A Relay Strategy Actuates Pre-Existing Trisubstituted Olefins in Monoterpenoids for Cross-Metathesis with Trisubstituted Alkenes

Abstract

A retrosynthetic disconnection–reconnection analysis of epoxypolyenessubstrates that can undergo cyclization to podocarpane-type tricyclesreveals relay-actuated Δ6,7-functionalized monoterpenoid alcohols for ruthenium benzylidene catalyzed olefin cross-metathesis with homoprenyl benzenes. Successful implementation of this approach provided several epoxypolyenes as expected (E/Z, ca. 2–3:1). The method is further generalized for the cross-metathesis of pre-existing trisubstituted olefins in other relay-actuated Δ6,7-functionalized monoterpenoid alcohols with various other trisubstituted alkenes to form new trisubstituted olefins. Epoxypolyene cyclization of an enantiomerically pure, but geometrically impure, epoxypolyene substrate provides an enantiomerically pure, trans-fused, podocarpane-type tricycle (from the E-geometrical isomer).

Relay Cross Metathesis for the Iterative Construction of Terpenoids and Synthesis of a Diterpene-Benzoate Macrolide of Biogenetic Relevance to the Bromophycolides

“…However, despite the long-term recognition that these linear compounds are essentially C 5 -repeating isoprene units, a general and iterative chemical protocol for their synthesis using naturally occurring, terpenoid building blocks does not exist . We recently reported an olefin cross metathesis reaction between relay-actuated Δ 6,7 -functionalized monoterpenoid alcohols with trisubstituted alkenes as partner olefins to form new trisubstituted alkenes (Figure b) . We now report that the use of readily available and nonexpensive citral as the partner olefina monoterpenoid with two electronically distinguishable alkenesallows for the iterative construction of terpenoids in line with the above aims (Figure c) .…”

“…To commence our investigations enantiopure epoxide 2 , as a relay-actuated Δ 6,7 -functionalized monoterpenoid derivative, was prepared from diol 1 using the method of Corey et al (Scheme ). Using our previously identified conditions (10 mol % ruthenium benzylidene precatalyst 5 , alkene [5 equiv], 50 °C, 1 h), attempted relay cross metathesis reaction between epoxide 2 and citral ( 3 ) , to give C 15 -sesquiterpenoid 4 using 5 was unsuccessful (Table , entry 1). Further attempts with 10 equiv of 3 (entry 2) or at room temperature (entry 3) or with 2 mol % catalyst loading (entry 4) also failed.…”

“…6 We recently reported an olefin cross metathesis reaction between relay-actuated Δ 6,7 -functionalized monoterpenoid alcohols with trisubstituted alkenes as partner olefins to form new trisubstituted alkenes (Figure 1b). 7 We now report that the use of readily available and nonexpensive citral as the partner olefina monoterpenoid with two electronically distinguishable alkenesallows for the iterative construction of terpenoids in line with the above aims (Figure 1c). 8 Furthermore, we report the application of this method for the synthesis of a diterpene-benzoate macrolide of biogenetic relevance to the bromophycolide natural product family.…”

“…3:1 at the newly formed olefin (Δ 6,7 ) and as ca. 2−3:1 at the α,βunsaturated aldehyde by 1 H NMR and assigned on the basis of characteristic 13 C NMR shielded methyl resonances for E-isomers (see the Supporting Information).…”

“…Alternatively, taking advantage of our previous observation 7 that prenylbenzene was unreactive to the ReXM conditions, geranyl benzoate 14 was combined in excess (5 equiv) with relay sesquiterpenoid 8 to also provide diterpene-benzoate 16 in good yield. Subsequent ester hydrolysis gave acid 17 and regioselective epoxide ring-opening with bromide gave bromohydrin 18, which was readily separated away from its minor bromohydrin regioisomer 18a.…”