Enantioselective hydrogenation cyclic imines

In contrast, the enantioselectivity of cyclic imine reduction is independent of hydrogen pressure. 

Table 6.5 Enantioselective hydrogenation of cyclic imines catalyzed by [(R,R,R)-(EBTHI)TiX2],...

Cyclic imines do not have the problem of syn/anti isomerism and therefore, in principle, higher enantioselectivities can be expected (Fig. 34.8). Several cyclic model substrates 6 were hydrogenated using the Ti-ebthi catalyst, with ee-val-ues up to 99% (Table 34.5 entry 5.1), whereas enantioselectivities for acyclic imines were <90% [20, 21]. Unfortunately, these very selective catalysts operate at low SCRs and exhibit TOFs <3 h-1. In this respect, iridium-diphosphine catalysts, in the presence of various additives, seem more promising because they show higher activities. With several different ligands such as josiphos, bicp, bi-... 

Table 34.5 Selected results for the enantioselective hydrogenation of cyclic imines (for structures, see Fig. 34.8) Catalytic system, reaction conditions, enantioselectivity, productivity and activity.

Particularly noteworthy is the discovery of a new type of the active catalyst 99,103,104 a crystalline, air-stable yellow-orange solid, which can serve as a highly enantioselective tool in the titanium-catalyzed hydrosilylation of imines. The reaction can be highly stereoselective for both acyclic and cyclic imines under a wide range of hydrogen pressures (Scheme 6-46). 

The Brintzinger-type C2-chiral titanocene catalysts efficiently promote asymmetric hydrogenation of imines (Figure 1.30). A variety of cyclic and acyclic imines are reduced with excellent enantioselectivity by using these catalysts. The active hydrogenation species 30B is produced by treatment of the titanocene binaphtholate derivative 30A with n-butyllithium followed by phenylsilane. 

Highly enantioselective hydrogenation of geometry-fixed cyclic imines has been achieved by the use of certain chiral Ti and Ir catalysts [14,17]. In particular, a chiral titanocene catalyst developed by Buchwald possess excellent enanti-odifferentiating ability for a variety of cyclic substrates [18]. 

The activity and enantioselectivity of chiral Ir catalysts have been tested by using 2,3,3-trimethylindolenine as a model substrate. Hydrogenation of the cyclic imine with [Ir(bdpp)Hl2 2 gives the corresponding chiral amine with 80% ce (Scheme 1.99) [350]. The stereoselectivity is somewhat better than that with acyclic substrates (see Scheme 1.94). A neutral BCPM-Ir complex with Bil3 effects asymmetric hydrogenation in 91% optical yield [354], A complex of MCCPM shows similar enantioselection [354], These complexes are not applicable to the reaction of other acyclic and six-membered cyclic imines. An MOD-DIOP-Ir complex is also usable with the aid of ( -C4H9)4NI [355], An Ir complex of BICP with phthalimide effectively... 

Asymmetric transfer hydrogenation of cyclic imines and iminiums in water was carried out in high yields and enantioselectivities with sodium formate as the hydrogen source and CTAB as an additive, catalysed by a water-soluble and recyclable ruthenium(II) complex of the ligand (23).371... 

An interesting effect of imide and amine additives was observed for Ir-bcpm and Ir-binap catalysts. The catalyst performance for the hydrogenation of im-ines 7 was affected by the addition of phthalimide or perfluorophthalimide [26]. The highest enantioselectivity were obtained with the Ir-bcpm catalyst system 87% ee with F4-phthalimide and 86% with phthalimide. Primary or secondary amines were found to be useful co-catalysts for the asymmetric hydrogenation of N-benzyl-iV-(l-methylbenzylidene)amine and the cyclic imine 6 (R=Ph) with cationic Ir-binap (or Ir-tol-binap) catalysts [27]. For example, the addition of... 

If 2 10 mol % of the chiral ansa-titanocene 1 is used as the catalyst for the hydrogenation/hy-drosilylation of cyclic imines excellent enantioselectivities (up to 98% ee) can be achieved140... 

Examination of the enantioselectivities in Table 7.5 indicates a striking difference in selectivity achieved in the reduction of cyclic (entries 1-8) vs. acyclic imines (entries 9-11). The former is very nearly 100% stereoselective. The simple reason for this is that the acyclic imines are mixtures of E and Z stereoisomers, which reduce to enantiomeric amines vide infra). The mechanism proposed for this reduction is shown in Scheme 7.11 [86]. The putative titanium(III) hydride catalyst is formed in situ by sequential treatment of the titanocene BINOL complex with butyllithium and phenylsilane. The latter reagent serves to stabilize the catalyst. Kinetic studies show that the reduction of cyclic imines is first order in hydrogen and first order in titanium but zero order in imine. This (and other evidence) is consistent with a fast 1,2-insertion followed by a slow hydrogenolysis (a-bond metathesis), as indicated [86]. Although P-hydride elimination of the titanium amide intermediate is possible, it appears to be slow relative to the hydrogenolysis. 

SCHEME 30.38. Enantioselective hydrogenation of cyclic imines 195 and 197 in the total syntheses of (7 )-levofloxacin and (N)-calycotomine, respectively. 

In 2009, Zhou and co-workers developed a general method for the synthesis of chiral 3-substituted cyclic sul-tam derivatives via asymmetric hydrogenation of the corresponding cyclic imines with Pd(CF3C02)2/(5, 5)-f-Binaphane as catalyst under mild reaction conditions to achieve enantioselectivities up to 91-99% ee Chiral sul-tam (5)-208 that possesses anti-HIV activity has been synthesized via domino Heck-aza-Michael reaction and asymmetric hydrogenation of the C=N bond allowed to install a single chirogenic center in the molecule (Scheme 30.40). 

Asymmetric transfer hydrogenation of imines using HC02H/Et3N as a hydrogen donor and catalyzed by suitably designed chiral Ru(II)-complexes was developed by Noyori et al., and since then, it has become the method of choice in enantioselective reduction of cyclic imines. Using this protocol, several asymmetric syntheses of... 

A method for the asymmetric hydrogenation of seven-membered cyclic imines of benzodiazepinones and benzodiazepines has recently been published. The chiral cyclic amines generated from these reactions make up the cores of many natural products and clinical drugs. Iridium-bisphosphine catalyst systems were investigated and found to give promising enantios-electivities which could be improved upon addition of morpholine tri-fluoroacetate. The optimum conditions, applied to model compound 50, are shown in Scheme 14.19, giving 51 in excellent enantioselectivity and complete conversion. 

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