BINAP resolution

The great selectivity of Ru-BINAP species is also evident when they are used in kinetic resolution of enantiomers. When a racemic allylic alcohol reacts with H2 in the presence of Ru-(A)-BINAP, the (R)-alcohol reacts preferentially, thus leaving the (S)-enantiomer unreacted (Equation (7)).71... 

A short five-step synthesis of a bifuran, namely ( )-2,2 -bis(diphenylphosphino)-3,3 -binaphtho[2,l-I>]furan (BINAPFu) from naphthofuranone via a low-valent titanium-mediated dimerization was reported. The newly developed resolution procedure for phosphines was utilized to provide the optically active bidentate phosphine ligands (BINAPFu), which consistently outperforms BINAP in the asymmetric Heck reaction between 2,3-dihydrofuran and phenyl triflate . Another way in which a benzofuranone can be converted into benzo[7 ]furan is by treatment of the former with 1-BU2AIH at -78°C followed by an acidic work up <00TL5803>. 

An efficient dynamic kinetic resolution is observed when an a-bromo- or a-acetylamino-/3-keto phosphate is subjected to the hydrogenation with an Ru-BINAP catalyst under suitable conditions. With RuC12[(A)-BINAP](DMF) (0.18 mM) as the catalyst, a racemic a-bromo-/3-keto phosphonate is hydrogenated at 25 °G under... 

In the case of acyclic allylic alcohols, an efficient kinetic resolution of l-buten-3-ol was achieved using [Ru((7 )-BINAP)(H)(CH3CN)(THF)2]BF4 as catalyst (Equation (16)).55... 

Kinetic resolution is achieved when racemic enynes are subjected to Zhang s Alder-ene conditions (Scheme 19).66 A single diastereomer of trans-94 (>99% ee) is accessible through the exposure of racemic enyne 93 to the Rh(i) catalyst in the presence of optically pure BINAP ligand. 

Kinetic resolution results of ketone and imine derivatives are indicated in Table 21.19. In the kinetic resolution of cyclic ketones or keto esters, ruthenium atrop-isomeric diphosphine catalysts 25 induced high enantiomer-discriminating ability, and high enantiopurity is realized at near 50% conversion [116, 117]. In the case of a bicyclic keto ester, the presence of hydrogen chloride in methanol served to raise the enantiomer-discriminating ability of the Ru-binap catalyst (entry 1) [116]. 

The sense of diastereoselectivity in the dynamic kinetic resolution of 2-substi-tuted / -keto esters depends on the structure of the keto ester. The ruthenium catalyst with atropisomeric diphosphine ligands (binap, MeO-biphep, synphos, etc.) induced syn-products in high diastereomeric and enantiomeric selectivity in the dynamic kinetic resolution of / -keto esters with an a-amido or carbamate moiety (Table 21.21) [119-121, 123, 125-127]. In contrast to the above examples of a-amido-/ -keto esters, the TsOH or HC1 salt of /l-keto esters with an a-amino unit were hydrogenated with excellent cwti-selectivity using ruthenium-atropiso-... 

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 stereoselective hydrogenation of a-substituted / -keto carboxylates and phosphonates via dynamic kinetic resolution catalyzed by a BINAP-Ru com-... 

Fig. 32.46 Hydrogenation of racemic 2-substituted cyclohexanones through dynamic kinetic resolution catalyzed by BINAP/chiral diamine-Ru complexes with base.

One of the first applications of the then newly developed Ru-binap catalysts for a,/ -unsaturated acids was an alternative process to produce (S)-naproxen. (S)-Naproxen is a large-scale anti-inflammatory drug and is actually produced via the resolution of a racemate. For some time it was considered to be one of the most attractive goals for asymmetric catalysis. Indeed, several catalytic syntheses have been developed for the synthesis of (S)-naproxen intermediates in recent years (for a summary see [14]). The best results for the hydrogenation route were obtained by Takasago [69] (Fig. 37.15), who recently reported that a Ru-H8-binap catalyst achieved even higher activities (TON 5000, TOF 600 h 1 at 15 °C, 50 bar) [16]. 

Many methods have been reported for the enantioselective synthesis of the remaining PG building block, the (J )-4-hydroxy-cyclopent-2-enone. For example, the racemate can be kinetically resolved as shown in Scheme 7-28. (iS )-BINAP-Ru(II) dicarboxylate complex 93 is an excellent catalyst for the enantioselective kinetic resolution of the racemic hydroxy enone (an allylic alcohol). By controlling the reaction conditions, the C C double bond in one enantiomer, the (S )-isomer, will be prone to hydrogenation, leaving the slow reacting enantiomer intact and thus accomplishing the kinetic resolution.20... 

Scheme 7-28. Ru(II)-BINAP-mediated kinetic resolution of 4-hydroxy-2-cyclopen-...

Similarly,110 (lR,2S )-ephedrine is an effective poison in the kinetic resolution of allylic alcohols using racemic BINAP instead of the expensive (R)-BINAP. (/ )-2-cycIohexenoI can thus be obtained in >95% ee using a racemic... 

Kinetic resolution ofallylic alcohols. The (R)- and (S)-BINAP-Ru diacetate complexes can resolve racemic allylic alcohols, both acyclic and cyclic, with high enantiomeric selectivity. Thus hydrogenation of ( )-2 catalyzed by (S)-l at 76% conversion provides (S)-2 (>99% ee) and anti-3 (49 1, 39% ee). Hydrogenation of (S)-2 catalyzed by either (R)- or (S)-l provides anti-3 (>23 1). Similar results obtain with ( )-4. 

Takaya and co-workers (256) disclosed that chiral copper alkoxide complexes catalyze the transesterification and kinetic resolution of chiral acetate esters. Selec-tivities are very poor (E values of 1.1-1.5) but it was noted that the Lewis acid BINAP CuOTf was not an effective catalyst. The observation thatp-chlorophcnyl-BINAP-CuOf-Bu complex gave faster rates than BINAP-CuOt-Bu suggests that both the Lewis acidic and Lewis basic properties of the copper alkoxide are required for optimal reactivity. 

If the 3-position is a quaternary stereocenter, then Rh(I)/Tol-BINAP is the catalyst of choice for the hydroacylation process. With this catalyst, both kinetic resolutions (Eq. 20) and desymmetrization reactions (Eq. 21) may be accomplished. 

If the 3-position is a tertiary, rather than a quaternary, stereocenter, Rh(I)/Tol-BINAP effects an intriguing parallel kinetic resolution - thus, one enantiomer of the substrate selectively undergoes hydroacylation to generate a cyclobutanone, while the other enantiomer is transformed into a cyclopentanone (Eq. 22) [24]. This observation is quite interesting, given the limited number of examples of parallel kinetic resolutions, particularly catalytic processes that involve carbon-carbon bond formation, and catalytic methods for the construction of cyclobutanones. 

The power of the rhodium(I)-catalyzed Alder-ene reaction is shown by a highly enan-tioselective kinetic resolution process [35]. The key result stems from an observation that a racemic mixture of 48, when treated with [Rh(COD)Cl]2 and ( )-BINAP, af forded roc49 (2i ,3S and 2S,3R, and not 2R,iR and 2S,3S Eq. (16). 

Substituted acrylates (which reseitible the enamide substrates employed 1n asymmetric hydrogenation) may be deracemized by reduction with an optically active catalyst, especially DIPAMPRh . Selectivity ratios of 12 1 to 22 1 have been obtained for a variety of reactants with compounds of reasonable volatility, separation of starting material and product may be effected by preparative GLC. Recovered starting material can then be reduced with an achiral catalyst to give the optically pure anti product. Examples of kinetic resolutions by this method are given in Table II. More recently very successful kinetic resolutions of allylic alcohols have been carried out with Ru(BINAP) catalysts. 

BINAP-ruthcnium(II)-catalyzed hydrogenation of the racemic cyclic / -oxo ester, methyl 2-ox-ocyclopentanecarboxylate, was found to lead to alcohol 3, one of the four possible stereoisomers135. The reaction is both enantioselective (kinetic resolution) and diastereoselective. Since racemization of the substrate is sufficiently faster than hydrogenation, the yield of the hydroxy ester was almost quantitative. Whereas the relative configuration was probably clear from NMR spectra (not reported), the absolute configuration of 3 had to be determined (see p 438)135. 

SCHEME 32. Kinetic resolution of allylic alcohols by BINAP -Ru-catalyzed hydrogenation. 

BINAP-Ru(II) diacetate complex also allows the resolution of chiral allylic secondary alcohols (66) (Scheme 32). 

Kinetic Resolution of a Racemic Ketone. Kinetic resolution is a process by which one of the enantiomeric constituents of a racemate is more readily transformed into a product than the other (63b). For example, in the presence of an (/ )-BINAP-Ru catalyst, the S enantiomer of the a-hydroxy ketone is hydrogenated 64 times faster than R enantiomer, and, after 50.5% conversion, both the syn 1,2-diol and unreacted R hydroxy ketone are obtained in high ee (Scheme 61). 

SCHEME 61. Kinetic resolution of a racemic hydroxy ketone by BINAP-Ru-catalyzed hydrogenation. 

SCHEME 67. Factors controlling the efficiency of dynamic kinetic resolution in (/ )-BINAP-Ru(H) catalyzed hydrogenation of 2-carbomethoxycycloheptanone. 

Scheme 21). Scheme 22 illustrates an example of kinetic resolution of a racemic allylic alcohol with a 1,3-hydrogen shift. When racemic 4-hydroxy-2-cyclopentenone is exposed to a cationic (/ )-BINAP-Rh complex in THF, the S enantiomer is consumed five times faster than the R isomer (32). The slow-reacting stereoisomer purified as the crystalline ferf-butyldimethylsilyl ether is an intermediate in prostaglandin synthesis (33). These isomerizations may occur via initial Rh-olefinic bond interaction (34). 

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