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The syntheses and biological evaluations of (23R)- and (23S)-24,24-difluoro-1 alpha,23,25-trithydroxyvitamin D3 (3a and 3b), new C-24 fluorinated analogs of 1 alpha,25-dihydroxyvitamin D3, are described. The syntheses of these compounds were achieved in 3 steps from (5Z,7E,20R)-1 alpha,3 beta-bis-[(tert-butyldimethylsilyl)oxy]-20-formylmethyl-9,10-seco- 5,7,10(19) pregnatriene (5) which is derived from vitamin D2. The absolute configuration at the C-23 position of 3a and 3b was determined by the modified Mosher method. The relative affinities of 3a and 3b to the vitamin D receptor were both 10 and 14 times lower than that of 1 alpha,25-dihydroxyvitamin D3 (1), and to vitamin D binding protein were also both 130 and 40 times lower. The HL-60 cell differentiating activity of 3a was 6 times more potent than that of 1, while there was no remarkable difference in activity between 3b and 1.

The first synthesis of the title compound 4, a novel analog of 1α-hydroxyvitamin D (α-calcidiol) that might be therapeutically useful, is described. A key feature in the synthesis is the radical deoxygenation of the diol 21, which was prepared according to the previously reported procedure starting from 17. The resulting deoxygenated product 22 with the desired side-chain moiety was finally led to 4 in a conventional manner. Some aspects of the unusual reactivity of 25-OH on radical deoxygenation are also discussed.

An alternative synthesis of the title compound 2, a highly potent analog of 1α, 25-dihydroxyvitamin D3 (1), is described. Starting with 1α, 3β-bis[(tert-butyldimethylsilyl)oxy]androst-5-ene (8), 2 was obtained in 3.8% total yield through 10 steps. This method provides compound 2 in much higher yield than that reported previously.

An improved synthesis of a highly potent vitamin D3 analog, 24, 24-difluoro-1α, 25-dihydroxyvitamin D3 has been accomplished. The total yield was 9.3% from inexpensive vitamin D2 in 11 steps.

4, 6-Dihydrothieno[3, 4-c]furan-5, 5-dioxide (1), a novel precursor of a bis-diene, reacts with quinones to afford the normal Diels-Alder adducts, the quinone-annelated 2, 3-bis (methlene)-7-oxabicyclo[2.2.1]-heptane derivatives. Promising building blocks(3b and 5) for the synthesis of the antineoplastic antibiotics are prepared by this method.

Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder caused by mutations in the vitamin D receptor, which lead to resistance to 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)]. We found that the A ring-modified analogues, 2alpha-(3-hydroxypropyl)- and 2alpha-(3-hydroxypropoxy)-1alpha,25(OH)(2)D(3), (O1C3 and O2C3) can bind better than the natural hormone to the mutant VDR (R274A), which similar to the HVDRR mutant, R274L, had lost the hydrogen bond to the 1alpha-hydroxyl group of 1alpha,25(OH)(2)D(3).

Novel oxidation of vitamin D 2 was achieved by an electrochemical method. Under the conditions employing a metal salt-hematoporphyrin-O 2 -cathodic reduction system, only the conjugated triene moiety of vitamin D 2 was affected, giving the cleavage products, while the double bond in the side chain remained intact.

The reaction of N-methoxy quinolinium methosulfate with malononitrile in dimethylsulfoxide afforded 2-and 4-dicyanomethylene-quinoline (II and III), N-methoxy-2- and 4-dicyanomethylene-quinoline (IV and V) in addition to quinoline and quinoline-1-oxide. The reaction at the higher temperature (100-110°) gave anomalous products (VI and VII). The assumed reaction mechanism was offered.

Chemical transformations of 1-methoxyimino-6-nitrohexa-2, 4-diene (II), resulted from the reaction of N-methoxypyridinium iodide (I) with nitromethane, were examined in relation to the nitro-aci-nitro prototropy. II reacted with diazomethane to afford methyl 1-methoxyimino-hexa-2, 4-diene-6-acinitronate (III), with acetic anhydride and with benzoyl chloride to give O-acetate and O-benzoate of 1-methoxyimino-hexa-2, 4-diene-6-hydroxamic acid (VI) respectively. The ultraviolet spectra of them were correlated to their structures.

A number of N, N-dibenzylaminoacetaldehyde diakyl acetales (1) double-cyclized in 70% perchloric acid or triflic acid (trifluoromethanesulfonic acid) to give good yields of 7, 12-dihydro-5H-6, 12-methanodibenz[c, f]azocines (2) even when a powerful electron-withdrawing substituent, for example a nitro group, was present on the benzene ring. Triflic acid treatment of α-dibenzylaminoketones (3) caused double-cyclization to give 12-substituted derivatives of 2.

The reactions of N-methoxypyridinium iodide with nitromethane, nitroethane, and 1-nitropropane in the presence of sodium ethoxide in anhydrous ethanol afforded 1-methoxyimino-6-nitrohexa-2, 4-diene, 1-methoxyimino-6-aci-nitrohepta-2, 4-diene, and 1-methoxyimini-6-aci-nitroocta-2, 4-diene, respectively. The spectral behaviors of these products were discussed in relation to the nitro-acinitro prototropy and the assumed reaction mechanism was also offered.

On the reaction of 5-, 6-, 7-, and 8-nitroquinoline with potassium cyanide in methanol solution, always two kinds of compound were obtained in a moderate yield. The one was o-methoxyquinoline-carbonitrile, in which the cyano group is introduced in ortho-position to the nitro group and then the nitro group is replaced by a methoxyl group, and the other was 1-aminosoxazoloquinoline, in which the nitro group was reduced to hydroxyamino group and this hydroxyamino group was cyclized to an isoxazole ring with the cyano group introduced at ortho-position of the original nitro group. However, in the reaction of 4-nitroquinoline, 4-methoxyquinoline was obtained as a sole product.

The synthesis of 25-hydroxy-24-oxovitamin D3 is described. The compound is identical in all respects with the natural product.