Total Synthesis of Platensimycin and Related Natural Products

Abstract

Platensimycin (1) is the flagship member of a new and growing class of antibiotics with promising antibacterial properties against drug resistant bacteria. The total syntheses of platensimycin and its congeners, platensimycins B 1 (7) and B 3 (9), platensic acid (2), methyl platensinoate (3), platensimide A (4), homoplatensimide A (5), and homoplatensimide A methyl ester (6) ( Figure 1) are described. The convergent strategy developed toward these target molecules involved construction of their cage-like core followed by attachment of the various side chains through amide bond formation. In addition to a racemic synthesis, two asymmetric routes to the core structure are described: one exploiting a rhodium-catalyzed asymmetric cycloisomerization, and another employing a hypervalent iodine-mediated dearomatizing cyclization of an enantiopure substrate. The final two bonds of the core structure were forged through a samarium diiodide-mediated ketyl radical cyclization and an acid-catalyzed etherification. The rhodium-catalyzed asymmetric reaction involving a terminal acetylene was developed as a general method for the asymmetric cycloisomerization of terminal enynes.

Platensimycin and platencin: promising antibiotics for future application in human medicine

“…Nicolaou et al 18,[30][31][32][33] reported several strategies for the total synthesis of platensimycin and related natural products. By using platensimycin/platencin as a starting point, they explored the relationship between structure and function.…”

Hypervalent iodine reagents in the total synthesis of natural products

“…398 Examples of applications are (±)-2-epi-validamine (Scheme 87), 402 pantocin B, 403,404 and (─)-platensimide A (Scheme 88). 299 An 66 application of this rearrangement in large scale has been reported using DIB. A lower yield was obtained when PIFA/pyridine was used (Scheme 89).…”

An Oxidative Prins–Pinacol Tandem Process and its Application to the synthesis of (−)‐Platensimycin

“…Subsequent Schreiber-Fenton fragmentation [18] would provide alkenes 27, which may be elaborated into advanced intermediate 31 as described by Nicolaou and co-workers. [8] The hypothesis was put into practice as shown in Scheme 9. Oxidation of compound 20 with DIB, as detailed earlier, followed by the addition of 30 % hydrogen peroxide, afforded a 3:2 mixture of unassigned diastereomers of hydroperoxyketal 25 in 64 % overall yield.…”

“…[5d] Nicolaou, [8] their co-workers, and us [3c,e] have shown that such reactive agents can be intercepted by allylsilanes. If the internal olefin were to add to the electrophilic carbon in 6, then cationic intermediate 7 would be primed to undergo a pinacol rearrangement to, ultimately, carbonyl compound 8, arguably through a cyclic, chair-like transition state that should permit control of the configuration of the emerging quaternary carbon.…”