What Could Be Clarified by Synthetic Chemistry?

Chem. Listy 97, s233 ñ s318 (2003) Conference on Isoprenoids 2003 THE FRANTIäEK äORM LECTURE: ENANTIOMERISM AND ORGANISMS: WHAT COULD BE CLARIFIED BY SYNTHETIC CHEMISTRY? KENJI MORI Emeritus Professor, The University of Tokyo, 1-20-6-1309, Mukogaoka, Bunkyo-ku, Tokyo 113-0023, Japan E-mail: [email protected] 1. The absolute configuration of bioactive natural products can be determined by synthesis and analysis. The stereochemistry of exo-brevicomin (the aggregation pheromone of the western pine beetle) was determined in 1974 by its synthesis from (ñ)-tartaric acid (Fig. 1), and that of plakoside A (an immunosuppressive marine galactosphingolipid) was determined in 2002 by HPLC comparison of its degradation products with synthetic samples (Fig. 2). Fig. 1. Synthesis of the enantiomers of exo-brevicomin Fig. 2. Determination of the absolute configuration of plakoside A s237 Chem. Listy 97, s233 ñ s318 (2003) Conference on Isoprenoids 2003 Fig. 3. Examples of natural products which are not enantiomerically pure Fig. 4. Only the depicted enantiomers show strong bioactivity 2. A natural product is not always a pure enantiomer. As shown in Fig. 3, natural (ñ)-karahana lactone and natural (+)-dihydroactinidiolide are almost racemic. The marine de- fense substance limatulone is biosynthesized by a limpet as a mixture of the racemate and the meso-isomer. Stigmolone (the aggregation pheromone of a myxobacterium) is biosynthesized as a racemate. Fig. 5. The depicted enantiomers are natural products, and their 3. Usually only one of the enantiomers is bioactive (Fig. 4), opposite enantiomers are also bioactive but sometimes both the enantiomers are active (Fig. 5) as in the cases of nepetalactone (cat attractant) and polygodial (insect antifeedant). 4. Latest enantioselective synthesis of the following new pheromones will be discussed: (4R,9Z)-9-Octadecen-4-olide (A, the sex pheromone of the currant stem girdler), (S)-3,7-di- methyl-2-oxo-6-octene-1,3-diol (B, the aggregation pheromone of the Colorado potato beetle), and (6S,19R)-6-acetoxy-19- -methylnonacosane (C, the sex pheromone of the screwworm fly) (Fig. 6). 5. Stereochemistry-bioactivity relationships among pheromones ñ Diversity is the keyword of pheromone response. Or- ganisms utilize chirality to enrich and diversify their communication system. The sterochemistry-biochemistry relationships are classified into 10 categories as shown in Fig. 7. 6. Conclusion. Through synthesis we can clarify the diversity in structure-activity relationships, the discovery of which has been the most unexpected and fascinating outcome of our work since I met Prof. F. äorm in 1970. Fig. 6. Structure of new pheromones as synthetic targets s238 Chem. Listy 97, s233 ñ s318 (2003) Conference on Isoprenoids 2003 Fig. 7. Stereochemistry and pheromone activity REFERENCES 1. Mori K.: Acc. Chem. Res. 33, 102 (2000). 2. Mori K.: Eur. J. Org. Chem. 1998, 1479. 3. Mori K.: Chirality 10, 578 (1998). 4. Mori K.: Chem. Commun. 1997, 1153. 5. Mori K.: Biosci. Biotechnol. Biochem. 60, 1925 (1996). s239 Chem. Listy 97, s233 ñ s318 (2003) Conference on Isoprenoids 2003 SOME FLUORINATED BRASSINOSTEROID steroids: Steroidal Plant Hormones (Sakurai A., Yokota DERIVATIVES AT THE A RING. APPROACH T., Clouse S., ed.), Chap. 9. Springer-Verlag, Tokyo 1999. TO THE TYPE OF BRASSINOSTEROID- 3. Brosa C., AmorÛs M., Vàzquez E., Pique M.: Collect. -RECEPTOR INTERACTION Czech. Chem. Commun. 67, 19 (2002). MARC AMOR”S, SÒNIA ESPELTA, CARME BROSA* THE CHEMISTRY AND BIOACTIVITY OF BRASSINOSTEROIDS AND THE SEARCH Institut QuÌmic de Sarrià, C.E.T.S., Universitat Ramon Llull, FOR NONSTEROIDAL MIMETICS Via Augusta 390, 08017 Barcelona, Spain E-mail: [email protected] THOMAS G. BACK Brassinosteroids are a kind of plant growth regulators Department of Chemistry, University of Calgary, Calgary, widely distributed in the plant kingdom1. Alberta, Canada, T2N 1N4 Since the discovery of brassinolide (I), which shows a high E-mail: [email protected] activity as a growth promoter, many studies have been focused on the synthesis of new analogs for a better understanding the Brassinolide (1) is a remarkably potent phytohormone that mode of action of such compounds. has attracted considerable attention since its discovery in 1979 In our aim in obtaining information about the structural by Grove et al.1 Although it offers exceptional promise for requirements for a brassinosteroid to be active in an efficient enhancing the yields of many commercially important crops, way, a quantitative structure-activity relationship (QSAR) has its high cost remains a formidable barrier to large-scale appli- been developed in our group based on molecular modeling cations. Our work on brassinosteroids is directed toward de- techniques. Our results confirm that electrostatic charges play veloping more efficient syntheses of brassinosteroids, toward an important role in displaying biological activity. Moreover, improving our understanding of their structure-activity rela- we have found that hydrogen-bonding could be one of the tionships2 (SAR) and toward applying this information to the types of interactions that could be taking place upon binding2. design of cheaper and more efficacious analogues. The assessment of H-bonding and the clarification of how The synthesis and bioassay of a series of side-chain and the functionalities present in a brassinosteroid could work on B-ring analogues of 1 have provided us with some fresh insight binding through hydrogen bonding with the receptor has be- into their SAR. During this work, two novel compounds 2 and come a priority aim in our group3. 3 were discovered that have bioactivity exceeding that of 1 by ca. 5ñ7-fold in the rice leaf lamina inclination bioassay. These products appear to be the most strongly active brassinsoteroids OH reported to date3. A major impediment to commercial exploitation of brassinosteroids stems from their rapid conversion by plants to less OH active metabolites. Studies elsewhere on the metabolism of brassinosteroids in various species of plants have revealed that HO OH HO O H OH O HO OH I O OH OH O Brassinolide (1) F O H O II OH In this communication, the substitution of some hydroxyl HO OH groups at the A-ring by fluor giving brassinosteroid analogs (II) will be specifically analyzed from different points of view: OH Mimetic 13 molecular modeling, synthesis and bioactivity. HO REFERENCES O 1. Khripach V. A., Zhabinskii V. N., de Groot A. E.: Bras- HO OH sinosteroid: A New Class of Plant Hormones. Academic OH Press, California 1999. OH O 2. Brosa C.: Structure-activity Relationship in Brassino- Fig. 1. Mimetic 14 s240 Chem. Listy 97, s233 ñ s318 (2003) Conference on Isoprenoids 2003 OH they undergo (inter alia) glucosylation of the hydroxyl groups 22 26 at C-2, C-3 and C-23, as well as enzymatic hydroxylation, 4 23 25 followed by glucosylation at C-25 and C-26 (ref. ). While the OH glucose conjugates appear to be metabolic deactivation pro- C D HO 2 ducts, there has been some controversy regarding the bioactivity of the 25- and 26-hydroxylated aglycones5. This has raised A B the question of whether the formation of these compounds HO 3 O H represents an activation or deactivation step. We therefore O Brassinolide (1) synthesized all of the stereoisomers of the 25- and 26-hydroxylated brassinolide derivatives (4ñ8), as well as the epoxide 9. All had very low bioactivity, thereby confirming that the OH OH naturally-occurring compounds in this series are deactivation products6. We then synthesized a series of O-methylated derivatives of brassinosteroids, in the hope of discovering com- OH OH pounds that retain the activity of 1, but where the glucosylation HO HO of key hydroxyl groups would be blocked. The methyl ethers 10ñ12 all displayed relatively strong bioactivity, while other HO O HO O derivatives (e.g. methyl ethers at C-2) were essentially devoid H H 7 2 O 3 O of activity . Methyl ether formation could, in theory, allow brassinolide or its congeners to resist deactivation through glycosylation and thus offer greater persistence in field appli- OH OH OH OH OH cations. It also permits us to conclude that free hydroxyl groups are not required at all positions, while at others (e.g. OH C-2), they are crucial for bioactivity. R OH R OH R OH Finally, we attempted to design nonsteroidal mimetics of 4 5 6 brassinolide that would have simpler structures, thus making them easier and cheaper to synthesize, but that would retain the bioactivity of natural brassinosteroids. Our approach in- OH OH OH OH OH volved the use of subunits containing the essential structural features of brassinosteroids (namely the two vicinal diol units O R OH OH R OH OH R OH and a polar functional group on the B-ring) held in the correct 7 8 9 spatial orientation. The subunits were then joined by rigid linkers designed to hold the subunits the required distance apart. A series of mimetics that had structures capable of superimposing closely with that of brassinolide (1) were iden- tified and synthesized8. Two of the mimetics (13 and 14; see HO Fig. 1; essential structural features are shown in bold) showed R= significant bioactivity when synergized by the auxin IAA. HO H O When applied under optimum conditions, 14 proved compa- O rable to 1 in the rice leaf lamina inclination bioassay. The relatively simple and symmetrical structure of such mimetics OMe may prove advantageous with respect to the cost of their OMe production. OMe REFERENCES OMe HO HO 1. Grove M. D., Spencer G. F., Rohwedder W. K., Mandava N., Worley J. F., Warthen Jr. J. D., Steffens G. L., Flip- HO O H pen-Anderson J. L., Cook Jr. J. C.: Nature 281, 216 (1979). MeO O O H 2.

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