Synthesis of highly substituted 2-spiropiperidines

Abstract

2-Spiropiperidines are a highly desirable, yet under represented structure in drug discovery. 2-Spiropiperidines were synthesised in either a two-pot or one-pot reaction. In the two-pot reaction, the addition of a Weiler dianion to N-Boc imines, followed by deprotection and in situ condensation with a cyclic ketone generated functionalised 2-spiropiperidines in good to excellent yields. In the one-pot reaction, the addition of Chan's diene to N-Boc imines under Maitland-Japp conditions, followed by the addition of sodium bicarbonate and a cyclic ketone formed functionalised 2-spiropiperidines in moderate to good yields.

Bis-Spiro-Oxetane and Bis-Spiro-Tetrahydrofuran Pyrroline Nitroxide Radicals: Synthesis and Electron Spin Relaxation Studies

“…Various synthetic methodologies for 2-oxa-5-azaspiro[3.4]­octane and its derivatives have been reported, but they are not readily extendable to the bis-spirocyclic structure of 1 . ,,, Our syntheses start from N -Boc protected 2,5-tetrasubstituted pyrrolines 3 and 4 , which are reduced to the corresponding tetraols 5 and 6 , using LiAlH 4 (Scheme ).…”

Ketones as strategic building blocks for the synthesis of natural product-inspired compounds

“…A conceptually-related TiCl 4 -mediated synthesis, starting from aryl aldehyde-derived N -Boc imines, was subsequently demonstrated in a one-pot fashion by the same authors (not shown). 127…”

Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment‐Based Drug Discovery

“…Recent advances in the synthesis of heterocyclic spirocycles (a) Wang and Bode generated unactivated imines and utilised metal hydride hydrogen atom transfer chemistry with manganese to generate a C‐centered radical, which underwent addition to the unactivated imine to generate the spirocycle with an N‐centered radical from which the unprotected‐N was unveiled by a second hydrogen atom transfer: 19 spirocycles with R = alkyl or aryl; X = NCbz, S or CH 2 ; n = 5 or 6; (b) Griggs et al formed highly substituted 2‐spiropiperidines in a one‐pot reaction from N ‐Boc imines via the addition of Chan's diene under Maitland–Japp conditions followed by in‐situ Boc‐deprotection and a sodium bicarbonate catalysed cyclisation onto a cyclic ketone: 10 spirocycles with R = alkyl or aryl; X = NCbz, O, S or CH 2 ; n = 4, 5 or 6; (c) Brady and Carreira used the addition of trifluoroborates to oxetanyl N , O ‐acetals to generate products with oxetane and alkyne functionalities from which spiro heterocycles can be generated by orthogonal activation, such as intramolecular opening of the oxetane by the alcohol followed by catalytic intramolecular alkyne hydroalkoxylation to close the spirocyclic ring: 5 spirocycles with R = alkyl, aryl or TMS …”

“…In particular, Wang and Bode utilised metal hydride hydrogen atom transfer chemistry to generate saturated heterocyclic spirocycles in a one‐pot reaction from unactivated imines (Figure a) . Work by Griggs et al also used a one‐pot reaction, this time to generate highly substituted 2‐spiropiperidines from N ‐Boc imines, by in‐situ Boc‐deprotection and cyclisation onto a cyclic ketone (Figure b) . Alternatively, the addition of trifluoroborates to oxetanyl N , O ‐acetals by Carreira and co‐workers provided compounds for spirocyclisation via orthogonal activation of the oxetane and alkyne functionalities (Figure c) …”