Abstract
Novel chiral thiophene-2,5-bis(β-amino alcohol) ligands (L1–L5) were designed and synthesized from thiophene-2,5-dicarbaldehyde (3) with chiral β-amino alcohols (4a–e) in 4 steps with overall 23% yields. An in situ generated L-Cu(OAc)2·H2O catalyst system was found to be highly capable catalyst for the asymmetric Henry reaction of nitromethane (7) with various substituted aromatic aldehydes (6a–m) producing chiral nitroaldols product (8a–m) with excellent enantiomeric purity (up to 94.6% ee) and up to >99% chemical yields. 20 mol% of L4-Cu(OAc)2 catalyst complex in EtOH was effective for the asymmetric Henry transformation in 24 h, at ambient temperature. Ease of ligand synthesis, use of green solvent, base free reaction, mild reaction conditions, high yields and excellent enantioselectivity are all key factors that make this catalytic system robust and highly desirable for the access of versatile building block β-nitro alcohol in practical catalytic usage via asymmetric Henry reaction.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
Asymmetric Henry approach has been widely reported in the literature; for example, Suami and coworkers employed the asymmetric Henry reaction as a key step during the total synthesis of nucleoside antibiotics ‘tunicamycin-V’ [12,19]
Was allowed to react with various chiral β-amino alcohols (2.2 eq 4a–e) in methanol under reflux for 24 h afforded the corresponding enamines (4a–e) those were successfully reduced by NaBH4 (2.6 eq.) [59], in ethanol to yield the desired chiral bis (β-amino alcohol) ligands (L1–L5) in 65–75% isolated yield and excellent optical purity (Scheme 1)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Henry reaction [10] (i.e., nitroaldol condensation) is one of the prominent transformations to access a wide range of strategically fundamental molecular structures such as β-hydroxy nitro alkanes, α-hydroxy carboxylic acids and 1,2-amino-alcohols, etc., in a forthright fashion [9,11]. Dixon et al reported an efficient process forprothe cess for for the total total synthesis of natural natural products marine alkaloidA’,. A’, total synthesis of synthesis natural products marine alkaloid ‘manzamine and ‘(−)-nakadomarin nakadomarin It is evident from the above nakadomarin and
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