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Total synthesis of leopolic acid A, a natural 2,3-pyrrolidinedione with antimicrobial activity

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ABSTRACT

The first total synthesis of leopolic acid A, a fungal metabolite with a rare 2,3-pyrrolidinedione nucleus linked to an ureido dipeptide, was designed and carried out. Crucial steps for the strategy include a Dieckmann cyclization to obtain the 2,3-pyrrolidinedione ring and a Wittig olefination to install the polymethylene chain. An oxazolidinone-containing leopolic acid A analogue was also synthesized. The antibacterial activity showed by both compounds suggests that they could be considered as promising candidates for future developments.

No MeSH data available.


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Synthesis of leopolic acid A. Reagents and conditions: a) p-methoxybenzylamine, EtOH, rt, 12 h, 98%; b) diethyl oxalate, NaOEt, EtOH, reflux, 3 h, 83%; c) BnBr, K2CO3, DMF, 0 °C to rt, 1 h, 50%; d) DIBAL-H, CH2Cl2, −78 °C, 2 h, 56%; e) PPh3, CBr4, CH2Cl2, rt, 5 h, 52%; f) PPh3, toluene, reflux, 5 h, 75%; g) n-nonanal, LiHMDS, THF, −78 °C to rt, 5 h, 52%; h) CAN, CH3CN:H2O, 0 °C to rt, 3 h, 73%; i) 2-tert-butoxycarbonylamino-3-methylbutyric acid pentafluorophenyl ester, n-BuLi, THF, −78 °C, 0.5 h, 71%; j) DIBAL-H, CH2Cl2, −78 °C, 2 h, 30%; k) PCC, CH2Cl2, 0 °C to rt, 12 h, 46%; l) n-nonyltriphenylphosphonium bromide, n-BuLi, THF, −78 °C to 0 °C, 2 h; m) TFA, CH2Cl2, 0 °C to rt, 1 h; n) L-phenylalanine benzyl ester DIEA, triphosgene, CH2Cl2, rt, 1 h, 60% over three steps; o) H2, Pd/C, EtOAc, rt, 2 h, 77%.
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C1: Synthesis of leopolic acid A. Reagents and conditions: a) p-methoxybenzylamine, EtOH, rt, 12 h, 98%; b) diethyl oxalate, NaOEt, EtOH, reflux, 3 h, 83%; c) BnBr, K2CO3, DMF, 0 °C to rt, 1 h, 50%; d) DIBAL-H, CH2Cl2, −78 °C, 2 h, 56%; e) PPh3, CBr4, CH2Cl2, rt, 5 h, 52%; f) PPh3, toluene, reflux, 5 h, 75%; g) n-nonanal, LiHMDS, THF, −78 °C to rt, 5 h, 52%; h) CAN, CH3CN:H2O, 0 °C to rt, 3 h, 73%; i) 2-tert-butoxycarbonylamino-3-methylbutyric acid pentafluorophenyl ester, n-BuLi, THF, −78 °C, 0.5 h, 71%; j) DIBAL-H, CH2Cl2, −78 °C, 2 h, 30%; k) PCC, CH2Cl2, 0 °C to rt, 12 h, 46%; l) n-nonyltriphenylphosphonium bromide, n-BuLi, THF, −78 °C to 0 °C, 2 h; m) TFA, CH2Cl2, 0 °C to rt, 1 h; n) L-phenylalanine benzyl ester DIEA, triphosgene, CH2Cl2, rt, 1 h, 60% over three steps; o) H2, Pd/C, EtOAc, rt, 2 h, 77%.

Mentions: A straightforward route to the intriguing 2,3-pyrrolidinedione system appeared to be the Michael addition of a suitable amine to ethyl acrylate, followed by a Dieckmann cyclization with diethyl oxalate [10–11]. We chose the p-methoxybenzyl (PMB) protecting group for the amine, because of its facile cleavage with cerium ammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). Thus, 2,3-pyrrolidinedione 3 was obtained by the reaction of ethyl acrylate with p-methoxybenzylamine, followed by treatment with diethyl oxalate (Scheme 1) [12]. On the basis of NMR data, the compound exists as an enol tautomer (see Supporting Information File 1). Indeed, perusal of the literature indicated that apparently all 4-monosubstituted 2,3-pyrrolidinediones are highly enolized [13–15]. Protection of the enolic OH with a benzyl group, using BnBr and K2CO3, gave compound 4. The reduction of 4 with DIBAL-H gave the corresponding primary alcohol, which was converted into bromide 5 by Appel reaction with PPh3 and CBr4. The phosphonium salt obtained from this bromide was subjected to a Wittig reaction with nonanal, to afford compound 6 [12].


Total synthesis of leopolic acid A, a natural 2,3-pyrrolidinedione with antimicrobial activity
Synthesis of leopolic acid A. Reagents and conditions: a) p-methoxybenzylamine, EtOH, rt, 12 h, 98%; b) diethyl oxalate, NaOEt, EtOH, reflux, 3 h, 83%; c) BnBr, K2CO3, DMF, 0 °C to rt, 1 h, 50%; d) DIBAL-H, CH2Cl2, −78 °C, 2 h, 56%; e) PPh3, CBr4, CH2Cl2, rt, 5 h, 52%; f) PPh3, toluene, reflux, 5 h, 75%; g) n-nonanal, LiHMDS, THF, −78 °C to rt, 5 h, 52%; h) CAN, CH3CN:H2O, 0 °C to rt, 3 h, 73%; i) 2-tert-butoxycarbonylamino-3-methylbutyric acid pentafluorophenyl ester, n-BuLi, THF, −78 °C, 0.5 h, 71%; j) DIBAL-H, CH2Cl2, −78 °C, 2 h, 30%; k) PCC, CH2Cl2, 0 °C to rt, 12 h, 46%; l) n-nonyltriphenylphosphonium bromide, n-BuLi, THF, −78 °C to 0 °C, 2 h; m) TFA, CH2Cl2, 0 °C to rt, 1 h; n) L-phenylalanine benzyl ester DIEA, triphosgene, CH2Cl2, rt, 1 h, 60% over three steps; o) H2, Pd/C, EtOAc, rt, 2 h, 77%.
© Copyright Policy - Beilstein
Related In: Results  -  Collection

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C1: Synthesis of leopolic acid A. Reagents and conditions: a) p-methoxybenzylamine, EtOH, rt, 12 h, 98%; b) diethyl oxalate, NaOEt, EtOH, reflux, 3 h, 83%; c) BnBr, K2CO3, DMF, 0 °C to rt, 1 h, 50%; d) DIBAL-H, CH2Cl2, −78 °C, 2 h, 56%; e) PPh3, CBr4, CH2Cl2, rt, 5 h, 52%; f) PPh3, toluene, reflux, 5 h, 75%; g) n-nonanal, LiHMDS, THF, −78 °C to rt, 5 h, 52%; h) CAN, CH3CN:H2O, 0 °C to rt, 3 h, 73%; i) 2-tert-butoxycarbonylamino-3-methylbutyric acid pentafluorophenyl ester, n-BuLi, THF, −78 °C, 0.5 h, 71%; j) DIBAL-H, CH2Cl2, −78 °C, 2 h, 30%; k) PCC, CH2Cl2, 0 °C to rt, 12 h, 46%; l) n-nonyltriphenylphosphonium bromide, n-BuLi, THF, −78 °C to 0 °C, 2 h; m) TFA, CH2Cl2, 0 °C to rt, 1 h; n) L-phenylalanine benzyl ester DIEA, triphosgene, CH2Cl2, rt, 1 h, 60% over three steps; o) H2, Pd/C, EtOAc, rt, 2 h, 77%.
Mentions: A straightforward route to the intriguing 2,3-pyrrolidinedione system appeared to be the Michael addition of a suitable amine to ethyl acrylate, followed by a Dieckmann cyclization with diethyl oxalate [10–11]. We chose the p-methoxybenzyl (PMB) protecting group for the amine, because of its facile cleavage with cerium ammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). Thus, 2,3-pyrrolidinedione 3 was obtained by the reaction of ethyl acrylate with p-methoxybenzylamine, followed by treatment with diethyl oxalate (Scheme 1) [12]. On the basis of NMR data, the compound exists as an enol tautomer (see Supporting Information File 1). Indeed, perusal of the literature indicated that apparently all 4-monosubstituted 2,3-pyrrolidinediones are highly enolized [13–15]. Protection of the enolic OH with a benzyl group, using BnBr and K2CO3, gave compound 4. The reduction of 4 with DIBAL-H gave the corresponding primary alcohol, which was converted into bromide 5 by Appel reaction with PPh3 and CBr4. The phosphonium salt obtained from this bromide was subjected to a Wittig reaction with nonanal, to afford compound 6 [12].

View Article: PubMed Central - HTML - PubMed

ABSTRACT

The first total synthesis of leopolic acid A, a fungal metabolite with a rare 2,3-pyrrolidinedione nucleus linked to an ureido dipeptide, was designed and carried out. Crucial steps for the strategy include a Dieckmann cyclization to obtain the 2,3-pyrrolidinedione ring and a Wittig olefination to install the polymethylene chain. An oxazolidinone-containing leopolic acid A analogue was also synthesized. The antibacterial activity showed by both compounds suggests that they could be considered as promising candidates for future developments.

No MeSH data available.


Related in: MedlinePlus