The total synthesis of the dienoyl tetramic acid antibiotic (i)-tirandamycin B is described. The key transformations of the strategy include (1) cyclization of pyranone 14 with fluorosilicic acid to provide the 2,6-dioxabicyclo[3.3.1 Jnonane system of the natural product, (2) reductive removal of the benzyl ether from enone 15, and (3) attachment of the tetramic acid moiety by using the Schlessinger phosphonate protocol. Protection of the primary hydroxyl function of tirandamycin B as the triisopropylsilyl (TIPS) ether was crucial to the success of the strategy. Tirandamycin B (l)1 is a member of the 3-dienoyl tetramic acid family of antibiotics. This family includes several structurally related substances such as tirandamycin A (2),2 streptolydigin (3),3 nocamycin,4 and Bu-2313 A and B.5 These substances display a diversity of biological activities. For example, tirandamycin B has been shown to possess antimicrobial activity by interfering with the function of bacterial DNA-directed RNA

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A new class of potent dopamine D4 antagonists was discovered with selectivity over dopamine D2 and the α‐1 adrenoceptor. The lead compound was discovered by screening our compound collection. The structure–activity relationships of substituted isoindoline rings and the chirality about the hydroxymethyl side chain were explored. The isoindoline analogues showed modest differences in potency and selectivity. The S enantiomer proved to be the more potent enantiomer at the D4 receptor. Several analogues with greater than 100‐fold selectivity for D4 over D2 and the α‐1 adrenoreceptor were discovered. Several selective analogues were active in vivo upon oral or intraperitoneal administration. A chiral synthesis starting from either D‐ or L‐O‐benzylserine is also described.

A Total Synthesis of (±)-Tirandamycin B.-The key steps are cyclization of the pyranone (II), reductive removal of the benzyl protecting group from the enone (III) and condensation of the phosphonate (VII) with the aldehyde (VI). -(SHIMSHOCK, S. J.; WALTERMIRE, R. E.; DESHONG, P.; J. Am. Chem. Soc. 113 (1991) 23, 8791-8796; Dep. Chem. Biochem., Univ. Md.,