Biomimetic diversity-oriented synthesis of benzannulated medium rings via ring expansion

Abstract

Nature has exploited medium-sized 8- to 11-membered rings in a variety of natural products to address diverse and challenging biological targets. However, owing to the limitations of conventional cyclization-based approaches to medium-ring synthesis, these structures remain severely underrepresented in current probe and drug discovery efforts. To address this problem, we have established an alternative, biomimetic ring expansion approach to the diversity-oriented synthesis of medium-ring libraries. Oxidative dearomatization of bicyclic phenols affords polycyclic cyclohexadienones that undergo efficient ring expansion to form benzannulated medium-ring scaffolds found in natural products. The ring expansion reaction can be induced using three complementary reagents that avoid competing dienone-phenol rearrangements and is driven by rearomatization of a phenol ring adjacent to the scissile bond. Cheminformatic analysis of the resulting first-generation library confirms that these molecules occupy chemical space overlapping with medium-ring natural products and distinct from that of synthetic drugs and drug-like libraries.

Figure 1. Overall strategy and precedents for the synthesis of benzannulated medium rings

(a) Proposed biosynthetic route and biomimetic synthesis of protostephanine. (b) Biomimetic syntheses of (homo)erythrina alkaloids^, (pathway A) and alternative dienone–phenol rearrangement (1,2-alkyl shift) pathway leading to a homoaporphine scaffold (pathway B). (c) Biomimetic oxidative dearomatization–ring-expanding rearomatization (ODRE) approach to benzannulated medium ring synthesis. NMO, N-methyl morpholine, N-oxide; TBS, tert-butyldimethylsilyl.

Figure 2. Proposed mechanisms for aromatization-driven ring expansion of 5 to benzannulated medium rings 6–8 and for formation of alternate tricycles 9 and 10

In the desired pathway, polarization of the cyclohexadienone carbonyl in oxocarbenium intermediates 83 induces bond scission to form tertiary carbocations 84, leading to ring expansion products 6–8. In alternative undesired pathways, dienone–phenol rearrangement of 83 or transannular Friedel–Crafts alkylation of 84 affords 85, which then undergoes 1,2-alkyl shift to 86 leading to tricycles 9 and 10.

Figure 3. Downstream modifications of ODRE-derived benzannulated medium ring scaffolds

(a) Diversification reactions of diaryl ether 77. (b) Dihydroxylation and detriflation of biaryl 78. (c) Additional dihydroxylated products synthesized from ODRE-derived benzannulated medium ring scaffolds. (i) trimethylsulfoxonium iodide, NaH, DMSO, 25 °C, 20 h, 80%. (ii) m-CPBA, CH₂Cl₂, 0 → 25 °C, 14 h, 61%. (iii) OsO₄, NMO, 3:1 acetone/H₂O, 0 °C, 15 min; 90: 82%; 94: 97%; 96: 50%; 97: 62%; 98: 80%; 99: 83%; 100: 77%; 101: 66%. (iv) NaBH₄, CeCl₃, MeOH, 0 → 15 °C, 3 h, 77%. (v) BBr₃, CH₂Cl₂, 0 → 25 °C, 2 h, 85%. (vi) methyl (2R)-lactate, DIAD, PPh₃, THF, 0 → 25 °C, 12 h, 84%. (vii) LiOH, MeOH, 0 → 25 °C, 30 min, 100%. DIAD, diisopropyl azodicarboxylate; DMSO, dimethylsulfoxide; m-CPBA, 3-chloroperoxybenzoic acid; NMO, N-methylmorpholine-N-oxide; Ph, phenyl; PMP, p-methoxyphenyl; THF, tetrahydrofuran.