Ken Kamikawa

Stereoselective Synthesis of Axially Chiral Natural Products, (−)-Steganone and O,O′-Dimethylkorupensamine A, Utilizing Planar Chiral (Arene)chromium Complexes

Abstract Palladium(0)-mediated Suzuki–Miyaura cross-coupling of planar chiral (2,6-disubstituted bromobenzene)chromium complexes with o-substituted arylboronic acids in the presence of sodium carbonate under refluxing in aqueous methanol gave stereoselectively axially chiral mono Cr(CO)3-complexed biaryls. The axial stereochemistry of the cross-coupling products was found to be largely dependent on the steric bulkiness of ortho substituent of arylboronic acids and reaction conditions. The cross-coupling with o-alkyl or hydroxymethyl substituted arylboronic acids gave kinetically controlled products in which the ortho substituents were oriented in syn-configuration to the tricarbonylchromium fragment. On the other hand, o-formyl phenylboronic acid produced thermodynamically stable anti-coupling products under the same conditions. By utilizing these methodologies, biologically active axially chiral natural products, (−)-steganone and O,O′-dimethyl derivative of the natural product of korupensamine A, were stereoselectively synthesized.

The lactone concept—a novel approach to the metal-assisted atroposelective construction of axially chiral biaryl systems

The atroposelective synthesis of axially chiral biaryls via configurationally unstable, lactone-bridged biaryls is reviewed. These key molecules are easily accessible by regioselective intramolecular cross-coupling of ester-linked, even sterically hindered aromatic portions and can be cleaved highly atropo-enantio- or -diastereoselectively by three principal options, either (a) by using a wide range of chiral metalated nucleophiles (usually with external asymmetric induction), (b) after Lewis acid activation of the lactone CO function using uncharged chiral or achiral nucleophiles, or (c) with internal asymmetric induction, using the stereoelement of planar chirality originating from η6-coordination (typically involving Cr or Ru complexes). The resulting ring-opened configurationally stable biaryls are obtained in mostly excellent chemical and optical yields. By the choice of the respective enantiomer of the nucleophile, the method allows the atropo-divergent synthesis of both atropisomers from the same immediate biaryl precursor and, if required, a recycling of the undesired minor atropisomer is possible, too. Such advantages are otherwise well-known for the stereoselective preparation of centrochiral compounds.

Synthesis of a Double Helicene by a Palladium‐Catalyzed Cross‐Coupling Reaction: Structure and Physical Properties

For this study, twisted π-extended helicene 1 and double helicene 2 with a helicene framework were synthesized through palladium-catalyzed C-H arylation or Suzuki-Miyaura coupling reaction. X-ray crystallography revealed grossly twisted structures that were soluble in various conventional organic solvents. Optical properties based on UV/Vis and fluorescence spectra were measured. Electrochemical properties were also studied by measurements of cyclic voltammetry in 1 and 2, which revealed their HOMO and the LUMO energies. Theoretical calculation supports their HOMO and LUMO energies and molecular orbitals. Furthermore, a racemization process of 2 predicted that the activation free energy at 300 K would be 31.8 kcal mol(-1) by DFT calculation, which indicated the static helicity at 300 K.

Kinetic Resolution of Planar-Chiral (η6-Arene)Chromium Complexes by Molybdenum-Catalyzed Asymmetric Ring-Closing Metathesis†

Planar-chiral (h-arene)chromium complexes are useful chiral scaffolds in asymmetric synthesis, and have found widespread application as chiral ligands for asymmetric catalysis, or as chiral building blocks for natural product syntheses. Typical methods for the preparation of enantiomerically enriched planar-chiral (arene)chromium species are based either on the optical resolution of racemates or on stereoselective transformations, which include diastereoselective complexation, diastereoor enantioselective ortho-lithiation by utilizing a chiral directing group or a chiral base, and diastereoor enantioselective nucleophilic addition/hydride abstraction. Whereas these methods require a stoichiometric amount of chiral reagents or auxiliaries, asymmetric catalysis is an attractive and effective alternative for preparing optically active (h-arene)chromium complexes. Since the first report on such a catalytic process by Uemura et al. in 1993, only a handful of examples of the desymmetrization of prochiral (arene)chromium substrates have been reported by Gotov and Schmalz, K ndig and co-workers, and Uemura and co-workers 11] . Recently, we reported the preparation of phosphinechelate (h-arene)chromium complexes by Ru-catalyzed ringclosing metathesis. We also demonstrated that Mo-catalyzed asymmetric ring-closing metathesis (ARCM) was highly effective for the asymmetric synthesis of the various planarchiral ferrocenes. Thus, we are interested in controlling the planar chirality of (h-arene)chromium complexes by ARCM. Indeed, the kinetic resolution of racemic (h1,2-disubstituted benzene)chromium complexes proceeds efficiently in the presence of a chiral Mo-alkylidene species to give the planar-chiral chromium complexes with excellent enantiomeric purity. Furthermore, a highly enantiomerically enriched (h-bromoarene)chromium complex that was prepared by using the present method is an excellent precursor to various planar-chiral (arene)chromium derivatives. A (phosphinoarene)chromium species was derived from the (hbromoarene)chromium complex and applied as a chiral ligand in Rh-catalyzed asymmetric reactions, which achieved excellent enantioselectivity of up to 99.5%. The (h-arene)chromium complexes (rac-1) that were used in this study contain an h-(2-substituted alkenylbenzene) ligand, which constructs the planar-chiral environment upon coordination to the chromium atom, and an alkenylphosphine ligand. The chiral catalysts were screened by using racemic [(h-2-methylstyrene)Cr(CO)2(methallyldiphenylphosphine)] (1a) as a prototypical substrate. The asymmetric reactions were carried out in benzene at 40 8C in the presence of an appropriate chiral Mo catalyst (10 mol%), which was generated in situ from the Mo precursor [(pyrrolyl)2Mo(= CHCMe2Ph)(=NC6H3-2,6-iPr2)] and an axially chiral biphenol derivative (Table 1). Under these conditions, the Mo catalyst that was generated with (R)-L1 gave the ARCM product 2 a in 32% yield with an ee value of 79 %, and unreacted 1a was recovered in 66% yield with an ee value of 50% (entry 1). The krel value ([reaction rate of the fastreacting enantiomer]/[reaction rate of the slow-reacting enantiomer]; selectivity factor) for this reaction is estimated to be 14. The Mo catalyst that was generated with (R)-L2 gives better enantioselectivity and the krel value improved to 41 (entry 2). Lowering the temperature worsened the selectivity; the krel value was 12 at 23 8C (entry 3). It was found that the reaction with the Mo catalyst coordinated with (S)-L3 shows excellent enantioselectivity; 2a was obtained in 96 % ee and 44 % yield, and 1a was recovered in 88% ee and 50% yield. The krel value for the reaction is 114 (entry 4), and a nearly perfect kinetic resolution of the two enantiomers of rac-1a was achieved. Considering the structural similarity between L1, L2, and L3, these results are quite surprising and indicate that the slight structural modification to the Mo catalysts affects the enantioselectivity of the asymmetric reaction. After the optimization studies, the Mo/(S)-L3 species was applied to the other substrates. The substrate rac-1b, which has an ethyl substituent in place of the ortho-methyl group in 1a, was also resolved as above. The enantioselectivity and the reaction efficiency (krel = 75 (entry 5)) of the kinetic resolution of rac-1b were still high. Substrate 1 c contains an hbromostyrene ligand. As the bromo substituents in 1c/2c can be easily replaced by other functional groups by standard organic transformations (see below), they serve as versatile precursors to various planar-chiral compounds. The reaction of rac-1c under the optimized conditions afforded complex 2c in 97 % ee and 47% yield. Unreacted 1c was also recovered in 89% ee and 50 % yield. The krel value for this reaction is 198 [*] Prof. M. Ogasawara, S. Arae, Dr. S. Watanabe, Prof. T. Takahashi Catalysis Research Center and Graduate School of Life Science Hokkaido University, Kita-ku, Sapporo 001-0021 (Japan) E-mail: ogasawar@cat.hokudai.ac.jp

Phosphine–Olefin Ligands Based on a Planar-Chiral (π-Arene)chromium Scaffold: Design, Synthesis, and Application in Asymmetric Catalysis

The NMR and X-ray crystallographic studies clarified that planar-chiral alkenylene-bridged (phosphino-π-arene)(phosphine)chromium complexes 3 were capable of coordinating to a rhodium(I) cation in a bidentate fashion at the (π-arene)-bound phosphorus atom and at the olefin moiety. The P-olefin chelate coordination of 3 constructs the effective chiral environment at the metal center, and thus, these rhodium complexes display high performances in various rhodium-catalyzed asymmetric 1,4- and 1,2-addition reactions with arylboron nucleophiles. The control experiments demonstrated that the (η(2)-olefin)-Rh interaction as well as the bridging structure in 3 played the pivotal roles in the high enantioselectivity of the Rh-catalyzed asymmetric reactions. To enhance the synthetic utilities of these phosphine-olefin ligands, an enantiospecific and scalable synthetic method was developed. The novel synthetic method is flexible in terms of the substituent variation, and a library of the planar-chiral (arene)chromium-based phosphine-olefin ligands was established by the combinatorial approach. Among the newly prepared ligand library, compound 3g, which is with a bis(3,5-dimethylphenyl)phosphino group on the η(6)-arene ring, was found to be a far better chiral ligand in the rhodium-catalyzed asymmetric reactions showing excellent enantioselectivity and high yields.

Synthesis of Azahelicene N‐Oxide by Palladium‐Catalyzed Direct CH Annulation of a Pendant (Z)‐Bromovinyl Side Chain

Driving benzene round the twist: Azahelicene derivatives were synthesized in high yields by utilizing palladium-catalyzed C-H annulation reactions. Functionalization at the C5 position in 6-azahelicene by using palladium-catalyzed C-H arylation also gave coupling products in good yields. A tandem intra- and intermolecular double C-H coupling reaction was performed to give a functionalized helicene in a one-pot procedure.

Diastereoselective synthesis of axially chiral biaryls via nucleophilic addition to (arene)chromium complexes with Grignard reagents

Abstract Nucleophilic substitution of tricarbonyl(2,4,6-trimethylphenyl 2-methoxybenzoate)-chromium complexes with aryl Grignard reagents affords stereoselectively axially chiral biaryls.

Simultaneous Induction of Axial and Planar Chirality in Arene–Chromium Complexes by Molybdenum‐Catalyzed Enantioselective Ring‐Closing Metathesis

The molybdenum-catalyzed asymmetric ring-closing metathesis of the various Cs -symmetric (π-arene)chromium substrates provides the corresponding bridged planar-chiral (π-arene)chromium complexes in excellent yields with up to >99 % ee. With a bulky and unsymmetrical substituent, such as N-indolyl or 1-naphthyl, at the 2-positions of the η(6) -1,3-diisopropenylbenzene ligands, both biaryl-based axial chirality and π-arene-based planar chirality are simultaneously induced in the products. The axial chirality is retained even after the removal of the dicarbonylchromium fragment, and the chiral biaryl/heterobiaryl compounds are obtained with complete retention of the enantiopurity.

Synthesis, Structures, and Properties of Hexapole Helicenes: Assembling Six [5]Helicene Substructures into Highly Twisted Aromatic Systems

Hexapole helicenes 1, which contain six [5]helicene substructures, were synthesized by Pd-catalyzed [2+2+2]cycloadditions of aryne precursor 6. Among the possible 20 stereoisomers, which include ten pairs of enantiomers, HH-1 was obtained selectively. Density functional theory (DFT) calculations identified HH-1 as the second most stable isomer that quantitatively isomerizes under thermal conditions into the most stable isomer (HH-2). Both enantiomers of HH-2 can be separated by chiral HPLC. Single-crystal X-ray diffraction analyses revealed a saddle-like structure for (P,M,P,P,M,P) HH-1 and a propeller-like structure for (P,M,P,M,P,M) HH-2. Because of the helical assembly and the resulting steric repulsion, the structure of HH-1 is significantly distorted and exhibits the largest twisting angle reported so far (up to 35.7° per benzene unit). Electrochemical studies and DFT calculations indicated a narrow HOMO-LUMO gap on account of the extended π-system. Kinetic studies of the isomerization from HH-1 to HH-2 and the racemization of enantiomerically pure HH-2 were conducted based on 1H NMR spectroscopy, HPLC analysis, and DFT calculations.

Divalent Dirhodium Imido Complexes: Formation, Structure, and Alkyne Cycloaddition Reactivity

Dirhodium amido complexes [(Cp*Rh)2(mu2-NHPh)(mu2-X)] (X = NHPh (2), Cl (3), OMe (4); Cp* = eta5-C5Me5) were prepared by chloride displacement of [Cp*Rh(mu2-Cl)]2 (1) and have been used as precursors to a dirhodium imido species [Cp*Rh(mu2-NPh)RhCp*]. The imido species can be trapped by PMe3 to give the adduct [Cp*Rh(mu2-NPh)Rh(PMe3)Cp*] (5) and undergoes a formal [2 + 2] cycloaddition reaction with unactivated alkynes to give the azametallacycles [Cp*Rh(mu2-eta2:eta3-R1CCR2NPh)RhCp*] (R1 = R2 = Ph (6a), R1 = H, R2 = t-Bu (6b), R1 = H, R2 = p-tol (6c)). Isolation of a relevant unsaturated imido complex [Cp*Rh(mu2-NAr)RhCp*] (7) was achieved by the use of a sterically hindered LiNHAr (Ar = 2,6-diisopropylphenyl) reagent in a metathesis reaction with 1. X-ray structures of 2, 6a, 7 and the terminal isocyanide adduct [Cp*Rh(mu2-NAr)Rh(t-BuNC)Cp*] (8) are reported.