Generation of novel pikromycin antibiotic products through mutasynthesis.

The pikromycin polyketide synthase (PKS) of S. venezuelae, which consists of one loading module and six extension modules, is responsible for the formation of the hexaketide narbonolide, a key intermediate in the biosynthesis of the antibiotic pikromycin. S.

The role of achiral pyrazolidinone templates in enantioselective Diels-Alder reactions: scope, limitations, and conformational insights.

We have evaluated the role of achiral pyrazolidinone templates in conjunction with chiral Lewis acids in room temperature, enantioselective Diels-Alder cycloadditions. The role of the fluxional N(1) substituent was examined, with the bulky 1-naphthylmethyl group providing enantioselectivities up to 99% ee, while templates with smaller fluxional groups gave lower selectivities. High selectivities were also observed in reactions of 7d with chiral Lewis acids derived from relatively small chiral ligands, suggesting the pyrazolidinone templates are capable of relaying stereochemical information from the ligand to the reaction center.

Total synthesis of narbonolide and biotransformation to pikromycin.

An improved total synthesis of narbonolide and its biotransformation to pikromycin is reported. This total synthesis utilized an intramolecular Nozaki-Hiyama-Kishi coupling that significantly improved macrocyclization yields (90-96%) and allowed for differentiation of the C3- and C5-oxidation states. A pikAI deletion mutant of Streptomyces venezuelae was used to biotransform synthetic narbonolide to pikromycin by glycosylation and oxidation in vivo.

Approaches to the synthesis of immunolides: selective immunomodulatory macrolides for cystic fibrosis.

The discovery of the clinical effectiveness of erythromycin and azithromycin in inflammatory airway diseases has inspired the discovery and development of macrolides with selective immunomodulatory activity. Erythromycin degradation continues to be a source of novel macrolides with a variety of selective biological activities. New technologies for drug discovery based in the emerging field of combinatorial biosynthesis provide the medicinal chemist with novel approaches toward the discovery of novel macrolides.

Formal total synthesis of the polyketide macrolactone narbonolide.

[reaction: see text] An improved synthesis of (3S)-3-dihydronarbonolide is reported that constitutes a formal total synthesis of the 14-membered macrolactone antibiotic narbonolide. The key step was an intramolecular Nozaki-Hiyama-Kishi coupling to accomplish macrocyclization in improved yield. The high level of convergence will also allow us to rapidly synthesize narbonolide analogues for the study of enzymes in the pikromycin biosynthetic pathway.

Chemoenzymatic synthesis of the polyketide macrolactone 10-deoxymethynolide.

The polyketide synthase-derived pikromycin thioesterase (Pik TE) is unique in its ability to catalyze the cyclization of 12- and 14-membered macrolactones. In this investigation, the total synthesis of the natural hexaketide chain elongation intermediate as its N-acetyl cysteamine (NAC) thioester has been achieved, and its reaction with Pik TE demonstrated the ability of Pik TE to catalyze its macrolactonization to the natural product 10-deoxymethynolide. A steady-state kinetic analysis of the hexaketide chain intermediate with Pik TE was done.

New Methods of Resolution and Enrichment of Enantiomeric Excesses of 1,1'-Bi-2-naphthol.

Partial resolution of racemic 1,1'-bi-2-naphthol (1) was readily achieved to obtain enriched (scalemic) 1 using (S)-proline (2). The structure of the complex 3 formed between 1 (2 equiv) and (S)-proline (1 equiv) was characterized by an X-ray diffraction method. Enantiomeric excesses of the incompletely resolved 1 were enriched to obtain essentially pure (R)- and (S)-1 following a simple procedure using B(OH)(3) and TMEDA.