:03:23 00:00:17   Chapter05.pdf 1.94 Mb 00:08:59 00:04:37 00:04:02 00:02:01 00:00:10   FullThesis.pdf 4.85 Mb 00:22:27 00:11:33 00:10:06 00:05:03 00:00:25