Palladium racemization

Scheme 2.28 DKR of racemic 56 using CALB and a palladium racemization catalyst.

Another protecting group of amines is 1-isopropylallyloxycarbonyl, which can be deprotected by decarboxylation and a /3-elimination reaction of the (tt-l-isopropylallyl)palladium intermediate under neutral conditions, generating CO2 and 4-methyl-1,3-pentadiene. The method can be applied to the amino acid 674 and peptides without racemization[437]. 

The chiral siloxycyclopropane 106 undergoes carbonylative homocoupling to form the 4-ketopimelate derivative 108 via the palladium homoenolate 107 without racemization. The reaction is catalytic in CHCI3, but stoichiometric in benzene[93]. 

Furukawa et al. also applied the above described palladium catalyst to the inverse electron-demand 1,3-dipolar cycloaddition of nitrones with vinyl ethers. However, all products obtained in this manner were racemic [81]. 

Racemization of amines is difficult to achieve and usually requires harsh reaction conditions. Reetz et al. developed the first example of DKR of amines using palladium on carbon for the racemization and CALB for the enzymatic resolution [35]. This combination required long reaction times (8 days) to obtain 64% yield in the DKR of 1-phenylethylamine. More recently, Backvall et al. synthesized a novel Shvo-type ruthenium complex (S) that in combination with CALB made it possible to perform DKR of a variety of primary amines with excellent yields and enantioselectivities (Figure 4.13) [36]. 

The reductive amination of ketones can be carried out under hydrogen pressure in the presence of palladium catalysts. However, if enantiopure Q -aminoketones are used, partial racemization of the intermediate a-amino imine can occur, owing to the equilibration with the corresponding enam-ine [102]. Asymmetric hydrogenation of racemic 2-amidocyclohexanones 218 with Raney nickel in ethanol gave a mixture of cis and trans 1,2-diamino cyclohexane derivatives 219 in unequal amounts, presumably because the enamines are intermediates, but with excellent enantioselectivity. The two diastereomers were easily separated and converted to the mono-protected cis- and trans- 1,2-diaminocyclohexanes 220. The receptor 221 has been also synthesized by this route [103] (Scheme 33). 

The hydrolytic DKR of allyl esters has been studied as a DKR of esters. The first DKR was accomplished through Pd-catalyzed racemization and enzymatic hydrolysis of allylic acetates in a buffer solution. However, the DKR under these conditions was limited to cyclohexenyl acetates to give symmetrical palladium-allyl intermediates. Among them, 2-phenyl-2-cyclohexenyl acetate 9 was the only substrate to have been resolved with good results (81% yield, 96% ee). 

Trost, B.M., Godleski, S.A., Genet, J.P. (1978) A Total Synthesis of Racemic and Optically Active Ibogamine. Utilization and Mechanism of a New Silver Ion Assisted Palladium Catalyzed Cyclization. Journal of the American Chemical Society, 100, 3930-3931. 

Unfortunately, it quickly became apparent that a shortfall in this proposal was an inability to prepare the desired vinyl halide 25 in a straightforward and selective manner [19]. In contrast, we reasoned that the selective formation of an enol sulfonate, such as the enol triflate 26a, could be controlled by judicious tuning of enolization conditions starting from the corresponding ketone, and that such an enol sulfonate would possibly be a substrate for a palladium-mediated coupling (Scheme 9.17). In this way a common intermediate from the previously defined synthesis, that is, the racemic ketone rac-13 or its cyano equivalent rac-5 could be used to generate the required enamide. 

An enantioselective variant of the enyne cyclization has been reported. For example, cationic palladium oxalzoline catalyst 111 and Et3SilI reductively cyclized 129a to 130a (shown in racemic form in Eq. 24) in 88% yield of the cyclized products with 24% ee [76]. 

The cyclooctapyrroles shown in Figure 55 appear predestined to form binuclear metal complexes since the loop-shaped conformation of these macrocycles exhibits two structurally identical, helical N4 cavities. Enantiomers of such complexes, which are presumably generally very stable towards racemization owing to the rigidity of the molecule imposed by the incorporation of the metal, are of interest as possible models for binuclear metalloenzymes and as potential catalysts in asymmetric synthesis. The first two ligands as well as their recently obtained palladium complexes601 were... 

The palladium-catalyzed substitution of the less reactive racemic ethyl 3-cyclohexe-nyl carbonate could, in a similar fashion, be completed with dimethyl malonate, p-methoxyphenol, or phthalimide as nucleophiles, with satisfactory ee (Eq. 11.38) [55]. These reactions, when irradiated for 1 min with temperatures up to 100 °C, delivered yields (91-96%) and ee values (94—95%) identical with those performed in... 

The reaction of racemic Sb-chiral l-phenyl-2-trimethylsilylstibindole with the optically active ortho-palladated benzylamine derivative, di-p-chlorobis (S)-2-[l-dimethylamino)ethyl]phenyl-C,N dipalladium, leads to diastereomeric complexes which were used for the separation of the enantiomers of the stibindoles.65 The molecular structures of the diastereomeric palladium complexes are depicted in Fig. 4. 

Most of the work on the C-N bond-forming crosscoupling reactions has concentrated on the formation of aromatic C-N bonds. Recent studies show that the application of cross-coupling reactions to alkenyl halides or triflates furnished enamines (Scheme 19) (for palladium-catalyzed reaction, see 28,28a-28d, and for copper-catalyzed reaction, see 28e-28g). Brookhart et al. studied the palladium-catalyzed amination of 2-triflatotropone 109 for the synthesis of 2-anilinotropone 110.28 It was found that the reaction of 109 proceeded effectively in the presence of racemic BINAP and a base. As a simple method for the synthesis of enamines, the palladium-catalyzed reactions of alkenyl bromide 111 with secondary amine were achieved under similar conditions.2841 The water-sensitive enamine 112 was isolated as pure compound after dilution with hexane and filtration through Celite. The intramolecular cyclization of /3-lactam 113, having a vinyl bromide moiety, was investigated by Mori s... 

A hydrosilylation/cyclization process forming a vinylsilane product need not begin with a diyne, and other unsaturation has been examined in a similar reaction. Alkynyl olefins and dienes have been employed,97 and since unlike diynes, enyne substrates generally produce a chiral center, these substrates have recently proved amenable to asymmetric synthesis (Scheme 27). The BINAP-based catalyst employed in the diyne work did not function in enyne systems, but the close relative 6,6 -dimethylbiphenyl-2,2 -diyl-bis(diphenylphosphine) (BIPHEMP) afforded modest yields of enantio-enriched methylene cyclopentane products.104 Other reported catalysts for silylative cyclization include cationic palladium complexes.105 10511 A report has also appeared employing cobalt-rhodium nanoparticles for a similar reaction to produce racemic product.46... 

The diastereofacial selectivity is explained by the proposed chelated intermediate 151. Internal delivery of the nucleophile takes place from the less hindered side. Removal of the chiral directing moiety with a catalytic amount of palladium hydroxide on carbon in absolute ethanol then furnishes the final product. This process yields the amino ester in 83-100% yield without observable racemization. 

Both enantiomers of racemic 2-propenyl acetate can be formed from meso-type 7r-alkyl palladium intermediates by oxidative addition. 7r-Allylpalladium complexes with two alkyl substituents at the 1- and 3-positons are known to... 

It is worth noting, however, that chiral phosphine-palladium complexes generated from palladium salts and BINAP or MOP cannot be used for this oxidation because phosphines will be readily oxidized to phosphine oxides under the reaction conditions, leading to the deactivation of the catalyst. As reaction without the chiral catalyst will give a racemic product, this deactivation of the catalyst will cause a drop in the enantioselectivity of the whole process. 

The hydrogenation of 109 over palladium on charcoal in acidic methanol produced (l/ ,7aA)-l,3-diphenyl-5,6,7,7a-tetrahydro-1 //-pyrrolo[ 1,2-r]imidazolc 110 in 61% isolated yield (Equation 14). This reaction was totally unexpected and the authors proposed a mechanism that explains this transformation <2005JOC2368>. The mechanism is shown in Scheme 13. Many of the steps are interchangeable, but the end product is the same. The partial racemization observed could occur by epimerization of the phenyl-substituted carbon adjacent to the imine produced after the cleavage of the bicyclo-adduct. 

The allenyl carboxylate 35 was obtained in an enantiomerically enriched form by the palladium-catalyzed reduction of the racemic phosphate 34 using a chiral proton source [53]. The two enantiomers of the (allenyl)samarium(III) intermediate are in rapid equilibrium and thus dynamic kinetic resolution was achieved for the asymmetric preparation of (i )-35 (Scheme 3.18). 

In 1986, Tsuji et al. developed the palladium(0)-catalyzed alkoxycarbonylation of racemic or achiral propargyl carbonates 128 in an alcohol solvent to afford 131 via carbonylation of 129 to 130 (Scheme 4.35) [55], Palladium(0)-catalyzed alkoxycarbonylation of 134 and isomerization to 136 were key steps for the total synthesis of (-)-kallolide B 138 (Scheme 4.36) [56],... 

The attempt of chiral induction in the cross-coupling of racemic l-bromo-4,4-di-methyl-l,2-pentadiene (22b) with PhZnCl in the presence of the chiral palladium complex Pd (R,R)-DIOP 2 was disappointing. Although the expected disubstituted allene 23 was formed in quantitative yield, the enantiomeric excess was at best 9% ee [15]. 

The amidocarbonylation of aldehydes provides highly efficient access to N-acyl a-amino acid derivatives by the reaction of the ubiquitous and cheap starting materials aldehyde, amide, and carbon monoxide under transition metal-catalysis [1,2]. Wakamatsu serendipitously discovered this reaction when observing the formation of amino acid derivatives as by-products in the cobalt-catalyzed oxo reaction of acrylonitrile [3-5]. The reaction was further elaborated to an efficient cobalt- or palladium-catalyzed one-step synthesis of racemic N-acyl a-amino acids [6-8] (Scheme 1). Besides the range of direct applications, such as pharmaceuticals and detergents, racemic N-acetyl a-amino acids are important intermediates in the synthesis of enantiomeri-cally pure a-amino acids via enzymatic hydrolysis [9]. 

When the reaction is carried out with a racemic mixture of complexes, the product is a racemic mixture of the isotactic polymers. It was of interest to see what would happen if, after formation of a chiral block with one enantiomer of the bisoxazoline ligand, an equivalent of the other enantiomer was added. It was found that an excess of ligand changes the tacticity completely and the second block was syndiotactic In these diimine palladium complexes exchange of ligand is relatively fast and it can often be observed on the NMRtime scale as a broadening in the H NMR spectra. The process may well be associative. 

When the allyl group is part of a cyclic structure, a k-g reaction cannot take place to epimerise one of the chiral carbon atoms after having formed the k-g intermediate, the same Jt-face comes back-on to palladium. Thus, if we start from a racemic cyclic alkenyl acetate mixture, racemisation at the complex is blocked and the product will also be a racemate at 100% conversion. Kinetic resolution is still an option to obtain chiral product and starting material. Nevertheless high ee s were obtained when cyclic alkenyl acetates were used. 

The palladium(II)-mediated ort/zo-quinone cyclization is also applied to the synthesis of racemic carquinostatin A ( )-55a (Scheme 39). Ether cleavage of... 

Dynamic Kinetic Resolution of Primary Amines with a Recyclable Palladium Nanocatalyst (Pd/A10(0H)) for Racemization... 

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