Absolute Asymmetric Synthesis Research Articles

A Different Approach to Enantioselective Organic Synthesis: Absolute Asymmetric Synthesis of Organometallic Reagents

Voilà, optical activity: Both enantiomers of 1-chloroindene have been synthesized in high selectivity from solely achiral starting materials, and without using optically active catalysts (see scheme). These symmetry-breaking syntheses provide a proof-of-concept for a new approach to asymmetric synthesis. NCS=N-chlorosuccinimide.

A Different Approach to Enantioselective Organic Synthesis: Absolute Asymmetric Synthesis of Organometallic Reagents

AbstractVoilà, optisch aktiv: Beide Enantiomere von 1‐Chlorinden wurden ausgehend von durchweg achiralen Ausgangsmaterialien und ohne die Verwendung optisch aktiver Katalysatoren mit hoher Selektivität synthetisiert (siehe Schema). NCS=N‐Chlorsuccinimid.magnified image

Total spontaneous resolution of nine-coordinate complexes

Because Na5[Dy(oda)3](H2O)6(BF4)2 (oda = oxodiacetate) (1a), Na5[Er(oda)3](H2O)6(BF4)2 (1b) and Na5[Pr(oda)3](H2O)6(BF4)2 (1c) all crystallise in a Sohncke space group (R32), absolute asymmetric synthesis has been possible; we have obtained an optically active crystal batch of eg1b without using chiral starting materials. Nine-coordinate enantiomers have thus been resolved (without the use of chiral ligands). The crystal structures have been analysed in order to identify factors favouring spontaneous resolution, and two racemic phases of Na3[Gd(oda)3](H2O)6 (2) and Na3NH4[Pr(oda)3](SCN)(H2O)4 (3) were prepared for comparison. The Na+, BF4−, and H2O building blocks in 1a–c result in a chiral network that can transfer stereochemical information between the chiral nine-coordinate [Ln(oda)3]3− anions, ultimately leading to the formation of enantiopure crystals. In the absence of NaBF4 (as in 2), or by the replacement of NaBF4 with NH4SCN (as in 3), neither stereochemical transfer nor spontaneous resolution occurred.

Control of chirality by spontaneous crystallization and absolute asymmetric synthesis in fluid media

Control of chirality by spontaneous crystallization and absolute asymmetric synthesis in fluid media

Why is Ribose the Sugar Component of Nucleic Acids? New Insights into Absolute Asymmetric Synthesis and Absolute Enantioselective Separation

Consequences of a chiral influence consisting of three independent factors orienting molecules are reviewed and discussed. This influence may affect mutual orientation of reacting molecules leading to absolute asymmetric synthesis. It may also exert different orientation of opposite enantiomers relative to a flat surface which can lead to absolute enantioselective separation. Besides the obvious although not trivial possible applicability in organic synthesis, such a process, when applied to a mixture of monosaccharides may have consequences related to the formation of enantiomerically pure ribose under prebiotic conditions. It is shown that α-DL-ribopyranose is the easiest racemic monosaccharide to get separated to enantiomers. Keywords: Asymmetric Synthesis, Ribose, Nucleic Acids, chiral, enantiomers, enantioselective separation, racemic monosaccharide, stereochemistry

Mechanism of Absolute Asymmetric Synthesis and Solid-State CD Spectroscopy of BPOB

1,3-bis(3-phenyl-3-oxopropanoyl)benzene (BPOB) was prepared by Claisen condensation of aceto-phenone and dimethyl isophthalate and characterized by elemental analysis, MS, 1H NMR, UV absorption spectrum, solid-state circular dichroism (CD) spectra, and X-ray single-crystal diffraction. The X-ray crystallographic data indicated that BPOB crystallized in a Sohncke group P212121, UV and 1H NMR showed that the enol tautomer was the most dominant form in solution, and the solid-state CD spectra and repeated recrytallization revealed that the formation of chiral BPOB crystals could be regarded as crystallization-induced asymmetric synthesis.

Absolute asymmetric synthesis from an isotropic racemic mixture of chiral molecules with the help of their laser orientation-dependent selection

We analyzed the absolute asymmetric synthesis (AAS) of enantiomers from an isotropic racemic mixture of chiral molecules, which employs the laser electrodipole interaction, and revealed a set of basic symmetry-based conditions on the parameters of field-molecule interaction. Using these conditions, we developed a novel scenario of the AAS (through selective photodestruction of the enantiomers of a given type) based on the joint action of the strong multicomponent femtosecond and picosecond laser pulses. Key mechanism of this scenario is the partly modified scheme of laser orientation-dependent selection of molecules proposed by us earlier [D. V. Zhdanov et al., JETP 130, 387 (2006)]. Calculations made on example of chiral molecule SiHNaClF show rather high efficiency and stability of the proposed AAS scenario with respect to the parameters of the incident laser pulses and even feasibility of its realization at room temperature.

Demonstration of spontaneous chiral symmetry breaking in asymmetric Mannich and Aldol reactions

Spontaneous symmetry breaking in reactive systems, known as a rare physical phenomenon and for the Soai autocatalytic irreversible reaction, might in principle also occur in other, more common asymmetric reactions when the chiral product is capable to promote its formation and an element of "nonlinearity" is involved in the reaction scheme. Such phenomena are long sought after in chemistry as a possible explanation for the biological homochirality of biomolecules. We have investigated homogeneous organic stereoselective Mannich and Aldol reactions, in which the product is capable to form H-bridged complexes with the prochiral educt, and found by applying NMR spectroscopy, HPLC analysis, and optical rotation measurements 0.3-50.8% of random product enantiomeric excess under essentially achiral reaction conditions. These findings imply a hitherto overlooked mechanism for spontaneous symmetry breaking and, hence, a novel approach to the problem of absolute asymmetric synthesis and could have also potential significance for the conundrum of homochirality.

Large Nonlinear Effect Observed in the Enantiomeric Excess of Proline in Solution and That in the Solid State

How homochiral amino acids and sugars arose out of a presumably prochiral prebiotic environment is a puzzling question, to which many answers have been proposed: for example, absolute asymmetric synthesis with circularly polarized light, photoreactions in chiral crystals, and asymmetric automultiplication with asymmetric autocatalysis, as exemplified by the recent work of Soai et al. There are reports describing a connection between the chirality of amino acids and sugars: Amplification of ee was observed in the aaminoxylation of an aldehyde using proline as catalyst to generate a key intermediate of sugars, while amino acids

Absolute Asymmetric Synthesis and Resolution Mechanism of Chiral cis-bromoamminebis(ethylenediamine)cobalt(III) Bromide

The absolute asymmetric synthesis of the title complexes Λ-(+) D- cis-[CoBr(NH 3)(en) 2]Br 2( 1) and Δ-(-) D- cis-[CoBr(NH 3)(en) 2]Br 2( 2) (en=1,2-ethylenediamine) as well as the improved optical resolution of cis-[CoBr(NH 3)(en) 2]Br 2·2H 2O( 3) are described in detail. The products were characterized by means of elemental analysis, TG-DTA, optical rotation, UV-Vis, and CD spectra. The distribution of enantiomeric excess (ee) of cis-[CoBr(NH 3)(en) 2]Br 2 in the absolute asymmetric synthesis was obtained by the measurements of their CD spectra. It was found that the complete resolution of rac- cis-[CoBr(NH 3)(en) 2]Br 2·2H 2O was achieved by the use of NH 4( d-BCS)(ammonium d-α-bromocamphor-π-sulfonate) or NH 4( l-BCS) while NH 4( dl-BCS) could only be resolved partially by chiral cis-[CoBr(NH 3)(en) 2]Br 2 under the same conditions. It is deduced that there are notable differences in the chiral discrimination of the reciprocal resolution between cis-[CoBr(NH 3)(en) 2]Br 2 and NH 4BCS. In addition, a new “catalysis-crystal induction” mechanism in the preparation of the chiral Co(III) complex is put forward.

Spontaneous absolute asymmetric synthesis in the presence of achiral silica gel in conjunction with asymmetric autocatalysis

An enantiomerically enriched pyrimidyl alkanol with either S or R configurations was obtained stochastically from the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc in the presence of achiral silica gel in conjunction with asymmetric autocatalysis with amplification of chirality.

Absolute enantioselective separation: Optical activity ex machina

The paper describes methodology of using three independent macroscopic factors affecting molecular orientation to accomplish separation of a racemic mixture without the presence of any other chiral compounds, i. e., absolute enantioselective separation (AES) which is an extension of a concept of applying these factors to absolute asymmetric synthesis. The three factors may be applied simultaneously or, if their effects can be retained, consecutively. The resulting three mutually orthogonal or near orthogonal directors constitute a true chiral influence and their scalar triple product is the measure of the chirality of the system. AES can be executed in a chromatography-like microfluidic process in the presence of an electric field. It may be carried out on a chemically modified flat surface, a monolithic polymer column made of a mesoporous material, each having imparted directional properties. Separation parameters were estimated for these media and possible implications for the natural homochirality are discussed.

Determination of the Absolute Stereochemistry and Asymmetric Total Synthesis of Madindolines A (I) and B (II): A Practical Improvement to a Second‐Generation Approach from the First‐Generation.

Determination of the Absolute Stereochemistry and Asymmetric Total Synthesis of Madindolines A (I) and B (II): A Practical Improvement to a Second‐Generation Approach from the First‐Generation.

Mirror-symmetry breaking in the Soai reaction: A kinetic understanding

Kinetic modeling using nonlinear differential equations is proposed to analyze the spontaneous generation of enantiomeric excess in the autocatalytic addition of diisopropylzinc to prochiral pyrimidine carbaldehydes (Soai reaction). Our approach reproduces experimentally observed giant chiral amplification from an initial enantiomeric excess of <10(-6)% to >60%, high sensitivity and positive response to the presence of minute amounts of chiral initiator at concentrations <10(-14) M, and spontaneous absolute asymmetric synthesis from achiral starting conditions. From our numerical simulations using kinetic schemes derived from the Frank model, including stereospecific autocatalysis and mutual inhibition, we have shown that it is possible to reproduce the mirror-symmetry-breaking behavior of the Soai reaction under batch conditions leading to a bimodal enantiomeric product distribution. Mirror-symmetry breaking was found to be resistant to a loss of stereoselectivity up to 30%. While the mutual inhibition between enantiomers seems to originate from the presence of dimerization equilibria, the exact nature of the autocatalytic stereoselective process still remains to be revealed. From the kinetic viewpoint, simple autocatalysis involving monomers as the catalytic species is consistent with all reported experimental effects of the Soai reaction.

Absolute Asymmetric Synthesis of Stereochemically Labile Aldehyde Helicates and Subsequent Chirality Transfer Reactions

Helical complexes formed between aluminum tris(2,6-diphenylphenoxide) (ATPH) and five different aldehydes have been prepared and structurally characterized by X-ray diffraction. It was found that [Al(OC6H3Ph2)3PhCHO] (2), [Al(OC6H3Ph2)3(4-CH3C6H4CHO)] (3), [Al(OC6H3Ph2)3(4-tBuC6H4CHO)] (4), and [Al(OC6H3Ph2)3(p-CH3OC6H4CHO)] (5) all crystallize as conglomerates, while crystals of [Al(OC6H3Ph2)3(o-CH3OC6H4CHO)] (6) are racemic. Supramolecular CH/pi interactions between molecules in crystals of 2-5 that enable stereochemical information to be mediated in three dimensions have been identified and explain the high frequency of conglomerate formation among ATPH helicates. Since 2-5 are stereochemically labile and thus enantiomerize rapidly in solution, the conglomerates can be resolved by crystallization-induced asymmetric transformation. The determination of the enantiomeric excess (ee) in solid samples of stereochemically labile molecules is not trivial, but solid-state CD spectroscopic data, anomalous dispersion data, and the ee values in alkylation reactions all indicate that preferential crystallization of 2-5 yields an essentially enantiopure product. Thus the preparation of 2-5 constitute new examples of absolute asymmetric synthesis. The helical chirality can be transferred (and thus trapped) to alcohols (with ee values of up to 16%) in crystal-to-crystal reactions with achiral organometallic reagents.

N,N′-Dimethyl-N,N′-diphenylethylenediamine

The centrosymmetric title compound, C16H20N2, was synthesized by deprotonation of N,N′-diphenyl­ethyl­enediamine with n-BuLi in tetra­hydro­furan. The coordination geometry around the N atoms is trigonal planar and the conformation about the ethane bond is staggered. The crystal structure displays inter­molecular C—H⋯π inter­actions which give rise to infinite pleated layers extended in the bc plane. The possibility of obtaining an amine that can undergo crystallization-induced asymmetric transformation is discussed. This would enable the preparation of the pure enantiomers by absolute asymmetric synthesis.

Towards absolute asymmetric synthesis. Synthesis and crystal structure of stereochemically labile MCl 2 (M = Co, Ni, Cu, Zn) complexes with diamine ligands

In search for new conglomerates, seven stereochemically labile complexes between MCl 2 (M = Co, Cu, Ni, Zn) and bidentate ligands, the commercially available N, N, N′-trimethylethane-1,2-diamine (trimeda) and the somewhat bulkier N-isopropyl- N, N′, N′-trimethylethane-1,2-diamine (itmeda), have been synthesized and characterized using single crystal X-ray diffraction. The trimeda and itmeda ligands exhibit chirogenic nitrogen centers and may form chiral metal complexes that are candidates for total spontaneous resolution. Copper(II) chloride forms the dimeric meso complexes [{CuCl 2(trimeda)} 2] ( 1) and [{CuCl 2(itmeda)} 2] ( 2), while [CoCl 2(trimeda) 2] ( 3) and [NiCl 2(trimeda) 2] ( 4) exhibit six-coordinate but chiral ( R, R)- and ( S, S)-complexes. Three examples of the chiral target complex, comprising four-coordinate stereochemically labile monomers, was successfully prepared, viz. [NiCl 2(itmeda)] ( 5), [ZnCl 2(itmeda)] ( 6), and [CoCl 2(itmeda)] ( 7). In all seven complexes, the λ-conformation of the five-membered trimeda-metal chelate ring corresponds to the ( S)-configuration at nitrogen, and vice versa. Supramolecular interactions in 3 and 4 form hydrogen-bonded heterochiral ribbons. However, crystals of 5– 7 display homochiral interactions resulting in polar phases. Weak CH–Cl interactions in 5 and 6 form homochiral layers. In 7, interactions form homochiral helices along the a-axis.

Catena-Poly[[(3-acetylpyridine)copper(I)]-μ3-chloro

In the search for ketone complexes suitable for absolute asymmetric synthesis, that is, complexes crystallizing in Sohncke space groups, we have studied complexes between copper(I) halides and acetyl­pyridines. The structure of polymeric [CuCl(3-acpy)]n (3-acpy is 3-acetyl­pyridine, C7H7NO), a compound which was found to form achiral chains crystallizing in a centrosymmetric space group, is reported here. The complex forms ladder-type chains, in which the CuI atom is coordinated by one N atom and three Cl atoms in a tetra­hedral geometry. In the crystal structure, the chains are inter­connected through C—H⋯Cl and C—H⋯O inter­molecular contacts.

Determination of the absolute stereochemistry and asymmetric total synthesis of madindolines A and B: a practical improvement to a second-generation approach from the first-generation

In this report, we describe an efficient, highly convergent, stereocontrolled first total synthesis and a second-generation synthesis of madindolines A 1 and B 2 , potent selective inhibitors of interleukin 6. The key steps include (1) asymmetric oxidative ring-closure reaction of tryptophol 3 to construct a chiral 3a-hydroxyfuroindoline 4 using the modified Sharpless asymmetric epoxidation condition, (2) highly diastereoselective acylation to build up the quaternary carbon center, and (3) intramolecular acylation of ester 32 with allylsilanes to produce the full substituted cyclopentenedione units. Our first synthetic route defines for the first time both their relative and absolute configurations. Moreover, a more efficient second-generation synthesis was designed, which is suitable for gram-scale preparation of these compounds.

Absolute Asymmetric Photocyclization of Isopropylbenzophenone Derivatives Using a Cocrystal Approach Involving Single-Crystal-to-Single-Crystal Transformation

Absolute asymmetric photocyclization of isopropylbenzophenone derivatives was achieved by means of a cocrystal approach. Three chiral salt crystals formed by carboxylic acid derivatives with achiral amines could be prepared by spontaneous crystallization. In the M-crystal of 4-(2,5-diisopropylbenzoyl)benzoic acid with 2,4-dichlorobenzylamine, a twofold helical arrangement occurs in a counterclockwise direction to generate the crystal chirality. Conversely, the clockwise helix exists alone in the P-crystal. Irradiation of the M-crystal at >290 nm caused highly enantioselective Norrish type II cyclization to give the (R,R)-cyclopentenol, (R)-cyclobutenol, and (R)-hydrol in a 6:3:1 molar ratio, resulting in successful absolute asymmetric synthesis, while irradiation at around 350 nm afforded the (R,R)-cyclopentenol as the sole product. The reaction proceeded via single-crystal-to-single-crystal transformation, and therefore the reaction path producing the (R,R)-cyclopentenol could be traced by X-ray crystallographic analysis before and after irradiation.