Asymmetric Synthesis of Lignans and of Α-(Heteroaryl)Alkylamines Employing the SAMP-/RAMP-Hydrazone Method
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Asymmetric Synthesis of Lignans and of α-(Heteroaryl)alkylamines Employing the SAMP-/RAMP-Hydrazone Method Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der Rheinisch-Westfälischen Technischen Hochschule Aachen zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigte Dissertation vorgelegt von Giuseppe Del Signore Aus Rom (Italien) Berichter: Universitätsprofessor Dr D. Enders Universitätsprofessor Dr. C. Bolm Tag der mündlichen Prüfung: 15.12.2003 Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfügbar. The work here reported has been carried out at the Institute of Organic Chemistry of the RWTH under the supervision of Prof. Dr. Dieter Enders between August 2000 and July 2003. Parts of this work have been published or submitted: 1) A General Approach to the Asymmetric Synthesis of Lignans: (−)-Methyl Piperitol, (−)-Sesamin, (−)-Aschantin, (+)-Yatein, (+)-Dihydroclusin, (+)- Burseran, and (+)-Isostegane. Dieter Enders, Vivien Lausberg, Giuseppe Del Signore, Otto Mathias Berner, Synthesis 2002, 515. 2) First Asymmetric Synthesis of (−)-Lintetralin via Intramolecular Friedel-Crafts- Type Cyclization. Dieter Enders, Giuseppe Del Signore, and Otto Mathias Berner, Chirality 2003, 15, 510. 3) Efficient Asymmetric Synthesis of α-(Heteroaryl)alkylamines by 1,2-Addition of Lithiated Heteroarenes to Aldehyde-SAMP-Hydrazones. Dieter Enders, Giuseppe Del Signore, Tetrahedron: Asymmetry 2004, in press. I would like to thank Prof. Dr. D. Enders for giving me the opportunity to work in his group, for the exciting research theme, and the stimulating discussions. Many thanks to Prof. Dr. C. Bolm for his kind assumption of the co-reference “Natura semina nobis scientiae dedit, scientiam non dedit.” (Seneca, Epist., 120, 4) “Apes debemus imitari, et quaecumque ex diversa lectione congessimus separare, deinde adhibita ingenii nostri cura et facultate in unum saporem varia illa libamenta confundere.” (Seneca, Epist., 84,5) A mia madre INDEX 1.1 Part one: Introduction 1 1.1.1 Definition and classification of lignans 1 1.1.2 Biological and clinical properties 2 1.1.3 Biogenesis 4 1.1.4 Synthesis of lignans 6 1.1.4.1 Diastereoselective alkylation of chiral butyrolactone 6 1.1.4.2 Diastereoselective conjugate addition to 2-(5H)-furanones 10 1.1.4.3 Routes involving cycloaddition reactions 13 1.1.4.4 Routes involving the use of chiral oxazolidines 15 1.1.5 α-Amino nitriles in organic synthesis 16 1.1.6 Goal of the study 18 1.2 Part two: Introduction 19 1.2.1 Importance and presence of α-(heteroaryl)alkylamines in nature 19 1.2.2 Asymmetric Synthesis of α-(heteroaryl)alkylamines 20 1.2.2.1 Routes utilizing chiral auxiliaries 21 1.2.2.2 Routes utilizing ligand-induced stereoselectivity 25 1.2.2.3 Routes utilizing enzymatic resolution 27 1.2.3 The SAMP-/RAMP-hydrazone methodology 28 1.2.4 The goal of the study 30 2.1 Part one: Results and discussion 31 2.1.1 Synthetic approach to lignans 31 2.1.2 Synthesis of the starting materials 32 2.1.2.1 Synthesis of the chiral auxiliary 32 2.1.2.2 Synthesis of the Michael acceptor 33 2.1.2.3 Synthesis of benzyl bromides 33 2.1.3 Asymmetric synthesis of 2,3-disubstituted-γ-butyrolactones 34 2.1.3.1 Improvement of the Syn/anti selectivity of the aldol addition 35 2.1.4 Asymmetric synthesis of lignans 36 2.1.4.1 Asymmetric synthesis of furofurans 36 2.1.4.2 Asymmetric synthesis of (+)-yatein 38 2.1.4.3 Asymmetric synthesis of (+)-dihydroclusin, (+)-burseran and (−)-isostegane 41 2.1.4.4 asymmetric synthesis of (+)-acon, (+)-lintetralin and (−)-dihydrosesamin 44 2.1.5 Conclusion 48 2.1.6 Outlook 49 2.2 Part two: Results and discussion 51 2.2.1 Retrosynthetic analysis of α-(heteroaryl)alkylamines 51 2.2.2 Synthesis of SAMP-RAMP-hydrazones 52 2.2.3 Asymmetric synthesis of α-(heteroaryl)alkylamines 53 2.2.3.1 Asymmetric synthesis of α-(heteroaryl)alkylhydrazines 53 2.2.3.2 Cleavage of the chiral auxiliary 55 2.2.3.3 Screening of different SAMP-hydrazones 59 2.2.4 Synthetic Applications 61 2.2.4.1 Asymmetric synthesis of α-aminoacids 61 2.2.4.2 Studies towards the Aza-Achmatowicz rearrangement 64 2.2.4.3 Asymmetric synthesis of ß-aminosulfones 67 2.2.5 Conclusion 72 2.2.6 Outlook 74 3 Experimental section 75 3.1 General remarks 75 3.1.1 Chemicals 75 3.1.2 Characterization of the products 75 3.2 General procedures 77 3.3 Michael acceptor 84 3.4 Benzylbromides 84 3.5 Aminonitriles 87 3.6 Michael-adducts 89 3.7 2-Substituted-3-aroyl-γ-butyrolactones 90 3.8 Reduction of the ketones 97 3.9 Tetraols 103 3.10 Friedel-Crafts-type cyclizations 108 3.11 Lignans 114 3.12 Synthesis of SAMP-/RAMP-hydrazones 127 3.13 Synthesis of furfuryl-hydrazines 129 3.14 Synthesis of hydrazides 137 3.15 Synthesis of N-benzoyl protected amines 157 3.16 Synthesis of N-Cbz-protected amines 176 3.17 Sulfones 205 3.18 Synthesis of ß-aminosulfones 216 3.19 Synthesis of ß-sulfonamine 227 3.20 N-protected aminoacids 228 3.21 Oxidation of 1-(2-furyl)alkylamines 236 4 Abbreviations 243 5 References 244 Introduction 1.1 Part one: Introduction 1.1.1 Definition and classification of lignans Lignans are a class of secondary metabolites widely encountered in the plant kingdom. The term lignan was originally introduced by Harworth1 to describe a group of plant phenols whose structure was determined by union of two cinnamic acids residues or their biogenetic equivalents, linked ß,ß’ (fig. 1). ß R3 4 R1 ß' R R2 Fig. 1. General structure of lignans. Several hundred lignans have been discovered in different parts of various plants, including wooden parts, roots, leaves, flowers, fruits and seeds. The range of natural structures encountered is very diverse and can be exemplified with a proposed classification according to their skeleton2 (fig. 2). In spite of recognizing the distribution of lignans in plants their biological purpose in nature is still unclear in most cases. It is however known, that the accumulation of lignans in the core of trees is important for the durability and longevity of the species. Lignans are also assumed to function as phytoalexins, which provide protection for the plants against diseases and pests. In addition, they may participate in controlling the growth of the plants. From a pharmacological point of view, these compounds display a wide array of interesting biological activities and have a long and fascinating history beginning with their use as folk remedies by many different cultures. No longer only a matter of interest for botanists, the lignans have thus attracted the attention of various branches of medicine as well as the pharmaceutical industry and have been the target of intensive synthetic studies. During the last twenty years, a plethora of publications have appeared on the subject, including books 3 and numerous reviews.4 Continued research is currently focused on structure optimization of the active natural lignans to generate derivatives with superior pharmacological profiles as well as broader therapeutic scope. 1 Introduction 1 O 1 Ar Ar2 Ar Ar1 (OH) O O Ar2 (OH) 1 2 2 O Ar Ar O Ar dibenzyl- tetrahydro- dibenzylbutyro- furofurans butan(diol)es furans lactones R1O 3 (OH) (OH) O (OR ) O O O RO RO Ar O Ar O R2O tetralins naphthalenes dibenzocyclooctadienes Fig. 2. Classification of lignans. 1.1.2 Biological and clinical properties A broad range of biological activities has been associated with lignans, including antitumor, antimiotic, antimicrobial and antiviral activities. The aryltetralin lactone, (–)-podophyllotoxin (1), has been under continued investigation due to its significant pharmacological activity (fig. 3). OH O O O O H3CO OCH3 OCH3 1 Fig. 3. Structure of (–)-podophyllotoxin. Podophyllin (an alcoholic extract from the roots and rhizome of may apple which contains as the main active ingredient podophyllotoxin) was considered such a popular cathartic and choalagogue in America that it was included in the U.S. pharmacopea. However, in 1942 it was removed from U. S. pharmacopea because of its severe gastrointestinal toxicity. Currently, it still remains an effective therapy for treatment of venereal warts.5 Furthermore, podophyllotoxin and 2 Introduction its derivatives have been extensively studied in the last 60 years for their powerful antitumor effects. Podophyllotoxin itself is a powerful microtubule inhibitor. Microtubules, which are the dynamic constituents of the cytoskeleton, could be defined as tubular polymers whose protomeric unit, consisting of α- and β-tubulins, forms a heterodimer. The cytoplasm of eukaryotic cells contains a soluble pool of unpolymerised tubulin protomers as well as an organised array of microtubules. Microtubules can be rapidly assembled or disassembled in response to various stimuli with little or no change in the total amount of tubulin. H C O O 3 O O O S O HO O HO O OH OH O O O O O O O O H3CO OCH3 H3CO OCH3 OH OH 2 3 NO2 HN O O O O H3CO OCH3 OH 4 Fig. 4. Structures of etoposide, teniposide and GL-331. Cytoplasmatic microtubules are implicated in an array of different processes as cellular mobility, intracellular transport, secretion, organization of cytoplasm and proteins growth factor signalling. The action of podophyllotoxin basically consists in disrupting the dynamic equilibrium of assembled and disassembled microtubules in vitro and in vivo. The net result is the destruction of the cytoskeletal framework in the cytoplasm and in the spindle fibres causing inhibition of cell division in the metaphase. As the result, the cell duplication at the miotic stage is impeded. However, since podophyllotoxin attacks both normal and cancerous cells, the toxic side effect has limited its application as a drug in cancer therapy.