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4-Acetoxy-3-[1-(2-arylamino-1-hydroxy)ethyl]azetidin-2-ones: Intermediates for the Synthesis of Novel Carbapenems

 

作者: Mary J. Meegan,  

 

期刊: Journal of Chemical Research, Synopses  (RSC Available online 1997)
卷期: Volume 0, issue 5  

页码: 158-159

 

ISSN:0308-2342

 

年代: 1997

 

DOI:10.1039/a700513j

 

出版商: RSC

 

数据来源: RSC

 

摘要:

N S N O Me NH2H H H CO2H Me 1 158 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 158–159 J. Chem. Research (M), 1997, 1101–1126 4-Acetoxy-3-[1-(2-arylamino-1-hydroxy)ethyl]azetidin- 2-ones: Intermediates for the Synthesis of Novel Carbapenems Mary J. Meegan,* Caroline M. Waldron, Raymond D. Keaveny and Anthony D. Neary Department of Pharmaceutical Chemistry, School of Pharmacy, Trinity College Dublin, 18 Shrewsbury Road, Dublin 4, Ireland 3-Vinyl- and 3-isopropenyl-azetidin-2-ones are transformed into the corresponding 4-acetoxy-3-[1-(2-arylamino- 1-hydroxy)ethyl]azetidin-2-ones and 4-acetoxy-3-[1-(2-arylamino-1-hydroxy)propyl]azetidin-2-ones, intermediates for the synthesis of novel carbapenems.Many carbapenems isolated and synthesised to date possess a 1-hydroxyethyl substituent at C-6, and the presence of this group consistently demonstrates potent antibacterial activity.1 Mastalerz et al.2 have reported improvements in activity against Gram negative bacteria, particularly against Pseudomonas aeruginosa, by replacing the hydroxy group of the hydroxyalkyl substituent at C-6 of carbapenems with an amino group.The 6-(1-aminoethyl)carbapenem 1 was demonstrated to be more active than the corresponding 6-(1-hydroxyethyl)carbapenem but was unstable in solution.3 In this work the synthesis of hitherto unreported 4-acetoxy- 3-[1-(2-arylamino-1-hydroxy)ethyl]azetidin-2-ones is described with a view to the introduction of such b-amino alcohol substituents at C-6 of carbapenems.The aminolysis of epoxides provides a convenient route to b-amino alcohols and such reactions are well documented.5,9 There are many methods available for the regioselective ring opening of epoxide with amines, e.g. using diethylaluminium amides7 and aminolead compounds.8 In this work, the cobalt(II) chloride catalysed aminolysis of 1,4-diaryl-3-(1,2- epoxyethyl)azetidin-2-ones 3a–e with aniline, p-anisidine, p-toluidine and p-chloroaniline under mild conditions was first investigated.The diastereomeric epoxides 3a–e required for this study were obtained by m-chloroperbenzoic acid (MCPBA) oxidation of trans-3-vinylazetidin-2-ones 2a–e, which were prepared by stereoselective addition of crotonyl chloride to the appropriate Schiff bases. The epoxides 3a–e were opened regioselectively on the least substituted carbon in all cases, giving rise to the corresponding b-amino alcohols 4a–i in moderate yield as diastereomeric mixtures, Scheme 1.As an alternative method for the regioselective aminolysis of b-lactam epoxides under mild conditions, the use of diethylaluminium amides7 was investigated, Scheme 2. The diethylaluminium amide nucleophiles were prepared by reaction of triethylaluminium with the appropriate aryl amines. The amides were reacted with epoxides 3a–e to generate after base catalysed hydrolysis the corresponding b-amino alcohols 4a,i, 5a–c as diastereomeric mixtures.Products 4a,i were found to be identical with those produced using the cobalt(II) catalyst reaction; however in most cases the cobalt (II) catalysed reaction afforded superior yields and ease of preparation. Additional proof of the regioselectivity of this reaction was provided by the oxidation of the b-amino alcohol product 4i to the corresponding b-aminoketone 7, Scheme 2. The aminolysis of 3-(1,2-epoxyethyl)azetidin-2-ones was now applied to 4-acetoxy-1-(4-methoxyphenyl)azetidin-2-ones affording products which could be considered as precursors for carbapenems having the b-amino alcohol type substituent at C-6.The 4-acetoxy-3-vinylazetidin-2-ones 11a,b were obtained from the 4-formyl-3-vinylazetidin-2-ones 9a,b. The 4-formyl-3-vinylazetidin-2-ones 9a,b were prepared by reaction of crotonic acid and 3,3-dimethylacrylic acid with N,Np-dip- anisylethylenediimine (8) using Mukaiyama’s reagent (2-chloro-N-methylpyridinium iodide)15 as the carboxylic acid *To receive any correspondence. †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J.Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). Scheme 1 Reagents and conditions: i, MCPBA, CH2Cl2; ii, R3C6H4NH2, CoCl2, MeCNN O CH2 HO R3R4N R2 R1 N Ph Ph O CH2 O PhNH 3a–e R1 = 3,4-OCH2O, R2 = CO2Me, R3 = Ph, R4 = H R1 = R2 = R4 = H, R3 = Ph R1 = 3,4-OCH2O, R2 = CO2Me, R3 = R4 = Ph R1 = 4-OMe, R2 = H, R3 = R4 = Ph R1 = Cl, R2 = CO2Me, R3 = R4 = Ph a i a b c 4 5 7 4i i ii N N N O CHO R N O CO2H R N O OCOMe R N O OCOMe HO CH2 10a b R = H R = Me N O OCOMe R a b 9 R = H R = Me R = H R = Me 11a b R = H R = Me HN Ph 13a b R = H R = Me R 12 O a b i 8 iii iv v OMe OMe OMe OMe OMe OMe MeO ii J.CHEM. RESEARCH (S), 1997 159 activating agent followed by acid hydrolysis of the resulting 4-imino b-lactam intermediate. This method offers an alternative direct synthetic route to the 4-formyl compounds as the previously reported procedures involved reaction of the acid chloride with the diimine.16 Decarboxylation–acetoxylation of the carboxylic acids 10a,b was carried out with lead tetraacetate to afford the 4-acetoxy b-lactams 11a,b.17 Epoxidation of 11a,b with MCPBA was carried out to afford the corresponding epoxides 12a,b respectively as diastereomeric mixtures. The trans 4-acetoxy-3-(1,2-epoxyethyl)azetidin-2-ones 12a,b were treated with aniline and cobalt(II) chloride and afforded the corresponding b-amino alcohol product 13a,b Scheme 3.A procedure for the synthesis of b-lactams containing a b-amino alcohol type substituent at C-3 is described, by aminolysis of 3-(1,2-epoxyethyl)azetidin-2-ones and 3-[2-(1,2- epoxypropyl)]azetidin-2-ones, under mild conditions and without destruction of the b-lactam ring. The products 13a,b represent synthetic precursors for analogues of thienamycin and carpetimycin type carbapenem antibiotics having a b-amino alcohol function rather than a 1-hydroxyethyl or 2-hydroxypropyl C-6 substituent.Work is in progress on the elaboration of these intermediates to novel carbapenems containing a b-amino alcohol substituent at C-6. On preliminary evaluation, the 3-[1-(2-amino-1-hydroxy)- ethyl]azetidin-2-ones 4a,f and 5a displayed antibacterial activity against Escherischia coli (18), Staphylococcus aureus (Oxford), Klebsiella pneumoniae 1588 and Bacillus subtilis (Oxford) at a concentration of 1 mg mlµ1, using a radial growth assay procedure.We thank Forbairt for Postgraduate Research Scholarships (A. D. N., C. M. W.). Techniques used: 1H and 13C NMR, IR, mass spectrometry, TLC Schemes: 3 References: 20 Received, 22nd January 1997; Accepted, 6th February 1997 Paper E/7/00513J References cited in this synopsis 1 R. Southgate, Contemp. Org. Synth., 1994, 1, 417. 2 H. Mastalerz, M. Menard, E. Ruediger and J. Fung-Tomc, J.Med. Chem., 1992, 35, 953. 3 M. Menard, J. Banville, A. Martel, J. Desiderio, J. Fung-Tomc and R. A. Partyka, in Recent Advances in the Chemistry of Antiinfective Agents, ed. P. H. Bentley and R. Ponsford, The Royal Society of Chemistry, Cambridge, 1993, pp. 3–20. 5 M. Bartok and K. L. Lang, in Heterocyclic Compounds, ed. A. Hassner, Wiley, New York, 1985, vol. 42, part 3, pp. 1–196. 7 L. E. Overman and L. A. Flippin, Tetrahedron Lett., 1981, 22, 195. 8 J. Yamada, M. Yumoto and Y. Yamamoto, Tetrahedron Lett., 1989, 30, 4255. 9 J. Iqbal and A. Pandey, Tetrahedron Lett., 1990, 31, 575. 15 G. I. Georg, P. M. Mashava and X. Guan, Tetrahedron Lett., 1991, 32, 581. 16 B. Alcaide, Y. Martin-Cantalejo, J. Perez-Castell, J. Rodriguez- Lopez, M. A. Sierra, A. Monge and V. Perez-Garcia, J. Org. Chem., 1992, 57, 5921. 17 A. C. O’Leary, A. D. Neary, C. M. Waldron and M. J. Meegan, J. Chem. Res., 1996, (S) 368; (M) 2162. Scheme 2 Reagents and conditions: i, R3R4NAlEt2, CH2Cl2; ii, pyridinium chlorochromate Scheme 3 Reagents and conditions: i, MeCR�CHCO2H, Mukaiyama’s reagent, Et3N, CH2Cl2; ii, Jones’ reagent, Me2CO; iii, Pb(OAc)4, DMF; iv, MCPBA, CH2Cl2; v, PhNH2, CoCl2, Me

 



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