The Control of Stereoselectivity and Regioselectivity both in Intramolecular and Intermolecular Carbon-Oxygen Bond-Forming Reactions Open Access

Ding, Dian (Spring 2019)

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The McDonald laboratory recently discovered epimerization of a chiral center in conversion of aldehyde to alkyne. We have now found that the Colvin rearrangement is a superior alternative for this conversion, proceeding without epimerization. Tungsten-catalyzed cycloisomerizations of the resultant cis- and trans-substituted benzylidene alkynes were performed to investigate the ring-size selectivity of tungsten cyclization. The results demonstrated that the regioselectivity of this cycloisomerization reaction was affected by the stereochemistry of the alkynyl diol substrate.

Stereoselective preparation of 1,2-cis-glycoside linkages are notoriously difficult. This type of structure is featured in many bioactive oligosaccharides such as the human tumor antigen Globo-H. Cyclization of alkenyl ether intermediate is a non-traditional way to prepare 1,2-cis-glycoside, but there lacks methodology for stereoselective synthesis of structurally complex alkenyl ethers. We aim to develop protocols for stereospecific intermolecular transalkenylations with alkenyl ester synthetic intermediate and carbohydrate alcohol to form the alkenyl ether. A model system starting from 1-hexyne has been developed to study the catalytic transalkenylation with an alcohol. Relay cross metathesis of a diene intermediate produced from a carbohydrate was also investigated as an alternative to stereoselectively synthesize the alkenyl ether. 

Table of Contents

Introduction                                                                                                                          1

Chapter 1: Alkynylation of Pentose Derivatives with Stereochemical Fidelity and Regioselective Cycloisomerization of the Alkynyldiol Products

1.    Background                                                                                                                   2

2.1 Ohira-Bestmann Protocol which leads to epimerization                                       3

2.2 Alkynylation via Colvin rearrangement of benzylidene protected pentose       4

i.              Alkynylation via Colvin rearrangement                                                           5

ii.            Spectroscopic data for all alkynyldiol diastereomers                                    6

2.3 Tungsten catalyzed cyclization of 3,4-cis and trans benzylidene alkyne           7

i.              Cycloisomerization of alkynyldiol products                                                    7

ii.            Stereochemistry, ring size, and spectroscopic data of cyclic enol ethers   9

3.    Conclusions                                                                                                                10

Chapter 2: Stereoselective Synthesis of Alkenyl Ether                                

1.    Background                                                                                                                 11

2.1 Intermolecular Transalkenylation of alkenyl acetate and alcohol                   12

i.              Substrate synthesis for model system                                                          13

ii.            Catalysts and ligands screening for transalkenylation                              14

2.2 Relay Cross Metathesis                                                                                              18

i.              1,6-Diene substrate synthesis                                                                        18

ii.            Relay metathesis using Grubbs catalyst                                                        20

3.    Conclusions                                                                                                                 20

Chapter 3: Experimental Methods                                                                                 22

Chapter 4: References                                                                                                       37


Figure 1. Structure of thalidomide enantiomers                                                                          1

Figure 2. Examples of pyranose and septanose nucleosides                                                      2

Figure 3. Proposed mechanism for epimerization                                                                       5

Figure 4. Proposed mechanism for regioselective cycloisomerization                                    8

Figure 5. Structure for the human tumor antigen Globo-H                                                      11

Figure 6. Non-traditional approach to synthesize the challenging glycoside linkage        12


Scheme 1. Synthesis of septanose 5 with epimerization                                                            3

Scheme 2. Synthesis of septanose 9a-b with epimerization                                                      4

Scheme 3. Colvin rearrangement to synthesize alkynes without epimerization                   5

Scheme 4. Cycloisomerization of ribo- and lyxo- alkynyl diols 10 and 11a-b                        8

Scheme 5. Synthesis of carbohydrate-derived alcohol 16 and alkenyl ester 19                    13

Scheme 6. Synthesis of hexenyl acetate 22                                                                                   14

Scheme 7. Preparation for precursor of Wittig reagent                                                              19


Equation 1. Synthesis of vinyl ether from galactose derivative                                             14

Equation 2. Proposed transalkenylation with 22 and 27                                                      15&17

Equation 3. Relay cross metathesis between diene and vinyl ether                                      18

Equation 4. Synthesis of diene 31                                                                                                 19


Table 1. Chemical shifts and coupling constants for alkynyl diols 4, 8a-b, 10, and 11a-b          6

Table 2. Chemical shifts and coupling constants for the septanose 5, and 9a-b, and the pyranose 12, and 13a-b                                     9

Table 3. Select catalysts and ligand screen results for transalkenylation and new proton NMR peaks found in 5 – 7 ppm                     16

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