Enantioselective alkylations of imines

The last five years have witnessed explosive advances in the development of catalytic enantioselective alkylation of imines. This chapter collects some of the important advances that have taken place during the past few years in catalytic enantioselective alkylation of imines. 

Catalytic Enantioselective Alkylation of Imines with Organozinc Reagents... 

Although quite specific, these two contributions of Itsuno and co-workers constitute an interesting example of organometalHc/chiral Hgand interaction for the catalytic enantioselective alkylation of imines [24]. 

All of catalytic enantioselective alkylations of imines that have been described up to this point used homogeneous chiral catalysts. In an effort to facilitate the separation process of the product from the reaction mixture, Soai and co-workers have employed copolymers of norephedrine for the enantioselective addition of diethylzinc to a phosphinoyl imine [35c]. 

The efficient enantioselective alkylation of the P/y-unsaturated ester 39 was achieved1351 by use of the N-anthracenylmethyl catalyst 12 (R=benzyl, X=Br) together with CsOH-H20 under phase transfer conditions analogous to those in the alkylation of the O Donnell imine 23, as shown in Scheme 13. The enantioselectivity of the alkylation correlates with Hammett o constants, and the N,N-dimethylamino substituents in 39 showed the most effective enantioselectivity. The tight ion pair in which the enolate... 

R Lygo, J. Crosby, J. A Peterson, Enantioselective Alkylation of Alanine-Derived Imines Using Quaternary Ammonium Catalysts , Tetrahedron Lett. 1999, 40, 8671-8674. 

J. J. Eddine, M. Cherqaoui, Chiral Quaternary Benzo-phenone Hydrazonium Salt Derivatives Efficient Chiral Catalysts for the Enantioselective Phase-Transfer Alkylation of Imines. Application to Synthesis of Chiral Primary Amines , Tetrahedron Asymmetry 1995, 6, 1225-1228. 

A Enantioselective Alkylation of Glycine Benzophenone Imine tert-Butyl... 

Preparation of 0-Allyl-N-(9)-anthracenylmethylcinchonidinium Bromide as a Phase Transfer Catalyst for the Enantioselective Alkylation of Glycine Benzophenone Imine tert-Butyl Ester. 

Enantioselective alkylation of ketones. Chiral imines prepared from cyclic ketones and 1 on metalation and alkylation are converted to chiral 2-alkyleyclo-alkanones in 87-100% enantiomeric purity.1 The high cnantioselectivity is dependent on chelation of the lithium ion in the anion by the methoxyl group, which results in a rigid structure. 

Enantioselective alkylation of acylic ketones is also possible,2 but in this case the enantioselectivity is dependent on the geometry of the chiral imine. Thus the product of thermodynamic alkylation (of the E-isomer) is the enantiomer of the... 

Quite recently, there has been significant expansion and development in the alkylation of imines with organozinc reagents using chiral Lewis acid catalysts. In 2000, Tomioka and co-workers reported a copper(II)-chiral amidophos-phine 4-catalyzed asymmetric process for the addition of diethylzinc to N-sul-fonylimines (Scheme 2) [8]. Excellent enantioselectivities (90-94%) and yields (83-99%) were obtained in reactions of N-sulfonylimines derived from arylal-dehydes. 

Asymmetric synthesis of ot-amino acids.1 This optically active phase-transfer catalyst (1) can effect enantioselective alkylation of the imine (2) derived from glycine. The highest enantioselectivity obtains with the t-butyl ester the lowest with benzylic type esters. Alkylation of 2 results in a mixture of enantiomers, but crystallization of the mixture removes the racemic product and leaves the highly pure optically active amino ester in solution. 

The products are converted into -lactams (3) on oxidative removal of the metal. The two optically active forms of 1 are known, and their use should permit enantioselective alkylation by imines. 

PREPARATION OF 0-ALLYL-N-(9-ANTHRACENYLMETHYL) CINCHONIDINIUM BROMIDE AS A PHASE TRANSFER CATALYST FOR THE ENANTIOSELECTIVE ALKYLATION OF GLYCINE BENZOPHENONE IMINE tert-BUTYL ESTER (4S)-2-(BENZHYDRYLIDENAMINO)PENTANEDIOIC ACID, 1-tert-BUTYL ESTER-5-METHYL ESTER... 

The advent during the early 1990s of the O DonneU-Corey-Lygo protocol for the highly enantioselective alkylation of amino acids imines under PTC conditions, catalyzed by quaternized cinchona alkaloids, led to a series of investigations on the use of supported catalysts in these reactions [15]. 

In seeking an efficient, economic, and scaleable route to the new potent nonnucleoside HIV-1 reverse transcriptase inhibitor 16 (L-738,372) [2a], process chemists at the Merck Research Laboratories have significantly contributed to the field of asymmetric alkylation of imines. Huffman and co-workers have reported a very efficient asymmetric route to 16 via the addition of a lithium acetylide to the cyclic N-acylketimine 14 in the presence of the lithium alkoxide of the alkaloid quinine as a stoichiometric chiral additive (Scheme 9) [31aj the previous route to the inhibitor 16 included a resolution step [31bj. Whereas other types of chiral additives were screened (e.g., diamines, diethers), only P-ami-no alkoxides were enantioselective. The search for readily available amino alcohols was dictated by the necessity of developing a practical process. The commer-... 

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