Widely Applicable Synthesis of Enantiomerically Pure (≥99 ee) Tertiary Alkyl-containing 1-Alkanols via ZACA–Pd- or Cu-Catalyzed Cross-Coupling

摘要

A highly enantioselective and widely applicable method for the synthesis of various chiral 2-alkyl-1-alkanols, especially those of feeble chirality, has been developed. It consists of zirconium-catalyzed asymmetric carboalumination of alkenes (ZACA) – lipase-catalyzed acetylation – Pd- or Cu-catalyzed cross-coupling. By virtue of the high selectivity factor (E) associated with iodine, either (S)- or (R)-enantiomer of 3-iodo-2-alkyl-1-alkanols (>1), prepared by ZACA reaction of allyl alcohol, can be readily purified to the level of ≥99% ee by lipase-catalyzed acetylation. A variety of chiral tertiary alkyl-containing alcohols, including those that have been otherwise difficult to prepare, can now be synthesized in high enantiomeric purity by Pd- or Cu-catalyzed cross-coupling of (S)->1 or (R)->2 for introduction of various primary, secondary and tertiary carbon groups with retention of all carbon skeletal features. These chiral tertiary alkyl-containing alcohols can be further converted to the corresponding acids with full retention of the stereochemistry. The synthetic utility of this method has been demonstrated in the highly enantioselective (≥99% ee) and efficient syntheses of (R)-2-methyl-1-butanol, (R)- and (S)-arundic acids.