Total Synthesis of Sarpagine Alkaloid (−)-Normacusine B

Abstract

An asymmetric total synthesis of the sarpagine alkaloid (−)-normacusine B is presented. Salient features of this synthesis include a photocatalytic nitrogen-centered radical cascade reaction to assemble the tetrahydro­carbolinone skeleton, a titanium-mediated intramolecular amide-alkene coupling to construct the bridged azabicyclo­[3.3.1]­nonane moiety, and a nickel-catalyzed reductive Heck coupling to assemble the azabicyclo­[2.2.2]­octane ring system.

Stereocontrolled Synthesis of the Fully Glycosylated Monomeric Unit of Lomaiviticin A

“…The α-phenylselenyl ketone 26 was obtained in 62% yield by treatment of the diastereomerically pure diol 5 with diphenyldiselenide and cesium carbonate under an oxygen atmosphere. 18 The coupling constants between H5 and H6 were comparable in 26 and the diol 5 (2.6 and 3.3 Hz, respectively), suggesting that the cis ring fusion was maintained. Unfortunately, the yields of this transformation diminished on scale-up.…”

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (−)‐Trinervine, Vellosimine, (+)‐Normacusine B, and (−)‐Alstomutinine C

“…Subsequently, other asymmetric syntheses of sarpagine alkaloids were reported by Kutney, [7] Cook, [8] Gaich, [9] Takayama, [10] Kerr, [11] She, [12] Zhang, [13] Zhang, [14] and Qin. [15] Other interesting synthetic studies toward the 1-azabicyclo[2.2.2]octane core structures of the sarpagine alkaloids have also been documented. [16] A survey of previous syntheses revealed that significant efforts were mainly focused on the synthetic challenge of the highly strained N-bridgehead 1-azabicyclo[2.2.2]octane ring system, which has also served to demonstrate innovative methodology development.…”

“…The first asymmetric syntheses of (+)‐koumidine and (+)‐koumine were disclosed by Magnus [6] in 1989. Subsequently, other asymmetric syntheses of sarpagine alkaloids were reported by Kutney, [7] Cook, [8] Gaich, [9] Takayama, [10] Kerr, [11] She, [12] Zhang, [13] Zhang, [14] and Qin [15] . Other interesting synthetic studies toward the 1‐azabicyclo[2.2.2]octane core structures of the sarpagine alkaloids have also been documented [16] .…”

“…Gold‐catalyzed alkyne activation and 6‐ exo cyclization can provide the vinyl group that is suitable for divergent synthesis [6, 10, 12, 13] . Other innovative strategies include transition‐metal‐catalyzed cross‐coupling, [8c, 9a, 15] oxyanion‐Cope rearrangement, [8b] and radical‐type cycloaddition [14, 16a] . The common features of previous syntheses—which require either the prefunctionalization of coupling partners or the participation of transition‐metal catalysts—have motivated us to pursue a distinct strategy that simplifies the assembly of the 1‐azabicyclo[2.2.2]octane moiety by adopting a step‐economic oxidative coupling strategy.…”

Total Synthesis of Vinorine

“…Since the pioneering work (synthesis of ajmaline) accomplished by Masamune and co-workers in 1967, the total syntheses of sarpagine/ajmaline type alkaloids have attracted considerable attention from organic chemists in the past decades. ,, For the synthesis of sarpagine/ajmaline type alkaloids, there are two key issues toward the construction of these cage-like alkaloids, namely the formation of indole-fused 9-azabicyclo-[3.3.1]­nonane scaffold and the late stage cyclization to fuse the 1-azabicyclo[2.2.2]­octane moiety via assembling the C15–C20 bond (highlighted in Figure A with red shadow). Representative methodologies for the construction of the ABNS are (a) the Pictet–Spengler cyclization approaches to form the C2–C3 bond, ,, (b) the intramolecular Dieckmann condensation/Michael addition methodologies to construct the C15–C16 bond, ,, (c) the Friedel–Crafts acylation approach to build the C6–C7 bond, (d) the cycloaddition/annulation strategies, , (e) the transition metal mediated cyclizations, − and (f) the Mannich-type cyclization to form the C5–C16 bond. , …”