Natural products are a rich source of lead compounds for treatment of cancer as well as other diseases. Researchers at the National Cancer Institute, as part of their continuing effort to discover anticancer agents from natural sources, created the 60 human tumor cell-line anticancer screen to test natural products for their potential against various types of cancer. Through this screening process a family of natural products called schweinfurthins was discovered to possess potent and differential activity. Of potentially great significance, the pattern of activity that the schweinfurthins displayed in the screen does not correlate with any currently used anticancer drug, indicating that the schweinfurthins likely act via a previously unknown mechanism or on a novel target. Our group has synthesized many of the natural schweinfurthins as well as numerous analogues in an effort to probe the pharmacophore and gain understanding of the key features that are important for potency as well as differential activity. During the course of these studies, it was discovered that the right-half of the molecule is most amenable for modifications. One potential modification to the schweinfurthins is to replace the resorcinol substructure seen in the right-half of the natural product with a heteroaromatic moiety such as a benzofuran or indole system. This change may produce analogues that are potentially more active, that contain motifs that are seen in many therapeutic drugs, and that have improved chemical stability relative to the natural products. With this goal in mind benzofuran and indole containing schweinfurthin analogues were synthesized. Once these compounds were prepared, it was found that such modifications were welltolerated, and in the case of the indole analogues activity in the 60 cell-line screen was equivalent to the corresponding natural product. In an effort to improve that activity, prenyl and geranyl side chains were added to the indole system, at both the C-2 and C-3 positions, to better match the structure of the natural schweinfurthins. In addition, analogues methylated selectively on the indole nitrogen or phenol were synthesized to improve stability. The impact of those modifications on the activity was tested, and potent compounds were found. The left-half of the schweinfurthins is prepared via a Lewis acid mediated cascade of a geranyl epoxide. The protecting group that is typically employed on the terminating phenol, a methoxymethyl ether or MOM group, is cleaved during the reaction. In the past preparation of an analogue that lacked a substituent at the C-5 position, it was found that the MOM cation released during the cyclization would participate in an electrophilic aromatic substitution reaction at the neighbouring position which resulted in the formation of a benzyl methyl ether. In order to probe the scope of this reaction and its potential utility in the synthesis of natural products, several geranyl epoxides with various "protecting groups" on the phenol were prepared and subjected to the cyclization conditions. These investigations have established that stabilization of the liberated cation determines the likelihood and regioselectivity of a tandem electrophilic aromatic substitution reaction.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第21051号 / 薬科博第94号 / 新制||薬科||10(附属図書館) / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 大野 浩章, 教授 竹本 佳司, 教授 高須 清誠 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Cancer is a serious family of disease that continues to cripple and claim those afflicted. For the last several decades, America has invested in a national program to alleviate cancer and cancer related suffering, ultimately seeking a cure. As part of this goal, the National Cancer Institute (NCI) has spent significant effort scouring the globe with the hope of finding naturally occurring compounds that can successfully combat cancer. Presently, this effort has uncovered many natural products with chemotherapeutic potential and many of the lead agents used in the fight against cancer are either natural products themselves or are compounds inspired by a natural product. This work describes one family of natural products uncovered by the NCI that is being explored for chemotherapeutic applications, namely the schweinfurthins. The schweinfurthins were isolated by the NCI; however the natural source, Macaranga schweinfurthii, did not provide these compounds in ample quantity to permit further study. The paucity of natural material indicated that a chemical synthesis of these compounds would be the most reliable method to provide meaningful amounts of schweinfurthins. The present work describes the chemical synthesis of four of the most potent schweinfurthins, describes the synthesis of numerous structural analogues, and details advances to the field of cascade cyclizations which makes their synthesis possible.

Lyconadin A is an alkaloid possessing a unique structure and antitumor activity. The total synthesis of Lyconadin A was proposed via an acyl radical cascade reaction. To investigate the possibility and stereoselectivity of the cascade cyclization, phenyl selenoester 16 was chosen as a model substrate to study the 7-exo-5-exo radical cyclization. A synthetic route to phenyl selenoester 16 was developed. The 7-exo-5-exo radical cyclization was found to occur with a high yield and excellent stereoselectivty. Attempts were also tried to synthesize another radical precursor 14 albeit with less success. A synthetic pathway to the synthesis of 14 as well as its potential use in the context of the synthesis of Lyconadin A was proposed.

The thesis entitled “Organocatalytic Cascade Cyclizations for the Enantioselective Synthesis of Spirooxindoles” is divided into three chapters. Chapter 1: Catalytic Enantioselective Michael Addition/Cyclization Cascade of 3-Isothiocyanato Oxindoles with Nitroolefins A myriad of spirocyclic frameworks present in natural product, and pharmaceutically important compounds, has attracted the synthetic organic chemists to explore their preparation in enantioselective manner. Consequently various strategies have been devised for efficiently accessing highly functionalized spirooxindoles. Among these strategies, the use of 3-isothiocyanato oxindoles as the building block appeared as the most popular one. The combination of 3-isothiocyanato oxindoles and a variety of electrophiles have already been reported. However one of the most popular electrophiles, nitroolefins, has never been used in the reaction with 3-isothiocyanato oxindoles. In this chapter, a highly efficient catalytic asymmetric Michael addition/cyclization cascade reaction between 3-isothiocyanato oxindoles and β-substituted nitroolefins with the help of a cinchonidine-derived bifunctional thiourea catalyst has been discussed. Highly functionalized spirooxindoles containing three successive stereocenters were obtained in high yield with moderate to good diastereo- and enantioselectivity. Reference: Kayal, S.; Mukherjee, S. Eur. J. Org. Chem. 2014, 6696-6700. Chapter 2: Catalytic Aldol-Cyclization Cascade of 3-Isothiocyanato Oxindoles with α-Ketophosphonates for the Enantioselective Synthesis of β-Amino-α-Hydroxyphosphonates The oxindole scaffold containing a quaternary stereocenter at the C3 position is a privileged structural motif present in many biologically active molecules and natural products. In this respect, spirooxindoles have received special attention during the past few years. Similarly, β-Amino and/or hydroxy functionalized phosphonic acids and their derivatives are found to display inhibitory activities towards a range of enzymes such as renin, HIV protease, thrombin, and various classes of protein tyrosine kinases and phosphatases. Considering the importance of both oxindole and β-amino-α-hydroxyphosphonic acid, we reasoned that highly functionalized phosphonic acid derivatives based on a spirooxindole framework could be of potential biological significance, if synthesized in enantiopure form This chapter deals with a cascade aldol-cyclization reaction between 3-isothiocyanato oxindoles and α-ketophosphonates for the enantioselective synthesis of spirooxindole-based β-amino-α-hydroxyphosphonate derivatives. Catalyzed by cinchona alkaloid-based bifunctional thiourea derivatives, this protocol delivers 2-thioxooxazolidinyl phosphonates bearing two adjacent quaternary stereogenic centers, generally in high yields with excellent diastereo- and enantioselectivities. Both the product enantiomers are accessible with nearly equally high level of enantioselectivity. Reference: Kayal, S.; Mukherjee, S. Org. Lett. 2015, 17, 5508-5511. Chapter 3: Catalytic Michael Addition/Cyclization Cascade of 3-Isothiocyanato Oxindoles with Cyclic α,β-Unsaturated Ketones: A Concise Enantioselective Synthesis of Bispiro[indoline-3,2'-pyrrolidine] Among different spirocyclic cores, the spirooxindole framework containing pyrrolidinyl ring represents a very important class owing to their biological activities such as antimicrobial, anticancer, antihypertensive, antidiabetic, antimycobacterial and antitubercular properties. Similarly, the bispirooxindole scaffold recently has drawn considerable interests because of its exclusive structural and stereochemical diversity. Only a few examples have been reported till date for enantioselective construction of the pharmaceutically important bispirooxindole architectures. Considering the importance of bispirooxindoles and pyrrolidinyl spirooxindole scaffolds, we were interested in merging them in a single molecular framework. In this chapter, a Michael addition/cyclization cascade reaction between 3-isothiocyanato oxindoles and exocyclic enones for the enantioselective synthesis of 3,2′-pyrrolidinyl bispirooxindole derivatives has been illustrated. With the help of a quinine-derived bifunctional squaramide as the catalyst, this protocol delivers bispirooxindoles bearing three contiguous stereogenic centers, in high yields and generally with outstanding diastereo- and enantioselectivity. Reference: Kayal, S.; Mukherjee, S. manuscript under preparation.