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Synthesis of Functionalized α,α-Dibromo Esters through Claisen Rearrangements of Dibromoketene Acetals and the Investigation of the Phosphine-Catalyzed [4 + 2] Annulation of Imines and Allenoates

  • Author(s): Dupper, Nathan
  • Advisor(s): Kwon, Ohyun
  • et al.

Allylic alcohols can be transformed into γ,δ-unsaturated α,α-dibromo esters through a two-step process: formation of a bromal-derived mixed acetal, followed by tandem dehydrobromination/Claisen rearrangement. The scope and chemoselectivity of this tandem process is broad and it tolerates many functional groups and classes of allylic alcohol starting material. The diastereoselectivity of the Claisen rearrangement was investigated with moderate to excellent diastereomeric selectivity for the formation of the γ,δ-unsaturated α,α-dibromo esters. The product α,α-dibromo esters are also shown to be valuable chemical building blocks. They were used in the synthesis of the ynolate reaction intermediate, as well as other carbon–carbon bond-forming reactions. Highly functionalized lactones were also shown to be simply prepared from the γ,δ-unsaturated α,α-dibromo ester starting materials formed via the Cliasen rearrangement.

A phosphine-catalyzed [4 + 2] annulation of imines and allenoates is also investigated herein. A synthesis of the core structure of the ergot alkaloid lysergic acid was attempted using an annulation of the alkyl imine derived from tert-butyl 4-bromo-3-(2-oxoethyl)-1H-indole-1-carboxylate and ethyl 2-methylbuta-2,3-dienoate to form the key tetrahydropyridine ring. The imine investigated was shown to have rapid tatomerization to the more stable enamine moiety, which was not conducive for the annulation process. Other routes for the synthesis of the ergot alkaloid core structure were also investigated.

Chiral bicyclic phosphines were applied to the annulation between ethyl 2-methylbuta-2,3-dienoate and various imines, which produces 6-substituted guvacine analogues in good yield with excellent enantiomeric excess. The bridged bicyclic chiral phosphines can be accessed quickly from trans-4-hydroxyproline. A new chiral phosphine (1S,4S,5R)-5-(4-anisyl)-2-tosyl-2-aza-5-phosphabicyclo[2.2.1]heptane was identified as an efficacious catalyst for the [4 + 2] annulation between ethyl 2-methylbuta-2,3-dienoate and aryl imines. A variety of aryl and heteroaryl imines were tested under this annulation process, affording 6-substituted guvacine esters. Utilizing this method, both (R) and (S)-aplexone were synthesized and tested to reveal that (R)-aplexone is the eutomer responsible for the reduction of cellular levels of cholesterol in the zebrafish model

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