Chapter 1. Total synthesis of Fumonisin B1 Chapter 2. Synthesis of Unnatural Sphingolipids: 1-deoxy-5-hydroxysphinganine and its diastereomers Chapter 3. Development of Methodology: Synthesis of cis- and trans-homoallylic alcohols Chapter 4. Human Milk Oligosaccharides: Synthesis of Natural and Unnatural oligomers Open Access

Pereira, Claney Lebev (2010)

Permanent URL: https://etd.library.emory.edu/concern/etds/fq977t86j?locale=en
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Abstract

Chapter 1. Total synthesis of Fumonisin B1: The first total synthesis of fumonisin
B1, a sphingolipid biosynthesis inhibitor was achieved. The synthesis used the 2-
oxonia-[3, 3]-sigmatropic rearrangement methodology developed in the Mc-
Donald laboratory, thereby demonstrating the utility of these rearrangements in
total synthesis. The synthesis also confirmed the assigned stereochemistry and
the biological profile of the natural product.
Chapter 2. Synthesis of Unnatural Sphingolipids, 1-deoxy-5-hydroxysphinganine
and its diastereomers: Utilizing 2-oxonia-[3, 3]-sigmatropic rearrangements, we
synthesized cis- and trans-homoallylic alcohols which were converted to the
epoxides. Epoxide opening using an azide nucleophile and azide reduction gave
the respective 1-deoxy-5-hydroxysphinganine sphingolipid compounds.
Chapter 3. Development of Methodology, Synthesis of cis- and trans- homoallylic
alcohols: Diastereo- and enantioselective synthesis of branched homoallylic
synthons were achieved. These were then used to synthesize the linear cis- and
trans-homoallylic alcohols through a 2-oxonia-[3, 3]-sigmatropic rearrangement.
Chapter 4. Human Milk Oligosaccharides (HMO), Synthesis of Natural and
Unnatural oligomers: Natural HMO's 2'-fucosyl actose, 3-fucosyl actose and
unnatural HMO 2'-glucoseptanosyl actose were synthesized using a lactose
derived acceptor and a fucosyl or septanosyl derived donor. The synthesis
utilised a greener approach of using non-toxic reagents and milder reaction
conditions for the preparation of mono- and disaccharide synthons.

Table of Contents

Table of Contents
Chapter 1. Total synthesis of Fumonisin B1

1.1. Introduction and background ............................................................................... 2
1.1.1. Biological significance of fumonisins .......................................................... 4
1.2. Synthetic studies on fumonisins ......................................................................... 8
1.3. Why a synthetic endeavour for fumonisin B1? ................................................ 10
1.4. Synthetic strategy towards the total synthesis of FB1 (1) .............................. 12
1.4.1. Initial approach ................................................................................................ 12
1.4.2. The unexpected rearrangement ................................................................ 15
1.4.3. Total synthesis of FB1 (1), the new approach .......................................... 19
1.5. Results and Discussions .................................................................................... 20
1.5.1. Synthesis of left hand alkyne fragment 38 ............................................... 20
1.5.2. Synthesis of synthon 47 for 2-oxonia-[3, 3]-Cope rearrangement ....... 22
1.5.3. Synthesis of aldehyde 48 for 2-oxonia-[3, 3]-Cope rearrangement .... 23
1.5.4. 2-oxonia-[3, 3]-Cope rearrangement studies ........................................... 24
1.5.5. Synthesis of right hand fragment 39, the Weinreb amide ..................... 25
1.5.6. A new approach towards tricarbal ylic acid (TCA) fragment 40 ........... 26
1.5.7. Coupling and completion of the total synthesis of fumonisin B1 (1) ..... 29
1.5.8. Towards the synthesis of FB1-aminopentol (HFB1) 11, and FB1-
hexaacetate 24 ........................................................................................................... 31


1.6. Biological evaluation of synthetic fumonisin B1 (1) ......................................... 33
1.7. Conclusions .......................................................................................................... 35
1.8. Experimental details ........................................................................................... 36
Chapter 2. Synthesis of Unnatural Sphingolipids: 1-deoxy-5-
hydroxysphinganine and its diastereomers

2.1. Introduction and Background ............................................................................ 84
2.2. De novo synthesis of sphingolipids .................................................................. 87
2.3. Biological significance of sphingolipids generated from biosynthesis ........ 89
2.4. Role of Sphingolipids in regulating cancer ...................................................... 90
2.5. Synthesis of 1-deoxy-5-hydroxysphinganine and their analogs .................. 91
2.5.1. Synthesis of 1-deoxy-5-hydroxysphinganine compounds by Liotta et al.

……………………………………………………………………………….92
2.5.2. Synthesis of 1-deoxy-5-hydroxy compound isoenigmol (32) by Sakia et
al………………………………………………………………………………………96
2.5.3. Synthesis of 1-deoxy-5-hydroxy analog compound, 2- N-Boc-amino-
3,5-diols by Dias et al. ............................................................................................... 96
2.5.4. Second generation approach towards 1-deoxy-5-hydroxysphinganine
compounds enigmol (31) and isoenigmol (32) ...................................................... 97
2.5.5. Synthesis of internal aminodiol 1-deoxy-5-hydroxy analog compound
80……………. ............................................................................................................. 99


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