Enantioselective Spirocyclopropanation of para-Quinone Methides Using Ammonium Ylides.

Lukas Roiser,Mario Waser

doi:10.1021/acs.orglett.7b00869

Abstract

The use of Cinchona alkaloid-based chiral ammonium ylides allows for the first highly enantioselective and broadly applicable spirocyclopropanation reactions of para-quinone methides. This strategy provides a straightforward protocol toward the chiral spiro[2.5]octa-4,7-dien-6-one skeleton, which is a frequently found structural motif in important biologically active molecules.

Highlights

The spirocyclopropane motif is a recurring important structural element in a variety of natural compounds.[1]
Among the different possible variations, the spiro[2.5]octa-4,7-dien-6-one skeleton has become increasingly relevant because of its presence in biologically active natural products with, e.g., DNA-alkylating properties.[2]. In addition to their interesting pharmacological properties, spirocyclopropanes may serve as versatile key-intermediates in the synthesis of complex targets.[3]
Very recently the first reports describing the use of these reactive substrates for Michael-initiated cyclopropanation reactions either with α-bromo malonates (Scheme 1A)[9] or sulfonium ylides (Scheme 1B)[4] have been reported, allowing for a straightforward construction of the spiro[2.5]octa-4,7-dien-6one skeleton of compounds of general structure 3

Summary

Me3N t-BuOK

An interesting observation was made when we attempted the synthesis of the dimethylamino-containing cyclopropane 3k. This product was clearly identified in the crude reaction mixture. Based on the proposed absolute configuration for transcyclopropanes 3, addition of an alcohol should result in compounds 6 with the configuration given in Scheme 3. During the ring opening of one example did we observe a measurable but still a rather small erosion of the enantiopurity (Δ = 1.8%), but with all of the other investigated transformations with different cyclopropanes 3 and different alcohols, they proceeded without any noticeable decrease in er (see the Supporting Information).[15]. The hereby obtained products can be used for stereospecific ring-opening reactions as exemplified by the addition of simple alcohols. Analytical details, and copies of NMR spectra and HPLC data of all the compounds (PDF) Crystallographic data for 3l (CIF)

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES