Cyclobutane Amino Acid Analogues of Furanomycin Obtained by a Formal [2 + 2] Cycloaddition Strategy Promoted by Methylaluminoxane

Abstract

The synthesis and conformational analysis of a new type of conformationally restricted alpha-amino acid analogue of the amino acid antibiotic furanomycin is presented. The restriction involves the cis-fused cyclobutane and tetrahydrofuran units, generating the unusual 2-oxabicyclo[3.2.0]heptane core, which is found in a great number of biologically active natural products. The synthetic strategy is based on a formal [2 + 2] cycloaddition between 2-(acylamino)acrylates as acceptor alkenes and 2,3-dihydrofuran as a donor alkene, promoted by bulky aluminum-derived Lewis acids, particularly by methylaluminoxane (MAO). Additionally, following the same strategy, the synthesis of furanomycin analogues incorporating the 2-oxabicyclo[4.2.0]octane is reported.

Dehydroamino acids: chemical multi-tools for late-stage diversification

“…The unique, push-pull electronic structures of dhAAs also allows them to participate in a variety of cycloaddition reactions. 53,54,[74][75][76][77][78] Together, the competing electronic forces of the pi-donating nitrogen substituent and electron withdrawing carbonyl polarize the dhAA exomethylene and compress the HOMO-LUMO gap, allowing it to serve as a 2π partner to a variety of electron rich 3π and 4π elements, as well as nucleophilic carbenes (figure 2C). [79][80][81][82][83][84] As opposed to conjugate addition chemistry, these cycloadditions provide access to α,α-disubstituted amino acid products, which have unique conformational properties.…”

Aluminum‐Based Catalysts for Cycloaddition Reactions: Moving One Step Ahead in Sustainability

“…Avenzoa and Peregrine et al . have developed a synthetic methodology for the preparation of cyclobutane R‐ amino acid derivative analogues of the antibiotic amino acid furanomycin promoted by methylaluminoxane.…”

Stereocontrolled Synthesis and Functionalization of Cyclobutanes and Cyclobutanones

“…Also, cyclobutane diacetate 77 was selectively hydrolyzed from PPL at pH 7.0, in absence of the acetate source, yielding the monoacetate (+)- 78 in 97% yield as reported in Scheme 18. The so obtained derivatives have been afterward used for the synthesis of important key intermediates in the synthesis of chiral cyclobutane nucleosides [30] and aminoacids [31,75,76,77].…”