Concise Syntheses of (+)-Macrosphelides A and B

Abstract

[reaction: see text]. Unified and highly convergent total syntheses of (+)-macrosphelides A and B are described. Key features of the syntheses include (1) concise synthesis of the optically active delta-hydroxy-gamma-keto alpha,beta-unsaturated acid fragment via the direct addition of a trans-vinylogous ester anion equivalent to the readily available Weinreb amide and (2) facile construction of the 16-membered macrolide core of the macrosphelide series via an intramolecular nitrile-oxide cycloaddition (INOC).

Total Synthesis of Punctaporonin C by a Regio‐ and Stereoselective [2+2]‐Photocycloaddition

“…Acidic elimination conditions were counterindicated by the acid-labile protecting groups, which is the reason why we screened elimination reactions under neutral conditions. The Burgess reagent [31] delivered only the respective methylcarboxysulfamate [32] by an addition reaction, while thiocarbonyldiimidazole (Im 2 CS) induced a quantitative elimination. Key to the success of this reaction was the use of a stoichiometric amine base [DMAP = 4-(N,N-dimethylamino)pyridine] to aid proton removal at 40 8C in the absence of solvent.…”

Binary fluorous tagging enables the synthesis and separation of a 16-stereoisomer library of macrosphelides

“…To test this idea of double tagging/double demixing, we selected the stereoisomeric natural products macrosphelides A, D and E, because they and their congeners have high anti-cancer activity, 18-22 because their syntheses are well established, 20,28-31 and especially because they have two identical sub-units (C5–C9 and C11– C15). Accordingly four stereoisomers of this sub-unit ( 2 , Figure 3a) will provide a stereoisomer library of macrosphelides containing all 16 diastereomers with the S configuration fixed at C3 and all possible configurations at the other four stereocenters.…”

Development of an Advanced Synthetic Route to Macrosphelides and Its Application to the Discovery of a More Potent Macrosphelide Derivative

“…However, its low potency still hampers further developments. To solve this limitation, a variety of approaches including total synthesis [10][11][12][13][14][15][16][17][18][19][20], medicinal chemistry [21][22][23], combinatorial chemistry [24], and fluorinated chemistry [25] have been carried out to establish the SAR and discover more promising derivatives of 1. As a result, it has been possible to improve its various biological activities slightly after extensive efforts, including the confirmation of natural isomer structures and the discovery of potent derivatives such as aza-1, ring size modified-1, fluorinated-1 and thiazoline linked-1.…”

“…With alkynone 10 in hand, stereoselective reduction of the ketone moiety was executed. Based on the reaction pattern of similar systems [17,31], Super-Hydride was chosen to obtain a chelation-controlled reduction product. Gratifyingly, the desired secondary alcohol 9 was obtained exclusively as the desired isomer, which was subjected to the Koide procedure.…”