Synthesis of fused tricyclic amines unsubstituted at the ring-junction positions by a cascade condensation, cyclization, cycloaddition then decarbonylation strategy.

Heating aldehydes that contain a protected hydroxymethyl group, a tethered alkyl chloride and a tethered alkenyl group at the α-position of the aldehyde with an amine sets up a cascade (tandem) reaction sequence involving condensation to an intermediate imine, then cyclization and formation of an intermediate azomethine ylide and then intramolecular dipolar cycloaddition. The fused tricyclic products are formed with complete or very high stereochemical control. The hydroxymethyl group was converted into an aldehyde - which could be removed to give the tricyclic amine products that are unsubstituted at the ring junction positions - or was converted into an alkene, which allowed the formation of the core ring system of the alkaloids scandine and meloscine.

Cascade cyclization, dipolar cycloaddition to bridged tricyclic amines related to the Daphniphyllum alkaloids.

A tandem one-pot reaction of an aldehyde with a primary amine involving condensation and then cyclization (N-alkylation), followed by intramolecular dipolar cycloaddition of the resulting nitrone or azomethine ylide, provides a synthesis of bridged tricyclic amines. The reaction was most successful using hydroxylamine, and when the dipolarophile was an unsaturated ester, subsequent reduction of the N-O bond and cyclization to the lactam provided the core ring system of the yuzurimine, daphnilactone B, and bukittinggine type Daphniphyllum alkaloids.

Synthesis of the core ring system of the stemona alkaloids by cascade condensation, cyclization, intramolecular cycloaddition.

Condensation of an aldehyde with an α-amino-ester, followed by a tandem process involving cyclization to a seven-membered ring, deprotonation to an intermediate azomethine ylide and intramolecular dipolar cycloaddition gave tricyclic products related to stenine and neostenine.

Synthesis of fused tricyclic amines from enolizable acyclic aldehydes by cyclization then dipolar cycloaddition cascade: synthesis of myrioxazine A.

A tandem one-pot reaction involving a condensation, then cyclization (N-alkylation), followed by an azomethine ylide or nitrone dipolar cycloaddition allows a synthesis of tricyclic amines from acyclic enolizable aldehydes. The reaction was unsuccessful using amino acids or esters but was successful with (tributylstannyl)methylamine or hydroxylamine. One of the products was converted in two steps to the alkaloid (+/-)-myrioxazine A.

Stereoselective formation of fused tricyclic amines from acyclic aldehydes by a cascade process involving condensation, cyclization, and dipolar cycloaddition.

The preparation of tricyclic amines from acyclic precursors is described using a cascade of tandem reactions involving condensation of an aldehyde with a primary amine, cyclization (with displacement of a halide), and then in situ deprotonation or decarboxylation to give an azomethine ylide or nitrone followed by intramolecular dipolar cycloaddition. The methodology is straightforward, and the aldehyde precursors are prepared easily and quickly in high yield using nitrile alkylations followed by DIBAL-H reduction. The relative ease of reaction of various substrates with different tether lengths between the aldehyde and the halide or dipolarophile has been studied.

The synthesis and properties of tricyclic analogues of S6-methylthioguanine and O6-methylguanine.

The syntheses of novel tricyclic pyrrolo[2,3-d]pyrimidine analogues of O(6)-methylguanine and S(6)-methylthioguanine are described. The crystal structures and pK(a) values of these analogues are reported. In a standard substrate assay with the human repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) only the oxygen-containing analogue displayed activity.

The syntheses and properties of tricyclic pyrrolo[2,3-d]pyrimidine analogues of S6-methylthioguanine and O6-methylguanine.

The syntheses of novel tricyclic pyrrolo[2,3-d]pyrimidine analogues of S6-methylthioguanine are described. The crystal structures and pKa values of these and related O6-methylguanine analogues are reported. All compounds display higher pKa values than O6-methylguanine with the sulfur-containing analogues being the more basic and exhibiting higher stability in aqueous solution.