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).
Highlights
Inspired polyene cyclizations have emerged as a powerful synthetic strategy for the stereocontrolled construction of complex polycarbocyclic scaffolds of biological significance,1 where epoxypolyene cyclizations of terminally functionalized geranyl units with nucleophilic aromatic headgroups have provided synthetic access to podocarpane-type tricyclic diterpene skeleta (Figure 1a)
We commenced our investigations with two main objectives in mind: (i) demonstration of proof-of-principle ReXM of monoterpenoid alcohol derivatives with homoprenylbenzenes to prepare representative epoxypolyene cyclization substrates; (ii) exemplification of the method as a general approach for the functionalization of pre-existing trisubstituted olefins in acyclic monoterpenoid alcohols
We prepared diols (S)- and (R)-5b via Sharpless dihydroxylation18 of triene (E)-4 in excellent enantiomeric purity confirmed by conversion to their respective benzoates 5c and chiral stationary phase highperformance liquid chromatography (HPLC) analysis and thence acetonides (S)- and (R)-5d (Scheme 2) by ketalization
Summary
Inspired polyene cyclizations have emerged as a powerful synthetic strategy for the stereocontrolled construction of complex polycarbocyclic scaffolds of biological significance, where epoxypolyene cyclizations of terminally functionalized geranyl units with nucleophilic aromatic headgroups have provided synthetic access to podocarpane-type tricyclic diterpene skeleta (Figure 1a). Such cyclization substrates are typically constructed in two steps via metalcatalyzed cross-coupling methodology of an electrophilic geranyl species in conjunction with a benzylic organometallic, and either before or after C−C bond construction regioselective functionalization of the geranyl alkene at the terminus of the chain (Figure 1a). Each of these steps is subject to a potential disadvantage: the former is subject to competing allylic SN2′ substitution, and the latter to nonperfect regioselective oxidation, regardless of the order of implementation. During the course of our studies, we had reason to consider an alternative disconnection of such functionalized linear monoterpenoid derivatives by olefin cross-metathesis, but of the two terminal olefin species that are revealed, the epoxide-containing component is synthetically nonsimplified (Figure 1b). Inspired polyene cyclizations have emerged as a powerful synthetic strategy for the stereocontrolled construction of complex polycarbocyclic scaffolds of biological significance, where epoxypolyene cyclizations of terminally functionalized geranyl units with nucleophilic aromatic headgroups have provided synthetic access to podocarpane-type tricyclic diterpene skeleta (Figure 1a).2 Such cyclization substrates are typically constructed in two steps via metalcatalyzed cross-coupling methodology of an electrophilic geranyl species in conjunction with a benzylic organometallic, and either before or after C−C bond construction regioselective functionalization of the geranyl alkene at the terminus of the chain (Figure 1a).. Robinson and coworkers showed that the cross-metathesis of sterically challenging allyl branched 1,1-disubstituted olefins performed considerably better using a (terpenoid) prenyl rather than an allyl partner using precatalyst 2 (Figure 1d).12 With this latter literature precedent in mind, we selected trisubstituted olefins as the cross-metathesis partners (Figure 1b, reconnection).. The catalyst(s) of choice for the above proposition would be the commercially available well-defined ruthenium benzylidenes as developed by Grubbs. Such catalysts are widely used to accomplish the ring-closing metathesis of disubstituted, trisubstituted, and even tetrasubstituted olefins. In contrast, and quite surprisingly, there are only limited reports on the formation of unfunctionalized trisubstituted olefins (as required here) by cross-metathesis using ruthenium benzylidene pre-catalysts. Grubbs and co-workers initially showed that ruthenium pre-catalyst 1 was competent for the crossmetathesis of geminally disubstituted olefins with terminal olefins (Figure 1c). Subsequently, Robinson and coworkers showed that the cross-metathesis of sterically challenging allyl branched 1,1-disubstituted olefins performed considerably better using a (terpenoid) prenyl rather than an allyl partner using precatalyst 2 (Figure 1d). With this latter literature precedent in mind, we selected trisubstituted olefins as the cross-metathesis partners (Figure 1b, reconnection). As envisioned, this overall stratagem opens up the possibility of an alternative, modular, synthetic route to such cyclization precursors, but perhaps more significantly could provide a general approach to the functionalization of pre-existing trisubstituted olefins in acyclic monoterpenoid alcohols by cross-metathesis (Figure 1e). we report the success of this unprecedented olefin− olefin combination to form new unfunctionalized trisubstituted
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