Asymmetric synthesis of 1,4-amino alcohol ligands with a norbornene backbone for use in the asymmetric diethylzinc addition to benzaldehyde

doi:10.1016/j.tetasy.2005.04.019

Tetrahedron: Asymmetry

Volume 16, Issue 11, 6 June 2005, Pages 2039-2043

https://doi.org/10.1016/j.tetasy.2005.04.019 Get rights and content

Abstract

The asymmetric synthesis of cis-1,4-amino alcohols with a norbornene backbone was performed starting with (2S,3R)-(−)-cis-hemiester 2 (98% ee). Chemoselective amination with NH₄OH and HMPTA followed by LAH reduction afforded 5 and 7, respectively. Amido ester 6 was transformed into chiral ligand 9 with Grignard reaction followed by LAH reduction. The chiral ligands 5, 7, and 9 were subjected to asymmetric diethylzinc addition to examine their effectiveness as chiral catalysts. Among these, chiral ligand 7 exhibited the highest enantioselectivity (88% ee).

Graphical abstract

Introduction

Amino alcohols are versatile chiral building blocks for organic synthesis¹ and have also been used extensively as chiral auxiliaries² or ligands in asymmetric synthesis.³ In particular, the formation of C–C bonds has always been one of the most challenging areas in organic synthesis. Among these, the enantioselective addition of diethylzinc to aldehydes in the presence of chiral ligands was first reported by Noyori et al.⁴ Although different types of chiral ligands, such as diamines,⁵ diols,⁶ aminothiols,⁷ and aminosulfides,⁷ were used in this reaction, amino alcohols are the most common type of ligands among them. Chiral 1,2-aminoalcohols are widely used in diethylzinc addition reactions, however, there are only just a few examples of chiral 1,4-amino alcohols used in this reaction.1, 8, 9, 10, 11, 12 1,4-Amino alcohols have more flexible structures with respect to 1,2-amino alcohols for complexation with various types of metals and thus may form more stable and selective catalysts in the reaction. This prompted us to develop new chiral 1,4-amino alcohols including a norbornene backbone and study their use in the alkylation of benzaldehyde by diethylzinc.

Section snippets

Asymmetric synthesis of 1,4-amino alcohols with a norbornene backbone

In our synthetic strategy, cis-monoester (−)-2 was chosen as the homochiral starting compound for the construction of a norbornene backbone. Bolm et al.¹³ have recently reported a highly efficient method for the enantioselective desymmetrizaton of meso-anhydrides via an alkaloid-mediated opening with methanol. Quinine and quinidine are used as the chiral directing agents and both enantiomers of the corresponding cis-monoester can be obtained with very high enantiomeric excesses (up to 99% ee)

Enantioselective addition of diethylzinc to benzaldehyde using 5, 7, and 9

The catalytic properties of the three new chiral 1,4-amino alcohols 5, 7, and 9 were explored in asymmetric diethylzinc addition to benzaldehyde. The results are summarized in Table 1.

All the ligands exhibited acceptable enantioselectivities (up to 82% ee) and afforded 1-phenylpropanol in good yields (up to 98%). The best result was obtained with amino alcohol 7, which has dimethyl substituents on the nitrogen atom (entry 2). Catalysts without any substituent on the nitrogen and

Conclusion

We have synthesized a series of chiral norbornene-based 1,4-amino alcohols (2S,3R)-5, (2S,3R)-7, and (2S,3R)-9. These compounds were used as ligands in the asymmetric diethylzinc addition to benzaldehyde. Ligand (2S,3R)-7 showed the best enantioselectivity over the others. We optimized the asymmetric diethylzinc addition condition. All the ligands directed the catalytic process toward the formation of (1S)-1-phenylpropanol.

Experimental

The ¹H and ¹³C NMR spectra were recorded in CDCl₃ on a Brucker Spectrospin Avance DPX 400 spectrometer. Chemical shifts are given in parts per million downfield from tetramethylsilane. Apparent splittings are given in all cases. Infrared spectra were obtained from KBr pellets on a Mattson 1000 FT-IR spectrophotometer. Mass spectra were recorded on a Varian MAT 212. Melting points are uncorrected. Optical rotations were measured in a 1 dm cell using a Bellingham and Stanley P20 polarimeter at 20

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Asymmetric synthesis of 1,4-amino alcohol ligands with a norbornene backbone for use in the asymmetric diethylzinc addition to benzaldehyde

Abstract

Graphical abstract

Introduction

Section snippets

Asymmetric synthesis of 1,4-amino alcohols with a norbornene backbone

Enantioselective addition of diethylzinc to benzaldehyde using 5, 7, and 9

Conclusion

Experimental

Chem. Rev.

Tetrahedron Lett.

J. Org. Chem.

J. Chem. Soc., Perkin Trans. 1

Org. Lett.

Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

J. Organomet. Chem.

Angew. Chem., Int. Ed. Engl.

J. Am. Chem. Soc.

Angew. Chem., Int. Ed.