A Domino Aldol Addition/Hemiketal Formation/Hemiketal Formation/Epimerization Route to a Heteroadamantane. A Crystal-Structure, NMR, and Computational Study

Abstract

It has been found by serendipity during the attempted synthesis of the potential tris-bidentate ligand 7 that this compound undergoes multiple ring-closure reactions to form the heterodamantane derivative 12. This reaction involves a domino aldol addition/hemiketal formation/hemiketal formation/epimerization sequence. Compound 12 was studied intensively by X-ray crystal-structure analysis, NMR, and AM1 computations. Complete assignment of all 1 H-and 13 C-NMR signals was achieved by a combination of HMQC, HMBC, DPFGSE-NOE, COSY, and long-range-COSY experiments. The NMR data agreed well with the crystallographic and computational results. Accordingly, 12 is present as the thermodynamically most-stable diastereoisomer with relative u-configuration at centers C(8) and C(9). In summary, five stereogenic centers were created starting from an achiral precursor in an efficient cascade reaction under thermodynamic control.Introduction. ± The fundamental moiety of adamantane (1) is found in numerous heteroatom analogs such as azaadamantane (2) and urotropine (3) [1] [2]. These types of compounds are of particular interest both from a scientific point of view as well as for industrial organic syntheses. Heteroatom analogs of adamantane are found in natural products, e.g., in the extremely toxic pufferfish tetrodotoxine (4) [3] (lethal dose for man ca. 1 mg). We report here the synthesis of the new dioxaazaadamantane derivative 12.Results. ± Synthesis. As part of our current research, we were interested in the synthesis of new tris-bidentate ligands. Starting from nitrilotriacetic acid triethyl ester (5) we expected that reaction with pinacolone (6) would lead in a Claisen condensation to tris(5,5-dimethyl-2,4-dioxohexyl)amine (7; H 3 L) (Scheme 1). The tris-enolate (L 3À ) of 7 should be potentially suitable for complexation of appropriate metal ions, leading Helvetica Chimica Acta ± Vol. 85 (2002) Scheme 1 1 ) The name was generated by Beilstein×s −AutoNom Software× [7].Scheme 2

Template and pH‐Mediated Synthesis of Tetrahedral Indium Complexes [Cs⊂{In4(L)4}]+ and [In4(HNL)4]4+: Breaking the Symmetry of N‐Centered C3 (L)3− To Give Neutral [In4(L)4]

“…Recently, we reported the intermediate generation of tris(5,5‐dimethyl‐2,4‐dioxohexyl)amine ( 8 ) and its isomerization in a domino cascade (aldol addition/hemiketal formation/hemiketal formation/epimerization) to dioxaazaadamantane ( 9 ) (Scheme ) 8. Threefold‐symmetric H 3 L ( 8 ) is now accessible by Claisen condensation from triethyl nitrilotriacetate with pinacolone and potassium hydride in tetrahydrofuran, and isomerizes to 9 simply by adding a catalytic amount of potassium hydroxide to a solution of 8 in methanol.…”

Supramolekulare Koordinationschemie – Synergie von Zufallsentdeckung und rationalem Design

“…In einer früheren Arbeit konnte gezeigt werden, dass das C 3 ‐symmetrische Tris(5,5‐dimethyl‐2,4‐dioxohexyl)amin H 3 L bei Zugabe einer katalytischen Menge an Kaliumhydroxid in Methanol spontan in einer Dominokaskade (Aldoladdition/Hemiketalbildung/Hemiketalbildung/Epimerisierung) zu Dioxaazaadamantan 56 isomerisiert (Schema ) 35. Darüber hinaus sollte sich der N‐zentrierte tripodale siebenzähnige Ligand (L) 3− zur Komplexierung sowie Verbrückung ausgewählter Metallionen und damit zum Aufbau mehrkerniger Aggregate eignen.…”