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Studies from a number of laboratories have led to prostaglandin analogs of high potency and increased specificity largely by variation of the ω chain, that is the alkyl unit beyond C-15: particularly intriguing analogs being the 16,16-dimethyl-,3 20-ethyl-,4 and various substituted 16-benzyloxy-nor-17,18,19,20-prostaglandin analogs.5 At present these are prepared by the standard Corey route,6 in which ω-ylation precedes α-ylation.

The optical resolution of three isomers of DL-β-(6-carboxy-α′-pyronyl)alanine was carried out by chemical as well as enzymatic methods and six optically active isomers were obtained. The configuration of each aspartic acid, derived from the ozonolysis of these optical isomers in aqueous solution, was analyzed enzymatically using glutamic-oxaloacetic transaminase and malate dehydrogenase. By the same procedure, the configuration of the two natural amino acids, stizolobic acid and stizolobinic acid, was confirmed and both were assigned the L-form. Thus the absolute configuration of six optical active isomers of β-(6-carboxy-α′-pyronyl)alanine and the two natural amino acids is assigned unequivocally, and the relationship between the synthetic and the natural amino acids is established.

A growth factor (TJF) for a malo-lactic fermentation bacterium has been isolated from tomato juice, and found to be a β-glucoside. The NMR spectra of TJF and its acetate revealed that the glucosyl residue linked to the hydroxyl group at C-2′ or C-4′ of d- or l-pantothenic acid moiety. Then, 2′-O-(β-d-glucopyranosyl)-dl-pantothenic acid (I), 4′-O-(β-d-glucopyranosyl)-dl-pantothenic acid (II) and 4′-O-(β-d-glucopyranosyl)-d(R)-pantothenic acid (II-a) were synthesized, and Il-a and 4′-O-(β-d-glucopyranosyl)-l-pantothenic acid (II-b) were obtained by the optical resolution of the acetate of II. Among the above compounds, II-a was identical with natural TJF regarding to the biological activity, NMR and ORD spectra, and thin-layer chromatography.

A growth factor (TJF) for a malo-lactic fermentation bacterium has been isolated from tomato juice, and found to be a β-glucoside. The NMR spectra of TJF and its acetate revealed that the glucosyl residue linked to the hydroxyl group at C-2′ or C-4′ of d- or l-pantothenic acid moiety. Then, 2′-O-(β-d-glucopyranosyl)-dl-pantothenic acid (I), 4′-O-(β-d-glucopyranosyl)-dl-pantothenic acid (II) and 4′-O-(β-d-glucopyranosyl)-d(R)-pantothenic acid (II-a) were synthesized, and Il-a and 4′-O-(β-d-glucopyranosyl)-l-pantothenic acid (II-b) were obtained by the optical resolution of the acetate of II. Among the above compounds, II-a was identical with natural TJF regarding to the biological activity, NMR and ORD spectra, and thin-layer chromatography.

Prostaglandin analogs of the PGF2 alpha, 15-epi-PGF2 alpha, and PGE2 type bearing the following methyl substitution patterns -- 15-Me, 16, 16-(Me)2, 17, 17-(Me)2, and 18, 18, 20-(Me)3 -- and analogs constrained to "hairpin" alignment [via 1, (omega-1)-olide formation] and to "non-hairpin" arrangements [via 1, 9- and 1, 15-olide formation] are compared in the following biological assays: contraction of uterine and gastro-intestinal smooth muscle strips, luteolytic antifertility potency in the hamster, binding affinity to two different PGF2 alpha-receptor preparations from bovine corpora lutea, binding to the PGE-specific receptors from rat kidney and liver, inhibition of ADP- induced aggregation of human platelet-rich-plasma, and the effect on rat blood blood pressure. The methylated prostaglandins were also concerted to the corresponding prostacyclins and examined as to action on the platelet and on rat blood pressure. All evidence points to topographically distinct receptors for F2 alpha-, E- and I2- type prostaglandins. Cross-reactivity is reduced in most of the analogs examined. Independent of the target organ or tissue, the receptors show common features based on the functional class of PG recognized. "Hairpin" alignment improves binding (and potency) only for the PGF2 alpha specific assays. PGE-specific binding and potency is disrupted to an increasing extent as the chain branching point is moved further from the 15-hydroxyl center. In contrast 16, 16-dimethylation is particularly disruptive for the PGI2/E1 platelet receptor interaction.

Our previously published prostaglandin (PG) synthesis route, in which the omega-chain is added in the penultimate step, provides facile access to a wide variety of omega-chain variant PG analogs. Each series requires only the synthesis of the appropriate methylated acylphosphonate for the Emmons' condensation. The syntheses of analogs bearing the following methylation patterns are detailed: 15-Me; 17,17-(Me) 2; 17, 17, 20-(Me) 3; 18, 18, 20-(Me) 3; 15, 18, 18, 20-(Me) 4; and 15-OMe-18, 18, 20- (Me) 3. The well-known 16., 16-dimethyl prostaglandins have also been prepared by this sequence. The synthesis of 16, 16-tetramethylene-PG analogs is also described.

Publisher Summary This chapter discusses the syntheses of glycosyl derivatives of pantothenic acid and pantetheine. It is well known that wine maturation involves a bacterial conversion of malic acid to lactic acid, this process is designated as “malo-lactic fermentation” (MLF). MLF occurs following an alcoholic fermentation in wine making; it not only reduces the acidity of wine but also improves its quality. The growth factor has been isolated from tomato juice and named TJF; it is characterized as 4'-O-(β-D-glucopyranosyl)-o-pantothenic acid. TJF can be substituted with a large amount (about 100 times) of D-pantothenic acid for its growth. D-Pantothenic acid is widely distributed in nature and well known to be a precursor of coenzyme A. The metabolism of pantothenic acid to coenzyme A in microorganisms is described in the chapter; the initial reaction is phosphorylation at the C-4' hydroxyl group of pantothenic acid.

Prostaglandin analogs of the E- and F2α-functional type, which are constrined to conformations in which the side-chains are close in space and specifically aligned in the terminal portions by covalent bonding, have been synthesized. These analogs are 1, (ω-1)-macrolides. The syntheses proceed from aldehyde intermediate I via the Emmon's condensation with dimethyl n-(dimethyl-t-butyl-silyloxy) 2-oxoalkylphosphonate anions (IIa or b). The macrolide closures were performed using 2,2′-dipyridyl disulfide. For the synthesis of 9-ketoprostaglandin macrolides, a free 9-hydroxy is available for oxidation after macrolide closure, so long as the 9-position is protected as the acetate rather than benzoate. Chiroptical data revealed that the conformations of the macrolide prostaglandins are unchanged (relative to the natural uncosntrained prostaglandins) in the vicinity of the five-membered ring and the allyl alcohol unit by the formation of the macrolide linkage.

Der Pantothensaureester (II) wird mit den Zuckerderivaten (I) nach den im Formelschema angegebenen einfachen Umsetzungen in die 4′-O-β-D- Glykoside (V) der Pantothensaure umgewandelt.