PYBOX, addition

Entry Pyruvate PyBOX Additive, mol% Yield, % exo. endo %ee (exo) % ee endo)... 

Jacobsen developed a method employing (pybox)YbCl3 for TMSCN addition to meso-epoxides (Scheme 7.22) [46] with enantioselectivities as high as 92%. Unfortunately, the practical utility of this method is limited because low temperatures must be maintained for very long reaction times (up to seven days). This reaction displayed a second-order dependence on catalyst concentration and a positive nonlinear effect, suggesting a cooperative bimetallic mechanism analogous to that proposed for (salen)Cr-catalyzed ARO reactions (Scheme 7.5). 

Related catalytic enantioselective processes [115] Two catalytic procedures for asymmetric addition of cyanides to meso epoxides have been reported [116]. One is the result of work carried out in these laboratories, shown in Eq. 6.24, promoted by Ti-peptide chiral complexes, while the other, developed by Jacobsen and Schaus, is a Yb-catalyzed enantioselective reaction that is effected in the presence of pybox ligands (Eq. 6.25) [117]. Although the Shibasaki method (Eq. 6.21) is not as enantioselective as these latter methods, it has the advantage that it accomplishes both the epoxidation and subsequent desymmetrization in a single vessel. 

By using this approach, Morken found a variety of interesting results, one of which is that [ RhCl(cod) 2] with dppe [bis(l,2-diphenylphosphino)ethane], PBu3, or P(OEt)3 as ligands acts as an active catalysts for this reaction. Another interesting finding is that [ IrCl(cod) 2] with i-Pr-pybox is an active catalyst for the addition of dimedone to the allyl carbonate (Scheme 27). 

Allenyltrimethylsilanes add to ethyl glyoxalate in the presence of a chiral pybox scandium triflate catalyst to afford highly enantioenriched homopropargylic alcohols or dihydrofurans, depending on the nature of the silyl substituent (Tables 9.39 and 9.40) [62]. The trimethylsilyl-substituted silanes give rise to the alcohol products whereas the bulkier t-butyldiphenylsilyl (DPS)-substituted silanes yield only the [3 + 2] cycloadducts. A bidentate complex of the glyoxalate with the scandium metal center in which the aldehyde carbonyl adopts an axial orientation accounts for the observed facial preference ofboth additions. 

The cationic complex [Ir(CO)(ic -N,N,N-(S,S)- Pr-pybox)][PF,5] [50] was also found to be catalytically active in the addition of Ph2SiPt2 to acetophenone, with complete conversion of the ketone into the corresponding silyl ether (I) at room temperature after 72 h of reaction. However, desilylation of the product (I) led to racemic 1-phenylethanol, which means that the reduction took place without asymmetric induction. 

CuOTf/PyBox System The first direct asymmetric addition of alkynes to imines, generated from aldehydes and amines in situ, was reported by using copper salts in the presence of chiral PyBox ligand (Scheme 5.2). The products were obtained in good yields and excellent enantioselectivities in most cases. When toluene was used as solvent, up to 93% yield and 99% ee were obtained. Up to 99.5% ee was obtained when the reaction was carried out in 1,2-dichloroethane. The reaction can also be performed in water smoothly, and good enantioselectivities (78-91% ee) were obtained. 

An alternative approach in the asymmetric catalysis in 1,3-dipole cycloaddition has been developed by Suga and coworkers. The achiral 1,3-dipole 106 was generated by intramolecular reaction of an Rh(ii) carbene complex with an ester carbonyl oxygen in the Rh2(OAc)4-catalyzed diazo decomposition of <9-methoxycarbonyl-o -diazoacetophenone 105 (Scheme 12). The asymmetric induction in the subsequent cycloaddition to G=G and G=N bond was achieved by chiral Lewis acid Sc(iii)-Pybox-/-Pr or Yb(iii)-Pybox-Ph, which can activate the dipolarophile through complexation. With this approach, up to 95% ee for G=0 bond addition and 96% ee for G=G bond addition have been obtained, respectively. ... 

Enantiopure amide derivatives (64) of -unsaturated a-hydroxy acids have been made by addition of a vinylsilane, R2R1C=(4ISiMe3, to /V-phcnylglyoxamide.181 The reaction is catalysed by scandium(III) triflate complexed to a C2-symmetric PYBOX ligand derived from (f )-norephedrine. 

Allylic oxidation of a variety of cyclic alkenes with copper complexes of different pybox ligands (8) and with various peresters shows high enantioselectivity (80-96% ee). Use of phenylhydrazine as an additive and acetone as solvent accelerates the reaction. It has been suggested that the phenylhydrazone is responsible for the observed acceleration. Using EPR spectra, it has been shown that the Cu(II) species is reduced to Cu(I) by phenylhydrazine and phenylhydrazone. It has been found that the presence of a gem-diphenyl group at C(5) and a secondary or tertiary alkyl substituent at the chiral centre at C(4) of the oxazoline rings is crucial for high enantioselectivity. 

The asymmetric conjugate addition of thiophenol to ( >3-crotonoyloxazolidin-2-one, catalysed by the scandium(III) triflate complex of Ph-PYBOX, gave the corre- sponding adduct in 66% ee. Lanthanoid triflates gave lower enantioselectivities (<28% ee).132... 

The enantioselective addition of allyltributylstannanes to aldehydes and ketones has been performed in the presence of various chiral indium(III) complexes derived from (R)-BINOL,136 (S )-BINOL,137,138 and PYBOX.139,140... 

The ACP with Ru Pybox- hm revealed that the use of single organic solvents, such as toluene and tetrahydrofuran (THF), resulted in lower yields and lower enantioselectivity. However, when water was added to THF or toluene solutions, the reaction proceeded smoothly, improving the enantioselectivity and the yields slightly. This phenomenon accounted for the increase of the solubility of the Ru(Pybox-hm)Cl2(vacant or solvent) species. The ACP carried out in toluene/water biphasic media attained 94% ee for the trans form (Scheme 4). As the active Ru Pybox-hm species still remained in the aqueous phase after the reaction, the second run( ) could be carried out by addition of diazoacetate and styrene to give a similar result. Thus, the water-soluble catalyst can be recycled. 

Jorgensen et al. reported that C2-symmetric bis(oxazoline)-copper(II) complex 25 also acts as chiral Lewis acid catalyst for a reaction of allylic stannane with ethyl glyoxylate [37]. Meanwhile, p-Tol-BINAP-CuCl complex 26 was shown to be a promising chiral catalyst for a catalytic enantioselective allylation of ketones with allyltrimethoxysilane under the influence of the TBAT catalyst [38]. Evans and coworkers have developed (S,S)-Ph-pybox-Sc(OTf)3 complex 27 as a new chiral Lewis acid catalyst and shown that this scandium catalyst promotes enantioselective addition reactions of allenyltrimethylsilanes to ethyl glyoxylate [39]. But, when the silicon substituents become bulkier, nonracemic dihydrofurans are predominantly obtained as products of [3+2] cycloaddition. 

Addition of the elements of Si—H to a carbonyl group produces silyl ethers which are synthetically equivalent to chiral secondary alcohols since the silyl groups are easily hydrolyzed. Hydrosilylation can be catalyzed by acids or transition metal complexes. Enantioselective hydrosilylation of prochiral ketones has been extensively studied using platinum or rhodium complexes possessing chiral ligands such as BMPP (86), DIOP (87), NORPHOS (88), PYTHIA (89) and PYBOX (90)." ... 

C2-symmetric bis(oxazolinyl)pyridine (pybox)-Cu (II) complex 27 has been shown to catalyze highly enantioselective Mukaiyaraa aldol reactions between (benzyloxy)acetaldehyde and silyl ketene acetals by Evans and co-workers as exemplified in Scheme 1-9 [38]. Here, the requirement for a chelating substituent on the aldehyde partner is critical to catalyst selectivity, as a-(terl-butyldimethylsil-oxy)acetaldehyde gave lower enantioselectivity (56% ee). In addition, P-(benzyl-oxy)propionaldehyde provided the racemic product, indicating a strict requirement for a five-membered catalyst-substrate chelate. 

Mukaiyama aldol reactions catalyzed by the pybox-copper complex 65 lead to high enantiocontrol with a range of nucleophiles adding to benzyloxy acetaldehyde [44]. As shown in Scheme 9-22, catalyst 66 also led to high enantioselectiv-ities (up to 99% ee) on addition to various pyruvate esters to generate adducts 67 [45]. 

Copper complexes of chiral Pybox (pyridine-2,6-bis(oxazoline))-type ligands have been found to catalyze the enantioselective alkynylation of imines [26]. Moreover, the resultant optically active propargylamines are important intermediates for the synthesis of a variety of nitrogen compounds [27], as well as being a common structural feature of many biologically active compounds and natural products. Portnoy prepared PS-supported chiral Pybox-copper complex 35 via a five-step solid-phase synthetic sequence [28]. Cu(l) complexes of the polymeric Pybox ligands were then used as catalysts for the asymmetric addition of phenylacetylene to imine 36, as shown in Scheme 3.11. tBu-Pybox gave the best enantioselectivity of 83% ee in the synthesis of 37. 

Propargylic oxidation of the acyclic alkyne (5.126) can be achieved with moderate enantioselectivity. It is noteworthy that in this case, the quoted yield is based on the starting material (rather than being based on the perester).One drawback with this procedure is the very slow reaction rate. It has been discovered that the rate of the oxidation can be enhanced using phenylhydrazine as an additive, to aid in the reduction of Cu(II) to Cu(I), and Cu-PYBOX ligand (5.127) as catalyst. 

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