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Organic Chemistry Highlights

Total Synthesis

Monday, February 1, 2021
Douglass F. Taber
University of Delaware

The Lei Synthesis of 1α-Hydroxykaurane-12-one

The crystalline 1α-hydroxykaurane-12-one (3), isolated from the New Zealand liverwort Paraschistochila innatifolia, showed anticancer activity. En route to 3, Xiaoguang Lei of Peking University used the Yu conditions to cyclize 1 to 2 (J. Am. Chem. Soc. 2020, 142, 2238. DOI: 10.1021/jacs.9b13722).

The cyclopropyl sidechain of 1 was prepared following the Boeckman procedure, alkylation of the inexpensive pentenenitrile (4) with 1,2-dichloroethane (5) to give 6. Dibal reduction followed by methylenation delivered the volatile diene 7.

Conjugate addition of 7 to 2,4,4-trimethylcyclohexenone (8) following the Fletcher protocol proceeded well. The enantioselective variants of this conjugate addition, however, failed with this challenging substrate. Alkynylation with 10 completed the assembly of 1.

The Yu Rh cyclization proceeds by initial opening of the cyclopropane, leading to the π-allyl complex 11. Insertion of the alkyne into this complex gives an intermediate, that reacted with carbon monoxide to give the crystalline tricyclic diketone 2. The cyclization proceeded with 5.8:1 diastereoselectivity.

The cyclization of 2 to 12, with an excess of Pd(OAc)2, was best carried out on the TIPS enol ether. The contrathermodynamic conversion to 13 was effected by hydration followed by dehydration. Hydrogenation of the resulting double bond consistently proceeded from the wrong face, so 13 was reduced to the diol 14. Hydroxyl-blocked reduction with Raney nickel then delivered 15, that was oxidized, then reduced with dissolving metal to give 1α-hydroxykaurane-12-one (3).

D. F. Taber, Org. Chem. Highlights 2021, February 1.