Enantioselective Total Syntheses of (−)-FR901483 and (+)-8-epi-FR901483

Abstract

The enantioselective total syntheses of the potent immunosuppressant FR901483 (1) and its 8-epimer (47) have been accomplished. Our approach features the use of building block 6 as the chiron, the application of the one-pot amide reductive bis-alkylation method to construct the chiral aza-quaternary center (dr = 9:1), regio- and diastereoselective intramolecular aldol reaction to build the bridged ring, and RCM to form the 3-pyrrolin-2-one ring.

Synthetic approaches towards alkaloids bearing α-tertiary amines

“…298 In this case, an Aubé-Schmidt reaction of azide 209 provided access to lactam 212, featuring the ATA of FR901483 (209 / 212, Scheme 46b). Additional synthetic strategies to set the ATA in FR901483 include a triple Michael addition, 299 a one-pot bisalkylation, 300,301 an aza-Cope rearrangement/Mannich cyclization 302,303 and an oxidative dearomatization. 297 The members of the galbulimima alkaloid family, such as himgaline and himandrine, also possess an ATA-containing quinolizidine core (Fig.…”

Recent Advances in the Synthesis of Hydrogenated Azocine-Containing­ Molecules

“…In their work on the total syntheses of (–)-FR901483 and (+)-8- epi -FR901483, Huang and co-workers successfully used the aldol condensation for the construction of the azocine ring. 101 102 Starting from the known chiron ( R )-1-allyl-3-benzyloxypiperidine-2,5-dione, piperidin-3-ol 324 was obtained in four steps. The oxidation of 323 gave a ketone that underwent an intramolecular aldol ring-closure reaction forming azocine derivative 324 (Scheme 95 ).…”

Amide activation: an emerging tool for chemoselective synthesis

“…[53][54][55] The (sequential) intermolecular double addition of carbon nucleophiles is another viable process that enables the formation of valuable structures, 56,57 such as biologically active sparteine derivatives (82) (Scheme 16a), 58 and as such this approach has also found application in natural product synthesis. [59][60][61] For example, this strategy has been applied to Huang's synthesis of FR901483 (86), using the added moieties for double cyclisation, 60 and cephalotaxine (90), employing ring-closing metathesis for the formation of spirocyclic intermediate 89 (Scheme 16b). 61…”