Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, February 1, 2016
Douglass F. Taber
University of Delaware

The Ma Synthesis of Leucosceptroid B

The flowering plant Leucosceptrum canum is rarely attacked by herbivores and only occasionally by pathogens. Leucosceptroid B (3), isolated from the plant, showed significant anti-feedant and anti-fungal activity. In pursuit of the total synthesis of 3, Dawei Ma of the Shanghai Institute of Organic Chemistry anticipated (Angew. Chem. Int. Ed. 2015, 54, 1298. DOI: 10.1002/anie.201410134) the late-stage reductive cyclization of 1 to 2. The trans six-five ring fusion of 3 had to be prepared directly, since it was unlikely that the proper diastereomer could be secured by equilibration. To this end, the authors planned to couple the ketone 14 with the aldehyde 7, each in enantiomerically-pure form.

The preparation of 7 began with commercial citronellol 4. Ozonolysis followed by Wittig reaction with the phosphorane 5 and oxidation delivered 6, that on further oxidation in the presence of a MacMillan organocatalyst cyclized to 7 with high diastereocontrol.

The furan of 14 was assembled by coupling 8 with 9, then exposing the product to a gold catalyst. Addition of the product 10 to the aldehyde 11 proceeded with high diastereocontrol, to give 12. Stereocontrolled addition of CH3MgBr led to the alkene 13, that was cyclized to 14.

Although the Li enolate derived from 14 did not add efficiently to the aldehyde 7, the combination of 14 with (hex)2BCl and Et3N followed by the addition of 7 led to the desired aldol product 15. The reductive cyclization of 15, however, led predominantly to seven-membered ring formation. Cyclization of the derived TMS ether 1 also gave the seven-membered ring product, accompanied by some of the six-membered ring product as a mixture of diastereomers (not illustrated).

Reasoning that the transition state for six-membered ring formation was not favorable for 15 or for its TMS ether, the authors converted 15 to its diastereomer 17. Reduction and selective protection of 15 gave 16, that was oxidized and then reduced, with concomitant removal of the acetate. Selective oxidation followed by protection completed the preparation of 17.

Pleasingly, reductive cyclization of 17 proceeded smoothly to give, after deprotection, the desired 18. Selective oxidation of the primary alcohol followed by Wittig reaction and oxidation led to Leucosceptroid B (3). Despite the necessity of adjusting the stereochemistry of 15, this approach was easily enough scaled that 1.2 g of 3 was prepared.

D. F. Taber, Org. Chem. Highlights 2016, February 1.