( + )-Superstolide A 3, isolated from the New Caledonian sponge Neosiphonia superstes, shows interesting cytotoxicity against malignant cell lines at ~ 4 ng/mL concentration. The key transformation in the synthesis of 3 described (J. Am. Chem. Soc. 2008, 130, 2722) by William R. Roush of Scripps Florida was the transannular Diels-Alder cyclization of 2, which established, in one step with high diastereocontrol, both the cis decalin and the macrolactone of 3. The octaene 1 was assembled from four stereodefined fragments. The first, the linchpin 6, was prepared from the stannyl aldehyde 4. Homologation gave the enyne 5, which on hydroboration and oxidation gave 6. Earlier, Professor Roush had optimized the crotylation of the protected alaninal 7. In this case, the Brown reagent 8 delivered the desired Felkin product 9. Protection followed by ozonolysis gave the aldehyde 10. Crotylation with the Roush-developed tartrate 11 then gave the alkene 12, setting the stage for conversion to the iodide 13. Coupling of 13 with 6 completed the preparation of 14. The third component of (+)-superstolide A 3, the phosphonium salt 21, was assembled by Brown allylation of the aldehyde 15, to give 17. Protecting group interchange followed by ozonolysis delivered 18, which via Still-Gennari homologation was carried on to 21. Condensation with the fourth component, the aldehyde 22 , and esterification with 14 then gave 1. Under high dilution Suzuki conditions 1 was converted to 2. Storage in CDCl3 for five days, or brief warming, cyclized 2 to a single diastereomer of the transannular Diels-Alder product, that was carried on to (+)-superstolide A 3. While acyclic trienes comparable to 2 could be induced to cyclize, the transannular Diels-Alder reaction proceeded with much higher diastereocontrol.
A group of bicyclic ketones and thiones have been synthesized for homenolization studies. Bicyclo[2.2.1]heptane-2,5-dione (6) undergoes unusually rapid tetramethylation giving 3,3,6,6-tetramethylbicyclo[2.2.1]heptane-2,5-dione (1) in good yield. Treatment of 1 with P2S5 in xylene gave 3,3,6,6-tetramethylbicyclo[2.2.1]heptane-2,5-dithione (2) and 3,3,6,6-tetramethyl 15-oxo-bicyclo[2.2.1]heptane-2-thione (3), which was converted into 4 with Raney nickel. Bicyclo[2,2,2]octane-2,5-dione (7), prepared via a Diels–Alder reaction between 2-trimethylsilyloxy-1,3-cyclohexadiene and and α-acetoxyacrylonitrile followed by a one-step desilylation/hydrolysis, also undergoes facile tetramethylation giving 3,3,6,6-tetramethylbicyclo[2.2.2]octane-2,5-dione (5) in good yield. AM1 calculations were carried out on the α-enolates of bicyclo[2.2.1]heptan-2-one, 6, 5-methylidenebicyclo[2.2.1]heptan-2-one, and 4-acetylbicyclo[2.2.1]-heptan-2-one in an attempt to gain information on the source of the enhanced acidity of the C-3 hydrogens of 6 and 7. Keywords: bicyclic ketones, thiones, synthesis.
Even at the end of the twentieth century, the view of the one-step [4+2] cycloaddition (Diels-Alder) reaction mechanism was widely accepted as the only possible one, regardless of the nature of the reaction components. Much has changed in the way these reactions are perceived since then. In particular, multi-step mechanisms with zwitterionic or diradical intermediates have been proposed for a number of processes. This review provided a critical analysis of such cases.
Enantioselective Catalysis of the Hetero-Diels-Alder Reaction between Brassard's Diene and Aldehydes by Hydrogen-Bonding Activation: A One-Step Synthesis of (S)-(+)-Dihydrokawain