Development of New Synthetic methods: Phosphine Catalysis of Allenes
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Catalysis facilitated by simple organic molecules (vs. transition metal catalyzed reactions) has recently garnered much attention from many research laboratories in academia and in industry. Our contribution to this exciting field of organocatalysis is the development of organic phosphine catalysis of allenes. The phosphine catalyses that we developed are operationally simple: they only require a catalytic amount of a phosphine as a reagent. Therefore, after the reaction, simple evaporation of the reaction solvent and flash column chromatography of the crude reaction mixture provides the desired products in pure forms in typically excellent yields. The phosphine-cacalyzed reactions we developed are illustrated below.
The first reaction is a phosphine-catalyzed [4 + 2] annulation of a-alkyl allenoates with aldimines to form tetrahydropyridines 1. In this reaction a-alkyl allenoates acted as a 1,4-dipole synthon. We have now expanded the utility of a-alkyl allenoates as a 1,4-dipole synthon by developing phosphine catalysis of a-alkyl allenoates with electron-deficient alkenes to form cyclohexenoate esters 2 and 3.
J. Am. Chem. Soc. 2003, 125, 4716–4717. [PDF]
The fourth reaction occurs between various aldehydes with isopropyl allenoate in the presence of a catalytic amount of trimethylphosphine leading to the formation of 2,6-diaryl-[1,3]-dioxan-4-ylidenes 4. Acid-mediated hydrolysis of the dioxane acetal in 4 provided d-hydroxy-b-ketoesters, which are recurrent subunits in polyketide antitumor antibiotic natural products.
Org. Lett. 2005, 7, 1387-1390. [PDF]
The fifth reaction occurs between ethyl allenoate and various aldehydes carried out using a catalytic amount of bulky trialkylphosphine, which forms 6-substituted-2-pyrones 5.
Org. Lett. 2005, 7, 2977-2980. [PDF]
The sixth reaction is an intramolecular phosphine-catalyzed annulation of salicylaldehyde-derived allenaotes to form coumarin derivatives 6. 2-(2-Nitrostyrenyl) allenoate provided a cyclopentene-fused dihydrocoumarin similar to 6 under the influence of triphenylphosphine in tetrahydrofuran solvent. On the other hand, in benzene 2-(2-nitrostyrenyl) allenoate was converted into cyclic nitronate-fused coumarin 7, which proved to be an excellent 1,3-dipole in facial, exo-, and regio-selective [3+2] cycloadditions with a variety of dipolarophiles.
Org. Lett. 2007, ASAP Web Release Date: July 13, 2007.
The eighth reaction is a [3+2] cycloaddition between allenoates and maleimides to form bicyclic succinimides 8. In the ninth reaction dihydrofurans 9 were synthesized from allenoates and aldehydes in the presence of a catalytic amount of phosphine and a stoichiometric amount of alcohol. Finally, a phosphine-catalyzed three-component coupling reaction among allenoates, aldehydes, and alcohols has been achieved to form 10. We also expanded the scope of Lu’s formal [3+2] cycloaddition between allenoates and imines: Incorporation of g-substituted allenoates into the reaction led to the production of tetrasubstituted dihydropyrroles 11.
Tetrahedron, 2005, 61, 6276-6282. [PDF]
II. Target Oriented Synthesis (TOS) of Natural Products