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. 2023 Sep 8;14(38):10508-10514.
doi: 10.1039/d3sc03936f. eCollection 2023 Oct 4.

Deaminative ring contraction for the synthesis of polycyclic heteroaromatics: a concise total synthesis of toddaquinoline

Emily K Kirkeby  1 , Zachary T Schwartz  1 , Myles A Lovasz  1 , Andrew G Roberts  1
Affiliations

Deaminative ring contraction for the synthesis of polycyclic heteroaromatics: a concise total synthesis of toddaquinoline

Emily K Kirkeby et al. Chem Sci. .

Abstract

A concise strategy to prepare polycyclic heteroaromatics involving a deaminative contraction cascade is detailed. The efficient deaminative ring contraction involves the in situ methylation of a biaryl-linked dihydroazepine to form a cyclic ammonium cation that undergoes a base-induced [1,2]-Stevens rearrangement/dehydroamination sequence. The presence of pseudosymmetry guides the retrosynthetic analysis of pyridyl-containing polycyclic heteroaromatics, enabling their construction by the reductive cyclization and deaminative contraction of tertiary amine precursors.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Polycyclic aromatic natural products as motivation for reaction invention: (a) ‘phenanthrene skeleton’ natural products as motivation for reaction invention; (b) nature diversifies scaffolds via tertiary amine rearrangements; (c) recognition of pseudosymmetry guides a convergent retrosynthetic analysis.
Fig. 2
Fig. 2. Deaminative contraction for the synthesis of polycyclic (hetero)aromatics: (a) developed deaminative contraction reactions; (b) a mechanism-based hypothesis.
Fig. 3
Fig. 3. Deaminative contractions for the convergent synthesis of polycyclic aromatics and substituted benzo[h]quinolines: (a) deaminative contraction optimization; (b) accessible polycyclic aromatics; (c) evaluation of electronically perturbed benzo[h]quinolines. nd = not detected.
Fig. 4
Fig. 4. Synthesis of polycyclic aromatics (a) a general strategy to prepare polycyclic heteroaromatics; (b) process scope: the final polycyclic heteroaromatics are shown for each three-step synthesis, the yields for each step are shown in order: build (step 1)-cyclize (step 2)-contract (step 3).
Scheme 1
Scheme 1. A build-cyclize-contract total synthesis of toddaquinoline 3. (a) 3 equiv. KOH, 10 mol% Pd2dba3, 40 mol% Me4t-BuXPhos, 1,4-dioxane/H2O, 100 °C; (b) CF3CO2H, CH2Cl2, rt. dba = dibenzylideneacetone.
Fig. 5
Fig. 5. Functionalization of methyl-substituted benzo[h]quinolines to access aminated benzo[h]quinolines and aza-helicenes: (a) Pd(OAc)2, NBS, CH3CN; (b) NBS, Bz2O2, PhH, 80 °C; (c) add 38 in THF; (d) NiBr2(PPh3)2, Et4NI, Zn, THF, 50 °C; (e) LiI, PO(OMe)3, THF, 65 °C; t-BuOK, 18-C-6, THF, 65 °C.
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