Regioselective Domino Metathesis of 7‐Oxanorbornenes and Its Application to the Synthesis of Biologically Active Glutamate Analogues

Abstract

A highly regioselective domino metathesis reaction of 7-oxanorbornene was developed that employed an intramolecular association of an amide carbonyl group to a ruthenium metal centre. By using this reaction, twelve glutamate analogues inspired by dysiherbaine were efficiently synthesized over 12-14 steps; one of the analogues exhibited bioactivity consistent with central nervous system depression.

Chemospecific Allylation and Domino Metathesis of 7‐Oxanorbornenes for Skeletal and Appendage Diversity

“…Indeed, we have recently successfully demonstrated the usefulness of this effect in the development of biologically active glutamate analogues. [16] Regiocontrol is one of the major concerns in metathesis reactions. [5,[25][26][27][28] Works directed towards the use of the associating effect in other types of metathesis reactions are in progress.…”

“…[5,29,31] In this context, we have further studied the associating effects of neighboring carbonyl functional groups in the domino metathesis of 7-oxanorbornenes, and have found that the effect essentially provides high level of regioselectivity in this reaction. [16] However, it should be noted here that a mechanism based on [2+2] cycloaddition/cycloreversion [5] can be also operative in the reaction of C-type 7-oxanorbornene 25. In this mechanism, the first ROM reaction by [Ru]=CH 2 takes place in an unselective manner, and all reaction intermediates finally lead to thermodynamically stable F-type prod-Scheme 7.…”

“…Importantly, the unreacted substrates were recovered intact after the reactions in reasonable yields in most cases, showing that the first metathesis reaction determines the overall domino transformation. Since we have recently found that the domino metathesis of the B-type N-monoallylamide (such as 24) proceeds in the order ROM/CM/ RCM, [16] the difference in yields must indicate that "the first ROM reaction" takes place more rapidly in the 7-oxanorbornene skeleton of 24 than in that of 25: the B-type norbornene 24 would be a matched substrate and the C-type norbornene 25 would be a mismatched substrate.…”

“…Here we report our efforts directed toward the syntheses of the heterotricycles E and F by a common pathway; [9] synthetic study of the heterobicycle D will be published elsewhere. [16] Evaluation of the chemical space of the products expected by these DOS processes is also included in the Supporting Information.…”

A Marriage of Convenience: Combining the Power of Isocyanide‐Based Multicomponent Reactions with the Versatility of (Hetero)norbornene Chemistry

“…[16] Scheme 14. Synthesis of glutamate analogues by elaboration of the adduct derived from a tandem Ugi/Diels-Alder reaction sequence.…”