Total synthesis

About: Total synthesis is a research topic. Over the lifetime, 25578 publications have been published within this topic receiving 489319 citations.

Total synthesis of thiostrepton. Assembly of key building blocks and completion of the synthesis.

Abstract: The completion of the total synthesis of thiostrepton (1) is described. The synthesis proceeded from key building blocks 2-5, which were assembled into a growing substrate that finally led to the target molecule. Thus, the dehydropiperidine peptide core 2 was, after appropriate manipulation, coupled to the thiazoline-thiazole fragment 3, and the resulting product was advanced to intermediate 11 possessing the thiazoline-thiazole macrocycle. The bis-dehydroalanine tail equivalent 4 and the quinaldic acid fragment 5 were then sequentially incorporated, and the products so obtained were further elaborated to forge the second macrocycle of the molecule. Several roadblocks encountered along the way were systematically investigated and overcome, finally opening the way, through intermediates 20, 32, 44, 45, and 46, to the targeted natural product, 1.

Asymmetric total synthesis of spongistatins 1 and 2.

Abstract: The total synthesis of spongistatin 1 (1) and spongistatin 2 (2) has been achieved through an advanced-stage intermediate. The synthesis is highlighted by a highly convergent assembly of the four k...

Total Synthesis of Rapamycin and Demethoxyrapamycin

Abstract: Rapamycin (1) and demethoxyrapamycin (2) have gained prominence as members of a growing family of macrocyclic natural products with marked immunosuppressive properties.' These targets have stimulated intensive synthetic activity, including three total syntheses of le2 Rapamycin and its structurallyrelated cousin FK506 both bind to the cytosolic immunophilin FKBP, a strict requirement for the observed physiological re~ponse.~ Although the specific role of 1 in signal transduction and immunosuppression remains unclear, it has been established that rapamycin interferes with a Ca2+-independent signaling pathway emanating from the IL-2 r e~ep to r .~ From the retrosynthetic perspective (Scheme l), we envisioned the elaboration of rapamycin and the 27-demethoxy congener via couplings of fully functionalized ABC fragments with a common DE element, all derived in turn from the building blocks A-E.5 Final assembly of the macrocycle could then be effected by intermolecular acylation at C(34) and intramolecular Pd(0)-catalyzed Stille coupling, or via initial formation of the triene seco acid followed by macrolactonization. Herein we report the application of the former strategem to the total syntheses of rapamycin (1) and demethoxyrapamycin (2). This f i s t successful route to 2 confirmed the proposed structure, which until now was assigned solely on the basis of spectral comparisons with l . l b Our highly convergent approach is also intended to permit the straightforward preparation of designed analogs. The ABC fragment of demethoxyrapamycin derived from the previously described AB acetonide (+)-3 (Scheme 2).5 Following ketal hydrolysis, standard manipulations provided a highly acid-labile terminal epoxide which was used without purification in coupling to dithiane (-)-CS5 Silylation of the resultant C(28) alcohol afforded (+)-4.6 To introduce the requisite C(27) oxygen in the analogous rapamycin ABC subunit (7, Scheme 3), we employed aldehyde (+)-66 as an electrophilic AB component. The aldehyde was assembled via lithiation of dithiane (+)-5,5 alkylation with primary iodide (-)-A,5 and acetal hydrolysis. Metalation of dithiane (-)-C and addition to 6 then furnished the epimeric