Synthesis of (±)-Bisavenanthramide B-6 by an Anionic Anhydride Mannich Reaction

Abstract

Bisavenanthramide B-6 (2) is a highly substituted γ-lactam derived from oat leaves. Development of a new base-promoted anhydride Mannich reaction with N-sulfonylated imines that forms the core structure of 2 in a single step is presented. Further elaboration allows for a facile one-pot double Buchwald N-arylation to install the final rings onto the densely substituted γ-lactam core. This route provides the natural product in a longest linear sequence of nine steps.

Diastereoselective Base-Catalyzed Formal [4 + 2] Cycloadditions of N-Sulfonyl Imines and Cyclic Anhydrides

“…Based on this understanding, we first reported the suppressed reactivity of N -sulfonyl imines to enolizable anhydrides as well as their base-mediated reactivity in the anionic AMR. 15 From that report, we formed the general hypothesis that a reduction in imine nitrogen basicity through thoughtful substitution would prevent enolate formation in the absence of exogenous base (Figure 2B). In such a catalytic system, imine 7 and anhydride 8 cannot form lactam 9 alone.…”

“…5 To this end, our group has previously contributed to advances in mechanistic understanding of the Castagnoli–Cushman reaction, 6,7 which we now call the anhydride Mannich reaction (AMR), developed a novel four-component reaction 8–14 (4CR), and reported the first base-promoted AMR variant using N -sulfonyl imines in the synthesis of bisavenanthramide B-6. 15 While the AMR has proven a powerful means of synthesizing complex lactams in diversity-oriented and natural product syntheses, most reports of such reactions employ N -alkylimines, which react readily with many anhydrides in the absence of catalyst. 9 Several reports of catalysis do not clearly show acceleration relative to the known background rate.…”

Acyclic Stereocontrol in the Additions of Nucleophilic Alkenes to α‐Chiral N‐Sulfonyl Imines

“…N-sulfonyl imines are of particular use, and have been used as electrophiles in natural product [1,2] and pharmaceutical target [3,4] syntheses. N-sulfonyl imines are of particular use, and have been used as electrophiles in natural product [1,2] and pharmaceutical target [3,4] syntheses.…”

“…Electrophilic imines are versatile substrates for the construction of nitrogen‐bearing stereogenic centers. N ‐sulfonyl imines are of particular use, and have been used as electrophiles in natural product and pharmaceutical target syntheses. Acyclic stereocontrol in the additions of nucleophiles to chiral aldehydes and ketones has been extensively studied.…”

Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation

“…We expected these compounds to display a similar profile to the natural models and, in particular, we were interested in studying them as inductors of Nrf2, the master regulator of the Phase II anti-oxidative response [17] and an emerging target in drug discovery in the neurodegeneration area [5]. While avenanthramides have been well characterized as Nrf2 inducers, a feature that was ascribed to their α,β-unsaturated amide moiety [12,13], bisavenanthramides have not been studied in this regard although they show the same structural feature.…”