Enantioselectivity palladium enolates

Sodeoka and co-workers have reported enantioselective aldol and Mannich reactions (Equations (106) and (J07)) 464,464a 464e Involvement of palladium enolates was confirmed by 111 NMR and ESI-MS spectrometry. /3-Keto esters (pronucleophiles) directly add to imines with high selectivity without preformation of silicon enolates (Equation (108)). 

Aldol reactions of silyl enolates are promoted by a catalytic amount of transition metals through transmetallation generating transition metal enolates. In 1995, Shibasaki and Sodeoka reported an enantioselective aldol reaction of enol silyl ethers to aldehydes using a Pd-BINAP complex in wet DMF. Later, this finding was extended to a catalytic enantioselective Mannich-type reaction to a-imino esters by Sodeoka s group [Eq. (13.21)]. Detailed mechanistic studies revealed that the binuclear p-hydroxo complex 34 is the active catalyst, and the reaction proceeds through a palladium enolate. The transmetallation step would be facilitated by the hydroxo ligand transfer onto the silicon atom of enol silyl ethers ... 

Palladium enolate chemistry has been exploited to perform a range of catalytic enantioselective reactions on carbonyl substrates, including aldol, Michael, Mannich-type, and a-fluorination.154... 

Enantioselective fluorination reactions catalyzed by chiral palladium enolate complexes have been the subject of considerable research . For instance, the fluorination of acyclic /S-ketoester (88, equation 24) using Af-fluorobenzenesulfonimide (NFSI) gave product 89 in high yields and with excellent enantioselectivity (ee up to 94%) . This reaction can be carried out in environmentally benign alcoholic solvents and provides valuable synthetic building blocks that find applications in medicinal chemistry, chemical biology and material sciences. 

Scheme 9) [48]. The enantioselectivity was highly dependent on the reaction temperature and almost enantiopure 2-methyl-1-indanone (59) was obtained at 52 °C. The reaction was assumed to proceed via an enol or palladium enolate intermediate which was produced by cleavage of the benzyl-oxygen bond and the subsequent decarboxylation. 

Nakai and a coworker achieved a conceptually different protonation of silyl enol ethers using a chiral cationic palladium complex 40 developed by Shibasaki and his colleagues [61] as a chiral catalyst and water as an achiral proton source [62]. This reaction was hypothesized to progress via a chiral palladium enolate which was diastereoselectively protonated by water to provide the optically active ketone and the chiral Pd catalyst regenerated. A small amount of diisopropylamine was indispensable to accomplish a high level of asymmetric induction and the best enantioselectivity (79% ee) was observed for trimethylsilyl enol ether of 2-methyl-l-tetralone 52 (Scheme 11). 

The Pd diaquo complex of BINAP 19 efficiently catalyzed the diastereoselective and enantioselective Michael addition of the y3-keto ester 20 to 3-penten-2-one (21), and the Michael adduct 22 was obtained in 89 % yield (diastereomeric ratio = 8/1) and the ee of the major isomer was 99%. Thus, congested vicinal tertiary and quaternary carbon centers were constructed. It is interesting to know that the Pd aquo complex 19 allows the successive supply of a Bronsted base and a Bronsted acid. The former activates the carbonyl compound to give the chiral palladium enolate and the latter cooperatively activates e enone [4]. 

Fujii, A., Hagiwara, E., Sodeoka, M. (1999) Mechanism of Palladium Complex-catalyzed Enantioselective Mannich-type Reaction Characterization of a Novel Bin-uclear Palladium Enolate Complex. J. Am. Chem. Soc. 121 5450-5458. 

Ricci and coworkers [64] studied oxazoline moiety fused with a cyclopenta[P]thio-phene as ligands on the copper-catalyzed enantioselective addition of Et2Zn to chalcone. The structure of the active Cu species was determined by ESI-MS. Evans and coworkers [65] studied C2-symmetric copper(II) complexes as chiral Lewis acids. The catalyst-substrate species were probed using electrospray ionization mass spectrometry. Comelles and coworkers studied Cu(II)-catalyzed Michael additions of P-dicarbonyl compounds to 2-butenone in neutral media [66]. ESI-MS studies suggested that copper enolates of the a-dicarbonyl formed in situ are the active nucleophilic species. Schwarz and coworkers investigated by ESI-MS iron enolates formed in solutions of iron(III) salts and [3-ketoesters [67]. Studying the mechanism of palladium complex-catalyzed enantioselective Mannich-type reactions, Fujii and coworkers characterized a novel binuclear palladium enolate complex as intermediate by ESI-MS [68]. 

Using chiral palladium enolates (143) as key intermediates, efficient catalytic enantioselective fluorination reactions of P-ketoesters and P-ketophosphonates (144) gave fluorinated products (145) (Scheme 51). ... 

Scheme 5.9 Diastereoselective and/or enantioselective palladium-catalyzed allylic alkylation of cyclohexanone through the magnesium or lithium enolate.

Scheme 5.10 Regioselective, diastereoselective, and enantioselective palladium

Scheme 5.11 Regioselective, diastereoselective, and enantioselective palladium-catalyzed allylic alkylation of acylsilanes through thar lithium enolates.

Scheme 5.12 Enantioselective palladium-catalyzed allylic alkylation of tertiary amides 32 through their lithium enolates.

Scheme 5.15 Diastereoselective and/or enantioselective palladium-catalyzed allylation of 5-valerolactone through the lithium enolate 46.

Scheme 5.47 Enantioselective palladium-catalyzed enolate arylation of racemic aminomethylene ketones 143 mediated by chiral ligands 144.

Scheme 5.50 Enantioselective palladium-catalyzed arylation of enolates derived from racemic oxindoles 152, mediated by the axially chiral and P-stereogenic ligand 153.

Shibasaki, Sodeoka, and coworkers disclosed the first enantioselective variant following this mechanism and noticed that sUyl enol ethers 220 undergo enantioselective additions to benzaldehyde when catalyzed by diaqua palladium(ll) complexes 268 of BINAP and Tol-BINAP to give, after treatment with acid, aldol products in up to 92% ee. Activation by tetramethylurea was found to be beneficial to enantioselectivity. NMR studies revealed that palladium enolates 269 function as real intermediates and identified them as active nucleophiles. In a key step of the... 

Whereas the protocols discussed rely on asymmetric induction by a chiral protonating agent, a conceptionally different approach is based on a chiral enolate that accepts a proton from a nonchiral source. An early validation of this concept was provided by Nakai and Sugiura, who were able to show that prochiral silyl enol ethers were protonated enantioselectivity through the palladium enolates that were generated catalytically by [(f )-(BINAP)PdCl2] in... 

Based upon the results of kinetic studies that revealed a zero-order decay of the P-keto ester, a catalytic cycle was proposed that is shown in a simplified manner in Scheme 5.122. In an oxidative addition, the palladium complex of ligand (S )-42b reacts with P-keto ester rac-489 to give palladium carboxylate 492, the decarboxylation of which generates palladium enolate 493. Next, Meldrum s acid 490 transfers a proton to the enolate in an enantioselective manner, so that the nomacemic ketone 491 results. Concomitantly, an ion pair consisting of allylpal-ladium cation 494 and the anion 495 of Meldrum s acid is formed. This anion then plays the role of a nucleophile for an allylic alkylation by accepting the allyl residue under formation of the stoichiometric by-product 496. This last step closes the cycle by releasing the chiral palladium catalyst [241b]. 

Scheme 5.122 Enantioselective protonation of chiral palladium enolates generated by decarboxylation of p-keto esters 487 and 489 simplified proposed catalytic cycle.

The survey of procedures for enantioselective protonation reveals a tendency from stoichiometric to catalytic versions, and the in situ generated palladium enolates are here again particularly promising. The methods outlined here clearly fill a gap in the repertoire of asymmetric syntheses inasmuch as auxiliary-based diastereoselective protonation was not developed to a significant extent. 

In these cases, NFSI was preferred to Selectfluor and the reactions were performed either in alcohol or in ionic liquids in which the palladium complexes can be immobilized and reused with excellent reproducibility even after 10 consecutive cycles. For example, the enantioselective electrophilic fluorination of 2-methyl-3-oxo-3-phenylpro-pionic acid tert-butyl ester in [hmim] [BF4] gives the corresponding fluorinated product in 93% yield with 92% ee, and still in 67% yield with 91% ee after 10 cycles. The fluorination of various cyclic and acyclic (3-keto esters was carried out with NFSI in ethanol in the presence of 2.5 mol% of catalyst, leading to excellent ee-values up to 94%. The reaction is not sensitive to water, can be run on a 1-g scale, and proceeds via a palladium enolate complex as for the titanium-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyl-dioxolane (TADDOL) catalyst. The reaction was extended to tert-butoxycarbonyl lactones and lactams. Reactions with lactones proceeded smoothly in an alcoholic solvent with 2.5 mol% of catalyst and NFSI, while the less acidic lactam substrates required concurrent use of the Pd complex and 2,6-lutidine as a co-catalyst. Under the reaction conditions, the fluorinated lactones and lactams were obtained in good yields with excellent enantioselectivities (up to 99%... 

An electron-rich metal can deprotonate the dicarbonyl derivative, affording the hydridopalladium intermediate 23, which can undergo a Tr-allyl 24 formation through diene insertion (which can be assimilated to a hydridopalladation of olefin) (Scheme 7). The attack of the enolate to the -jr-allyl species occurs with good enantioselectivity in the presence of the chiral ligand. The final product 21 is released and the palladium(O) complex 22 is regenerated. 

The a-arylation of carbonyl compounds (sometimes in enantioselective version) such as ketones,107-115 amides,114 115 lactones,116 azlactones,117 malonates,118 piperidinones,119,120 cyanoesters,121,122 nitriles,125,124 sul-fones, trimethylsilyl enolates, nitroalkanes, esters, amino acids, or acids has been reported using palladium catalysis. The asymmetric vinylation of ketone enolates has been developed with palladium complexes bearing electron-rich chiral monodentate ligands.155... 

The method involves a regioselective, trans-diastereoselective, and enantioselective three-component coupling, as shown in Scheme 7.26. In this case, the zinc enolate resulting from the 1,4-addition is trapped in a palladium-catalyzed allyla-tion [64] to afford trans-2,3-disubstituted cyclohexanone 96. Subsequent palladium-catalyzed Wacker oxidation [82] yields the methylketone 97, which in the presence of t-BuOK undergoes an aldol cyclization. This catalytic sequence provides the 5,6-(98) and 5,7- (99) annulated structures with ees of 96%. 

Enantioselective deprotonation can also be successfully extended to 4,4-disubstituted cyclohexanones. 4-Methyl-4-phenylcyclohexanone (3) gives, upon reaction with various chiral lithium amides in THF under internal quenching with chlorotrimethylsilane, the silyl enol ether 4 having a quaternary stereogenic carbon atom. Not surprisingly, enantioselectivities are lower than in the case of 4-tm-butylcyclohexanone. Oxidation of 4 with palladium acetate furnishes the a./i-unsaturated ketone 5 whose ee value can be determined by HPLC using the chiral column Chiralcel OJ (Diacel Chemical Industries, Ltd.)59c... 

---