Synthesis of Piperidines and Dehydropiperidines

A Stereoselective aza-Prins Reaction: Rapid Access to Enantiopure Piperidines and Pipecolic Acids

“…Therefore we prepared mono-( 8) 32 and di-phenyl ( 7) [33][34] allylmorpholin-2-ones in both enantiomeric forms in just 4 steps, as two new chiral platforms containing a homoallylic amine. Following the rationale presented in Scheme 1 (2), the phenyl substituents were chosen as these would both facilitate rapid removal of part of the chiral platform post Prins cyclisation and crucially block one face from anion trapping. Treatment of either (7) or (8) with NaHMDS and an allyl or propargylic bromide gave a small library of enantiomerically pure secondary amines (Table 1).…”

“…The vast majority of these drugs require careful stereocontrol of the substitutents around the ring during manufacture. Methods for their synthesis have been widely reviewed [2][3][4][5] but the greatest problem has always been the asymmetric construction of the piperidine ring. Furthermore, there is an emerging need for sp 3 -rich heterocyclic frameworks, again with both relative and absolute stereocontrol of the substituents.…”

Leveraging the 1,3-azadiene-anhydride reaction for the synthesis of functionalized piperidines bearing up to five contiguous stereocenters

“…10 Indeed, sterically challenged 1b failed to react even at elevated temperatures (up to 150 C) even though constitutionally isomeric 2,2-dimethylglutaric anhydride reacted efficiently with 1,3-azadienes of type 2 at 110 C. 10 In the current study, we seek to evaluate the performance (with respect to reactivity, diastereoselectivity, and chemoselectivity) of 3-methylglutaric anhydride (1c) toward 1,3-azadiene partners, and elaborate the product (i.e., 3c) to several synthetically and pharmaceutically attractive topologies (see 4-7). Since many existing cyclization strategies for piperidine synthesis tend to exhibit poor generality, suffer from low regio-and stereochemical control, require protecting group manipulations, or depend on a specic directing group, 11 we anticipate that the current approach, which side-steps these aforementioned limitations, would greatly expand the structural space for the discovery of new piperidine pharmacophores. Indeed, this anhydride-imine reaction is known to be a powerful tool for the synthesis of combinatorial and targeted compound libraries as well as for producing building blocks in multigram (up to 100 g) scale.…”

“…, 3c) to several synthetically and pharmaceutically attractive topologies (see 4–7). Since many existing cyclization strategies for piperidine synthesis tend to exhibit poor generality, suffer from low regio- and stereochemical control, require protecting group manipulations, or depend on a specific directing group, 11 we anticipate that the current approach, which side-steps these aforementioned limitations, would greatly expand the structural space for the discovery of new piperidine pharmacophores. Indeed, this anhydride-imine reaction is known to be a powerful tool for the synthesis of combinatorial and targeted compound libraries as well as for producing building blocks in multigram (up to 100 g) scale.…”

Gold(I)-Catalyzed Enantioselective Annulations between Allenes and Alkene-Tethered Oxime Ethers: A Straight Entry to Highly Substituted Piperidines and aza-Bridged Medium-Sized Carbocycles

“…4 Moreover, the number of enantioselective approaches that allow a one-step access to these scaffolds is rather limited. 5 These drawbacks are even more pronounced in the case of piperidines containing highly substituted carbon stereocenters adjacent to their nitrogen atom. 6 The piperidine scaffold is also embedded in the skeleton of many polycyclic natural products exhibiting complex structures.…”