Aza-adamantane

Daphnezomines A and B consisting of all six-membered rings are the first natural products containing an aza-adamantane core with an amino ketal bridge. A bioge-netic pathway for daphnezomine B is proposed in Scheme 18.7. Daphnezomines A... 

RLsch, N., Langhals, M., and Hohbcrg, T., Triple (Grob) fragmentation. Retro-Mannich reactions of 1-aza-adamantane derivatives. Tetrahedron Lett... 42, 4465, 1991. 

Procedures for the conversion of the readily available nitrile (52) into 4-aza-homoadamantanes, e.g. (53), and alternative procedures, avoiding the use of mercury salts, for the conversion of pinenes into 1-aza-adamantanes are noted. 

We note further studies concerning the ethanolysis of l-chloro-2-aza-adamantanes, the rearrangement " of iV-chloro-tropanes, the dealkylation " of (76) with PhSeH, the formation of a stable adduct between (77) and sulphur dioxide " and also between aaa-trifluoroacetophenone and 1,4-diazabicyclo-octane, "" and the use of (78) as an intermediate " in the synthesis of the antifungal antibiotic aristeromycin (79), which is a carbocyclic analogue of adenosine. The acid-catalysed cyclization "" of (80) gave (81) the structure of the product was determined by X-ray analysis. 

Oxa-6-aza-adamantanes have been prepared by all five pathways A—E. 

By treatment of N(9)-methyl-7-ethoxy-granat-3a-ol (38) with hydrogen bromide Stetter Mehren obtained in 1967 unsubstituted N(6)-methyl-2-oxa-6-aza-ada-mantane (40). This was the first synthesis of a 2-oxa-6-aza-adamantane. 

Kashman and Benaiy reported the successful ring closure of the hicyclic alcohol S9 by lead tetraacetate (without or with iodine added) to the N(6)-acetyl-2-oxa-6-aza-adamantane (41). 

N(9)-Phenylsu]fonyl-9-azabicycloi3,3.1 ] nona-2,6-diene (44) is another suitable starting material for the synthesis of C(4),C(8)-disubstituted 2-oxa-6-aza-adamantanes, the two substituents being equal The configurations at C(4) and C(8) may either... 

Ring closures to 2-oxa-6-aza-adamantanes starting from bicyclic dienes were also accomplished by hydroxybromination of the 9-aza-diene 62 with N-bromo-succinimide (-> 63 53%) and by reaction of the 9-oxa-diene 1 with N -dibromo-p-tolylsulfonamide (- 64 25%). Both dibromides were converted to 63 (raney-nickel/Hj), which itself by treatment with sodium in liquid ammonia, yielded unsubstituted 2-oxa-6-aza-adamantane (5S), also characterized as its hydrochloride 38 HCl and N-benzoyl-derivative 66. 

Heating a solution of the syn-exo-diepoxide 74 in 0.5N HCl yielded 61% of N(6)-phenylsulfonyl4 8 -dihydroxy-2 -oxa-6-aza-adamantane (76) as the sole tricyclic compound, which was also characterized as its diacetate 49. Analogous treatment of the anti-epoxide 75 led to a mixture of adamantane-diol 76 (48%) and the isomeric N(7)-phenylsulfonyl-4 l0 -dihydroxy-2-oxa-7-aza-isotwistane (77) (22%). Both diols were also converted to the corresponding diacetates 49 and 78 K... 

Reaction of the syn-exo-diepoxide 20 (9-oxa) with methylamine under pressure gave 61%of N(6)-methyl-4 8 -dihydroxy-2-oxa-6-aza-adamantane (79), which by subsequent acetylation yielded the diacetate 80. 

Transannular addition of sulfur dichloride to 9-azabicyclo[3.3.1]nona-2,6-dienes (42 N-formyl 9l 44 N-phenylsulfonyl 94 and 62 N-tolylsulfonyl p 3i, 32)j applied as an entry to the 2-thia-6-aza-adamantane system. The chlorine atoms in 91 were easily exchangeable with sodium iodide in boiling diethyl ketone (-> 92, 82%)" or with silver acetate in acetic acid (- 93, 70%)" resp. Under analogous reaction conditions the dichloride 94 was transformed into the diacetate 95 (95%) " LiAlH4-reduction of the diacetate 93 yielded 74% of N(6)-methyl-4 8 -dihydroxy-2-thia-6-aza-adamantane (97). The C(4) and C(8)... 

Using N(6)-formyl-4 1,8 1 1-dichloro-2-thia-6 -aza-adamantane 91) as starting material, reaction with sodium iodide in diethyl ketone yielded 82% of the diiodide 92 (episulfonium ion) and reaction with silver acetate in acetic acid gave 69% of the diacetate 93 (episulfonium ion) (2.1.9.) Under analogous conditions the dichloride 94 was transformed to the diacetate 95 (95%) (2.1.9.) ... 

A special case is the observed substitution with retention as the result of the reaction of N(6)-phenylsulfonyl-4° 8° -diiodo-2-oxa-6-aza-adamantane 54) with silver acetate in acetic acid during 9 hrs at 60°, which yielded 4° -acetoxy-8 -iodo-adamantane 55 (20% relative to reacted 54) and 4° 8° l-diacetoxy-ada-mantane 56 (66% relative to reacted 54). Because of the reduced basicity of N(6) by the sulfone group this reaction will not be classified as one involving normal neighboring group participation (2.1.5.2.) . 

In both cases studied using G 56-adamantanes as starting materials rearranged products were observed where oxonium ions occurred as intermediates, namely on treatment of 4°l l,8°l l-diiodo-2,6-dioxa-adamantane (J 2.1.2.1.) and N(6)-phenylsulfonyl-4N(6)8N(S),diiodo.2 -oxa-6-aza-adamantane (47 2.1.5.2.) with silver acetate in acetic acid, see G 36 - G 38 (oxonium ion) - G 39 (adamantane) + G 40 (isotwistane) ... 

A further example was the reaction of N(6)-phenylsulfonyl-4 8° -diiodo-2-oxa-6-aza-adamantane (50) with silver acetate (Table 6). The d -acetoxy-S U... 

In this section several characteristic NMR-data of 2-oxa-6-aza-adamantanes [X(2) = O, Y(6) = NR] diall be discussed standing as typical examples for the rather large number of 4,8-disubstituted 2,6-dihetero-adamantanes known so far. 

While nitroxyl radicals, e.g., (2,2,6,6-tetramethylpiperidin-l-yl)oxyl (TEMPO) (2014COR459) and 2-aza-adamantane-Al-oxyl (AZADO) (2006JA8412), have been used extensively as catalysts in the oxidation of alcohols, there have been no reports of analogous uses for hydrazyls and... 

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