Allylmalonate as an activator subunit for the initiation of relay ring-closing metathesis reactions

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 2nd 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. Scheme 1 Sequenced Metatheses Leading to (+)-Gigantecin.[1] TIPS = triisopropylsilyl. 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 1H 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 chloride resulted in clean formation of the two RRCM products 10a and 10b in a 4:1 ratio (tabular inset, Scheme 3). Even more exciting was the observation that the malonate ester 9b, now containing the C8/C8’ terminal vinyl group and, therefore, a direct analog of the substrates 8a-e, also cleanly cyclized to 10b in 88% yield following purification.[5] Surprisingly, we did not detect the symmetrical C8-C8 dimer what would arise from cross metathesis of two molecules of 10 in either of these experiments. Scheme 2 RRCM with Various Relay Activator Units. Scheme 3 RRCM with Allyl Malonate as the Relay Activator. HG2 = second generation Hoveyda-Grubbs initiator, [Ru=CH(oisopropoxyPh)(Cl)2(H2IMes)]. Two factors likely contribute to the far greater efficiency of the RRCM with malonate ester derivatives 9a-b compared with any of 8a-e (Scheme 2). First, a buttressing/Thorpe-Ingold/gem-dimethyl-like effect should accelerate the initial stage of the relay event (i.e., kon for 11a to 11b, Scheme 4). Second, ejection of the dimethyl cyclopentene-1,1-dicarboxylate moiety from the coordination sphere of the ruthenium center (cf. 11d to 11e, Scheme 4) should be faster than the corresponding decomplexation of the relay by-products for substrates 8a-e. This second point deserves addition commentary. Scheme 4 Mechanistic Cascade for the Relay Stage of RRCM. [Ru*] = Ru(Cl)2(H2IMes)Ln. The reversible nature of many individual steps in olefin metathesis, including dissociation of the product alkene from the metal center, has been examined fundamentally and in detail by Piers and co-workers.[6] We suggest that the slowest step in some RRCM reactions is loss of the relay alkene (a cyclopentene derivative here) from 11d [i.e., koff for 11d (or an associative counterpart involving the C16/C16’ vinyl group)[4]]. In this scenario it could be that the steric repulsion between the added bulk of the geminal dicarboxylates with moieties in the metal ligand sphere reduces the avidity of Ru-alkene binding. This would serve to speed ejection of the relay-generated remnant from 11d relative to the analogous event in the reactions emanating from any of 8a-e. Regardless of the mechanistic details of the transformation of 9b to 10b, the practical advantage of the malonate relay activator in the setting of tetraene 9 is unmistakable and suggests a potentially wider utility of this subunit to combat premature macrocyclization[7],[8] or truncation,[2] processes that have plagued a number of applications of the RRCM strategy.[2] In the context of a different study, we made an observation that bears on the question of ease of ejection of the relay remnant from the ruthenium coordination sphere. Triene 12 produced the hindered Z-alkene 14[2],[9].[10] along with several by-products upon treatment with the first generation Grubbs precatalyst (Scheme 5). These additional, minor by-products were isolated and shown to be the macrocyclic dienes (E)-13, (Z)-13, and 15. The last is most intriguing, since it is, formally, the constitutional isomer of 13 in which the allylic methyl substituent has moved from C9 to C7. We suggest that diene 15 was produced via the reinsertion process indicated by 16a-d. Wenzel and Grubbs have reported the dynamic nature of a π-bound alkene to a ruthenium N-heterocyclic carbene (NHC) in a simpler system.[11] Scheme 5 Rearranged Macrocylic Diene 15, Formed during the RRCM Reaction of Triene 12. G1 = first generation Grubbs initiator [Ru=CHPh(Cl)2(PCy3)2]. In summary, the studies reported here shed light on regioselectivity issues associated with the application of the RRCM strategy in a complex molecular setting. A practical solution to overcome competitive premature macrocyclizations within 8 was uncovered. In particular the efficiency and selectivity of RRCM reactions of substrates 9a/b, each armed with an allylmalonate relay moiety, was achieved. This example demonstrates that the structure of the relay moiety can be crucial in structurally complex RRCM substrates. We propose that faster ejection of dimethyl cyclopentene-1,1-dicarboxylate, the remnant from the relay event, contributes to the dramatic benefit (9b to 10b, 88% yield) afforded by use of the allylmalonate relay.