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Organic Chemistry Highlights

Total Synthesis

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

The Gao Synthesis of Perovskatone D and Perovskone

Perovskone (4), isolated from Perovskia abratanoides, contains a complex heptacyclic framework and eight adjacent stereogenic centers. En route to 4 and other Salvia triterpenoids, Shuanhu Gao of East China Normal University set the absolute configuration of the ring system by photolysis of the Ti-TADDOL complex of the aldehyde 1 with the aldehyde 2 (J. Am. Chem. Soc. 2021, 143, 6370. DOI: 10.1021/jacs.1c02674). Majetich described an alternative strategy (not illustrated) for establishing the absolute configuration of these natural products (Tetrahedron 2011, 67, 10129. DOI: 10.1016/j.tet.2011.09.072).

The aldehyde 1 was readily prepared following the Moore protocol from commercial dimethyl squarate 5. Addition of isopropyl Grignard 6 followed by trifluoroacetic anhydride led to 7. Addition of the Li reagent derived from 8 followed by thermal rearrangement and methylation gave 9, that was formylated with 10 to give 1.

The preparation of the aldehyde 2 began with the inexpensive ketone 11. The derived β-keto ester was cyclized to 12, that was O-benzylated, leading to the enol ether 13. Reduction followed by oxidation then completed the synthesis of 2.

The photochemically-driven combination of 1 and 2 was envisioned as proceeding via the photo enol 14. The chiral backbone of the Ti complex imparts a twist to that intermediate, favoring one diastereomer over the other. The crystalline product 3 was readily brought to near enantiopurity.

The aldehyde 3 was oxidized, then debenzylated. The resulting keto aldehyde was selectively reduced to the alcohol 15. Conversion to the iodide followed by free radical reduction led, via Dowd-Beckwith rearrangement, to the ring expanded ketone 16 along with its hemiketal 17. Dissolving metal reduction of the mixure removed the benzylic oxygenation. Oxidation then led to the quinone 18, the natural product perovskatone D.

Following the Majetich precedent, intermolecular Diels-Alder reaction of the quinone 18 with trans-ocimene (19) followed by acid-catalyzed cyclization gave the heptacyclic natural product perovskone (4). This approach also enabled the synthesis ofs several other of the Salvia triterpenoids.

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