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Progress Toward the Total Synthesis of Polyether Ionophore Antibiotics


Norbeck, Daniel Word (1985) Progress Toward the Total Synthesis of Polyether Ionophore Antibiotics. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/92jg-h841.


Several subunits for the convergent synthesis of polyether ionophore antibiotics via the ester enolate Claisen rearrangement of furanoid and pyranoid carboxylic acids and glycals are prepared from carbohydrates. Key steps from D-fructose to the monensin spiroketal include the ester enolate Claisen rearrangement of a glycal propionate, expansion of a furanoid to a pyranoid ring, and the acid catalyzed equilibration of a bicyclic ketal to a spiroketal. An alternative approach, entailing the hetero-Diels-Alder condensation of a 2-methylenetetrahydropyran and acrolein is thwarted by facile isomerization to the endocyclic enol ether. The monensin bis-tetrahydrofuran is prepared from D-xylose and Dmannose. In the key step, in situ silylation of an ester enolate with a beta leaving group allows the tetrahydrofuran rings to be joined by Claisen rearrangement. The monensin tetrahydropyran is prepared from D-fructose and then joined to the bis-tetrahydrofuran by the ester enolate Claisen rearrangement. Methodology for the radical induced, reductive decarboxylation of the resulting acid via its phenyl selenoester is described. Anomeric stabilization of the intermediate tetrahydrofuran-2-yl radical is an important factor in the stereochemical outcome of this process. Reduction of 2,3-Q-(1-methylethylidene)furanosyl and pyranosyl chloride with lithium 4,4'-di-t-butylbiphenyl affords the corresponding glycals in high yield. The direct addition of nucleophilic reagents to crude Swern oxidation reaction mixtures circumvents the deleterious side reactions characteristic of highly reactive carbonyl compounds. Hexylglyoxal, produced by Swern oxidation of 1,2-octanediol, condenses with methyl (triphenylphosphoranylidene)acetate to give the γ-oxo-crotonate. Addition of methyl magnesiun bromide to an unstable 2-ketofuranoside delivers the branched chain carbohydrate derivative. The transient existence of monomeric trimethylsilyl formaldehyde, generated at -78°C by Swern oxidation of trimethylsilylmethanol, is established by isolation of a Wittig condensation product.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Chemistry
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Grubbs, Robert H. (advisor)
  • Ireland, Robert E. (co-advisor)
Thesis Committee:
  • Ireland, Robert E. (chair)
  • Dougherty, Dennis A.
  • Chan, Sunney I.
  • Grubbs, Robert H.
Defense Date:17 September 1984
Funding AgencyGrant Number
Record Number:CaltechTHESIS:04052019-154201556
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11444
Deposited By: Mel Ray
Deposited On:10 Apr 2019 15:38
Last Modified:16 Apr 2021 23:12

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