Study On The Asymmtric Synthesis Of 2,3-Disubstituted 1-Aminocyclopropane-1-carboxylic Acid Derivatives

Since the first report on the isolation of 1-amino-1-cyclopropane- carboxylic acid (AAC), the sythesis of this compound and its derivatives have attracted special interest,because of their biological activity and potencial use in conformationally restricted pepties. ACCs, conventionally classified as 2-substituted, 2,2-disubstituted and 2,3-disubstituted.We have reported our studies on the stereoselective synthesis of 2,3-diarylsubstituted ACCs. In this context,extensive efforts have been diverted toward the asymmetric sythesis of 2-alkyl-3-aryl- disubstituted ACCs.In the review part of the dissertation,we summarized up the applica- tions of D-mannital in the organic synthesis as a potentially chiral material. Then we give some representative examples of organic synthesis started from D-mannital.We organize them in three routes as following: (1) Synthesis of 1-amino-1-cyclopropanecarboxylic acid and its derivatives; Synthesis of cyclopropane and its derivatives; Synthesis of а-substituted glycine (2) Synthesis of natural compound (3) Coordination with metal and kinds of metallic element.In the experimental part two sections are covered. The first one is dealed with the preparation of starting material and the construction of precursor of cyclopropane derivatives. Our previous studies have covered the first section. 6 new products(each contains four chiral carbon atoms) are synthesized and characterized. Starting from the easily available D-mannitol, reacted with acetone in the presence of anhydrous zinc chloride to give 1,2:5,6-di-O-isopropylidene-D-mannitol. Then the protect- ed D-mannitol, mixed with lead tetraacetate, hippuric and acetic anhydride, was refluxed in tetrahydrofuran for 18 h in a one-pot two steps reaction to afford a chiral precursor(Z)-2-phenyl-4-[(S)-2,3-O-(isopropylidene)]-prop- ylidene-5(4H)-oxazolones. This precursor reacted with aryldia- zomethane in toluene to provide three spirocyclopropane derivatives. Ring opening of these spirocyclopropane derivatives in Anhydrous methanol containing catalytic amounts of sodium methoxide afforded three corresponding benz- oylamino methyl esters.In section two we studied on the synthesis of the 2,3-disubstituted ACCs. The products obtained in the first section can be easily converted to 2-glycol-3-aryl- disubstituted ACCs by acid hydrolysis of the acetonide in quantitative yields. The uncompletely oxidative cleavage of the diols with lead tetra-acetate in anhydrous tetrahydrofuran in low temperature afford aldehydes in over 90% yields. Following the oxidation of the aldehydes with hydrogen peroxide 30% water solution, carboxylates are obtained in good yields(83-86%). Reductions of the aldehydes were carried out in methanol with sodium borohydride in 0.2mol/L sodium hydroxide to afford substituted methanols. The chloridization of the substituted methanols with triphenylphosphine in carbon tetrachloride give chloromethano derivatives, followed with the reductions of the chloromethano derivatives to afford 2-alkyl-3-aryl-disubstituted ACCs in high yields (over 90%). The last step of the experimental part was the acid hydrolysis of the previous products to give 2-alkyl-3-aryl-disubstituted ACC in good yields.All the 21 new products were characterized by IR and 1H-NMR. The results indicated that the strategy using in our synthesis of 2-alkyl-3-aryl-disubstituted ACCs has significant advantages: common av- ailable materials, mild reaction condition, simple operations, high yields. The key step in our synthesis procedure: we succeeded in incorporating a chiral center into the ACCs' precursor. Because of the existent of the potential diols in the products,they can be converted to many other desired ACCs by acid hydrolysis of the acetonide, following the oxidative cleavage of the diol and the function group inversion of the resulting oxidative products.