Molybdenum-Mediated Deconjugation of α,β-Unsaturated Fused-Cyclopentenone Phosphonates

Abstract

The synthesis of diethyl (3-alkyl-5-oxo-4,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-yl)phosphonates from the corresponding 3-allyloxy-1-propynylphosphonates is described. The in situ reaction involves two steps: an intramolecular Pauson-Khand reaction followed by an unusual double bond deconjugation mediated by molybdenum hexacarbonyl in dimethyl sulfoxide.Organophosphonate compounds possess important pharmacological activity. 1-3 Phosphonates and aminophosphonates have been found to possess chelating properties toward metals, 4 irreversible inhibition properties against serine proteases 5 and the ability to inhibit zinc-dependent enzymes of the metalloprotease family. 6-8 As part of ongoing research in our laboratory, we have reported different synthetic methods for the synthesis of novel, highly substituted vinyl phosphonate compounds from 1-alkynylphosphonates using zirconium(II) or titanium(II) reagents, 9-20 as well as the synthesis of fusedcyclopentenone phosphonates from 1-alkynylphosphonates via an intramolecular Pauson-Khand reaction 21 using molybdenum hexacarbonyl [Mo(CO) 6 ]. 22In the course of our research on fused-cyclopentenone phosphonate compounds, 21 we encountered double bond migration. This involved deconjugation from the cyclopentenone ring to the furan ring, a process that gave the double bond regioisomer of the classical Pauson-Khand reaction product (Scheme 1). Scheme 1 Deconjugation to form b,g-unsaturated phosphonatesA similar double bond migration in vinyl phosphonates to form allyl phosphonates is known in the literature for noncyclic systems. According to Gerber et al., 23 the phosphonate group has a very weak stabilizing effect on an adjacent double bond. Herein, in the isomerization reaction of a,b-to b,g-unsaturated phosphonates, formation of the thermodynamically favored product will be determined by structural factors (such as allylic hydrogens, alkyl substituents, etc.) and not by the relative positions of the alkene bond and the phosphonate group. 23 For example, Kiddle et al. showed that vinyl phosphonates can isomerize into the corresponding allyl phosphonates by treatment with a catalytic quantity of potassium tert-butoxide in dimethyl sulfoxide. The basicity of the tert-butoxide anion in dimethyl sulfoxide plays a crucial role in the isomerization. 24 Modro et al. concluded that during the isomerization of a vinyl phosphonate into an allyl phosphonate under basic conditions, the a,b-unsaturated phosphonate was the kinetic product while the b,g-unsaturated phosphonate was the thermodynamic product. In addition, Modro suggested that the isomerization of a,b-into b,gunsaturated phosphonates proceeds via an allylic carbanion intermediate. 25 The use of metal complexes under neutral conditions for double bond isomerization has also been explored. [26][27][28][29][30][31] However, to the best of our knowledge, the deconjugation of an a,b-unsaturated enone in a fused-cyclopentenone phosphonate system into the corresponding b,g-unsaturated ketone product has not been reported. In t...