Catalytic enantioselective addition to imin

Catalytic enantioselective addition to imines, in particular, aza-Diels-Alder reaction 99CRV1069. 

As the follow up to our studies in connection to the development of Ti-cat-alyzed cyanide additions to meso epoxides [4], we developed the corresponding catalytic enantioselective additions to imines [5]. A representative example is shown in Scheme 1 chiral non-racemic products maybe readily converted to the derived cx-amino acids (not available through catalytic asymmetric hydrogenation methods). In these studies, we further developed and utilized the positional optimization approach effected by examination of parallel libraries of amino acid-based chiral ligands (e.g., 1 and 2). Thus, the facile modularity of these ligands and their ease of synthesis were further exploited towards the development of a new catalytic enantioselective method that delivers various ar-... 

Kleinmann EF (1991) In Trost BM, Fleming I (eds) Comprehensive organic synthesis, vol 2. Pergamon, Oxford, p 893 Knowles WS (2002) Angew Chem Int Ed Engl 41 1998 Kobayashi S, Ishitani H (1999) Catalytic enantioselective addition to imines. Chem Rev 99 1069-1094... 

Kobayashi, S. Ishitani, H. Catalytic Enantioselective Addition to Imines, Chem. Rev 1999, 99, 1069-1094. 

For a recent review on the ligand-mediated addition of organometallic reagents to azome-thine fimctions, see Denmark SE, Nicaise OJ-C (1996) Chem Commun 999 For a recent review on the catalytic, enantioselective addition to imines, see Kobayasni S, Ishitani H (1999) Chem Rev 99 1069... 

Catalytic Enantioselective Addition To Imines," Kobayashi, Sh. Ishitani, H. 

In comparison with the extensive developments in catalytic asymmetric additions to aldehydes and ketones (Chapters 2, 4, and 5), the corresponding catalytic enantioselective additions to imines are less well developed. The lower electrophilicity of the imine carbon in relation to carbonyls, together... 

Nucleophilic additions to imines are generally more challenging than additions to carbonyls, owing to the lower electrophilicity of the imine and the greater propensity for a-deprotonation. Furthermore, stereoselective processes may be complicated by the presence of synlanti imine isomers. Nevertheless, the direct, enantioselective synthesis of substituted amines is an attractive goal and, while catalytic asymmetric additions to imines are less developed than the corresponding... 

To solve this problem, Pericas and co-workers have introduced a dual catalytic system consisting of a chiral amino alcohol 2, to control the enantioselectivity of the addition process, and a bulky silylating agent, to further activate the inline substrate (Scheme 1) [7]. When the 2/TIPSC1 system was used to promote the addition to imines derived from aromatic aldehydes, the addition reactions took place with good yield (63-75%) and high enantioselectivities (72-91%). Even in this case, a substoichiometric amount of chiral amino alcohol is required for a satisfactory result. 

In 1997, Kobayashi and colleagues reported the first truly catalytic enantioselective Mannich-type reactions of aldimines 24 with silyl enolates 37 using a novel chiral zirconium catalyst 38 prepared from zirconium (IV) fert-butoxide, 2 equivalents of (R)-6,6 -dibromo-l,l -bi-2-naphthol, and N-methylimidazole (Scheme 13) [27, 28], In addition to imines derived from aromatic aldehydes, those derived from heterocyclic aldehydes also worked well in this reaction, and good to high yields and enantiomeric excess were obtained. The hydroxy group of the 2-hydroxyphenylimine moiety, which coordinates to the zirconium as a bidentate ligand, is essential to obtain high selectivity in this method. 

It was also reported that diastereo- and enantioselective Mannich reactions of activated carbonyl compounds with a-imino esters were catalyzed by a chiral Lewis acid derived from Cu(OTf)2 and a bisoxazoline (BOX) ligand [31] [(Eq. (6)]. Catalytic enantioselective addition of nitro compounds to imines [32], and aza-Henry reactions of nitronates with imines [33] also proceeded under similar reaction conditions. 

Catalytic enantioselective addition reactions of alkyllithium or -zinc reagents to preformed imines have been described [34, 35]. Hoveyda, Snapper, and co-workers have described a direct three-component variant of this reaction [36]. Accordingly, several chiral, non-racemic aromatic as well as aliphatic amines were synthesized by the reaction of the corresponding aldehydes, o-anisidine 132, and alkylzincs using a Zr catalyst with a chiral peptide ligand 133 (Scheme 9.24). 

Kobayashi S, Ishitani H (2000) Novel binuclear chiral zirconium catalysts used in enantioselective strecker reactions. Chirality 12 540-543 Kobayashi S, Ishitani H, Nagayama S (1995) Synthesis 1995 1195 Kobayashi S, Ishitani H, Ueno M (1998) J Am Chem Soc 120 431 Kobayashi S, Kobayashi J, Ishitani H, Ueno M (2002) Catalytic enantioselective addition of propionate units to imines an efficient synthesis of anti-alpha-methyl-beta-amino acid derivatives. Chem Eur J 8 4185 1190 Krohn K, Kirst HA, Maag H (eds) (1993) Antibiotics and antiviral compounds. VCH, Weinheim... 

Other organometallic compounds, including aUylic stannanes, allylic samarium, allylic germanium, and allylic indium compounds add to aldi-mines in the same manner. Aryltrialkylstannanes also add the aryl group to Al-tosyl imines using a rhodium catalyst and sonication. Catalytic enantioselective addition reactions are well known, including reactions in an ionic liquid.Allylic... 

The catalytic enantioselective addition of arylboronic acids to aliphatic imines proceeds with broad substrate scope, high yields, and enantiocontrol (Table 1.18) [ 116], In this case, DeguPHOS (57) was found to be the optimal chiral ligand. 

This chiral diene ligand displays a clear superiority over chiral phosphorus ligands in both enantioselectivity and catalytic activity. A second generation catalytic system tvas later reported for the highly enantioselective addition to N nosyl imines, for which the product is more easily converted into the free amine than that bearing a N tosyl group [120]. The more effective chiral ligand 60 had to be used (Scheme 1.36). 

Antilla and coworkers further extended their methodology to the addition of an oxygen nucleophile, instead of a nitrogen nucleophile (see Scheme 3.54), to imines (Scheme 3.56) [115]. They successfully developed the catalytic enantioselective addition reaction of alcohols as oxygen nucleophiles with N benzoyl imines using chiral phosphoric acid Ig. The method provides straightforward access to chiral hemiaminal ethers with high enantioselectivities. 

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]. 

Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched P-amino ketones or esters [48a, 48b]. For the most part, these methods involve the use of chirally modified enolates or imines. Only a handful of examples has been reported on the reaction of imines with enolates of carboxylic acid derivatives or silyl ketene acetals in the presence of a stoichiometric amount of a chiral controller [49a, 49b, 49c]. Reports describing the use of a substoichiometric amount of the chiral agent are even more scarce. This section contains some of the most recent advances in the field of catalytic enantioselective additions of lithium enolates and silyl enol ethers of esters and ketones to imines. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones and esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds. In recent years, various enantioselective Mannich reactions have been developed. Among them, catalytic enantioselective additions of silicon enolates to imines have been elaborated into one of the most powerful and efhcient asymmetric Mannich-type reactions, primarily because sihcon enolates can be prepared regio- and stereoselectively from various carbonyl compounds. ... 

Pioneering studies of the catalytic, enantioselective arylation of imines date back to 2000, when Hayashi disclosed a rhodium/phosphine-catalyzed addition of arylstannanes to N-tosylarylimines (31). Whereas, the method gave rise to highly enantioenriched diarylmethylamines, five equivalents of the stannane were required to obtain high yields. 

Direct additions of aryl groups to the C=N bond has been a popular method in the past [2a], although the poor electrophilicity of the azomethine carbon severely complicated this transformation, due to a tendency for the imine substrates and derivatives to undergo enolization. To circumscribe this problem, several arylating agents were studied, and it was in fact the pioneering studies of the catalytic enantioselective arylation of imines reported by Hayashi and coworkers that have led to the application of rhodium catalysts in this particular catalytic transformation. Their work dates back... 

Table 6 Catalytic, enantioselective additions of silyl ketene imines to 2-naphthaldehyde...

This book chapter is limited to Lewis acid-mediated reactions, and does not discuss the important field of Lewis base-mediated allylations, nor does it describe the reactions of allylsilanes with other electrophiles such as epoxides, imines, and allyl-X (X = -Cl, -OR, -OAc). The SaJcurai reaction has been covered under different forms in reviews focusing on The Stereochemistry of the Sakurai reaction , Intramolecular Addition Reactions of Allylic and Propargylic Silanes ," Selective Reactions Using Allylic Metals , Catalytic Enantioselective Addition of Allylic Organometallic Reagents to Aldehydes and Ketones , and Modem Carbonyl Chemistry . ... 

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