(s) - Malic Acid As The Source Of The Chiral Pyrrolidine Alkaloids In Asymmetric Synthesis Research

Pyrrolidine-ring containing alkaloids is a class of natural product, which possess a variety of important bioactivities. Many of them have shown high potential for medical and biological applications. Consequently, the asymmetric synthesis of these compounds continues to attract much current attention. In this context and in combination with the structural diversity of pyrrolidine-ring containing alkaloids, the development of building block-based flexible asymmetric synthesis methods is of primordial importance.The development of synthetic methodology based on cheap and easily available (S)-malic acid 1 is the major research theme in these laboratories. In this thesis we will focus on the development of new chiral pyrrolidine and / or pyrrolidinone N-a-carbanion based synthetic methodology, which includes the studies on their formation, reactivities and reaction with aldehydes and ketones, as well as their application in the asymmetric synthesis of indolizidine alkaloid, swaninsonine. Besides, the work will conduct in order to clarify the question on the regioselectivity of Grignard reagent addition to (S)-malimide, which has been used in these laboratories as the key step in a formal asymmetric synthesis of anisomycin. The main results and observations from these studies are listed as follows.1. Further studies on the reductive alkylation of malimide 3 were undertaken. This allowed revealing that the regioselectivity in the p-methoxybenzyl mangesium chloride addition to (S)-N-benzy1 malimide 3 is 80% to 20% in favored of addition at C2 carbonyl. While the addition to 2 showed nearly 100% regioselectivity at C2. The reductive alkylation product was then converted to known (R)-pyrroline 4. This constitutes an improved formal asymmetric synthesis of natural (-)-anisomycin 5.2. In the aim to study the possibility for use of 7 and 9 as synthetic equivalentsto pyrrolidinone carbanion chiron 6, the formers were synthesized from (S)-malic acid. Treatment of phenyl sulfone 7 with lithium-naphthalenide and followed by addition of benzaldehyde afforded the expected compound 8 in only 16.6% yield. However this is the best result obtained in such system. Barbier-type reactions of pyridyl sulfone 9 in the presence of an eletrophile using samarium diiodide have also been studied, which showed disappointing results.3. In order to develop pyrrolidine carbanion chiron 14 -based synthetic methodology, pyrrolidines 11-13 were designed and synthesized in view of their use as synthetic equivalents to 14. Thus, starting from (S)-malic acid, (S)-3-hydroxy-pyrrolidinone 10 was prepared as a key intermediate, which was then converted to phenyl sulfide 11, pyridyl sulfide 12 and 13. The reductive lithiation of phenyl sulfide (11) using lithium-naphthalenide followed by addition of an electrophile such as aldehyde did not afforded the expected products. While Sml2-promoted reductive metallation of pyridyl 12 and 13 sulfide followed by addition of ketones or aldehydes under Barbier conditions provided the desired products 15 in 30-83% yields. These results show that the reaction of synthon 14 with carbonyl compounds proceeds with high C2/C3 trans diastereoselectivity at and mediocre diastereoselectivity at newly formed carbinolic center when using an aldehyde as electrophile. Thus pyridyl sulfide 12 and 13 are two valuable synthetic equivalents of the chiron 14, based on this, a new asymmetric hydroxy-alkylation method has been developed.4. Based on the observations made during the above mentioned studied, a new amidating method for the conversion of esters to amides, including Weinreb's amides, was developed. The method consists in the reaction of a lactone or an ester with organoaluminum species generated from DIBAL-H-H2NR or DIBAL-H-HNR1R2 HCl complexes. The replacement of AlMe3 with user-friendlier and more easily available DIBAL-H is of practical importance.5. Following the procedure for the preparation of (S)-3-hydroxy-pyrrolidinone 10, the key building block (S)-l-benzy...