Enantioselective catalyst effect

The hydride-donor class of reductants has not yet been successfully paired with enantioselective catalysts. However, a number of chiral reagents that are used in stoichiometric quantity can effect enantioselective reduction of acetophenone and other prochiral ketones. One class of reagents consists of derivatives of LiAlH4 in which some of die hydrides have been replaced by chiral ligands. Section C of Scheme 2.13 shows some examples where chiral diols or amino alcohols have been introduced. Another type of reagent represented in Scheme 2.13 is chiral trialkylborohydrides. Chiral boranes are quite readily available (see Section 4.9 in Part B) and easily converted to borohydrides. 

To overcome these problems with the first generation Brmsted acid-assisted chiral Lewis acid 7, Yamamoto and coworkers developed in 1996 a second-generation catalyst 8 containing the 3,5-bis-(trifluoromethyl)phenylboronic acid moiety [10b,d] (Scheme 1.15, 1.16, Table 1.4, 1.5). The catalyst was prepared from a chiral triol containing a chiral binaphthol moiety and 3,5-bis-(trifluoromethyl)phenylboronic acid, with removal of water. This is a practical Diels-Alder catalyst, effective in catalyzing the reaction not only of a-substituted a,/ -unsaturated aldehydes, but also of a-unsubstituted a,/ -unsaturated aldehydes. In each reaction, the adducts were formed in high yields and with excellent enantioselectivity. It also promotes the reaction with less reactive dienophiles such as crotonaldehyde. Less reactive dienes such as isoprene and cyclohexadiene can, moreover, also be successfully employed in reactions with bromoacrolein, methacrolein, and acrolein dienophiles. The chiral ligand was readily recovered (>90%). 

The reaction was first tested with these substances as ligands but the organic molecule, in the absence of any added metal ion, proved to be the most enantioselective catalyst (library 1 19% ee vs. less than 13% ee for the best metal catalyst). The effects of selective variations of the amino acid nature and of the salicylidene moiety on the diamine structure were investigated for urea and thiourea derivatives via HTS (library 2 48 urea compounds and... 

Other effective enantioselective catalysts include Yb(OTf)3 with BINOL,160 Mg2+-to-oxazolines,161 and oxazaborolidinones.162... 

The axially chiral 2,2 -bipyridine E is also an effective enantioselective catalyst for addition of allyltrichlorosilane to aldehydes.109... 

Enantioselective catalysts have been developed for cyclization of dienyl aldehydes and coupling of aldehydes with alkynes (Equations (74) and (75)). For reactions with dienes see Refs 433 and 433a, and for reactions with alkynes see Refs 433b I33e. Chiral monodentate phosphines have proved to be effective. 

Chiral bis-phosphine acylplatinum complex 210 with a strong acid such as TfOH serves as an effective enantio-selective catalyst for aldol-type reactions of aldehydes with ketene silyl acetals (Equation (127)).486 The presence of water and oxygen in the catalyst preparation step is required to obtain the highly enantioselective catalyst. The intermediacy of a C-bound platinum enolate was suggested by IR and 31P NMR spectroscopies. 

The current research areas with ruthenium chemistry include the effective asymmetric hydrogenation of other substrates such as imines and epoxides, the synthesis of more chemoselective and enantioselective catalysts, COz hydrogenation and utilization, new methods for recovering and recycling homogeneous catalysts, new solvent systems, catalysis in two or three phases, and the replace-... 

Concept A variety of metal-based chiral catalysts effect enantioselective chemical transformations that allow for concise and efficient synthesis of optically pure organic molecules. These transformations,... 

Uemura and co-workers (91) demonstrated that copper catalysts effectively transfer nitrenoid groups to sulfides generating chiral sulfimides. A complex obtained from CuOTf and 55d catalyzes nitrenoid transfer to prochiral sulfides to afford products such as 139 in moderate to poor enantioselectivities (<71% ee, Eq. 78). Nitrenoid transfer occurs selectively to the sulfur atom of allylic sulfides generating allylic sulfenamide (140) in moderate selectivity, after [2,3] sigmatropic rearrangement of the initial sulfimide 141, Eq. 79. 

The allylic acyloxylation of alkenes, the Kharasch-Sosnovsky reaction, Eq. 81, would be an effective route to nonracemic allylic alcohol derivatives, if efficient, enantioselective catalysts were available. The reaction is mediated by a variety of copper salts, and as such, has been the target of considerable research in an attempt to render the process enantioselective. The original reaction conditions described by Kharasch require high temperatures when CuBr is used as the catalyst (93). However, the use of CuOTf (PhH)0 5 allows the reaction to proceed at temperatures as low as -20°C. Unfortunately, long reaction times are endemic in these processes and the use of excess alkene (2-100 equiv) is conventional. Most yields reported in this field are based on the oxidant. 

The considerable Lewis acidity of bis(oxazoline)-copper(II) complexes held promise for catalyzing the ene reaction, a process that usually requires strong Lewis acids. Indeed, these catalysts effect a highly selective ene reaction between a variety of alkene partners and glyoxylate esters to produce a-hydroxy esters in good yield, Eq. 210 (245). The ene reaction between cyclohexene and ethyl glyoxylate proceeds in excellent diastereoselectivity and enantioselectivity, Eq. 211. As a testament to the Lewis acidity of these complexes, it is noteworthy that... 

However, the use of the heterogeneous catalysts in applicative enantioselective syntheses has a limited success. Several factors contribute to this situation (1) a long time is required to achieve an effective heterogeneous enantioselective catalyst compared with the homogeneous ones, (2) a more complex structure of the heterogeneous catalyst surface on which centers coexist with different catalytic activity and selectivity, which can lead to undesired secondary reactions, and (3) an increased difficulty to create an effective asymmetric environment and to accommodate it with the multitude of reactions that are interesting to be carried out under enantioselective restrictions. 

To develop effective enantioselective catalysts for asymmetric hydrogenation, the research groups in this area have fully investigated the factors controlling the OY (Figure 14.5). 

The product of this preparation is the most enantioselective catalyst developed to date for asymmetric epoxidation of a broad range of unfunctionalized olefins.6 The procedure includes a highly efficient resolution of trans-1,2-diaminocyclohexane as well as a convenient analytical method for the determination of its enantiomeric purity. This method is general for the analysis of chiral 1,2-diamines. The Duff formylation described in Step B is a highly effective method for the preparation of 3,5-di-tert-... 

In practice, any of these four approaches might be the most effective for a given synthesis. If they are judged on the basis of absolute efficiency in the use of chiral material, the ranking is resolution < natural source < chiral auxiliary < enantioselective catalyst. A resolution process inherently employs only half of the original racemic material. A starting material from a natural source can, in principle, be used with 100% efficiency, but it is consumed and cannot be reused. A chiral auxiliary can, in principle, be recovered and reused, but it must be used in stoichiometric amount. A chiral catalyst can, in principle, produce an unlimited amount of an enantiomerically pure material. 

It was clear that 1 would be derived from a Diels-Alder adduct. There has been a great deal of work in recent years around the development of enantioselective catalysts for the Diels-Alder reaction, but the catalysts that have been developed to date only work with activated dienophile-diene combinations. For less reactive dienes, it is still necessary to use chiral auxiliary control. One of the more effective of those was the known camphor-derived tertiary alcohol, so that was used in this project. Diels-Alder cycloaddition of the diene 4 with the enantiomerically-pure enone 5 led to the adduct 6 with high diastereocontrol. Oxidative cleavage led to the acid 7, which was carried on to the bis-enone I. 

The catalytic hydrosilylation of ketones is a useful substitute for hydrogenation. As shown in Scheme 7, the strong affinity of silicon for oxygen facilities the reaction of ketones 11a, 18). The DIOP-based Rh catalysts effect enantioselective hydrosilylation of a- and 7-keto esters... 

Scandium(III) and lutetium(ni)133 and zinc134 complexes of C2-symmetric pyri-dine-bis(oxazoline) (PYBOX) ligands are highly effective enantioselective catalysts of Mukaiyama aldol reactions. 

Samarium iodobinaphtholate (222) has been reported to act as an efficient enantioselective catalyst for the Michael addition of aromatic amines to fumaryl oxazolidinone (220), affording the aspartic acid derivatives (221) in good yields. Elucidation of the influence of temperature on the addition of p-anisidine revealed an isoinversion effect with a maximum ee of 88% at —40 °C.257 A non-enantioselective version of this reaction has also been reported.258... 

It was soon recognized that in specific cases of asymmetric synthesis the relation between the ee of a chiral auxiliary and the ee of the product can deviate from linearity [17,18,72 - 74]. These so-called nonlinear effects (NLE) in asymmetric synthesis, in which the achievable eeprod becomes higher than the eeaux> represent chiral amplification while the opposite case represents chiral depletion. A variety of NLE have been found in asymmetric syntheses involving the interaction between organometallic compounds and chiral ligands to form enantioselective catalysts [74]. NLE reflect the complexity of the reaction mechanism involved and are usually caused by the association between chiral molecules during the course of the reaction. This leads to the formation of diastereoisomeric species (e.g., homochiral and heterochiral dimers) with possibly different relative quantities due to distinct kinetics of formation and thermodynamic stabilities, and also because of different catalytic activities. 

Indeed, when we studied various phosphoric acid catalysts for the reductive amination of hydratopicaldehyde (16) with p-anisidine (PMPNH2) in the presence of Hantzsch ester 11 to give amine 17, the observed enantioselectivities and conversions are consistent with a facile in situ racemization of the substrate and a resulting dynamic kinetic resolution (Scheme 16). TRIP (9) once again turned out to be the most effective and enantioselective catalyst for this transformation and provided the chiral amine products with different a-branched aldehydes and amines in high enantioselectivities (Hoffmann et al. 2006). 

Dirhodium(ll) tetrakis[methyl 2-pyrrolidone-5(R)-oarboxylate], Rh2(5R-MEPV)4, and its enantiomer, Rh2(5S-MEPY)4, which is prepared by the same procedure, are highly enantioselective catalysts for intramolecular cyclopropanation of allylic diazoacetates (65->94% ee) and homoallylic diazoacetates (71-90% ee),7 8 intermolecular carbon-hydrogen insertion reactions of 2-alkoxyethyl diazoacetates (57-91% ee)9 and N-alkyl-N-(tert-butyl)diazoacetamides (58-73% ee),10 Intermolecular cyclopropenation ot alkynes with ethyl diazoacetate (54-69% ee) or menthyl diazoacetates (77-98% diastereomeric excess, de),11 and intermolecular cyclopropanation of alkenes with menthyl diazoacetate (60-91% de for the cis isomer, 47-65% de for the trans isomer).12 Their use in <1.0 mol % in dichloromethane solvent effects complete reaction of the diazo ester and provides the carbenoid product in 43-88% yield. The same general method used for the preparation of Rh2(5R-MEPY)4 was employed for the synthesis of their isopropyl7 and neopentyl9 ester analogs. 

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