The design and implementation of cascade reactions is a challenging facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to synthetic strategies. The application of cascade reactions to natural products synthesis represents a particularly demanding task, but the results can be both stunning and instructive. This Review highlights selected examples of cascade reactions in total synthesis, with particular emphasis on recent applications therein. The examples discussed herein illustrate the power of these processes in the construction of complex molecules and underscore their future potential in chemical synthesis.

Cascade reactions in total synthesis.

Natural products to drugs: natural product derived compounds in clinical trials

A gene which confers resistance to the herbicide bialaphos (bar) has been characterized. The bar gene was originally cloned from Streptomyces hygroscopicus, an organism which produces the tripeptide bialaphos as a secondary metabolite. Bialaphos contains phosphinothricin, an analogue of glutamate which is an inhibitor of glutamine synthetase. The bar gene product was purified and shown to be a modifying enzyme which acetylates phosphinothricin or demethylphosphinothricin but not bialaphos or glutamate. The bar gene was subcloned and its nucleotide sequence was determined. Interspecific transfer of this Streptomyces gene into Escherichia coli showed that it could be used as a selectable marker in other bacteria. In the accompanying paper, bar has been used to engineer herbicide-resistant plants.

Characterization of the herbicide-resistance gene bar from Streptomyces hygroscopicus.

Natural products: an evolving role in future drug discovery.

Factors affecting the isolation of CCC DNA from Streptomyces lividans and Escherichia coli

A linear plasmid-like DNA was isolated by Agarose gel electrophoresis from a lysate of Streptomyces sp. 7434-AN4 which produces lankacidin group antibiotics. The DNA (pSLA2) with a molecular weight of 11.2×106 was cleaved into five and three fragments, respectively, with XmaI and BamNI on the definite sites from the end, but not digested by EcoRI and HindIII. Upon treatment of the strain with ethidium bromide, variants were obtained which have lost the ability to produce the antibiotics. These variants were found to have lost pSLA2. These results suggest that the linear plasmid-like DNA is involved in the production of lankacidin group antibiotics.

A linear plasmid-like dna in streptomyces sp. producing lankacidin group antibiotics

A new antibiotic capuramycin was isolated from the culture filtrate of Streptomyces griseus 446-S3 by adsorption and partition column chromatography. Based on its chemical structure being an uracil nucleoside with a caprolactam substituent, this substance was named as capuramycin. This paper describes the taxonomy of a producing organism, fermentation, isolation, characterization and biological properties of capuramycin.

Capuramycin, a new nucleoside antibiotic. Taxonomy, fermentation, isolation and characterization.

Mycotrienins I and II have been isolated from the cultured broth of Streptomyces rishiriensis. Taxonomical studies of the producing organism, fermentation, isolation and characterization of the antibiotics are described.

Studies on mycotrienin antibiotics, a novel class of ansamycins. I. Taxonomy, fermentation, isolation and properties of mycotrienins I and II.

The structures of mycotrienins I and II have been determined mainly by their NMR spectral analysis. Mycotrienins are unique ansamycin antibiotics containing a 21-membered macrocyclic lactam ring and a cyclohexylcarbonyl moiety. The labeling experiments with sodium [1-13C]acetate and sodium [1-13C]propionate revealed that six acetate units and two propionate units were incorporated into the molecule of mycotrienin I.

Studies on mycotrienin antibiotics, a novel class of ansamycins. II. Structure elucidation and biosynthesis of mycotrienins I and II.

Sir: Stem rust caused by the infection of Puccinia graminis f. sp. tritici is known as one of the several limiting factors of wheat production. We have previously reported the isolation and structural elucidation of rustmicin active against this pathogen with the screening systems using an inhibition assay of spore germination in vitro and plant inoculation test in green housel1). During the course of further screening, a new antibiotic neorustmicin A (I) was found in the cultured broth of Micromonospora chalcea 1302AV2. This communication reports the isolation, structural elucidation and some biological activities of I. Fermentation was carried out at 27°C for 4 days in 500-m1 Erlenmeyer flasks each containing 100 ml of the same medium used for fermentation of rustmicin. The active substance was isolated from the mycelium. The mycelial cake was obtained by centrifugation of the whole broth (ca. 10 liters) and extracted with acetone (10 liters). The extract was evaporated in vacuo to give an aqueous solution which was extracted with three 1.5-liter portions of EtOAc. The combined organic layer was washed successively with 5% NaHCO3, 0.01 N HCl and H2O, dried over anhydrous Na2SO4 and concentrated in vacuo. The oily residue (850 mg) was chromatographed on a silica gel column developing with EtOAcbenzene (1: 3). The active fractions were combined and concentrated in vacuo to give a brownish oil (20 mg). Further purification of the oily material by preparative TLC (EtOAc benzene, 1 : 3, Rf 0.35) gave 5.3 mg of I as a yellowish oily material. Physico-chemical properties of neorustmicin A are as follows: UV AMeOHmax 212 (r 13,700) and 233 nm (11,000); IR vCHCl3max 3540, 1740 (sh) and 1720 cm-1; EI-MS ,n/z 364 (M+); [a]21D -83.1° (c 0.25, MeOH). The molecular formula of I was established to be C21H32O5 by high resolution mass spectral data (obsd 364.2288; calcd 364.2251). Its molecular formula is one less oxygen than that of rustmicin. In addition to the UV and IR spectra, 1H and13C NMR spectral data of I are very close to those of rustmicin (1H NMR data will be given below and 13C NMR data were shown in Table 1). Comparison of 1H and 13C NMR spectral data between rustmicin and I indicated that a methoxy signal at 31, 3.48 and o, 57.0 of rustmicin was lost and a methyl signal at o. 1.64 and o, 17.5 was newly observed in I. This finding suggested that the methoxy group at C-6 of rustmicin has been replaced by a methyl group at C-6 in I. At the same time, a quaternary carbon signal attached to the methyl group and the adjacent carbon signals in 13C NMR spectrum of I must Fig. 1. Structure of neorustmicin A (I).

Noboru Otake

Papers

A linear plasmid-like dna in streptomyces sp. producing lankacidin group antibiotics

Capuramycin, a new nucleoside antibiotic. Taxonomy, fermentation, isolation and characterization.

Studies on mycotrienin antibiotics, a novel class of ansamycins. I. Taxonomy, fermentation, isolation and properties of mycotrienins I and II.

Studies on mycotrienin antibiotics, a novel class of ansamycins. II. Structure elucidation and biosynthesis of mycotrienins I and II.

Neorustmicin A, a new macrolide antibiotic active against wheat stem rust fungus.