Single-atom logic for heterocycle editing

Abstract

Medicinal chemistry continues to be impacted by new synthetic methods. Particularly sought after, especially at the drug discovery stage, is the ability to enact the desired chemical transformations in a concise and chemospecific fashion. To this end, the field of organic synthesis has become captivated by the idea of 'molecular editing'-to rapidly build onto, change or prune molecules one atom at a time using transformations that are mild and selective enough to be employed at the late stages of a synthetic sequence. In this Review, the definition and categorization of a particularly promising subclass of molecular editing reactions, termed 'single-atom skeletal editing', are proposed. Although skeletal editing applies to both cyclic and acyclic compounds, this Review focuses on heterocycles, both for their centrality in medicinal chemistry and for the definitional clarity afforded by a focus on ring systems. A classification system is presented by highlighting methods (both historically important examples and recent advances) that achieve such transformations, with the goal to spark interest and inspire further development in this growing field.

Fig. 1 |. Definition and classification of single-atom molecular editing.

a, The anatomy of molecular editing. Examples of peripheral editing (left) and skeletal editing (right) conceptually applied towards the diversification of apixaban. b, Classification of single-atom editing. A depiction of single-atom editing applied to a representative molecule (left) and the related classification scheme (right).

Fig. 2 |. Ring contractions that leverage classical carbonyl chemistry.

a, General reaction mechanism for the Favorskii rearrangement reaction (top) with synthetic applications demonstrated in the syntheses of (+)-epoxydictymene and (−)-iridomyrmecin (bottom). b, General reaction mechanism for the benzilic acid rearrangement reaction (top) and applications towards (+)-K252a and (−)-isatisine A (bottom). Contracted rings are highlighted in blue for clarity. LG, leaving group; Nu, nucleophile; DCM, dichloromethane; BOM, benzyloxymethyl acetal group; Ts, para-toluenesulfonyl group.

Fig. 3 |. Select developments in single-atom ring contractions of heterocycles.

a, Photomediated ring contractions of acyl piperidine scaffolds. b, Photochemical ring contractions of pyridine N-oxides^–. Contracted rings are highlighted in blue for clarity. d.r., diastereomeric ratio; e.r., enantiomeric ratio.

Fig. 4 |. Single-atom deletions that leverage carbonyl chemistry.

a, General reaction mechanism for the Favorskii rearrangement reaction and decarboxylation (top) with the application demonstrated in the synthesis of cubane^, (bottom). b, General reaction mechanism for photodecarbonylation (top) and the application towards (+)-α-cuparenone (bottom). Deleted carbon atoms are circled, and contracted rings are highlighted in blue for clarity. Tol, tolyl group.

Fig. 5 |. Select developments in single-atom deletions from nitrogenous heterocycles.

a, Representative examples of a carbon deletion reaction in nitrogen heterocycles. b, Representative examples of nitrogen deletion reactions applied to azacyclic frameworks^,. Deleted atoms are circled, and contracted rings are highlighted in blue for clarity. AGE, advanced glycation end product; DBU, diazabicycloundecene. r.t., room temperature.

Fig. 6 |. Ring expansions that leverage carbonyl chemistry.

a, General reaction mechanism for the Dowd–Beckwith rearrangement reaction (top) with application demonstrated in the synthesis of salvileucalin C (bottom). b, Representative example of a rhodium-catalysed cyclobutanone rearrangement. Expanded rings are highlighted in red for clarity. AIBN, azobisisobutyronitrile; COD, 1,5-cyclooctadiene; dppp, 1,3-bis(diphenylphosphino) propane.

Fig. 7 |. Select advances in single-atom ring expansions.

a, Representative examples of oxidative ring expansions in benzylic alcohols (top) and amines (bottom). b, Photochemical ring expansion of pyridinium salts. Expanded rings are highlighted in red for clarity. HFIP, hexafluoroisopropanol; Tf, trifluoromethanesulfonyl.

Fig. 8 |. Single-atom insertions that leverage carbonyl chemistry.

a, General reaction mechanism for a Beckmann rearrangement reaction (top) with the application demonstrated in the synthesis of azithromycin (bottom). b, Representative example of a cyclopropanation reaction used to achieve ring expansion (top) and a synthetic application shown in the synthesis of (+)-pepluanol A (bottom). Inserted atoms are circled, and expanded rings are highlighted in red for clarity. TMS, trimethylsilyl; TBS, tert-butyldimethylsilyl.

Fig. 9 |

Recent advances in single-atom insertions into heterocycles. a, Representative azole-carbon insertion reaction (top), and applications of a related insertion reaction in the synthesis of complanadine A (bottom). b, Ether–boron insertion reactions. The inserted atoms are circled, and the expanded rings are highlighted in red for clarity. Boc, tert-butoxycarbonyl group; Pin, pinacol; Mes, mesityl group.

Fig. 10 |. Dream reactions in single-atom skeletal editing and promising precedents.

a, Wishlist of single-atom editing reactions applied to a complex molecule. b, Examples of the idealized single-atom editing logic in drug discovery shown through carbon-to-nitrogen (left) and nitrogen-to-carbon (right) atom swaps. c, Selected examples of carbon–nitrogen transmutations from Mindola and co-workers (top) and Kano and co-workers (bottom). d, Representative example of oxygen–nitrogen transmutation. ‘Edited’ atoms are highlighted for clarity. Cdc7, Cell division cycle 7; PARP, polyadenosine diphosphate ribose polymerase; IC₅₀, half maximal inhibitory concentration; K_i, inhibitory constant.