Asymmetric imine reduction

Table 7.5. Examples of asymmetric imine reduction using Buchwald s chiral titanocene catalyst. Reactions were run at 45° and 80 psi, with 5 mol% s,S catalyst, unless noted otherwise.

The titanocene catalyzed asymmetric imine reduction may be used in kinetic resolutions of racemic pyrrolines [96]. The most efficient kinetic resolution was observed for 5-substituted pyrrolines, and the mechanistic postulate outlined above readily accomodates the experimental results, as shown by the matched pair transition structure in Scheme 7.12 [96]. Pyrrolines substituted at the 3- and 4-positions were reduced with excellent enantioselectivity, but kinetic resolution of the starting material was only modest [96]. 

Scheme 7.13 Asymmetric imine reduction using complex 17 in the presence of...

D- and L-Threose derivatives have been utilized as chiral auxiliaries for asymmetric imine reductions in the total synthesis of quinocarcin 271 and 1-decarboxyquinocarcin 272 (Scheme 57) 119 7he methodology has also been applied to a range of model conqiounds. 20,121... 

Fig. 45 Asymmetric imine reduction promoted by a chiral phosphoric acid...

Reductions of C-N Bonds. An ethanolic mixture of PMHS and Pd/C will reduce oximes (eq 18) to amines and reduc-tively open aziridines (eq 19). Either (a) PMHS plus catalytic w-butyltin tris(2-ethylhexanoate) (eq 20) or (b) PMHS plus ZnCl2 reduces imines. The PMHS/DBATO combination reduces azides, while PMHS/Ti(0-i-Pr)4 can be applied to reductive aminations (eq 21). Asymmetric imine reductions via chiral titanium complexes and PMHS are also viable, but very substrate dependent with nonaromatic imines working best (69-99% ee vs. 6-97% ee for aromatic imines). ... 

Inspired by the pioneering work of Matsumura in 2001, many groups developed protocols for the asymmetric imine reduction with silanes. The following paragraph gives... 

Reductive amination is a well-known methodology in organic synthesis as is evident from the literature reviews. There are a large number of reports available in the literature that deal with the asymmetric imine reduction, but there are few reports available on asymmetric reductive amination. The asymmetric version of this brilliant methodology was introduced in 1999 when Blaser et al. reported on the first asymmetric reductive amination for the synthesis of metolachlor. ... 

TABLE 34. ASYMMETRIC ORGANOSILANE REDUCTION OF IMINES (Continued)... 

Supplemental References for Table 34. Asymmetric Organosilane Reduction of Imines... 

The isolation of product is usually possible after evaporation of the solvent and extraction with hexane, ether, or toluene. Supported versions, for example on polystyrene grafted with PPh2 groups, have proved unsatisfactory because the rate of deactivation is greatly enhanced under these conditions [37]. Asymmetric versions exist, but the ee-values tend to be lower than in the Rh series [38]. With acid to neutralize the basic N lone pair, imine reduction is fast. Should it be necessary to remove the catalyst from solutions in order to isolate a strictly metal-free product, a resin containing a thiol group should prove satisfactory. A thiol group in the substrate deactivates the catalyst, however. 

Asymmetric catalytic reduction reactions represent one of the most efficient and convenient methods to prepare a wide range of enantiomerically pure compounds (i.e. a-amino acids can be prepared from a-enamides, alcohols from ketones and amines from oximes or imines). The chirality transfer can be accomplished by different types of chiral catalysts metallic catalysts are very efficient for the hydrogenation of olefins, some ketones and oximes, while nonmetallic catalysts provide a complementary method for ketone and oxime hydrogenation. 

In order to place later chapters in proper context, the first chapter offers a comprehensive overview of industrially important catalysts for oxidation and reduction reactions. Chapters 2 and 3 describe the preparation of chiral materials by way of the asymmetric reduction of alkenes and ketones respectively. These two areas have enjoyed a significant amount of attention in recent years. Optically active amines can be prepared by imine reduction using chiral catalysts, as featured in Chapter 4, which also discloses a novel reductive amination protocol. 

Asymmetric variants of imine reduction have also been developed towards enantiopure aziridines. Reduction of chiral /V-tert-butanesulfinyl a-halo imines afforded enantiopure aziridines in good to excellent yields <07JOC3211>. Enantioselective catalytic reduction of a-chloroimines utilizing metal-free L-valine-derived formamide 45 followed by base-mediated ring closure provided aziridines with preserved enantiopurity <07AG(I)3722>. 

Oxazaborolidines have been found to be a unique catalyst for asymmetric borane reduction of ketones and imines [35,36]. Coordination of BH3 to the nitrogen atom of 24 serves to activate BH3 as a hydride donor and to increase the Lewis acidity of the boron atom (Eq. 9). The Lewis acidity of the boron atom in the oxazaborolidine plays an important role in the reduction. Several types of polymer-supported oxazaborolidine have been reported and are considered to be polymer-supported boron-based Lewis acids. 

We pointed out in chapter 27 that Schultz s asymmetric Birch reduction can be developed with iodolactonisation to remove the chiral auxiliary and set up new chiral centres. Now we shall see how he applied that method to alkaloid synthesis.1 The first reaction is the same as in chapter 27 but the alkyl halide is now specified this gave diastereomerically pure acetate in 96% yield and hydrolysis gave the alcohol 4. Mitsunobu conversion of OH to azide and enol ether hydrolysis gave 5, the substrate for the iodolactonisation. Iodolactonisation not only introduces two new chiral centres but cleaves the chiral auxiliary, as described in chapter 27. Reduction of the azide 6 to the amine with Ph3P leads to the imine 7 by spontaneous ring closure. 

The asymmetric catalytic reduction of ketones (R2C=0) and imines (R2C=NR) with certain organohydrosilanes and transition-metal catalysts is named hydrosilylation and has been recognized as a versatile method providing optically active secondary alcohols and primary or secondary amines (Scheme 1) [1]. In this decade, high enantioselectivity over 90% has been realized by several catalytic systems [2,3]. Therefore the hydrosilylation can achieve a sufficient level to be a preparative method for the asymmetric reduction of double bond substrates. In addition, the manipulative feasibility of the catalytic hydrosilylation has played a major role as a probe reaction of asymmetric catalysis, so that the potential of newly designed chiral ligands and catalysts can be continuously scrutinized. 

A study comparing asymmetric borane reductions of kctoxime ethers and /V-substituted ketimines mediated by selected chiral oxazaborolidines 8-14 has been carried out. The corresponding amines were obtained with up to 99% ee50-52. The enantioselective reduction of imines using chiral dialkoxyboranes has also been the subject of a study60. 

The creation of an asymmetric center by C-H bond formation is a very common process which can involve several types of reactions. Hydrogenation of prochiral olefins is often used with the rhodium catalysts of the Wilkinson type (5). These catalysts were shown to be inactive for ketone or imine reduction except in some cases (15), It was then interesting to develop an alternate method for asymmetric synthesis of chiral alcohols or amines. Since it was found that RhCl(PPh3)3 was able to catalyze silane additions to ketones (16,17) or imines (18), preparation of chiral alcohols or amines by asymmetric hydrosilylation could be envisaged (Figure 2). The 1,4-addition of silanes to conjugated... 

---