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.2018 May 23;140(20):6483-6492.
doi: 10.1021/jacs.8b03404. Epub 2018 May 15.

Enantioselective Total Syntheses of Methanoquinolizidine-Containing Akuammiline Alkaloids and Related Studies

Affiliations

Enantioselective Total Syntheses of Methanoquinolizidine-Containing Akuammiline Alkaloids and Related Studies

Elias Picazo et al. J Am Chem Soc..

Abstract

The akuammiline alkaloids are a structurally diverse class of bioactive natural products isolated from plants found in various parts of the world. A particularly challenging subset of akuammiline alkaloids are those that contain a methanoquinolizidine core. We describe a synthetic approach to these compounds that has enabled the first total syntheses of (+)-strictamine, (-)-2( S)-cathafoline, (+)-akuammiline, and (-)-Ψ-akuammigine. Our strategy relies on the development of the reductive interrupted Fischer indolization reaction to construct a common pentacyclic intermediate bearing five contiguous stereocenters, in addition to late-stage formation of the methanoquinolizidine framework using a deprotection-cyclization cascade. The total syntheses of (-)-Ψ-akuammigine and (+)-akuammiline mark the first preparations of akuammiline alkaloids containing both a methanoquinolizidine core and vicinal quaternary centers. Lastly, we describe the bioinspired reductive rearrangements of (+)-strictamine and (+)-akuammiline to ultimately provide (-)-10-demethoxyvincorine and a new analogue thereof.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Representative methanoquinolizidine-containing akuammiline alkaloids.
Figure 2.
Figure 2.
Synthetic routes to 16-epi-2(S)-cathafoline (35).
Figure 3.
Figure 3.
Structural rearrangement to access pyrrolidinoindolines (−)-10-demethoxyvincorine (57) and58.
Scheme 1.
Scheme 1.
Retrosynthetic Analysis of (+)-Strictamine (1) and (−)-2(S)-Cathafoline (2)
Scheme 2.
Scheme 2.
Trost Desymmetrization and Synthesis of Enone 16
Scheme 3.
Scheme 3.
Gold-Catalyzed Cyclization To Construct the [3.3.1]-Azabicycle and Elaboration to Enal 20
Scheme 4.
Scheme 4.
Synthesis of Ketolactone 9, the Substrate for the Reductive Fischer Indolization Reaction
Scheme 5.
Scheme 5.
Reductive Interrupted Fischer Indolization Reaction Delivers 6
Scheme 6.
Scheme 6.
Undesired C16 Epimerization
Scheme 7.
Scheme 7.
Synthesis of 16-epi-Strictamine (34)
Scheme 8.
Scheme 8.
Total Syntheses of (+)-Strictamine (1) and (−)-2(S)-Cathafoline (2)
Scheme 9.
Scheme 9.
Retrosynthetic Analysis of (−)-Ψ-Akuammigine (4)
Scheme 10.
Scheme 10.
Scalable Preparation of Aldehyde 42
Scheme 11.
Scheme 11.
Attempted Introduction of the Furoindoline Motif and Undesired Isomerization To Afford 46
Scheme 12.
Scheme 12.
Reassessment of Synthetic Approach
Scheme 13.
Scheme 13.
Introduction of the Methanoquinolizidine Framework and Fortuitous Amine–Borane Complexation
Scheme 14.
Scheme 14.
Total Synthesis of (−)-Ψ-Akuammigine (4)
Scheme 15.
Scheme 15.
Total Synthesis of (+)-Akuammiline (3)
See this image and copyright information in PMC

References

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