Synthetic intramolecular Mannich reaction

Systematic bond disconnection of porantherine [151] with recognition of the double bond-carbonyl equivalence for synthesis generated a synthetic pathway which is based on two intramolecular Mannich reactions. The symmetrical nature of the amino diketone precursor identified by the retrosynthetic analysis facilitates its preparation and subsequent transformations. Moreover, all the hetero atoms (donors) are separated by odd-numbered carbon chains and such arrangements are most amenable to normal modes of assembly. 

The approach to haplophytine proposed by Fukuyama and Tokuyama et al. did not rely on the synthesis of aspidophytine previously reported [75]. One of the main synthetic problems was the connection of the left-hand segment to the indole moiety of aspidophytine. Retrosynthetically, Fischer indole synthesis of the fully elaborated left-hand fragment 186 and the tricychc ketone 187 gave haplophytine. 186 was generated through oxidative skeletal rearrangement from precursor 188, which was accessible from indole 189 by Friedel-Crafts alkylation. Optically active ketone 187 was assembled through a stereoselective intramolecular Mannich reaction from aldehyde 190 (Scheme 33). 

In addition to the oxy-Cope and anionic oxy-Cope rearrangements, an important variant is the aza-Cope rearrangement of A -butenyl-iminium ions (3.175). This rearrangement occurs under mild conditions, but suffers as a synthetic method because of its reversibility. However, with a hydroxy group attached to the butenyl chain (R=OH), the reaction is driven in the forward direction by capture of the rearranged iminium ion in an intramolecular Mannich reaction, to provide an excellent synthesis of substituted pyrrolidines. ... 

Heathcock and co-workers have now published full details of their synthetic work amongst lycopodium alkaloids which demonstrates further the powerful use of the intramolecular Mannich reaction in synthesis. ... 

Two new approaches to the synthesis of deoxynupharidine (14) and its C-l and C-7 epimers were reported. Arata et al. (67) made use of the Mannich reaction of a suitable derivative of isopelletierine and 3-furylaldehyde ( )-7-epideoxy-nupharidine (15) and ( )-l-epideoxynupharidine (8) were proved to be the main products of the reaction. The synthetic route is shown in Scheme 11. Intramolecular Diels-Alder condensation of 1-Azadienes was shown (68) to be a stereoselective route to the total synthesis of (-)-deoxynupharidine (14). The key steps are shown in Scheme 12 from synthon A in four steps alkaloid 14 was obtained. 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

Usually, a Mannich reaction involves substrate and amine moieties present in the same molecule, thus producing intramolecular cyclization. The aldehyde moiety may be linked to the above reactive system before cyclization takes place, as shown in Fig. 166, which summarizes the final step of the synthetic routes leading to ring formation. 

An intramolecular photocycloaddition of a vinylogous amide tethered at C-3 of a 1-acylindole has also been achieved in a stereospecific reaction, in which the cyclobutane adduct (332) undergoes a retro-Mannich reaction to give the imino ketone (333), a synthetic precursor of vindorosine (Scheme 104) <90JA8971>. 

Huperzine B (2) exhibits a memory facilitating effect in mice and may be useful as an acetylcholinesterase inhibitor for the treatment of Alzheimer s disease (90-92). An efficient synthetic approach to huperzine B (2) has been established successfully. The tetracyclic intermediate 140 is constructed by means of a tandem Michael addition and an intramolecular Mannich cyclization using 139 and 6-methyl-3,4-dihydropyridin-2-one as the two reactants. Racemic huperzine B (2) is obtained via a reaction sequence of 12 steps in 6.6% overall yield (Scheme 17) (89). 

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