Pd-catalyzed racemization

Jacobs et al. have found that the efficiency of the Pd-catalyzed racemization of amines can be improved by using Pd immobilized on supports such as BaS04, CaC03, or BaC03. The racemization was combined with a KR catalyzed by CALB affording enantiopure acetylated benzylamines in high yields [37]. 

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). 

To utilize these reactions, a few conditions must be met. A selective enzyme is crucial and the metal-organic catalyst must facilitate a fast racemization of the substrate. Last but not least the catalyst should not influence the enzyme in terms of selectivity and reactivity. In the ideal case the enzyme hydrolyzes one enantiomer of the allylic acetate, giving rise to the allylic alcohol, which itself is not susceptible to Pd-catalyzed racemization. 

On the other hand, the racemization of amines is more difficult compared to that of alcohols. Several metal systems based on palladium (Pd), Ru, nickel (Ni), cobalt (Co), and Ir have been employed as the racemization catalysts. Pd-based catalysts include Pd/C, Pd/BaSO, and Pd/A10(0H). They are readily available but require higher temperatures for satisfactory racemization. So they should be coupled with thermostable enzymes such as Novozym 435 for the successful DKR. A possible mechanism for the Pd-catalyzed racemization of amine is described in Scheme 5.5. The racemization occurs via reversible dehydrogenation/hydrogena-tion steps including an imine intermediate. The imine intermediate can react with starting material to afford a secondary amine as the byproduct. The deamination of substrate and byproduct are also possible at elevated temperature. In case the... 

The Backvall group reported the DKR of p-amino acids using CAL-A and Ru or Pd catalyst (Scheme 5.38) [61]. CAL-A was immobilized in the functionalized meso-cellular form (MCF) to improve its stability and enantioselectivity. The DKR with Pd catalyst and the MCF-immobilized CAL-A provided (S)-products, with better yields and higher enantiopurities (Chart 5.34). Our group explored the DKR of p-amino acids for preparing Ihe products of opposite configuration with PSL and Pd/ AIO(OH) (Scheme 5.39) [62]. As PSL was not thermally stable, the PSL-catalyzed resolution and Pd-catalyzed racemization were performed alternatively at two different temperatures (RT and 70 °C) to give (R)-product with 90% yield and >99% ee (Scheme 5.39). 

Choi, E., Kim, Y., Ahn, Y., Park, J., and Kim, M.-J. (2013). Highly enantioselective enzymatic resolution of aromatic 3-amino acid amides with Pd-catalyzed racemization. Tetrahedron Asymmetry, 24,1449-1452. 

Pd-catalyzed coupling of racemic secondary alkylzincs with aryl halides had been reported by Hayashi (Scheme 8.9) [14]. 

Related catalytic enantioselective processes It is worthy of note that the powerful Ti-catalyzed asymmetric epoxidation procedure of Sharpless [27] is often used in the preparation of optically pure acyclic allylic alcohols through the catalytic kinetic resolution of easily accessible racemic mixtures [28]. When the catalytic epoxidation is applied to cyclic allylic substrates, reaction rates are retarded and lower levels of enantioselectivity are observed. Ru-catalyzed asymmetric hydrogenation has been employed by Noyori to effect the resolution of five- and six-membered allylic carbinols [29] in this instance, as with the Ti-catalyzed procedure, the presence of an unprotected hydroxyl function is required. Perhaps the most efficient general procedure for the enantioselective synthesis of this class of cyclic allylic ethers is that recently developed by Trost and co-workers, involving Pd-catalyzed asymmetric additions of alkoxides to allylic esters [30]. 

Scheme 15. Trost s approach to aflatoxin B involves the Pd-catalyzed dynamic asymmetric transformation of chiral racemic 103 to optically pure 104 (1999).

The chiral nonracemic bis-benzothiazine ligand 75 has been screened for activity in asymmetric Pd-catalyzed allylic alkylation reactions (Scheme 42) <20010L3321>. The test system chosen for this ligand was the reaction of 1,3-diphenylallyl acetate 301 with dimethyl malonate 302. A stochiometric amount of bis(trimethylsilyl)acetamide (BSA) and a catalytic amount of KOAc were added to the reaction mixture. A catalytic amount of chiral ligand 75 along with a variety of Pd-sources afforded up to 90% yield and 82% ee s of diester 303. Since both enantiomers of the chiral ligand are available, both R- and -configurations of the alkylation product 303 can be obtained. The best results in terms of yield and stereoselectivity were obtained in nonpolar solvents, such as benzene. The allylic alkylation of racemic cyclohexenyl acetate with dimethyl malonate was performed but with lower yields (up to 53%) and only modest enantioselectivity (60% ee). 

Widenhoefer and co-workers have developed an effective Pd-catalyzed protocol for the asymmetric cyclization/ hydrosilylation of functionalized 1,6-dienes that employed chiral, non-racemic pyridine-oxazoline ligands." " " Optimization studies probed the effect of both the G(4) substituent of the pyridine-oxazoline ligand (Table 7, entries 1-6) and the nature of the silane (Table 7, entries 6-15) on the yield and enantioselectivity of the cyclization/ hydrosilylation of dimethyl diallylmalonate. These studies revealed that employment of isopropyl-substituted catalyst (N-N)Pd(Me)Gl [N-N = (i )-( )-4-isopropyl-2-(2-pyridinyl)-2-oxazoline] [(i )-43f and a stoichiometric amount of benzhydryldimethylsilane provided the best combination of asymmetric induction and chemical yield, giving the corresponding silylated cyclopentane in 98% yield as a single diastereomer with 93% ee (Table 7, entry 15). 

Whereas Pd-catalyzed asymmetric allylic substitution reactions, with carbon as well as with heteronucleophiles, are widespread in stereoselective catalysis, it seems unusual that sulfur nucleophiles are less commonly used. Therefore we tested our ligands in such a reaction. We employed ligands 2 and 3 successfully in the reaction of racemic 3-methoxycarbonyloxyhept-4-ene with lithium t-butylsulfinate in the presence of 1.5 mol% of Pd2dba3 and 4.5 mol% of the ligands. In all cases full conversion was achieved, but with marked differences in the product selectivities (Scheme 1.4.9, Table 1.4.7). 

At the same time and in the years to follow, several other groups reported the observation of high selectivities in the Pd-catalyzed resolution of racemic substrates [6]. The kinetic resolution depicted in Scheme 2.1.4.2 gives access to both the enantio-enriched allylic acetate and sulfone. Because of the many applications chiral allylic alcohols and allylic sulphur derivatives have found in the synthesis... 

Scheme 2.1.4.2 Pd-catalyzed enantioselective allylic alkylation of a sulfinate ion and kinetic resolution of a racemic allylic ester.

The sense and degree of asymmetric induction of the Pd(0)-catalyzed rearrangement of the cyclic and acyclic O-allylic thiocarbamates in the presence of BPA are the same as, or similar to, those in the Pd-catalyzed substitutions of the corresponding cyclic and acyclic racemic allylic carbonates and acetates with sulfinates and thiols. It is therefore proposed that Pd(0)/BPA reacts with the racemic O-allylic thiocarbamate with formation of a jt-allyl-Pd(II) complex, which contains as counter ion the corresponding thiocarbamate ion (Scheme 2.1.4.19) [23, 24]. Substitution of the jt-allyl-Pd(II) complex by the thiocarbamate ion gives the S-allylic thiocarbamate and the Pd catalyst. 

The Pd-catalyzed allylic alkylation of thiocarboxylate ions was carried out with potassium thioacetate (KSAc) and potassium thiobenzoate (KSBz) and the racemic cyclic and acyclic carbonates rac-3aa, rac-3ba, rac-lda, rac-laa, rac-lba, and rac-lca, respectively (Scheme 2.1.4.21). The carbonates rac-3aa, rac-3ba, rac-lda, rac-laa, and rac-lba were treated with KSAc (1.4 equiv) or KSBz (2.0 equiv) in the presence of Pd(0)/L (2 mol%) and BPA (8 mol%) in CH2CI2/H2O. Under these conditions the acyclic carbonates rac-3aa and rac-3ba gave the thioesters 18aa, 18ab and 18ba, respectively (Table 2.1.4.14, entries 1-3), with high enantioselec-tivities in high yields [26]. 

The kinetic resolution of the racemic allylic acetates rac-3ab, rac-ldb, rac-lab, and rac-lbb with thiocarboxylate ions and BPA were investigated in more detail (Scheme 2.1.4.22). The acetates were selected instead of the corresponding carbonates in order to avoid the competing formation of the corresponding allylic alcohols (vide supra). All reactions were carried out in CH2CI2/H2O (9 1) using 2 mol% of Pd(0)/L and 8 mol% of BPA. Termination of the reaction of the pen-tenyl acetate rac-3ab with KSAc at 35% conversion showed the operation of highly selective kinetic resolution (entry 4). However, 50% conversion of the substrate could be achieved neither at room nor at reflux temperature. This is in contrast to the reactivity of carbonate roc-3aa (cf. Table 2.1.4.14, entry 1) and perhaps reflects the lower reactivity of allylic acetates in Pd-catalyzed alkylation. This... 

Preparative HPLC of the racemic cyclopentenyl naphthoate rac-ldc afforded the enantiopure a-naphthoates Idc and ent-ldc, each in 46% yield (Scheme 2.1.4.23). Hydrolysis of Idc and ent-ldc furnished the enantiopure alcohols 9d and ent-9d, respectively, which were converted to the enantiopure acetates Idb and ent- Idb, respectively. Both acetates ent-ldb and Idb were submitted separately to a Pd-catalyzed reaction with KSAc (1.4 equiv) in the presence of Pd(0)/L (2 mol%) and BPA (4mol%) in CH2CI2/H2O (9 1) (Scheme 2.1.4.24). The reaction of the matched acetate Idb was faster than that of the mismatched acetate ent-ldh. 

The Pd-catalyzed allylic alkylation of sulfinate ions, thiols, and thiocarboxylate ions with racemic cyclic and acyclic allylic esters in the presence of bisphosphane BPA generally provides for an efficient asymmetric synthesis of allylic sulfones, sulfides, and thioesters. The Pd-catalyzed rearrangements of allylic sulfinates and allylic O-thiocarbamates, both of which proceed very efficiently in the presence of BPA, are attractive alternative ways to the asymmetric synthesis of allylic sulfones and allyUc thioesters also starting from the corresponding racemic alcohols. 

The Pd-catalyzed rearrangements most probably follow an ionization-substitution pathway with the intermediate formation of a jc-allyl-Pd complex. The Pd-catalyzed allylic alkylation is generally accompanied by a highly selective kinetic and synthetically useful resolution of the racemic allylic acetates and carbonates. 

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