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. 2020 Jul 29;142(30):12937-12941.
doi: 10.1021/jacs.0c05766. Epub 2020 Jul 7.

Synthesis of Anhydroryanodol

Kang Du  1 , Matthew J Kier  1 , Zachary D Stempel  1 , Valer Jeso  1 , Arnold L Rheingold  2 , Glenn C Micalizio  1
Affiliations

Synthesis of Anhydroryanodol

Kang Du et al. J Am Chem Soc. .

Abstract

A stereoselective entry to ryanoids is described that culminates in the synthesis of anhydroryanodol and thus the formal total synthesis of ryanodol. The pathway described features an annulation reaction conceived to address the uniquely complex and highly oxygenated polycyclic skeleton common to members of this natural product class. It is demonstrated that metallacycle-mediated intramolecular coupling of an alkyne and a 1,3-diketone can proceed with a highly functionalized enyne and with outstanding levels of stereoselection. Furthermore, the first application of this technology in natural product synthesis is demonstrated here. More broadly, the advances described demonstrate the value that programs in natural product total synthesis have in advancing organic chemistry, here through the design and realization of an annulation reaction that accomplishes what previously established reactions do not.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Introduction to ryanoids and anhydroryanodol.
Figure 2.
Figure 2.
Initial retrosynthetic analysis of ryanoids featuring an oxidative annulation reaction between an enyne and a 1,3-diketone.
Figure 3.
Figure 3.
Synthesis of the annulation substrate 12.
Figure 4.
Figure 4.
Investigation of an oxidative annulation and observation of an undesired late-stage Payne rearrangement.
Figure 5.
Figure 5.
Preparation of (+/−)-anhydroryanodol from 1,3-diketone 12; formal total synthesis of (+/−)-ryanodol.
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