Methylenomycins

A few natural products with oxirane rings fused to five-membered rings are known. These include the antibiotic methylenomycin-A (82) (79H(13)353, 79JOC4210,80JA3904, 81CC714) and the truly remarkable fungal metabolite trichoviridine (83), which appears to be the first example of an isocyanide epoxide (76CPB832). 

An alternative strategy for (1) would have been to reconnect both substituents into a ring to ensure their ais arrangement. This strategy was used in syntheses of the antibiotic methylenomycin (4) and the trail pheromone of pharaoh s ant, faranal (5). 

Methylenomycin (4) contains three adjacent chiral centres but two are related as the epoxide. This... 

Epoxldation of (12) with a nucleophilic agent occurred only from the outside of the molecule and the necessary oxidation to (7) could be carried out with RuC and NalO. The remaining steps required new reactions based on selenium chemistry and gave methylenomycin in 12% overall yield from maleic anhydride. 

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. 

The only limitation noted in the synthesis of related methylenomycins is that only the adducts of (E)-enones undergo cyclization. 

Methoxatin, 29 a-Methyldopa, 250 Methylenomycin B, 177, 198 Methyl (Z)-jasmonate, 292 Mitomycins, 245 Muscone, 275... 

Cyclopentenones. Reaction of the Fittig bislactone 2 with methyllithium results in the substituted cyclopentenone 3 in moderate yield. This product on oxidative decarboxylation gives methylenomycin B (4).2... 

Mcthy lene-y-butyrolactones, 136 0-Methylene cyclic ethers, 270 6-Methylene-3-ketoA -steroids, 193 3-Methyleneoxolanes, 136 Methylenetriphenylphosphorane, 338-339 Methyl enol ethers, 273-274, 401 Methylenomycin B, 14, 162 14a-Methylestrone 3-methyl ester, 95 0-Methylhomoallyl alcohols, 143 Methylidenation, 182 Methyl jasmonate, 279, 301 Methylketcne methyl trimethylsilyl ketal, 340 Methyl lithiodithioacetate, 340 Methyl 5-lithiotetronates, 72, 73 Methyllithium-Tetramethylethylcnediamine,... 

The antibiotic methylenomycin 21 was synthesised via the key intermediate 22. Aldol disconnection reveals a diketo-ester with a 1,4-relationship and an obvious disconnection next to the branchpoint 23. The starting materials 24 and 25 are available. 

Scheme 4. Syntheses of dihydrojasmone and of a methylenomycin B precursor Reagents, a) BF3—Et20, CHC13, r.t., 15 min, 100% b) MeS03H—P205, Ether, r.t., 5 mn c) neat CH3S03H—P205, r.t.

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... 

Dehydration of the related ketone 3 with DCC and CuCl proceeds in low yield to give 4, originally believed to be methylenomycin B. ... 

Methylenetiiphenylphosphorane, 307 Methylenomycin A, 183 Methylenomycin B, 184 N-Mcthylephedrine, 308 N-Methyl-i//-ephedrine, 421 Methyl fluorosulfonale, 302, 307 (+)-(S)-4-Methyl-3-heptanone, 17 Methyl 3-hydroxybutyrate, 406 Methyl hydroxymethoxyacetate, 19, 20 Methyl hypobromite, 501 Methyl iodide, 308-309 5-Methylisoxazole, 309 3-Methyl-5(4/0-isoxazolone, 309 Methyl jasmonate, 92, 358 Methylketene methyl trimethylsilyl acetal, 310... 

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). ... 

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