Ricardo Alonso

Synthesis of isoindoloisoquinoline alkaloids. A revision of the structure of (±)-nuevamine

Abstract An easy and efficient method for the synthesis of isoindoloisoquinolines, and the assignment of a new structure for the alkaloid (±)-nuevamine are reported.

Synthesis, Structure, and E−Z Isomerization of β-(Hetero)aryl-α-nitro-α,β-enals

The first general methodology for the gram-scale preparation of previously overlooked beta-(hetero)aryl-alpha-nitro-alpha,beta-enals (3) is reported. Condensation of (hetero)aromatic aldehydes with 2-nitroethanol gave the E-isomers of uncommon beta-(hetero)aryl-alpha-hydroxymethyl-alpha,beta-unsatured-nitroalkenes (2), as determined by NOE and X-ray studies. alpha-Nitro-alpha,beta-enals 3 were subsequently obtained by hypervalent iodine oxidation of 2 as E-Z-mixtures in solid form. They showed varied stability and solvent-dependent thermal-promoted and photopromoted E-Z interconversion. Starting with furfural, experimental conditions were developed to prepare the corresponding nitroenal 3a enriched in either the E or the Z isomer: E-3a/Z-3a approximately 90/10 and 20/80, respectively. In contrast with other structurally related compounds, nitroenals 3 have their (hetero)aryl-vinyl unit and their formyl and nitro groups all in a planar arrangement, both in solid form and in solution; accordingly, they are colored compounds with predicted high dipole moments. As deduced from solution-NMR and X-ray data, the C=C and the C=O double bonds in 3 are exclusively s- cis-oriented; this disposition corresponds in fact to the DFT-computed most stable conformer.

Enantioselective synthesis of protected nitrocyclohexitols with five stereocenters. Total synthesis of (+)-pancratistatin.

2-Methoxymethylpyrrolidine best performed, among several other proline derivatives, to control the enantioselective [3+3] annulation of β-(hetero)aryl-α-nitro-α,β-enals with commercial 2,2-dimethyl-1,3-dioxan-5-one, a procedure that renders highly oxygenated nitrocyclohexanes endowed with five new stereocenters. Use of this reaction allowed the development of a total synthesis of the antitumoral natural product (+)-pancratistatin; it also converted our previous racemic route to tetrodotoxin into an enantioselective one.

An approach to the total synthesis of ribasine alkaloids

Abstract The first total synthesis of A- and D-ring unsubstituted ribasine compound ( 14 ) is reported, the key step being the formation of the azepine ring by an intramolecular Wittig reaction.

A convergent approach to the dioxaadamantane core of (±)-tetrodotoxin.

A fully stereocontrolled 1,3-diol orthoesterification and a water-promoted intramolecular Henry addition, combined with the previously reported formal (3 + 3) annulation of α-nitro-α,β-enals and 2,2-dimethyl-1,3-dioxan-5-one, provided for a short convergent pathway to the dioxaadamantane core of (±)-tetrodotoxin.

β-Aryl-α-nitro-α,β-enals as heterodienes and dienophiles.

As demonstrated with the β-(2-furyl)-substituted analogue 1b, β-aryl-α-nitro-α,β-enals (1) behave as heterodienes against enamines and enol ethers using their enal unit (e.g., 1b → 12). α-Nitro-α,β-enals can act as well as highly reactive dienophiles to render adducts endowed with nitrogenated quaternary centers (e.g., 1b → 15a). A hetero-Diels-Alder (HDA)/Diels-Alder (DA) sequence from 1b also proved feasible on serial treatment with ethyl vinyl ether and Danishefskys diene (1b → 14).

A Cascade Annulation Based Convergent Approach to Racemic Tetrodotoxin (Eur. J. Org. Chem. 35/2010)

The cover picture shows furfural and dihydroxyacetone, which are two compounds that can be obtained from plant sources, for example, from olive stones and sugar beets, respectively. These compounds can be used as building blocks for a convergent, cascade annulation based synthetic approach to the sodium channel blocker tetrodotoxin isolated from puffer fish. Details are discussed in the article by F. Cagide-Fagin and R. Alonso on p. 6741 ff.