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Amino Acid Peptides

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Amino Acid Peptides Synthesis of New Spirocyclopropanated β-Lactams and Their Application as Building Blocks for β-Amino Acid Peptides DISSERTATION zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultäten der Georg-August Universität zu Göttingen vorgelegt von Alessandra Zanobini aus Florenz (Italien) Göttingen 2005 D7 Referent: Prof. Dr. A. de Meijere Korreferent: Prof. Dr. L. Tietze Tag der mündlichen Prüfung: 02 November 2005 Die vorliegende Arbeit wurde in der Zeit von Oktober 2002 bis September 2005 im Institut für Organische und Biomolekulare Chemie der Georg-August-Universität Göttingen unter der wissenschaftlichen Anleitung von Herrn Prof. Dr. Armin de Meijere angefertigt. Meinem Lehrer, Herrn Prof. Armin de Meijere danke ich herzlich für die interessante Themenstellung, für hilfreiche Diskussionen und Anregungen und die während dieser Arbeit erwiesene Unterstützung. Herrn Prof. Dr. A. Brandi danke ich herzlich für die hilfreichen Diskussionen und seine stetige Unterstützung. To my mother Table of Contents A. Introduction 1 B. Main Part 11 1. Synthesis of 3-Spirocyclopropanated-2-Azetidinones 11 1.1. Considerations ................................................................................................................ 11 1.2. Background and Mechanicistic Aspects......................................................................... 13 1.3. Synthesis of Nitrones...................................................................................................... 14 1.4. 1,3-Dipolar Cycloaddition of Nitrones to Bicyclopropylidene ...................................... 17 1.5. Thermal Rearrangement of Spirocyclopropanated Isoxazolidines Under Acidic Conditions....................................................................................................................... 19 2. New One-Pot Approach to 3-Spirocyclopropanated Monocyclic β- Lactams 21 2.1. Considerations ................................................................................................................ 21 2.2. Development of a Selective One-Pot Synthesis for 2-Azetidinones .............................. 21 2.3. Extension of the One-Pot 2-Azetidinone Synthesis to Different Substrates .................. 23 2.4. Conclusions about the newly developed one-pot reaction.............................................. 32 3. Microwave Heating to Accelerate the 1,3-Dipolar Cycloadditions of Nitrones to Bicyclopropylidene 35 3.1. Considerations ................................................................................................................ 35 3.2. Synthesis of Isoxazolidine or Piperidone Derivatives .................................................... 36 4. β-Lactam Ring-Opening with N- and O-Nucleophiles and Formation of Dipeptides Containing 1- (Aminomethyl)cyclopropanecarboxylic Acid Residues 40 4.1. Considerations ................................................................................................................ 40 4.2. Attempted Ring-Opening of β-Lactams with N-Nucleophiles....................................... 41 4.3. Changing the Character of the N-Protecting Group........................................................ 42 4.4. Dipeptides Containing 1-(Aminomethyl)cyclopropanecarboxylic Acid Residues ........ 47 4.5. Ring Opening of β-Lactams with O-Nucleophiles......................................................... 49 5. Attempted Synthesis of a Poly(β-peptide), Consisting of 1- (Aminomethyl)cyclopropanecarboxylic Acid 51 5.1. Considerations ................................................................................................................ 51 5.2. Synthesis of 5-Azaspiro[2.3]hexan-4-one ...................................................................... 53 5.3. Ring Closure of Methyl 1-(Aminomethyl)cyclopropane carboxylate............................ 55 5.4. Polymerizations .............................................................................................................. 58 5.5. Synthesis and Characterization of New Poly(2-Azetidinones)....................................... 60 C. Experimental Part 65 1. General Notes 65 2. Procedures for the Synthesis and Spectral Data of the Compounds 67 2.1. Synthesis of the Compounds in Chapter 1...................................................................... 67 2.2. Synthesis of Compounds in Chapter 2............................................................................ 78 2.3. Synthesis of Compounds in Chapter 3............................................................................ 90 2.4. Synthesis of Compounds in Chapter 4............................................................................ 94 2.5. Synthesis of Compounds in Chapter 5.......................................................................... 103 D. Summary 109 E. References 113 F. Spectral Data 125 G. Crystal Structural Data 134 1. 8-Benzyl-9-phenyl-8-aza-7-oxadispiro[2.0.2.3]nonane (47a) 134 2. Methyl 5-Benzoyl-6-oxo-5-azaspiro[2.3]hexane-4-carboxylate (107b) 139 3. tert-butyl (2S,2'R)-2-{[1-(tert- butoxycarbonylaminocyanomethyl)cyclopropylcarbonyl]amino}- 3-phenylpropionate [(2S,2'R)-118] 143 A. Introduction β-Lactam antibiotics are the most frequently employed kind of antimicrobial agents. The first example ever observed was discovered by Sir A. Fleming in 1929.[1] He found out how the growth of some bacteria stams was significantly stopped from a mold, belonging to the genus Penicillium, and named it Penicillin. In the year 1943 the group of investigators E. Chain, H. W. Florey and E. P. Abraham succeeded to isolate Penicillin G (1) (Figure 1), and postulated the structure of penicillin derivatives 2 (Figure 2).[2] In 1945 Hodgkin and Law could obtain the X-Ray crystal analysis of Penicillin G (1).[3] BnCONH S N O CO2H 1 Figure 1. Penicillin G. During the nineteenfifties Cephalosporin derivatives 3 were isolated (Figure 3),[4] after Cephalosporium acremonium was isolated by Brotzu from the sea near a sewer outlet off the Sardinian coast. Crude filtrates of this fungus were found to inhibit the growth of some bacteria and to cure infections in humans. In the subsequent decades, the researchers working with the microbiological sources as well as in the synthetic field could collect a very large number of β-lactam antibiotics. Sometimes the addition of side chains to natural nuclei made possible to produce semisynthetic compounds with greater antibacterial activity than that of the parent natural substance. The actually available β-lactam antibiotics could be separated in nine classes: Penicillins 2, Cephalosporins 3, Penems 4, Clavulanic acid 5, trans-Carbapenems 6, cis-Carbapenems 7, en-Carbapenems 8, Nocardicines 9, Monobactams 10 (Figure 2). 1 2 R R R S S S R1CONH X N N X N O O O CO2H CO2H CO2H 2 3 4 R R O OH R1 R1 N N N O H O O CO2H CO2H CO2H 5 6 7 R3 2 2 1 R 1 R R2 R CONH R CONH R3 R3 R1 N N N OH O O SO3H O CO2H CO2H 8 9 10 Figure 2. Basic structures of the most important classes of β-lactam antibiotics. A typical aspect of the research in this field is the limited number of original skeletons. The class of antibiotics received its name from the four-membered heterocycle, the β-lactam ring. This 2-azetidinone skeleton is the center of the activity respect to biological substrates.[5] The antibacterial activity derives from inhibition of enzymes, called “Penicillin binding proteins“ (PBPs) that are important for the peptidoglycan layer construction, by stabilyzing the bacterial membrane. These enzymes are transpeptidases and interact with the β-lactam ring through amide bond breaking (N1-C2 fragmentation). The reactivity toward PBPs is strongly influenced by the presence of substituents on the β-lactam or by eventually present fused rings.[6] The latter ones can increase the ring strain energy and so, favour the interaction with the transpeptidases, whose activity release this additional strain.[5,7] Because of its unusual electronic and sterical properties, expecially cyclopropyl rings are able to influence the conformational constraint of a molecule and so its biological activity.[6] For this reason, the spirocyclopropane unit has been several times introduced onto β-lactam antibiotics skeletons, trying to modify their reactivity, respect to biological systems. 2 The spirocyclopropane has been introduced on the five-membered ring in penicillin derivatives 11,[8,9] in carbapenems 12[10] and in azapenames 13[11] (Figure 3). OH CO2R RCONH (PhCO) N S 2 N N N N O O O CO2H CO2H CO2H 11 12 13 Figure 3. β-Lactam antibiotics containing a spiroanellated cyclopropyl moiety. A geminal disubstitution is known to generate a decrease in angle deformation, incurred upon a cyclization (Thorpe-Ingold effect). In analogy, a spirocyclopropane ring, resembling this kind of substitution, gives to the system an additional strain, which is expected to be released in the interaction toward the transpeptidases. For this reason the spirocyclopropane moiety has already been introduced on the 2- azetidinone ring in penem systems 14 and cephem systems 15 (Figure 4).[12] R3 R4 2 R S SR 1 N R N 5 O O R CO2H 6 CO2R 14 15 Figure 4. β-Lactam antibiotics in which the cyclopropane ring is spirofused to the β- lactam ring. Some monocyclic spirocyclopropanated β-lactam derivatives 16 and 17 have also already been prepared by carbene addition to a preformed heterocycle, containing an exocyclic double bond (Figure 5).[13] 3 Ph Cl Ph Cl N N H O Ph O 16 17 Figure 5. First examples of monocyclic spirocyclopropanated 2-azetidinones. Already in the middle of the last century,
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