1239897-05-2Relevant articles and documents
Addition of heteroatom nucleophiles to ketene dimers
Elledge, Beth,Harzmann, Gero D.,Ibrahim, Ahmad A.,Kerrigan, Nessan J.,Nalla, Divya,van Raaphorst, Max
, (2021/05/26)
An investigation of the reaction of heteroatom nucleophiles with ketene dimers, with an emphasis on a discussion of diastereoselectivity where applicable, is described. During this study we focused on the reaction of nitrogen-centred nucleophiles (Weinreb amine, lithiated Weinreb amide, and an amino acid derivative), and oxygen-centred nucleophiles (alkoxides). Simple Weinreb amide derivatives of ketene heterodimers were formed in moderate to excellent yield (up to 89%) and excellent retention of chirality (ee up to 91%), albeit with poor diastereoselectivity. The 2-pyridone-catalysed amine ring-opening was also applied to the asymmetric synthesis of a cinnabaramide A intermediate. Finally, the use of amide and alkoxide ring-opening nucleophiles enabled the development of a sequential one-pot reaction with benzaldehyde to afford δ-lactones in moderate yields (up to 47%) but with good diastereoselectivity (dr up to 24:1).
Bioinspired total synthesis and human proteasome inhibitory activity of (-)-salinosporamide A, (-)-homosalinosporamide A, and derivatives obtained via organonucleophile promoted bis-cyclizations
Nguyen, Henry,Ma, Gil,Gladysheva, Tatiana,Fremgen, Trisha,Romo, Daniel
supporting information; experimental part, p. 2 - 12 (2011/03/23)
A full account of concise, enantioselective syntheses of the anticancer agent (-)-salinosporamide A and derivatives, including (-)-homosalinosporamide, that was inspired by biosynthetic considerations is described. The brevity of the synthetic strategy stems from a key bis-cyclization of a β-keto tertiary amide, which retains optical purity enabled by A1,3-strain rendering slow epimerization relative to the rate of bis-cyclization. Optimization studies of the key bis-cyclization, enabled through byproduct isolation and characterization, are described that ultimately allowed for a gram scale synthesis of a versatile bicyclic core structure with a high degree of stereoretention. An optimized procedure for zincate generation by the method of Knochel, generally useful for the synthesis of salino A derivatives, led to dramatic improvements in side-chain attachment and a novel diastereomer of salino A. The versatility of the described strategy is demonstrated by the synthesis of designed derivatives including (-)-homosalinosporamide A. Inhibition of the human 20S and 26S proteasome by these derivatives using an enzymatic assay are also reported. The described total synthesis of salino A raises interesting questions regarding how biosynthetic enzymes leading to the salinosporamides proceeding via optically active β-keto secondary amides, are able to maintain the stereochemical integrity at the labile C2 stereocenter or if a dynamic kinetic resolution is operative.
A1,3-strain enabled retention of chirality during bis-cyclization of β-ketoamides: Total synthesis of (-)-salinosporamide A and (-)-homosalinosporamide A
Nguyen, Henry,Ma, Gil,Romo, Daniel
supporting information; experimental part, p. 4803 - 4805 (2010/09/16)
A concise, enantioselective synthesis of the Phase I anticancer agent, (-)-salinosporamide A, is described. The brevity of the described strategy stems from a key bis-cyclization of a β-keto tertiary amide, accomplished on gram scale, which retains optical purity enabled by A1,3-strain rendering epimerization slow relative to the rate of bis-cyclization. The versatility of the strategy for derivative synthesis is demonstrated by the synthesis of (-)-homosalinosporamide A.
