Palladium-catalyzed allylic substitution between C-based nucleophiles and 6-azabicyclo[3.1.0]-hex-3-en-2-oxy derivatives: A new selectivity paradigm

Abstract

The reaction between a-hydroxy-(or a-acetoxy) cyclopenten-aziridines (6-azabicyclo[3.1.0]hex-3-en-2ols or acetates) and C-based nucleophiles in the presence of Pd(0)-catalysis was investigated. In all the cases studied, the reaction was totally regio-and diastereo-selective, affording a single adduct in moderate to good yields. Specifically, attack of the nucleophile at position 3 of the cyclopentene moiety, anti to the vicinal oxy group, with vinylogous ring opening of the aziridine ring, was observed. When the carbon acid is a very acidic methylene (pK a (DMSO) 7.3), the resulting adduct is a zwitterion, resulting from an intramolecular proton transfer between the amino group and the carbon acid moiety taking place after the CeC bond formation. A plausible mechanism for this transformation is put forward.

(1R,4S,5S)-5-((3-Hydroxypropyl)amino)-4-((1-methyl-1H-tetrazol-5-yl)thio)cyclopent-2-en-1-ol

“…The starting material, 1-(3-hydroxypropyl)pyridin-1-ium chloride (1c), was prepared from pyridine and 3-chloropronanol following our reported method. 6-(3-hydroxypropyl)-6-azabicyclo[3.1.0]hex-3-en-2-ol (2c) was obtained by photohydration of the pyridinium salt 1c (Scheme 3), also taking advantage of our previous reported synthetic methodology [18]. In this work, the bicyclic vinyl aziridine 2c was subjected to thiol-nucleophilic attack by 1-methyl-1H-tetrazole-5-thiol, applying our reported optimized conditions [17].…”

“…We also studied several bicyclic vinyl aziridines transformations. In collaboration with G. Poli, we reported a palladium-catalyzed allylic substitutions using C-nucleophiles [18] (Scheme 2B). Additionally, we accomplished several ring-opening reactions using sulfur and nitrogen-based nucleophiles in an aqueous medium, including a bioconjugation with the peptide hormone salmon calcitonin (sCT) [17] (Scheme 2C).…”

“…[14,15] The implementation of flow enabled the synthesis of bicyclic vinyl aziridines with larger productivity when compared to reported batch methods [16] and also the achievement of a gram scale production [15] (Scheme 2A). [14,15], improvements over batch methodology [16,17]; previous work on (B) palladium-catalyzed allylic substitutions on bicyclic vinyl aziridines using carbon-based nucleophiles [18] and (C) nucleophilic ring-opening reactions of bicyclic vinyl aziridines with thiol and nitrogen nucleophiles [17]; (D) this work: nucleophilic ringopening reaction of bicyclic vinyl aziridine ring (2c) by 1-methyl-1H-tetrazole-5-thiol to produce 3c. Mannostatin A is a natural product, first isolated from a soil microorganism Streptoverticillus, and is among the most potent inhibitors of class II α-mannosidase.…”

“…[14,15] The implementation of flow enabled the synthesis of bicyclic vinyl aziridines with larger productivity when compared to reported batch methods [16] and also the achievement of a gram scale production [15] (Scheme 2A). [14,15], improvements over batch methodology [16,17]; previous work on (B) palladium-catalyzed allylic substitutions on bicyclic vinyl aziridines using carbon-based nucleophiles [18] and (C) nucleophilic ring-opening reactions of bicyclic vinyl aziridines with thiol and nitrogen nucleophiles [17]; (D) this work: nucleophilic ringopening reaction of bicyclic vinyl aziridine ring (2c) by 1-methyl-1H-tetrazole-5-thiol to produce 3c. [14,15], improvements over batch methodology [16,17]; previous work on (B) palladium-catalyzed allylic substitutions on bicyclic vinyl aziridines using carbon-based nucleophiles [18] and (C) nucleophilic ring-opening reactions of bicyclic vinyl aziridines with thiol and nitrogen nucleophiles [17]; (D) this work: nucleophilic ring-opening reaction of bicyclic vinyl aziridine ring (2c) by 1-methyl-1H-tetrazole-5-thiol to produce 3c.…”

Strain Release Chemistry of Photogenerated Small‐Ring Intermediates

“…Ligand exchange liberates the 3,4,5‐trisubstituted cyclopentenes 35 in low to high yield (Scheme 4). [19] …”