Cyclohemiacetals

Furo[3,4-c]pyridin-4-one derivatives have been prepared from 3,4-disubstituted furans (Scheme 20). Thus Michael addition of acetoacetic esters to /rans-3-hexene-2,5-dione gives adducts with a cyclohemiacetal structure (90) which easily dehydrates to furan derivatives (91) by treatment with acid. These compounds are suitable intermediates for the preparation of furo[3,4-c]pyridin-4-ones and furo[3,4-c]pyranones (Section 3.17.2.2.1) (78JHC993). These latter compounds are far more stable than the previously described furo[3,4-c]-pyridine itself. 

Probing the Oxo-Cyclo Tautomerism of Natural Enantiomeric Cyclohemiacetals with 2,4-Dihydroxy-2i7-l,4-benzoxazin-3(4Ff)-one Skeleton... 

Due to the existence of additional four chiral centres to the anomeric centre a- and p-D-glucose are diastereomers and can be analytically distinguished and separated, easily. It shall be pointed out, that the same process has not been investigated yet on the level of enantiomeric cyclohemiacetals, which have no chiral centre besides the anomeric one. Therefore, hemiacetals like DIBOA or DIMBOA have also been of interest from the viewpoint of physical organic chemistry (Fig. (6)). 

On principle, both the hydroxamic acid and the hemiacetal are partially oxidised structures. Thus, the hydroxamic acid should be accessible both fi-om a nitro precursor by reductive cyclisation and from a lactam by N-oxidation (Fig. (7)). Similarly, access to the hemiacetal should e.g. be possible by oxidation of a 2-methylene group as well as by reduction of a 2-carbonyl group, and also by hydrolysis of a 2-haIogen function. The influence of substituents at the aromatic ring on the synthesis of the 1,4-benzoxazinone ring is hardly foreseeable. However, another circumstance has a very rational basis. Due to the fact that the structural instability arises from the cyclohemiacetal (see Fig. (4)) this tmit is prepared at the very end of most syntheses. 

The ring-opening addition of 2-dialkyIamino tetrahydropyran [59] or 1,3-oxazoIidine [60], leading to formation of acetylenic alkylamino alcohols has been reported. In the same way, substituted aldose, which has the structure of cyclohemiacetals, yields dihydroxy alkynes (see Table 4, entries 7-9) [61]. 

Modern concepts of organic chemistry have provided interpretation and explanation for a variety of supposedly anomalous and unusual reactions of carbohydrate compounds. These concepts have often been derived from a study of relatively more simple substances in which there has been little complication resulting from interfering and conflicting factors. Consequently, direct application of these concepts to the more complex carbohydrate compounds without due consideration of alternative possibilities may result in oversimplification and a false picture. Despite such inherent hazards, it is believed that a useful purpose can be served by the correlation and discussion of the carbohydrate reactions with direct reference to analogous properties of simpler organic compounds. For this objective, we can define the acyclic forms of the aldoses as polyhydroxy-aldehydes, and their cyclic forms as polyhydroxy-cyclohemiacetals. In these compounds, besides the additive, inductive effect of the hydroxyl... 

Acetyl chloride added with stirring to a mixture of dry benzene, abs. pyridine, and abs. methanol, after 20 min. 16 g. dl-z1 -3-ethylenedioxy-llj -hydroxy-14,15f-oxido-16,18-dioxoandrostene cyclohemiacetal and dihydropyran added, and... 

The reduction of the lactone grouping of compound (119) required the preliminary protection of the two keto groups. Reaction with ethylene glycol formed the diketal, the controlled reduction of which with lithium aluminum hydride enabled the cyclohemiacetal (118) to be obtained. In itself, the reduction takes place with a high yield and the main difficulty is the deketalization of the extremely unstable compound (118). Consequently, the products of lithium aluminum hydride reduction were immediately acetylated with acetic anhydride to a mixture of the 21-mono-and 18,21-diacetates. Hydrolysis of this mixture with 90% acetic acid at 100 C led to the 21-acetate of dl -aldosterone (123). Deacetylation of the latter with potassium carbonate gave not only dl -aldosterone (124) with a yield of 50%, but also its 17o -epimer. Natural -aldosterone was obtained by the same route from the tZ-enantiomer of (119). By Wettstein s first method (Scheme 66), cZZ-aldosterone (124) was formed from Sarett s ketone (67) in 22 stages with an over-all yield of 1.7%. 

An attempt has also been made to form ring D from Sarett s ketone (67) by cyclizing 14,16-diketones to D-homo derivatives [761] (Scheme 69). On undergoing the Michael reaction in an anhydrous medium, the oxalyl and formyl derivatives (168) R = C02Et and R = H, respectively) of the initial ketone (67) formed, with the axial entry of the side chain, compounds with the 13q -configuration of the angular substituent (169) which shows the unsuitability of these products for the formation of 11,18-cyclohemiacetals. The cyclization of (169) under mild conditions gave the spirane derivatives... 

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