Chiral Initiators Research Articles

Enantioselective synthesis induced by chiral epoxides in conjunction with asymmetric autocatalysis

5-Pyrimidyl alkanol with an enantiomeric excess of up to 96% was formed using chiral epoxides as a chiral initiator in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, in conjunction with asymmetric autocatalysis.

Asymmetric anionic polymerization of optically active N‐1‐cyclohexylethylmaleimide

AbstractChiral (S)‐(−)‐N‐1‐cyclohexylethylmaleimide [(S)‐CEMI] and (R)‐(+)‐N‐1‐cyclohexylethylmaleimide [(R)‐CEMI] were synthesized successfully and then polymerized with chiral complexes of (−)‐sparteine or (S,S)‐(1‐ethylpropylidene)bis(4‐benzyl‐2‐oxazoline) [(S,S)‐Bnbox] and organometal as initiators in toluene or tetrahydrofuran to obtain optically active polymers. The effects of the polymerization conditions on the optical activity and structure of poly(N‐1‐cyclohexylethylmaleimide)s were investigated with gel permeation chromatography, circular dichroism, specific rotation, and 13C NMR measurements. Poly[(R)‐CEMI] obtained with dimethylzinc (Me2Zn)/(S,S)‐Bnbox had the highest specific rotation ([α]435 = +323.7°). Complexes of Bnbox and diethylzinc or Me2Zn were used very effectively as chiral initiators for the asymmetric anionic polymerization of (S)‐CEMI and (R)‐CEMI. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4682–4692, 2004

Asymmetric anionic polymerization of 2,6‐dimethyl‐7‐phenyl‐1,4‐benzoquinone methide

AbstractAsymmetric anionic polymerizations of 2,6‐dimethyl‐7‐phenyl‐1,4‐benzoquinone methide (1) were performed with various chiral anionic initiators, and the specific rotations of the obtained polymers were investigated. Optically active poly(1)s with configurational chirality were obtained with all the initiators, and a complex of fluorenyllithium (FlLi) with (−)‐sparteine [(−)‐Sp] produced poly(1) with the largest negative specific rotation ([α]435 = −26.8°). The specific rotations of poly(1)s obtained with FlLi/(−)‐Sp depended on the initiator concentration and the solvent polarity. The maximum specific rotations were obtained at an almost constant initiator concentration (ca. 0.03 mol/L), regardless of the monomer concentration, in toluene, whereas a higher initiator concentration was required in more polar solvents. These results suggested that the aggregation state of the propagating chain end significantly affected the specific rotation of poly(1). © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4548–4555, 2004

Discovery and Development of Asymmetric Autocatalysis

Abstract Asymmetric autocatalysis occurs when a chiral product operates as an asymmetric catalyst for its own production. We have discovered an asymmetric autocatalytic reaction in the enantioselective addition of dialkylzinc to pyridine-3-carbaldehyde, where the product, 3-pyridyl alkanol, acts as an asymmetric autocatalyst. A diol, ferrocenyl alkanol, 5-pyrimidyl alkanol, and 3-quinolyl alkanol were also found to be asymmetric autocatalysts for the enantioselective isopropylation of the corresponding aldehydes. Of these compounds, 5-(2-alkynyl)pyrimidyl alkanol was the best asymmetric autocatalyst, and the asymmetric autocatalytic isopropylation of the corresponding pyrimidine-5-carbaldehyde proceeded quantitatively ( >99%), affording itself as a near enantiomerically pure ( >99.5% ee) chiral product. When an asymmetric autocatalyst with an extremely low ee was used, the asymmetric autocatalytic reaction proceeded along with amplification of the ee, and a highly enantiomerically enriched product was obtained. When the enantioselective isopropylation of pyrimidine-5-carbaldehydes was examined in the presence of chiral organic compounds with a very low ee acting as chiral initiators, then highly enantiomerically enriched 5-pyrimidyl alkanols were obtained. Their absolute configurations were dependent upon the slight excess of enantiomer in the chiral initiators. Chiral inorganic crystals, such as quartz and sodium chlorate, also act as chiral initiators. In conjunction with asymmetric autocatalysis, the chirality of organic compounds with a high enantiomeric excess has been correlated for the first time with the circularly polarized light and chiral inorganic crystals. Moreover, when an enantioselective isopropylation was examined in the absence of a chiral initiator, asymmetric induction above the detection level was observed in the product, with the ratio of the resulting predominant S- and R-isomers being almost equal. This result fulfills one of the conditions necessary for spontaneous absolute asymmetric synthesis.

Highly enantioselective asymmetric autocatalysis induced by chiral ionic crystals of sodium chlorate and sodium bromate

Chiral crystals of sodium chlorate and sodium bromate induced highly enantioselective organic synthesis in combination with asymmetric autocatalysis. (S)-5-Pyrimidyl alkanols with up to 98% ee were obtained in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehydes in the presence of d-sodium chlorate. On the other hand, (R)-5-pyrimidyl alkanols with up to 98% ee were obtained for the corresponding reaction in the presence of l-sodium chlorate. Chiral crystals of d- and l-sodium bromate were also found to work as chiral initiators.

Stereocontrolled polymerization of racemic lactide with chiral initiator: combining stereoelection and chiral ligand-exchange mechanism.

New opportunities, provided by the 2,2'-[1,1'-binaphthyl-2,2'-diylbis(nitrylomethilidyne)]diphenol (SB(OH)2)/Al(OiPr)3/racemic lactide (rac-LA) polymerization system, employing a combination of stereoelection with (S) and (R) ligand-exchange mechanism at Al-alkoxide active centers were explored. The stereoelectivity was comparable to that determined for the process with an additional synthetic step of isolation and purification of the SBO2Al-OiPr alkoxide. The resultant poly(rac-LA) had a gradient stereocopolymer structure and exhibited enhanced thermal stability due to a stereocomplex formation (Tm = 210 degrees C). This is the highest melting temperature reported until now for poly(lactide) (PLA) prepared directly from rac-LA.

不斉触媒および反応場の設計に基づく高エナンチオ選択的不斉合成反応の研究

Highly enantioselective asymmetric syntheses, i.e., enantioselective addition of alkylmetal reagents to aldehydes and imines, enantioselective conjugate addition of dialkylzincs to enones, and asymmetric autocatalysis have been developed by designing asymmetric catalysts (or chiral ligands) and chiral environment of the reactions. Automultiplication of chiral compounds by asymmetric autocatalysis was discovered where a chiral product acts as a chiral catalyst for its own production. Asymmetric autocatalysis with>99.5% ee in a yield of > 99% was attained using pyrimidyl alkanol as an asymmetric autocatalyst in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde. The asymmetric autocatalysis exhibits significant positive non-linear effect on ee. Asymmetric autocatalyst with very low (ca. 0.00005%) ee enhances its ee significantly up to > 99.5% ee during the consecutive asymmetric autocatalysis without the assistance of any other chiral auxiliary. Moreover, amino acids and [6] helicene with very low ee which are produced by asymmetric photolysis and photosynthesis using circularly polarized light serve as chiral initiators of asymmetric autocatalysis, and pyrimidyl alkanol with high ee is obtained. Inorganic chiral crystals such as quartz and sodium chlorate, [2.2] paracyclophanes, allenes, chiral cobalt complexes due to the topology of coordination, chiral primary alcohols due to the deuterium substitution also work as chiral initiators. Asymmetric autocatalysis is capable to discriminate efficiently the chirality of various chiral compounds. Moreover, the reactions of pyrimidinecarbaldehyde with diisopropylzinc without adding chiral substance exhibit the formation of enantioenriched S or R pyrimidyl alkanols with approximate stochastic distribution, which indicates the reaction is a spontaneous absolute asymmetric synthesis. These results correlate for the first time the proposed origins of chirality of organic compounds with the chirality of organic compounds with very high ee.

Asymmetric Polymerization of N-ortho- or para-Substituted Phenylmaleimide Using Chiral Anionic Initiators

N-Phenylmaleimide (PhMI) and its derivatives were polymerized using chiral anionic initiators consisting of diethylzinc (Et2Zn) and chiral ligands to investigate the effect of the bulkiness, flexibility and polarity of the ortho- or para-substituents on optical activity of the obtained polymer. The optical activity of the polymer was extremely influenced by N-substituents, initiators, and other polymerization conditions. Poly(N-2-biphenylmaleimide) (poly(2-BPMI)) formed with Et2Zn-(–)-2,2’-(1-ethylpropylidene)bis(4-benzyl-2-oxazoline) (Bnbox) showed the highest specific rotation ([α]25435) of +164.7 °. From 13C NMR spectroscopy, optically active poly(2-BPMI) and poly(N-(2-phenoxy)-phenylmaleimide) (poly(2-POPMI)) mainly possessed threo-diisotactic structures in the main chains. Chiral stationary phase prepared from optically active poly(PhMI) optically resolved racemic 1,1’-bi-2-naphthol.

Asymmetric Autocatalysis and Its Application to Chiral Discrimination

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric autocatalysis induced by chiral hydrocarbon [2.2]paracyclophanes.

Chiral hydrocarbon [2.2]paracyclophanes act as chiral initiators in asymmetric autocatalysis in the addition of diisopropylzinc to pyrimidine-5-carbaldehyde and give highly enantiomerically enriched 5-pyrimidyl alkanol with a reversed sense of the enantioselectivity to that of other [2.2]paracyclophanes with heteroatoms.

Asymmetric Automultiplication of Chiral Compounds by Asymmetric Autocatalysis

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly Enantioselective Asymmetric Autocatalysis of Pyrimidin-5-yl Alkanol Induced by Chiral 1,3-Disubstituted Hydrocarbon Allenes

1,3-Disubstituted chiral allenes without any heteroatoms act as chiral initiators in the addition of (i-Pr)2Zn to pyrimidine-5-carbaldehyde to afford, in combination with the subsequent asymmetric autocatalysis, chiral pyrimidin-5-yl alkanols with up to 98% ee. The absolute configuration of the pyrimidin-5-yl alkanol formed depend on that of the chiral allene.

Asymmetric Autocatalysis of Pyrimidyl Alkanol Induced by Optically Active 1,1′-Binaphthyl, an Atropisomeric Hydrocarbon, Generated from Spontaneous Resolution on Crystallization

Abstract An atropisomeric hydrocarbon, (R)-1,1′-binaphthyl, acts as a chiral initiator of asymmetric autocatalysis of pyrimidyl alkanol in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde to afford (S)-5-pyrimidyl alkanol 2 with 96% ee. On the other hand, in the presence of (S)-1,1′-binaphthyl, the reaction affords (R)-2 with 94% ee.

不斉自己触媒反応によるキラル化合物の不斉自己増殖

Asymmetric automultiplication of chiral compounds by asymmetric autocatalysis is realized for the first time where a chiral product acts as a chiral catalyst for its own production. Practically perfect asymmetric autocatalysis (>99%, >99.5% ee) is attained using pyrimidyl alkanol as an asymmetric autocatalyst in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbalde-hyde. Moreover, asymmetric autocatalyst with very low ee enhances its ee significantly up to >99.5% ee during the automultiplication without the assistance of any other chiral auxiliaries. Amino acids and [6] helicene with very low ee which are produced by asymmtric photolysis and photosynthesis using circularly polarized light (CPL) serve as chiral initiators of asymmetric auto-catalysis, and pyrimidyl alkanol with high ee is obtained. Inorganic chiral crystals such as quartz and sodium chlorate also work as chiral initiators. These results correlate for the first time the proposed origins of chirality of organic compounds such as CPL and quartz with the chirality of organic compounds with very high ee.

Asymmetric autocatalysis and its application to chiral discrimination

Chiral pyrimidyl, quinolyl, and pyridyl alkanols act as asymmetric autocatalysts with significant amplification of enantiomeric excess (ee) in the enantioselective addition of diisopropylzinc to pyrimidine-5-, quinoline-3-, and pyridine-3-carbaldehydes, respectively. 2-Alkynyl-5-pyrimidyl alkanol with as low as 0.6% ee automultiplies during the consecutive asymmetric autocatalysis with increasing ee to as high as >99.5%. Asymmetric autocatalysis is applied to chiral discrimination of organic compounds. In the presence of methyl mandelate or 2-butanol with very low ee's (0.05-0.1%) as chiral initiators, the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc affords pyrimidyl alkanol with higher ee's with the correlated absolute configurations to those of the chiral initiators. Chirality of amino acids (such as leucine) and helicenes with very low ee's are also discriminated by asymmetric autocatalysis, affording pyrimidyl alkanol with very high ee's. Asymmetric autocatalysis also discriminates the chirality of primary alcohols-alpha-d, monosubstituted [2.2]paracyclophanes and octahedral cobalt complex with achiral ligands of which the chirality is due to the topology of coordination of the achiral ligand. Even the chirality of inorganic crystals such as quartz and sodium chlorate is discriminated by asymmetric autocatalysis of pyrimidyl alkanol. Thus, asymmetric autocatalysis provides a unique method for the discrimination of chiral compounds and crystals.

Asymmetric Polymerization of N-1-Naphthylmaleimide with Chiral Anionic Initiator: Preparation of Highly Optically Active Poly(N-1-naphthylmaleimide)

Asymmetric anionic homopolymerizations of N-1-naphthylmaleimide (1-NMI) were carried out with chiral anionic initiator consisting of diethylzinc (Et2Zn) and (4S)-2,2‘-(1-ethylpropylidene)bis(4-benzyl-4,5-dihydrooxazole) (Bnbox) to obtain optically active polymers. Poly(1-NMI) obtained with diethylzinc (Et2Zn)−Bnbox complex in THF exhibited high specific optical rotation of +296.6°. The high molecular weight part of the poly(1-NMI) resolved by gel permeation chromatography (GPC) showed the highest specific optical rotation of +762.3°. Optical activity of poly(1-NMI) with high specific optical rotation was attributed to not only configurational chirality due to asymmetric carbons in the polymer main chain but also a conformational one based on higher-order structures, i.e., partial helical conformation, judging from the dependence of specific optical rotation on temperatures and molecular weights.

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.

Asymmetric autocatalysis of a pyrimidyl alkanol induced by chiral monosubstituted [2.2]paracyclophanes.

[figure: see text] Monosubstituted[2.2]paracyclophanes 3a-c with planar chirality were found to act as chiral initiators in an enantioselective addition of diisopropylzinc to 2-alkynylpyrimidine-5-carbaldehyde 1 to afford 2-alkynylpyrimidyl alkanol 2 with up to 97% ee.

Synthesis and asymmetric polymerization of a series of methyl-substituted triphenylmethyl methacrylate

Five novel ortho-, meta-, and para-methyl-substituted triphenylmethyl methacrylate monomers, such as o-tolyldiphenylmethyl methacrylate (o-MeTrMA), di-o-tolylphenylmethyl methacrylate (o-Me2TrMA), tris-o-tolylmethyl methacrylate (o-Me3TrMA), tris-m-tolylmethyl methacrylate (m-Me3TrMA), and tris-p-tolylmethyl methacrylate (p-Me3TrMA) have been synthesized. The methanolysis rates of these monomers were measured in CDCl3-CD3OD (1:1, v/v) by 1H NMR spectroscopy at 30 °C. It was found that the order of the methanolysis rates would be TrMA<o-MeTrMA<o-Me2TrMA<o-Me3TrMA<m-Me3TrMA except p-Me3TrMA, which exhibited very good stability to methanolysis. The asymmetric polymerization of these monomers was investigated by chiral anionic complexes as initiators. The results showed that the ability to form a helical chain was effected not only by the types of chiral complex initiators, but also by the position and number of methyl-substituted groups at the benzene rings of TrMA. The order of the ability of polymerization was o-MeTrMA >o-Me2TrMA>o-Me3TrMA and m-Me3TrMA> p-Me3TrMA>o-Me3TrMA. These differences would be attributed to the different sizes and “propeller” steric structures of the bulky side groups. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 430–436, 2001

Vertebrate left and right: Finally a cascade, but first a flow?

Vertebrate development gives rise to systematic, normally reliably coordinated left-right asymmetries of body structure. This “handed asymmetry” of anatomy must take its ultimate origin from some chiral molecular assembly (one exhibiting no planes of symmetry and thus, having an intrinsic “handedness”) within the early embryo's cells. But which molecules are involved, how is their chiral property coordinately aligned among many cells, and how does it “seed” the differential cascades of gene expression that characterise right and left halves of the embryo? Recent molecular characterisations of mouse mutations that randomise or reverse body asymmetries have offered tantalising clues to the chiral initiator molecules, but the findings in a subsequent Cell paper (Nonaka S, Yosuke T, Okada Y, Takeda S, Harada K, Kanai Y, Kido M, Hirokawa N. Randomisation of left-right asymmetry due to loss of nodal cilia generating a leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 1998;95:829–837. [Reference 1]) may help us understand how the first gene expression asymmetries occur. BioEssays 21:537–541, 1999. © 1999 John Wiley & Sons, Inc.