Total Synthesis of (+)-Phomopsolide C by Ring-Size Selective Ring-Closing Metathesis/Cross-Metathesis

Abstract

[reaction: see text]A new strategy for the synthesis of chiral 6-substituted 5,6-dihydro-5-hydroxypyran-2-ones by ring-size selective ring-closing metathesis (RCM) and its application to a short total synthesis of (+)-phomopsolide C are described. The key bond-forming reactions in this approach are a chemoselective cross-metathesis (CM) and RCM.

Synthesis of Dihydrofurans and Dihydropyrans with Unsaturated Side Chains Based on Ring Size‐Selective Ring‐Closing Metathesis

“…Functionalization of the second OH group is unfavorable due to steric hindrance. Compounds 5a [24] and 5b [22] have previously been obtained via this method. Method C is a Pd-catalyzed O-allylation [39] which has proven useful in cases where a protecting group migration or rather low reactivity has to be expected.…”

“…[49] For olefin metathesis reactions such effects are less common, although they have been proposed, e.g., for MOM protecting groups. [22] Another variable site of the substrate structure is the terminus of the "a" double bond. Introducing a substituent R here will disfavor initiation at this particular site and hopefully support a catalyst-directed initiation at "b".…”

“…Apart from steric effects, coordinative or electronic effects might have an influence on ring size-selectivity, as outlined above. Alkoxymethyl ethers have previously been proposed as catalyst-directing groups [22] in olefin metathesis and we wanted to examine the influence of such a potentially coordinating protecting group by investigating the outcome of an RCM reaction of BOM-protected 6f. The result was very similar to those observed for trienes 6b-d and we can, from these experiments, discover no piece of evidence for a catalyst-directing effect of BOM ethers (entries 12 and 13).…”

“…This would be particularly attractive from the synthetic point of view, as 1 is easily available in multi-gram quantities from d-mannitol, [20,21] while its enantiomer ent-1 can be synthesized from R,R-dimethyl tartrate. [22] Both 1 and ent-1 have previously been used as building blocks for the synthesis of metathesis precursors: for instance, Quinn et al reported the total synthesis of the five-membered ring lactones muricatacin [23] and rollicosin [24] from 1, while Michaelis and Blechert recently published a synthesis of the sixmembered ring lactone phomopsolide C from ent-1. [22] Burke et al exploited the C 2 -symmetry of dienediol 1 in the total synthesis of several natural products, such as brevicomin, [25] sialic acids, [26] and densely functionalized spiroacetals.…”

“…[22] Both 1 and ent-1 have previously been used as building blocks for the synthesis of metathesis precursors: for instance, Quinn et al reported the total synthesis of the five-membered ring lactones muricatacin [23] and rollicosin [24] from 1, while Michaelis and Blechert recently published a synthesis of the sixmembered ring lactone phomopsolide C from ent-1. [22] Burke et al exploited the C 2 -symmetry of dienediol 1 in the total synthesis of several natural products, such as brevicomin, [25] sialic acids, [26] and densely functionalized spiroacetals. [27] Finally, Donohoe et al used a mixture of racemic 1 and its meso-diastereomer, after acetalization with methoxyallene and double RCM of the resulting tetraene, as a precursor for bisfuran.…”