Abstract
It was developed a concise synthetic route resulting in the first syntheses of bis-Strychnos alkaloids (-)-sungucine, (-)-isosungucine, and (-)-strychnogucine B from commercially available (-)-strychnine. Employing a highly convergent synthetic strategy, it was demonstrated that both Strychnos monomers could be efficiently prepared from commercially available (-)-strychnine. The venerable Mannich reaction was enlisted to join the two Strychnos monomers in a biomimetic fashion. Subsequent epimerization and olefin isomerization yielded (-)-strychnogucine B. Functional group manipulation transformed (-)-strychnogucine B into (-)-sungucine and (-)-isosungucine. Computational chemistry was employed to rationalize the regiochemical course of key steps en route to the bis-Strychnos targets.
Highlights
As part of our research program aimed at developing and applying novel synthetic methods for efficiently accessing complex indole alkaloids over the past decade,[10,11,12,13,14,15,16,17,18,19,20] we recently communicated the first enantiospecific syntheses of bis-Strychnos alkaloids 1-3.21 we provide a full account of our synthetic efforts, from failure to success, employed in the preparation of these unique natural products
For the retrosynthesis of (–)-3, we disconnected at the C23–C5’ bond, which could arise from the late-stage biomimetic coupling of a Northern C23‐anionic synthon with a Southern C5’-cationic synthon
The Mg amide enolate in turn could be obtained from the Li amide enolate via transmetallation with MgBr2 OEt2.70,71 For the generation of iminium ion 11 from the Southern fragment 12, BF3 OEt2 was employed because of its successful reaction with carbinolamine 8 in our model Mukaiyama-Mannich studies (Scheme 4)
Summary
Since the first isolation of the infamous indole alkaloid strychnine from the African plant Strychnos icaja by Sandberg et al.,[1] many other mono- and dimeric indole alkaloids have been isolated from the roots of this African Strychnos species.[2,3,4,5,6] Among them, the unsymmetric dimeric Strychnos alkaloids (–)-sungucine (1),[3,4] (–)-isosungucine (2),[4] and (–)-strychnogucine B (3)[5] captured our attention owing to their potential anticancer and antiplasmodial activities[4,5,6,7,8,9] in addition to structural complexity (Figure 1). As part of our research program aimed at developing and applying novel synthetic methods for efficiently accessing complex indole alkaloids over the past decade,[10,11,12,13,14,15,16,17,18,19,20] we recently communicated the first enantiospecific syntheses of bis-Strychnos alkaloids 1-3.21 we provide a full account of our synthetic efforts, from failure to success, employed in the preparation of these unique natural products
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