Direct Aldol Strategy in Enantioselective Total Synthesis of Thuggacin B

Abstract

An enantioselective total synthesis of thuggacin B, a natural product exhibiting antibiotic activity against Mycobacterium tuberculosis, is described. Asymmetric direct aldol reactions promoted by Cu and Zn catalysts play a pivotal role in constructing four stereogenic centers. The use of direct aldol reactions as the initial steps for the synthesis of two key fragments allowed the construction of the other stereogenic centers through chirality transfer.

Total and Semi‐Syntheses of Antimicrobial Thuggacin Derivatives

“…Both published thuggacin syntheses reported macrocyclisation via the carbinol at C17 to yield 2 as a major product and 1 as a minor by‐product 3. 4 In the present study, we also noted the presence of both macrocycles for the oxazole analogues of the thuggacins. Finally, in the absence of the aliphatic side chain at C2, the formation of thuggacin C derivative 38 is favoured because it is presumably the thermodynamically more stable macrocycle.…”

“…and our group (Scheme ) 2. In addition to reported partial syntheses,3 Shibasaki and co‐workers recently disclosed a second successful synthesis of thuggacin B ( 2 ) 4…”

Leptolyngbyolides, Cytotoxic Macrolides from the Marine Cyanobacterium Leptolyngbya sp.: Isolation, Biological Activity, and Catalytic Asymmetric Total Synthesis

“…The resultant thioamide moiety of the aldol products is a versatile functionality from which diverse substructures, including aldehydes, methylketones, primary alcohols, carboxylic acids, β‐ketoester, amines, and amides, are accessible in a single operation . This catalytic asymmetric process was incorporated into the reaction schemes toward the total synthesis of biologically relevant compounds such as thuggacin B, membrenones, caprazamycin B, and atorvastatin ,. Moreover, iterated use of this reaction facilitates the construction of the polypropionate backbone of natural products; propionate‐derived thioamide gave the corresponding aldol adducts in good to excellent enantio‐ (up to >99 % ee ) and syn ‐selectivity (up to >20:1), after which the thioamide substructure was converted into a formyl group to serve in the subsequent thioamide‐aldol reaction.…”

“…The cyclic ether structure should be formed through allylative cyclization of δ‐hydroxy enal 11 , which was expected to be prepared from cross metathesis with homoallylic alcohol 12 , a product of Krische allylation . The primary alcohol 13 should be readily obtained by sequential manipulation of the functional group from the product ( 14 ) of the initial catalytic asymmetric thioamide‐aldol reaction of 15 and 16 , which we already optimized in our synthetic studies of thuggacin B and scytophycin C . Segment B ( 9 ) should be readily available by the hydrogenation of 17 , which can be prepared by cross metathesis between the two olefins, 18 and 19 ; the latter has been reported previously .…”

Catalytic asymmetric synthesis of key intermediate for scytophycin C

“…This reaction is advantageous due to its atomeconomical proton transfer process without the need for preactivation of a prenucleophile by a structural modification (i.e., formation of silylenol ether), and the feasibility of the thioamide substructure transformation into variety of functionalities. The reaction was effective for the enantio-and diastereoselective synthesis of natural products and clinical drug such as thuggacin, 6 (-)-membrenones, 7 caprazamycin B, 8 and atorvastatin. 9 The present formal total synthesis of scytophycin C started with the catalytic asymmetric thioamide-aldol reaction using 5 and 6 as the substrates (Scheme 1).…”