Synthesis of new derivatives of D 3-trishomocubane

Abstract

The only published procedure of preparation of D 3 -trishomocubane-4-carboxylic acid (I) [1] consists in the radical substitution in the hydrocarbon under the action of oxalyl chloride initiated by benzoyl peroxide. Therewith the chlorocarbonylation provided a certain admixture of isomers β (~3%) [1].Aiming at the preparation of D 3 -trishomocubane-4-carboxylic acid (I) we synthesized D 3 -trishomocubyl 4-iodide (II) in ~60% yield by treating with hydroiodic acid corresponding alcohol III obtained from Cookson's diketone by the known procedure [2]. It should be mentioned that the conversion should be kept below 80-85%, for at higher temperature or at prolonged heating diiodides formed, products of trishomocubane framework fragmentation.In order to obtain acid I the Grignard reagent prepared from iodide II was treated with CO 2 . However instead of the expected reaction product compound IV was obtained, m/z 290. 13 C NMR spectrum of compound IV (registered with the decoupling from protons and using the APT-sequence) contained 22 separate signals among which two pairs of signals belonged to the secondary carbon atoms R H H IV I _ III, V, VI R = COOH (I), I (II), OH (III), CN (V), CONH 2 (VI).at 33 ppm corresponding to the bridging atoms and indicating that this compound was 4,4'-bi-D 3 -trishomocubyl. Formerly on compound IV only an XRD study was published without a description of the synthesis and properties of the compound [3].We obtained from iodide II D 3 -trishomocubane-4-carboxylic acid nitrile (V). As expected, the reaction with potassium cyanide in aqueous-alcoholic solution did not proceed with the secondary halides. As an alternative we used DMF as high-boiling strongly polar solvent, but at 150°C after 20 h the yield of nitrile V attained only 5%. Proceeding from published date [4] we carried out the reaction of trishomocubyl iodide II with potassium cyanide in DMSO at 150°C. As a result we isolated a mixture containing 78% of trishomocubane-4-carbonitrile (V) and 22% of alcohol III. The mixture was separated on a column packed with aluminum oxide, eluent hexane-ethyl acetate, 8: 1.The hydrolysis of nitrile V with aqueous alkali was carried out for 50 h, and here predominantly formed D 3 -trishomocubane-4-carboxamide (VI); no more than 20% of nitrile was converted in acid I.Nitrile V was utilized in the synthesis of a series of D 3 -trishomocubane amino derivatives. Amine VII was obtained by nitrile V reduction with LiAlH 4 . At boiling nitrile V with Grignard reagents in benzene followed by treating the formed complexes with methanol and then reduction of the arising imines with sodium borohydride we obtained compounds VIII and IX (see the scheme). 4-Iodo-D 3 -trishomocubane (II).To 10 g of D 3 -trishomocuban-4-ol was added 60 ml of freshly distilled hydroiodic acid , the mixture was heated over 3 h at 100°C

D3-Trishomocubane-4-carboxylic Acid as a New Chiral Building Block: Synthesis and Absolute Configuration

“…9 In accordance with this prediction, a convenient synthetic route to (±)-D 3 -trishomocubane-4carboxylic acid (4) followed by enantiomeric separation on a multigram scale (10-100 g) is required. Racemic acid 4 was previously prepared by us 10 and by others, 11 however all these procedures are difficult to use on a large scale.…”

“…In our previous work 10 we described attempts to develop a preparative method of synthesis of 4 from alcohol 12 through a standard sequence (iodination, CN-substitution, and hydrolysis). It was found, however that this approach gave acid 4 in low yields.…”