The Vinylfluoro Group as an Acetonyl Cation Equivalent: Stereoselective Synthesis of 6-Substituted 4-Hydroxy Pipecolic Acid Derivatives

Abstract

An unprecedented cascade of reactions after acid-catalyzed hydrolysis of tert-butyl (2S,5S)-2-tert-butyl-5-(2-fluoroallyl)-3-methyl-4-oxoimidazolidine-1-carboxylate 3a leading to pipecolic acid derivative 5 is presented. The vinylfluoro group is shown to be an acetonyl cation equivalent under acidic conditions. Interestingly, vinylchloro and vinylbromo groups do not show such transformation under the same conditions. The pipecolic acid derivative 5 produced in this way is further used to synthesize (2R,4R,6S)-6-tert-butyl-4-hydroxypiperidine-2-carboxylic acid 9.

Di‐tert‐Butyl Peroxide‐Mediated Atom‐Transfer Radical Addition of 2‐Chlorodithiane to Aryl Alkynes under Mild Conditions

“…The ATRA method allowed for the rapid synthesis of the corresponding β‐chloro‐α,β‐unsaturated imide derivatives 7 by aminolysis with phenylhydrazine 15. Alternatively, the alkenyl dithiane 3 a could be oxidatively transformed into β‐ketodithiane 8 through exposure to aqueous H 2 SO 4 16. Particularly interesting is the example that led to the methoxy‐substituted dithiane derivative 9 ; the reaction sequence was completed by addition of MeONa in MeOH.…”

“…[15] Alternatively,t he alkenyl dithiane 3a could be oxidatively transformed into b-ketodithiane 8 through exposure to aqueous H 2 SO 4 . [16] Particularly interesting is the example that led to the methoxy-substituted dithiane derivative 9;t he reactions equence was completed by addition of MeONa in MeOH. Finally,t he activated 10,c ontaining au seful aziridine dithianem otif, was obtained in 81 %o verall yield.…”

Asymmetric Synthesis of Pipecolic Acid and Derivatives

“…Seebach's imidazolidinone auxiliaries 57 have been utilised in a novel acid-mediated rearrangement for the synthesis of 6-substituted 4-hydroxypipecolic acids (Scheme 16). 58,59 The Boc-protected imidazolidinone 90 was alkylated under standard conditions with 2-fluoroallyltosylate which gave the alkylated product 91 in 95% yield and in excellent diastereoselectivity (99%). Reaction of 91 under acidic conditions led to the formation of cis-pipecolinamide 92 in a 57% yield.…”

A one-pot, reductive amination/6-endo-trig cyclisation for the stereoselective synthesis of 6-substituted-4-oxopipecolic acids

“…11,12 More recently, methods for the stereoselective synthesis of higher analogues such as 6-substituted-4-hydroxy-and 4-oxopipecolic acids have been reported. [13][14][15] In each of these examples, the key step leads to the formation of the 2,6-cis-isomer as the major product. As part of a program to identify new biologically active pipecolic acids, we were interested in developing a new approach for the stereoselective synthesis of 2,6-trans-6-substituted-4-oxo-Lpipecolic acids such as 2 (Fig.…”