In the thesis, the development of asymmetric organocatalytic [3+3] sequences for
the assembly of aminocyclitols is described. A water-based Wittig reaction was
developed in order to produce the key enal-based starting materials, which were
otherwise difficult to obtain commercially and synthetically. The enals derived from the
Witig reaction were employed in the synthesis of both natural products and synthetic
analogs of compounds in the amaryllidaceae family.
The [3+3] Michael-aldol sequence described herein provided regio-, diastereoand
enantioselective access to the core of the various targeted molecules, containing 3 to
4 defined stereocenters. The sequence was optimized via manipulation of the structures of
both the organocatalyst and base used leading to increased selectivity and yield.
Complete total synthesis of the natural product (+)-trans-dihydrolycoricidine was
achieved using the optimized organocatalytic Michael-aldol sequence. The most effective
catalyst/base combination for this synthesis was found to be a comercial
diphenylsilylprolinol ether and quinidine, which led to a dramatic reduction in the number
of synthetic steps taken to the final product, and highest yield, when compared to other
reported approaches: in 9 chemical steps, 12% overall yield and 98% e.e. were achieved.
Two non-natural analogues were also synthesized using this methodology in order
to probe the minimum pharmacophore of the amaryllidaceae derivatives, as they are
known to express anti-viral and anti-cancer activity for certain cell lines. (+)-3-
Deoxydihydrolycoricidine containing 4 chiral centers, was synthesized via the same [3+3]
Michael-aldol sequence as the natural product in 6 steps with 15% yield and >99% e.e.
Similarly, (+)-trans-3-epidihydrolycoricidine was obtained in 6 steps, 27% yield and
>99% e.e. The biological activity of these derivatives is yet to be examined.
This highly effective method for the preparation of chiral aminocycllitols can be
generalized toward the synthesis of numerous targets, which will be the focus of future
research. / Thesis / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/18192 |
| Date | 11 1900 |
| Creators | Zepeda-Velazquez, Carlos Armando |
| Contributors | McNulty, James, Chemistry |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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