Organic Chemistry Portal
Organic Chemistry Highlights

Monday, December 20, 2021
Douglass F. Taber
University of Delaware

Diels-Alder Cycloaddition: Lepadin F (Chen), Lammelodysidine A (Molga/ Mlynarski/Grzybowski/Mrksich), Cannogenol (Nakazaki), cis-crotonin (Cai), Salvinorin A (Metz), Cephanolide A (Sarpong)

Lepadin F (4), isolated from the tunicate Didemnum sp, showed antiplasmodial and antitrypanosomal activity. Xiaochuan Chen of Sichuan University prepared the precursor 3 by the Diels-Alder cycloaddition of the enone 1 with the amino diene 2 (Chem. Eur. J. 2021, 27, 4141. DOI: 10.1002/chem.202004778).

Based on their analysis using the synthesis program Chematica, Karol Molga, Jacek Mlynarski and Bartosz A. Grzybowski of the Polish Academy of Sciences and Milan Mrksich of Northwestern University envisioned preparation of lammelodysidine A (7) by the internal cycloaddition of 5, leading to 6. Remarkably, the proposed cyclization proceeded smoothly, under microwave irradiation (Nature 2020, 588, 83. DOI: 10.1038/s41586-020-2855-y).

Cannogenol (10) is the aglycone of a family of cardiotonic steroids. Atsuo Nakazaki of Nagoya University assembled 10 by way of the cyclization of the pyrone 8 to 9 (J. Org. Chem. 2021, 86, 3605. DOI: 10.1021/acs.joc.0c02966).

Quan Cai of Fudan University also used a pyran 11 in the synthesis of cis-crotonin (14). Diels-Alder cycloaddition with enantiomerically-pure 12 to 11 promoted by a chiral Yb catalyst, followed by exposure of the intermediate silyl enol ether to HF, delived the ketone 13 (Angew. Chem. Int. Ed. 2020, 59, 18412. DOI: 10.1002/anie.202006841).

Salvinorin A (17), isolated from the leaves of the Mexican mint Salvia divinorum, is a potent κ opioid receptor agonist. En route to 17, Peter Metz of the Technische Universitšt Dresden cyclized the triene 15 to the tetracyclic lactone 16 (Chem. Eur. J. 2021, 27, 7968. DOI: 10.1002/chem.202100560).

The power of pyrone dienes was also illustrated by Richmond Sarpong of the University of California, Berkeley. In the course of a synthesis of cephanolide A (20), he demonstrated that formation of the silyl enol ether from the indanone 18 led directly to the pentacyclic lactone 19 (J. Am. Chem. Soc. 2021, 143, 2710. DOI: 10.1021/jacs.1c00293).

We note the passing on December 19th of Robert H. Grubbs of Caltech. Professor Grubbs, by making alkene metathesis readily available to all, had a seminal impact on the practice of organic synthesis.

D. F. Taber, Org. Chem. Highlights 2021, December 20.