Asymmetric synthesis of lignans and of {α-(heteroaryl)alkylamines [alpha-(heteroaryl)alkylamines] employing the SAMP-/RAMP-hydrazone method [Elektronische Ressource] / vorgelegt von Giuseppe Del Signore

Mathias Berner

Informations

• Publié par: rheinisch-westfalischen_technischen_hochschule_-rwth-_aachen
• Publié le: 01 janvier 2003
• Nombre de lectures: 10
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

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 discusion 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
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
3.1.2 Characterization of the products 75
3.2 General procedures 77
3.3 Michael acceptor 84
3.4 Benzylbromides
3.5 Aminonitriles 87
3.6 Michael-adducts 89
3.7 2-Substituted-3-aroyl-γ-butyrolactones 90