Chiral ligand optimization in the asymmetric zirconium–zinc transmetalation aldehyde addition reaction

Abstract

The in situ hydrozirconation-transmetalation-aldehyde addition process is a convenient method for the generation of allylic alcohols. Ongoing research has focused on enhancing the enantioselectivity and substrate scope of this process. A chiral beta-amino thiol scaffold was evaluated in the addition reaction. Amino thiols tend to provide the highest ee's, in part due to the higher affinity of sulfur for zinc over zirconium. A class of valine-based thiol ligands was identified to be effective for the formation of enantiomerically enriched allylic alcohols in terms of low ligand loading and high % ee.

A Simple Synthesis of Nβ-Fmoc/Z-Amino Alkyl Thiols and their use in the Synthesis of Nβ-Fmoc/Z-Amino Alkyl Sulfonic Acids

“…40 Evaporation of the solvent followed by a single recrystallization of the crude material, afforded the intermediate isothiouronium salt as a pure white, stable solid in good yield (91%). Similar results with respect to both yield and purity were observed when the reaction was repeated with several other N-protected amino acids (Table 1); all the products were characterized by 1 H, 13 C NMR and mass analyses, 41 and all were found to be stable for several weeks at room temperature.…”

“…12 They are also being employed as catalysts for enantioselective organic synthesis. 13 Thiols can be synthesized through deprotection of thioacetates by heating at reflux with NaBH 4 , 14 by reaction of an alkyl halide with NaSH, 15 or through reaction of an activated alcohol in the form of tosylate/mesylate or that of alkyl bromides with thiourea followed by hydrolysis using 1 N NaOH. 16 However, in the latter cases, the harsh conditions employed for such deprotection often leads to dialkyl sulfides.…”

Are Organozirconium Reagents Applicable in Current Organic Synthesis?

“…As the alkenylzirconium species 5 were unreactive themselves, the hydrozirconation reaction was only employed to generate the organometallic reagent from alkynes that would not be otherwise accessible. [101][102][103][104][105][106][107][108][109][110] However, we have decided to highlight the following examples.…”