69(P-53) Asymmetric Synthesis of Macrolactin A Analogue
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Macrolactin A, which was isolated from a deep sea marine bacterium in 1989, exhibits a broad spectrum of activity with significant antiviral and cancer cell cytotoxic properties, for example controlling human HIV replication and inhibiting Herpes simplex types I and II. Because of its unique structural architecture and broad therapeutic application, Macrolactin A has been an attractive target for total synthesis and has further led to the development of novel synthetic methodology. However, it would be difficult to apply Macrolactin A for clinical use due to its structural instability. Therefore, we designed new structural analogues of Macrolactin A by replacing the (8E,10Z)-dienic system to a more rigid aromatic ring. We report herein the asymmetric synthesis of Macrolactin A analogue. Our initial strategy involved the asymmetric addition of conjugated dienylanion species derived from Fragment A to the aldehyde (Fragment B). The C23 stereocenter of Fragment A was introduced by asymmetric methylation with (+)-TADDOL as a chiral ligand, and the C7 and C13 stereocenters of Fragment B were constructed by asymmetric propargylation according to Yamamoto's procedure and asymmetric aldol addition with (S)-4-isopropyl-1,3-thiazolidine-2-thione, respectively. The absolute configurations of these stereocenters (C7, C13) were determined by modified Mosher's method. Unfortunately, the reaction of dienylzinc species prepared from Fragment A with Fragment B afforded no addition products, while the desired product 14 could be obtained by the Cr(II)-mediated cross-coupling in moderate yield with no stereoselectivity. To improve the stereoselectivity of C15 stereogenic center, we developed a new synthetic strategy involving isomerization of ynone 23 to E,E-conjugated dienone followed by diastereoselective reduction of β-hydroxyketone 24. Subsequent CuTC [copper(1) 2-thiophenecarboxylate]-mediated coupling with methyl (Z)-3-iodopropenoate gave the macrocyclization precursor 26 in much higher yield than the palladium-catalyzed Stille cross-coupling. Macrolactonization using a Yamaguchi protocol followed by deprotection of the protected macrocycle 28 gave the desired Macrolactin A analogue 1.
