1,5-Diazadecalin Copper(II) Catalysts

Aldrich ChemFiles 2006, 6.1, 5.

Aldrich ChemFiles 2006, 6.1, 5.

The Kozlowski group at the University of Pennsylvania has developed a practical method for the oxidative biaryl coupling of substituted naphthols, resulting in the expeditious construction of highly functionalized BINOL derivatives in an asymmetric fashion.1 BINOL compounds are precursors to a class of natural products generically called the perylenequinones,2 and are represented by the protein kinase C inhibitors cercosporin, phleichrome, and the calphostins.3

These architecturally complex compounds are promising therapeutic agents for photodynamic cancer treatment.4

Enantiopure BINOL compounds are also powerful and “privileged” ligands utilized primarily in homogeneous asymmetric catalysis (cf. commercialized BINOLs on following page). Kozlowski and coworkers have applied a 1,5-diaza-cis-decalin copper(II) catalyst in the presence of molecular oxygen, in the enantioselective couplings of a diverse array of substituted naphthols from simple achiral starting materials (Scheme 9, Table 2).1,5

Scheme 9.

Table 2.

The advantages of this catalyst system include 1) the enantioselectivies range from 53 to 94% ee; however, many substrates undergo highly (>89%) selective couplings; 2) enantiomeric enrichment is facilitated by product crystallization; 3) the mild nature of this catalyst system ensures wide functional group fidelity carried forward, produces H2O as the byproduct, and uses O2 as the oxidant under bench-top conditions; and 4) reactions have been run on 50 mmol (~35 g) preparative scale to afford material of 93% enantiopurity. It should be noted that competing BINOL formation from achiral starting materials was reported by Nakajima and others,6 but their system was not as selective as this Cu(II) methodology.

The reaction conditions have been optimized, wherein 10 mol % of catalyst, a high dielectric solvent (CH3CN), moderate temperatures (usually 40 °C), and reasonable reaction times combine to accelerate biaryl asymmetric induction. High enantioselectivities were seen for phenyl ketone naphthols, whereas moderate enantioselectivities were observed for naphthol substrates containing phenylsulfonyl groups in the 3-position. Most importantly, from an application standpoint, chiral 3,3’-diester BINOL 4 can be prepared on multigram scale from inexpensive starting material. Precipitation afforded > 99% enantiomerically pure BINOL, without subjecting the crude material to column chromatography (Scheme 10). BINOL 4 provides ready access to the chiral carboxamides that, in turn, can be reduced by LiAlH4 to yield BINOLAM ligands 5–7. These amino BINOL derivatives facilitate asymmetric transformations such as Michael additions, C‑alkylations of alanine Shiff bases, and cyanosilylation reactions.7

Scheme 10.

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  1. Kozlowski, M. C. et al. J. Org. Chem. 2003, 68, 5500.
  2. Kozlowski, M. C. et al. J. Am. Chem. Soc. 2003, 68, 6856.
  3. (a) Kobayashi, E. et al. Prog. Chem. Org. Nat. Prod. 1987, 52, 1–71. (b) Tasler, S. et al. Prog. Chem. Org. Nat. Prod. 2001, 82, 1-249.
  4. Lown, J. W. Can. J. Chem. 1997, 75, 99.
  5. Kozlowski, M. C. et al. Org. Lett. 2001, 3, 1137.
  6. Reference 1 vide supra: footnote references 3c and 3d contained therein.
  7. (a) Katsuki, T. et al. Tetrahedron 1997, 53, 17015. (b) Vega, M. et al. Tetrahedron: Asymmetry 2001, 12, 699. (c) Saa, J. M. et al. Org. Lett. 2002, 4, 2589.

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