Diastereoselective scalable synthesis of 2,6-trans-Piperidines using an aza-Michael reaction Somenath Chowdhury, Jianmin Mao, Jacek Martynow, He Zhao, Erin Duffy, Yusheng Wu, Vinay Thakur, Gopal Sirasani, Yuanqing Tang, Florine Collin, Sandra Sinishtaj, Ashoke Bhattacharjee ⇑ Department of Chemistry, Melinta Therapeutics Inc., 300 George Street, New Haven, CT 06511, United States article info Article history: Received 31 October 2018 Revised 19 December 2018 Accepted 24 December 2018 Available online xxxx Keywords: trans-piperidine aza-Michael cyclization Diastereoselective Base catalyzed tert-butanesulfinamide abstract Highly efficient substrate and reagent controlled stereoselective synthesis of 2,6-trans-piperidine deriva- tive (1) using an aza-Michael reaction is reported. This method was utilized to synthesize a variety of trans-piperidines on hundred-gram scales. Ó 2018 Elsevier Ltd. All rights reserved. Piperidines are extremely important core motif in a wide vari- ety of natural products and active pharmaceutical ingredients [1]. Due to its intrinsic conformational preferences 2,6-disubstitued piperidine derivatives are broadly used in chemical synthesis to generate various compounds with therapeutic potential [2]. The nucleophilic and basic nitrogen in the piperidine framework offers numerous synthetic opportunities to tune SAR and explore a vari- ety of biological and physicochemical properties. Therefore, under- standing the combined structural and functional properties of piperidine derivatives plays a critical role in de novo drug design and development [3]. Although thermodynamically stable cis-2,6- disubstituted piperidines can be prepared relatively easily, con- structing multigram-scale chiral 2,6-trans-piperidines is a daunt- ing challenge. Herein, we report a highly efficient substrate and reagent controlled diastereoselective synthesis of 2,6-trans-piperi- dine derivatives 1 from easily available starting materials through an intramolecular aza-Michael reaction. Although a number of synthetic methods are available to con- struct a wide variety of piperidine analogs, intramolecular Michael reaction is still the most popular route to generate 2,6-disubstitued analogs in a chiral fashion [4]. A plethora of organic and inorganic catalysts are known to promote this reaction, but none of these are applicable in large-scale synthesis. A recent example [4e] of a fully functionalized a,b-unsaturated carbonyl compound caught our attention where the reaction has been catalyzed either by triflic acid or by a Pd (II) species. For our ongoing drug discovery program, we needed to prepare a large stock of compound 1 or an analog that contains an easily removable protecting group on the piperidine nitrogen to explore a variety of SAR. We planned to use an a,b-unsaturated ester as a starting material which eventually, after cyclization, can be further manipulated to a variety of functional groups to improve or tune properties of biologically active compounds. Although a,b-unsaturated esters are known to be poor Michael acceptors [4e], we wanted to use this substrate so that we can have better control in trans/cis selectivity during piperidine construction. Our investigation started from a suitable intermediate as shown in Scheme 1. The condensation of 4-bromo benzaldehyde with (S)-tert-butanesulfinamide gave sulfinimine 5a, which was then treated with pent-4-enylmagnesium bromide at low temperature. Although the overall yield of this reaction was very good, we noticed moderate stereoselectivity where desired 6a is the major product. Repeated attempts (Scheme 2) to achieve better selectivity failed. All the sulfinimines (5a–c) yielded similar diastereomeric mixtures of 6/7. At this point 6a was purified from its diastereomer 7a by tradi- tional chromatography and its absolute stereochemistry was con- firmed by NMR analysis of its Mosher amide. 6a was converted to 8 (Scheme 1) which was reacted with ethyl acrylate in presence of Hoveyda-Grubbs catalyst to furnish intermediate 9. The alkene 9 was a suitable precursor for aza-Michael reaction. A recent litera- ture described the acid catalyzed aza-Michael cyclization using https://doi.org/10.1016/j.tetlet.2018.12.061 0040-4039/Ó 2018 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. E-mail address: bashoke@hotmail.com (A. Bhattacharjee). Tetrahedron Letters xxx (xxxx) xxx Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet Please cite this article as: S. Chowdhury, J. Mao, J. Martynow et al., Diastereoselective scalable synthesis of 2,6-trans-Piperidines using an aza-Michael reac- tion, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.061