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problems, i.e. toxicity and rapid development of resistance. l,3-/?-Glucan synthase, the enzyme complex responsible for the synthesis of l,3-/3-glucan, a major component of the fungal cell wall, is an attractive antifungal target since it is essential to most pathogenic fungi, but is not present in mammalian cells.4) Therefore, in recent years, echinocandin and pneumocandintypes of antifungal lipopeptides have been studied intensively.5'6) FR901469 (1) is a novel antifungal cyclic depsipeptide that was isolated from the culture broth of an unidentified fungus No. 1 1243 as a water-soluble 1,3-/3-glucan synthase inhibitor, and is composed of twelve amino acids and a 3-hydroxypalmitoyl moiety (Figure 1).7~9) Since intramolecular attack to the ester bond by the ornithine amino group leads to a pH-dependent ring opening process, wehave investigated the preparation of novel analogs lacking the propensity to ring-open. In this paper, we describe the synthesis and antifungal activity of FR203903 (2), an ornithine-modifled analog of FR901469, prepared by a novel semi-synthetic approach. The synthetic routes to FR203903 (2) and the key coupling component 6 are outlined in Schemes 1 and 2. /3-Ketoester 3, easily obtained by coupling of myristoyl chloride with Meldrum's acid and subsequent methanolysis,10) was subjected to Ru(II)-BINAP catalyzed asymmetric hydrogenationn~13) to give /3-hydroxy ketone 4. The absolute configuration of 4 was shown to be (R) from the specific rotation ([a]£ -14.7° (c 1.00, CHC13) [lit.14) [a]% 14.3° (c 2.5, CHC13)]). The optical purity was determined to be over 99% ee by gas chromatography of the corresponding (*S)-a-methoxy-a-(trifluoromethyl)-

Site-specific Structural Transformation of the Novel Antifungal Cycle Depsipeptide FR901469. Synthesis and Biological Activity of FR203903.