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Organic Chemistry Highlights

Total Synthesis

Monday, March 7, 2022
Douglass F. Taber
University of Delaware

The Zhang Synthesis of Talassamine

The structure of talassamine (3), isolated from the epigeal part of Aconitum talassicum (Ranunculaceae), a perennial herb of Tibet and western China, was established by x-ray analysis. En route to 3, Min Zhang of Chongqing University cyclized the tosylhydrazone 1 to the hexacyclic diene 2 (J. Am. Chem. Soc. 2021, 143, 7088. DOI: 10.1021/jacs.1c01865).

The preparation of 1 began with the acyl oxazolidinone 4. Evans asymmetric aldol reaction followed by protection and reduction led to the alcohol 5. The derived aryl stannane was coupled with 3-bromocyclohexenone 6, leading to the enone 7. Oxidation of the alcohol to the aldehyde and condensation with methyl glycinate was followed by intramolecular dipolar cycloaddition, leading after protection to the amine 8. Reaction with the phosphorane 9 followed by reductive cleavage of the C-N bond led to a lactam, that was deprotected and alkylated to give 10. Exposure of the derived mesylate to NaOCH3 led via intramolecular N-alkylation to the ester 11. Oxidation to the lactam followed by reduction to the aldehyde and condensation with TsNHNH2 completed the assembly of the tosylhydrazone 1.

Heating with anhydrous K2CO3 converted the tosylhydrazone 1 to the diazoalkane 12. This was long-lived enough to combine with the Rh(II) catalyst to give an intermediate carbene, that added to the aromatic ring to give the cyclopropane 2. The more soluble Rh2(octanoate)4 was more effective in this application than the less-soluble, oligomeric Rh2(acetate)4.

Reduction of the lactam to the amine was followed by acid-mediated cleavage of the cyclopropane, that installed the requisite equatorial secondary hydroxyl group. Hydrogenation followed by protection led to the ketone 13. Desilylation was followed by oxidation and intramolecular aldol reaction to give the mesylate 14. Exposure of the derived alcohol to the Tebbe reagent led to 15. Dissolving metal removed the mesylate, after which allylic oxidation followed by reduction, deprotection, and oxidation of the secondary amine to the imine completed the synthesis of talassamine (3).

The approach outlined here to talassamine (3) underlines the strategic power of in situ-generated alkyl and dialkyl diazo intermediates, pioneered by Aggarwal (Angew. Chem. Int. Ed. 2001, 40, 1430, DOI: 10.1002/1521-3773(20010417)40:8<1430::AID-ANIE1430>3.0.CO;2-W); 1433, DOI: 10.1002/1521-3773(20010417)40:8<1433::AID-ANIE1433>3.0.CO;2-E). We can expect many more such applications.

D. F. Taber, Org. Chem. Highlights 2022, March 7.