Nargenicins

Analogous deoxygenations were carried out with antibiotics such as nargenicin,[42] fortimicin,[43] seldomycin,[44 erythromycin,[45H47] with baccatin (taxol group),[48] the triquinane hirsuten,[49] the tuberculosis inhibitor a-C-mannobioside,[49a] and the steroids alisol,[50] and progesterone.[51]... 

The second example [Scheme 2.126] shows how a latent carboxyl function was released from the a-hydroxyoxazoline by /V-methylation to give an iminium salt that was then hydrolysed to an advanced intermediate in a synthesis of the macrolide antibiotic Nargenicin.257... 

Recently, workers at Abbott Laboratories reported the isolation and prelintinary characterization of a new nargenicin-type Z u-macrolide antibiotic, coloradocin, 8, from cultures of Actinoplanes coloradoensis. H The novel bislactonic structure proposed for 8 was based on a detailed spectroscopic examination which included extensive homo- and heteronuclear 2D NMR studies. 12 Although these investigations failed to unequivocally define the relative configuration of the macrocyclic chirality, the key structural elements of 8, including an oxa-bridged octalin... 

The activities of nargenicin Ai and Bi against S. aureus strains are conopaiable to that of ... 

Studies by the Upjohn group confirmed the potent activity of nargenicin Ai against multiple-drug resistant strains of S. aureus and demonstrated the in vivo activity of the antibiotic in mice (Table 3)7... 

Cane has demonstrated that advanced di-, tri- and tetraketide fatty acid precursors are incorporated directly into the nargeiucins, and has noted that an early intermediate in the nargenicin pathway is common to the biosynthetic scheme leading to erythromycin A and... 

As part of an effort to prepare compounds for correlation with advanced synthetic intermediates, Plata examined the stepwise degradation of the nargenicin C19-C14 macrolide subunit.21 Following the earlier work of Whaley,3 ester 20 was subjected to periodate oxidation and the remaining C9 and Cll hydroxyls protected as methoxymethyl ethers (Figure 9). 

Model Studies Synthesis of the Nargenicin Oxa-Bridged Octalin System. 

C8-C13 ether bridge spans two axial sites of the cis-fused octalin system, and molecular mechanics calculations predict a relatively strain-fiee tricyclic array. Based on these observations, our initial strategic considerations focused on approaches in which the nargenicin ether bridge would be established by intramolecular addition of C8 or C13 alcohols to complementary electrophilic sites at C13 or C8 (Figure 10). The diaxial orientation of the vicinal oxygens at C8 and C9 further suggested that intramolecular addition to a C8-C9 epoxide would serve as an efficient vehicle for tricycle construction with concurrent development of C9 stereochemistry. 

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