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. 2020 Jan 23;5(4):2005-2014.
doi: 10.1021/acsomega.9b03990. eCollection 2020 Feb 4.

Combined Enzyme- and Transition Metal-Catalyzed Strategy for the Enantioselective Syntheses of Nitrogen Heterocycles: (-)-Coniine, DAB-1, and Nectrisine

Donald R Deardorff  1 , Scott W Niman  1 , Mark I Paulsen  1 , Anasheh Sookezian  1 , Meghan E Whalen  1 , Christopher J Finlayson  1 , Collrane Frivold  1 , Hilary C Brown  1 , Jeffrey S Cannon  1
Affiliations

Combined Enzyme- and Transition Metal-Catalyzed Strategy for the Enantioselective Syntheses of Nitrogen Heterocycles: (-)-Coniine, DAB-1, and Nectrisine

Donald R Deardorff et al. ACS Omega. .

Abstract

The enantioselective syntheses of (-)-coniine, DAB-1, and nectrisine have been developed, utilizing a complementary strategy of enzyme- and transition metal-catalyzed reactions. The initial stereocenter was set with >99% enantioselectivity via an enzyme-catalyzed hydrocyanation reaction. Substrate incompatibilities with the natural enzyme were overcome by tactical utilization of ruthenium-catalyzed olefin metathesis to functionalize an enzyme-derived (R)-allylic fragment. The piperidine and pyrrolidine alkaloid natural products were obtained by a route that leveraged regio- and stereoselective palladium-catalyzed 1,3-substitutive reactions.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Target alkaloids: (−)-coniine (1), DAB-1 (2), and nectrisine (3).
Scheme 1
Scheme 1. Retrosynthetic Analysis of (−)-Coniine and DAB-1
Scheme 2
Scheme 2. Synthesis of Building Blocks Utilizing the Oxynitrilase Enzyme
Figure 2
Figure 2
Competing π-allyl addition pathways.
Scheme 3
Scheme 3. Piperidine Synthesis by Ring-Closing Metathesis
Scheme 4
Scheme 4. Catalytic Reactions to Generate the Key Nitrogen Stereocenter
Scheme 5
Scheme 5. Synthesis of Polyhydroxylated Carbamate 18
Scheme 6
Scheme 6. Syntheses of DAB-1 and Nectrisine
See this image and copyright information in PMC

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