Development of novel pyrrolidine organocatalysts

Abstract

Chapter 1. Development of Novel Pyrrolidine Organocatalysts A substantial asymmetric catalysis have been developed with proline and its derivatives in the research field of organocatalysis. Proline is particularly interesting due to their chirality, abundance, non-toxicity, inexpensive commercially availability and extensive applications to asymmetric reaction. Economical catalytic process as well as broad range of applications led us to be engaged in its synthetic studies. The stereoselective synthesis of $\alpha$ -alkylated-D-proline catalysts 20a, 20b and cis-fused bicyclic pyrrolidine 21 are described. The enantioselective quaternary carbon centers of 20a, 20b were installed by desymmetrization developed in our group. Pyrrolidine ring was formed by ring-closing metathesis. After hydrogenolysis, the completed enantioselective synthesis of $\alpha$ -alkylated-D-proline catalyst was achieved. The synthesis of bicyclic pyrrolidine 21 commenced with D-manitol 69. Tetramethanesulfonate 78 was exposed to benzylamine to deliver the bicyclic pyrrolidine framework. The dicarboxylic acid 21 was prepared from diol 66. These organocatalysts were explored for asymmetric aldol reaction, intramolecular Michael reaction and alkylation of aldehyde under various conditions, respectively.

Chapter 2. Stereocontrolled Synthesis of the C1-C11 Fragment of Arenaric Acid Arenaric acid 85a was produced by the Streptomyces sp. (isolate No. CNH-248) which was originally isolated from shallow sandy sediments of an estuary near Daheny beach in the north of San Diego. Its structure was determined by various NMR techniques and comparison with well-defined similar compounds. In addition, the absolute configuration was elucidated based on modified Mosher’s method. Its complex and unique structure was expected to attribute the structural particularity of many other polyether natural products. The polycyclic back-bond and a terminal carboxyl group play an important role in the formation of oxygen-rich internal cavity to interact with metal cation. Although its family, K41-A 95 and oxolonomycin 96, possess antibacterial and potent antimalarial activity, the total syntheses of these structural and biologically interesting compounds have not been reported yet. To achieve the enantiodivergent total synthesis of Arenaric acid 94a, stereocontrolled synthesis of the C1-C11 fragment has been developed. Desymmetrization of triol 134 and Sharpless asymmetric epoxidation of 106 have been employed to install the enantioselective quaternary carbon center C6. Subsequent Roush allylation, Evans aldol reaction, acid-catalyzed lactone formation and insertion of enolate formed the desired C1-C11 fragment of arenaric acid.

Chapter 3. Formal Total Synthesis of (+)-Dihydromayurone The tricyclic sesquiterpene thujopsene 230 was originally isolated from the wood oil of the Japanese Hiba tree and has been found in many confiers aontaining the natural order Cupressaceae. The stereostructure of thujopsene 230 was determined by Norin and co-workers which was soon confirmed by the total synthesis by Dauben and Aschcraft. Especially, dihydromayurone 231 has been regarded as a key intermediate in total synthesis of thujopsene 230. These are very attractive and challenging targets due to the structure composed of tricycle [5.4.0.0] undecane framework including a cyclopropane ring, in particular the presence of three contiguous quaternary carbon atoms. To approach the synthesis of these terpenoids, we have developed the enantioselective desymmetrization and adopt this protocol to total synthesis of dihydromayurone. (+)-Dihydromayurone 231 would be attained by rhodium-catalyzed cyclization of diazo ketone 239 prepared from 247 as a key intermediate. The terminal olefin was secured by Peterson olefination. Introduction of vinyl group followed by ring closing metathesis provided cyclohexene 264. Enantioselective quarternary carbon center was installed by desymmetrization of diol 275-277 in the presence of Pybox (278)- $CuCl_2$ complex. In the second approach, the synthesis commenced with dihydroxy methylation of cyclohexenone 354. The key intermediate 247 was prepared from 402 via hydrogenolysis and olefinations. Enantioselective desymmetrization of several cyclohexenes was developed to introduce all carbon quarternary center. Especially, desymmetrization was achieved by monobenzoylation of diol 372 to provide the highly enantioselective 394 as a starting chiral building block for (+)-Dihydromayurone 231.