Total Synthesis of Brasilicardins A and C

Abstract

The first total synthesis of brasilicardins A and C, novel diterpenoid-saccharide-amino acid hybrid metabolites with unique immunosuppressive activity, is described. The key step is a Diels-Alder/reductive angular methylation sequence capitalizing on a trans-fused bicyclic α-cyano-α,β-enone as its precursor to construct the 8,10-dimethyl-trans/syn/trans-perhydrophenanthrene skeleton. Other notable features include an anti-selective aldol reaction, a stereocontrolled glycosylation of a C2 alcohol, and a one-pot, two-step global deprotection sequence that did not damage these sensitive molecules.

Sulfonyl Hydrazides in Organic Synthesis: A Review of Recent Studies

“…They were successfully used for the total synthesis of natural products, which included Brasilicardins A and C, (+)‐Frondosin A, (+)‐Tanikolide, Lundurines A−C, Onoseriolid, Isobolivianine, (−)‐Crinipellin A, Panaginsene, Echinopines, (+)‐ and (−)‐Isolaurepan, (−)‐Strychnofoline, (−)‐Clovan‐2,9‐dione, (+)‐Sarcophytin, [2 ° ] (+)‐Chatancin, [2 ° ] (−)‐3‐Oxochatancin, [2 ° ] (+)‐Cyperolone . In these cases, TsNHNH 2 reacted with aldehydes (or ketones) to form hydrazones that underwent cycloaddition or reduction subsequently. Banford‐Stevens reaction and Shapiro reaction were reported in this decade.…”

“…In these cases, TsNHNH 2 reacted with aldehydes (or ketones) to form hydrazones that underwent cycloaddition or reduction subsequently. Banford‐Stevens reaction and Shapiro reaction were reported in this decade.…”

Asymmetric Total Synthesis of Brasilicardins

“…Zuschriften succeeded in glycosylation of the C3-protected aglycon of 1 with the trichloroacetimidate donor of the disaccharide unit, [8,10] this procedure could not be applied to diol 8 because the formation of complex mixtures including the inseparable C3 glycosylation product and degradation of 8 were observed. To our delight, after extensive screening of glycosyl donors and their activation conditions,t he metallocene-based activator Cp 2 HfCl 2 /AgOTf [27] allowed the regio-and stereoselective coupling of peracetyl glycosyl fluoride 38 (2 equiv) with 8 to give the desired a-glycoside 39 (with 43 %of8 recovered).…”

“…[6][7][8][9] However,t heir complex and unique three-dimensional structure has hampered their chemical synthesis.D espite considerable synthetic efforts over the last twenty years,t he sole successful total synthesis was the de novo construction of 1 and 3 by Anada, Hashimoto,a nd co-workers in 2017, [10] which involved sequential functionalization of the Wieland-Miescher ketone derivative and aD iels-Alder reaction/reductive angular methylation sequence [7] (Scheme 1a). [6][7][8][9] However,t heir complex and unique three-dimensional structure has hampered their chemical synthesis.D espite considerable synthetic efforts over the last twenty years,t he sole successful total synthesis was the de novo construction of 1 and 3 by Anada, Hashimoto,a nd co-workers in 2017, [10] which involved sequential functionalization of the Wieland-Miescher ketone derivative and aD iels-Alder reaction/reductive angular methylation sequence [7] (Scheme 1a).…”

Chemical Synthesis of Brasilicardins

“…Prior to our total synthesis, Anada and Hashimoto s 2017 syntheses of 1 and 3, 4 highlighted by a Diels Alder reaction/ reductive angular methylation sequence 3a for the construction of the ABC ring (Scheme 1), represented the sole successful total synthesis of brasilicardins. We began our synthetic studies of brasilicardins in 2008, aiming for the development of an ef cient route that was suf ciently exible to provide access to all of the brasilicardins A D (1 4), while allowing for the synthesis of various analogs and substructures for biological testing.…”