Synthesis Of A Chiral Auxiliary: Non-Cross-linked Polystyrene-supported Thiazolidine-2-thione

Thiazolidine-2-thione is a novel chiral auxiliary, which is widely used in asymmetric synthesis, such as asymmetric aldol condensation and conjugate addition, and so on. And compared with other chiral auxiliary, it displays better steroselctivity in application. However, its purification is inconvenient. Although insoluble polymer supported chiral auxiliaries contributes to the efficience of purification and convenience of recycling, there are several shortcomings we have to face:heterogeneous-phase reactions, hard to online analysis. Soluble polymer supported organic synthesis combines the superiorities of solid phase synthesis such as easy separation and purification, and the advantages of classical liquid phase synthesis such as homogenous reaction, ease detection reaction procedure by routine analytic methods, so it has been widely used in asymmetric synthesis.We summarized the application of small molecule chiral auxiliaries and polymer supported chiral auxiliaries in asymmetric synthesis. Based on the consideration above, we investigated the synthesis of non-cross-linked polystyrene (NCPS) supported chiral thiazolidine-2-thione. The main work contained the following aspects:1. Using N-Boc-L-tyrosine ether ester as starting material, and it reacted with allyl bromide and 4-vinylbenzyl chloride respectively in the presence of K2CO3, and then obtained amino alcohols by reduction and deprotection of Boc group. Treatment the amino alcohols with CS2 under the solution of KOH gave the target molecular of 4-(4-(allyloxy)benzyl)thiazo-lidine-2-thione and (S)-4-(4-(4-vinyl-benzyloxy)benzyl)thiazolidine-2-thione. The overall yields were 56.5%and 44.6%respectively.2. In order to obtain (S)-4-(4-hydroxybenzyl)thiazolidine-2-thione and support it on NCPS by its hydroxyl group, deprotecting the allyl group of 4-(4-(allyloxy)benzyl)thiazolidi-ne-2-thione was investigated. We explored the deprotecting of allyl group in different conditions, and expanded a new method for deprotecting of allyl group using NaBH4/BF3·Et2O, the yield was 75%.3. In order to study the asymmetic induction effect,4-(4-(allyloxy)benzyl)thiazolidine-2-thione was treated with propionyl chloride using Et3N as base and DMAP as catalyst agent, and then N-propionyl-4-(4-(allyloxy)benzyl)thiazolidine-2-thione was afforded in the yield of 53.6%.4. We chose three routes to prepare NCPS supported (4S)-thiazolidine-2-thione:(1) (S)-4-(4-hydroxybenzyl)thiazolidine-2-thione was linked to chloromethylation polystyrene, but we got the product of alkylation in the atom of sulfur and oxygen instead of the target molecular. (2) Copolymerized styrene with 2-amino-3-(4-(4-vinylbenzyloxy)phenyl)propan-1-ol to get the NCPS supported 2-amino-3-(4-(4-vinylbenzyloxy)phenyl)propan-1-ol. And then it was treated by CS2 under the base condition to obtain the target molecular in the overall yield of 34.7%. (3) (S)-4-(4-(4-vinylbenzyloxy)benzyl)thiazolidine-2-thione copolym-merized with styrene, and the target product was afforded in 39.2% yield5. The intermediates were characterized by traditional analytic methods(IR, NMR, and so on), and the results were according with the structures of compounds.