Novel Cu(II)-mediated methodologies for PET-induced cyclizations, including asymmetric induction, and a biomimetic approach to the basic taxane sceleton [Elektronische Ressource] / by Yevgeny Makhynya

Yevgeny Makhynya

Informations

• Publié par: universitat_duisburg-essen
• Publié le: 01 janvier 2005
• Nombre de lectures: 21
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Novel Cu(II)-mediated Methodologies for PET-induced
Cyclizations, including Asymmetric Induction, and a Biomimetic
Approach to the Basic Taxane Skeleton






DISSERTATION
submitted to the Universit t Duisburg-Essen
Standort Essen
Fachbereich Chemie
in fulfilment of the Dr. rer. nat. degree




by
Yevgeny Makhynya
from
Kiev, Ukraine




M lheim an der Ruhr
Germany
2004




























Tag der mndlichen P? r fung: 21.01.2005
Pr fungsvorsitzender: Prof. Dr. R. Boese
1. Gutachter: Prof. Dr. M. Demuth
2. Gutachter: Prof. Dr. R. Sustmann This work was conducted at the Max-Planck-Institut f r Bioanorganische Chemie (former
Max-Planck-Institut f r Strahlenchemie ), M lheim an der Ruhr , between August 2001 and
November 2004 under the direction of Prof. M. Demuth.


My sincerest thanks goes to Prof. M. Demuth for his constant help and advises in research, for
his kind help in giving the possibility to perform the practical part of my diploma thesis and for
his valuable help and support at all stages of my Ph.D. studies.


I am very grateful to the State of North-Rhine Westfalia, Ministry for Education and Research,
for partial support of the present Ph.D. work.


The kind support of this work at the Max-Planck-Institut f r Bioanorganische Chemie by Prof.
W. Lubitz and K. Wieghard are gratefully acknowledged.


I thank Prof. W. G rtner for his ki nd help and support of this work.


I thank Prof. R. Sustmann, Department of Organic Chemistry, University of Duisburg-Essen,
Campus Essen, for acting as co-referee.


I sincerely appreciated to all co-workers and friends for their assistance and friendly working
atmosphere which made the work enjoyable. Parts of this work have been published:

18. Vortragstagung der Fachgruppe Photochemie mit Sonderforum Molekulare Photomedizin,
April 7-9, 2003, Muelheim an der Ruhr, Germany.
Authors: Yevgeny Makhynya (Talk), Mustafa E. Ozser, Andriy S. Kuklya, Martin Demuth.
Title: Kaskadische lichtinduzierte Elektronentransfercyclisierungen von terpenoiden
Polyalkenen in Gegenwart von Cu(II). Untersuchung von diastereoselektiven und
enantioselektiven Photoreaktionen in Metallkomplexen ,

GDCh-Jahrestagung Chemie 2003,
October 6-11, 2003, M nchen, Germany.
Section: Radikal- und Photochemie f r die Organische Synthese (gemeinsam mit der
Fachgruppe Photochemie)
Authors: Yevgeny Makhynya, Mustafa E. Ozser, Frank Goeller, Frank Heinemann, Xuechao
Xing, Martin Demuth (Talk).
Title: Biomimetische Reaktionskaskaden mittels Photoelektronentransfer .

Electron Transfer-Initiated Cas cade Cyclizations of Terpenoid Polyalkenes in Low-polarity
Solvent: One-step Synthesis of Mono- and Polycyclic Terpenoids With Various
Functionalities , Mustafa E. Ozser, Huriye Icil, Yevgeny A. Makhynya, Martin Demuth, Eur.
J. Org. Chem. 2004, 3686-3692.















My Parents
My dear Viktoria
and juniorCONTENTS


1 1. Abstract
5 2. Introduction
2.1 Biomimetic and enzymatic cyclizations 5
2.1.1 Biotransformations of squalene: The processes catalyzed by proteins 5
without metal cofactors
2.1.2 Biosynthesis of taxadiene. A process catalyzed by the taxadiene cyclase, 9
being a protein with a metal cofactor
2.1.3 Biomimetic transformations 12
2.2 Theoretical aspects of photochemically-induced electron transfer (PET) in 15
biomimetic cyclizations
2.3 Previous attempts of the synthesis of the basic taxane skeleton and total 22
synthesis of taxol

29 3. Results and discussions
3.1 Our own synthetic, biomimetic approach toward the basic taxane skeleton 29
3.1.1 General concept for the synthesis of substrates of type 73 29
3.1.2 The choice of protecting groups R , R , R 31 1 2 3
3.1.3 Synthesis of the potential pro-taxoid substrates for cationic cyclization 33
3.1.3.1 geranylphenylsulfone 86 33
3.1.3.2 Synthesis of aldehyde 79
3.1.3.3 Coupling of geranylphenyl sulfone 86 with aldehyde 79 to give alcohol 87 34
3.1.3.4 Protection of alcohol 87 with a benzoyl group 34
3.1.3.5 Protection of alcohol 87 with a tert-butyl group (→87a) 35
3.1.4 Synthesis of potential pro-taxoid substrates for anionic cyclizations 36
3.1.4.1 aldehyde 89 36
3.1.4.2 Alkylation of geranylphenylsulphone 86 with aldehyde 89 to alcohol 90 37
3.1.4.3 Protection of alcohol 90 with a benzoyl group 37
3.1.4.4 Epoxidation of 91 38
3.1.5 Unsuccessful attempts toward cationic and anionic macrocyclization 38 3.1.5.1 Cyclization attempt using BuLi and LDA 40
3.1.5.2 pt using CF COH 41 3 2
3.1.5.3 Attempt to cyclize 88 with BF •EtO 41 3 2
3.2 PET-induced cyclizations in presence of Cu(II)-acetate 42
3.2.1 Use and role of Cu(II)-acetate in PET-induced cyclizations 42
3.2.2 Cu(II)-acetate as oxidant in PET-induced cyclizations with water as 45
nucleophile
3.2.2.1 Oxidation of geranyl acetate (77) 46
3.2.2.2 the allylic alcohol 78 and of the TBDMS-protected alcohol 47
81
3.2.2.3 Oxidation of all-trans-farnesol (106) in the presence of water as 48
nucleophile and Cu(II)/Mn(III)-acetates as oxidant mixture
3.2.3 Cu(II)-acetate-mediated PET-initiated cyclizations with methanol as 49
nucleophile
3.2.3.1 Oxidative cyclization of geranyl acetate (77) with methanol as nucleophile 50
3.2.3.2 Cyclization of geraniol (74) with methanol as nucleophile 51
3.2.3.3 Cyclization of farnesol (106) 51
3.2.3.4 Cyclization of farnesyl acetate (118) 52
3.2.4 Proposed reaction mechanism and experiments for mechanistic studies 53
3.2.5 Experimental approach toward cyclizations including intramolecular or 57
combined intra- and intermolecular trapping
3.2.5.1 The synthesis of geranyl diethylmalonate (124) 58
3.2.5.2 Decarbethoxilation of geranyl diethylmalonate. Synthesis of bis- 58
homogeranic acid ethylester. Reduction of bis-homogeranic acid to bis-
homogeraniol.
3.2.5.3 Irradiation of bis-homogeraniol with Cu(II)-acetate as co-oxidant 59
3.3 Photochemistry of the Cu(II)-complexes and experiments for asymmetric 61
induction
3.3.1 Considerations on substrate, chiral ligand and complex formation 62
3.3.2 Synthesis of the β-ketoesters 132-134 64
3.3.3 bis(methyl 7-methyl-3-oxo-oct-6-enoato)copper(II) (138) 65
3.3.4 Irradiation of bis(methyl 7-methyl-3-oxo-oct-6-enoato)copper(II) (138
3.3.5 Proposed reaction mechanism and experiments for mechanistic 67 considerations
3.3.6 Attempts toward enantioselective cyclizations with Cu(II)-complexes 72
3.4 Quantum mechanical calculations to establish the viability of the crucial 75
macrocyclization

79 4. Outlook
4.1 Cu(II)-mediated processes 79
4.2 Ionic cyclizations 81
4.3 Calculations
4.4 Biochemical approach 81

82 5. Experimental section
5.1 Instruments, methods and materials 82
5.2 Nomenclature and general synthetic procedures 86
5.2.1 General procedure for the PET-initiated reactions with Cu(OAc) as a 86 2
cooxidant
5.2.1.1 Typical procedure when water was used as nucleophile 86
5.2.1.2 Typical procedure when methanol was used as nucleophile 87
5.2.2 General procedure for the irradiation of Cu(II)-complexes 87
5.3 Synthesis of pro-taxoid precursors and attempts toward their cyclization 88
via cationic and anionic pathways
5.3.1 Synthesis of acetic acid 9-benzenesulfonyl-8-hydroxy-3,7,11,15- 88
tetramethyl-hexadeca-2,6,10,14-tetraenyl ester (87)
5.3.2 Synthesis oflfonyl-8-benzoxy-3,7,11,15- 89
tetram88)
5.3.3 Synthesis of 1,9-bis-benzenesulfonyl-3,7,11,15-tetramethyl-hexadeca- 91
2,6,10,14-tetraen-8-ol (90)
5.3.4 Synthesis of 1,9-bis-benzenesulfonyl-8-benzoxy-3,7,11,15-tetramethyl- 92
hexadeca-2,6,10,14-tetraen (91)
5.3.5 Synthesis ofethyl- 94
14-oxiranyl-hexadeca-2,6,10-trien (92)
5.3.6 An attempt to cyclize 88 with trifluoroacetic acid 95 5.3.7 Synthesis of acetic acid 9-benzenesulfonyl-8-tert-butoxy-3,7,11,15- 98
tetramethyl-hexadeca-2,6,10,14-tetraenyl ester (87a)
5.4 Photochemical oxidations with water as nucleophile and Cu(OAc) as a 99 2
co-oxidant
5.4.1 Irradiation of geranyl acetate (77) (→ 100, 101, 102, 103) 99
5.4.2 Oxidation of the allylic alcohol 78 (→ 104a, 104b
5.4.3 TBDMS-protected allylic alcohol 81 (→ 105) 101
5.4.4 Irradiation of all-trans-farnesol (106) (→ 107, 108
5.5 Photochemical oxidations with methanol as nucleophile and Cu(OAc) as 103 2
a co-oxidant
5.5.1 Oxidative cyclization of geranyl acetate (77). Experiment for mechanistic 103
studies
5.5.2 Irradiation of geraniol (74) (→ 115, 116) 107
5.5.3 Irradiation of all-trans-farnesol (106) (→ 117) 109
5.5.4 Irradiation of all-trans-farnesyl acetate (118) (→ 119) 111
5.5.5 Experiments toward intramolecular or combined intramolecular and 112
intermolecular cyclizations including trapping
5.5.5.1 Synthesis of geranyldiethylmalonate (