Adamantane, amino derivatives

Amination of alkanes (cyclohexane, heptane, adamantane) was achieved with iron and manganese porphyrin catalysts by tosylimidoiodobenzene to yield tosyl-amino derivatives.200 Selective 1-substitution of adamantane (56% yield) and 2-substitution of heptane (66% selectivity) were reported. 

CyD conjugates have also been used as novel carriers of antisense ODNs. Habus et al. linked the adamantane molecule (adamantane-ODN conjugate) or amino derivatives of j8-CyD ( 8-CyD-ODN conjugate) to the 3 -end of the ODN and found that stability to nuclease, hybridization properties with their complementary RNA, and their cellular uptake all increased [131]. Thus, the combination of the adamantane-ODN conjugate and 6 may be of value for antisense ODN delivery. In addition,... 

Another example of a carbon skeleton that contains several six-membered rings, all of which are locked into chair conformations, is adamantane (c). To understand how the carbon skeleton of adamantane can be constructed, imagine that you (a) start with a chair cyclohexane, (b) add the three axial bonds on the top side of the ring, and (c) then connect each of the axial bonds to a CH group. You now have adamantane, a compound first isolated from petroleum. Amantadine, a 1 ° amino derivative of adamantane, is an antiviral agent used to treat influenza A. 

In pharmacology, two adamantane derivatives. Amantadine (1-adamanta-neamine hydrochloride) and Rimantadine (a-methyl-1-adamantane methyla-mine hydrochloride) (see Fig. 24), have been well known because of their antiviral activity [129]. The main application of these drugs is prophylaxis (treatment to prevent the onset of a particular disease) and treatment of influenza-A viral infections. They are also used in the treatment of parkinsonism and inhibition of hepatitis-C virus. Memantine (1-amino-3,5-dimethyladaman-tane) (see Fig. 24) has been reported effective in slowing the progression of Alzheimer s disease [130]. 

Some derivatives of adamantane with antagonist or agonist effects have also been synthesized. For instance, monocationic and dicationic adamantane derivatives block the a-amino-3-hydroxy-5-methylisoxazole -propionic acid (AMPA) receptors, A-methyl-o-aspartate (NMDA) receptors [134—136] and 5-hydroxytryptamine (5-HT3) receptors [137]. 

Some other types of macrocycle compounds have been synthesized using adamantane and its derivatives. Recently, a new class of cyclobisamides has been synthesized using adamantane derivatives, which shows the general profiles of amino acid (serine or cystine)-ether composites. They were shown to be efficient ion transporters (especially for Na+ ions) in the model membranes [159]. Another interesting family of compounds to which adamantane derivatives have been introduced in order to obtain cyclic frameworks is crown ethers [160]. The outstanding feature of these adamantane-bearing crown ethers (which are also called diamond crowns ) is that ot-amino acids can be incorporated into the adamantano-crown backbone [160]. This family of... 

Rhodopsin is a seven ot-helix trans-membrane protein and visual pigment of the vertebrate rod photoreceptor cells that mediate dim light vision. In this photoreceptor, retinal is the chromophore bound by opsin protein, covalently linked to Lys296 by a Schiff base linkage. Kpega et al.64 have studied NMR spectra of Schiff bases being derivatives of all-frans retinal and amino-p-cyclodextrins as a model of rhodopsin, where p-cyclodextrin plays a role of a binding pocket. On the basis of analysis of the chemical shift differences for the model compound in the presence and in the absence of adamantane carboxylate, it has been shown that the derivative of 3-amino-p-cyclodextrin forms dimer in water and retinoid is inserted into p-cyclodextrin cavity [31]. 

Disubstituted adamantanes are most frequently obtained from internal cyclization reactions of a bridgehead substituent. Thus, photolysis of the azido-formate 79 gives 80 by nitrene insertion 279). 80 may be readily hydrolyzed to 2-amino-1-adamantanol (81) 75 Subsequent oxidation gives l-hydroxy-2-ada-mantanone (82) from which other derivatives may be prepared 280>2S1). An analogous carbene insertion is initiated by the thermal decomposition of the... 

The reagents for the synthesis of Al -l-adamantyloxycarbonyl amino acid derivatives are similar to those used for other urethane-type protecting groups (Scheme 36). Although the related 1-adamantyl chloroformate (Adoc-Cl, 68) is obtained as crystalline solid, the acylation of amino acids under Schotten-Baumann conditions leads to significant decomposition of the reagent and thus its use does not result in satisfactory yields in all cases. Better results are obtained with 1-adamantyl fluoroformate (Adoc-F, 69) (yields of A -Adoc amino acids 85-95%)P I which is conunerciaUy available or readily prepared from adamantan-l-ol and... 

Protoadamantanone is a versatile intermediate for the synthesis of not only protoadamantane derivatives,but also 1,2- and 2,4-disubstituted adamantanes, 2-substituted noradamantanes, and 4(5)-substituted 4-homoprotoadamantanes. 4-Protoadamantanone has been prepared by the nitrous acid deamination of 2-amino-l-adamantanol (77%), by aprotic diazo-tization of endo-7-aminomethylbicyclo[3.3.1]nonan-3-one in benzene with an equivalent amount of acetic acid (67%), and by thermolysis of 1-adamantyl hypohalites followed by base-promoted cyclization of the resulting halo ketones (32-37%).In spite of low and erratic yields, the last reaction sequence has provided the most convenient route to the protoadamantanes, since the other two approaches require lengthy syntheses of the starting materials. 

The reaction of 1-adamantane carboxylic acid proceeded smoothly at 80 °C, providing Boc-protected amine 92 in high yield, but the slow step of the process was addition of the ert-butoxy nucleophile (butoxide or butanol) to the isocyanate intermediate. Of numerous catalysts and conditions screened to accelerate that addition, zinc triflate in tetrahydrofuran solvent proved optimal, allowing the process to occur smoothly at 40 °C for a range of alkyl carboxylic acids. In some cases, such as the stereoretentive conversion of or-methyl-y -siloxy propionic acid 93 to Boc-protected chiral amine 94, inclusion of additional tert-butanol was required. Catalysis was proposed to occur via an isocyanate-derived, zinc-complexed carbamoyl bromide. The Lebel conditions were also applied to malonate monoesters as a route to cr-disubstituted-cr-amino acids. 

From the data presented, it is clear that the tetrameric macrocycles bind alpha substituted naphthalene derivatives, simple aromatic compounds or 1-amino-adamantane very poorly, a beta substituted... 

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