Stereospecific Synthesis of New 4-Amino-1,2,3-cyclohexanetricarboxylic Acids and 4-Amino-1,3-cyclohexanedicarboxylic Acids

Abstract

We recently reported the stereospecific synthesis of 2,3,4,5-piperidinetetracarboxylic acids and 2,3,5-piperidinetricarboxylic acids with a cis-2,5-dicarboxy configuration from N-methoxycarbonyl-1,2-dihydropyridine (1), as a study of the synthesis of amino acids using Diels-Alder (D-A) adducts of dienophiles and N-containing dienes.1) The intermediate products, isoquinuclidines 2-7, 1) seemed to be convertible to other amino acids. In the present paper, we would like to report the synthesis of new 4-amino-1,2,3-cyclohexanetricarboxylic acids and 4-amino-1,3-cyclohexanedicarboxylic acids with a 1,4-cis-configuration. Aminocyclohexanecarboxylic acid derivatives have been examined for bioactive compounds such as the inhibitor of the g-aminobutyric acid (GABA) receptor.2) Although ethyl esters of 4-amino-1,3-cyclohexanedicarboxylic acids were synthesized by Skarić et al., 3) free amino acids have not yet been synthesized and isolated.First, D-A adducts 2-7 were hydrogenated in the presence of 10% Pd/C under ordinary pressure to give compounds 8-13 (Fig. 2) quantitatively, respectively. Although no effective data regarding the stereochemistry of compound 3 in comparison with that of compound 2 were obtained by a nuclear Overhauser effect (NOE) experiment in the 1 H-NMR analysis, in the analysis of 9, ϩNOEs were observed between H 5 and H 8b between H 6 and H 7b , and ϪNOE was observed between H 6 and H 7a (Fig. 3). Therefore, the stereochemistry of 3 simultaneously became clear.Next, as removal of the N-methoxycarbonyl (Moc) group seemed to be difficult in the later steps, Moc groups of 8-13 were converted into tert-butoxycarbonyl (Boc) groups (Chart 1). Compounds 8-11 were treated with trimethylsilyl iodide [4][5][6][7][8] in CCl 4 followed by treatments with water, respectively, to cause removal of the N-Moc groups as well as dealkylation and hydrolysis of the ester groups. Thus obtained hydroiodides of amino acids were esterified with SOCl 2 -MeOH, and introductions of a Boc group were achieved by treatments with Boc 2 O in CHCl 3 , giving 14-17 in 87, 90, 84, and 85% yields, respectively. In the case of 12 and 13, as these carboxylic acids were sparingly soluble in CCl 4 , CHCl 3 was used as a solvent for removal of the Moc group. Similar treatments of the corresponding amino acids gave 16 and 17 in 85% yields, respectively. No epimerization was observed in the above cases, although when 10 and 11 were similarly treated with trimethylsilyl iodide in CHCl 3 , the epimerizations occurred and the resultant products became mixtures of 16 and 17, respectively.Conversion of the methylene groups adjacent to N-atoms into carbonyl groups was achieved by ruthenium tetroxide (RuO 4 ) oxidation. 9-13) Under similar conditions employing AcOEt as a reaction solvent, compounds 14-17 disappeared after 2, 3.5, 1.5, and 3 h and gave lactams 18-21 in 92, 95, 96, and 97% yields, respectively. Although the yields of the resultant lactams were almost quantitative, the longer reaction times were required when the ester groups were si...

A Unified Approach to Polycyclic Alkaloids of the Ingenamine Estate: Total Syntheses of Keramaphidin B, Ingenamine, and Nominal Njaoamine I

“…l -Selectride had served this purpose well before (see above) but was found inadequate for 68 , as it led to extensive reduction of the vic -dibromoalkenes present in this substrate (see below). The problem was ultimately circumvented by recourse to TMSI . Subsequent attachment of the quinoline-containing side chain via reductive amination furnished diyne 69 as necessary for the first macrocyclization event.…”

“…The problem was ultimately circumvented by recourse to TMSI. 113 Subsequent attachment of the quinoline-containing side chain via reductive amination furnished diyne 69 as necessary for the first macrocyclization event.…”