Carboxylic acid amid 4,5-dihydroxy

Ring closures with ninhydrin 4,5-Dihydroxy-2-pyrrolidone ring from carboxylic acid amides... 

It was anticipated that fragments 147 and 214 could be united through an amide bond linking the nitrogen atom of the latter with C-8 of the former. Indeed, the active ester formed by treatment of carboxylic acid 147 with 1,3-diisopropylcarbodiimide and 1-hydro-xybenzotriazole reacts efficiently with amine 214 to afford dihydroxy amide 215 in 95 % yield. This convergent union creates a molecule that possesses all but two carbon atoms of the natural product. 

The highly ordered cyclic TS of the D-A reaction permits design of diastereo-or enantioselective reactions. (See Section 2.4 of Part A to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.80 The cycloaddition proceeds to give two diastereomeric products that can be separated and purified. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best diastereoselectivity is observed in catalyzed reactions. Several chiral auxiliaries that are capable of high levels of diastereoselectivity have been developed. Chiral esters and amides of acrylic acid are particularly useful because the auxiliary can be recovered by hydrolysis of the purified adduct to give the enantiomerically pure carboxylic acid. Early examples involved acryloyl esters of chiral alcohols, including lactates and mandelates. Esters of the lactone of 2,4-dihydroxy-3,3-dimethylbutanoic acid (pantolactone) have also proven useful. 

In the second route to l,20 acid chloride 23, prepared by treatment of 5-chlorothiophene-2-carboxylic acid 28 with SOCl2 is coupled with (5)-3-amino-1,2-propanediol hydrochloride 29 in the presence of NaHCCh to furnish the dihydroxy amide 30 (Scheme 3). The primary alcohol in 30 is then brominated by a solution of HBr in HOAc to produce the bromohydrin 31, which is then condensed with the morpholinoaniline derivative 18 to yield 32. Finally, the ring closure with N,N -carbonyldiimidazole (CDI) afforded 1. 

Sphingosine is a base with a technical name of D-erythro-1,3-dihydroxy-2-amino-4-/ra -octadecene. In gangliosides, the base forms an acid amide linkage between the amino group in position 2 of the base and the carboxyl group of the fatty acid. This complex of base and fatty acid is named ceramide. 

The biosynthesis of novobiocin has been reviewed 52, and the formation in cell-free extracts of novobiocic acid has been described 53. The latter can be formed from 3-am1no-4, 7-dihydroxy-8-methvl coumarin (B ring) and 4-hydroxy-3(3-methyl-2-butenyl)benzoic acid (A ring) by an enzyme that forms an amide bond between these precursors. Energy (ATP) is required but the mode of activation of the carboxyl group is unknown. Novobiocin itself possesses a sugar (noviose) but its biosynthesis and the formation of the glycosidic link are little studied 52. 

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