Enantioselective Allylation and Vinylation of Carbonyls, Imines and Alkenes

220 Pages·2016·7.8 MB·English

by  Shiyong Peng

Enantioselective Allylation and
Vinylation of Carbonyls, Imines and
Alkenes
Huang Yuan
(M. Sc. NUS)
ATHESIS SUBMITTED
FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
DEPARTMENT OF CHEMISTRY
NATIONALUNIVERSITY OF SINGAPORE
2016
Declaration
I hereby declare that this thesis is my original work and it has been written by me in
its entirety, under the supervision of Prof. Zhao Yu, Department of Chemistry,
National University ofSingapore, betweenJan. 2012and Dec.2015.
I have duly acknowledged all the sources of information which have been used in the
thesis.
This thesis has also notbeen submittedforany degree in any university previously.
The content ofthe thesis has been published in:
1)Y.Huang,L. C.Yang, P.L.Shao,Y.Zhao,Chem. Sci. 2013,4,3275-3281.
2) Y. Huang, C. Ma, Y. X. Lee, R. Z. Huang, Y. Zhao, Angew. Chem. Int. Ed.
2015,54,13696-136700.
3) Y. Huang §, R. Z, Huang §,Y. Zhao, J. Am. Chem. Soc. 2016, just accepted.(§
Co-first author)
HuangYuan
Name Signature Date
I
Acknowledgements
Itis my great pleasure to take this opportunity to express my gratitudeand thanks
to all the people who have helped and encouraged me during my Ph.D. studies.
Nothing in this thesis would have been possible without each and every one of you.
Thank you!
First and foremost, I want to express my deepest respect and most sincere
gratitude tomy supervisor, Prof. Dr. Zhao Yu, foroffering me the great opportunity to
be his Ph.D. student and guiding me to the intriguing and challenging field of
asymmetric Lewis base and cobalt catalysis. Dr. Zhao is a great supervisor to me. He
has great passion and enthusiasm for organic chemistry. As my advisor, he has
inspired me in the research and helped me out with a lot of things in life. I was lucky
to have him as my advisor. His influence on me will be a fortune for the rest of my
life.
I wish to express my warm and sincere thanks to Dr. Shao Pan Lin, Dr. Ma
Chao, Dr.Zhang Yao, Dr.Liu Tan Lin,Dr.Lu Shen Ci and Dr.Pederes, Monissa who
have helped me enormously with my research projects in National University of
Singapore. Special thanks to Huang Rui Zhi, Yang Li Cheng, Ng Jie Qi, Lee Yi Xin,
Tan Li Hong for their contribution in exploring novel chiral Lewis base catalysis and
asymmetric cobalt catalysis. This thesis would be impossible without their generous
help.
I am truly grateful to all my labmates in Dr. Zhao’s lab, past and present, Dr.
Yan Hai Long, Dr. Sim, Sui Boon Derek, Siau Woon Yew, Pan Hui Jie, Liao Jia Yu,
II
Wang Min, Lim Ching Si, Rong Zi Qiang, Poh Si Bei, Wang Ya Nong, Kok,
Germaine Pui Yann, Lee, Jin Tu Danence, Chen Yong Jun, Ng Teng Wei etc., whose
effective collaboration, helpful discussion and friendship have greatly helped me
during my fouryears’life and studies.
I also want to thank the research scholarship provided by National University of
Singapore. In addition, I want to extend my gratitude to all the laboratory staff of our
department of chemistry, particularly Madam Tan Geok-Kheng and Mr. Bruno
Donnadieu for X-raycrystallography analysis, Dr.Wu Ji-En and Madam HanYan-Hui
forNMR training and problem shooting, Madam WongLai Kwai and Dr.Yuan Cheng
Hui for mass analysis. Thanks also go to the administrative and technical staff,
especially Madam Suriawati Binte Sa’Ad in our department administrative office, Mr.
Lee Yoon-Kuang, Mr. Phua Wei-De Victor, Mr. Ong Shao-Ren and Madam Lim May
-Lee in our lab supply store.
I would also like to express my sincere thanks to all my friends in Singapore for
their help during the past four years. I will definitely miss and treasure their
friendships.
Finally, my deepest gratitude goes to my family for their unflagging love and
supportthroughoutmy life. THANK YOU!
III
Table ofContents
Declaration...........................................................................................................................I
Acknowledgements...........................................................................................................II
Table ofContents.............................................................................................................IV
Summary........................................................................................................................VIII
List ofTables......................................................................................................................X
List ofFigures..................................................................................................................XI
List ofSchemes...............................................................................................................XII
List ofAbbreviations................................................................................................XVIII
Chapter 1 Review on Asymmetric Vinylation of Carbonyls, Imines and Alkenes
Using Organometallic Reagents....................................................................................23
1.1Importance of asymmetric vinylation.................................................................24
1.2Synthetic utility ofasymmetric vinylation.........................................................25
1.3Asymmetric vinylation ofaldehydes..................................................................27
1.3.1Vinylzinc addition......................................................................................27
1.3.2Vinylsilane reagent....................................................................................30
1.3.3Vinylboronreagent....................................................................................34
1.4Asymmetric vinylation ofketones......................................................................36
1.4.1Vinylzirconocene reagent..........................................................................36
1.4.2Vinylaluminum reagent.............................................................................38
1.4.3Vinylboronreagent....................................................................................38
1.5Asymmetric vinylation ofimines........................................................................39
IV
1.5.1Organocatalytic asymmetric vinylationof imines..................................39
1.5.2Asymmetric vinylation ofimines mediatedby transition metal............46
1.5.2.1Hydrozirconation/transmetallation withzinc................................46
1.5.2.2 Transition metal catalyzed diastereoselective 1,2-addition of
alkenylboronreagents toimines.................................................................48
1.5.2.3 Transition metal catalyzed enantioselective 1,2-addition of
alkenylboronreagents toimines.................................................................49
1.6Asymmetric vinylation ofalkenes......................................................................52
1.6.1Enantioselective 1,4-conjugatevinylation...............................................52
1.6.1.1Vinylic zirconium reagent..............................................................53
1.6.1.2Vinylic aluminum reagent..............................................................55
1.6.1.3Vinylic silane reagent......................................................................56
1.6.1.4Vinylic organoboronreagent..........................................................57
1.6.2Enantioselective asymmetric allylic vinylation.......................................60
1.6.2.1Vinylaluminum reagent..................................................................60
1.6.2.2Vinylboronate reagent.....................................................................62
1.7Conclusions and futureperspectives..................................................................65
Chapter 2 Practical, Highly Stereroselective Allyl- and Crotysilylation of
Aldehydes Catalyzed byReadilyAvailable CinchonaAlkaloidAmides................66
2.1Introduction...........................................................................................................67
2.1.1Importance of allylation............................................................................67
2.1.2Types ofallylation.....................................................................................67
V
2.1.3Cinchona alkaloid derivatives in asymmetric catalysis..........................69
2.2Results and discussion.........................................................................................75
2.3Conclusions...........................................................................................................88
2.4Experimentalsection............................................................................................88
2.4.1General information...................................................................................88
2.4.2General procedureforenantioselective allylationofaldehydes............90
2.4.3General procedureforone-potcatalyst synthesis.................................102
2.5Miscellaneous.....................................................................................................105
Chapter 3 Cobalt-Catalyzed Allylation of Heterobicyclic Alkenes: Ligand-
InducedDivergent Reactivities...................................................................................109
3.1Introduction.........................................................................................................110
3.1.1The stereoselective allylation..................................................................110
3.1.1.1Conjugateallylation ofα,β-unsaturated carbonyls.....................110
3.1.1.2Allyl-allyl cross coupling reactions.............................................111
3.1.2Asymmetric cobalt catalysis...................................................................113
3.2Results and discussion.......................................................................................116
3.3Conclusions........................................................................................................126
3.4Experimentalsection..........................................................................................127
3.4.1General information................................................................................127
3.4.2General procedureforCo-catalyzedallylationofoxabicylic alkenes128
3.4.3Analytical dataofhydroallylationproducts..........................................129
3.4.4Analytical dataofallylative ring opening products..............................138
VI
3.4.5Procedures forderivatizationofallylation products.............................146
3.5Miscellaneous.....................................................................................................153
Chapter 4 Cobalt-Catalyzed Asymmetric Vinylation of Alkenes, Carbonyls and
Imines...............................................................................................................................155
4.1Introduction........................................................................................................156
4.2Results and discussion.......................................................................................158
4.3Conclusions........................................................................................................170
4.4.1General information................................................................................170
4.4.2General procedureforcobalt-catalyzed enantioselective vinylation...172
4.4.2.1Cobalt-catalyzed enantioselective vinylation of oxabicyclic
alkenes........................................................................................................172
4.4.2.2Cobalt-catalyzed enantioselective vinylation ofketone esters..178
4.4.2.3Cobalt-catalyzed enantioselective vinylation ofaldehydes.......189
4.4.2.4Cobalt-catalyzed enantioselective vinylation ofimines.............191
References.......................................................................................................................207
VII
Summary
One research interest of Dr. Zhao’s group is to develop efficient methodologies
for the enantioselective C－C bond formation for constructing potentially useful
building blocks. The catalytic allylation and vinylation have been developed into one
of the powerful tools for C－C bond forming reaction. This thesis describes my
efforts during my Ph.D. research aimed towards the development of Lewis
base/cobalt-catalyzed enantioselective allylation and vinylation reactions that result in
the formationofmany biologically and pharmaceutically important intermediates.
Chapter 1 provides a comprehensive review of catalytic asymmetric vinylation of
carbonyls, imines and alkenes by the use of organometallic reagents.
Chapter 2 describes Lewis base-catalyzed practical, enantioselective allylation and
crotylation of aldehydes (and imines). It has been demonstrated that bidentate Lewis
base catalysts can be constructed based on the Cinchona alkaloild structure, which
promote highly stereoselective reaction of allyl- and crotyltrichlorosilane with
aromatic as well as aliphatic aldehydes. Gram-scale reactions with catalyst recovery
and reuseshowcased the practicality ofthe catalytic system.
Chapter 3 presents cobalt-catalyzed allylation of heterobicyclic alkenes. By using
inexpensive cobalt salt as the catalyst and easy-to-handle potassium
allyltrifluoroborate as the reagent, an unprecedented formal hydroallylation of the
bicyclic alkenes is realized in high efficiency. When a chiral cobalt-bisphosphine
complex is used instead, the alternative ring opening products can be obtained in high
yield and excellent enantioselectivity.
VIII
Chapter 4 introduces an efficient method of cobalt-catalyzed enantioselective
vinylation of alkenes, carbonyls and imines. The method utilizes commercially
available vinyl boronic acid and readily available starting material, and employs a
direct Co(II)-catalyzed addition procedure. The efficiency, selectivity and operational
simplicity of the transformations and the broad range of electrophiles are expected to
render this methodology important for the synthesis of chiral allylic alcohols and
amines which areuseful in chemistry,biology and medicine in the future.
IX