T1 - General Ring-Closing Metathesis

Ring The Enyne-Metathesis Reaction The Enyne-Metathesis Reaction synthesis of large rings, a number of selectivity issues arise relating to the orientation of ring closure.

KW - Ring-closing metathesis (RCM)

Sure, there are things that can go wrong, but Solvents for ring-closing metathesis reactions - Chemical A study of the influence of eight diverse solvents on a Grubbs II-catalysed ring-closing metathesis (RCM) reaction reveals a complex dependence of the different Factors influencing ring closure through olefin metathesis Ring closure through olefin m etathesis 225 NHC and PCy 3 as the ligands (L 1 and L 2 in 3) show enhanced metathesis activity.

And in many cases Ring Closing Metathesis (RCM) is both.

Ring Closing Metathesis Reaction Planning Ring closing metathesis (RCM) has evolved into one of those coveted “predictable” reactions in organic synthesis.

and ring closing enyne metathesis ..

The illudins are a family of naturally occurring sesquiterpenes isolated from the poisonous mushroom, Omphalotus illudens. Illudins M and S (1 and 2, respectively) are among the most cytotoxic members of this family of natural products. They inhibit DNA synthesis through a two-step sequence involving enzyme assisted hydride/nucleophilic addition to the C8 enone followed by DNA alkylation through cyclopropyl-ring opening and B-ring aromatization. Significantly, two semi-synthetic derivatives of illudin S (2), namely acylfulvene (3) and irofulven (4), have shown very promising antitumor activity. In particular, the hydroxymethyl derivative irofulven (4) has demonstrated efficacy in clinical trials for treatment of various cancers both as a monotherapy and in combination with other known chemotherapeutic agents. In light of this promising therapeutic potential, these targets have received considerable interest from scientists, leading to several inventive syntheses. We reported enantioselective syntheses of (–)-acylfulvene (3) and (–)−irofulven (4) employing a key enyne ring closing metathesis (EYRCM) cascade reaction. Herein, we describe our observations in the context of related studies directed toward a general strategy for the synthesis of the functional spirocyclic pharmacophore common to all of these cytotoxic agents.

General Ring-Closing Metathesis — Experts@Minnesota

Observations concerning the synthesis of the core spirocyclic AB-ring system of illudins using an enyne ring closing metathesis (EYRCM) cascade are discussed. Substituent effects, in addition to optimization of the reaction conditions and the olefin tether for the key EYRCM reaction, are examined.

Ring closing enyne metathesis mechanism - …

In the context of these studies, we evaluated several olefin tethers for the key EYRCM using model substrates 9 in order to identify optimal tethers that were both stable to the EYRCM reaction conditions and readily removable (). Both Grubbs’ first- and second-generation metathesis catalysts (G1 and G28b, respectively) were evaluated, with G2 generally providing the desired product 10 with greater efficiency compared to G1. Under optimal EYRCM reaction conditions, neither the carbonate nor the carbamate tethers (entries 1 and 2, ) provided the desired EYRCM product 10. Instead, the carbonate tether fragmented to afford the corresponding propargylic alcohol, and the Lewis basic carbamate likely reduced the activity of the G2 metathesis catalyst through an unproductive coordination event. Interestingly, when the cyclohexyl (Cy) carbamate (entry 3, ) was submitted to the EYRCM conditions, the product 10 was generated in 47% yield. We attribute this enhanced reactivity to the expected substrate preference to adopt the carbamate rotamer that positions the allyl substituent trans to the carbonyl. In this conformation the olefin is oriented in close proximity to the alkyne and is poised for the ensuing EYRCM with minimal interference by the Lewis basic carbonyl. In light of this, we also prepared the t-butyldimethylsilyl allylamide (entry 4, ), which would enable access to a more hydrolytically labile cyclic–carbonate by treatment with tetra-n-butylammonium fluoride (TBAF). However, the tandem EYRCM–TBAF treatment provided the desired product in only 15% yield, due to the lability of the silylcarbamate under the EYRCM conditions.