1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Isothiocyanate Strategy for the Synthesis of Quaternary a-Amino Acids Bearing a Spirocyclic Ring System Sebastian Frankowski, a Tadeusz Gajda, a and Łukasz Albrecht a, * a Institute of Organic Chemistry, Department of Chemistry, Lodz University of Technology, Zeromskiego 116, 90–924 Ło ´ dz ´, Poland Tel. + 48426313157www.a-teamlab.p.lodz.pl E-mail: lukasz.albrecht@p.lodz.pl Received: December 28, 2017; Revised: March 15, 2018; Published online: &&&, &&&& Dedicated to the memory of Professor Henryk Krawczyk, our friend and mentor, who passed away too soon Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201701642 Abstract: This study demonstrates that isothiocyanates derived from a-substituted a-amino acids are useful building blocks in the heteroannulation reactions with electron-deficient olefins. The developed strategy proceeds in a cascade manner and involves Michael addition followed by a cyclization via nucleophilic addition. Target, spirocyclic heterocycles bearing either a quaternary a-amino acid moiety or a-amino- phosphonate group have been efficiently synthesized in very high yield (up to 99%) and with excellent stereocontrol. The usefulness of heterocycles obtained has been demonstrated in selected transformations. Keywords: Asymmetric synthesis; Bifunctional catalysis; Isothiocyanates; Quaternary a-amino acids; Pyrrolidine 1 Introduction Quaternary a-amino acids are an important group of biologically relevant molecules. [1] Such a structural motif is present in various natural products and compounds relevant for the life-science industry (with representative examples I–III shown in the Figure 1). [2] Furthermore, the incorporation of quaternary a-amino acid motif into a target molecule results in increased resistance to enzymatic and chemical degradation and, in many cases, enhanced biological properties. Nota- bly, the biological activity of such systems is directly correlated with the absolute stereochemistry of the quaternary stereogenic center. For this reason, the development of methods for their preparation in an enantioselective fashion is of particular importance. Barbituric acid constitutes another structural motif widely distributed in nature that is highly relevant in the contemporary medicinal and organic chemistry. Compounds containing that scaffold possess strong and diverse biological activity (Figure 1, compounds IV ,V). [3] In this context, the spirocyclic architecture present in the biologically relevant barbituric acid derivatives is worth noticing. Surprisingly, the enantio- selective methods for their preparation remain lim- ited. [4] Target-oriented-synthesis of privileged structural motifs is the ultimate goal of the contemporary organic chemistry. [5] This field of research has been recently dominated by the enantioselective ap- proaches with the chiral catalysts used to achieve chiral discrimination. [6] In particular, biomimetic cas- cade reactivities have recently emerged as a conven- Figure 1. Examples of biologically relevant quaternary a- amino acid and barbituric acid derivatives. FULL PAPER DOI: 10.1002/adsc.201701642 Adv. Synth. Catal. 2018, 360, 1 – 12 1  2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! ÞÞ