Stemaphylline (1) is a recently isolated Stemona alkaloid (see Image 1) with interesting insecticidal and antimicrobial properties.1 Its complex structure contains a challenging pyrrolo–azepine core and five stereogenic centres, three of which are contiguous. To date there has been a single total synthesis of 1, which was obtained in low yield and as an inseparable mixture of diastereomers.2 Herein we present our efforts towards a stereocontrolled synthesis of 1 using lithiation–borylation methodology (see Image 2),3 which has the ability to assemble multiple stereogenic centres in a completely stereospecific manner. According to our retrosynthetic analysis (see Image 1), 1 can be disconnected into three simple building blocks: 3, 6 and 7, which can be assembled by sequential lithiation–borylation protocols setting all the 5 stereogenic centres. The synthesis of building blocks 3, 6 and 7 and the optimisation of all key steps of the total synthesis of 1 will be described. Furthermore, during our studies we have identified boronic ester 7 as bearing a very slow migrating group4 and special conditions required for the success of the homologation will be discussed (see Image 2). References: 1. P. Mungkornasawakul, S. Chaiyong, T. Sastraruji, A. Jatisatienr, C. Jatisatienr, S.G. Pyne, A.T. Ung, J. Korth, W. Lie, J. Nat. Prod. 2009, 72, 848. 2. M.L. Schulte, M.L. Turlington, S.S. Phatak, J.M. Harp, S.R. Stauffer, C.W. Lindsley, Chem. Eur. J. 2013, 19, 11847. 3. D. Leonori, V.K. Aggarwal, Acc. Chem. Res. 2014, 47, 3174. 4. a) S. Roesner, J.M. Casatejada, T.G. Elford, R.P. Sonawane, V.K. Aggarwal, Org. Lett. 2011, 13, 5740. b) S. Essafi, S. Tomasi, V.K. Aggarwal, J.N. Harvey, J. Org. Chem. 2014, 79, 12148.

Total synthesis of (-)-stemaphylline using lithiation-borylation methodology

251st National Meeting (2016)

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