Asymmetric Syntheses of (+)-Preussin B, the C(2)-Epimer of (−)-Preussin B, and 3-Deoxy-(+)-preussin B

Abstract

Efficient de novo asymmetric syntheses of (+)-preussin B, the C(2)-epimer of (-)-preussin B, and 3-deoxy-(+)-preussin B have been developed, using the diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 4-phenylbut-2-enoate and diastereoselective reductive cyclizations of γ-amino ketones as the key steps to set the stereochemistry. Conjugate addition followed by enolate protonation generated the corresponding β-amino ester. Homologation using the ester functionality as a synthetic handle gave the corresponding γ-amino ketone. Hydrogenolytic N-debenzylation was accompanied by diastereoselective reductive cyclization in situ; reductive N-methylation then gave 3-deoxy-(+)-preussin B as the major diastereoisomeric product. Meanwhile, the same conjugate addition but followed by enolate oxidation with (+)-camphorsulfonyloxaziridine gave the corresponding anti-α-hydroxy-β-amino ester. α-Epimerization by oxidation and diastereoselective reduction then gave access to the corresponding syn-α-hydroxy-β-amino ester. Homologation of both of these diastereoisomeric α-hydroxy-β-amino esters gave the corresponding β-hydroxy-γ-amino ketones. N-Debenzylation and concomitant diastereoselective reductive cyclization, followed by reductive N-methylation, provided the C(2)-epimer of (-)-preussin B and (+)-preussin B as the major diastereoisomeric products, respectively. The overall yields (from phenylacetaldehyde) were 19% for 3-deoxy-(+)-preussin B over seven steps, 8% for the C(2)-epimer of (-)-preussin B over nine steps, and 7% for (+)-preussin B over eleven steps.

Preussins with Inhibition of IL-6 Expression from Aspergillus flocculosus 16D-1, a Fungus Isolated from the Marine Sponge Phakellia fusca

“…The second, preussin B ( 11 ), was isolated from Simplicillium lanosoniveum TAMA 173 and shown to exhibit weak antifungal activity . Owing to these desirable pharmacological activities, 10 − and 11 have been popular targets of total and analogue syntheses. Structurally, compounds 1 – 11 are the same except for the C-5 side chains.…”

“…Considering the carboxy termini of 1−5 and the stereogenic elements of the C-5 side chains of 6−9 are all on the flexible chains and remote from the western chromophoric systems, these C-5 side chains should all have insignificant effects on the specific rotations of 1−9. Thus, all the absolute configurations of the preussin core moieties of 1−9 were suggested to be 2S, 3S, 5R by comparison of their specific rotations ( 25 D +22 (c 0.19, CHCl 3 )). This inference was supported by the close resemblance of the experimental electronic circular dichroism (ECD) spectra of 1−9 (Figures S18, S29, S40, S51, S62, S75, S88, S101, and, S116) and the negative Δδ values of H-4α and H-4β of the (S)-and (R)-MTPA esters of 6/7 (6a/7a and 6b/ 7b) in the modified Mosher's method (Figure 3).…”

Effects and Mechanisms of Action of Preussin, a Marine Fungal Metabolite, against the Triple-Negative Breast Cancer Cell Line, MDA-MB-231, in 2D and 3D Cultures

“…More recently, preussin was also obtained from the culture extract of A. candidus KUFA 0062, isolated from a marine sponge, Epipolasis sp., which was collected from the Similan Islands National Park’s coral reef, in Phang-Nga province, Southern Thailand [ 23 ]. Given the importance of preussin, various authors have described different methods for its synthesis [ 21 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ].…”