The Development of a Convergent and Efficient Enantioselective Synthesis of the Bengamides via a Common Polyol Intermediate

Abstract

Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday An efficient, general synthetic route to the bengamide family of antitumor agents from a common polyol thioester is described. Consecutive aldol condensations afford the protected polyol thioester side chain suitable for coupling to the bengamides. A novel chiral-phase-transfer-catalyzed enantioselective alkylation affords the properly functionalized caprolactams required for the synthesis of more-complex members of the bengamide family. Use of the methyl 2-naphthyl ether protecting group, compatible with the boron Lewis acids required for enantioselective aldol condensation, allows direct access to all the bengamides.

Marine natural products

“…225 An enantioselective synthesis of bengamide Z, originally isolated from a Jaspis sp., 226 has been reported. 227,228 Two potently cytotoxic amides, theopederins K 252 and L 253, were obtained from a Discodermia species collected from Honduras. 229 Sponges continue to be a rich source of novel and biologically active peptides.…”

The Development of the Bengamides as New Antibiotics against Drug-Resistant Bacteria

“…After the publication of our review about the chemistry and biology of the bengamides and bengazoles in 2014 [1], a new review was published in 2017 by Crews et al [36]. In summary, until 2014, a total of 111 analogues of the bengamides were synthesized [27,[37][38][39][40][41], together with numerous total syntheses of the natural congeners [42][43][44][45][46], by different research groups, and biologically evaluated against different tumor cell lines, which, overall, represents an extensive and thorough structure-activity relationship study that has allowed for the establishment of a consistent and well-defined pharmacophore for the bengamides, summarized in the following points: (a) the importance of the substituent at the terminal olefinic position; (b) the essential role of the polyketide fragment, whose hydroxyl groups and stereochemistries are essential for their biological properties; and; (c) the beneficial impact of the modification of the caprolactam fragment in their antitumor properties. Among the analogues that displayed improved pharmacological properties in comparison with the natural counterparts, were the bengamide A analogue 25, known as LAF389, which presented a greater solubility in water with respect to bengamide A (1), or the modified caprolactam analogue 26, the cyclopentyl analogue of bengamide E 27, or the ring-opened bengamide analogue 28, which exhibited a major antitumor potency compared with bengamide E (5), being analogue 28 the most potent analogue identified so far (Figure 3).…”

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

“…A new approach to the bengamides, based again on aldol reactions, was conducted by the Boeckman’s group who described the total synthesis of bengamides B ( 39 ), E ( 42 ) and Z ( 57 ) [ 86 , 87 ]. For these synthesis, the C10 side chain was entirely constructed through sequential syn and anti asymmetric aldol reactions from the α,β-unsaturared aldehyde 95 .…”