Exploring the Synthetic Application of Allylic Alcohol Isomerization by Youwei Xie BS, Jilin ...

199 Pages·2014·4.25 MB·English

Exploring the Synthetic Application of Allylic Alcohol Isomerization
by
Youwei Xie
B.S., Jilin University, Changchun, China, 2006
M.S., Syracuse University, Syracuse, US, 2009
Submitted to the Graduate Faculty of the
Dietrich School of Arts and Sciences in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy
University of Pittsburgh
2014
UNIVERSITY OF PITTSBURGH
DIETRICH SCHOOL OF ARTS AND SCIENCES
This dissertation was presented
by
Youwei Xie
It was defended on
December 1, 2014
and approved by
Dr. Karen Arndt, Professor, Department of Biological Sciences
Dr. Kay M. Brummond, Professor, Department of Chemistry
Dr. Kazunori Koide, Associate Professor, Department of Chemistry
Dissertation Advisor: Dr. Paul E. Floreancig, Professor, Department of Chemistry
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Copyright © by Youwei Xie
2014
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Exploring the Synthetic Application of Allylic Alcohol Isomerization
Youwei Xie, PhD
University of Pittsburgh, 2014
Allylic alcohol transposition lacks a thermodynamic driving force and usually displays stereo-
infidelity and poor regioselectivity. However, regio- and stereoselectivity can be achived by
coupling allylic alcohol transposition to a subsequent step that is kinetically and
thermodynamically favorable. Based on this rationale, the allylic alcohol transposition and
capture sequence was delevoped and applied successfully in heterocycle synthesis. Regio- and
stereoselectivity were achieved when a pre-existing stereogenic center in the substrates could
induce significant thermodynamic difference between diastereomeric products and when the
individual steps toward these diastereomeric products were reversible.
Epoxides were later used as ennantioenriched electrophiles in this transposition/trapping
sequence for stereoselective synthesis of heterocycles. The mechanism for this transformation
was elucidated and a cascade approach using epoxides as trapping agents in the transposition of
allylic alcohols was developed and applied in the stereoselective formation of polycyclic ethers.
Finally, an improved sequence using “traceless trapping agents” was developed. This
new method did not leave any vestige in the resulting product and offered much more freedom
for the application of allylic alcohol transposition in heterocycle synthesis. Understanding the
relative rates of the steps in this new sequence led to the design of reactions that created multiple
stereogenic centers with good to excellent levels of control.
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TABLE OF CONTENTS
PREFACE ................................................................................................................................... XV

1.0
  INTRODUCTION ............................................................................................................... 1

1.1
  ALLYLIC ALCOHOL ISOMERIZATION ............................................................. 2

1.1.1
  Allyl ester isomerization .................................................................................. 2

1.1.2
  Allylic alcohol isomerization catalyzed by metal-oxo complexes ................. 3

1.2
  MECHANISM OF METAL-CATALYZED [1,3]-TRANSPOSITIONS OF
ALLYLIC ALCOHOLS ...................................................................................................... 7

1.2.1
  Mechanism of allylic isomerization catalyzed by oxovanadium complexes 7

1.2.2
  Mechanism of Ph SiOReO -catalyzed [1,3]-allylic alcohol transposition by
3 3
Osborn ........................................................................................................................... 8

1.2.3
  Mechanism of Ph SiOReO -catalyzed [1,3]-transposition proposed by
3 3
Grubbs ......................................................................................................................... 11

1.3
  APPLICATION OF ALLYLIC ALCOHOL ISOMERIZATION ....................... 12

1.3.1
  Enhanced selectivity by extended conjugation ............................................ 13

1.3.2
  Enhanced selectivity by consecutive transposition and silylation ............. 15

1.3.3
  Enhanced selectivity by trapping with boronates ....................................... 16

1.3.4
  Enhanced selectivity by ring contraction ..................................................... 17

1.3.5
  Enhanced selectivity via reversible trapping by benzylidene acetal ......... 18

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1.3.6
  Enhanced selectivity by dynamic kinetic resolution (DKR) ....................... 19

2.0
  STEREOSELECTIVE HETEROCYCLE SYNTHESIS THROUGH A
REVERSIBLE ALLYLIC ALCOHOL TRANSPOSITION AND NUCLEOPHILIC
ADDITION SEQUENCE ........................................................................................................... 20

2.1
  RESEARCH OBJECTIVES AND SUBSTRATE DESIGN .................................. 21

2.2
  RESEARCH RESULTS AND DISCUSSIONS ...................................................... 22

2.2.1
  Application to the synthesis of medium-sized cyclic ethers ........................ 22

2.2.2
  Application to the synthesis of bridged bicyclic acetals .............................. 28

2.2.3
  Application to the synthesis of bicyclic spiroketals ..................................... 29

2.2.4
  Application to the synthesis of spirotricycles .............................................. 33

2.3
  CONCLUSION .......................................................................................................... 35

3.0
  CASCADE APPROACH TO STEREOSELECTIVE POLYCYCLIC ETHER
FORMATION: EPOXIDES AS TRAPPING AGENTS FOR TRANSPOSING ALLYLIC
ALCOHOLS ................................................................................................................................ 36

3.1
  RESEARCH DESIGN AND OBJECTIVES ........................................................... 37

3.2
  INITIAL RESULTS ON MONOCYCLIZATION AND DISCUSSIONS ........... 38

3.2.1
  Results for monocyclization .......................................................................... 38

3.2.2
  Efforts toward understanding the lack of selectivity .................................. 41

3.3
  INCORPORATION OF EPOXIDE OPENING INTO A CASCADE
PROCESS...………………………………………………………………………………..44

3.3.1
  Trapping the hydroxyl group following epoxide opening .......................... 44

3.3.2
  Cascade reactions using ketones as stereochemical conduits ..................... 46

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3.3.3
  Combined use of a ketone as a stereochemical conduit and an enone as a
trapping agent............................................................................................................. 51

3.4
  DEVELOPMENT OF A EASILY USABLE CATALYST .................................... 51

3.5
  CONCLUSION .......................................................................................................... 53

4.0
  HETEROCYCLE SYNTHESIS BASED ON ALLYLIC ALCOHOL
TRANSPOSITION USING TRACELESS TRAPPING GROUPS ....................................... 54

4.1
  RESEARCH DESIGN AND OBJECTIVES ........................................................... 55

4.2
  RESULTS AND DISCUSSIONS .............................................................................. 56

4.2.1
  Validation of the new method and initial substrate reactivity studies ...... 56

4.2.2
  Establishment of the reaction scope ............................................................. 58

4.2.3
  Development of a reaction with diastereocontrol ........................................ 62

4.3
  CONCLUSION .......................................................................................................... 68

APPENDIX A .............................................................................................................................. 70

APPENDIX B ............................................................................................................................ 103

APPENDIX C ............................................................................................................................ 135

BIBLIOGRAPHY ..................................................................................................................... 177

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LIST OF TABLES
Table 1.1 Isomerization of aryl secondary allylic alcohols .......................................................... 14

Table 2.1 Exploration of the reaction scope ................................................................................. 25

Table 3.1 Efforts toward improving the diastereoselectivity in the epoxide opening .................. 42

Table 4.1 Factors that influence the diastereoselectivity .............................................................. 64

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LIST OF FIGURES
Figure 2.1 HPLC traces of racemic and enantioenriched 2-70 from racemic and enantioenriched
substrate 2-69 using a chiral stationary phase ............................................................................... 32

Figure 2.2 HPLC traces of 2-78 and 2-79 using chiral stationary phase ...................................... 34

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LIST OF SCHEMES
Scheme 1.1 [1,3]-transposition of allylic alcohols or allylic silyl ethers catalyzed by metal-oxo
complexes ....................................................................................................................................... 1

Scheme 1.2 Mechanism of “cyclization-induced” rearrangement .................................................. 3

Scheme 1.3 Metal-oxo complex vs late transition metal-catalyzed isomerization ......................... 4

Scheme 1.4 Examples of isomerizations catalyzed by Bu NReO /pTsOH•H O ........................... 5

4 4 2
Scheme 1.5 Mechanism of the [1,3]-transposition of allylic alcohols proposed by Chabardes ..... 9

Scheme 1.6 Mechanism of [1,3]-allylic alcohol transposition proposed by Osborn ..................... 9

Scheme 1.7 Consequence of E/Z isomerization on selectivity ..................................................... 10

Scheme 1.8 Mechanism of allylic [1,3]-transposition proposed by Grubbs and coworkers ........ 11

Scheme 1.9 Oxorhenium complex catalyzed allylic alcohol isomerization ................................. 13

Scheme 1.10 Enhancing regioselectivity by selective silylation .................................................. 15

Scheme 1.11 Allylic transposition of silyl ethers and subsequent Suzuki coupling of cyclic vinyl
boronic acid ................................................................................................................................... 16

Scheme 1.12 Ring-contractive allylic transposition of cyclic silyl ethers .................................... 17

Scheme 1.13 Regio- and stereocontrol of allylic alcohol isomerization by benzylidene acetal
formation ....................................................................................................................................... 18

Scheme 1.14 Synthesis of optically active allyl esters via Lipase-Vanadium combo catalysis ... 19

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