Predictive Bioinformatic Assignment of Methyl-Bearing Stereocenters, Total Synthesis, and an Additional Molecular Target of Ajudazol B

Abstract

Full details on the evaluation and application of an easily feasible and generally useful method for configurational assignments of isolated methyl-bearing stereocenters are reported. The analytical tool relies on a bioinformatic gene cluster analysis and utilizes a predictive enoylreductase alignment, and its feasibility was demonstrated by the full stereochemical determination of the ajudazols, highly potent inhibitors of the mitochondrial respiratory chain. Furthermore, a full account of our strategies and tactics that culminated in the total synthesis of ajudazol B, the most potent and least abundant of these structurally unique class of myxobacterial natural products, is presented. Key features include an application of an asymmetric ortholithiation strategy for synthesis of the characteristic anti-configured hydroxyisochromanone core bearing three contiguous stereocenters, a modular oxazole formation, a flexible cross-metathesis approach for terminal allyl amide synthesis, and a late-stage Z,Z-selective Suzuki coupling. This total synthesis unambiguously proves the correct stereochemistry, which was further corroborated by comparison with reisolated natural material. Finally, 5-lipoxygenase was discovered as an additional molecular target of ajudazol B. Activities against this clinically validated key enzyme of the biosynthesis of proinflammatory leukotrienes were in the range of the approved drug zileuton, which further underlines the biological importance of this unique natural product.

Polyene macrolide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studies

“…The stereospecificity motifs have been used to predict accurately the stereochemistry of many polyketides (Tietz and Mitchell, 2015;Essig et al, 2016). It is now known that the stereostructure of filipin agrees with that inferred from the sequence of the polyketide synthase (Gao et al, 2014;Ikeda et al, 2014).…”

Isobenzofurans as Synthetic Intermediates: Synthesis and Biological Activity of 8‐epi‐(–)‐Ajudazol B

“…NaOH solution (143 mL, 215 mmol) was then cautiously added, and the resulting mixture was stirred at rt for 18 h. The layers were separated, and the aqueous phase was extracted with CH 2 Cl 2 (3 × 250 mL). The aqueous layer was then cooled down to 0°C, and acidified to pH ≤ 2, by the slow addition of 3…”

“…[2] Ajudazol B was also shown to be an effective inhibitor of 5-lipoxygenase (5-LO), which is a molecular target for the treatment of asthma and allergic rhinitis. [3] The exciting combination of unique structural features and their interesting antifungal activity has made the ajudazols attractive targets. Rizzacasa [4] and Taylor [5] have published elegant approaches towards the total synthesis of the ajudazols; with the only completed total synthesis to date reported by Menche.…”

“…[ 2 ] Ajudazol B was also shown to be an effective inhibitor of 5‐lipoxygenase (5‐LO), which is a molecular target for the treatment of asthma and allergic rhinitis. [ 3 ]…”

Synergistic approach to polycycles through Suzuki–Miyaura cross coupling and metathesis as key steps

“…Owing to the mild reaction conditions and ease of handling of organoboron reagents [ 13 – 17 ] have propelled the growth of the SM cross coupling. A synergistic combination of these two elegant methods (i.e., SM coupling and metathesis) [ 18 ] was found to increase the synthetic efficiency of complex targets (e.g., macrocycles [ 19 – 22 ], oligomers [ 23 – 24 ], polycyclic ethers [ 25 ], heterocycles [ 26 ], nonbenzenoid aromatics [ 27 ], and spirocycles [ 28 – 29 ]) by decreasing the number of steps. Different metathesis catalysts used in this study are shown in Fig.…”