Allylmalonate as an Activator Subunit for the Initiation of Relay Ring‐Closing Metathesis Reactions

Abstract

We have previously described a total synthesis of (+)-gigantecin (5, Scheme 1) in which the importance of sequencing competitive ring-closing vs. cross metathesis events was revealed.[1] The most significant results (Scheme 1) were that the direct RCM reaction of key substrate 2 [using the Hoveyda-Grubbs 2 nd generation initiator (HG2)] gave the 11-membered alkene 1 rather than the desired silacycloheptene derivative that would have arisen from closure of C15 with C16. By contrast, initial cross metathesis of 2 with 3 to form the C7/C8 bond was followed by RCM to give 4, which was carried on in straightforward fashion to 5.Relay metathesis, of both the ring-closing (RRCM) [2] and cross metathesis (Relay-CM) [3] flavors, is an alternative strategy for redirecting the outcome(s) of competitive metathesis pathways in complex polyfunctional substrates. We felt that polyene intermediates like 2 and 4 held further promise as vehicles for exploring new aspects of the RRCM process. Here we report observations that extend both the utility and our understanding of RRCM.We wondered if we could use RRCM to solve the regioselectivity problems outlined in Scheme 1, we considered arming the C15/C15' (or C16/C16') vinyl group in 2 with a relay activator unit as shown generically in 6 (or 7, Scheme 2). The goal was to have the process implied by arrows a then b in 6 (or a' then b' in 7) dominate, thereby closing the C15/C16 bond selectively over that of the C8/C16 (cf. numbering in 2). Also shown in Scheme 2 is a set of relay activated, terminal allyl-containing substrates 8a-e that we prepared (along with the malonate derivative 9b, Scheme 3) in order to test this idea. Each substrate was exposed to a variety of olefin metathesis conditions, differing principally in the choices of initiators, solvents, and temperature. Reaction progress and outcome were monitored by ESI-MS and 1 H NMR analyses. In most cases complete consumption of starting material 8 was observed and most, if not all, of the identified product(s) were macrocyclic alkenes in which ethylene, but not the relay unit, had been lost. The preponderance of evidence pointed to reaction pathways via c and d in 6 (and c' in 7), rather than the desired RRCM process via a/ b (or a'/b'). In turn, this suggested that at least in the setting of the family of complex polyenes 8, the rate constant of the critical relay event (a/a') within the relay subunits (cf. I-III, Scheme 2) was too slow to compete with the undesired macrocyclizations. This led us to then study the allylmalonate ester derivatives 9a and 9b. Although we had used malonate ester derivatives in our initial demonstrations of RRCM[2] (and dimethyl diallylmalonate itself has served as an important test substrate for many aspects of olefin metathesis, including incisive mechanistic studies [4]), this structural subunit had not been explored previously as the expendable relay activator moiety. The tetraene substrate 9a contains a capping terminal n-butyl group on C8'. Treatment of 9a with HG2 in hot methylene chlor...

American Chemical Society 2015 National Award Winners

“…He subsequently joined the faculty at the University of Minnesota. Hoye and his research group are interested in the development of new strategies for the total synthesis of natural products 9 …”

Träger der nationalen Preise der American Chemical Society 2015

“…Danach ging er an die University of Minnesota. Sein Interesse gilt der Entwicklung neuer Strategien für die Totalsynthese von Naturstoffen 9 …”

Geminal Alkene–Alkyne Cross Metathesis Using a Relay Strategy

“…Hoye had studied various relay tethers in his relay ring-closing metathesis reaction, mostly employing ethers and malonates . These were mainly selected based on synthetic convenience, although Hoye has noted distinction of the malonate relay tether . In our attempted cycloheptylidene transfers, the ether-containing tether 15 did not perform well; only 22% of the desired product was obtained (Scheme ).…”