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Inactivation of ptmB1, ptmB2, ptmT2, or ptmC in Streptomyces platensis SB12029, a platensimycin (PTM) and platencin (PTN) overproducer, revealed that PTM and PTN biosynthesis features two distinct moieties that are individually constructed and convergently coupled to afford PTM and PTN. A focused library of PTM and PTN analogues was generated by mutasynthesis in the ΔptmB1 mutant S. platensis SB12032. Of the 34 aryl variants tested, 18 were incorporated with high titers., Competing Interests: The authors declare no competing financial interest.

A protection strategy is described for the efficient synthesis of peptide o-aminoanilides using in situ neutralization protocols for Boc-SPPS. On-resin protection of Boc-protected aminoacyl o-aminoanilides is achieved with 2-chlorobenzyl chloroformate. Activation through a peptidyl-benzotriazole intermediate allows for facile conversion to peptide-thioesters for use in native chemical ligation. In addition to providing a robust alternative to established thioester resins, as a latent thioester, the peptide o-aminoanilide has broad utility in convergent ligation strategies.

A mild and efficient bifunctional Lewis acid induced cascade cyclization reaction has been developed for construction of the tricyclic core of ent-kaurenoids. With ZnBr(2) as the bifunctional Lewis acid, a series of substituted enones and dienes underwent cascade cyclization smoothly at room temperature and provided the tricyclic products in one pot with good yields (75-91%) and high diastereoselectivity. The cyclized product has been successfully employed for the formal synthesis of (±)-platensimycin.

A stereocontrolled approach to a key platensimycin intermediate was achieved from a commercially available furylcarboxylate. Key to our approach is the highly efficient formal [4 + 3] cyclocondensation of a substituted furan with tetrabromocyclopropene along with an intramolecular γ-alkylation to construct the final ring of the caged intermediate.

The synthesis of 13, an advanced intermediate in the Nicolaou synthesis of platensimycin 1, was made from 9 by autoxidation to give 10, which was stereoselectively reduced providing 12. Finally, dehydration of 12 by heating in DMSO resulted in 13.

A highly diastereoselective synthesis of trans-2-substituted cyclopentylamines via a tandem hydrozirconation/Lewis acid-mediated cyclization sequence applied to butenyl oxazolidines is described. The method allows an easy preparation of diversely substituted cyclopentylamines which appear to be useful synthetic intermediates. This was further illustrated by the syntheses of (±)-Rodocaine, (±)-trans-pentacin, and enantiomerically enriched trans-cyclopentane-1,2-diamine.

The caged structure of platensimycin, known as Nicolaou's key intermediate for total synthesis of platensimycin, was synthesized stereoselectively by using the following key steps: (i) diastereoselective Diels-Alder reaction between gamma-benzoyloxy enone and tert-butyldimethylsiloxydiene, (ii) formation of a dihydropyran ring by intramolecular catalytic oxypalladation, and (iii) transannular radical cyclization of monothioacetal with tributyltin hydride and AIBN.

A close structural relative of platensimycin was synthesized efficiently in nine steps.

An efficient enantiocontrolled synthetic pathway to platensimycin has been developed.

An enantioselective route to the oxatetracyclic core of (-)-platensimycin (1) has been investigated by using an intramolecular Diels-Alder reaction as the key step. The thermal reaction of E/Z mixture (1:1) provided oxatetracyclic core 2 from the E-diene and the Z-diene was recovered unchanged. The Diels-Alder substrate was conveniently assembled in optically active form with use of (S)-carvone as the starting material.

An enantioselective route for the synthesis of oxatetracyclic core of platensimycin is reported for the first time using a 5-exo-trig cyclization followed by intramolecular etherification as key reactions. The requisite dienynone for the radical cyclization is synthesized in eight steps from the Wieland-Miescher ketone employing a Claisen rearrangement.

[reaction: see text] Reductive alkylation of 5-methoxy-1-tetralone (6) with 2,3-dibromopropene gave an equilibrium mixture of bicyclic diones 7 (51%) and 8 (35%). Radical cyclization of 7 afforded tricyclic dione 5 (84%), which was reduced, cyclized, and dehydrated to give tetracyclic alkene 13 in 63% yield. Allylic oxidation of 13 with SeO2 and activated MnO2 afforded enone 2 in 85% yield, thereby completing a short formal synthesis of (+/-)-platensimycin.

[reaction: see text] Peptide p-nitroanilides are useful compounds for studying protease activity; however, the poor nucleophilicity of p-nitroaniline makes their preparation difficult. We describe a new efficient approach for the Fmoc-based synthesis of peptide p-nitroanilides using an aryl hydrazine resin. Mild oxidation of the peptide hydrazide resin yields a highly reactive acyl diazene that efficiently reacts with weak nucleophiles. We have prepared several peptide p-nitroanilides, including substrates for the Lethal Factor protease from B. anthracis.