GABOB and carnitine

This section will focus on 4-amino-3-hydroxybutanoic acid (GABOB, 6.27) and its trimethylammonium derivative (carnitine, 6.25). The R and S enantiomers of each amino acid are designated 6.27a and 6.27b ox 628a and 6.28b, respectively. These amino acids are generally prepared by the methods described in previous chapters, but their biological importance has led to a variety of synthetic approaches. 

R-(-)-GABOB is an inhibitory neurotransmitter24 that has been used in the treatment of human epilepsy.25 It also has hypertensive properties.26 Interestingly, GABOB was first prepared by Tomita in 1923.27 Carnitine is used to treat myocardial ischemia and carnitine deficiency. a it is also important for the transport of long chain fatty acids through the mitochondrial membrane and is used for the treatment of myopathic deficiency.39 

Synthetic Strategies Based on Functional Group Interchange Reactions 

A common synthetic approach to GABOB uses epichlorohydrin (6.29) as a starting material. In a simple example, 6.29 was treated with potassium phthalimide and sodium cyanide to give GABOB (6.27), after hydrolysis and removal of the phthalimidoyl group.3 In one variation of this reaction, the intermediate phthal-imidoyl product was isolated prior to ti atment with cyanide. 2 The reaction can be 

A strikingly different strategy reaeted 6.29 with methanolie carbon monoxide to give 6.30 via reaction at the epoxy carbon. When the chlorine moiety in 6.30 

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The silatropic ene pathway, that is, direct silyl transfer from an silyl enol ether to an aldehyde, may be involved as a possible mechanism in the Mukaiyama aldol-type reaction. Indeed, ab initio calculations show that the silatropic ene pathway involving the cyclic (boat and chair) transition states for the BH3-promoted aldol reaction of the trihydrosilyl enol ether derived from acetaldehyde with formaldehyde is favored [60], Recently, we have reported the possible intervention of a silatropic ene pathway in the catalytic asymmetric aldol-type reaction of silyl enol ethers of thioesters [61 ]. Chlorine- and amine-containing products thus obtained are useful intermediates for the synthesis of carnitine and GABOB (Scheme 8C.26) [62],... 

C4 chiral synthetic units are also important for the syntheses of pharmaceuticals and their intermediates. For example, optically active 4-chloro-3-hydroxybutyrate (CHB) and 4-chloro-3-hydroxybutyronitrile (BN) are key compounds as C4 chiral building blocks for the syntheses of L-carnitine [16], l-GABOB [17], / -hydroxybuty-ric acid, 3-hydroxy-y-butyrolactone, and 4-hydroxy-2-pyrrolidone. Recently, CHB has been reported as being used for synthesizing an intermediate for HMG-CoA reductase inhibitor for hyperlipidemia (Fig. 11) [18]. 

The use of bromodeoxy lactones as chiral building blocks for the stereoselective preparation of natural compounds was also explored. Thus, both (5)-and (J )-carnitine, (S)- and (J )-4-amino-3-hydroxybutanoic acid (GABOB), compounds of high relevance for the central nervous system, as well as musc-aridine and 6-deoxyascorbic acid, were prepared by simple transformations of the bromodeoxy aldonolactones. 

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