Show simple item record

dc.contributor.advisorFisher, Jed F.
dc.contributor.authorDeZwaan, Jennifer
dc.description.abstractTryptamine (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.en
dc.description.sponsorshipMedicinal Chemistry Resaerch . Pharmacia and Upjohn, Inc. Kalamazoo, Michigan.
dc.relation.ispartofseriesSenior Individualized Projects. Chemistry.en
dc.rightsU.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder.
dc.titleAsymmetric Synthesis of B-Substituted Tryptaminesen

Files in this item


This item appears in the following Collection(s)

  • Chemistry Senior Individualized Projects [889]
    This collection includes Senior Individualized Projects (SIP's) completed in the Chemistry Department. Abstracts are generally available to the public, but PDF files are available only to current Kalamazoo College students, faculty, and staff.

Show simple item record