Two nice alkaloid syntheses published last week; I'm not sure which I like more, so I'll cover them both. Look out for the second one in part two in a day or so. Also, I don't have any internet access at home for the next three weeks, so posts this month may be less well referenced, or just less existent.
Total Synthesis of (-)-Leuconicine A and B
The leuconicines, like their more popular brethren strychnine and akuammicine, are members of the family of Strychnos alkaloids, and bear a strong resemblance to these natural products. They've got two fewer stereocentres and one less ring than strychnine itself, but they still look pretty formidable to me. The Andrade group accomplished syntheses of (±)-strychnine and (±)-akuammicine last year using a neat one pot spirocyclisation-Baylis-Hillman sequence to add the C and E rings to the indole core, but this paper is the first report of the use of their methodology to access enantioenriched targets.
The work began with the formation of a chiral N-tert-butanesulfinimine from the aldehyde shown and readily available (R)-tert-butanesulfinamide, which was then allylated stereoselectively using an organoindium species. Treatment of the product with 4 M HCl followed by magnesium in methanol cleaved off the chiral auxiliary and the tosyl group to give the chiral homoallylic amine. This was alkylated with known (Z)-2-iodobutenyl bromide and then acylated with bromoacetyl chloride. Cross metathesis with methyl acrylate was (unsurprisingly) selective for the unhalogenated double bond, and the a,b-unsaturated ester required for the cascade sequence was obtained in good yield. Treatment of this compound with silver triflate and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) effected the anticipated cyclisation to the spiroindolenine, and subsequent addition of DBU caused formation of the E ring by a Baylis-Hillman reaction. I've never seen this reaction done with DBU, which is notoriously non-nucleophilic, but it seems to work well here.
The Raucher protocol (Tetrahedron Lett., 1980, 21, 4061) for the reduction of amides to amines was then used as a milder and more chemoselective alternative to just bashing the molecule with LiAlH4. This involves conversion to the thioamide, S-alkylation with Meerwein's salt (Et3OBF4) and finally, elimination of ethanethiol from the resulting thioimidate with reduction by sodium borohydride. Athough this sounds like a lot of work, the reaction only required two flasks (simple concentration and a change of solvent is all that was required after the alkylation), and the yield over the two steps was very good. Reduction of the ester to the aldehyde worked best in two steps via the Weinreb amide. Methyl malonyl chloride was then used in a one pot N-acylation-Knoevenagel sequence to install the fifth ring of the natural product. Finally, the two-decade old Heck protocol establised by Rawal for the formation of Strychnos alkaloid D-rings was applied, using triethylamine as solvent and forming the hexacyclic skeleton of the natural product in good yield. Reduction of the ethylidene unit using Raney nickel (as platinum and palladium catalysts proved ineffective) gave (-)-leuconicine A, which was converted to (-)-leuconicine B using the Weinreb method for amide formation with trimethylaluminium.
All in all, a nice short chiral auxilliary based route to (-)-leuconicines A (14 steps, 9% yield) and B (13 steps, 10% yield), which could be easily adapted to make more of these popular alkaloids.
1. I also didn't have a blog back then. See J. Org. Chem., 2010, 75, 3529. (free Syn. Arch. here)