New Gold-Catalyzed Reactions and Applications for the Synthesis of Alkaloids

202 Pages·2013·7.12 MB·English

by  Ana Escribano Cuesta (auth.)

Springer Theses
Recognizing Outstanding Ph.D. Research
Ana Escribano Cuesta

New Gold-Catalyzed
Reactions and
Applications for
the Synthesis of
Alkaloids
Springer Theses
Recognizing Outstanding Ph.D. Research
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Ana Escribano Cuesta
New Gold-Catalyzed
Reactions and Applications
for the Synthesis
of Alkaloids
Doctoral Thesis accepted by
the Institute of Chemical Research
of Catalonia (ICIQ), Spain
123
Author Supervisor
Dr. AnaEscribano Cuesta Prof.Dr. AntonioM.Echavarren
Lead Optimization Fungicides Institution ofChemical Research of
BASFSE Catalonia, ICIQAvgda
Ludwigshafen Tarragona
Germany Spain
ISSN 2190-5053 ISSN 2190-5061 (electronic)
ISBN 978-3-319-00701-4 ISBN 978-3-319-00702-1 (eBook)
DOI 10.1007/978-3-319-00702-1
SpringerChamHeidelbergNewYorkDordrechtLondon
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Parts of this thesis have been published in the following journal articles:
Encapsulation Studies of Cationic Gold Complexes within a Self-Assembled
Hexameric Resorcin[4]arene Capsule
Adriaenssens, L.; Escribano-Cuesta, A.; Homs, Anna.; Echavarren, A. M.;
Ballester, P. Eur. J. Org. Chem. 2013, DOI: 10.1002/ejoc.201201592
The Role of Cyclobutenes in Gold(I)-Catalyzed Skeletal Rearrangement of 1,6-
Enynes
Escribano–Cuesta, A.; Perez–Galan, P.; Herrero-Gomez, E.; Sekine, M.;
Braga, A. C.; Masseras, F.; Echavarren, A. M. Org. Biomol. Chem. 2012, 10,
6105–6111
Gold–Catalyzed Alkyne Cyclizations with Alkenes and Arenes
López–Carrillo,V.;Escribano–Cuesta,A.;Huguet,N.;Echavarren,A.M.Organic
Reactions, accepted
Synthesis of the Tetracyclic Core Skeleton of the Lundurines by Gold–Catalyzed
Cyclization
Ferrer, C.; Escribano–Cuesta, A.; Echavarren, A. M. Tetrahedron 2009, 65,
9015–9020
Gold-Catalyzed Reactions of 1,5- and 1,6-Enynes with Carbonyl Compounds:
Cycloaddition vs. Metathesis
Escribano-Cuesta, A.; López-Carrillo, V.; Janssen, D.; Echavarren, A. M. Chem.
Eur. J. 2009, 15, 5646–5650
To my family
The difference between persistence
and stubbornness is success
S. J. Danishefsky
Life is what happens to you
while you’re busy
making other plans
John Lennon
Supervisor’s Foreword
Gold chemistry has attracted increasing attention in recent years in the realm of
homogeneous catalysis. In particular, gold complexes have been found to be the
most powerfulcatalysts for electrophilic activation ofalkynes toward avarietyof
nucleophiles under homogeneous conditions. Moreover, allenes and alkenes can
also be effectively activated by gold complexes. Our group at the Institute of
Chemical Research of Catalonia (ICIQ) has developed new gold-based method-
ologies for the formation of carbon–carbon bonds based on the attack of different
nucleophileslikealkenes,arenes,andelectron-richheteroarenestoalkynes.Ithas
been the purpose of this Ph.D. thesis to discover new gold-catalyzed transforma-
tions of alkynes and to develop new transformations for the ready build up of
molecular diversity and complexity, in particular in the selective formation of
tricycliccompounds,dihydropyrans,1,3-dienes,andcyclobutenes.Furthermore,an
approach for the synthesis of the tetracyclic core of the lundurines has been
developed by using a gold-catalyzed cyclization reaction as the key step. The
lundurines are a new type of indoles alkaloids, characterized by an unusually
complexarchitecturewithacyclopropanefragmentembeddedwithinahexacyclic
ringsystemthatincludesa1H–azocine[5,4–b]indolering.Interestingly,lundurines
BandDhaveshownsignificantinvitro cytotoxicitytowardB16melanomacells.
This work is an important contribution in the development of new synthetic
methodology using gold catalysts. The synthesis of the tetracyclic core of the
lundurinesisamajorsteptowardtheachievementofanefficienttotalsynthesisof
this class of antitumor compounds.
Tarragona, May 2013 Antonio M. Echavarren
ix
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Metal-Catalyzed Alkyne Activation. . . . . . . . . . . . . . . . . . . . . 1
1.2 Gold Properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.3 Gold Complexes for Alkyne Activation . . . . . . . . . . . . . . . . . . 3
1.4 Gold-Catalyzed Nucleophilic Additions to Alkynes. . . . . . . . . . 5
1.4.1 Gold-Catalyzed Addition of Carbon-and
Heteronucleophiles to Alkynes . . . . . . . . . . . . . . . . . . . 5
1.4.2 Gold-Catalyzed Friedel-Crafts-Type Reactions. . . . . . . . 7
1.4.3 Gold-Catalyzed Cyclization of 1,n-Enynes. . . . . . . . . . . 11
1.4.4 Gold-Catalyzed Nucleophilic Additions to 1,n-Enynes. . . 21
1.5 General Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2 Gold(I)-Catalyzed Reactions of 1,6-Enynes with Aldehydes:
Cycloaddition Versus Metathesis-Type Reactions . . . . . . . . . . . . . 37
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2.2 Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
2.3 Results and Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
2.3.1 Optimization of the Reaction Conditions. . . . . . . . . . . . 41
2.3.2 Scope of the Reaction . . . . . . . . . . . . . . . . . . . . . . . . . 44
2.4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
2.5 Experimental Section. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
2.5.1 General Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
2.5.2 Preparation of Substrates . . . . . . . . . . . . . . . . . . . . . . . 50
2.5.3 Cyclization Products . . . . . . . . . . . . . . . . . . . . . . . . . . 50
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
3 Formation of Cyclobutene Compounds via
Gold(I)-Catalyzed Cycloisomerization of 1,n-Enynes . . . . . . . . . . . 61
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
3.2 Objectives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
3.3 Results and Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
xi
xii Contents
3.3.1 Synthesis of Cyclobutene Compounds via
Gold(I)-Catalyzed Intramolecular Addition
of Carbonyl Compounds to 1,6-Enynes . . . . . . . . . . . . . 66
3.3.2 Synthesis of Cyclobutene Compounds via
Gold(I)-Catalyzed Cycloisomerization of 1,8-Enynes. . . . 70
3.4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
3.5 Experimental Section. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
3.5.1 General Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
3.5.2 Preparation of Substrates . . . . . . . . . . . . . . . . . . . . . . . 73
3.5.3 Cyclization Products . . . . . . . . . . . . . . . . . . . . . . . . . . 79
3.5.4 Crystallographic Data . . . . . . . . . . . . . . . . . . . . . . . . . 85
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
4 Approach Toward the Total Synthesis of Lundurines . . . . . . . . . . 105
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
4.1.1 The Importance of the Indole Nucleus: An Overview . . . 105
4.1.2 Indoloazocine Framework: Important Indole Alkaloids . . 106
4.1.3 Lundurines A-D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.1.4 Synthesis of Other Indoloazocine Derivatives. . . . . . . . . 109
4.1.5 Gold-Catalyzed Reaction of Indoles with Alkynes . . . . . 113
4.2 Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
4.3 Results and Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
4.3.1 Intermolecular Approach . . . . . . . . . . . . . . . . . . . . . . . 118
4.3.2 Intramolecular Approach . . . . . . . . . . . . . . . . . . . . . . . 128
4.4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
4.5 Experimental Section. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
4.5.1 General Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
4.5.2 Preparation of Substrates . . . . . . . . . . . . . . . . . . . . . . . 162
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
5 Summary and Outlook. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195