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. 2022 Jun 29;144(25):11088-11093.
doi: 10.1021/jacs.2c04487. Epub 2022 Jun 14.

Symmetry-Driven Total Synthesis of Myrioneurinol

Jake M Aquilina  1 , Myles W Smith  1
Affiliations

Symmetry-Driven Total Synthesis of Myrioneurinol

Jake M Aquilina et al. J Am Chem Soc. .

Abstract

We report a total synthesis of the Myrioneuron alkaloid myrioneurinol enabled by the recognition of hidden symmetry within its polycyclic structure. Our approach traces myrioneurinol's complex framework back to a symmetrical diketone precursor, a double reductive amination of which forges its central piperidine unit. By employing an inexpensive chiral amine in this key desymmetrizing event, four stereocenters of the natural product including the core quaternary stereocenter are set in an absolute sense, providing the first asymmetric entry to this target. Other noteworthy strategic maneuvers include utilizing a bicyclic alkene as a latent cis-1,3-bis(hydroxymethyl) synthon and a topologically controlled alkene hydrogenation. Overall, our synthesis proceeds in 18 steps and ∼1% yield from commercial materials.

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Figures

Figure 1.
Figure 1.
(A) Representative Myrioneuron alkaloids. (B) Prior racemic total syntheses of myrioneurinol (2). (C) Our symmetry-driven approach to myrioneurinol.
Scheme 1.
Scheme 1.
Synthesis of tetracyclic alkene 19 via desymmetrizing double reductive amination and its attempted stereoselective hydrogenation.
Scheme 2.
Scheme 2.
Completion of (±)-myrioneurinol (2) via a topologically controlled HAT hydrogenation.
Scheme 3.
Scheme 3.
Formal synthesis of (−)-myrioneurinol [(−)-2] via asymmetric desymmetrization of 14.
See this image and copyright information in PMC

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