Concise syntheses of (±)-protoemetinol and related alkaloids using radical cyclisation Matthew J. Palframan a , Andrew F. Parsons a,⇑ , Paul Johnson b a Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK b AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK article info Article history: Received 8 November 2010 Revised 10 December 2010 Accepted 4 January 2011 Available online 12 January 2011 Keywords: Alkaloid Cyclisation Radical Tributyltin hydride abstract Both (±)-protoemetinol, its 3-epi-isomer and (±)-3-desmethyl protoemetinol have been prepared in five linear steps from a dihydroisoquinoline using a 6-exo-trig cyclisation of a vinyl radical in the key step. This novel and particularly short route has potential application in the synthesis of Alangium and Mit- ragyna alkaloids. Ó 2011 Elsevier Ltd. All rights reserved. The Alangium family of alkaloids, such as psychotrine (1) and deoxytubulosine and Mitragyna alkaloids, including mitragynine (2)( Fig. 1), have attracted interest due to their use as folk remedies for numerous ailments, including dysentery. 1 These types of quin- olizidine alkaloids have been shown to exhibit potent biological activities. For example, psychotrine (1), isolated from the root of the Ipecacuanha plant, is a potent inhibitor of HIV-1 reverse trans- criptase, 2 while mitragynine (2) shows analgesic activity at opioid receptors. 3 As part of a programme to develop a general, efficient and concise synthesis of these types of alkaloid, we report a novel and particularly concise synthesis of (±)-protoemetinol (3), its 3- epi-isomer and 3-desmethyl derivatives, which are useful starting materials for a range of natural quinolizidines. 4 The key step in the synthetic approach to (±)-protoemetinol (3) involves the radical cyclisation of vinyl bromide 4, as illustrated in the retrosynthetic analysis in Scheme 1. Reaction of bromide 4 with tributyltin hydride (Bu 3 SnH) and a radical initiator was ex- pected to lead to a 6-exo-trig cyclisation reaction and the formation of a 6,6,6-tricycle, which could be elaborated to 3. Although the use of 5-exo-trig radical cyclisations to form pyrrolidine rings is preva- lent in the literature, the use of related 6-exo-trig cyclisations to form piperidine rings is comparatively scarce. 5,6 This may partly be explained by the relatively low rates of 6-exo-trig radical cycli- sations and competing radical pathways such as 1,5-hydrogen atom abstractions. Initial studies of the radical cyclisation using a model system proved to be very encouraging (Scheme 2). Slow addition of a solu- tion of Bu 3 SnH (1.2 equiv) and AIBN (0.5 equiv) in THF, to a solu- 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.01.007 ⇑ Corresponding author. Tel.: +44 1904 322608; fax: +44 1904 322516. E-mail address: andy.parsons@york.ac.uk (A.F. Parsons). N O O H H N OMe HO H 1 N H N H H MeO 2 C 2 OMe H O Figure 1. Structures of psychotrine (1) and mitragynine (2). 3 N Br O O 4 N O O H OH H O OMe Scheme 1. Retrosynthetic analysis of (±)-protoemetinol (3). Tetrahedron Letters 52 (2011) 1154–1156 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet