Enantioselective Diels-Alder-lactamization organocascades employing a furan-based diene

Abstract

α,β-Unsaturated acylammonium salts are useful dienophiles enabling highly enantioselective and stereodivergent Diels-Alder-initiated organocascades with furan-based dienes. Complex polycyclic systems can thus be obtained from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe the use of furan-based dienes bearing pendant sulfonamides leading to the generation of oxa-bridged, trans-fused tricyclic γ-lactams. This process constitutes the first highly enantio- and diastereoselective, organocatalytic Diels-Alder cycloadditions with these typically problematic dienes due to their reversibility. Computational studies suggest that the high diastereoselectivity with these furan dienes may be due to a reversible Diels-Alder cycloaddition for the endo adducts. In addition, the utility of this methodology is demonstrated through a concise approach to a core structure with similarity to the natural product isatisine A and a nonpeptidyl ghrelin-receptor inverse agonist.

Figure 1

Comparison of enantioselective Diels-Alder cycloadditions with furans as dienes. Lewis-acid catalyzed, iminium-based, and the current asymmetric, α,β-unsaturated acylammonium salt-based, Diels-Alder-lactamization organocascade.

Figure 2

Calculated TSSs for the DA step (optimized with SMD(DCM)-M06-2X/6-31G(d)). Free energies (ΔG, normal text) and enthalpies (ΔH, bold, italic) are shown relative to separated reactant species, furan 8a, acryloyl chloride (9), and (S)-(−)-BTM (energies in kcal/mol).

Figure 3

Potential funneling of endo 10′ diastereomer to the thermodynamically favored exo (+)-10 diastereomer involving a retro-Diels-Alder/Diels-Alder-lactamization sequence. Optimized geometries of endo 10′ and exo (+)-10 lactams calculated using SMD(DCM)-M06-2X/6-31G(d). Select dihedral angles (O-C-C-N, green) are shown.

Figure 4

Epoxidation of tricyclic γ-lactam (+)-12a to a fully substituted oxa-bridged cyclohexane (+)-14 with six contiguous stereocenters. Transformation of (+)-12a to a fully substituted tetrahydrofuran (−)-15 with correspondence to the natural product, isatisine A. (Inset: single crystal X-ray structure in ORTEP format of (+)-14; 50% probability, see ESI Figure S1).

Scheme 1

Diels-Alder-lactamization of furan-based sulfonamide 8a and acryloyl chloride (9) mediated by (R)-(−)-levamisole hydrochloride providing bridged cycloadduct (+)-10.

Scheme 2

Diels-Alder-lactamization of furan 8a and trifluorocrotonyl chloride (11b) delivering bridged cycloadduct (+)-13.