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Attempts to synthesize spirocyclic GABA derivatives with a 5-membered heterocycle

Taschauer, Alexander (2012) Attempts to synthesize spirocyclic GABA derivatives with a 5-membered heterocycle.
Diploma thesis, University of Vienna. Faculty of Life Sciences
Supervisor: Urban, Ernst

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Abstract in German

The main task of this diploma thesis was the development of synthetic experiments to obtain spirocyclic GABA analogues with a 2-azaspiro [4.5] decane structure. We started with the alkylation of the carboxylic acid ester 1 with allyl bromide. The alkylated product 8 was converted to the corresponding aldehyde 10 by means of a Lemieux-Johnson oxidation. Reacting 10 with benzylamine gave us the imine 11. We then tried to synthesize the lactam 3 using NaCN (BH3), which is a mild reducing agent. Instead, however, an intramolecular reductive amination of the carbonyl function resulted in amine 15 as the main product. We therefore tried to develop a new synthetic scheme based on pimelic acid (16). We first synthesized cyclic pimelic anhydride (17). However, this reaction also produced a pimelic acid polymer (21). We then prepared the monoamide of pimelic acid (18) using benzylamine. The synthesis of the carboxylic acid ester 19 was carried out with the aid of methanol and p-TOS. We then tried to produce the β-ketoamide 20 by Dieckmann condensation with potassium tert-butoxide as a catalyst, although the β-ketoester 23 was the main product.

Keywords in German

GABA / epilepsy / spirocyclic GABA derivatives / ethyl cyclohexanone-2-carboxylate / pimelic acid / allyl bromide / Lemieux-Johnson oxidation / Dieckmann condensation

Abstract in English

The main task of that diploma thesis was the development of experiments for the synthesis of spirocyclic GABA analogues with a 2-Azaspiro [4.5] decane structure. First we started with the alkylation of the carboxylic ester 1 with allyl bromide. The alkylated product 8 was oxidized to the corresponding aldehydes 10 by a Lemieux-Johnson oxidation. By the reaction of 10 with Benzylamine we obtained the Imine 11. After that we tried to synthesize the Lactam 3 by use of NaCN (BH3) as a moderate reducing agent. But the reaction finally resulted in an intramolecular amination of the carbonyl group yielding the amine 15 as the main product. For that reason we tried to develop a new synthesis pathway by using pimelic acid (16) as the first reactant. First we synthesized the cyclic anhydride of the pimelic acid (17). A further product of that reaction was a polymer of the pimelic acid (21). After that we produced the Monoamide of the pimelic acid (18) by using Benzylamine. The synthesis of the carboxylic ester 19 was achieved by using Methanol and PTSA. Then we tried to synthesize the β-ketoamide 20 by Dieckmann-Condensation with Potassium tert.-butoxide as a catalyst, but we obtained the β-ketoester 23 as the main product.

Document Type: University thesis (diploma thesis)
Author:Taschauer, Alexander
Title:Attempts to synthesize spirocyclic GABA derivatives with a 5-membered heterocycle
Circumference:65, [approx. 110] p.: Graf. Darst.
Institution:University of Vienna
Faculty:Faculty of Life Sciences
Publication year:2012
Language:ger ... German
Supervisor:Urban, serious
Assessor:Urban, serious
Classification:35 Chemistry> 35.50 Organic Chemistry: General
AC number:AC09587906
Document ID:21727
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