Development of New Reactions Employing Boron-Enolate Wittig Rearrangements.

Abstract

Wittig rearrangements are useful carbon-carbon bond forming reactions that have been prominently featured in a number of total syntheses, however narrow functional group tolerance and issues with competing reaction pathways have limited the utility of these transformations. Consequently, recent innovations focus on improving functional group tolerance and selectivity. The Wolfe group has reported a tandem Wittig rearrangement/aldol reaction of O-allyl or O-benzyl glycolate esters to generate enantioenriched α-alkyl-α,β-dihydroxy esters and α-alkyl-α-hydroxy-β-amino esters under mild Lewis acid conditions with excellent stereoselectivity. The work herein describes recent advances in the application of this Wittig rearrangement methodology for the synthesis of 3-hydroxy-2-furanones, N-aryl phenylalanine and allylglycine methyl esters, and α-alkyl-α,β-dihydroxy esters. Under strongly basic conditions, O-propargyl ethers are capable of undergoing [2,3] Wittig rearrangements to afford structurally rearranged allenic alcohols. However, O-propargyl glycolate methyl esters, when subjected to dibutylboron triflate and Hunig’s base, were observed to undergo a [2,3] Wittig rearrangement and subsequent alkylative cyclization sequence resulting in 3-hydroxy-2-furanone derivatives that have incorporated an alkyl group from the boron reagent. This unusual reaction sequence is explored in Chapter 2. Nitrogen analogs of Wittig rearrangements are investigated in Chapter 3. These aza-Wittig rearrangements of tertiary amines are less common and typically less facile than rearrangements of the corresponding ethers. Rearrangements of N-benzyl and N-allyl glycine methyl esters required higher temperatures and N-aryl protecting groups in order to undergo the desired [1,2] and [2,3] rearrangements. When N-carbonyl protecting groups were used, 1,4,2-oxazaborole derivatives were formed instead of the expected secondary amines. Additionally, N-allyl N-aryl glycine methyl esters in the presence of excess dibutylboron triflate undergo the [2,3] rearrangement as well as a hydroboration reaction to generate secondary amines bearing pendant primary alcohols. The final chapter describes an asymmetric tandem Wittig rearrangement/aldol reaction of O-benzyl and O-allyl glycolate esters coupled with ketone electrophiles. With the use of the trans-2-phenylcyclohexyl chiral auxiliary, these reactions generate α,β-dihydroxy esters bearing vicinal quaternary stereocenters with excellent enantio- and diastereoselectivity.