Adaptation of a small-molecule hydrogen-bond donor catalyst to an enantioselective hetero-Diels-Alder reaction hypothesized for brevianamide biosynthesis

Abstract

Chiral diamine-derived hydrogen-bond donors were evaluated for their ability to effect stereocontrol in an intramolecular hetero-Diels-Alder (HDA) reaction hypothesized in the biosynthesis of brevianamides A and B. Collectively, these results provide proof of principle that small-molecule hydrogen-bond catalysis, if even based on a hypothetical biosynthesis construct, holds significant potential within enantioselective natural product synthesis.

Figure 1

Representative members of the brevianamide class of natural products (A) and Sammes’ postulated biogenetic hetero-Diels–Alder reaction to create the diazabicyclooctane core (B).

Figure 2

Lateral application of bis(amidine) catalyst design features to a hetero-Diels–Alder reaction.

Figure 3

Preparation of 6(34) and study of its thermal (25 °C) cycloaddition rate to 7. Isomerization of purified 5 was effected by treatment with base in two temperature stages, followed by a careful workup procedure at low temperature to minimize thermal [4 + 2] cycloaddition prior to a specific experiment. These conditions were developed to minimize formation of 7, but at the expense of residual 5 carried through (6:5 ≈ 9:1). Time: t = 0 established as time of first analysis by ¹H NMR for this experiment. Selected peaks labeled for 6 (red circle) and 7 (blue square). Residual CH₂Cl₂ (5.3 ppm) used as an internal standard and reference point. See the Supporting Information for complete details. Composition calculated using integrations of 6 and 7, defined as 7/(6 + 7).