Lactone Hudson rule

The absolute chemistry of reserpine has been derived directly (135), by making use of Klyne s extension of the Hudson lactone rule (147) as applied to reserpic acid and its lactone, as well as by the application of Prelog s asymmetric synthesis (148) to methyl reserpate (149). These results are in agreement with the conclusions obtained by more indirect but no less accurate means (91). 

Digitoxose, therefore, represents a case wherein the Hudson lactone rule fails insofar as the lactones of digitoxonic and digitoxosecarboxylic acids are concerned, a behavior paralleled by D-allonic acid lactone of which digitoxose is a derivative. At the same time, the diamide of the glutaric acid obtained on oxidation of digitoxose now obeys Hudson s amide rule in the light of the above observations and also the lactone of this acid obeys the lactone rule. 

Hudson lactone rule. The value of the rotation of aldonic acid lactones is decisively affected by the configuration of that carbon atom whose hydroxyl group is engaged in the cyclization. If, in the normal Fischer projection formula, the lactone ring is written on the right, the lactone is dextrorotatory if it is written on the left, the lactone is levorotatory. 

Absolute configurations were first assigned to alkaloids of this section both by chemical transformations to compounds in the lycorine series where Mills rule had been applied and by Klyne s modification of the Hudson lactone rule. This extension states that lactones possessing the absolute configuration of XLVII are more positive in molecular rotation than derivatives in which the lactone ring is opened. If this rule is applicable to the alkaloids of this section, the conversion of homolycorine (XLVIII [M]d -f-268°) to tetrahydrohomolycorine (XLIX [M]d —322°) requires that homolycorine and tetrahydrohomolycorine have the absolute configurations shown in XLVIII and XLIX. These assign-... 

The a-oriented lactone configuration (LXVIII) was originally favored by us (8) and by Stork and Newman (33). The latter authors arrived at this conclusion from their observed molecular rotation difference between the C-2-epi-tetrahydrogibberellic acid and the corresponding dibasic acid obtained by opening the lactone ring. They interpreted this value (+75°) in a rather doubtful manner in terms of Klyne s application (24) to polycyclic compounds of Hudson s lactone rule. 

In the process of lactonization of L-tryptophan or its DNP-derivative a second asymmetric center is formed, probably stereoselectively, by induction from the existing center. Opening of this DNP-lactone and application of Hudson s rule (cf. Witkop, 1956 Vanderhaeghe and Parmentier, 1961) has so far pointed to the Dq structure for the spirooxindole-/3-carbon (Ramachandran, 1961), but this preliminary observation on a colored lactone derivative must await conformation from, e.g., a carbobenzyloxy lactone derivative. 

Fried, Walz and Wintersteiner isolated 4-desoxy-i/-glycero-tetrose phenylosazone (XLII) from the reaction of streptobiosamine hydrochloride with phenylhydrazine and thus demonstrated that streptose was configurationally an l sugar. The levorotation ([a] o —37°, water ) of streptosonic acid monolactone (XXIII) might also be adduced as contributory evidence for the l configuration of the penultimate carbon of streptose, should Hudson s lactone rule be applicable to this rather complex structure. 

Although the adoption of Hudson s lactone rule allowed the tentative assignment of configuration, 3R,6R, to the (— )-tropan-3a,6)3-diol (37) (see Volume VI, pp. 161-162), corroboration by correlation seemed necessary. 6/3-Methoxytropinone 38) was resolved and correlated with natural valeroidine and with (S -methoxysuccinic acid 39a). The dextrorotatory ketone XXIX was converted into (— )-3 ,6 S-diacetoxytropane... 

A comparison of the molecular rotations of lycorine and 2-epilycorine provided the first evidence for the absolute configuration of alkaloids of the lycorine type by the application of Mills rule. The development of suitable chemical methods of interconversion between the lycorine- and lycorenine-type alkaloids permitted an additional correlation between the two types by the Hudson-Klyne lactone rule. These assignments have recently been shown to be correct by X-ray crystallographic methods (65). With these findings the structure and absolute configuration of lycorine is described by I (R, Ri = H). The absolute configurations of many of the alkaloids discussed in Section III also are secure because these alkaloids have been interrelated and converted to known compounds of the lycorine series. 

The absolute configuration of annotinine shown in I was resolved by Wiesner et al. (76). Three independent methods were used, all of which led to the same conclusion. The ORD-curve of XXVI, the relative stereochemistry of which has been demonstrated, showed a negative rotation maximum at 322 mp, [a] — 3450°. Application of the octant rule led to the absolute configuration shown in structure XXVI. Application of Hudson s lactone rule on annotinine hydrate led to the same conclusion. The Prelog method, when applied to compound VII, which must have the C-11 hydroxyl group cis to the bridge, was in agreement with the other methods. 

The first of these was van t Hoff s principle of optical superposition, namely, that, in a compound having two or more asymmetric carbon atoms, the optical activities of the individual atoms can be added algebraically. This principle was applied with considerable success to carbohydrates by Hudson, in the form of his well known isorotation, lactone, and amide rules. These rules have been reviewed elsewhere, " and will not be discussed here. 

Stiller and associatesin the Merck laboratories a little less than a year after the collaboration began isolated the lactone from concentrates, and determined its structure by classical methods to be -hydroxy-/5,/ -dimethyl-y-butyrolactone. This was synthesized and resolved into its optical isomers. The levo-rotatory lactone when condensed with /3-alanine by various pro-ceduresi >22>2 yields dextro-rotatory pantothenic acid with full biological activity. The antipode was found to be inactive. The biologically active form has, according to Hudson s amide rule, the D-configuration24.2s. 

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