Enantioselective Addition of Trimethylsilyl Cyanide to Aldehydes Induced by a New Chiral Ti(IV) Complex

Abstract

Optically active cyanohydrins are synthetic precursors of R-hydroxy carboxylic acids, R-amino carboxylic acids, β-hydroxy amines, and several other classes of organic compounds of biological importance. Existing methods for the preparation of chiral cyanohydrins include both enzymatic 1,2 and chemical processes. 1,3 Chemically, several efficient methods have been developed. In most of these methods, however, the chiral ligands are rather unstable and cannot be easily recovered. We now describe a new chiral Ti(IV) catalyst with dihydroxy-trans-1,2-diamide 3a as the ligand, which effects the enantioselective addition of trimethylsilyl cyanide to aldehydes.Ligand 3a and its diastereoisomer 3b were prepared from ketopinic acid chloride (1) 4 according to the Scheme 1. On treatment with optically pure (+)-or (-)-trans-1,2-diaminocyclohexane in dichloromethane in the presence of triethylamine, ketopinic acid chloride was converted to the trans-diketoamide 2a or 2b, respectively. Diketoamide 2a and 2b could also be obtained in pure form by reacting ketopinic acid chloride with (+)-trans-1,2-diaminocyclohexane in the same fashion as above followed by separation of the resulting diastereomeric mixture by column chromatography on silica gel. Subsequent reduction of 2a and 2b using L-selectride in tetrahydrofuran at -78 °C for 1 h and then at room temperature for 2 h gave 3a and 3b, respectively with the hydroxy group at the exo position. 5 The absolute stereochemistry of ligand 3a was further determined by X-ray crystallographic analysis. Ligand 3a was found to be an useful chiral ligand for asymmetric induction (eq 1). In conjunction with titanium tetraisopropoxide, ligand 3a was shown to effect the enan-

Asymmetric Synthesis of Cyanohydrins

“…[134] Additionally, recovery of the ligand 46a in 92% yield also highlighted the advantage of this catalyst. In contrast, the catalyst derived from its diastereoisomer 46b only gave 5% ee in the case of (R)-mandelonitrile under the same conditions as a result of chiral dismatching within the catalyst.…”

Synthesis of a New Chiral Cyclico-Hydroxynaphthylphosphonodiamide and its Application as Ligand Catalyst in Asymmetric Silylcyanation of Aromatic Aldehydes

“…Excellent results (up to 98.3% ee) were achieved in the asymmetric silylcyanation of aromatic aldehydes using (+)-2 as the ligand catalyst in the presence of Ti(Oi-Pr) 4 . 10 Investigations on further extending the range of substrates and application of this compound for other asymmetric reaction are continuing in our laboratory.…”

“…The catalytic effect of the titanium complex formed in situ from (+)-(S)-2 and Ti(Oi-Pr) 4 in asymmetric silylcyanation of aromatic aldehydes was investigated. The experimental results were listed in Table 1.…”

Asymmetric Two‐Center Catalysis

“…We assumed that the aluminum would work as a Lewis acid to activate the carbonyl group, and the oxygen atom of the phosphine oxide would work as a Lewis base to activate the silylated nucleophiles. Catalyst 123 has been found to be a highly efficient catalyst for the cyanosilylation of aldehydes [27] with broad generality, affording products in excellent chemical yields and excellent enantioselectivities. One of the key issues for designing a Lewis acid -Lewis base catalyst is how to prevent the internal complexation of these moieties.…”