Methylenomycin B, synthesis

Methylenomycins.1 The cyclopentannelation reaction (12,310) has been modified to provide a general synthesis of methylenomycins. Thus, the adduct (2) of a-lithio-a-(methoxymethyl)allene (1) with 3-methyl-3-butene-2-one cyclizes to methylenomycin B (3) in the presence of trifluoroacetic anhydride and 2,6-lutidine. 

Moreto and coworkers have made improvements to the Chiusoli reaction, the Ni(CO)4-mediated carbonylation cyclization of allyl halides and alkynes, by conducting it in methanol403. It has subsequently been applied in the synthesis of methylenomycin B, in an intramolecular sense to provide bicyclo[3.3.0]octenones, and in intermolecular cases to form both fused bicyclic cyclopentenones and spirocyclopentenones (equations 203 and 204)403-405. 

Assereg, J.H., Glase, S.A., and Welch, S.C. 1987. 3-Chloro-2-[(diethoxyphosphoryl)oxy]-l-propene a new reagent for a one-pot cyclopentenone annelation. Synthesis of desoxyal-lethrolone, cw-jasmone, and methylenomycin B. Journal of Organic Chemistry, 52(8) 1440-50. 

In a synthesis of methylenomycin B (5), the methylthiomethylene group, the precursor of the cjco-methylene group, was introduced at an early stage by alkylation of a p-keto... 

A recent synthesis of methylenomycin-B (74), based on these observations, features an allylation/car-bonylation (69) - (70) followed by a C-1—C-2 bond/nickel acyl insertion (70) -> (71) and a final meth-oxycarbonylation (71) -> (72). Thus 2-butyn-l-ol (1,2-dialkylacetylenes are inert) afforded in one synthetic operation a 1 4 mixture (78%) of regioisomeric cyclopentenones (72) and (73) which was converted to the antibiotic (74) (Scheme 16). ... 

Mikolajczyk, M., and Balczewski, P., A new, total synthesis of methylenomycin B using organic sulfur and phosphorus reagents. Synthesis, 691, 1984. 

A recent synthesis of methylenomycin-B (74), based on these observations, features an allylation/car-bonylation (69) (70) followed by a C-1—C-2 bond/nickel acyl insertion (70) - (71) and a final meth-... 

Numerous synthetic applications of the inteimolecular Pauson-Khand reaction have been reported. Pauson has reported a number of very direct tqrplications of cycloadditions of ethylene in the synthesis of prostanoids and jasmone analogs (e.g. equations 15 and 16). - This is a reliable entry to 2-sub-stituted cyclopentenones. The suitability of cyclopentene and dihydrofuran as substrates has permitted the extension of this work to the preparation of still further varieties of prostaglandin analogs (e.g. equations 27 and 51). Simple 4,5-disubstituted 2-cyclopentenones are not as directly accessible, but may be prepared from the cycloaddition products of norbomadiene (equation 45). A sequence of conjugate addition followed by retro-Diels-Alder reaction affords the product (Scheme 5). Dihydrofuran cycloadditions have been used by Billington in the syntheses of the antibiotic methylenomycin B (Scheme 6), as well as cyclomethylenomycin A (synthetic precursor to the antibiotic methylenomycin A), cyclosarko-mycin (precursor to the antitumor agent sarkomycin) ° and the iridoid Jq>anese hop ether. ... 

Unsaturated acyl chlorides react with substituted alkynes to give mixtures of linear and cyclopentenyl products, the latter being formed in greater yield at higher temperatures (Scheme 22). ° This offers a convenient access to a variety of S-chlorocyclopentenones bearing substituents at the 4- and S-positions, with control over the location of the double bond. Application of this method includes a short synthesis of the antibiotic methylenomycin B (17 Scheme 23). ° ... 

Methylenomycin B (1) isolated from the culture broth of Streptomyces species in 1974, is a new antibiotic with inhibitory activity against Gram-positive and Gram-negative bacteria [11 -13]. Since the first total synthesis [14], which led to the revision of the original structure proposed by Haneishi et al. [11], methylenomycin B (1) has attracted considerable attention of many research groups as a synthetic target [15,16]. 

Continuing studies on the application of organic phosphorus and sulfur compounds for the synthesis of 1,4-dicarbonyl compounds and functionalized cyclopentenones, Mikolajczyk and Zatorski [17] developed a short and efficient synthesis of methylenomycin B starting from and y-ketophosphonates 2 and 3. These two reagents were revealed by retro synthetic analysis shown in Scheme 1. 

In the first synthetic key step, the -ketophosphonate 2 was alkylated with 1-bromo-2-methoxyprop-2-ene. Then, the product of monoalkylation was hydrolyzed under acidic conditions to the corresponding phosphorylated 1,4-diketone 4 that was cyclized to the precursor of methylenomycin B, the 5-phospho-rylcyclopentenone 5. The Horner-Wittig reaction of the latter with formaldehyde under very mild conditions completed the synthesis of 1 in 39% overall yield (Scheme 2). 

A conceptually different approach to the synthesis of methylenomycin B was developed by Mikolajczyk and Zurawinski [18]. In this case, the construction of the cyclopentenone ring was based on an intramolecular carbenoid cyclization. The four-step synthesis starts from diethyl methanephosphonate 7 which was... 

Motoyoshiya et al. in the course of their studies on the Nazarov reaction [19] found a convenient method for the synthesis of 1, whose substituted cyclopen-tenone ring with the exocyclic a-methylene group was constructed in one operation [20]. This synthesis began with the acylation of dimethyl methanephos-phonate 9 with tigloyl chloride to produce the unsaturated jS-ketophosphonate 10 which in the next step was reacted with aqueous formaldehyde to give the dienone 11. The Nazarov reaction of the latter provided methylenomycin B (1) in 12% overall yield (Scheme 5). 

Recently, Balczewski [21] reported a formal synthesis of methylenomycin B based on a new free-radical strategy for the synthesis of a-functionalized... 

Balczewski P,Mikolajczyk M (1998) Rev Heteroatom Chem 18 37 Haneishi T, Kitahara N, Takiguchi Y, Aral M, Sugawara S (1974) J Antibiot 24 386 Haneishi T, Terehara A, Aral M (1974) J Antibiot 24 398 Hornemann U, Hopwood DA (1978) Tetrahedron Lett 19 2977 Jernow J, Tautz W, Rosen P, Williams TH (1979) J Org Chem 44 4212 Mathew J (1993) Synthetic Approaches to Methylenomycin B and Analogs. In Lukas G (ed). Recent Progress in the Chemical Synthesis of Antibiotics and Related Microbiological Products. Springer, Berlin, Vol 2 435... 

Methylenomycin B (75) has been prepared by a route, which is notable for the simplicity of the classical methods used, whereas a synthesis of ( )-methylenomycin A (76) involves the application of more modern reagents. Total syntheses of the related ( )-xanthocidin (77), and of the unique isonitrile (78) have also been achieved. 

Example of the Khand reaction [53, 54]. An efficient synthesis of methylenomycin B from (2-butyne)-hexacarbonyldicobalt has been reported [54] the complex (X, R = R = CH3) reacts with allyloxy-TPH under milder conditions and with higher regioselectivity than with other olefinic substrates a cyclopentenone is obtained without contamination by any isomeric adduct. 

A total synthesis of methylenomycin B has appeared which involves a new synthesis of a five-membered ring whereby the anion (52) reacts with the acrylate (53) to produce the enone (54). A further novel three-carbon annula-... 

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