Enantioselective synthesis induced by chiral organic-inorganic hybrid silsesquioxane in conjunction with asymmetric autocatalysis

5-Pyrimidyl alkanol with up to 96% ee was formed using chiral organic-inorganic hybrid silsesquioxane in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, in conjunction with asymmetric autocatalysis.     

Enantioselective synthesis mediated by chiral crystal of achiral hippuric acid in conjunction with asymmetric autocatalysis

Enantiomorphous crystals composed of achiral hippuric acid, i.e., naturally occurring N-benzoylglycine, have been used successfully as chiral inducers in enantioselective synthesis in combination with asymmetric autocatalysis to afford the product with extremely high enantiomeric excess.     

Enantioselective synthesis induced by tetrathia-[7]-helicenes in conjunction with asymmetric autocatalysis

Highly enantioenriched 5-pyrimidyl alkanol was formed using tetrathia-[7]-helicenes as a chiral initiator in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, in conjunction with asymmetric autocatalysis.     

Enantioselective synthesis of near enantiopure compound by asymmetric autocatalysis triggered by asymmetric photolysis with circularly polarized light

Right- and left-handed circularly polarized light (CPL) has been proposed as one of the origins of homochirality of biomolecules. However, the enantiomeric excess induced by CPL has been only very low (<2% ee). We found the unprecedented example of asymmetric autocatalysis triggered directly by a chiral physical factor, that is, right- and left-handed CPL, leading to a near enantiopure compound. Asymmetric photolysis of racemic pyrimidyl alkanol by r-CPL irradiation followed by asymmetric autocatalysis affords (R)-pyrimidyl alkanol with >99.5% ee. On the other hand, irradiation with l-CPL affords (S)-pyrimidyl alkanol with >99.5% ee. Thus, chiral physical power, such as CPL, in conjunction with asymmetric autocatalysis, provides a highly enantioenriched compound.     

Enantioselective synthesis utilizing enantiomorphous organic crystal of achiral benzils as a source of chirality in asymmetric autocatalysis

Chiral crystals of achiral benzils act as efficient chiral initiators of asymmetric autocatalysis to afford highly enantioenriched pyrimidyl alkanols whose absolute configurations depend upon the enantiomorph of the crystal used in conjunction with asymmetric autocatalysis with amplification of enantiomeric excess.     

Asymmetric synthesis of pyrimidyl alkanol without adding chiral substances by the addition of diisopropylzinc to pyrimidine-5-carbaldehyde in conjunction with asymmetric autocatalysis

Enantiomerically enriched pyrimidyl alkanol with either S or R configuration was obtained stochastically from the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc without adding chiral substances in conjunction with subsequent asymmetric autocatalysis, leading to amplification of the enantiomeric excess.     

The asymmetric power of chiral ligands determined by competitive asymmetric autocatalysis

Asymmetric autocatalytic reactions were initiated by using two competing chiral ligands bearing opposite configurations. The absolute configuration of the resulting highly enantioenriched product reflects the different efficiencies of the two catalysts. Thus, our method provides a simple and efficient way to compare the asymmetric power of chiral ligands for enantioselective catalysis both qualitatively and quantitatively.     

Reflections on spontaneous asymmetric synthesis by amplifying autocatalysis

Spontaneous generation of chirality was observed in the course of studying the mechanism of asymmetric autocatalysis by NMR in ZnR2 alkylation of pyrimidin-5-aldehydes. A systematic study was carried out in order to discover its origins. Even in clean fresh non-glass reaction vessels spontaneous ee was clearly observed, and was not dependent on any single reaction parameter. For comparison it was demonstrated that enantiomerically pure Zn alkoxide catalyst could control the configuration of the reaction product even when present at below micromolar concentrations. The high propensity of the Soai reaction system to produce an enantiomerically enriched product without initial bias is suggested to result from stochastic effects. These are especially important in autocatalysis because all the final products can be derived by breeding from a small number of initial events. The statistical excess of one enantiomer in that set is sufficient to generate a measurable ee in the product. The process is aided by the requirement for dimerisation before the product is an active catalyst. An enumeration that rationalises these observations is provided.     

Enantioselective synthesis of chiral carbocyclic pyrimidine nucleosides via asymmetric cyclopropanation

An efficient method to construct chiral cyclopropyl pyrimidine carbocyclic nucleoside analogues bearing a quaternary center was developed via asymmetric Michael-initiated cyclopropanation. The axis chirality was observed in cyclopropyl pyrimidine carbocyclic nucleoside analogues for the first time, which was caused by the rotationally restricted NC bond in N-COPh moiety. Using (DHQD)₂AQN as the organocatalyst, diverse cyclopropyl pyrimidine carbocyclic nucleoside analogues were generated in 76–93% yields and 73–96% ee.     

Stochastic aspects of asymmetric autocatalysis and absolute asymmetric synthesis

The main goal of the present review is to collect in a unified framework the deterministic and stochastic models of emergence and amplification of chirality by mechanisms such as asymmetric autocatalysis and absolute asymmetric synthesis. Empirical approach and modeling have recently provided a good insight into these phenomena. Our groups in Italy and Hungary have a wide variety of expertise both in fields of experiments and modeling. In the last decade important results have been achieved, however, more experiments and more detailed deterministic and stochastic models are needed for a better understanding of details and significance of asymmetric autocatalysis and absolute asymmetric synthesis.     

Enantioselective synthesis of ring-C aromatic steroids by asymmetric Michael-type alkylation of chiral imines.

Optically active phenanthrones 7 and 12 were prepared, using the asymmetric process involving Michael-type alkylation of chiral imines. Compound 12 was then transformed into the ring-C aromatic steroid 16.     

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.     

Enantioselective synthesis of alpha-substituted ketones by asymmetric addition of chiral zinc enamides to 1-alkenes

A zinc enamide of a chiral imine derived from a ketone and (S)-valinol or (S)-t-leucinol undergoes addition to 1-alkene to generate a gamma-zincioimine intermediate, which reacts with a carbon electrophile to give upon hydrolysis an optically active alpha-substituted ketone in good yield. The stereoselectivity of the addition reaction may reach 99% for the reaction of a cyclohexanone imine with ethylene.     

Enantioselective synthesis of a chiral fluoropiperidine via asymmetric hydrogenation of a vinyl fluoride

Asymmetric hydrogenation of a vinyl fluoride derivative gives efficient access to enantioenriched 1,3,4-trisubstituted piperidine 1 with a stereogenic alkyl fluoride center. Extensive catalyst screening across transition metals and chiral ligands identified only one catalyst, a Rh/Walphos complex, that gives high conversion, enantioselectivity and chemoselectivity for olefin reduction over defluorination. The presence of acid additives in the hydrogenation exerts a profound effect on reaction outcome. The results of deuterium labeling studies demonstrate that significant olefin isomerization accompanies the undesired defluorination side-reaction.     

Enantioselective synthesis of Garner's aldehyde by asymmetric hydroformylation

Both enantiomers of Garner's aldehyde (3) are prepared from the same alkene 4 by catalytic asymmetric hydroformylation.     

Stochastic kinetic models of chiral autocatalysis: a general tool for the quantitative interpretation of total asymmetric synthesis

A continuous time discrete state stochastic kinetic approach is used to study various chiral autocatalytic models in which the possibility of total asymmetric synthesis arises. It is shown that this approach is superior to the deterministic approaches used earlier and is able to interpret many aspects of chiral autocatalysis. First-order autocatalysis, independently of further kinetic details of the system, leads to a unique final statistical distribution of enantiomers. Higher order autocatalysis, on the other hand, leads to a final state where one of the enantiomers is in overwhelming excess over the other. Criteria are postulated to differentiate between inherently stochastic phenomena in chiral autocatalytic reactions and irreproducibility because of insufficient control of external factors.