Asymmetric autocatalysis of a ferrocene-containing chiral compound with amplification of chirality

Chiral ferrocene-containing pyrimidyl alkanol can be efficiently synthesized via asymmetric autocatalysis as an enantiomerically pure product. Moreover, a remarkable positive nonlinear effect occurs during this autocatalytic reaction. Starting from a nearly racemic seed, it is thus possible to produce a larger amount of the same compound with high ee.     

Asymmetric autocatalysis of pyrimidyl alkanol and related compounds. Self-replication,amplification of chirality and implication for the origin of biological enantioenriched chirality

We discovered asymmetric autocatalysis in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, where the product 5-pyrimidyl alkanol acts as a highly efficient asymmetric autocatalyst to afford more of itself (Soai reaction). Asymmetric autocatalysis proceeded quantitatively (>99% yield), affording itself as a near enantiomerically pure (>99.5% ee) product. An extremely low enantiomeric excess (ca. 0.00005% ee) can automultiply during three rounds of consecutive asymmetric autocatalysis to >99.5% ee by asymmetric amplification. Circularly polarized light, and inorganic and organic crystals, act as the origin of chirality to trigger asymmetric autocatalysis. Asymmetric autocatalysis has enormous power to recognize and amplify the chirality of hydrogen, carbon, oxygen, and nitrogen isotopomers. Moreover, absolute asymmetric synthesis, i.e., the formation of enantioenriched compounds without the intervention of any chiral factor, is realized by asymmetric autocatalysis. By using designed molecules based on 5-pyrimidyl alkanol, the intramolecular asymmetric control, self-replication, and improvement of chiral multifunctionalized large molecules has been developed by applying asymmetric autocatalysis.     

Asymmetric autocatalysis and the origin of chiral homogeneity in organic compounds

The discovery and development of asymmetric autocatalysis, in which the structures of the chiral catalyst and the chiral product are the same, are described. Chiral 5-pyrimidyl, 3-quinolyl, and 5-carbamoyl-3-pyridyl alkanols act as highly enantioselective asymmetric autocatalysts in the enantioselective addition of diisopropylzinc to the corresponding aldehydes, such as pyrimidine-5-carbaldehyde. 2-Alkynyl-5-pyrimidyl alkanol with an enantiomeric excess (ee) of >99.5% automultiplies practically perfectly as an asymmetric autocatalyst in a yield of >99% and >99.5% ee. Asymmetric autocatalysis with an amplification of ee has thus been realized. Consecutive asymmetric autocatalysis starting with chiral 2-alkynylpyrimidyl alkanol of only 0.6% ee amplifies its ee significantly, and yields itself as the product with >99.5% ee. The reaction of pyrimidine-5-carbaldehyde and diisopropylzinc in the presence of chiral initiators with low ee's, such as secondary alcohol, amine, carboxylic acid, mono-substituted [2.2]paracyclophane, and chiral primary alcohols due to deuterium substitution, regulates the absolute configuration of the resulting pyrimidyl alkanols, and the ee of the resulting pyrimidyl alkanol is much higher than that of the chiral initiator. Leucine and [6]helicene with very low ee's, which are known to be induced by circularly polarized light (CPL), also serve as chiral initiators to produce pyrimidyl alkanol with higher ee's. Overall, the process represents the first correlation between the chirality of CPL and an organic compound with very high ee. Chiral inorganic crystals, such as quartz and sodium chlorate, act as chiral inducers in the asymmetric autocatalysis of pyrimidyl alkanol. The process correlates for the first time ever the chirality of inorganic crystals with an organic compound with very high ee.     

Amplification of chirality as a pathway to biological homochirality

Amplification of enantiomeric enrichment is a key feature for the chemical evolution of biological homochirality from the origin of chirality. The aggregations of the enantiomers by diastereomeric interactions enable the modification of their enantiomeric excess during some chemical processes. Fluorine-containing chiral compounds possess large amplification effect via distillation, sublimation and achiral chromatography by self-disproportionation. Asymmetric amplifications in enantioselective catalysis occur by the differential formation and reactivity between homochiral and heterochiral aggregate in solution.We described the amplification of ee in asymmetric autocatalysis of 5-pyrimidyl alkanol in the reaction between diisopropylzinc and pyrimidine-5-carbaldehdye. During the reactions extremely low ee (ca. 0.00005% ee) can be amplified to achieve more than 99.5% ee. Since the proposed origins of chirality such as CPL, quartz, chiral organic crystals of achiral compounds and statistical fluctuation of ee can initiate the asymmetric autocatalysis with amplification of ee, the proposed origin of chirality can be linked with enantiopure organic compound in conjunction with amplification of ee by asymmetric autocatalysis. In addition, we described that the carbon isotopically chiral compound triggers the asymmetric autocatalysis of 5-pyrimiodyl alkanol to afford the enantioenriched product with the absolute configuration correlated with that of carbon isotope chirality, that is, isotope chirality including hydrogen isotopes can control the enantioselectivity of asymmetric addition of alkyl metal reagent to aldehyde.     

Nonlinear Effects in Asymmetric Catalysis

There is a need for the preparation of enantiomerically pure compounds for various applications. An efficient approach to achieve this goal is asymmetric catalysis. The chiral catalyst is usually prepared from a chiral auxiliary, which itself is derived from a natural product or by resolution of a racemic precursor. The use of non‐enantiopure chiral auxiliaries in asymmetric catalysis seems unattractive to preparative chemists, since the anticipated enantiomeric excess (ee) of the reaction product should be proportional to the ee value of the chiral auxiliary (linearity). In fact, some deviation from linearity may arise. Such nonlinear effects can be rich in mechanistic information and can be synthetically useful (asymmetric amplification). This Review documents the advances made during the last decade in the use of nonlinear effects in the area of organometallic and organic catalysis.     

Synthesis of optically active methyl 4-(4-biphenylyl)-3-hydroxybutanoate via enantioselective hydrogenation using a tartaric acid-modified nickel catalyst and recrystallization

Enantioselective hydrogenation of methyl 4-(4-biphenylyl)-3-oxobutanoate over a tartaric acid-modified Raney nickel catalyst gave the title compound in 82% ee, which was enantiomerically enriched by recrystallizations. The product was converted to an (R)-3-acetoxyglutaric acid half ester via a ruthenium-catalyzed oxidation.     

不对称自催化反应

不对称自催化反应是指由不对称反应生成的手性产物自身作为催化剂的反应过程。不对称自催化具有手性自动放大、反应活性较高、产物处理较易、反应体系连续等特点,是不对称化学的一个新的领域。不对称自催化反应结合手性放大作用,使人们对手性起源有了新的认识。自1990年代以来该方面的探索和研究取得令人注目的重大突破。本文综述了近年来不对称自催化反应的新进展。     

A Closer Look at Spontaneous Mirror Symmetry Breaking in Aldol Reactions

The aldol reaction between acetone and 4‐nitrobenzaldehyde run in the nominal absence of any enantioselective catalyst was monitored by chiral HPLC with the aid of an internal standard. The collected data show the presence of a detectable initial enantiomeric excess of the aldol product in the early stages of the reaction in about 50 % of the experiments. Only a small fraction of the reaction contained the non‐racemic aldol product after 24 h. This temporary emergence of natural optical activity could be the signature of a coupled reaction network that leads to a spontaneous mirror‐symmetry‐breaking process, which originates at very low conversions (i.e., strongly depends on events taking place at the very first stages of the process). The reaction is not autocatalytic in the aldol product, which rules out a simple Frank‐type reaction network as the source of the observed symmetry breaking. On the other hand, the isolation and characterisation of a double‐aldol adduct suggested a reaction network that involved both indirect autocatalysis and indirect mutual inhibition between the enantiomers of the reaction product.     

Dynamic processes in the copper-catalyzed substitution of chiral allylic acetates leading to loss of chiral information

Copper-catalyzed alpha-substitution of enantiomerically pure secondary allylic esters with Grignard reagents was studied with the aim to find conditions that give racemic products. It was observed that the degree of chiral transfer is strongly dependent on the temperature. The loss of chiral information is consistent with an equilibration of the Cu(III)(allyl) intermediates prior to product formation. Equilibration of the reaction intermediates is of importance for a possible development of a dynamic kinetic asymmetric transformation (DYKAT) process, in which a chiral catalyst is used to produce an optically active product from a racemic substrate, by means of a dynamic equilibrium of the diastereomeric reaction intermediates.     

Features and applications of [Rh(CO)(2)Cl](2)-catalyzed alkylations of unsymmetrical allylic substrates

A novel regio- and stereoselective [Rh(CO)2Cl]2-catalyzed allylic alkylation of unsymmetrical allylic carbonates was discovered. The regioselectivity of the reaction favors product ratios in which substitution occurs at the carbon bearing the leaving group. When an enantiomerically enriched carbonate (> or = 99% ee) was examined, the Rh(I)-catalyzed allylic alkylation proceeded stereoselectively to provide the alkylation product with retention of absolute stereochemistry (98% ee). To establish the scope of the [Rh(CO)2Cl]2-catalyzed allylic alkylation, a variety of carbon and heteroatom nucleophiles were examined and the results described. As an application of the Rh(I)-catalyzed allylic alkylation, a series of novel domino reactions have been developed that couple the unique regio- and stereoselective [Rh(CO)2Cl]2-catalyzed alkylation of allylic trifluoroacetates with an intramolecular Pauson-Khand annulation, a cycloisomerization, or a [5+2] cycloaddition. A unique aspect of the method described is the use of a single catalyst to effect sequential transformations in which the catalytic activity is moderated simply by controlling the reaction temperature. Implementation of such processes provides a rapid and efficient entry to a variety of bicyclic carbon skeletons from simple precursors.     

Catalytic enantioselective Reissert-type reaction: development and application to the synthesis of a potent NMDA receptor antagonist (-)-L-689,560 using a solid-supported catalyst.

Full details of the first catalytic enantioselective Reissert-type reaction are described. Utilizing the Lewis acid-Lewis base bifunctional catalyst 5 or 6 (9 mol %), the Reissert products were obtained in 57 to 99% yield with 54 to 96% ee. Electron-rich quinolines produced better yields and enantioselectivities than electron-deficient substrates. Kinetic studies indicated that the reaction should proceed via the rate-determining acyl quinolinium formation, followed by the attack of a cyanide. The catalyst does not facilitate the first rate-determining step; however, it strongly facilitates the second cyanation step. The reaction was successfully applied to an efficient catalytic asymmetric synthesis of a potent NMDA receptor antagonist (-)-L-689,560. A key step is the one-pot process using the Reissert-type reaction from quinoline 1f, followed by stereoselective reduction of the resulting enamine 2f. This step gave the key intermediate 20 in 91% yield with 93% ee, using 1 mol % of 6. The enantiomerically pure target compound was obtained through 10 operations (including recrystallization) in total yield of 47%. Furthermore, 6 was immobilized to JandaJEL, and the resulting solid-supported catalyst 11 afforded 20 in a comparable yield to the homogeneous 6, but with slightly lower enantioselectivity.     

Highly enantioselective asymmetric hydrogenation of alpha-phthalimide ketone: an efficient entry to enantiomerically pure amino alcohols

A new type of alpha-phthalimide ketones was hydrogenated in excellent enantioselectivity by using a Ru-(C3-TunePhos) complex as the catalyst. Up to 10 000 turnovers have been achieved in more than 99% ee in the hydrogenation reaction. A dynamic kinetic resolution study for the synthesis of threonine was performed, and high anti selectivity (>97:3) was observed for the first time. An efficient method to synthesize enantiomerically pure amino alcohols has been developed.     

Rh-catalyzed kinetic resolution of enynes and highly enantioselective formation of 4-alkenyl-2,3-disubstituted tetrahydrofurans

Rh-catalyzed cycloisomerization of enynes ether with a substituent at the allylic position was examined using (rac)-BINAP, and excellent selectivity was observed. When enantiomerically pure BINAP was used as the ligand, a process that combines kinetic resolution and diastereoselectivity together was developed, in which an enantiomeric product with multiple stereogenic centers was obtained in >99% ee from a racemic starting material via single step, and half of the remaining starting material was recovered in >99% ee, also.     

Dramatic catalyst evolution in the asymmetric addition of diethylzinc to benzaldehyde

We have observed product ee's that begin at 20% at low reaction conversion and rise to 79% ee at the completion of the reaction in the asymmetric addition of alkyl groups to benzaldehyde. This rare behavior is attributed to autoinduction, in which the catalyst evolves by incorporation of the product. Based on this, we have been able to optimize the catalyst by variation of achiral, rather than enantiopure ligands.     

Diastereo- and enantioselective conjugate addition of 3-substituted oxindoles to nitroolefins catalyzed by a chiral Ni(OAc)2-diamine complex under mild conditions

A simple catalyst system assembled from an enantiomerically pure diamine ligand and Ni(OAc)(2) efficiently generates chiral metal enolates derived from 3-substituted oxindoles bearing an N-1 carbonyl group. The enolates smoothly undergo diastereo- and enantioselective conjugate addition to a wide range of nitroolefins under mild reaction conditions, furnishing 3,3-disubstituted oxindole products bearing two vicinal quaternary/tertiary stereocenters in 74-95% yields and 60:40 to 99:1 dr, 71-97% ee.     

Catalytic enantioselective synthesis of chiral phthalides by SmI2-mediated reductive cyclization of 2-acylarylcarboxylates

A significant new and efficient catalytic asymmetric approach for the highly enantioselective synthesis of chiral phthalides by SmI2-induced reductive cyclization of 2-acylarylcarbonylates was developed. The combination of (4S,5R)-4,5-diphenyloxazolidin-2-one and 2,2,6,6-tetramethylpiperidine was found to be a very effective catalyst system in the reaction. This method provides a ready access to a broad range of enantiomerically enriched phthalides (up to 99% ee).     

Asymmetric double ring-opening of a C(2h)-symmetric bis-epoxide: improved enantiomeric excess of the product through enantioselective desymmetrisation and 'proof-reading' steps

A new strategy in asymmetric synthesis is described in which the desymmetrisation of a C(2h)-symmetric molecule is followed by a subsequent enantioselective 'proof-reading' step. The double asymmetric ring-opening of the bis-epoxide (1R*,3R*,5S*,7S*)-4,8-dioxa-tricyclo[5.1.0.0(3,5)]octane with azidotrimethylsilane, catalysed by a chiral chromium Salen catalyst, was studied. The reaction involves the initial asymmetric ring-opening of the bis-epoxide to give the intermediate in moderate enantiomeric excess (ca. 50% ee); the second ring-opening step yields the required diazido diol, (1S,3S,4S,6S)-4,6-diazidocyclohexane-1,3-diol, in 72% yield and 70% ee. The origin of proof reading stems from the diversion of the minor enantiomer of the intermediate to a centrosymmetric by-product, a process which improves the enantiomeric excess of the required product. Using alternative conditions, the reaction was optimised to yield the required product in >98% ee.     

Chiral Lewis base promoted trichlorosilane reduction of ketimines. An enantioselective organocatalytic synthesis of chiral amines

The reduction of the carbon-nitrogen double bond is an important transformation. Here we report our studies on a family of chiral organic catalysts able to promote the stereoselective reduction of ketimines with trichlorosilane. The very cheap, metal-free catalysts were easily prepared in one step from commercially available products, namely a chiral aminoalcohol and picolinic acid derivatives. The catalyst structure was extensively modified in a study that allowed to identify an extremely active species, able to promote the reduction on a large variety of substrates with high efficiency (up to 95% ee). A three component methodology has been also developed, where the enantiomerically enriched amine was isolated after performing the reaction by mixing a ketone and an amine in the presence of trichlorosilane and the catalyst. Its synthetic potentiality was demonstrated by employing the present metal-free catalytic procedure in the preparation of (S)-metolachlor, a potent and widely used herbicide.     

化学酶法合成光学纯亮氨酸

用化学酶法合成L-亮氨酸，先在PdCl2/PPh3/LiBr/H2SO4催化体系作用下，异戊醛酰胺羰基化合成消旋的N-乙酰基亮氨酸；然后在酰基转移酶催化下水解，得到L-亮氨酸和N-乙酰基-D-亮氨酸．文中对酰胺羰基化反应条件进行了优化，分离得到消旋N-乙酰基亮氨酸产率为66．4％．经酶对映选择地水解后得L-亮氨酸，产率为41％，产物L-亮氨酸经衍生化后由气相色谱测定其光学纯度达99％ee．     

Reaction development and mechanistic study of a ruthenium catalyzed intramolecular asymmetric reductive amination en route to the dual Orexin inhibitor Suvorexant (MK-4305)

The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the treatment of sleep disorders. This challenging transformation is mediated by a novel Ru-based transfer hydrogenation catalyst that provides the desired diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO(2), produced as a necessary byproduct of this transfer hydrogenation reaction, has pronounced effects on the efficiency of the Ru catalyst, the form of the amine product, and the kinetics of the transformation. A simple kinetic model explains how product inhibition by CO(2) leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO(2) on reaction rates and product isolation can be overcome by purging CO(2) from the system. Moreover, the rate of ketone hydrogenation can be greatly accelerated by purging of CO(2) or trapping with nucleophilic secondary amines.