Among the plethora of microbial secondary metabolites produced by the soil bacterium of the Streptomyces family is pactamycin, a structurally unique member of aminocyclopentitol-containing natural products (Scheme 1).Pactamycin was isolated in 1961 from a fermentation broth of Streptomyces pactum var pactum by scientists at the former Upjohn Company.[1] It exhibits activity against Grampositive and Gram-negative bacteria, in addition to potent in vitro and in vivo cytotoxic effects.[2] Its further development as a chemotherapeutic agent was curtailed owing to its toxicity. The potent protein synthesis inhibitory activity of pactamycin is attributed to the stage of translocation from the A and P sites to the P and E sites during formation of certain m-RNA-t-RNA complexes in prokaryotes as well as in eukaryotes.[3] Pioneering X-ray crystallographic studies [4] involving binding to the 30S site of Thermus thermophilus show unique interactions, whereby pactamycin adopts a spatial orientation so as to mimic an RNA nucleotide. The two aromatic moieties stack against each other like consecutive RNA bases, while the core cyclopentane motif mimics the RNA sugar-phosphate backbone, which results in an intricate network of hydrogen-bonded interactions within the 30S site of the ribosome. Recent elegant studies on the biosynthesis of pactamycin by Mahmud and coworkers [5a] revealed a gene cluster which also produced pactamycate, de-6-MSA-pactamycin and de-6-MSA-pactamycate, the natural congeners lacking the 6-methyl salicylic acid moiety.

This article describes synthetic studies that culminated in the first total synthesis of pactamycin and pactamycate and, in parallel, the two known congeners, de-6-MSA-pactamycin and de-6-MSA-pactamycate, lacking the 6-methylsalicylyl moiety. Starting with L-threonine as a chiron, a series of stereocontrolled condensations led to a key cyclopentenone harboring a spirocyclic oxazoline. A series of systematic functionalizations led initially to the incorrect cyclopentanone epoxide, which was "inverted" under solvolytic conditions. Installation of the remaining groups and manipulation of the oxazoline eventually led to pactamycin, pactamycate, and their desalicylyl analogues.

Straightforward palladium mediated syntheses of calothrixin B and murrayaquinone A are described. Regioselective palladium mediated intramolecular multiple C-X/C-H cross coupling reaction on N-(4-((2-bromophenyl)amino)-2,5-dimethoxybenzyl)-N-(2-iodophenyl)acetamide followed by CAN oxidation afforded calothrixin B in excellent yield in two steps. A linear synthesis has also been developed for calothrixin B. Utilizing C-H functionalization as well as palladium mediated intramolecular C-X/C-H cross coupling reaction, murrayaquinone A synthesis was achieved. Overall, these synthetic methodologies provide an expedient entry to these biologically active alkaloids in a short reaction sequence.

[structures: see text] Synthesis of both enantiomers of a highly functionalized cyclopentenol derivative, versatile building block for a vast array of biologically active compounds, is described. The key steps involve stereocontrolled synthesis of a diene with two syn-disposed substituents from a (R)-(+)-glyceraldehyde derivative, ring-closing metathesis of this diene, and functional group manipulation of the resulting trans-disubstituted cyclopentene. One of the enantiomers of the cyclopentenol thus obtained has been converted to an amino cyclopentene, the carbocyclic core of the nucleoside (-)-BCA, a potent inhibitor of HIV reverse transcriptase.

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