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.     

Achiral Inorganic Gypsum Acts as an Origin of Chirality through Its Enantiotopic Surface in Conjunction with Asymmetric Autocatalysis

Achiral inorganic gypsum (CaSO₄⋅2 H₂O) triggers the asymmetric autocatalysis of pyrimidyl alkanol on its two‐dimensional enantiotopic faces to give highly enantioenriched alkanol products with absolute configurations corresponding to the respective enantiotopic surfaces. This is the first example of highly enantioselective synthesis on the enantiotopic surface of an achiral mineral.     

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.     

Regio- and Enantioselective Prenyl Anion Transfer: Application to the Total Synthesis of (−)-Rosiridol

At elevated temperature (refluxing THF) prenyl anion adds regio- and enantioselectively to aldehyde 1 when a chiral, borneol-derived ligand is present. This reaction is the key stepin the first total synthesis of the monoterpene (−)-rosiridol (retrosynthesis is shown on the right). In addition, the absolute configuration of this natural product has been assigned conclusively. M=Zn, R=tBuMe₂Si.     

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.     

Absolute Asymmetric Synthesis in Enantioselective Autocatalytic Reaction Networks: Theoretical Games,Speculations on Chemical Evolution and Perhaps a Synthetic Option

The Soai reaction and the Viedma deracemization of racemic conglomerate crystal mixtures are experimental pieces of evidence of the ability of enantioselective autocatalytic coupled networks to yield absolute asymmetric synthesis. Thermodynamically open systems or systems with non‐uniform energy distributions may lead to chiral final states and, in systems able to come into thermodynamic equilibrium with their surroundings, to kinetically controlled absolute asymmetric synthesis. The understanding of network parameters and of the thermodynamic scenarios that may lead to spontaneous mirror symmetry breaking (SMSB) could assist in the development of new methods for asymmetric synthesis and enantioselective polymerizations (e.g., replicators), and to frame reasonable speculations on the origin of biological homochirality.     

Absolute Asymmetric Synthesis of Enantiopure Organozinc Reagents,Followed by Highly Enantioselective Chlorination

We report the absolute asymmetric synthesis (AAS) of indenylzinc reagents by using total spontaneous resolution followed by enantiospecific conversion into 1‐chloroindene. The chiral complex [Zn(dcp)(ind)(tmeda)] (dcp=2,6‐dichlorophenoxy and tmeda=N,N,N′,N′‐tetramethylethylenediamine) ( 3 ) was prepared from the achiral starting materials indene, potassium, zinc chloride, TMEDA, and 2,6‐dichlorophenol. The reagent resolved spontaneously on crystallization, and single crystals of 3 react with N‐chlorosuccinimide in the presence of benzoquinone in 2‐propanol to give 1‐chloroindene in >98 % enantiomeric excess. It was found that (R)‐ 3 gave (R)‐1‐chloroindene upon reaction, indicating an S_E2′‐mechanism. Since bulk samples of 3 gave optically active product upon chlorination, total spontaneous resolution must have occurred. This demonstrates that enantiopure products can be obtained through the absolute asymmetric synthesis of organometallic reagents starting from achiral materials. The general absolute asymmetric synthesis (AAS) method offers easy access to both enantiomers and an almost limitless variation in the design of the product.     

A few molecules can control the enantiomeric outcome. Evidence supporting absolute asymmetric synthesis using the Soai asymmetric autocatalysis

[reaction: see text] Experiments were carried out to investigate whether the Soai asymmetric autocatalysis can accomplish true absolute asymmetric synthesis. In 54 reactions, R and S enantiomeric products were obtained 27 times each. Of 25 pairs of side-by-side identical reactions, 12 afforded opposite enantiomers. In a test of the mechanistic viability of a random-chance process, it was found that a very few molecules (approximately 60 000) were sufficient to control the enantiomeric outcome of these reactions. These observations appear most consistent with asymmetric synthesis originating from the chance enantiomeric excess in a racemate.     

An RCM‐Based Total Synthesis of the Antibiotic Disciformycin B

The total synthesis of the potent new antibiotic disciformycin B ( 2 ) is described, which shows significant activity against methicillin‐ and vancomycin‐resistant Staphylococcus aureus (MRSA/VRSA) strains. The synthetic route is based on macrocyclization of a tetraene substrate to the 12‐membered macrolactone core by ring‐closing olefin metathesis (RCM). Although macrocyclization was accompanied by concomitant cyclopentene formation by an alternative RCM pathway, conditions were established to give the macrocycle as the major product. Key steps in the construction of the RCM substrate include a highly efficient Evans syn‐aldol reaction, the asymmetric Brown allylation of angelic aldehyde, and the stereoselective Zn(BH₄)₂‐mediated 1,2‐reduction of an enone. The synthesis was completed by late‐stage dehydrative glycosylation to introduce the d ‐arabinofuranosyl moiety and final chemoselective allylic alcohol oxidation.     

Facile synthesis of 3-substituted indoles containing highly polarized double bonds

In this paper, an effective procedure is described for the synthesis of novel indoles containing highly polarized double bonds. The strategy involves the preparation of (indolylmethyl)malononitriles via the one-pot three-component reaction of an aldehyde, malononitrile and indole in the presence of Zn(OAc)₂/NaOAc under silent and ultrasonic conditions. The reaction further proceeds through oxidative elimination under solvent-free conditions in the presence of Ca(OCl)₂ to furnish indolylacrylonitriles in high yields and short reaction times.     

The stereoselective synthesis of α-substituted β-amino secondary alcohols based on the proline-mediated, asymmetric, three-component Mannich reaction and its application to the formal total synthesis of nikkomycins B and Bx

A general method for the asymmetric synthesis of α-substituted β-amino secondary alcohols is described, which comprises the four-reaction sequence (1) the proline-mediated, asymmetric, three-component Mannich reaction of two different aldehydes, (2) nucleophilic carbon addition to aldehyde, (3) oxidation of the resulting alcohol to the corresponding ketone, and (4) diastereoselective reduction with LiAlH(O-t-Bu)₃ or catecholborane. The former reductant afforded the 1,2-syn isomer, while the latter gave the 1,2-anti isomer stereoselectively. The present method was successfully applied to the efficient asymmetric synthesis of the N-terminal amino acid moiety of nikkomycin B and B_X.     

Synthesis and catalytic applications of soluble polymer-supported BINOL

The synthesis of a soluble polymer containing BINOL residues is described. Titanium-BINOLate and AlLibis(binaphthoxide) catalysts are easily generated from this polymer and applied to the asymmetric reaction of Et₂Zn with benzaldehyde and the asymmetric Michael addition, respectively. The products are obtained in good yields with high enantioselectivities.     

Preparation of Polyfunctional Arylzinc Organometallics in Toluene by Halogen/Zinc Exchange Reactions

A wide range of polyfunctional diaryl‐ and diheteroarylzinc species were prepared in toluene within 10 min to 5 h through an I/Zn or Br/Zn exchange reaction using bimetallic reagents of the general formula R′₂Zn?2 LiOR (R′=sBu, tBu, pTol). Highly sensitive functional groups, such as a triazine, a ketone, an aldehyde, or a nitro group, were tolerated in these exchange reactions, enabling the synthesis of a plethora of functionalized (hetero)arenes after quenching with various electrophiles. Insight into the constitution and reactivity of these bimetallic mixtures revealed the formation of highly active lithium diorganodialkoxyzincates of type [R′₂Zn(OR)₂Li₂].     

Absolute Asymmetric Synthesis: Viedma Ripening of [Co(bpy)3]2+ and Solvent‐Free Oxidation to [Co(bpy)3]3+

Syntheses of [Co(bpy)₃]²⁺ yield racemic solutions because the Δ‐ and Λ‐enantiomers are stereochemically labile. However, crystallization and attrition‐enhanced deracemization can give homochiral crystal batches of either handedness in quantitative yield. Subsequently, solvent‐free oxidation with bromine vapour fixes the chirality because [Co(bipy)₃]³⁺ does not enantiomerize in solution at ambient temperature. This combination of Viedma ripening and the labile/inert Co^II/Co^III couple constitutes a convenient method of absolute asymmetric synthesis.     

Synthesis of Recyclable Fluorous Chiral Ligands and Evaluation of Their Catalytic Activity toward Asymmetric Addition of Dimethylzinc to Aldehydes

The asymmetric addition of Me₂Zn to aldehydes is very slow and mostly gives low ee values. Previously, we reported the synthesis of a fluorous chiral ligand, (4R,5S,α′R)‐2,2‐dimethyl‐α,α,α′‐tris(perfluorooctyl)‐2,3‐dioxolane‐4,5‐dimethanol ( 1 a ), derived from tartarate as a chiral pool. Ligand 1 a showed high activity toward the addition of Me₂Zn to aldehydes with high enantiomeric excess. However, the very high content of fluorine makes 1 a difficult to dissolve in common solvents; hence, much solvent is required, which limits its use. This report describes the modification of 1 a by replacing either the perfluorooctyl groups with shorter perfluoroalkyl ones or the acetone ketal part with cyclohexanone ketal. The perfluorobutyl analogue 1 c is much more soluble than 1 a and shows comparable asymmetric induction toward the addition of Me₂Zn to aldehydes. Furthermore, 1 c has a much lower molecular weight than 1 a . This means that 1 c is used in smaller amounts (weight) than 1 a . The cyclohexanone ketal analogue 1 d is more soluble than 1 a and more easily synthesized owing to its high solubility and ease of crystallization. Ligand 1 d showed much higher asymmetric induction toward cyclohexanecarbaldehyde, a branched aldehyde, than 1 a . Thus, 1 a was modified into ligands with higher performance.     

Synthesis of 4,4′-biquinazoline alcohols as chiral catalysts in enantioselective alkynylation of aldehydes with phenyl acetylene

Optically active propargylic alcohols are important chiral-building blocks in asymmetric synthesis, while the asymmetric addition of a terminal alkyne to an aldehyde is one of the most important procedures to prepare these chiral-building blocks. In this work, a family of chiral 4,4′-biquinazoline alcohols has been conveniently prepared from the easily accessible (S)-2-acetoxycarboxylic acid chlorides by reaction sequences beginning with condensation and followed by key synthetic steps including chlorination, nickel(0)-mediated homocoupling, and deprotection in addition to being examined as potential ligands in the enantioselective addition of phenylacetylene to aldehydes. These chiral ligands can be combined with Ti(OiPr)₄ and then used to catalyze the asymmetric addition of zinc acetylide, produced in situ by the reaction of phenylacetylene with diethylzinc, to aldehydes. The best enantiomeric excess obtained in this study was 75%.     

Absolute stereochemistries and total synthesis of (+)-arisugacins A and B, potent, orally bioactive and selective inhibitors of acetylcholinesterase

In the current studies, we used the Kakisawa-Kashman modification of the Mosher NMR method to determine the complete absolute stereochemistry of arisugacins. We also report the convergent total synthesis of (+)-arisugacins A and B by a sequence including (i) ruthenium complex-catalyzed asymmetric reduction of the cyclohexenone derivative; (ii) stereoselective construction of the arisugacin skeleton by a Knoevenagel-type reaction of an α,β-unsaturated aldehyde derivative with production of a 4-hydroxy-2-pyrone derivative as a key reaction; and (iii) stereoselective dihydroxylation to give the diol derivative, followed by deoxygenation. Accordingly, we defined the absolute structures of arisugacins A and B as 4a-(R),6a-(R),12a-(R), and 12b-(S). Finally, we characterized the bioactivities of the synthetic intermediates to understand the structure-activity relationships of the arisugacins.     

Synthetic studies on statins. Part 1: a short and cyanide-free synthesis of atorvastatin calcium via an enantioselective aldol strategy

A short and cyanide-free enantioselective synthesis of atorvastatin calcium has been achieved starting from a commercially available highly substituted 1,4-diketone in an overall yield of 40%. The key step in this approach is the asymmetric aldol reaction of an aldehyde with diketene in the presence of Ti(O-i-Pr)₄–Schiff base complex to create the (5R)-stereochemistry of atorvastatin calcium.     

The stereoselective total synthesis of (+)-18-(6S,9R,10R)-bovidic acid

An expedient stereoselective total synthesis of 18-carbon (+)-(6S,9R,10R)-bovidic acid, isolated from the pelage and skin of a gaur B. frontalis is described using l-proline catalysed sequential α-aminoxylation and Horner-Wadsworth-Emmons olefination of aldehyde, cross metathesis and tandem Sharpless asymmetric dihydroxylation-S_N2 cyclization reaction as the key steps.     

Practically Perfect Asymmetric Autocatalysis with (2‐Alkynyl‐5‐pyrimidyl)alkanols

Extremely high enantioselectivity (>99.5% ee) and chemical yield (>99%) are achieved in an asymmetric autocatalytic reaction. A (5‐pyrimidyl)alkanol with a tert‐butylethynyl group at its 2‐position ( 1 ) is a very efficient asymmetric autocatalyst in the enantioselective alkylation in Equation (1).