JAST 2015 M.U.C.Women s College, Burdwan ISSN

Transcription

1 JAT 2015 M.U.C.Women s College, Burdwan I a peer reviewed multidisciplinary research journal Vol.-01, Issue- 01 ynthesis of Chiral β-lactam, a Constituent or Precursor of Important Drugs: A hort eview Gautam Bhattacharya Department of Chemistry M.U.C. Women s College, Burdwan gautam31@hotmail.com Abstract: Chiral β-lactams are important constituents of various biologically active drugs, or precursor of them. This review describes some syntheses of these chiral β-lactams. These include our own effort to synthesize them. Keywords: β-lactam, chiral ketene, penicillin 1. eview of the Work Chiral β-lactams (Fig. 1) are important constituents of different antibiotics. 2 C -lactam ring Fig.1. β-lactam ring in penicillin This spectrum of this types of antibiotic [1] ranges from the first discovered antibiotic and peptide enzyme inhibitors penicillin (1) to newer derivatives like amoxicillin (2), clavulinic acid (3), tabtoxin (4)(Fig.2) bestatin, etc [2-4]. They are also important precursors of β- amino acid derivatives like that present in anticancer drug taxol. Penicillin (1) was discovered in 1928 by Alexander Flemming, and it was the beginning of a new series of drug called antibiotic. It was a wonder drug at that time due to its efficacy to kill bacteria. It was used extensively during World War II to save people from different viral or bacterial diseases. The mechanism was found to be blocking the action of cell wall synthetaze by inhibiting the peptide enzyme responsible for synthesizing the cell wall and thus killing the bacteria or virus (Fig. 3). From the above mentioned structure it can be observed that a 4 member lactam ring called β-lactam is present in the compounds (Fig.2). It can also be observed that the β-lactam rings present in the system are asymmetric and, hence, chiral in nature. The mechanism of action of these antibiotics are found to be [Article istory: eceived on , Accepted on ] [58]

2 ynthesis of Chiral β-lactam, a Constituent or Precursor of Important Drugs: A hort eview Author: G. Bhattacharya blocking peptide present in cell wall syhthetaze by binding with the β-lactam ring as shown in Fig.3. This necessitates the presence of β-lactam in the system for their activity, and, hence, the synthesis of it is important. 2 C Penicillin C Amoxycillin 2 C 2 C 2 Clavulinic acid 3 C 2 2 Tabtoxin 4 Fig.2. Different β-lactam antibiotics Enz-u 2 C Enz-u 2 C Fig.3. Mechanism of action of penicillin From this discussion and structures it is clear that β-lactam ring which is essential for the activity of these antibacterial drugs is present in all these biologically important drugs, and they are chiral in nature. As per World ealth rganization directive, it is important to use the β-lactams in optically pure form to minimize the side effect of other enatiomer. o efforts are on to synthesize this β-lactam ring in optically pure form, and also chirally the most active form. ne of these methods is to achieve the synthesis of β-lactam ring by ketene-imine cycloaddition reaction. By synthesizing the ketene or imine in optically pure form by incorporating a chiral auxiliary in either ketene or imine, synthesis of optically active pure β-lactam ring was achieved by the cycloaddition reaction of them. Chiral β- lactams were also synthesized from naturally occurring chiral β-lactams. ere are some methods to synthesize chiral β-lactam ring. 2. Different synthesis of chiral β-lactam ring (1) From optically active ketene (5) and (7) (cheme 1) ere acid chloride derivatives were used as ketene precursor, and different chiral auxiliaries [5] were used attached with acid chloride. The enantioselectivity was very high with more than 80 % enantiomeric excess of β-lactams (6, 8). (2) tarting from optically active imine (12) and (15) (cheme 2) - ere the imine was attached with a chiral auxiliary and a with enantiomeric [6] excess of chiral β-lactams (12, 15). JAT -2015, Vol.-01, Issue-01 [59]

3 JAT-a peer reviewed multidisciplinary research journal Vol.-01, Issue-01 Et + 3 Cl Et C PMP 3 C Cl PMP cheme 1: ynthesis of chiral using chiral ketene + Cl Cl + 2 Et 3 Et cheme 2: ynthesis of chiral using chiral imine 3. My contribution to this field We in our laboratory synthesized optically pure β-lactams by kinetic resolution of synthesized racemic β-lactams using enzymes like Pig Pancreatic Lipase (PPL) or Pig Liver Esterase (PLE). The synthesized chiral β-lactams were converted to important biologically active molecule. The reaction scheme started by Kinugasa [7] reaction of nitrone (18) and propargyl alcohol. The mixture was heated in dimethyl formaide (DMF) in presence of CuI and then purification of the product was made in silica gel column chromatography. The β-lactams were converted to racemic acetates by acetic anhydride and triethyl amine in methylene chloride (20, cheme 3). The acetates were then resolved kinetically using PPL or PLE [8-11] as catalysts to get pure β-lactam derivatives in high enantiomeric excess (varies from 86 % to 98 %) (cheme 4, and cheme 5). The yield of the product was kept in less than 50 % to achieve high enantimeric purity. The reactions were carried out in acetone and buffer. Various derivatives or and 1 were synthesized as shown in Fig.4. The optically active alcohols (22 and 25) were converted to tabtoxin (4) derivatives (28) following cheme 6 [8, 9, 10, 11, 12]. [60]

4 ynthesis of Chiral β-lactam, a Constituent or Precursor of Important Drugs: A hort eview Author: G. Bhattacharya 1 2 Zn/Ac CuI,Et 3, DMF Ac Ac 2, Et 3 DCM cheme 3: ynthesis of racemic β-lactam acetate Ac 21 1 PPL/Acetone Buffer 1 22 (+)-(3,4) + Ac 1 23 (-)-(3,4) cheme 4: ynthesis of chiral β-lactam alcohol using PPL Ac 1 24 (-)-(3,4) PLE/Acetone Buffer 1 25 (-)-(3,4) cheme 5: ynthesis of chiral β-lactam alcohol using PLE, 1 =, Me,, Fig.4: Different substituent in β-lactam ring JAT -2015, Vol.-01, Issue-01 [61]

5 JAT-a peer reviewed multidisciplinary research journal Vol.-01, Issue-01 MsCl/Et 3 Ms DBU DCM DCM /Pd The advantages of our method with respect to others are the high degree of enantiomeric excess we obtained, and the cost effectiveness of the scheme. The method is also easy to carry out. o from the above discussion we may conclude that it is a challenge to synthesize optically pure β-lactam ring present in different antibiotic. The synthesis is going on in different labs. We also synthesize the optically pure β-lactam ring in our laboratory by a cheap and easy method using enzymes, and it was converted to important drug derivatives. eferences cheme 6: ynthesis of chiral tabtoxin derivatives [1] jima I., abus I., Zhao M., Park Y. M., un C. M., Brigaud T., ew and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of -lactam synthon method, Tetrahedron, 1992, 48, [2] [3] [4] jima I., ecent advances in the.beta.-lactam ynthon method, Accounts of Chemical esearch, 1995, 28, 383. [5] Evans D. A., jogren E.B., The asymmetric synthesis of -lactam antibiotics I application of chral oxalididones in the taudinger reaction, Tetrahedron Letters, 1985, 26, 3783, [6] Cutrona, K. J., anderson P. E. J., The synthesis of thrombin inhibitor L via an -hydroxy- lactam, Tetrahedron Letters, 1996, 37, 5045, [7] Kinugasa M., Mashimoto., The reaction of copper(i)phenylacetylide with nitrones, Journal of Chemical Comminication, 1972, 466 ; cis and trans-azetidin-2-ones from nitrones andcopper acetylide, Ding L. K., Irwin W. J.,. [8] Lucha J. L., Kagan. B., Parthasarathi., Tsoucario G., ango C., Zewlar C., A route to chiral -lactam, Tetrahedron, 1968, 24, [9] Zhu L. M., Tedford M. E., ecent advances in enzyme catalyzed reaction, Tetrahedron, 1990, 46, [10] Basak A., Bhattacharya G., Bdour. M., An Enantioselective Cycloaddition oute to 3-ydroxy 2- Azetidinones, Tetrahedron Letters, 1997, 38, [11] Basak, A., Mahato. T., Bhattacharya. G., Mukherjee. B., Differential effects of tereochemistry and C-4 ubstituents on the Enantioselectivity of PLE and PPL Catalysed ydrolysos of 3, 4-disubstituted b- lactams, Tatrahedron Letters, 38, 1997, pp [12] Corey E. J., chimdt G., Useful procedures for the oxidation alcohols using pyridinium dichromate in aprotic media, Tetrahedron Letters, 1979, 399. [62]