Vermiculin antibiotics

The potential of the reverse polarity approach has been spectacularly demonstrated in a plethora of synthetic studies. A representative example can be found in Seebach s preparation of the antibiotic vermiculin. The key step of this synthesis involved the preparation of a polyfunctional intermediate 253 via the sequence shown in Scheme 2.102. The first stage of this sequence couples the formyl anion equivalent 244 with bromoepoxide 254. The primary bromide is more active as an electrophile than epoxide and therefore, under carefully controlled conditions, the product 255 is formed selectively. Under somewhat more stringent conditions the epoxide ring present in the latter adduct reacts as an electrophile with the second acyl anion equivalent 256 to yield adduct 257. In this sequence, 254 was used as an equivalent to the 1,4-doubly charged synthon CH2CH2CH(OH)CH. In the final step of this scheme, carbanion 258 was generated and reacted with dimethylformamide to produce the required product 253. It is remarkable that all of these sequential operations are carried out in one reaction vessel without the isolation of any intermediate products. The overall yield of 253 is rather high (approximately 52%). 

In this last case there are no problems with the choice of the reductant, but where the substrate bears groups themselves liable to reduction then catalytic hydrogenation can sometimes be used. This has been adopted by Kametani et al. in the formation of the P-lactams (132), related to thienamycin, from isoxa-zoline-4-carboxylic esters (131 Scheme 4). DIBAL has also been employed as reductant, and this reagent was selected by Burn et al. in their synthesis of the antibiotic vermiculine (134) from the 2-methyl-2-isoxazoline (133 Scheme 5). ... 

An instructive example of using a dithiane Umpolung approach to synthesize a complex natural product is the one-pot preparation of the multifunctional intermediate shown below, which ultimately was elaborated to the antibiotic vermiculin. ... 

The condensation of (130) with the aldehyde (131) has been used in the synthesis of the antibiotic vermiculine, to give a diene ester with the desired /rara-configura-tion. ... 

This method of lactonization has been used successfully in a total synthesis of the antibiotic ( )-vermiculine (6). ... 

Diethyl azodicarboxylate (Et02C-N=N-C02Et, DEAD) is a key reagent in the Mitsunobu reaction (sec. 2.7.A.ii) and has also been used for macrolactonization. Reaction of 230 with DEAD gave 15% of 231 in White s synthesis of the antibiotic vermiculine. ... 

Fuska J, Ivanitskaya LP, Makukho LV, Volkova L (1974) Effect of the Antibiotics Vermiculin, PSX-1, Eikaverin, and Duclauxin isolated from Fungi on Synthesis of Nucleic Acids in Cells of Some Tumors. Antibiotiki 19 890... 

Examples of the use of these chiral building blocks in the synthesis of drugs and natural products abound in the literature. They include the synthesis of grahamimycin the macrocyclic component of the antibiotic elaiophylin, fungicides norpyrenophorin, pyrenophorin and vermiculin, phorcantholide I and J, which are defensive secretions of the eucarypt longicorn beetle,citronellol and a pheromone of the western corn rootworm. Clearly the monomeric chiral derivatives of PHB have a role to play in enantiomer-specific synthesis. 

The covalent-template approach has been used to carry out intramolecular esterification of co-hydroxy carboxylic acids in the presence of catalytic amounts of stannoxanes to form monomacrolactones, including natural macrolide antibiotics such as nodusmicin, pyrenophorin, vermiculine and ingramycin. The course of the synthetic reaction is shown in Scheme 7-4 [21-23]. 

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