Noradamantanes

Noradamantanes.—Reaction of noradamantan-2-one oxime (662 synianti = 33 67) with polyphosphate ester afforded products of Beckmann rearrangement and of fragmentation (663)—(667). The products (663) and (665) originate from syn-(622), whereas (664), (666), and (667) arise from anti-(662) product distribution was found to be time-dependent, and (663) and (664) were converted into (665)-(667) under the 

Noradamantanes.—The synthesis of 2- and 9-noradamantanone has been achieved by an enamine route in which the key intermediate (726) is obtained the imminium function if readily replaced by a selective carbonyl protecting group, and ring closure is then achieved by base-catalysed elimination of the analogous mesylate esters. Homoketonization of 2-acetoxytriaxane (727) in deuteriated media produces[4- H]-noradamantan-2-one (728) with almost complete retention in acid solution and with 

The structure of the product obtained from this reaction has been confirmed by X-ray analysis 122 Details of this analysis are summarized in Table 3. 

Analogous transannular carbene insertion reactions have also been reported as illustrated in Eq. (37). Both 9-noradamantanone,23) and N-methyl-9-aza-noradamantane124 have been prepared in this manner. 

Photochemically induced transannular ring closure of bicyclo[3-3.1 -nonane-3,7-dione to 3,7-noradamantane diol is illustrated in Eq. (38)12S). 

An extremely easy synthesis of 3-substituted noradamantanes is derived from the cleavage of the 2-methyl-2-adamantyloxy radical. Pyrolysis of 2- 

The single Favorskii ring contraction of 1,5-dibromoadamantane-2,6-dione (55) also enables the preparation 3-substituted noradamantanes as illustrated in Eq. (40) 126 . Unfortunately, the starting material, 55, is diffi- 

---

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. ... 

One other farily strained adamantoid molecule which has been found to be readily available via the rearrangement route is noradamantane (23). Brexane (24), a C9 tricyclic hydrocarbon, rearranges smoothly in the presence of A1C13 to the lower adamantane homologue, 23, in 75 % yield (Eq. (11)) 36 This rearrangement, however, is consistent with thermodynamic principles. (See Section 111. E and Scheme 8 for other preparations of this hydrocarbon). 

Synthetically useful skeletal rearrangements in concentrated sulfuric acid are also occasionally encountered. For example, treatment of tetracyclo [4.3. -0.0 2>3.0 3,7] nonane (deltacyclane) with sulfuric acid in the presence of pentane (which serves as a hydride donor) results in good yields of noradamantane (23) 721. In the absence of pentane, 2-noradamantanol is obtained 73> which, on longer reaction times, subsequently rearranges (presumably intermolecu-larly) to 1 -noradamantanol 72 These reactions are summarized in Scheme 8. 

In addition to the facile aluminum halide and sulfuric acid catalyzed rearrangement routes to noradamantane and substituted noradamantanes discussed above (see Eq. (11) and Scheme 8), a variety of ring closure reactions have also been employed for the preparation of these systems. The most useful reaction for this purpose involves a transannular ring closure of the bicyclo [3.3.1 Jnonyl system. Thus, 7-methyl-3-noradamantanol is obtained 12°) from the treatment of 3-keto-7-methylenebicyclo[3.3.1 jnonane 121) with sodium in moist ether (Eq. (36)). 

Similar symmetry problems confront the substitution reactions of other systems, e.g. noradamantane, homoadamantane and ethanoadamantane. Nor-adamantane, for example, may be brominated when treated with bromine under vigorous conditions but a difficult to separate mixture of bromides results72. At the present time, derivatives of noradamantane (see also Scheme 8), homoadamantane, and related systems are most readily obtained by more indirect methods as discussed in Section III. Bromination of ethanoadamantane (25) gives a single monobromide, however 38b). 

For a review of the Demjanow and Tiffeneau-Demjanow ring expansions, see ref. [2] [16]. Other references Comparison of diazomethane and Tiffeneau-Demjanow homologation in the steroid field [17] [18], 9-(aminomethyl)noradamantane [19], 2-adamantanone derivatives [20], in bicyclo[3.3.1]nonan-2-one [21]. 

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 rearrangements of cage-like structures have been discussed in some detail in refs. 11 and 12, and can be divided into three main classes (i) homocubane to cubane (ii) adamantane to noradamantane and (iii) homoadamantane to twist-brendane and these are depicted (together with strain energy estimations from ref. 79) in Scheme 39. It can be seen that in each case rearrangement provides a system with... 

With the aza-adamantyl prototype in hand, we undertook a systematic effort to probe for subtle variations in 1) scaffold bulk, and 2) spatial orientation of the bridgehead nitrogen with respect to the benzamide attachment site. Additionally, the syn/anf/-epimeric analog relationship at the attachment site was further developed. Figure 4 illustrates the target aza-noradamantane scaffolds 1-5. Each of these scaffolds is the... 

Removal of the enantiotopic methano bridges 1 and 2 produced the corresponding aza-noradamantanes as shown in table 3. Compound SC-52491 of Type 1 is very potent in the ratTMM assay, EC50 = 51 nM [15]. However, the enantiomer SC-52490 of Type 2 is 70-fold less active. This indicated that the combination of removal of the C-1 methano bridge and retention of the C-2 methano bridge leads to an aza-noradamantane with a... 

Given the desired 5-HT4/5-HT3 receptor profile and pharmacological efficacy of SC-52491, a scalable synthesis was developed. The aza-noradamantane ring system found in this agent possesses four contiguous chiral centers within its tricyclic framework. An asymmetric route was deemed to be superior to resolution of racemates, as previous efforts along the latter pathway resulted in difficult separations of fairly end-stage intermediates [22]. 

With sodium selenide the hexaiodide (281) forms the noradamantane (284). The structure of (284) was also confirmed by x-ray <80ZN(B)i 5i4,84CB2675, 84ZN(B)1344>. The reduction of (282) with alkaline hypophosphite leads to the noradamantane (285) <84CB2675>. The noradamantanes (284) and (286) result from melting the 4-methyl-1,2,6-triarsatricyclo[2.2.1.0 ]heptane (287) with elemental sulfur or selenium (Scheme 47) <84CB2675>. 

The noradamantanes (308) result from heating of (305) with elemental sulfur or selenium in a... 

Norboman-7-ylium (7-Nb+) (C7H i) (24) Bicyclo[2.2.2]octan-l-ylium (CgHi s) (26) Noradamantan-3-ylium (CioHj ) (27)... 

---