Sulan Yao

Catalytic Enantioselective Aza-Diels-Alder Reactions of Imines-An Approach to Optically Active Nonproteinogenicα-Amino Acids

A catalytic enantioselective aza-Diels-Alder reaction of imines has been developed. The reaction of N-tosyl alpha-imino ester with different dienes including activated, non-activated, cyclic, and acyclic dienes has been investigated in the presence of various chiral Lewis acids. A series of phosphino-oxazoline ligands have been synthesized and evaluated for the reaction. It was found that the combination of phosphino-oxazoline ligands with copper(I) salts gives the best results for the activated dienes, while BINAP-copper(I) complexes are good catalysts for all the dienes studied. In the case of activated acyclic dienes the aza-Diels-Alder products can be obtained in higher than 80% isolated yield and 96% ee, while for the unactivated cyclic dienes the exo diastereomer is formed as the major product in up to 95 % ee. For an activated cyclic conjugated diene, 2-trimethylsilyloxy-1,3-cyclohexadiene, the reaction proceeds as a Mannich-type addition reaction giving optically active gamma-oxo alpha-amino acid derivatives in good yields and up to 96% ee. The reaction of an unactivated acyclic diene, 2,3-dimethyl-1,3-butadiene, with the N-tosyl alpha-imino ester gives both the aza-Diels-Alder and aza-ene products, in a ratio of 9:1 favoring the aza-Diels-Alder product. Furthermore, a series of different imines have been synthesized and investigated as possible substrates for the present catalytic enantioselective aza-Diels-Alder reaction in order to obtain mechanistic insight. All imines studied gave moderate to high ee. Particularly, the reaction of the N-phenyl and N-p-methoxyphenyl substituted glyoxylate imines with Danishefskys diene proceeded well affording the corresponding aza-Diels-Alder product in high yield with up to 91% ee at room temperature. The present catalytic enantioselective reaction of imines provided an effective route to optically active nonproteinogenic alpha-amino acids. The products of the catalytic enantioselective aza-Diels-Alder reaction of the cyclic dienes can be used for the preparation of key compounds such as natural products and compounds of pharmaceutical interest. The absolute configurations of five products have been solved by X-ray structural analysis, and it is found that the absolute configuration of the aza-Diels-Alder adduct is dependent on the substituent on the imine nitrogen atom. It turned out that the N-tosyl glyoxylate imine and N-p-methoxyphenyl glyoxylate imine give the aza-Diels-Alder adduct with opposite absolute configuration using the same enantiomer of the catalyst. On the basis of the results the mechanistic aspects for the reactions are discussed.

Metal-catalyzed asymmetric hetero-DielsAlder reactions of unactivated dienes with glyoxylates

The development of a catalytic asymmetric hetero-Diels- Alder methodology for the reaction of unactivated dienes with gly- oxylates is presented. Several different asymmetric catalysts can be used, but copper-bisoxazolines and aluminium-BINOL give the highest yield, and the best chemo- and enantioselectivities. The re- action course is dependent on several factors such as the solvent and the anions coordinated to the catalyst. The scope of the reaction is outlined by the total synthesis of a natural occurring actinidi- olide.

ZINC(II)-CATALYSED ASYMMETRIC HETERO-DIELS-ALDER REACTIONS OF CONJUGATED DIENES WITH GLYOXYLATE

The zinc(II)-catalysed hetero-Diels–Alder reaction of the conjugated dienes 2,3-dimethylbuta-1,3-diene and cyclohexa-1,3-diene with ethyl glyoxylate has been studied in the presence of different C2-symmetric bisoxazolines. The zinc(II)-catalysed reaction of 2,3-dimethylbuta-1,3-diene with ethyl glyoxylate gives both the hetero-Diels–Alder and ene products, the former being the major product with an enantiomeric excess up to 87%. The hetero-Diels–Alder∶ene ratio is relatively independent of the catalytic system and the solvent and is in the range 1∶0.5–1∶0.8. For the zinc(II)-catalysed reaction of cyclohexa-1,3-diene with ethyl glyoxylate, the hetero-Diels–Alder product is formed in up to 84% isolated yield and with an enantiomeric excess up to 65%. The enantiomeric excess for this reaction is very dependent on the solvent, with MeNO2 generally lowering the enantiomeric excess compared with CH2Cl2. Based on the absolute stereochemistry of the hetero-Diels–Alder products and semi-empirical calculations on different bisoxazoline–zinc(II)–ethyl glyoxylate intermediates the mechanism for the reaction is discussed.

The first highly enantioselective catalytic hetero-Diels–Alder reaction of ketones

The first highly enantioselective catalytic hetero-Diels–Alder reaction of various aliphatic and aromatic ketones with an activated conjugated diene catalysed by chiral copper(II) complexes with enantiomeric excesses up to 99% is presented.

Catalytic enantioselective ene reactions of imines: a simple approach for the formation of optically active α-amino acids

A highly enantioselective ene reaction of readily available tosyl α-imino esters with alkenes catalysed by only 0.1 mol% of chiral CuPF6–BINAP complexes is presented.

Catalytic enantioselective addition of enol silanes to ketomalonate mediated by C2-symmetric bisoxazoline Lewis acid complexes

A catalytic enantioselective addition reaction of silyl enol ethers to ketomalonate in the presence of C2-symmetric copper(II) bisoxazolines as catalysts is presented; the reaction has been studied for different ligands and substrates under various reaction conditions and proceeds in good yield and with ee’s >90% and a procedure for the preparation of an optically active hydroxy acid is shown.