Superimposed lateral control of structure and reactivity exemplified by enantiospecific synthesis of (+)- and (-)-gabaculine

Abstract

Gabaculine (6, R = H), a naturally occurring amino acid,2 is a potent inhibitor of 4-aminobutyrate:2-oxoglutarate animotransferase (GABA-T), the major GABA catabolizing enzyme. Blocking of this enzyme leads to a buildup of GABA brain levels which may be useful in the treatment of certain diseases characterised by a deficiency of GABA function, e.g., Parkinsonism,3 epilepsy and, Schizophrenia.4 The synthesis of analogues for pharmacological examination is therefore desirable. The enzyme-activated mechanism of action of gabaculine has been studied5 and is shown in Scheme I.

An iron carbonyl approach to the influenza neuraminidase inhibitor oseltamivir

“…Introduction of the BOC-amine was then achieved through a protocol similar to that used by Birch and co-workers in their synthesis of (+)-and (2)-gabaculine. 19 Treatment of each individual enantiomer of 3 with an excess of BOC-NH 2 in CH 2 Cl 2 at 0 uC over 20 min gave (+)-5 and (2)-5, respectively. Slow addition of the base, as well as dry and inert conditions, are important to achieve high yields (86%) in this reaction.…”

“…It should be noted that while the selected chiral reagent is used in excess and is quite expensive, the majority can readily be recovered from both the initial reaction and upon elimination. While assignment of absolute configuration can be suggested at this point, through comparison to literature for the corresponding methyl ester cationic iron carbonyl complexes, 19 it was necessary to advance both enantiomers to an identical known literature compound for confirmation.…”

Applications of biocatalytic arene ipso,ortho cis-dihydroxylation in synthesis

“…The chemistry outlined in Scheme 17 was also applied to formal syntheses of oseltamivir 33 and gabaculine. 34 In 2013 we revisited the inosaminoacid chemistry we had described two years previously, this time targeting structures bearing a side chain in a lower oxidation state; 35 these were anticipated to have differing solubilities to the zwitterionic inosaminoacids 107-108 shown in Scheme 13. The chemistry bears many similarities to the previous report, but one notable difference is the reversal in regioselectivity for the acylnitroso cycloaddition when the side chain is in a lower oxidation state (Scheme 18).…”

Nucleophile Cleavable Linker Units

“…The fact that PS-TFP is also commercially available makes the active ester 62 more suitable as a linker system. Nevertheless, amine nucleophiles react very rapidly with cationic complexes [25] making this a useful approach even for less sterically hindered amines.…”