Catalytic Asymmetric Reactions between Alkenes and Aldehydes

240 Pages·2017·2.92 MB·German

Catalytic Asymmetric Reactions
between Alkenes and Aldehydes

Inaugural-Dissertation

zur
Erlangung der Doktorwürde
der Mathematisch-Naturwissenschaftlichen Fakultät
der Universität zu Köln

vorgelegt von
Luping Liu
aus Hebei (VR China)

Köln 2017
Berichterstatter: Prof. Dr. Benjamin List
Prof. Dr. Hans‐Günther Schmalz
Tag der mündlichen Prüfung: 11.10.2017
TABLE OF CONTENTS

TABLE OF CONTENTS
ABSTRACT ......................................................................................................................................... III
LIST OF ABBREVIATIONS ..................................................................................................................... V
1 INTRODUCTION ................................................................................................................................ 1
2 BACKGROUND .................................................................................................................................. 3
2.1 ASYMMETRIC ORGANOCATALYSIS ............................................................................................................ 3
2.1.1 Introduction ............................................................................................................................ 3
2.1.2 Asymmetric Brønsted Acid Catalysis ........................................................................................ 7
2.2 ASYMMETRIC REACTIONS BETWEEN ALDEHYDES AND OLEFINS ..................................................................... 16
2.2.1 Asymmetric Carbonyl−Ene Cyclization ................................................................................... 16
2.2.2 Asymmetric Hetero-Diels–Alder Reaction of Dienes and Aldehydes ........................................ 21
3 OBJECTIVES OF THIS THESIS ............................................................................................................ 26
3.1 CATALYTIC ASYMMETRIC REACTIONS OF SIMPLE ALKENES WITH ALDEHYDES ................................................... 26
3.2 HIGHLY ACIDIC AND CONFINED BRØNSTED ACIDS ..................................................................................... 29
4 RESULTS AND DISCUSSION .............................................................................................................. 31
4.1 ORGANOCATALYTIC ASYMMTRIC CARBONYL−ENE CYCLIZATION ................................................................... 31
4.1.1 Reaction Design and Initial Study .......................................................................................... 31
4.1.2 Substrate Scope ..................................................................................................................... 33
4.1.3 Mechanistic Studies and Discussion ....................................................................................... 36
4.2 ORGANOLCATALYTIC ASYMMETRIC TRANSFORMATIONS VIA OXOCARBENIUM IONS ........................................... 44
4.2.1 Catalytic Asymmetric Prins Cyclization .................................................................................. 44
4.2.2 Catalytic Asymmetric Oxa-Pictet−Spengler Reac.on .............................................................. 53
4.3 ASYMMETRIC [4+2]-CYCLOADDITION REACTION OF DIENES WITH ALDEHYDES ................................................ 60
4.3.1 Reaction Design and Initial Study .......................................................................................... 60
4.3.2 Catalyst Design and Synthesis ............................................................................................... 63
4.3.3 Utilization of New Catalysts .................................................................................................. 65
4.3.4 Substrate Scope of Aromatic Aldehydes ................................................................................. 67
4.3.5 Substrate Scope of Aliphatic Aldehydes ................................................................................. 69
4.3.6 Diene Scope ........................................................................................................................... 71
4.3.7 Gram-Scale Synthesis and Derivatization ............................................................................... 73
4.3.8 Discussion ............................................................................................................................. 74
5 SUMMARY ...................................................................................................................................... 78
5.1 ORGANOLCATALYTIC ASYMMTRIC CARBONYL−ENE CYCLIZATION .................................................................. 78
5.2 ORGANOLCATALYTIC ASYMMETRIC TRANSFORMATIONS VIA OXOCARBENIUM IONS ........................................... 79
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TABLE OF CONTENTS

5.2.1 A General Organolcatalytic Asymmetric Prins Cyclization ...................................................... 79
5.2.2 Organolcatalytic Asymmetric Oxa-Pictet−Spengler Reaction ................................................. 80
5.3 CATALYTIC ASYMMETRIC [4+2]-CYCLOADDITION OF DIENES WITH ALDEHYDES ................................................ 81
5.4 HIGHLY ACIDIC AND CONFINED BRØNSTED ACIDS ..................................................................................... 82
6 OUTLOOK ....................................................................................................................................... 84
6.1 A HIGHLY ENANTIOSELECTIVE SYNTHESIS OF MENTHOL .............................................................................. 84
6.2 AN ORGANOLCATALYTIC ASYMMETRIC ALLYLATION OF ALDEHYDES ............................................................... 85
7 EXPERIMENTAL PART ...................................................................................................................... 86
7.1 GENERAL EXPERIMENTAL CONDITIONS ................................................................................................... 86
7.2 ORGANOLCATALYTIC ASYMMTRIC CARBONYL−ENE CYCLIZATION .................................................................. 89
7.2.1 Substrates Synthesis .............................................................................................................. 89
7.2.2 Products ................................................................................................................................ 94
7.2.3 Mechainsitic Studies ............................................................................................................. 102
7.2.4 X-Ray Data ........................................................................................................................... 125
7.3 ORGANOLCATALYTIC ASYMMETRIC TRANSFORMATIONS VIA OXOCARBENIUM IONS .......................................... 131
7.3.1 Prins Cyclization ................................................................................................................... 131
7.3.2 Oxa-Pictet−Spengler Reaction .............................................................................................. 149
7.4 CATALYTIC ASYMMTRIC [4+2]-CYCLOADDITION REACTION OF DIENES WITH ALDEHYDES .................................. 168
7.4.1 Products ............................................................................................................................... 168
7.4.2 Catalyst Synthesis ................................................................................................................ 185
7.4.3 X-Ray Data ........................................................................................................................... 192
7.4.4 Mechanistic Studies .............................................................................................................. 218
8 BIBLIOGRAPHY ............................................................................................................................. 221
9 ACKNOWLEDGEMENTS.................................................................................................................. 228
10 APPENDIX ................................................................................................................................... 229
10.1 ERKLÄRUNG .................................................................................................................................. 229
10.2 TEILPUBLIKATIONEN ........................................................................................................................ 230

II
ABSTRACT

ABSTRACT
This doctoral work describes catalytic asymmetric reactions between alkenes and
aldehydes, enabled by the development of chiral Brønsted acids. Valuable and
functionalized enantiomerically enriched cyclic compounds were efficiently furnished
from inexpensive and commercially available reagents with high degrees of atom
economy.
In the first part of this thesis, the first highly enantioselective organocatalytic
intramolecular carbonyl−ene cyclization of olefinic aldehydes is presented. In the second
part, asymmetric cyclizations via oxocarbenium ions are described. One is a general
asymmetric catalytic Prins cyclization of aldehydes with homoallylic alcohols, in which
the oxocarbenium ion is attacked intramolecularly by a pendent alkene. The other one is
an asymmetric oxa-Pictet−Spengler reaction between aldehydes and homobenzyl
alcohols, in which the oxocarbenium ion is trapped by an intramolecular arene. The first
general asymmetric [4+2]-cycloaddition of simple and unactivated dienes with aldehydes
is developed in the last part of this thesis. This methodology is extremely robust and
scalable. Valuable enantiomerically enriched dihydropyran compounds could be readily
obtained from inexpensive and abundant dienes and aldehydes.
New types of confined Brønsted acids were rationally designed and synthesized,
including imino-imidodiphosphates (iIDPs), nitrated imidodiphosphates (nIDPs), and
imidodiphosphorimidates (IDPis). Beyond the application of these catalysts in various
asymmetric reactions between simple alkenes and aldehydes, mechanistic investigations
are also disclosed in this doctoral work.

III
ABSTRACT

Diese Doktorarbeit beschreibt hochenantioselektive Reaktionen zwischen einfachen
Alkenen und Aldehyden, welche durch chirale Brønsted-Säuren als Katalysatoren
ermöglicht wurden. Wertvolle, hochfunktionalisierte und enantiomerenangereicherte
zyklische sowie heterozyklische Verbindungen wurden effizient und hochgradig
atomökonomisch, ausgehend von kommerziell erhältlichen und günstigen
Startmaterialien, hergestellt.
Im ersten Teil der Arbeit wird eine hochenantioselektive und organokatalytische
intramolekulare Carbonyl–En-Zyklisierung von olefinischen Aldehyden vorgestellt. Im
zweiten Teil werden zwei verschiedene asymmetrische Zyklisierungsreaktionen über
Oxocarbenium-Ionen beschrieben. Eine dieser Reaktionen stellt die katalytische Prins-
Zyklisierung von gängigen Aldehyden und homoallylischen Alkoholen dar, in welcher
das Oxocarbeniumion intramolekular mit einem nukleophilen Alkenrest reagiert. Die
andere Transformation beschreibt eine asymmetrische Oxa-Pictet–Spengler-Reaktion von
Aldehyden mit homobenzylischen Alkoholen, wobei das Oxocarbeniumion mit dem
aromatischen Ringsystem reagiert. Im letzten Teil der Arbeit wird die erste generelle
asymmetrische [4+2]-Cycloaddition zwischen einfachen und nichtaktivierten Dienen und
Aldehyden entwickelt. Diese Methode ist extrem robust und skalierbar. Wertvolle
enantiomerenangereicherte Dihydropyran-Verbindungen konnten ausgehend von
kommerziell erwerbbaren Dienen und Aldehyden hergestellt werden.
Neue Klassen sterisch anspruchsvoller Brønsted-Säuren wurden konzipiert und
synthetisiert. Hierbei standen Imino-Imidophosphate (IDPs), nitrierte Imidodiphosphate
(nIDP) und Imidodiphorsphoimidate (IDPi) im Fokus. Neben der Anwendung dieser
Katalysatoren in verschiedenen asymmetrischen Reaktionen, werden die erarbeiteten
mechanistischen Studien am Ende dieser Doktorarbeit beschrieben und erläutert.

IV
LIST OF ABBREVIATIONS

LIST OF ABBREVIATIONS
Ac acyl
ACDC asymmetric counteranion-directed catalysis
ad adamantyl
AIBN 2,2'-azo bisisobutyronitrile
Alk alkyl
An p-anisyl
aq. Aqueous
Ar aryl
9-BBN 9-borabicyclo[3.3.1]nonane
BHT 2,6-di-t-butyl-p-cresol
BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
BINOL 1,1'-bi-2-naphthol
BLA Brønsted acid assisted chiral Lewis acid
Bn benzyl
Boc tert-butyloxycarbonyl
BOM benzyloxymethyl
Bz benzoyl
Bu butyl
cacld calculated
cat. catalyst
Cbz benzyloxycarbonyl
conv. conversion
Cy cyclohexyl
d day
DCE 1,1-dichloroethane
DCM dichloromethane
DFT density functional theory
V
LIST OF ABBREVIATIONS

DIBAL diisobutylaluminum hydride
DIPEA diisopropylethylamine
DMAP N,N-4-dimethylaminopyridine
DMF dimethylformamide
DMP Dess-Martin periodinane
DMS dimethylsulfide
DMSO dimethylsulfoxide
dr diastereomeric ratio
DSI disulfonimide
EDG electron donating group
ee enantiomeric excess
EI electron impact
er enantiomeric ratio
equiv equivalents
Et ethyl
ESI electronspray ionization
EWG electron withdrawing group
FMO frontier molecular orbital
Fmoc 9-fluorenylmethoxycarbonyl
GC gas chromatography
h hour
HMDS 1,1,1,3,3,3-hexamethyldisilazane
HOMO highest occupied molecular orbital
HPLC high performance liquid chromatography
HRMS high resolution mass spectrometry
i iso
IDP imidodiphosphate
IDPi imidodiphosphorimidate
iIDP imino-imidodiphosphate
IR infrared spectroscopy
VI
LIST OF ABBREVIATIONS

L ligand
LA Lewis acid
LAH lithium aluminum hydride
LB Lewis base
LDA lithium diisopropylamide
m meta
m multiplet
M molar
mCPBA meta-chloroperbenzoic acid
Me methyl
MeCy methylcyclohexane
Mes mesityl
Ms mesyl (methanesulfonyl)
MS mass spectrometry or molecular sieves
MTBE methyl t-butyl ether
nd not determine
nIDP nitrated imidodiphosphate
nr no reaction
NMR nuclear magnetic resonance spectroscopy
Nu nucleophile
Ns 2-nitrobenzenesulfonyl
o ortho
P product
p para
piv pivaloyl
Ph phenyl
Pr propyl
PTC Phase transfer catalyst
Py pyridine
quant. quantitative
VII
LIST OF ABBREVIATIONS

quint quintet
rac racemic
rt room temperature
R retention factor in chromatography
f
S substrate
Salen bis(salicylidene)ethylenediamine
t tert, tertiary
t triplet
TADDOL α,α,α´,α´-tetraaryl-1,3-dioxolan-4,5-dimethanol
TBAF tetra-n-butylammonium fluoride
TBS tert-butyl(dimethyl)silyl
TEA triethylamine
Tf trifluoromethylsulfonyl
TFA trifluoroacetic acid
THF tetrahydrofuran
THP tetrahydropyran
TLC thin layer chromatography
TMEDA N,N,N’,N’-tetramethyl ethylenediamine
TMS trimethylsilyl
TOF turnover frequency
Tol p-tolyl
TON turnover number
TRIP 3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl-hydrogen
phosphate
TsOH para-toluene sulfonic acid
k Boltzmann constant: 1.3806488 × 10-23 J/K,
B
h Planck constant: 6.62606957 × 10-34 J⋅s.

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