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 Público
Pereira, Claney Lebev (2010)
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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