3 - Alkyl-2 ,3 - Dihydro-1h-isoindole-1 - One Of The Asymmetric Synthesis,

The 3-substituted-2,3-dihydro-JHisoindol-l-ones (I) are found as core units in many natural and/or bioactive compounds, they have broad prospect in fields of medicine and biochemistry. After amide carbonyl reduction, they can serve as a group of promising cbiraL auxiliaries in asymmetric synthesis.Our laboratory has developed a general method for the asymmetric synthesis of pyrrolidines, 2-pyrrolidinones and related compounds, starting from cheap and easily available (S)- malic acid. On this ground, the aim of this thesis has been to develop a new and versatile asymmetric synthetic method to isoindolone, so as to provide new chiral auxiliaries for asymmetric synthesis.First, starting from phthalic anhydride (II) and (R)- (-)-phenylglycinol(III), we prepared N-substituted phthalimide(V). After protecting the hydroxy group VI was formed, then it was subject to reductive alkylation process( Grignard reagent then reduced by Et3SiH in the presence of BF3OEt2). When methyl magnesium iodide was used, compound VIII was obtained as a mixture of two inseparable diastereoisomers in the ratio of 3:2. To overcome the difficulties, we studied the direct reductive alkylation of V. Grignard reagent addition led to two diastereoisomers that can be separated through column chromatography. Comparing with the literature methods, our method present advantages of flexibility and versatility, since side chain can be introduced easily through Grignard addition. We have introduced in such way methyl, ethyl, butyl, isobutyl, heptyl, phenyl and benzyl. The yield of Grignard addition was about 96%; in the reduction step, the yield was generally above 85% and the d.e. ranged from 42 to 82% . X-ray analysis showed that the major products have (1 R ) - (3R) configurations.Second, X was prepared through cyclization of VII, then it was reduced byEt3SiH in the presence of TiC14 affording TX with higher diastereoselectivity(when R=Me, d.e.=90%, y~66%). And benzal phthalide IV, a cheap and easily available compound, can condense with III in place of II, and give IX with a benzyl side chain after cyclization and reduction(d.e.=84%, y'98%).Finally, removal of protecting group of IX has been attempted, optically active 3-substituted-2,3-dihydro--JH-isoindol-1-one J( R i- Bu ) can be obtained (e.e. 69%) although racemization can not be excluded under the conditions used.