Ruthenium-BINAP

Ruthenium complexes containing this ligand are able to reduce a variety of double bonds with e.e. above 95%. In order to achieve high enantioselectivity, the reactant must show a strong preference for a specific orientation when complexed with the catalyst. This ordinarily requires the presence of a functional group that can coordinate with the metal. The ruthenium-BINAP catalyst has been used successfully with unsaturated amides,23 allylic and homoallylic alcohols,24 and unsaturated carboxylic acids.25... 

Dynamic kinetic resolution is possible for a-alkyl or a-alkoxy cyclic ketones in the presence of KOH, which causes mutation of the stereogenic center syn-alco-hols were obtained selectively with high enantioselectivity using ruthenium-3,5-xyl-binap. Dynamic kinetic resolution of 2-arylcycloalkanones also proceeded with extremely high syn-selectivity and with high enantioselectivity using ruthenium-binap-diamine as catalyst (Table 21.23) [12, 139, 140]. 

The modified BINAP catalyst 5 has been used for the hydrogenation of a number of analogues of substrate 1 (substrates 32-35, Fig. 30.8 Table 30.6), though again, enantioselectivities were modest [4]. Substrate 31 has also been hydrogenated with a ruthenium-BINAP-hydride cluster with low selectivity (11% ee) [27]. 

Lin et al. [106] studied the hydrogenation of yS-aryl ketoester using a ruthenium BINAP system with different substituents at the 4,4 -position of the BINAP ligand. The best enantioselectivities were achieved with steric demanding and electron-donating 4,4 -substituents. For example, ee-values of 97.2% and 99.5% were obtained for the hydrogenation of ethyl benzoylacetate with R=trimethylsilane (5,... 

BINAP was introduced by Noyori [18], It has been particularly explored for reduction with ruthenium catalysts. While the first generation rhodium catalysts exhibited excellent performance with dehydroamino acids (or esters), the second generation of hydrogenation catalysts, those based on ruthenium /BINAP complexes, are also highly enantioselective for other prochiral alkenes. An impressive list of rather complex organic molecules has been hydrogenated with high e.e. s. 

A further example of ion-exchange of an organometallic complex onto a layered support has been provided by the anion exchange of a sulfonated ruthenium BINAP complex onto the external surface of layered double hydroxides [119]. Although achvihes and enantioselechvities for the hydrogenation of dimethyl itaconate were comparable to the homogeneous catalyst, and catalyst deactivation was not detected, with geraniol as substrate, catalyst deactivation was unavoidable. 

Thus, a synthetic cycle for the formation of enantiomerically pure propargylic alkylated compounds from an achiral propargylic alcohol has been accomplished by starting from the ruthenium-BINAP complex 66 (Scheme 12). This stepwise reaction provides the first synthetic approach to highly enantioselective propargylic substitution reactions. 

The asymmetric hydrogenation of 2-(6-methoxy-2-naphthyl)acrylic acid using ruthenium-BINAP complexes also yields enantiomerically pure naproxen. 

Diketone 5 is reduced to diol 23 by the method of Noyorv hydrogenation with catalysis by the chiral ruthenium-BINAP complex [(S)-BINAP]RuCE 2-NEt ... 

The reductions of /i,<5-dikcU)cslcrs 51 with ruthenium/BINAP catalysts result in formation of the /raw.v-diols 52 in high selectivity and e.e. Experiments have revealed that it is likely that the reduction takes place via the coordination of both ketones to the metal—the selectivity matches that obtained in the reduction of /1-diketones222. Biaryl diphosphines closely related in structure to BINAP have also given excellent results223. Other excellent... 

A remarkable high enantioselectivity was observed in the asymmetric hydrogenation of a cyclic sultam precursor using ruthenium/BINAP (Scheme 63)275. The factors which control this reaction are not fully understood, and it appears to be uniquely suited to... 

From a practical standpoint, it is of interest to devise a one-step synthesis of the catalyst. Since both reactions 2 and 3 are ligand substitution reactions, it is quite conceivable that both steps can be carried out at the same time. When we reacted [Ru(COD)Cl2]n with BINAP and sodium acetate in acetic acid, we indeed obtained Ru(BINAP)(OAc)2 in good yields (70-80%). Interestingly, when the reaction was carried out in the absence of sodium acetate, no Ru(BINAP)(OAe)2 was obtained. The product was a mixture of chloro-ruthenium-BINAP complexes. A 3ip NMR study revealed that the mixture contained a major species (3) (31P [ H] (CDCI3) Pi=70.9 ppm P2=58.3 ppm J = 52.5 Hz) which accounted for more than 50% of the ruthenium-phosphine complexes (Figure 2). These complexes appeared to be different from previously characterized and published Ru(BINAP) species (12,13). More interestingly, these mixed complexes were found to catalyze the asymmetric hydrogenation of 2-(6 -methoxy-2 -naphthyl)acrylic acid with excellent rates and enantioselectivities. 

Rychnovsky and his group have recently developed new synthetic methods that lead to the total syntheses of the polyene macrolides roxaticin [2], roflamycoin [3], and filipin III [4]. The polyol chains of all three natural products were constructed by iterative, stereoselective alkylation of lithiated cyanohydrin acetonides and subsequent reductive decyanation, illustrated here by the synthesis of the polyol framework of filipin III (1) (Scheme I). The bifunctional cyanohydrin acetonide 2, prepared by ruthenium/BINAP catalyzed enantioselective hydrogenation of the corresponding ) -keto ester (BINAP = [ 1,1 -binaphthyl]-2,2 -diylbis(diphenylphosphane)), is deprotonated with LiNEt2 and alkylated with 2-benzyloxy-l-iodoethane. The alkylation product 3 is converted by a Finkelstein reaction into the iodide 4, which is used to alkylate a second... 

BINAP complexes of ruthenium are one of the most intriguing catalysts for asymmetric hydrogenation of olefins. Because both R- and 5-forms of BINAP (Figure 10.5) are also commercially available, a series of ruthenium(binap) complexes can be prepared without difficulty [170-172]. For example, Ru(OAc)2(binap) is obtained by the reaction of [RuCLCcod)], with AcONa and BINAP in the presence of Et N [170]. 

Ruthenium(binap) complexes effectively catalyze asymmetric hydrogenation of a-amidocinnamic acids [172], allylic alcohols [173] and acrylic acids with almost quantitative enantiomeric excess [174]. For example, one of the largest-selling anti-inflammatory agents, Naproxen should be supplied as the enantiomerically pure 5-isomer, because the R-isomer is expected to be toxic to the liver. Asymmetric hydrogenation of the precursor by RuCL[(5)- binap] produces 5-Naproxen with 96-98 % ee (eq (47)) [175-176]. 

Furthermore, these ruthenium(binap) complexes are remarkably effective catalysts for the hydrogenation of C=0 bond of 3-ketoesters giving optically active alcohols [175]. 

Taber and co-workers developed a convergent route to ( - )-432 based on the enantioselective hydrogenation of the p-ketoesters 629 and 630 over a ruthenium-BINAP catalyst, which introduced two of the required stereogenic centers with excellent enantioselectivity (ee 98%) (Scheme 83) 485). The products 631 and 632 were transformed into aldehyde 633 and phosphonium salt 634, respectively, after... 

The positive effect of acyl substituents in the N-l and N-4 positions is striking, both for the ester experiments above and also for the corresponding experiments with the amides 14. The ruthenium BINAP system performed similarly to the rhodium (R)-(S)-PPF-P( Bu)2 system, but as the (R)-(S)-PPF-P( Bu)2 ligand had... 

The achievements of the Noyori group using ruthenium BINAP catalysts are extensive and remarkable. Simple alkenes are reduced whether conjugated or not the very efficient synthesis of the analgesic and anti-inflammatory naproxen 25 from an unsaturated acid 24 resembling 1 is a good example. 

Asymmetric hydrogenation was boosted towards synthetic applications with the preparation of binap 15 by Noyori et al. [55] (Scheme 10). This diphosphine is a good ligand of rhodium, but it was some ruthenium/binap complexes which have found spectacular applications (from 1986 up to now) in asymmetric hydrogenation of many types of unsaturated substrates (C=C or C=0 double bonds). Some examples are listed in Scheme 10. Another important development generated by binap was the isomerization of allylamines into enamines catalyzed by cationic rhodium/binap complexes [57]. This reaction has been applied since 1985 in Japan at the Takasago Company for the synthesis of (-)-menthol (Scheme 10). 

Similar kinetic resolution of Baylis-Hillman adducts may be effected by ruthenium BINAP catalysts, with comparable efficiency. But for some cyclic allylic alcohols, the level of discrimination between the enantiomers is so high that pre-paratively useful routes have been developed to the reactant and both hands of the product in the course of a single set of experiments [70]. In related fashion... 

Fig. 20. Substituent direction and kinetic resolutions in ruthenium BINAP hydrogenations...

Table 7. 3-Hydroxy Esters by Hydrogenation of 3-Oxo Esters in the Presence of a Ruthenium binap Complex Catalyst ...

A further interesting contrast between rhodium and ruthenium hydrogenation catalysts in kinetic resolution is provided. Most of the published work for the latter relates to ruthenium (BINAP) chemistry but a wider spectrum of allylic alcohols is reduced with satisfactory selectivity the need for an electron-withdrawing group at the a -position is no longer evident. Where a direct comparison can be drawn between rhodium(BINAP) and ruthenium(BlNAP) (Table 6, entry 1), the reduction with a given enantiomer of catalyst gives the opposite enantiomer of a... 

Ruthenium-BINAP complexes have proved to be efficient catalysts for the enantioselective hydrogenation of a,/ -unsaturated carboxylic acids79. Using these catalysts, a variety of a- or /i-disubstitnted substrates have been converted to the corresponding saturated carboxylic acids with good to excellent enantioselectivity and in high yield79. 

Allylic alcohols, such as gcraniol (42) and nerol (43), can be converted to citronellol (44) with high efficiency and excellent enantioselectivity by hydrogenation using ruthenium BINAP complexes108 or related catalysts76. Enantiomeric excesses between 96-98%, essentially quantitative yields, and very high substrate/catalyst ratios (up to 50000 1) are attractive attributes of... 

---