Metathesis And Substitution

Metathesis And Substitution-33
Unlike the parent compound, vinylphosphonates substituted with an aryl or alkyl group on the alkene appear to have somewhat limited reactivity.

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Similarly, Hansen and Lee employed an allyl ether to activate enynes toward cross metathesis [22].

Furthermore, there are several examples of vinylphosphonates participating in ring closing metathesis (RCM) reactions [23-25].

An alternative approach could involve an alkene cross metathesis reaction between the vinylphosphonate and a styrene (5 to 7).

Since substituted vinylphosphonates are reluctant to participate in cross metathesis reactions (Scheme 3), this approach to the synthesis of cetrolobine appeared to have little merit. reported the concept of “relay ring closing metathesis (RRCM)”, wherein typically unreactive α,ω-dienes bearing 1,1-disubstituted ethylene moieties 9 would react via the intermediacy of an additional terminal alkene 11 (Scheme 3) [19-21].

Dimethyl (β-substituted) vinylphosphonates do not readily undergo cross metathesis reactions with Grubbs catalyst and terminal alkenes.

However, the corresponding mono- or diallyl vinylphosphonate esters undergo facile cross metathesis reactions.Vinylphosphonates formed in this way, for example 2a–e (Figure 1), have been used in the synthesis of the natural products turmerone [4] and enterolactone [5], the phosphonate derivatives of the natural product cyclophostin [6], the C18–C34 fragment of amphidinolide C [7], and the oxylipids from Australian brown algae [8].The potential of vinylphosphonates as intermediates in organic synthesis is limited by their chemistry.Not surprisingly, the terminal vinylphosphonate 15 underwent smooth cross metathesis with either 1-hexene or 1-heptene using our standard conditions (2% Grubbs II, 4% Cu I, CH reflux) [2,26,27] to give the substituted vinylphosphonates 12a or 12b in good yield.In contrast, when vinylphosphonate 12a was subjected to a cross metathesis reaction with methyl acrylate, the cross metathesis product 16a was formed in low yield (~11%) as part of a complex mixture.The reaction proceeded to 96% conversion and gave 1:1.8 ratio of mono- and diallyl vinylphosphonates 21a and 21b.The products were isolated by silica gel chromatography to give 27% yield of the mono-allyl and 36% yield of the diallyl phosphonate esters.Therefore, given the propensity for vinylphosphonates to undergo RCM, it was proposed that an allyl phosphonate ester 14 would act as an initial site of metathesis, which would lead to a relay cross metathesis and thus render vinylphosphonates reactive.A series of cross metathesis reactions were performed to establish the baseline reactivity of vinylphosphonates (Scheme 4).In particular, carbonate derivatives 1 (phosphono allylic carbonates) of allylic hydroxy phosphonates undergo palladium-catalyzed addition of nucleophiles to give γ-substituted vinylphosphonates 2 in high yield (Scheme 1).The nucleophile adds exclusively to the 3-position, with migration of the double bond into “conjugation” with phosphoryl group.


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