Stereoselectivity and conformational control in the synthesis of ajmaline and epi-ajmaline alkaloids Patrick D. Bailey a,⇑ , Mark A. Beard b , Mark Cresswell a , Hoa P. T. Dang b , Ravindra B. Pathak a , Theresa R. Phillips a , Richard A. Price b a EPSAM Research Institute, Keele University, Keele, Staffordshire ST5 5BG, UK b School of Chemistry, University of Manchester, Manchester M13 9PL, UK article info Article history: Received 9 June 2012 Revised 4 January 2013 Accepted 17 January 2013 Available online 25 January 2013 Keywords: Stereoselective synthesis Indole alkaloids Ajmaline abstract Careful choice of the N-protecting group provides crucial conformational control, allowing ring-closure to the indole 3-position in the late stages of the synthesis of ajmaline alkaloids; the choice of protecting group and reducing agent can also provide access to either the natural or epi configuration at the indole 2-position. Ó 2013 Elsevier Ltd. All rights reserved. Despite its modest molecular weight (M r 326), the alkaloid ajmaline (1) has nine contiguous chiral centres packed into a tetra- cyclic cage-like structure. 1 The synthetic challenge of this polycy- clic region, combined with the important medicinal properties of ajmaline as an antiarrhythmic agent, 2 have led to claims of total syntheses and numerous partial syntheses over the past 45 years. 3–6 Of these, only Cook 6 has actually completed the prep- aration of a synthetic sample of ajmaline, with other ‘total synthe- ses’ relying on comparison with semi-synthetic intermediates which could themselves be transformed into ajmaline (sometimes called ‘relay syntheses’). All of the synthetic approaches have essentially involved two phases (see Scheme 1): (a) construction of an advanced core 4 that is common to the family of ajmaline/sarpagine alkaloids, but lacking the bond to the indolic 3-position; (b) introduction of the bond to the indolic 3-position (creating 3 new chiral centres), which can be carried out earlier (route a) or towards the end (route b), before relatively simple transformations to complete the synthesis. One important consideration has been whether the closure of the 3-indolyl bond should precede or follow the formation of the south-east (SE) ring (see Scheme 1). Bartlett et al. 7 carried out stud- ies on compounds derived from ajmaline, and found that prior clo- sure of the SE ring led to the epi-ajmaline series when reductive ring-closure to the 3-indolyl position was carried out. Cook’s group also chose to close this SE ring fairly early in their total synthesis, as this facilitates 3-indolyl ring-closure (see Scheme 4); they ob- served either totally or partially selective reduction to the epi- ajmaline stereochemistry, although they managed to develop con- ditions in which the desired isomer was only disfavoured by a fac- tor of 3:2. 6 With this in mind, our approach was to leave the formation of the SE ring until the end of the synthesis, and this Letter describes our findings on the 3-indolyl ring-closure, which would set three of the chiral centres in ajmaline; our results also have an important bearing on some previous synthetic claims. The synthetic studies described herein were directed at a de- ethyl derivative of ajmaline (i.e., ethyl absent from SE ring of 1), for which the aldehyde 9 (see Scheme 3) was a key advanced inter- mediate (cf. structure 4 in Scheme 1). The synthesis of 9 involved a homologation sequence starting from L-tryptophan (Scheme 2) to generate the nitrile 5, 8 followed by a kinetically controlled Pic- tet–Spengler reaction 9 to generate 6, with complete stereo-control of two of the chiral centres; fairly standard steps allowed conver- sion into 7 in which a third chiral centre was installed, and lacton- ization of this involved an epimerization such that 8 had four asymmetric centres installed with complete control of the stereo- chemistry (Scheme 2). 10 Ring-opening of 8 to give the Weinreb amide, 11 protection of the OH as the methyl ether, then reduction with LiAlH 4 gave aldehyde 9 (Scheme 3). Using this N-benzyl deriv- ative 9, we investigated a series of ring-closure conditions based on early work using ajmaline derivatives, 7 and modified subsequently 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.01.074 ⇑ Corresponding author. Tel.: +44 01782 734583; fax: +44 01782 734593. E-mail address: p.bailey@natsci.keele.ac.uk (P.D. Bailey). Tetrahedron Letters 54 (2013) 1726–1729 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet