Total Syntheses of Bengamides B and E

Abstract

Total syntheses of the cytotoxic marine natural products bengamides B and E are described. Both bengamides are prepared via amide coupling of a protected polyhydroxylated lactone intermediate 9 with a suitably substituted aminocaprolactam intermediate. Lactone 9 is prepared in five steps from commercially available alpha-D-glucoheptonic gamma-lactone. The key reactions are a selective deprotection of a 1,2-acetonide in the presence of a 1,3-acetonide and an (E)-selective olefination of an unstable aldehyde using a gem-dichromium reagent. The bengamide B lactam intermediate 10 is prepared in seven steps from commercially available (5R)-5-hydroxy-L-lysine (12). The desired S-configuration at the gamma-OH lactam position is established using the Mitsunobu reaction.

Proteomics-based Target Identification

“…Purification and Synthesis of Bengamide Analogues-The syntheses of bengamide E, LAF153, and LAF389 have been reported previously (3,7). Structures of the compounds are given in Fig.…”

“…Confirmation of the assignment of the N-terminal sequences was performed by nano-ESMS/MS sequencing. Direct selection of the triply charged parent ion at m/z 421.22 from the Lys-C digest of the induced 14-3-3␥ isoform and subsequent fragmentation produced sufficient y and b type fragment ions to identify unambiguously the sequence of the peptide as M(oxi)-VDREQLVQK (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). A similar analysis of the aminoterminal peptide of the tryptic digest of the constitutive 14-3-3␥ confirmed the complete sequence as acetyl-VDREQLVQK (2-10) (data not shown).…”

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

“…The most efficient route to date is that reported recently by Kinder et al, which employs a sensitive carbohydrate-derived g-lactone aldehyde from which the required olefin is elaborated in modest yield by a Takai olefination [12]. This route is especially efficient, since coupling to the amino caprolactam subunit can be accomplished directly with the g-lactone playing the active ester component.…”

“…This route is especially efficient, since coupling to the amino caprolactam subunit can be accomplished directly with the g-lactone playing the active ester component. Most prior syntheses had taken advantage of standard peptide-bond-forming methods that require multiple steps or amination of esters with dimethylaluminum amides [11] [12].…”

“…Installation of the two stereogenic C-atoms of 5 was envisioned via an enantioselective alkylation of 9 with the functionalized oxirane 10. An alternative synthesis of the caprolactam moiety 5, starting from hydroxylysine, was recently reported [12].…”