N-heterocycle synthesis with SnAP chemistry

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Saturated N-heterocyclic building blocks are of growing importance in modern small molecule pharmaceuticals, but their synthesis often requires long, inflexible routes or difficult to remove N-protecting groups. In order to establish a cross-coupling approach to C-substituted, N-unprotected morpholines, piperazines, thiomorpholines, diazepanes, and other compounds, including bicyclic and spirocyclic N-heterocycles, we have developed SnAP Reagents for the one-step synthesis of these compounds from aldehydes and ketones.

SnAP Reagents are an ever-expanding class of reagents, which are now available for the convenient one-step synthesis of medium-ring (6-9 membered) saturated N-heterocycles, including bicyclic and spirocyclic structures. They are easy to use, work with a wide variety of aldehydes and ketones – including heteroaromatics, and provide predictable access to some of the most valuable structures in modern drug development. Thanks to the support of an ERC Proof of Concept Grant, many of the SnAP Reagents are now commercially available from Sigma-Aldrich.

More recently, we have developed catalytic variants and established that the mechanism involves a radical pathway. [112] Based on these findings, we are developing new reagent classes using different precursors, such as silicon and halogen based reagents. 

Notable Publications:

(80) Vo, C.-V.; Mikutis, G.; Bode, J. W. "SnAP Reagents for the Transformation of Aldehydes into Substituted Thiomorpholines—An Alternative to Cross-Coupling with Saturated Heterocycles"Angew. Chem. Int. Ed. 201352, 1705–1708.

(86) Luescher, M. U.; Vo, C.-V.; Bode, J. W. "SnAP Reagents for the Synthesis of Piperazines and Morpholines"Org. Lett. 201416, 1236–1239.

(87) Vo, C.-V.; Luescher, M. U.; Bode, J. W. "SnAP Reagents for the One-Step Synthesis of Medium Ring Saturated N-Heterocycles from Aldehydes"Nature Chem. 20146, 310–314. 

(89) Review article: Vo, C.-V.; Bode, J. W. "Synthesis of Saturated N-Heterocycles"J. Org. Chem. 201479, 2809–2815.

(101) Siau, W.-Y.; Bode, J. W. "One Step Synthesis of Saturated Spirocyclic N-Heterocycles with SnAP Reagents and Ketones"J. Am. Chem. Soc. 2014136, 17726–17729. 

(108) Geoghegan, K.; Bode, J. W. "Bespoke SnAP Reagents for the Synthesis of C-Substituted Spirocyclic and Bicyclic Saturated N-Heterocycles"Org. Lett. 201517, 1934–1937. 

(112) Luescher, M. U.; Bode, J. W. "Catalytic Synthesis of N-Unprotected Piperazines, Morpholines, and Thiomorpholines from Aldehydes and SnAP Reagents"Angew. Chem. Int. Ed. 2015, Early View. (DOI: 10.1002/anie.201505167)

(113) Review article: Luescher, M. U.; Geoghegan, K.; Nichols, P. L.; Bode, J. W. "SnAP Reagents for a Cross-Coupling Approach to the One-Step Synthesis of Saturated N-Heterocycles"Aldrichim. Acta 201548, 43–48.

(119) Hsieh, S.-Y.; Bode, J. W.; "Silicon Amine Reagents for the Photocatalytic Synthesis of Piperazines from Aldehydes and Ketones" Org. Lett. 201618, 2098–2101

(120) Luescher, M. U.; Bode, J. W.; "SnAP-eX Reagents for the Synthesis of Exocyclic 3-Amino- and 3-Alkoxypyrrolidines and Piperidines from Aldehydes" Org. Lett. 201618, 2652–2655

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