Synthesis of racemic, 2-(alkylthio)-6-(1-hydroxyethyl) penems; attempted penem synthesis copper (I) - promoted cyclisations

McCombie, Stuart W.; Ganguly, Ashit K.; Girijavallabhan, Viyyoor; Jeffrey, P.D.; Lin, Sheng H.; Pinto, Pedro; McPhail, Andrew T.

doi:10.1016/s0040-4039(01)81939-0

“…For instance, incompatibility between sulfur-containing substrates and a necessary catalyst or promoter (e.g., Rh) beset the metallo–carbenoid insertion approach . Difficulties in the construction and handling of starting materials for a key transformation complicated the vinyl halide cross-coupling and intramolecular imine formation strategies. Finally, other routes reached a proof-of-concept phase in the laboratory, but were either too lengthy (e.g., thiolactonization and enolate addition to thiocarbonate approaches) or technically challenging/costly for commercial-scale application (azomethine ylide and Eschenmoser sulfide contraction routes).…”

Section: Resultsmentioning

confidence: 99%

Development of a Practical and Convergent Process for the Preparation of Sulopenem

Brenek

¹

,

Caron

²

,

Chisowa

³

et al. 2012

Org. Process Res. Dev.

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Previous synthetic processes for the preparation of sulopenem involved multistep linear sequences in which the chiral sulfoxide side chain was introduced early in the process. This contribution summarizes the development of a practical and convergent process for the large-scale preparation of 1. The key step in the synthesis involves cyclization of an oxalimide intermediate to provide the thiopenem core. This convergent strategy allows for late introduction of the expensive and labile chiral sulfoxide subunit. Additionally, a regioselective sulfur oxidation and an improved deprotection sequence were developed. The latter provides API of high purity without the need for recrystallization.

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“…Nucleophilic displacement of the acetate function of the acetoxy-azetidinone ( The naturally occurring carbapenems provided the impetus for the synthesis of the four racemates of 6-(1-hydroxyethyl)-2-ethylthiopenem-3-carboxylate (91). As seen in Figure 3, conversion of (3, R = OCOCH 3 ) to the N-protected azetidinone followed by aldol type addition gave a mixture of alcohols.…”

Section: Extension Of the Phosphorane Routementioning

confidence: 99%

Carbapenems and Penems

Southgate

¹

,

Osborne

²

2000

Kirk-Othmer Encyclopedia of Chemical Technology

2

0

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In the period up to 1970 most β‐lactam research was concerned with the penicillin and cephalosporin group of antibiotics. Since that time, however, a wide variety of new mono‐ and bicyclic β‐lactam structures have been described. The carbapenems originated from natural sources; the penem ring and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are: 7‐oxo‐( R )‐1‐azabicyclo[3.2.0]hept‐2‐ene‐2‐carboxylic acid, C 7 H 7 NO 3 , and 7‐oxo‐( R )‐4‐thia‐1‐azabicyclo[3.2.0]hept‐2‐ene‐2‐carboxylic acid, C 6 H 5 NO 3 S, respectively. Carbapenems include thienamycin (C 11 H 16 N 2 O 4 S), MM 4550 (C 13 H 16 N 2 O 9 S 2 ), MM 13902 (C 13 H 16 N 2 O 8 S 2 ), MM 17880 (C 13 H 18 N 2 O 2 S 2 ), PS‐5 (C 13 H 18 N 2 O 4 S), carpetimycin A (C 14 H 18 N 2 O 6 S), asparenomycin A (C 14 H 16 N 2 O 6 S), and pluracidomycin A (C 9 H 11 NO 10 S 2 ). Only S. cattleya and S. penemfaciens have been reported to give thienamycin. Thienamycin is isolated as a colorless, hygroscopic, zwitterionic solid. Carbapenems are extremely sensitive to many reaction conditions. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin have been prepared primarily to study structure–activity relationships. One consequence of the discovery of the carbapenem natural products has been the development of new synthetic methods. Only chemical synthesis could provide the quantities of N ‐formimidoyl thienamycin (MK 0787) necessary for clinical trials and commercial production. A synthetic approach that involves the [3,4] bond formation using a carbene insertion reaction has been highly successful. A second method makes use of the lactone from acetone dicarboxylate. Thienamycin, the olivanic acids, and the majority of carbapenems are highly active broad‐spectrum antibiotics. Of the natural products, thienamycin is the most potent. Unlike carbapenems, no penems have been found in nature. The penem acid was shown to possess antibacterial activity in spite of its rather limited stability. Penems include SCH 29482 (C 10 H 13 NO 4 S 2 ), SCH 34343 (C 11 H 14 N 2 O 6 S 2 ), FCE 221201 (C 10 H 12 N 2 O 6 S), and others. 6‐Unsubstituted penems exhibit good activity against both gram‐positive and gram‐negative bacteria. Extensive carbapenem and penem antibiotic research has been ongoing since thienamycin was discovered in 1978. However, only the imipenem–cilastatin combination has become a commercial product. Meropenem was expected to be the second carbapenem on the market.

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“…[4][5][6] In the b-lactam field, the Ullmann-type condensation under basic conditions leads to decomposition of the starting material instead of the expected formation of penem and cephem analogues. [7][8][9][10] In about 100 years of study of Ullmann-type condensations, there have been only limited examples where no base is used and the copper metal or copper salt catalyst itself acts as the acceptor of halogen. [9][10][11][12] However, all of these reactions suffer from one or more disadvantages such as higher reaction temperatures, longer reaction times, and lower yields.…”

mentioning

confidence: 99%

“…It is noteworthy that the present method is also successfully applicable to intramolecular N-arylation of b-lactam derivatives leading to penem and cephem analogues ( Table 2) where most of the methods are unsuccessful and lead to the decomposition of the starting material because of the presence of a base. [7][8][9][10] In summary, we have developed a general method for mild, rapid, and efficient N-arylations of amines, amides, imides and b-lactams with aryl halides. These N-arylations are promoted by active copper and are performed in the absence of a base employing microwave irradiation either under solvent-free conditions or in aqueous media.…”

mentioning

confidence: 99%

Active-Copper-Promoted Expeditious N-Arylations in Aqueous Media under Microwave Irradiation

Yadav¹,

Yadav²,

Vijai³

2006

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Active-copper-promoted mild and expeditious N-arylations of amines, amides, imides, and b-lactams with aryl halides under microwave irradiation conditions are reported. These reactions can be performed at 85-90 °C in aqueous media as well as under solvent-free conditions to give good yields. However, under solvent-free conditions, lower yields are obtained.Aryl-nitrogen bonds are prevalent in many compounds that are of academic, pharmaceutical, and industrial interest. Transition-metal-mediated C-N bond-forming processes are important fundamental transformations and are extensively utilized for N-arylations. The Ullmann condensation has been a powerful method for the coupling of aryl halides with amines. 1-3 Typically, Ullmann coupling protocols necessitate the use of copper metal or copper salts, base, and high reactions temperatures. Recently, the palladium-catalyzed aryl amination has received attention as a synthetically useful method due to the lower temperature required. [4][5][6] In the b-lactam field, the Ullmann-type condensation under basic conditions leads to decomposition of the starting material instead of the expected formation of penem and cephem analogues. 7-10 In about 100 years of study of Ullmann-type condensations, there have been only limited examples where no base is used and the copper metal or copper salt catalyst itself acts as the acceptor of halogen. 9-12 However, all of these reactions suffer from one or more disadvantages such as higher reaction temperatures, longer reaction times, and lower yields.Microwave (MW) irradiation has now gained popularity as a powerful tool for rapid and efficient synthesis of a variety of organic compounds in various solvents as well as solvent-free conditions. 13-16 The application of MW irradiation to provide enhanced reaction rates and improved product yields in chemical synthesis has been extended to modern drug discovery processes, 17,18 and it is proving quite successful in the formation of carbon-heteroatom and carbon-carbon bonds. 19,20 Water is the cheapest, safest, and most non-toxic solvent in the world. It is a good absorber of microwave energy 21,22 and has been successfully employed as solvent for various organic syntheses. 23-27 Utilization of water as an eco-friendly reaction medium in conjunction with MW irradiation is gaining widespread acceptance. [28][29][30][31][32] Considering the above valid points and in pursuing our work on the development of green synthetic processes, 33-36 we have devised active-copper-promoted mild and expeditious N-arylations with aryl halides under MW irradiation. These reactions can be preformed at 85-90 °C in aqueous media as well as under solvent-free conditions. However, the yields are lower under solvent-free conditions, especially in the case of b-lactam derivatives (Tables 1 and 2).The present method in its entirety involves intermittent irradiation of an intimate mixture of an aryl halide, a R 2 NH compound (an amine, amide, imide or b-lactam), and active copper 37 in neat conditions or their aqueous ...

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Synthesis of racemic, 2-(alkylthio)-6-(1-hydroxyethyl) penems; attempted penem synthesis copper (I) - promoted cyclisations

Cited by 21 publications

References 5 publications

Development of a Practical and Convergent Process for the Preparation of Sulopenem

Development of a Practical and Convergent Process for the Preparation of Sulopenem

Carbapenems and Penems

Active-Copper-Promoted Expeditious N-Arylations in Aqueous Media under Microwave Irradiation

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