Kazuhiro Takenaka

PdII/PdIV Catalytic Enantioselective Synthesis of Bicyclo[3.1.0]hexanes via Oxidative Cyclization of Enynes

The first asymmetric Pd(II)/Pd(IV) catalysis has been achieved by employing the combination of a hypervalent iodine reagent and a chiral ligand, SPRIX. Enantioselective cyclization of enyne derivatives catalyzed by the Pd-i-Pr-SPRIX complex furnished lactones bearing a bicyclo[3.1.0]hexane skeleton with up to 95% ee.

Enantioselective Cyclization of 4-Alkenoic Acids via an Oxidative Allylic C–H Esterification

An enantioselective intramolecular oxidative cyclization of 4-alkenoic acids was developed. The reaction proceeded via a π-allyl Pd intermediate generated by an allylic C-H activation to give γ-lactone derivatives with moderate to good enantioselectivity. Spiro bis(isoxazoline) ligand, SPRIX, was indispensable for this asymmetric transformation.

Enantioselective intramolecular oxidative aminocarbonylation of alkenylureas catalyzed by palladium-spiro bis(isoxazoline) complexes.

An enantioselective synthesis of tetrahydropyrrolo[1,2-c]pyrimidine-1,3-diones via a palladium-catalyzed intramolecular oxidative aminocarbonylation is described. The carbon-carbon double bond of alkenylurea substrates has been shown to react intramolecularly with a nitrogen nucleophile in the presence of a palladium catalyst under a carbon monoxide atmosphere. The use of a chiral spiro bis(isoxazoline) ligand (SPRIX) is essential to obtain the desired products in optically active forms. In comparison with the coordination ability of other known ligands, this peculiar character of SPRIX originates from two structural characteristics: low sigma-donor ability of the isoxazoline coordination site and rigidity of the spiro skeleton.

Enantioselective Wacker-type cyclization of 2-alkenyl-1,3-diketones promoted by Pd-SPRIX catalyst.

An enantioselective intramolecular Wacker-type cyclization of 2-alkenyl-1,3-diketones catalyzed by a Pd(II)-SPRIX complex was developed. The reaction proceeded in a 6-endo-trig mode to give the desired chromene derivatives with moderate to good enantioselectivity. Isomerization of C-C double bonds via a pi-allyl Pd intermediate was involved as the key step.

Asymmetric Auto‐Tandem Catalysis with a Planar‐Chiral Ruthenium Complex: Sequential Allylic Amidation and Atom‐Transfer Radical Cyclization

The efficient synthesis of complex molecules with multiple stereogenic centers is a challenging task in synthetic organic chemistry. One-pot reactions have received considerable attention for the improvement of reaction efficiency, because they can avoid time-consuming workups and the often formidable isolation of intermediary products. A representative example is domino catalysis, in which two or more mechanistically similar reactions proceed in only one operation. 2] Another method, auto-tandem catalysis is also an ideal and eco-friendly synthetic process, which involves two or more mechanistically distinct reactions promoted by only a single catalyst. Despite numerous examples of domino catalysis, there are limited numbers of reports on autotandem catalysis, this is probably due to the difficulty of optimizing the reaction conditions. We have shown that planar-chiral cyclopentadienylruthenium (Cp’Ru) complex 1 is a proficient catalyst for asymmetric allylic substitutions. 6] Recently, we succeeded in the development of regioand enantioselective reactions of monosubstituted allylic halides with oxygen nucleophiles, which produced enantiomerically enriched branched allylic ethers, esters, and alcohols in good yields. These products possess a reactive terminal olefin, which can be potentially applied in a further transformation. 8] As the catalytic activity of 1 is preserved, even at the end of the allylic substitution, and ruthenium complexes show various desirable oxidation states for catalytic behavior, we conceived an extension of our system to auto-tandem asymmetric catalysis. As a candidate for the transformation of a terminal olefin on a branched allylic compound, we focused on the atomtransfer radical cyclization (ATRC) because half-sandwiched Ru complexes similar to 1 are known to promote this reaction. ATRC is an atom-economical method for the formation of cyclic compounds, which proceeds under mild conditions and exhibits broad functional group tolerance. Hence, it was hypothesized that complex 1 could realize an asymmetric auto-tandem catalysis consisting of allylic substitution and ATRC. To test this theory, we envisioned the facile synthesis of optically active g-lactams, an important structural motif found in a variety of biologically active molecules. Nagashima and co-workers reported that ATRC reaction of branched allylic amides using a Ru catalyst proceeded diastereoselectively, 13] with the configuration at the new stereogenic carbon controlled by the stereochemistry of the substrate. The preparation of optically active allylic amides by 1-catalyzed enantioselective allylic amidation would therefore provide g-lactams with multiple stereogenic centers in a pure form through 1-catalyzed ATRC (Scheme 1). Herein, we report

Enantioselective Synthesis of C2-Symmetric Spirobilactams via Pd-Catalyzed Intramolecular Double N-Arylation

A Pd/BINAP-complex-catalyzed enantioselective intramolecular double N-arylation of malonamides bearing 2-bromoarylmethyl groups furnished C(2)-symmetric spirobi(3,4-dihydro-2-quinolone) derivatives in up to 70% ee.

Palladium Enolate Umpolung: Cyclative Diacetoxylation of Alkynyl Cyclohexadienones Promoted by a Pd/SPRIX Catalyst

A novel palladium-catalyzed reaction involving an unusual nucleophilic attack on a palladium enolate was developed using a spiro-bis(isoxazoline) (SPRIX) ligand. Treatment of alkynyl cyclohexadienone substrates with a Pd/SPRIX catalyst in acetic acid under an oxygen atmosphere furnished diacetoxylated benzofuranone derivatives in good yields. This cyclative diacetoxylation proceeded enantioselectively in the presence of an optically pure SPRIX ligand.

Palladium-Catalyzed Direct CH Arylation of Isoxazoles at the 5-Position†

A palladium-catalyzed direct arylation of isoxazoles with aryl iodides has been achieved. The C-H bond at the 5-position is activated selectively to give coupling products in moderate to good yields. This direct arylation was applied to the synthesis of a spiro-type chiral ligand, which proved to be most effective to the palladium-catalyzed tandem cyclization of a dialkenyl alcohol.

Enantioselective Pd(II)–Pd(IV) catalysis utilizing a SPRIX ligand: efficient construction of chiral 3-oxy-tetrahydrofurans

Novel enantioselective catalysis involving a Pd(II)-Pd(IV) cycle was developed by utilizing a SPRIX ligand. Treatment of alkenyl alcohols with a catalytic amount of Pd-SPRIX and TfOH in the presence of PhI(OAc)2 gave optically active 3-oxy-tetrahydrofuran derivatives in good yields.

DFT Study of a 5‐endo‐trig‐Type Cyclization of 3‐Alkenoic Acids by Using Pd–Spiro‐bis(isoxazoline) as Catalyst: Importance of the Rigid Spiro Framework for Both Selectivity and Reactivity

The reaction pathway of an enantioselective 5-endo-trig-type cyclization of 3-alkenoic acids catalyzed by a chiral palladium-spiro-bis(isoxazoline) complex, Pd-SPRIX, has been studied by density functional theory calculations. The most plausible pathway involves intramolecular nucleophilic attack of the carboxylate moiety on the C=C double bond activated by Pd-SPRIX and β-H elimination from the resulting organopalladium intermediate. The enantioselectivity was determined in the cyclization step through the formation of a π-olefin complex, in which one of the two enantiofaces of the olefin moiety was selected. The β-H elimination occurs via a seven-membered cyclic structure in which the acetate ligand plays a key role in lowering the activation barrier of the transition state. In the elimination step, the SPRIX ligand was found to behave as a monodentate ligand due to the hemilability of one of the isoxazoline units thereby facilitating the elimination. Natural population analysis of this pathway showed that the more weakly electron-donating SPRIX ligand, compared with the bis(oxazoline) ligand, BOX, facilitated the formation of the π-olefin complex intermediate, leading to a smaller overall activation energy and a higher reactivity of the Pd-SPRIX catalyst.