Chiral Sulfur Ylides for the Synthesis of Bengamide E and Analogues

Abstract

A new synthetic methodology of asymmetric epoxidation developed in our laboratories has been employed for the stereoselective synthesis of bengamide E (16) and analogues at the terminal olefinic position. In the event, the chiral sulfonium salt 30 was transformed into its corresponding sulfur ylide and reacted with aldehydes 21 and 44 to efficiently provide epoxy amides 31 and 45, respectively. To access the bengamides from these epoxy amides, we combined a synthetic strategy previously reported by us, using an olefin cross metathesis reaction to introduce various alkyl substituents at the terminal olefinic position of amide 33, with reactions mediated by palladium (Negishi or Suzuki couplings) from amide 49. This latter route of introduction of alkyl groups proved to be more efficient than the metathesis approach and allowed access to the generation of a wide array of new bengamide analogues.

Asymmetric trapping of zwitterionic intermediates by sulphur ylides in a palladium-catalysed decarboxylation-cycloaddition sequence

“…For example, in the well-known JohnsonCorey-Chaykovsky reaction 6 , which was first discovered in the 1960s (refs 7,8), sulphur ylides can react with polar substrates (for example, aldehydes, ketones, imines and electron-deficient alkenes) to produce a wide range of significant small-ring molecules such as epoxides, aziridines and cyclopropanes. More importantly, their synthetic potential has been well demonstrated in the synthesis of numerous bioactive natural products and pharmaceuticals 6,9,10 . In the past decade, the cycloaddition chemistry of sulphur ylides has evolved dramatically beyond three-membered rings, largely as a consequence of the valuable contributions made by Aggarwal and co-workers [11][12][13][14][15][16][17][18][19][20][21][22] , among others.…”

Myxobacteria versus sponge-derived alkaloids: The bengamide family identified as potent immune modulating agents by scrutiny of LC–MS/ELSD libraries

“…Analysis of literature 13 C NMR shifts provides a diagnostic pattern, shown in Figure 3, to further address the configurations at these centers noted above. The comparison of Panel A plots differences in 13 C shifts of natural bengamide E ( 8 ) from J. coriacea 36 versus data published for 8 from three different enantiospecific total syntheses; 40–42 and documents that the variation in shifts at each site is < 1ppm. By contrast, the information of Panel B shows that modification of the absolute configurations at C-6 and C-7 in the synthetic 8 diastereomer of 5 R , 6 R , 7 S , 8 R configuration, also obtained by an enantiospecific total synthesis, 43 imparts a >1 ppm change in the 13 C NMR chemical shifts at the 3/4 sites.…”

Chemistry and Biology of Bengamides and Bengazoles, Bioactive Natural Products from Jaspis Sponges

“…The last contribution to this numerous family of natural products was generated also by Crews [28] in 2012, who identified the bacteria Myxococcus virescens as a new source of bengamide E ( 42 ), and two new congeners, bengamides E′ ( 59 ) and F′ ( 60 ), isolated as an inseparable mixture of diastereomers, thus being the second example, in the peer-reviewed literature, of a sponge-derived natural product reported from a cultured microbial source (the first one being Makaluvamine A, isolated from the sponge Zyzzya fuliginosa [35] and myxomycetes Didymium bahiense [36]). It is also interesting to point out that bengamide E′ was initially synthesized in the laboratory prior to its isolation from a natural source [37]. Currently, 23 members of the bengamide family have been described and their molecular structures determined by spectroscopic methods.…”

“…Bengamide E was finally synthesized after a deprotection step of the acetal group (Scheme 4). In a second and improved synthesis by the same authors in 2010 [37], and as an application of the group’s methodology in the field of amide-stabilized sulfur ylides [90], aldehyde 100 was reacted with a chiral sulfonium salt to obtain in good yield and excellent diastereoselectivity (>98%) an epoxy amide that was reduced to epoxy alcohol 104 . From this epoxy alcohol, the methodology proceeded in a similar manner as the previous synthesis, although the processes of ring opening reaction and the formation of the substituted olefin were remarkably improved with respect to the first synthesis.…”