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Organic Chemistry Highlights

Total Synthesis

Monday, June 6, 2022
Douglass F. Taber
University of Delaware

The Dai Synthesis of Hamigeran M

Of the several hamigerans isolated from the marine sponge Hamigera tarangaensis, only two contain nitrogen. Mingji Dai of Purdue University devised a route to one of those, hamigeran M (3), using the oxaxole ring as a central organizing element (J. Am. Chem. Soc. 2021, 143, 20084. DOI: 10.1021/jacs.1c11060).

The benzene ring of 3 was prepared by Ir-catalyzed borylation of p-cresol 4. The borate 5 was stable to purification by silica gel chromatography.

Alkylation of commercial 6 followed by retro-Dieckmann/Dieckmann reorganization delivered the β-keto ester 7. Coupling of the derived enol triflate with 5 led to the lactone 8. After some experimentation, diastereoselective reduction to 9 was accomplished by Co-catalyzed hydrogen-atom-transfer (HAT). Alkylation to 10 followed by combination with the metalated oxazole 11 completed the assembly of the triflate 1.

Further metalation of the oxazole 1 led to the organozinc 12, that was cyclized via Pd-catalyzed Negishi coupling to the cycloheptanone 2.

To complete the synthesis, the TIPS group was removed. Rh-catalyzed ortho borylation followed by oxidation then delivered the phenol 13. Bromination substantially favored the ortho position, to give hamigeran M (3).

Enantioenriched organosilanes have great potential for pharmaceutical development. Jianbo Wang of Peking University demonstrated that ring expansion of the prochiral ketone 14 with trifluoromethyl diazomethane 15 led to cyclic silane 16 in high de and ee (Angew. Chem. Int. Ed. 2022, 61, e202115098. DOI: 10.1002/anie.202115098). Frances Arnold of Caltech reviewed biocatalytic transformations of silicon (ACS Central Sci. 2021, 7, 944. DOI: 10.1021/acscentsci.1c00182).

D. F. Taber, Org. Chem. Highlights 2022, June 6.