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Electrophilic substitutions on lithiated Schöllkopf's bis-lactim ethers derived from cyclo-[L-AP4-D-Val] take place regio- and stereoselectively at the alpha-position of the phosphonate ester. Subsequent olefination of alpha-silyl-, alpha-phosphoryl-, and alpha-stannyl-stabilized phosphonate carbanions give rise exclusively to vinylphosphonates. Both processes allow a direct and stereoselective access to a variety of 4-substituted and 3,4-disubstituted 2-amino-4-phosphonobutanoic acids (AP4 derivatives) in enantiomerically pure form that may be useful tools for characterizing the molecular pharmacology of metabotropic glutamate receptors (mGluRs) of group III. The relative stereochemistry was assigned from X-ray diffraction analyses or NMR studies of 1,2-oxaphosphorinane and other cyclic derivatives. In accordance to density functional theory (DFT) calculations, the syn-selectivity in the electrophilic substitutions may originate from the intervention of seven- and eight-membered chelate structures in which the bis-lactim ether moiety shields one of the faces of the phosphonate carbanion. DFT calculations for the tin-Peterson olefination of alpha-stannyl stabilized phosphonate carbanions indicate that rate and selectivity are determined in the initial carbon-carbon bond formation step where the unlike transition structures leading to (Z)-vinylphosphonates are favored both in the gas phase and in THF solution.

The ruthenium-catalyzed reaction of allylbenzene with several types of alkene provides good yields of the cross-metathesis products regardless of the structural characteristics of the alkene.In the course of our research on sugars we wished to prepare the mannose derivative 4. Our first approach, involving a Wittig-Horner reaction between the aldehyde 1 and the stabilized anion of phosphonate 2, afforded very low yields whatever the base and reaction conditions used. We then decided to try an intermolecular cross-metathesis reaction 1 , despite the lack of precedents, because the necessary precursors are readly prepared. Compound 3 2 reacted with acrolein dimethyl acetal in the presence of 5% of Grubbs' catalyst (Cl 2 (PCy 3 ) 2 Ru = CHPh; Ru) to give compound 4 in 77% yield with a 20:1 E/Z ratio (Scheme 1) 3 .There is considerable uncertainty as to the factors that influence the selectivity of intermolecular metathesis reactions: some authors 4-6 suggest that electronic factors predominate, while others 7,8 seem to have found that steric parameters and the influence of neighbouring heteroatoms may be the most important determinants of high selectivity. In view of this, the finding that the reaction of Scheme 1 was highly selective for cross-metathesis, no self-metathesis products having been detected, led us to study this type of process more thoroughly. Using allylbenzene as reference alkene and two equivalents of the alkene partner, we found that the reaction proceeds crossselectively for a variety of olefins (Table 1) 9 . The results obtained with allyltrimethylsilane and allyloxytrimethylsilane are similar to those previously reported by other authors 10,11 . However, reports that electron-poor olefins do not participate in Ru-catalyzed cross-metathesis reactions 12,13 were not corroborated: on the contrary, we found that acrylonitrile and acrolein couple to allylbenzene with high cross-selectivity and in good yield. We also obtained good results with allylalcohol, allylacetamide and in particular allylbromide. The unprecedented achievement of cross-metathesis with this last reagent shows that the presence of a neighboring heteroatom is not strictly necessary for cross-selectivity 9 .Although both allylbenzene and the other olefins underwent self-metathesis when subjected to the reaction conditions in the absence of a partner 14 , no significant amounts of self-metathesis products were detected when the two partners were present in the above 1:2 ratio; as expected, when just one equivalent of the second olefin was used, the self-metathesis product of allylbenzene was obtained in 20% yield as well as the cross-metathesis product (39%). In conclusion, the cross-metathesis reaction is favoured under the reaction conditions described above, is not totally dependent on the structural characteristics of the alkenes, and constitutes a simple method for functionalization of a variety of terminal olefins. It should prove particularly useful for obtaining primary allylic bromides, a type of compound of great synthet...

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