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Ainara Lecumberri Munárriz recently defended her PhD thesis at the Public University of Navarre, in which the applicability of new inductors derived from camphor in asymmetric alkylation and Diels-Alder reactions was studied.
Spatially selective synthesis
Assymetric synthesis is the process by which the molecule is made to react solely on one side. This is of interest because carbons are tetrahedral and the properties of the molecules depend on how their atoms are situated in space. In order to understand the importance of this process, we can look to the thalidomide drug of the 1970s, which was given to pregnant women to allay vomiting. The medicine had a spatial formation which, while stopping vomiting, caused malformations in the fetus, and the result was children born without hands, or arms or legs. It was as a result of this that the synthesis f molecules with a specific spatial situation was seen to be significant and, since then, great importance has been attached to stereoselective or 'spatially selective' synthesis.
In the Phd entitled, "The use of a´-hydroxyketones derived from camphor in asymmetric alkylation and Diels-Alder reactions", it was proposed to optimise the conditions for producing this type of asymmetric reactions, based on camphor derivatives. After attempting different types of reactions, the ones chosen for investigation were the alkylation and Diels-Alder reactions, used for the synthesis of organic molecules, i.e. to form carbon links. In concrete, the alkylation ones to introduce substituents - alkyl or carbonated chains -, and the Diels-Alder reactions to form more complex molecules.
Her research confirmed the viability of the alkylation reactions carried out with ketones derived from camphor. Thus, using acetylene and alkyl halides, easily accesible and cheap products provide a wide variety of optically active alpha-substituted carbonylic compounds, incorporating all the carbon atoms of the substrates of the initial batch, which gives a sequence with a significant economy of atoms, i.e. a number of traditional steps in obtaining the end product are avoided. Thus, we undertook the first asymmetric variant of the classical method for transforming acetylene into alpha-substituted carboxyl compounds in a chemo-, regio- and stereoselective manner.
Also determined, for the first time, was a procedure for the asymmetric alpha-chiral hydroxyketone Diels-Alder reaction obtained from the(R)-(+)-camphor and methoxyalene, using Brönsted acids as catalysts. To date metallic catalysts have been used – derivatives of titanium, aluminium, copper, etc. Nevertheless, given that the absence of metal traces is evermore important in medication, effective organic actalysts are of great interest. Thus, in the PhD thesis it was demonstrated that, based on the corresponding cycloaducts, high-purity enantiomeric acids and ketones can be accessed easily and, moreover, the Chiral information source is recovered.
Alzheimer therapeutic agent
Over the past three decades alkylation in the alpha position of carbonylic compounds has been one of the most popular ways of forming carbon-carbon links in a regio- and stereoselective manner. The use, as Chiral auxiliaries, of oxazolidinones developed by Evans has laid down the guidelines in this field for more than a decade. Amongst the camphor derivatives used in asymmetric alkylation, special attention has been given to the Oppolzer N-acyl sultames.
Aminoalcohol derivatives have also been used. However, asymmetric alkylation based on the employment of ketone enolates has been considerably less developed, above all due to problems of regioselectivity and polyalkylation. Ketones,which have been used in aldolic and Mannich reactions, are both easily accesible from commercial products and also the alkylation aducts are transformed easily to carboxylic acids, aldehydes or alkylated ketones, and enable the recovery of the Chiral source of information. In this way, first, preparation of the camphor-derived a-hydroxymethylketone was carried out by means of a sequence of two reactions that involve the addition of lithium acetylide to camphor and the subsequent hydratation of the triple link. Once the a´-trimethylsiloxyketones were prepared, we decided to carry out a study of the reaction of their corresponding enolates with methyl iodide as the electrophile. In every case just one isomer was obtained with yields of between 78 and 85%.
The end target was to enantiomerically synthesise pure carbonylic a-substituted compounds with recovery of the Chiral source of information. Obtaining a-substituted acids was achieved using oxidant excision with cerium nitrate and ammonia at 0şC for an hour, obtaining acids with yields of about 90%. With the same treatment and in a simple manner, the initial batch of camphor was obtained from the organic phase with yields of between 85% and 90%, thus recovering the Chiral source of information, one of the other aims put forward. It should be emphasised that, by a simple change in the alkylation sequence, we can access one or other of the isomers.
The method described above for the alkylation of a´-hydroxyketonts derived from (R)-(+)-camphor is efficient both for reactive halides as well as for less reactive ones. Thus, it was decided to apply the same to obtaining (R)-2-propyloctanoic acid, a therapeutic agent for the treatment of Alzheimer and its enantiomere, the (S)-2-propyloctanoic acid, obtaining both with a global yield in the region of 50 % and with optical purities greater than 98%.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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