Asymmetric Amination of Ketones

Overview of selected techniques to shift the equilibrium, (a) Volatile carbonyl coproduct, (b) LDH/GDH multienzyme network. (c) AlaDH in combination with formate or glucose dehydrogenase (FDH/GDH). 

Nevertheless, the search for alternative amination systems is still ongoing, aiming to increase the overall efficiency of the methodology and, therefore, making the strategy more attractive for practical applications. 

---

In recent years there has been emerging interest in one-pot asymmetric amination of ketones, but this subject is beyond the scope of this chapter. However, an interesting observation by Borner and coworkers is that different catalysts seem to be required to carry out this process compared to those used for hydrogenation of the corresponding imines or enamines [81, 82]. 

The nonfavorable thermodynamic equilibrium for the asymmetric amination of ketones as well as the frequent occurrence of coproduct inhibition turns the... 

FG. Mutti, C.S. Fuchs, D. Pressnitz, J.H. Sattler, W. Kroutil, Stereoselectivity of four (R)-selective transaminases for the asymmetric amination of ketones, Adv. Synth. Catal. 353 (17)... 

The asymmetric amination of ketones is by far the most preferred approach for the preparahon of chiral amines using co-TAs. However, alternative methodologies may be considered if the carbonyl precursor is unstable or the synthesis of the racemic amine is easier to provide better results in economic and/or yield terms. Using racemic amines deracemization strategies allow the preparation of the desired amines in enantiopme form and a theoretical 100% yield [84- ]. This can be achieved by the combination of two stereocomplementary w-TAs. In the first step, the enantioselec-tive deamination of the racemic amine affords enantiopure untouched amine (50%) and the corresponding ketone (50%). In the second step, an enantiocomplementary -TA catalyzes the asymmetric amination of the ketone, leading to the optical pure amine in 100% theoretical yield (Scheme 2.18). 

The reductive amination of ketones can be carried out under hydrogen pressure in the presence of palladium catalysts. However, if enantiopure Q -aminoketones are used, partial racemization of the intermediate a-amino imine can occur, owing to the equilibration with the corresponding enam-ine [102]. Asymmetric hydrogenation of racemic 2-amidocyclohexanones 218 with Raney nickel in ethanol gave a mixture of cis and trans 1,2-diamino cyclohexane derivatives 219 in unequal amounts, presumably because the enamines are intermediates, but with excellent enantioselectivity. The two diastereomers were easily separated and converted to the mono-protected cis- and trans- 1,2-diaminocyclohexanes 220. The receptor 221 has been also synthesized by this route [103] (Scheme 33). 

The DKR processes for secondary alcohols and primary amines can be slightly modified for applications in the asymmetric transformations of ketones, enol esters, and ketoximes. The key point here is that racemization catalysts used in the DKR can also catalyze the hydrogenation of ketones, enol esters, and ketoximes. Thus, the DKR procedures need a reducing agent as additional additive to enable asymmetric transformations. 

The synthesis of amines by the in-situ reductive amination of ketones is termed the Leuckart-Wallach reaction. Recently, an asymmetric transfer hydrogenation version of this reaction has been realized [85]. Whilst many catalysts tested give significant amounts of the alcohol, a few produced almost quantitative levels of the chiral amine, in high enantiomeric excess. 

Other silicon derivatives containing Si—X—C bonds (where X is O and/or N) can be successfully prepared by using iridium-catalyzed reachons such as the asymmetric hydrosilylation of ketones and amines, the silylcarbonylation of alkenes, and the alcoholysis of Si—H bonds. Indeed, oxygenation of the latter bond to silanol also proceeds smoothly in the presence of iridium compounds. 

The Tsogoeva group, in 2006, reported the introduction of newly designed bifunctional secondary amine-functionalized proline-based thioureas (95 and 96) and the primary amine-functionalized thioureas (97-99) for catalysis of the asymmetric addition of ketones to trans-P-nitrostyrenes (Figure 6.30) [260, 261]. Using... 

Asymmetric hydrometallation of ketones and imines with H-M (M = Si, B, Al) catalyzed by chiral transition-metal complexes followed by hydrolysis provides an effective route to optically active alcohols and amines, respectively. Asymmetric addition of metal hydrides to olefins provides an alternative and attractive route to optically active alcohols or halides via subsequent oxidation of the resulting metal-carbon bonds (Scheme 2.1). 

A dynamic kinetic resolution has been employed to achieve a catalytic asymmetric reductive amination of aldehydes.332 Reductive amination of ketones and aldehydes by sodium triacetoxyborohydride has been reviewed, highlighting its advantage over other reagents.333... 

A catalytic asymmetric amination of enecarbamates has been attained using a chiral Cu(II) complex of diamine (210) as catalyst. Thus, azodicarboxylates have been shown to react with various enecarbamates (208) derived from aromatic and aliphatic ketones and aldehydes to provide acylimines (209) in good yields with high enantioselectivity (<99% ee). The catalyst loading required for high enantioselectivity was generally low (0.2 mol% in some cases).259... 

Scheme 14. Organocatalytic asymmetric reductive amination of ketones...

Kumaragurubaran N, Juhl K, Zhuang W, Bpgevig A, Jorgensen KA (2002) Direct L-proline-catalyzed asymmetric alpha-amination of ketones. J Am Chem Soc 124 6254-6255... 

Asymmetric reduction of ketones. Lithium aluminum hydride, after partial decomposition with 1 equiv. of 1 and an amine additive such as N-benzylmethylamine, can effect asymmetric reduction of prochiral ketones at temperatures of —20°. The highest... 

Asymmetric a-amination of enolates has also been described. For example, treatment of a-silyl ketone 109 with LDA followed by addition of oxaziridine 65a gave the A -BOC-amino ketone 110 in 29% yield and 88% de <1998TA3709>. Asymmetric amination of the prochiral enolate of 111 with chiral nonracemic oxaziridine 112 afforded amino ester 113 in 51% yield and 21% de <2001TA535>. 

Synthesis of Chiral Reagents. An efficient chiral a-chloro-a-nitroso reagent derived from 10-camphorsulfonyl chloride (1, Cy2NH 2, NH2OH 3. t-BuOCl 70-78%) has been developed for the asymmetric a-amination of ketone enolates (eq 7). The resulting p-keto /V-hydroxylamine can be converted to the anti-1,2-hydro y amine under reducing conditions (NaBHt Zn, HCl, AcOH),... 

Optically active alcohols, amines, and alkanes can be prepared by the metal catalyzed asymmetric hydrosilylation of ketones, imines, and olefins [77,94,95]. Several catalytic systems have been successfully demonstrated, such as the asymmetric silylation of aryl ketones with rhodium and Pybox ligands however, there are no industrial processes that use asymmetric hydrosilylation. The asymmetric hydrosilyation of olefins to alkylsilanes (and the corresponding alcohol) can be accomplished with palladium catalysts that contain chiral monophosphines with high enantioselectivities (up to 96% ee) and reasonably good turnovers (S/C = 1000) [96]. Unfortunately, high enantioselectivities are only limited to the asymmetric hydrosilylation of styrene derivatives [97]. Hydrosilylation of simple terminal olefins with palladium catalysts that contain the monophosphine, MeO-MOP (67), can be obtained with enantioselectivities in the range of 94-97% ee and regioselectivities of the branched to normal of the products of 66/43 to 94/ 6 (Scheme 26) [98.99]. 

The carbon-nitrogen double bonds of nitrones N1-N3 (Fig. 14) were catalytical-ly reduced with diphenylsilane in the presence of Ru2Cl4(Tol-BINAP, L24)2(NEt3) to give hydroxylamines in high % ees [56]. The hydroxylamine HI was obtained in 63% yield with 86% ee (S) and the hydroxylamine H3 was formed in 91% ee. It was also proposed that this process opened a new access to optically active amines from racemic amines, via nitrones and hydroxylamines. The iron complex [(Cp)2Fe2(HPMen2> L25)(CO)2] was reported to be a catalyst in the asymmetric hydrosilylation of ketones under irradiation, where acetophenone was reduced in up to 33% ee [57]. 

S )-Dibenzyl l-(l-Oxo-l,2,3,4-tetrahydronaphthalen-2-yl)hydrazine-l,2-dicarboxylate (Catalyzed Asymmetric Amination of a Ketone Silyl Enol Ether with an Azo Ester).244 A solution of silver perchlorate (0.040 mmol) and (R)-BINAP (0.048 mmol, 12 mol%) in THF (1 mL) was stirred at room temperature for 30 minutes, cooled to —45°, and treated with dibenzyl azodicarboxylate (0.44 mmol). After stirring for 10 minutes, (3,4-dihydronaphthalen-l-yloxy)trimethylsilane (0.4 mmol) in THF (0.5 mL) was added and the mixture was stirred at —45° for 5 hours. Aqueous HF (20%) and THF (1 1) were added and the mixture was stirred at room temperature for one hour after which time it was made basic with aqueous NaHCC>3 solution and extracted with CH2CI2. 

H. Sakuraba, N. Inomata, Y. Tanaka, Asymmetric reduction of ketones with crystalline cyclodextrin complexes of amine-boranes, J. Org. Chem., 1989, 54, 3482. 

Scheme 5.16 Direct (S)-proline-catatysed asymmetric a-amination of ketones.

Scheme 19.74 Asymmetric reduction of ketones promoted by a secondaiy amine-thiourea 64.

Directed and Asymmetric Reduction The principles of directed and asymmetric reactions were first developed for hydrogenation, as discussed in Section 9.2. Asymmetric hydrosilation of ketones can now be carried out cata-lytically with rhodium complexes of diop (9.22). The new chiral ligand Et-duPHOS, made by Burk at du Pont, allows chiral amination of ketones via Eq. 14.50. Note how the use of the hydrazone generates an amide carbonyl to act as a ligand, as is known to favor high e.e. (see Section 9.2). Noyori s powerful BINAP ligand has been applied to a large number of asymmetric reactions. 

In 2015, Zhao and co-workers described the first dynamic kinetic asymmetric amination of alcohols via borrowing hydrogen methodology under the cooperative catalysis of iridium complex 25 and chiral phosphoric acid 27 (Schemes 31, 32) [179]. The authors proposed that, initially, the two stereocenters in the alcohols were both racemized to ketone by the first oxidation, followed by tautomerization of the iminium intermediates 28 and 30 through enamine intermediate 29. Then, the... 

---