Chiral Synthesis And Mechanism Study Of Biotin Intermediate Lactone

Biotin is a "star molecule" for either organic total synthesis or molecular biology. Ever since it was discovered, biotin has attracted the attention of synthetic chemists, industrial engineer and biologist due to the fundamental and commercial importance. This dissertation will concentrate on the above aspects to work over. A continuous endeavor of about 60 years has resulted in more than 40 original routes in this field. The present dissertation reviews the total synthesis of biotin, particularly on Hoffmann-La Roche's Lactone-Thiolactone approach. The Lactone-Thiolactone approach is presently the most competitive commercial route, which gives an excellent illustration of the gradual construction of the functionalized skeleton with the simultaneous solution of the stereochemical issues in a minimal number of steps.In 1970, Gerecke etc. of Roche Corp. reported an approach of synthesis of d-biotin, which began from optical lactone to optical thiolactone with the same configuration. From then on, optical lactone cis-1, 3-dibenzyl-hexahydrofuro [3, 4-d] imidazole-2, 4-dione became an important intermediate of biotin. Although many researches on the synthesis of lactone have been proceeded, it is still very important to research deeply, such as to find better synthesis method, or to change the ligands to improve the e.e. value and yield. The aim is to reduce the cost. So firstly all the synthesis methods of this lactone till now were introduced in this thesis, and then the merit and shortcoming of each method were discussed. Deeper research about the reduction of asymmetric cyclo-imide by sodium borohydride to optical lactone is proceeded in this thesis. A new method to find proper ligand amine is put forward from the experiment result and semi-experimental calculations. Then quantum mechanism and the selectivity about the reduction of carbonyl oxygen by sodium borohydride were studied. A new synthesis method about chiral lactone of biotin was found also.The mainly research results were showed below: (1): The procedure reacting from (lS,2S)-(+)-threo-(p-nitrophenyl)-2-aminol-l,3-propan-di-ol to cyclo-imide, then reduced by sodium borohydride was studied deeply; (2): basing on the above method, reacting from the other chiral amines, to synthesize cyclo-imide, then get lactone by reduction of sodium borohydride; (3): Correlating the structure of chiral amines and the [α] value of the relating lactone by semi-empirical PM3 calculation. Basing on it, a total new method to find chiral ligand has been set up; And a chiral amine, which leads to higher e.e. value's lactone, is found by this method. (4): develop a new method to synthesis high e.e. value lactone. (5): using B3LYP method, the mechanism of NaBH₄ reducing carbonyl function and its selectivity was studied. The ee value got by calculation is similar with the experiment value. This method is a supply to the semi-empirical method metioned in above (3) item.