Asymmetric Transformations Catalyzed By Chiral BINOL Alkaline Earth Metal Phosphate Complexes

205 Pages·2017·14.77 MB·English

University of South Florida
Scholar Commons
Graduate Theses and Dissertations Graduate School
10-26-2016
Asymmetric Transformations Catalyzed By Chiral
BINOL Alkaline Earth Metal Phosphate
Complexes
Sri Krishna Nimmagadda
University of South Florida, [email protected]
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Nimmagadda, Sri Krishna, "Asymmetric Transformations Catalyzed By Chiral BINOL Alkaline Earth Metal Phosphate Complexes"
(2016).Graduate Theses and Dissertations.
http://scholarcommons.usf.edu/etd/6554
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Asymmetric Transformations Catalyzed By

Chiral BINOL Alkaline Earth Metal Phosphate Complexes

by

Sri Krishna Nimmagadda

A dissertation submitted in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy
Department of Chemistry
College of Arts and Sciences
University of South Florida

Major Professor: Jon Antilla, Ph.D.
James Leahy, Ph.D.
Wayne Guida, Ph.D.
Jianfeng Cai, Ph.D.

Date of Approval:
October 19, 2016.

Keywords: asymmetric catalysis, organocatalysis, chiral alkaline earth metal phosphate,
oxazolidines, oxazinanes, hemiaminals, desymmetrization, dynamic kinetic resolution.

Copyright © 2016, Sri Krishna Nimmagadda
Acknowledgments

Firstly, I would like to thank my advisor Dr. Jon Antilla for giving me the opportunity to work
under his supervision and pursue my dream. He is an exceptional mentor, constantly motivating
me by giving suggestions personally and professionally and also believing in me to work
independently on my own projects and his guidance in times of need. I’m grateful that he allowed
me to do internship, which helped me not only to hone my skills in research but also enhanced my
exposure in the field of organic chemistry. I’m always indebted to him for the guidance,
exceptional support and being a good friend.
I would sincerely thank my committee members Dr. Wayne Guida, Dr. Jianfeng Cai, Dr. James
Leahy and Dr. Mark McLaughlin for their valuable insights during the meetings. I also like to
express my gratitude to Dr. Mike Shi for his passion towards chemistry and allowing me to sit in
his group meetings which really helped me to learn new chemistry and also kept me motivated.
I’m lucky to have very friendly colleagues in our lab, Dr. Guilong Li, Dr. Gajendrasingh Ingle,
Dr. Shawn Larson, Dr. Tao Liang, Dr. Youngran Ji, Dr. Susana Lopez, Trang and the
undergraduates who worked with me Jalak, Ian, Karissa, and like to thank everyone who helped
me directly or indirectly. Especially Dr. Pankaj Jain and Dr. Zuhui Zhang helped me during my
early years of grad school by teaching lab skills, science discussions and patiently answering my
questions.
I’m thankful for my friends outside lab Dr. Naga Duggirala, Dr. Srinivas Harinath, Dr.
Ramakanth, Dr. Padmini, Dr. Sridhar, Dr. Cyndi, Dr. Kurt, Dr. Praveen, Dr. Raghu, Dr. Xiaohan
Ye, Stephen Motika, Ankush Kanwar, Zachary Shultz, Robert Leon, Tirupathi Reddy for having
fun during weekends playing tennis, pool and softball. It always feels good to have good friends
especially when staying far away from family and I’m grateful to everyone.
Lastly, I would like to thank my parents, especially my dad who is a real role model for me
since childhood for encouraging me in everything, giving me confidence during bad times and all
his sacrifices. I would also like to thank my brother Pavan and sister Sarojini for being there all
the time for me. I would also thank my family members Prasad, Raja Sree, Subrahmanyam, Durga
Prasad, Jaya Sree and Venu for their continuous support.
Table of Contents
List of Tables ........................................................................................................................... iii

List of Figures .......................................................................................................................... iv

List of Abbreviations ............................................................................................................. viii

Abstract ................................................................................................................................ ix

1. Asymmetric reactions catalyzed by chiral alkaline earth metal complexes ........................1
1.1 Chirality and asymmetric synthesis .........................................................................1
1.2 Chiral alkaline earth metal complexes .....................................................................2
1.3 Activation mode of alkaline earth metal complexes ................................................3
1.4 Complexes with chiral bissulfonamide type ligands ...............................................4
1.5 Complexes with chiral BINOL type ligands ............................................................4
1.5.1 Reactions catalyzed by BINOL derived calcium complexes .............................6
1.5.2 Reactions catalyzed by BINOL derived barium complexes ..............................7
1.6 Complexes with chiral diol ligands..........................................................................8
1.7 Complexes with chiral phosphoric acid ligands ....................................................10
1.8 Complexes with chiral Bisoxazoline (Box) ligands...............................................14
1.9 Complexes with chiral Pyridine Bisoxazoline (Pybox) ligands ............................17
1.10 Conclusion .............................................................................................................19
1.11 References ..............................................................................................................19

2. Asymmetric one-pot synthesis of 1,3-oxazolidines and 1,3-oxazinanes via
hemiaminal intermediates ..................................................................................................22
2.1 Introduction ............................................................................................................22
2.2 1,3-oxazolidines as chiral auxiliaries .....................................................................23
2.3 1,3-oxazolidines as chiral ligands in asymmetric reactions ...................................24
2.4 Synthesis of chiral 1,3-oxazolidines ......................................................................25
2.4.1 Stereospecific synthetic methods .....................................................................25
2.4.2 Stereoselective synthetic methods ...................................................................27
2.5 Chiral BINOL phosphoric acids and alkaline earth metal phosphates ..................28
2.6 Asymmetric one-pot synthesis of 1,3-oxazolidines ...............................................32
2.7 Optimization of reaction conditions.......................................................................34
2.8 Substrate scope for one-pot synthesis of chiral 1,3-oxazolidines ..........................36
2.9 Asymmetric one-pot synthesis of 1,3-oxazinanes .................................................37
2.10 Substrate scope for one-pot synthesis of chiral 1,3-oxazinanes ............................39
2.11 Conclusion .............................................................................................................40
2.12 Experimental data ..................................................................................................40
2.13 References ..............................................................................................................51
i
3. Desymmetrization of 4-substituted cyclohexanones: Enantioselective synthesis of
novel axially chiral cyclohexylidene oximes .....................................................................55
3.1 Introduction ............................................................................................................55
3.2 Desymmetrization of cyclic ketones ......................................................................55
3.3 Desymmetrization reaction of cyclic ketones catalyzed by chiral BINOL
phosphoric acid ......................................................................................................62
3.4 Desymmetrization of cyclic ketones to form axially chiral compounds................63
3.4.1 Synthesis of axially chiral cyclohexylidenes ...................................................64
3.4.2 Synthesis of axially chiral cyclohexylidene oximes ........................................65
3.5 Optimization of reaction conditions for the asymmetric synthesis of
cyclohexylidene oximes .........................................................................................67
3.6 Substrate scope for the asymmetric synthesis of cyclohexylidene oxime
ethers ......................................................................................................................69
3.7 Conclusion .............................................................................................................72
3.8 Experimental data ..................................................................................................72
3.9 X-ray crystallography data .....................................................................................83
3.10 References ..............................................................................................................86

4. Dynamic Kinetic Resolution of 2-substituted cyclohexanones .........................................90
4.1 Introduction ............................................................................................................90
4.2 DKR by asymmetric transfer hydrogenation of 2-substituted
cyclohexanones ......................................................................................................91
4.3 Optimization of reaction conditions for dynamic kinetic resolution of
2-substituted cyclohexanones ................................................................................94
4.4 Substrate scope for the DKR of 2-substituted cyclohexanones .............................97
4.5 Conclusion .............................................................................................................97
4.6 Experimental data ..................................................................................................98
4.7 References ............................................................................................................106

Appendix I - HPLC and NMR data for Chapter 2 .................................................................109

Appendix II - NMR and HPLC data for Chapter 3 ................................................................143

Appendix III - NMR and HPLC data for Chapter 4 ..............................................................172

Appendix IV - Copyrights and Permissions ..........................................................................191

ii
List of Tables
Table 2.1 Optimization to find real catalyst ...........................................................................31

Table 2.2 Trace element analysis by ICP-OES ......................................................................31

Table 2.3 Optimization of reaction conditions for alcohol addition to imines ......................34

Table 2.4 Optimization of base mediated intramolecular cyclization ...................................35

Table 2.5 Optimization of reaction conditions.......................................................................38

Table 2.6 Optimization of base mediated intramolecular cyclization ...................................38

Table 3.1 Optimization of reaction conditions.......................................................................68

Table 3.2 Solvent and temperature screening ........................................................................69

Table 4.1 Optimization for DKR of 2-substituted cyclohexanones .......................................95

iii
List of Figures
Figure 1.1 Asparagine (1), Thalidomide (2)..............................................................................2

Figure 1.2 Activation mode .......................................................................................................3

Figure 1.3 Asymmetric reactions catalyzed by chiral bissulfonamide alkaline earth
metal complexes.......................................................................................................5

Figure 1.4 Chiral BINOL derived alkaline earth metal complexes ...........................................5

Figure 1.5 Calcium-BINOL complex catalyzed Morita-Baylis-Hillman reaction ....................6

Figure 1.6 Asymmetric reactions catalyzed by calcium-BINOL complexes ............................6

Figure 1.7 Asymmetric Aldol reaction catalyzed by barium-BINOL complex ........................7

Figure 1.8 Friedel-Crafts type alkylation catalyzed by barium-BINOL complex ....................8

Figure 1.9 Chiral calcium alkoxide catalyzed asymmetric aldol reaction ................................8

Figure 1.10 Asymmetric Mannich reaction catalyzed by barium biphenolate ............................9

Figure 1.11 Asymmetric reactions catalyzed by chiral barium and strontium
alkoxide complexes ..................................................................................................9

Figure 1.12 Chiral BINOL derived alkaline earth metal phosphate complexes .......................10

Figure 1.13 Asymmetric Mannich reaction catalyzed by calcium-BINOL
phosphate complex.................................................................................................11

Figure 1.14 Asymmetric reactions catalyzed by calcium-VAPOL phosphate complexes ........11

Figure 1.15 Asymmetric synthesis of aziridines .......................................................................12

Figure 1.16 Asymmetric phosphination, Diels-Alder and hetero-Diels-Alder
reactions catalyzed by metal-BINOL phosphate complexes .................................12

Figure 1.17 Asymmetric carbonyl-ene reaction and Friedel-Crafts reaction
catalyzed by calcium-BINOL phosphate complex ................................................13

iv
Figure 1.18 Calcium-BINOL phosphate catalyzed asymmetric amination reactions ...............14

Figure 1.19 Chiral bisoxazoline-calcium complexes ................................................................14

Figure 1.20 Chiral Box-calcium complexes catalyzed asymmetric 1,4-addition
and [3+2] cycloaddition reactions ..........................................................................15

Figure 1.21 Asymmetric 1,4-addition and [3+2] cycloaddition reactions ................................16

Figure 1.22 Chiral calcium-Pybox complexes ..........................................................................17

Figure 1.23 Calcium-Pybox catalyzed asymmetric 1,4-addition and Mannich reactions .........17

Figure 1.24 Asymmetric 1,4-addition and Mannich reactions ..................................................18

Figure 2.1 Polycyclic tetrahydroisoquinoline alkaloids ..........................................................22

Figure 2.2 Reactions with 1,3-oxazolidines as chiral auxiliaries ............................................23

Figure 2.3 Chiral 1,3-oxazolidine ligands ...............................................................................24

Figure 2.4 Asymmetric allylic alkylation and Diels-Alder reactions ......................................24

Figure 2.5 Condensation of chiral aminoalcohols with aldehydes and ketones ......................25

Figure 2.6 Double Michael addition reaction ..........................................................................26

Figure 2.7 Formal cycloaddition of vinyl epoxides with imines .............................................26

Figure 2.8 Asymmetric oxyamination and formal cycloaddition reactions for
stereoselective synthesis of chiral oxazolidines .....................................................27

Figure 2.9 Chiral phosphoric acids..........................................................................................28

Figure 2.10 General synthetic scheme for the preparation of chiral BINOL phosphoric
acid .........................................................................................................................29

Figure 2.11 Asymmetric Mannich reactions catalyzed by chiral BINOL phosphoric
acid .........................................................................................................................30

Figure 2.12 Chiral BINOL metal phosphate complex ..............................................................32

Figure 2.13 Enantioselective addition of alcohols to imines.....................................................33

Figure 2.14 Retrosynthetic pathway ..........................................................................................33

v
Figure 2.15 Substrate scope for chiral 1,3-oxazolidines ...........................................................37

Figure 2.16 Substrate scope for one-pot synthesis of chiral 1,3-oxazinanes ............................39

Figure 3.1 Tandem aminoxylation and O-N bond heterolysis of cyclohexanones .................56

Figure 3.2 Asymmetric aldol reaction of cyclohexanones with aldehydes .............................56

Figure 3.3 Asymmetric intramolecular aldolization................................................................57

Figure 3.4 Desymmetrization and intramolecular aldolization ...............................................58

Figure 3.5 Enantioselective Friedländer condensation ............................................................59

Figure 3.6 Asymmetric alkylation of cyclohexanones catalyzed by functionalized
chiral ionic liquids (FCIL) .....................................................................................59

Figure 3.7 Desymmetrization of cyclohexanones by asymmetric Michael addition ..............60

Figure 3.8 Catalytic desymmetrizing asymmetric ring expansion ..........................................61

Figure 3.9 Asymmetric Baeyer-Villiger oxidation ..................................................................61

Figure 3.10 Chiral BINOL phosphoric acid catalyzed Baeyer-Villiger oxidation....................62

Figure 3.11 Catalytic enantioselective Fischer indolization .....................................................63

Figure 3.12 Axially chiral compounds ......................................................................................63

Figure 3.13 Asymmetric HWE reaction ....................................................................................64

Figure 3.14 Asymmetric Peterson reaction ...............................................................................65

Figure 3.15 First isolation of optically active cyclohexylidene oximes ....................................66

Figure 3.16 Enzyme catalyzed kinetic resolution of cyclohexylidene oxime ethers ................67

Figure 3.17 Substrate scope with different aryloxyamines .......................................................70

Figure 3.18 Substrate scope with different 4-substituted cyclohexanones ...............................71

Figure 3.19 Synthesis of 4-aryl cyclohexanones……………………………………………...73

Figure 3.20 Synthesis of aryloxyamines………………………………………………………73

Figure 4.1 Dynamic Kinetic Resolution (DKR) process .........................................................90
vi