Milbemycins structure

The avermectins are closely related to another group of pesticidal natural products, the milbemycins. First described by Japanese workers, milbemycins were later found to be more abundant in nature than the avermectins (7—12). Both the avermectins and milbemycins are sixteen-membered lactones, with a spiroketal system containing two six-membered rings. The principal difference between them is that the avermectins have an a-L-oleandrosyl-a-L-oleandrosyl disaccharide attached at the 13-position whereas the milbemycins have no 13-substituent. Milbemycin structures are shown in Figure 2. 

Structure Determination. The structures of a new group of pesticidal sixteen-membered lactones named milbemycin B, B2, and B were described in 1975 (4) on the basis of X-ray analysis. A later publication (5) gave details of isolation and structures of thirteen milbemycins, with spectral data. 

For structural details of more recently isolated milbemycins see G. H. Baker, S. E. Blanchflower, R. J. Dorgan, J. R. Everett, B. R. Manger,... 

The milbemycins are a family of 16 membered lactones produced by Streptomyces hygroscopicus. The structures are character zed By a b.b spiroketal unit, a side chain with eight carbon atoms, and a complex cyclohexene carboxylic acid. A synthetic route for the spiroketal and connecting chain, and an approach to a southern portion analog via Diels Alder Chemistry are described. 

The naturally occuring avermectins are a family of eight, pentacyclic structures containing a sixteen-membered macrolide ring which are produced by Streptomyces avermitilis (Fig. 6) [60]. These eight compounds differ in structure due to the variability of PKS starter unit at C-25, the 0-methylation pattern at C-5, and the hydration-dehydration pattern at C-22/C-23. Other closely related natural products include the milbemycins and the nemadectins. The avermectins exhibit potent broad spectrum antiparasitic activity, and the semi-synthetic Ivermectin 29 (hydrogenated avermectin Bl) displays even greater efficacy [60,61]. 

These are a family of novel macrolide antibiotics with high order of insecticidal and ascaricidal properties. The miibemycins are structurally related to the aver-mectins except for the fact that they have no substitution at position 13 and, therefore, may be called 13-deoxyavermectin aglycones. Originally nine miibemycins were isolated from the broth of Streptomyces hygroscopicus, subsp. aureolacrimosus [24,25]. Various other milbemycin derivatives were produced by fermentation of different strains of Streptomyces such as strain MA-5920 (prepared by fusion of S. aver-mitilis protoplast with S. hygroscopicus protoplast) [26], E-225 [27] and S. eurythermus [28]. The structure of the miibemycins is represented by the general formula 14 the important members of this class are milbemycin-D (15) and nemadectin (16) [29,30]. 

Like avermectins, the milbemycins have also undergone extensive molecular modifications. A number of synthetic milbemycins have been found to possess a wide-spectrum of parasiticidal and insecticidal activities [67-83]. The structure-achv-ity analysis would indicate that the milbemycins having different functional groups at positions 13,14 and 5 generally retain biological activity. The important milbemy-cin derivatives thus prepared include 13-substituted milbemycins of the type 31 [64,73-75] and 32 [76-78], 14-substituted milbemycins (33) [79], 5-keto/oximinomilbe-mycins (34) [81,82], 35 [80] and 36 [83]. 

A few semi-synthetic analogues of nemadectin (16) have also been prepared [84]. In general, most of the structural modifications yielded milbemycin derivatives... 

Milbemycin P3 (383) is a 16-membered macrocyclic lactone isolated from the fermentation broth of Streptomyces B-41-146 and is the simplest member of a family of compounds structurally related to the avermectins. Milbemycin P3 has been demonstrated to have marked insecticidal as well as limited antibiotic activity. Structurally, 383 is a 16-membered lactone fused to an aromatic ting. Although nearly devoid of asymmetric centers on the cyclic framework, it does contain the rather unusual spiroketal moiety. 

Interestingly, the latter was subsequently also obtained from a milbemycin fermentation and given the name milbemycin B41-D (see Fig. 2 for structure... 

Increasing resistance towards anthelmintics has also become evident with various parasites. The need for a more ecologically rational pest management strategy has refocused attention on natural products. The discovery in 1979 of the potent anthelmintic and insecticidal activity of the aver-mectins and milbemycins (eg 1, 2), structurally related 16-membered macrocycles from Streptomyces species [4], has stimulated a search for other new and specific naturally occurring anthelmintics. 

Ivermectin is the catalytic reduction product of avermectin, a macroHde containing a spiroketal ring system. Two other related antibiotics having significantly different structural features and biological properties, moxidectin and milbemycin oxime, were more recently introduced into the market. Although these compounds have no antimicrobial activity, they are sometimes referred to as antibiotics because they are derived from fermentation products and have very selective toxicities. They have potent activity against worms or helminths and certain ectoparasites such as mites and ticks. 

Other Endectocides The structures of the avermectins and the milbemycins were interrelated by the conversion of 22,23-dihydroavermectin Bji, (9) to milbemycin B-41D (1 ).23 Compound 10, the first of the C-25 isopropyl-bearing milbemycins is more potent as an anthelmintic than mixtures of milbemycins 02 and 4. 24 Review articles describing the producing organism, 25 structure determination 26 and biosynthesis2T of the milbemycins are available as is a brief account of all three aspects. ... 

The avermectins, which possess potent anthelmintic and insecticidal activities, have structural features similar to the milbemycins. The C-15 to C-28 spiroketal-containing unit (690) of avermectin Bia aglycone (691) is s)mthesized in optically pure form by coupling L-malic acid-derived lactone 687 with D-glucose-derived acetylene 688. Partial reduction of the... 

Cover picture The molecule depicted on the cover is (+)-milbemycin pa along with its electrostatic isopotential surface. Milbemycin was chosen because the spiroketal portion of the structure was synthesized from both malic and tartaric acids. 

On account of their interesting structure and the analogies to the spiroketal partial structures of, e.g., the milbemycins and avermectins, T. have been the target of numerous enantioselective syntheses. 

The whole family of macrocyclic lactones, consisting of the closely related aver-mectins and milbemycins, displays unprecedented potency against mites, insects, and nematodes. LC90 values in greenhouse trials are often in the range 0.1-0.01 ppm, in some cases even lower. The structure-activity relationships of this chemical class have been the subject of many publications. The present section discusses selected key findings. 

First structure-activity relationships relating to crop protection targets were reported by Fisher in 1984 [47]. This study showed that avermectin Bia was somewhat more active then mUbemydn D against Tetranychus urticae, Hdiothis virescens, and Mdoidogyne incognita. As milbemycin D can be viewed as the 22,23-dihydro-13-desoxy derivative of avermectin Bib, this comparison reflects the influence of the disaccharide portion of avermectins on their activity as pesticides. 

M. H. Fisher, Structure-Activity Relationships of the Avermectins and Milbemycins, ACS Symposium Series No 658, American Chemical Society, Washington DC, pp. 221-238, 1997. 

The avermectins and the related milbemycins, because of their important biological activity and interesting complex structures, have led to an enormous effort in synthetic chemistry, both total syntheses and synthetic manipulation of the natural products used as starting materials. Some of these studies have been reported in recent reviews [1, 2]. 

The structure of a recently isolated 22,23-dioxygenated milbemycin was determined by NMR studies to contain the 22a,23P-stereochemistry and it is suggested that the 22,23-trans-diaxial configuration advanced for milbemycins OL to ag may need correction [52]. 

The spiroketal moiety is a common structural unit in a variety of biologically active products such as milbemycins (insecticides) [55], avermectins (anthelmintic activity) [56], and phyllanthosides (antileukemic) [57]. Iwata has described the... 

Figure 1 Scanning electron micrograph of a novel Strepto-myces species from which compound (I) and many other related milbemycins have been isolated. (See Baker GH, Dorgan RJJ, Everett JR, Hood JD, and Poulton ME (1990) A novel series of milbemycin antibiotics from Streptomyces strain E225. II. Isolation, characterisation, structure elucidation and solution conformations. Journal of Antibiotics 43 1069-1076.)...

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