Isomerism enantiopure preparation

There are few examples of isomerization of achiral unfunctionalized olefins into enantiomerically enriched olefins. The most successful is the transformation of meso,trans-4-tert-butyl-l-vinylcyclohexane (1) into the corresponding alkene (S)-2 (Scheme 1) [6]. When a C2-symmetric titanocene catalyst, which can easily be prepared in three steps from enantiopure starting material, is used in the presence of LiAlH4 as activator the product is obtained in 80% ee. The rate of the reaction and the optical purity of the product are highly dependent on reaction temperature. The lower enantiomeric purity obtained at higher temperatures is apparently because of racemization by equilibration of the product, a process which is promoted by longer reaction times. 

The number of enzymes for industrial synthetic applications is growing fast. Enzymatic synthesis can be performed under mild reaction conditions so that many problems of chemical synthesis like isomerization orracemization can be prevented. Furthermore, enzymes are highly specific and selective, especially for enantio- or regio-selective introduction of functional groups. For the preparation of chiral enantiopure compounds, the resolution of racemic mixtures by hydrolases is a well-established route, which has the advantage to be able to use enzymes free of coenzymes. Otherwise, only a maximum yield of 50% can be reached by the primary reaction and further steps of reracemization must follow to avoid loss of the undesired enantiomer. 

We obtained some preliminary results in the isomerization of the benzyUm-ine derivative 39 to benzylidene derivative 40. The catalyst solution was prepared by reducing Co(acac)2 with DIBALH in the presence of DIOP or BINAP. This isomerization may open a new access to the enantiopure a-amino acids 41 by introducing the modern concept of homogeneous catalysis, (Scheme 6) [38]. 

During their enantiocontrolled total synthesis of 18,18,18-trifluoro-steroid 26, Fukumoto and co-workers used a five-step Wichterle sequence to install the A-ring beginning from a previously prepared enantiopure precursor. Alkylation of the enamine of ketone 25 was followed by subsequent reprotection and hydrolysis of the vinylic chloride to afford the diketone intermediate 26, which underwent cyclization and acetylative isomerization to afford 18,18,18-trifluorosteroid 27 in 24% yield over the five-step sequence. 

The model studies demonstrated that an exo-(tether)-[4-1-2] cycloaddition on the a-unsubstimted nitroalkene, and the construction of the piperidine ring are possible. In the next stage of the synthesis the elements needed to create rings A, D, E, and F were installed in a suitable precursor. Thus, enantiopure nitroalkene (S)-165 (prepared as a 5/1 mixture of nitroalkene isomers, Scheme 16.83) [47, 147] undergoes tandem, double-intramolecular [4 + 2]/[3- -2] cycloaddition in the presence of SnCLj to provide an inseparable mixture of nitroso acetals 167. Assuming that the substrate does not isomerize prior to the [4 + 2] cycloaddition, the reaction proceeds via the cnt/o-(tether)-transi-tion stmcture. Calculations suggest that the reaction is... 

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