Antibiotics macrolactam

In the early 1990s, Smith and co-workers reported on the total synthesis of the antitumor antibiotic macrolactam (+)-hitachimycin 35 (Figure 12.1) using a Noyori three-component coupling to assemble the polysubstituted cyclopentane unit [24]. 

Rifampicin is a semisynthetic derivative of rifamicin B, a macrolactam antibiotic and one of more than five antibiotics from a mixture of rifamicins A, B, C, D, and E, which is called a rifamicin complex, which is produced by actinomycetes Streptomyces mediteranei (Nocardia mediteranei). It was introduced into medical practice in 1968. Synthesis of rifampicin begins with an aqueous solution of rifamicin, which under the reaction conditions is oxidized to a new derivative of rifamicin S (32.7.4), with the intermediate formation of... 

Macrolactamization has limitations. All macrolactamization methods studied to date are ineffective at forming 14-membered cycloisodityrosines of the type found in deoxy-bouvardin (2) and RA-VII (3).[1° In addition, macrolactamization was not successful at preparing 16-membered rings that are structurally similar to cycloisodityrosines, such as the type found in the vancomycin family of glycopeptide antibiotics.[11 12 ... 

Ogasawara Y, Katayama K, Minami A et al (2004) Cloning, sequencing, and functional analysis of the biosynthetic gene cluster of macrolactam antibiotic vicenistatin in Streptomyces halstedii. Chem Biol 11 79-86... 

In 1972 Ito and Flirata reported on the isolation and structure elucidation of (-i-)-ikarugamycin as the first representative of a new class of macrolactam antibiotics [5]. Besides its remarkable biological activity, ikarugamycin is of interest because of its unusual architeeture and it represents an attractive target strueture for organic synthesis [6, 7, 8]. 

A,A-Bis(2-oxo-3-oxazolidinyl)phosphorodiamidic chloride (BOP-Cl, 64) has been found to be an efficient macrolactamization reagent [69]. Tatsuta and coworkers [69c] used it in the synthesis of the ansamycin antibiotic rifamycin W 123). As shown in Scheme 41, amino acid 121 was cyclized to 122 using 4 equiv of BOP-Cl and 10 equiv of diisopropylethylamine in toluene at 85 °C for 3 h. Upon deprotection and oxidation 123 was obtained in 30% yield from 121. 

Kurokawa and Ohfune [71] employ i DPPA in the synthesis of the hexapeptide echinocandin D 125). As shown in Scheme 42, the cyclization of the Unear peptide 124 was accomplished by DPPA to give 125 in 50% yield. There are more applications of DPPA in the synthesis of macrocycUc natural products [72]. DEPC is relatively less commonly used than DPPA. Kishi and coworkers [73] have successfully achieved the synthesis of the macrocyclic antibiotic rifamycin S using DEPC as a macrolactamization promoter. 

Durette et al. [74] have achieved the total synthesis of the hexadepsipeptide antibiotic L-156,602 128) using the mixed phosphonic anhydride method as key macrolactamization step. As shown in Scheme 43, treatment of the linear depsipeptide 126 with n-propylphosphonic anhydride and DMAP in dichloro-methane at high dilution afforded the macrocycle 127 in more than 57% yield. 

Cyclization via intramolecular olefination of complex phosphonates remains the most important method of synthesis for complex natural macrocycles. Examples include syntheses of 20-membered macrolide antibiotic, aglycones of venturicidins A and B,108 oleandomycin (a 14-membered macrolide antibiotic), 109 the 19-membered macrocyclic antibiotic, anti-tumour agent (-t-)-hitachimycin,ll0 and the macrocyclic lactones (183).1H Cyclization of the phosphonate (184) under Masamune-Roush conditions has been used to synthesize the 28-membered macrolactam myxovirescin B.112... 

Macrocyclic motifs are usually essential for the unique biological properties of natural products. In most cases, linear NRP and PK scaffolds are cyclized to form macrolactones or macrolactams prior to further post-modification. Macrocyclization is usually carried out by cyclases towards the end of elongation. For example, in the biosynthesis of the antibiotic tyrocidine A, a linear enzyme-bound decapeptide is cyclized via an intramolecular SN2 reaction between the N-terminal amine nucleophile and the C-terminal thioester, which is covalently linked to the synthase [reactions (a) and (b), Scheme 8.3] [22], This cyclase shows great versatility. Not only does it catalyze the formation of macrolactams of ring sizes from 18 to 42 atoms from... 

The biosynthesis of the macrolactam polyketide glycoside anti-tumour antibiotic vicenistatin L (1), including its vicenisamine moiety, has been studied using heavy atom-labelled precursors. The bicyclic branched-chain diaminohep-turonic acid derivative 2, a tyrosyl tRNA synthetase inhibitor of unknown absolute stereochemistry, has been isolated from a Microsmonospora species fermentation medium. ... 

New 14-membered macrolactam antifungal antibiotics isolated from the broth of a new species of Actinomadura contain either mycosamine or its 4-epimer, 3-amino-3,6-dideoxy-L-talopyranose, attached to the macrolide ring. " ... 

In a total synthesis of the macrolactam herbimycin A, the known mannose-derived epoxide (53) (Vol. 22, p. 150) was converted to (54), and hence to the ansa-chain unit (55). The epoxide ring in (53) was opened regioselectively using disiamyl borane/NaBH4. In a route to glidobamine (56), the core structure of the antibiotic glidobactin, the chirality of the allylic... 

Trienomycin A (64) and the related geldanamycin (65) are ansamycin antibiotics containing metacyclophane-macrolactams. With an eye toward preparation of structurally simpler analogs, Peng and Blagg synthesized trienes 61a and 61b and studied their RCM reactivities (Scheme 9.15) [20]. Upon being exposed to [Ru]-I,... 

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