Sch725675 Sch725675 O O OH C5H11 OH OH Sch725674 is a novel macrolide isolated from the culture of an Aspergillus sp. by a team of researchers at Schering-Plough in 2005. The compound showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 8 and 32mg/ml (micrograms per milliliter), respectively. The 2D structure of Sch725674 was rigorously assigned via 2D NMR data analyses including HSQC, HSQC-TOCSY, and HMBC. However, the stereochemistry of the four oxygenated methine carbon atoms could not be assigned due to the limited amount of sample isolated (about 1 mg). Fourteen-membered macrolactones lacking methyl substitution like Sch725674 are very rare in nature, which makes stereoisomer library generation more interesting in the context of structural assignment and biological evaluation. Ref.: Journal of Antibiotics 58 (8): 535-538, 2005 Tetrafibricin Tetrafibricin HOOC HO OH H2 N OH OH OH OH OH OH OH O OH Tetrafibricin is a novel nonpeptidic fibrinogen receptor isolated from the culture broth of Streptomyces neyagawaensis NR0577. Tetrafibricin competitively inhibited (Ki = 9.9 nM) the binding of biotinylated fibrinogen to purified active glycoprotein GPIIb/IIIa immobilized on plastic plate. Tetrafibricin strongly inhibited the binding of fibrinogen to its receptors with an IC50 of 46 nM. It also inhibited ADP-, collagen-, and thrombininduced aggregation of human platelets with IC50s of 5.6, 11.0 and 7.6 μM, respectively. To our knowledge, there is no total synthesis of tetrafibricin done yet. Only two papers have been published toward the total synthesis of tetrafibricin. Cossy’s group synthesized the C1-C13, C15-C25, C27-C40 fragments of tetrafibricin by a sequence of chemoselective cross-metathesis reactions and enantioselective allyltitanations of aldehydes. And Roush’s group reported the synthesis of the C1C19 fragment of tetrafibricin via a highly diastereoselective double allylboration developed in their laboratory. Tulearin A Tulearin A O O OH HO O O NH2 Tulearin A is a representative marine macrolide that was isolated by Kashman and coworkers in 2008. Bioguided separation (brine shrimp set) of the CHCl3/CH3OH (1:1) extract of Madagascar Fascaplysinopsis sp. sponge collected in Salary Bay north of Tulear provided 6.6 mg of 18-membered macrolactone, tulearin A, in yield of 0.019 wt %. Until now, there is no total synthesis of tulearin A. In 2009, one stereoisomer (C2-epi, C15-epi) of tulearin A was synthesized by Cossy, Curran and co-workers. Ref. 1. Bishara, A.; Rudi, A.; Aknin, M.; Neumann, D.; Ben-Califa, N.; Kashman, Y. Org. Lett. 2008, 10, 153. 2. Mandel, A. L.; Bellosta, V.; Curran, D. P.; Cossy, J. Org. Lett. 2009, 11, 3282. Dictyostatin Dictyostatin and its analogs OH OH HO HO O OH O O OH OH O OH The synthesis of various analogs of the marine natural product dictyostatin have been of great interest in our laboratory. Dictyostatin is a 22-membered macrolactone isolated in 1994 by Pettit and coworkers from the marine sponge Spongia sp. It inhibits the growth of a variety of cancer cell lines at the low nanomolar range. Since its isolation, structure elucidation and biological activity came to light, we have synthesized a number of analogs in our laboratory in order to gain more insight regarding structure-activity relationships (SAR) studies. We aim to develop a practical, more convergent and higher yielding route to easily access dictyostatin and its simplified analogs. OH 16 HO 26 16 HO 21 O OH O O 1 9 OH OH Dictyostatin 16 HO OH OH 6-epi-dictyostatin 26 16 HO 21 O O 9 OH 26 21 O 1 OH O 1 9 OH 26 21 O 1 9 OH 16-desmethyl-25,26-dihydrodictyostatin OH OH 16-desmethyl-25,26-dihydro-6-epi-dictyostatin Reference for the isolation: 1) Pettit, G. A.; Cichacz, Z. A.; Gao., F.; Boyd, M. R.; Schmidt, J. M. J. Chem. Soc., Chem Commun. 1994, 1111-1112. Reference for the re-isolation: 2) Isbrucker, R. A.; Cummins, J.; Pomponi, S. A.; Longley. R. E.; Wright, A. E. Biochem. Pharmacol. 2003, 66, 75-82. References for Dictyostain total syntheses: 1) Shin, Y.; Fournier, J-H.; Fukui, Y.; Brückner, A. M.; Curran, D. P. Angew. Chem. Int. Ed. 2004, 43, 4634-4637. 2) Paterson, I.; Britton, R.; Delgado, O.; Meyer, A.; Poullennec, K. G. Angew. Chem. Int. Ed. 2004, 43, 4629-4633. 3) O’Neil, G. W.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 5340. 4) Ramachandran, P. V.; Srivastava, A.; Hazra, D. Org. Lett. 2007, 9, 157-160.