Total Syntheses and Biological Reassessment of Lactimidomycin, Isomigrastatin and Congener Glutarimide Antibiotics

Abstract

Lactimidomycin (1) was described in the literature as an exquisitely potent cell migration inhibitor. Encouraged by this claim, we developed a concise and scalable synthesis of this bipartite glutarimide-macrolide antibiotic, which relies on the power of ring-closing alkyne metathesis (RCAM) for the formation of the unusually strained 12-membered head group. Subsequent deliberate digression from the successful path to 1 also brought the sister compound isomigrastatin (2) as well as a series of non-natural analogues of these macrolides into reach. A careful biological re-evaluation of this compound collection showed 1 and progeny to be potently cytotoxic against a panel of cancer cell lines, even after one day of compound exposure; therefore any potentially specific effects on tumor cell migration were indistinguishable from the acute effect of cell death. No significant cell migration inhibition was observed at sub-toxic doses. Although these findings cannot be reconciled with some reports in the literature, they are in accord with the notion that lactimidomycin is primarily a ribosome-binder able to effectively halt protein biosynthesis at the translation stage.

Progress in the trans-Reduction and trans-Hydrometalation of Internal Alkynes. Applications to Natural Product Synthesis

“…67,68 The trans-hydrosilylation reaction was also utilized for the preparation of the antibiotic macrolide myxovirescin A 1 ( . 70 In this case, the cycloalkyne produced by RCAM was subjected to transhydrosilylation in neat (EtO) 3 SiH 29b as it would not react with BnMe 2 SiH under the standard Trost conditions.…”

“…101 Although this route was deemed satisfactory, an alternative entry based on RCAM/ trans-reduction ultimately proved shorter and better suited for material throughput; it was implemented in the form of a first and second generation synthesis. 67,68 Somewhat counterintuitively, RCAM 3 allowed the fairly strained 12-membered lactone ring 34 to be closed without difficulty. Even though one might argue that the supposedly linear alkyne group increases ring strain even further, the cyclization of diyne 112 proceeded with excellent yield at 80°C under the aegis of the molybdenum alkylidyne 113 endowed with triarylsilanolate ligands (Scheme 9).…”

“…67 The second generation synthesis was designed to avoid the organoselenium chemistry altogether; this improvement facilitated the up-scaling. 68 To this end, it sufficed to place a benzoate group at the C3 position of the cyclization precursor, which served as a surrogate for the α,β-unsaturation of the target (Scheme 10). Once again, RCAM proceeded readily as did the subsequent ruthenium-catalyzed trans-hydrosilylation to give alkenyl silane 122 as the only regioisomer.…”

“…Product 38 was then transformed into lactimidomycin 36 by the sequence outlined above (Scheme 9). 68 With a scalable synthesis established, Fürstner and coworkers used the flexibility of the underlying blueprint to prepare a set of non-natural analogues for investigations into structureactivity relationships. In one of these modifications, the key alkenyl silane 122 was subjected to a Hiyama Denmark cross coupling 31,32 with phenyl iodide in the presence of [Pd 2 (dba) 3 ]¢CHCl 3 .…”

“…AIBN) of the methyl propargylic ether 240 followed by tiniodine exchange to form the alkenyl iodide 241 (Table 5, Entry 12). 68 Subsequent dehalogenation (n-Bu 3 SnH/cat. AIBN) gave the desired (E)-alkene.…”