Asymmetric Synthesis of B-Substituted Tryptamines
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Authors
DeZwaan, Jennifer
Issue Date
2001
Type
Thesis
Language
en_US
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Abstract
Tryptamine (3-indoleethanamine) is the core structure of not only an important
neurotransmitter (serotonin, 5-hydroxy-3-indoleethanamine) but many eNS-active
natural products (for example, lysergic acid) and synthetic drugs (for example, the triptan
anti-migraines). An important limitation in the synthesis of tryptamine derivatives is the
absence of an enantiospecific method for tryptamine ~-substitution. This limitation was
the objective of this study. The specific objectives of this research addressed these related
questions: Is the Yonemitsu reaction - a versatile three-component, proline-catalyzed
condensation that is an excellent method for the synthesis of racemic ~-substituted
tryptamine derivatives - applicable to the synthesis of indole-substituted tryptamine
(especially indoles having electron-withdrawing substitution)? What is the role of the proline
catalyst, and can this catalyst be dispensed with (or replaced by another catalyst)? Is
there, among the catalysts available to control reaction enantioselectivity, one applicable
to the Yonemitsu reaction? The following observations were made. The Yomemitsu
reaction is applicable to indoles with electron-withdrawing substitution. Although this
substitution attenuates the indole nucleophilicity, excellent yields were obtained for the
(racemic) Yonemitsu when both a chloro and fluoro-substituted indole was used. Proline
was confirmed as a kinetic catalyst for the Yonemitsu. With L-proline as a catalyst, the
isolated Yonemitsu product is racemic. Moreover, the requirement for proline can be
bypassed. Using a new method to generate the reactive 5-alkylidene-l,3-dioxane-4,6-
dione Yonemitsu intermediate, the second step (that of indole alkylation) is seen to
proceed in good yield. These observations identify the optimal experimental approach for
the development of an enantioselective Yonemitsu reaction. Rather than a one-pot
reaction, where proline catalyzes the formation of the 2-alkylidene-l ,3-dioxane-4,6-dione
intermediate, this intermediate is generated separately. This intermediate is then added to
the indole, in the presence of a new catalyst to control enantioselective indole alkylation.
Several new catalysts were examined using this protocol, one of which was [3aS-
[2(3'aR*, 8'aS*), 3'aa, 8'a]l(-)-2,2' Methylenebis [3a,8a-dihydro-8H-indeno[1,2,-d]-
oxazole]. The reaction using this catalyst along with the 5-alkylidene-l ,3-dioxane-4,6-
dione Yonemitsu intermediate and the indole did not produce an enantiomeric enriched
product. The rationale for this was believed to be due to the catalyst's inability to bind
with the 5-alkylidene-l, 3-dioxane-4, 6-dione. The project then shifted towards making
Yonemitsu intermediates whose geometry were more conducive for the binding of the
box catalyst. Possible methods include using malonate instead of Meldrum's acid and 2-
pyridinecarbaldehyde as the aldehyde. These Yonemitsu reactions were most
successfully made using the Bigi protocol, and will be the focus of future research.
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