Asymmetric Amine-Intercepted Nazarov Cyclization

Link: JACS ASAP

Francis Dhoro, Tor E. Kristensen, Vegar Stockmann, Glenn P. A. Yap, and Marcus A. Tius*

Department of Chemistry, 2545 The Mall, University of Hawaii, Honolulu, Hawaii 96822, and Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716

This is a work on amine-intercepted Nazarov cyclization. The reaction yielded alpha'-amino-, alpha, beta-unstaturated cyclobutenone. Initial result is as shown in Scheme 1.

In this paper, a camphor-derived derivative of 1 was used in the studies as shown in Scheme 2.

Subsequently, the following substrates were used in the study, all were made from addition of the organolithium to the corresponding morpholine amide.

The reaction conditions were very mild, essentially on exposure to activated silica gel, alumina, or florisil. For 12, reaction did not work well and mixture of unidentifiable products were obtained. Otherwise, the products obtained from other substrates are summarized in Table 1.

The structures of these products were assigned based on the x-ray crystal structure of the picrate salt of 20. Streochemistry observed was the result of conrotatory electrocyclic ring closure.

Additionally, the intermediate of type 8 as in Scheme 2 could be trapped intramolecularly by a tethered amino group as in 26 to give a unique compound 27 in good yield. Interestingly, due to the steric constraint, trapping of nitrogen occurred on the same face of the cyclopentenone (which is different from other intermolecular trapping cases, see Table 1).

The products from this reaction could be further utilized. The TIPS group and chiral auxiliary are easily cleaved from the products. Exposure of 23 to tetra-n-butylammonium fluoride in THF led to rapid cleavage of the TIPS group (28, 92% yield). Subsequent exposure of the product to chlorotrimethylsilane in methanol at 0 °C led to cleavage of the chiral auxiliary (29, 93% yield). (See the paper and the Supporting Information for details.)