Design and synthesis of 3,3'-disubstituted-binaphthyl alkynyl boron reagents for asymmetric conjugate addition of alkynyl groups to enones and 1,2-addition to aldehydes

Abstract

The preparation of a variety of 3,3'-disubstituted-2.2'-dihydroxy-1,1'-binaphthyls is described and their utility in the preparation of lithium binaphthylisopropylalkynylborates is demonstrated. The use of the resulting boronates in asymmetric conjugate addition and 1,2-addition is described.

A number of 3,3'-diaryl-2,2'-bis(methoxymethoxy)-1,1'-binaphthyls were prepared by Suzuki cross-coupling methodology in excellent yields from 3,3'-dibromo-2,2'-bis(methoxymethoxy)-1,1'-binaphthyl. Preparation of the dibromide by the DoM method, followed by trapping with BrCl2CCCl2Br, is successful and practical. 3,3'-Dicyanated binaphthyl can be prepared by trapping the dilithiated intermediate in the DoM process by phenyl cyanate. 3.3'-Bis(trifluoromethyl) binaphthyl was effectively prepared by the reaction between methyl fluorosulphonyldifluoroacetate and 3,3'-diiodo-2,2'-bis(methoxymethoxy)-1,1'-binaphthyl.

Attempts to obtain B-methoxybinaphtholborane by a few related literature methods were unsuccssful. Trials on the preparation of binaphtholborane also failed.

Lithium binaphthylisopropylalkynylborate was prepared successfully using a simple procedure that required only one step from binaphthol and lithium alkynyltriisopropylborate. The procedure can be used as a general method to synthesize lithium (3,3'-disubstituted-binaphythyl)-isopropyl-alkynyl-boronate. Decomposing the boronates by BF3.OEt2 or HCl produced the corresponding alkynylbinaphthylboronates. However, the borates are unstable after isolation from the reaction solution. It was possible to employ the boronates in situ in the asymmetric syntheses such as conjugate addition to enones and 1,2-addition to aldehydes.

Asymmetric conjugate addition of alkynyl groups to prochiral enones with chiral boronates was performed. A variety of alkynyl binaphthyl boronates with different groups on 3,3'-positions of the binaphthyl moietry were utilized in the conjugate addition. All enantiomeric excesses of products from the addition with the chiral boron reagents were significantly increased by changing ligands from (R)-2,2'-binaphthyl to (R)-3,3'-diaryl-2,2'-binaphthyl groups. The boronates having iodo and trifluoro groups on 3,3'- positions of binaphthyl moiety provided enantioselectivities comparable to those observed with the 3,3'-diarylbinaphthyl boronates.

The anantioselectivity of the conjugate addition was found to be dependent on the size and electronegativity of the 3,3'-substituents, as well as on the connectivity between the binaphthyl and the substituents. Electron withdrawing groups on 3,3'-positions of binaphthyl moiety increased the rate of the conjugate addition. Both steric and electronic differences of the substituents attached to B carbon of enones were found to be significant in determining the steric outcome of the conjugate addition reaction.

The asymmetric alkynylation of hydrocinnamaldehyde and isobutryaldehyde was performed successfully using several boronates. However, the 1,2-adduct yields were low and enantioselectivities were poor. Nevertheless, these initial results provide the basis for further improvement of the reaction.

HPLC with a Chiracel OD column was found to be an efficient analytical tool in the determination of enetiomeric excesses of the 1,4-adducts and 1,2-adducts.