Direct catalytic asymmetric aldol reaction of hydroxyketones: Asymmetric Zn catalysis with a Et2Zn/linked-BINOL complex

Naoya Kumagai, Shigeki Matsunaga, Tomofumi Kinoshita, Shinji Harada, Shigemitsu Okada, Shigeru Sakamoto, Kentaro Yamaguchi, Masakatsu Shibasaki

Research output: Contribution to journalArticlepeer-review

194 Citations (Scopus)

Abstract

Full details of our newly developed catalyses with asymmetric zinc complexes as mimics of class II zinc-containing aldolase are described. A Et2Zn/(S,S)-linked-BINOL complex was developed and successfully applied to direct catalytic asymmetric aldol reactions of hydroxyketones. A Et2Zn/(S,S)-linked-BINOL 1 = 2/1 system was initially developed, which efficiently promoted the direct aldol reaction of 2-hydroxy-2′-methoxyacetophenone (7d). Using 1 mol% of (S,S)-linked-BINOL 1 and 2 mol% of Et2Zn, we obtained 1,2-dihydroxyketones syn-selectively in high yield (up to 95%), good diastereomeric ratio (up to 97/3), and excellent enantiomeric excess (up to 99%). Mechanistic investigation of Et2Zn/(S,S)-linked-BINOL 1, including X-ray analysis, NMR analysis, cold spray ionization mass spectrometry (CSI-MS) analysis, and kinetic studies, provided new insight into the active oligomeric Zn/(S,S)-linked-BINOL 1/ketone 7d active species. On the basis of mechanistic investigations, a modified second generation Et2Zn/(S,S)-linked-BINOL 1 = 4/1 with molecular sieves 3A (MS 3A) system was developed as a much more effective catalyst system for the direct aldol reaction. As little as 0.1 mol% of (S,S)-linked-BINOL 1 and 0.4 mol% of Et2Zn promoted the direct aldol reaction smoothly, using only 1.1 equiv of 7d as a donor (substrate/ligand = 1000). This is the most efficient, in terms of catalyst loading, asymmetric catalyst for the direct catalytic asymmetric aldol reaction. Moreover, the Et2Zn/(S,S)-linked-BINOL 1 = 4/1 system was effective in the direct catalytic asymmetric aldol reaction of 2-hydroxy-2′-methoxypropiophenone (12), which afforded a chiral tetrasubstituted carbon center (tert-alcohol) in good yield (up to 97%) and ee (up to 97%), albeit in modest syn-selectivity. Newly developed (S,S)-sulfur-linked-BINOL 2 was also effective in the direct aldol reaction of 12. The Et2Zn/(S,S)-sulfur-linked-BINOL 2 = 4/1 system gave aldol adducts anti-selectively in good ee (up to 93%). Transformations of the aldol adducts into synthetically versatile intermediates were also described.

Original languageEnglish
Pages (from-to)2169-2178
Number of pages10
JournalJournal of the American Chemical Society
Volume125
Issue number8
DOIs
Publication statusPublished - 2003 Feb 26
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Fingerprint

Dive into the research topics of 'Direct catalytic asymmetric aldol reaction of hydroxyketones: Asymmetric Zn catalysis with a Et<sub>2</sub>Zn/linked-BINOL complex'. Together they form a unique fingerprint.

Cite this