Total Synthesis of (−)-Tirandamycin C Utilizing a Desymmetrization Protocol

Abstract

A highly stereoselective total synthesis of (-)-tirandamycin C has been achieved following a desymmetrization protocol developed in our group, Horner-Wadsworth-Emmons olefination, acid-catalyzed ketalization, Still-Gennari (Z)-selective olefination, and Dieckmann cyclization as key reactions.

Naturally occurring tetramic acid products: isolation, structure elucidation and biological activity

“…17944 in 2011. 102 Tirandamycins H-J (109,112,113) were subsequently isolated from the same strain following the application of medium optimization methods. 103 Espinosa and co-workers re-isolated tirandamycin A from the marine-derived Streptomyces sp.…”

“…111,112 More recently, the total synthesis of tirandamycin C was achieved. 113,114 Similar to streptolydigin, tirandamycin A is an inhibitor of RNA polymerase interfering with transcription initialization and elongation although its activity in this manifold is inferior to streptolydigin by $40 fold. 115 The tirandamycins display numerous activities and the C-18 hydroxyl group along with different oxidative modications in the bicyclic ketal, are essential to tirandamycin activity.…”

Catalytic asymmetric synthesis of (S,4E,15Z)-docosa-4,15-dien-1-yn-3-ol, an antitumor marine natural product

“…13 Treatment of THP ether 5 with p-toluenesulfonic acid furnished acetylenic alcohol 6, 14 which was oxidized to acetylenic aldehyde 7 in 91% yield with PhI(OAc) 2 and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). 15 …”

“…16 Finally, diolefinc alcohol 9 was obtained in 89% yield via the selective reduction of 8 with a P2-Ni system, 17 followed by oxidation to give diolefinc aldehyde 10 with PhI(OAc) 2 and TEMPO. 15 With diolefinc aldehyde 10 in hand, we accomplished the synthesis of the marine natural product 1 (Scheme 2). The enantioselective addition of trimethylsilylacetylene to 10 provided chiral propargyl alcohol 11 in 81% yield and with 80% ee using 20 mol % of the (R,R)-ProPhenol ligand.…”

Recent Advances in the Total Synthesis of Tetramic Acid-Containing Natural Products

“…Obviously, the racemic tetramic acid fragment 33 could be easily accessed by subjecting phosphonate 31 to glycine methyl ester to provide the amide 32 that further proceeded with a typical Lacey-Dieckmann cyclization and a DMB protection (Schlessinger et al had prepared similar tetramic acid core via the same method in his synthesis of tirandamycin A; see [48]) [49]. In contrast, the bicyclic ketal fragment 36 asks for precautious design to achieve the desired stereochemistry presented in tirandamycin C [25,48,[50][51][52][53][54][55][56]. The starting homoallylic alcohol 34, prepared from the mismatched double asymmetric stannylcrotylboration of an aldehyde, was treated with excess MeLi at low temperature to trigger the formation of the lactol intermediate C.…”