Azepan

Natriumalanat7, Natrium-bis-[2-methoxy-athoxy]-dihydrido-aluminat8 und Dialkyl-aluminiumhydride reduzieren Lactame ahnlich wie Lithiumalanat zu cyclischen Aminen. Mit den beiden letzteren Hydriden kann auch in Benzol/Kohlen-wasserstoff gearbeitet werden. Eine Arbeitsvorschrift zur Herstellung von Azepan aus c-Caprolactam durch Reduktion mit Diathyl-aluminiumhydrid ist in ds. Handb., Bd. XIII/4, S. 220, mit Bis-[2-methyl-propyl]-aluminiumhydrid in der Lit. angegeben9. 

A somewhat unusual sequence to generate azepanones 80 involved the intramolecular addition of hydroxylamines to alkynes 76 to form cyclic nitrones 77. A vinyl magnesium bromide addition at low temperatures and a reduction with TiCls followed by N-Boc protection led to the azepane 78. Double bond bromination and subsequent RUO4 oxidation gave the lactam 79. Several further steps allowed the generation of the lactam structure 80 proposed for d,/-aca-cialactam, but the spectral data of the synthetic material differed from that of the natural product (Scheme 16)] [23 a, b]. 

Azepanes and azepanones continue to attract attention synthetically because of their incorporation in compounds of biological significance. A new diastereoselective and enantioselective lithiation - addition methodology has been described to provide access to the azepine precursors 25 (Ar1 = jb-BrPh, Ar = p-MeOPh)) these were then converted into 27 via 26, and subsequently to the further substituted azepan-2-ones 30 via 28 and 29 <06JA2178>. 

Raney Nickel was also used as the catalyst for the reduction of nitro sugars to amino sugars by hydrogenation.87 Under these conditions, nitro sugar 127 was reduced to amino sugar derivative 128, without removal of the benzyl protecting group. Compound 128 was finally converted into azepane 129 (Scheme 39).88... 

Scheme 4.12 Synthesis of polyhydroxylated azepanes based in the combined use of aldolases and isomerases.

An example of an intriguing ring-size dependency of the reaction pathway is that of the cyclization of vinylogous urethanes 328a-c with cinnamaldehyde (08T883). Pyrrolidine- and azepane-based esters 328a and c, respectively, give via aza-[3+3] annulation the expected... 

FIG. 2. Polyhydroxylated azepanes 9-13 that have been assayed as glycosidase inhibitors. These structures were inspired by the natural-product glycosidase inhibitors nojirimycin (14) and fagomine (15). 

F. Marcelo, Y. He, S. A. Yuzwa, L. Nieto, J. Jimenez-Barbero, M. Sollogoub, D. J. Vocadlo, G. D. Davies, and Y. Bleriot, Molecular basis for inhibition of GH84 glycoside hydrolases by substituted azepanes Conformational flexibility enables probing of substrate distortion, J. Am. Chem. Soc., 131 (2009) 5390-5392. 

Related imino alditols such as azepanes or lactam derivatives have been obtained and have shown to be glycosidase inhibitors [96, 100]. Both d- and l-gulonolactone have been converted into polyhydroxylated 1,6-aldonolactams of type 79 in a sequence of straightforward functional transformations, including sulfinylation of the corresponding aldonolactone-derived acetonides 76 that gave 5,6-cyclic sulfites 77 (Scheme 23) [101]. The latter reacted with sodium azide... 

Two reports on the preparation of polyhydroxylated [13]thiazolo[3,2a]azepane derivatives have been published. The one reports the synthesis of the p-tum mimetic 22 from D-glucurono-3,6-lactone and L-cysteine <99TL477>, whilst the other describes, for example the preparation of 23 in 78% yield from 6-0-tosyl-23-0 isopropylidene-D-mannofuranose and 2-aminothioethanol <99S839>. 

Dimethoxy-l-methyl-azepan setzt sich mit Benzoesaure-amid-hydroximid entsprechend zu 5-(5-Methylamino-pentyl)-3-phenyl-1,2,4-oxadiazol [72% Sdp. 138—141 °/0,l Torr (13,3 Pa)]... 

X 0CH3 t 1 HsC6Na/Benzo 20 30 mehrere h och3 J-( 2,5-Dimethoxy-phenyl) -azepan 47 1... 

Bei der analogen Umsetzung von l,2-Bis-[4-methyl-benzolsulfonylamino]-ethan mit 2,3-Dibrom-propanol entsteht ebenfalls l,4-Bis-[4-methyl-benzolsulfonyl]-6-hydroxy-azepan (56%) neben wenig l,4-Bis-[4-methyl-benzolsulfonyloxy]-2-hydroxymethyl-piperazin. 

Erhitzen von N-substituierten 6-Amino-hexanolen mit azeotroper Entfemung des Reaktionswassers eignet sich auch zur Synthese der nachst hoheren Homologen6, der 1-sub-stituierten Azepane, ist jedoch zur Synthese von cyclischen Aminen mit acht oder neun Ring-Atomen kaum (z. B. 14% Ausbeute) oder nicht mehr anwendbar. 

Analog eriialt man 1 -(2-Methyl-propyl)-azepan (70%) und 1-Phenyl-azepan (mit doppelter Menge = 0,8 Gewichtsanteil Raney-Nickel bei 6 h Reaktionszeit 60%). 

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