New class of nucleophiles for palladium-catalyzed asymmetric allylic alkylation. Total synthesis of agelastatin A

Abstract

New classes of nucleophiles, pyrroles, and N-methoxyamides were developed for Pd-catalyzed AAA reactions. By varying the functional groups at the 2-position of pyrroles, either regioisomer of the piperazinone is available. Using one regioisomer, the total synthesis of (+)-agelastatin A in 10 total steps is accomplished. For this synthesis, a new copper-catalyzed aziridination and an indium-catalyzed oxidative ring opening of a N-tosylaziridine were developed. The feasibility of accessing (-)-agelastatin A from the same enantiomer of the chiral catalyst from the other regioisomeric piperazinone is indicated.

Figure 1

Agelastatins

Scheme 1

Piperazinone synthesis a) LiOH (1N), THF/water = 3/1, 48hr, rt; b) oxalyl chloride, cat. DMF in THF then, NH₂Ome·HCl, K₂CO₃, and H₂O, rt.

Scheme 2

Total synthesis of (+)-agelastatin A a) catalyst 14 (0.5 eq.), PhI=NTs (5 eq.), 4Å M.S., benzene, 0 °C to rt; b) TFA (10 eq.), microwave, dioxane/water = 3/2, 150 °C, 2.5 hr; c) DMP, DCM, rt; d) In(OTf)₃ (0.7 eq.), DMSO, 80 °C, 6h; e) CH₃NCO(1.2 eq.), Cs₂CO₃ (0.2 eq.), DCM, 0 °C to rt; f) SmI₂ (10 eq.), THF, 0 °C to rt.