5,11-methanomorphanthridine alkaloids

The montanine-type alkaloids, also deriving from the hemanthamine series, are very unusual. Only two, namely pancracine (73) and nangustine (74), have been isolated from two species, both belonging to the Narcissus section of this genus. Nangustine has a unique substitution pattern (80), being the first 5,11-methanomorphanthridine alkaloid with a C-3/C-4 substitution, instead of a typical C-2/C-3. 

The allenylsilane ene reaction is also well suited for the synthesis of cyclohexane rings. Jin and Weinreb have described the process of Eq. 13.55 in a synthesis of 5,11-methanomorphanthridine, an Amaryllidaceae alkaloid [64], Conversion of aldehyde 163 to imine 164 with piperonylamine took place in situ. Heating the solution of imine at reflux in mesitylene for 2 h led to cyclization through the conformer shown. The yield of 165 from aldehyde 163 was 66%. 

Following their syntheses of ( )-pancracine and related alkaloids (vide supra), Hoshino et al [106] had described a different approach involving radical cyclisation of an isoquinoline derivative which permitted a rapid assembly of keto-5,11-methanomorphanthridine skeleton. The syntheses of 413, 414 and 415 commenced with the known 4-hydroxy-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoIine (439) (Scheme 62). Subsequent to protection of the amino group as the trifluoroacetyl derivative, the amide alcohol 440 was converted into the amide thioether 441, by reaction with phenylthiol in the presence of zinc iodide. Alkaline hydrolysis of 441,... 

The alkaloids related to crinine (359), which possess the 5,10b-ethanophen-anthridine nucleus, have been the subject of extensive synthetic investigations (190). Alkaloids of this family bearing oxygen functionality at C-ll occupy a special position since they are possible biosynthetic and chemical precursors of the subgroups that incorporate a 2-benzopyrano[3,4-c]indole ring such as those alkaloids related to pretazettine (395), tazettine (397), and macronine (401) and the methanomorphanthridines such as montanine (584). 

Montanine alkaloids are members of the alkaloids of the plant family of Amarylli-daceae. They represent a relatively small class of compounds with the typical methanomorphanthridine skeleton exhibiting some anxiolytic, anti-depressive and anti-convulsive activities [135, 136]. The total syntheses of the natural (-)-mon-tanine enantiomers are only mentioned, not described, here (for these (—(-enantiomers see, e.g. literature cited in [137]). 

Although synthetic approaches toward the montanine-type alkaloids had been made by intramolecular cyclization of 3-(3,4-methylenedioxy)phenyl-hexahydroindoline derivatives (176), these attempts were thus far unsuccessful. The 5,11-methanomorphanthridine ring systems 341-343 (Fig. 21)... 

Radical-mediated reaction of a radical precursor tetrahydroisoquinoline derivative has been found to produce the 5,11-methanomorphanthridine ring system 182). Thus, a formal total synthesis of this type of alkaloid was performed by means of the present methodology. Namely, the reaction of l,2,3,4-tetrahydro-A -(4-oxocyclohex-2-enyl)-4-phenylthioisoquinoline (357) with BusSnH in boiling o-xylene containing AIBN led to 5,11-methanomorphanthridin-2-one (358) in 80% yield, which was transformed to A -5,ll-methanomorphanthridine 359 by way of a mesate. In continuation, 359 provided the 2,3-O-benzylidene derivative 349 in two steps (OSO4 oxidation and O-benzylidenation), which was previously 179) converted into this type of alkaloid (Scheme 37). 

The alkaloids derived from 5,10b-ethanophenanthridine (crinine and haemanthamine types), 2-benzopyrano[3,4c]indole (tazettine type), phenanthridine (narciclasine type) and 5,11b-methanomorphanthridine (montanine type) originate from a para-para oxidative phenolic coupling (Fig. 9). 

The mass spectral fragmentation patterns observed for alkaloids containing the 5,11-methanomorphanthridine nueleus greatly depend on the nature and particular configuration of the substituents at C-2 and C-3. Thus, all the alkaloids that possess a methoxyl group give rise to an M -31 ion. 

Jin and Weinreb [137, 138] reported enantioselective total syntheses of the 5,11-methanomorphanthridine Amaryllidaceae alkaloids (—)-pancracine and (-)-coccinine. They nsed a specific Mizoroki-Heck-cyclization to convert bromo olefin 197 into seven-membered exocyclic alkene 198 in good yield (Scheme 6.57). 

Jin, J. and Weinreb, S.M. (1997) Enantioselective total S3mtheses of the 5,11-methanomorphanthridine class of AmarylUdaceae alkaloids (—)-pancracine and (—)-coccinine. 

Montanine-type alkaloids constitute a limited group in Amaryllidaceae alkaloids and show a characteristic 5,11-methanomorphanthridine framework (Table 17.7). There are two classes of C = C double bond substitution patterns in the C ring of alkaloid skeletons. Alkaloid nangustine 151 is the first member in this subgroup with a hydroxyl group at the C4 [42]. 

Still in 2013, Fan and co-workers also described a remarkable total synthesis of a series of montanine-type Amaryllidaceae alkaloids [113], The homochiral cherylline-type phenolic isoquinoline precursor 188 was treated with DIB in methanol in the presence of TFE to generate the orf/io-quinone dimethyl monoketal 189, which underwent in situ a fully diastereoselective intramolecular aza-Michael addition to furnish exclusively the pivotal pentacyclic 5,11 -methanomorphanthridine 190 in good yield. Diastereoselective ketone reductions then afforded the separable alcohols 191a/b, which were independently converted in one to two simple steps into inter alia (-)-manthidine, (-)-brunsvigine, (-)-coccinine, (—)-m(Mitanine, and (-)-pancracine (Fig. 47) [113]. 

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