A practical and scalable system for heteroaryl amino acid synthesis.

Chemical Science View Article Online Open Access Article. Published on 02 October 2017. Downloaded on 15/03/2018 14:26:43. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. EDGE ARTICLE Cite this: Chem. Sci., 2017, 8, 7998 View Journal | View Issue A practical and scalable system for heteroaryl amino acid synthesis† R. A. Aycock, D. B. Vogt and N. T. Jui * A robust system for the preparation of b-heteroaryl a-amino acid derivatives has been developed using photoredox catalysis. This system operates via regiospecific activation of halogenated pyridines (or other Received 17th August 2017 Accepted 2nd October 2017 heterocycles) and conjugate addition to dehydroalanine derivatives to deliver a wide range of unnatural amino acids. This process was conducted with good efficiency on large scale, the application of these DOI: 10.1039/c7sc03612d conditions to amino ketone synthesis is shown, and a simple protocol is given for the preparation of rsc.li/chemical-science enantioenriched amino acid synthesis, from a number of radical precursors. Introduction Amino acids play a central role in the chemical and biological sciences. As primary members of the chiral pool, they are precursors to drugs,1 chiral auxiliaries,2 and catalysts.3 In addition, they are fundamental building blocks for the construction of biomolecules. The use of peptides as therapeutic agents is attractive because they can display extremely diverse, potent, and selective biological activities.4 However, there are signicant challenges in peptide drug design, including low metabolic stability or poor physical properties. One proven strategy for overcoming these challenges involves substitution of the native residues with unnatural amino acids (synthetic mutagenesis).5 Nitrogen-containing heteroaromatics are common in pharmaceuticals because they directly alter the solubility, metabolic stability, and binding affinity of the molecules that they comprise.6 As such, heteroarene-containing unnatural amino acids are promising tools in the design of peptide therapeutics. Pyridine incorporation has a dramatic impact on the properties of amino acids and peptides. For example, azatyrosine— a natural product that differs from the essential amino acid tyrosine by substitution of a single atom—displays potent antibiotic and antitumor properties (Fig. 1A).7 Installation of the 3-pyridylalanine (3-pyr-Ala) residue in the gonadotropinreleasing hormone antagonist cetrorelix (Fig. 1B) was found to improve both aqueous solubility and receptor affinity,8 and similar effects were observed in the development of other peptide hormones (not shown).5b–d As part of a program centered on the catalytic functionalization of heteroaromatics, we target the development of impactful synthetic methods for Department of Chemistry and Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. E-mail: † Electronic supplementary 10.1039/c7sc03612d information 7998 | Chem. Sci., 2017, 8, 7998–8003 (ESI) available. See DOI: the construction of novel b-heteroaryl a-amino acids through a radical conjugate addition mechanism. We have found that pyridyl halide activation via single electron reduction using photoredox catalysts9 can be accomplished, and that the intermolecular reactivity of the resulting radical species can be dictated by the reaction conditions.10,11 More specically, we found that pyridyl radicals display nucleophilic reactivity in aqueous DMSO, and they readily couple with electron-poor alkenes. We questioned whether this approach could be translated to heteroaryl amino acid synthesis through radical conjugate addition to dehydroalanine derivatives. There are a number of powerful methods for the synthesis Fig. 1 Impact of pyridine incorporation into amino acids and peptide drugs. This journal is © The Royal Society of Chemistry 2017 View Article Online Open Access Article. Published on 02 October 2017. Downloaded on 15/03/2018 14:26:43. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Edge Article of unnatural b-heteroaryl a-amino acids, including malonate (or enolate) alkylation,12 cross-coupling of serine-derived organometallic reagents,13 and reduction of dehydroamino acid derivatives.14 However, strategies based on radical addition to DHA derivatives are unique due to the highly-chemoselective nature of radical species, and the broad functional group tolerance that results.15 Alkyl radical addition to DHA has been effectively accomplished even in the complex setting of intact proteins.16 While this is a highly attractive attribute, a radical approach to heteroaryl amino acids is currently unknown. Here, we describe the successful translation of our reductive heteroarene activation system to amino acid synthesis. Results and discussion Shown in Fig. 2 is a mechanistic picture that is consistent with our observations. Excitation of the photocatalyst [Ir(ppy)2 (dtbbpy)]PF6 ([Ir]1+), followed by reductive quenching of the excited state by Hantzsch ester (HEH) gives rise to the [Ir]0 (E1/2 ¼ 1.51 V).17 Stern–Volmer quenching studies indicated that Hantzsch ester is the most signicant excited state quencher (see ESI for details†). Single electron reduction of halo pyridine I, followed by rapid mesolytic cleavage in polar solvents (X ¼ Br, I)18 affords heteroaryl radical intermediate II, which exhibits nucleophilic radical behavior in aqueous DMSO.10a It is possible that halopyridine reduction is assisted by protonation, as each catalytic turnover produces an nominal equivalent of Hantzsch pyridinium bromide (HEH+ Br). Hydrodehalogenation (HDH) of the arene is observed as a common Chemical Science byproduct, but this undesired pathway can be suppressed by limiting the solubility of the stoichiometric reductant, Hantzsch ester (HEH), in accord with our previous ndings. Radical conjugate addition (RCA) to dehydroalanine III and subsequent single electron reduction of the nascent radical IV would deliver the corresponding enolate V. The intermediacy of V is supported by the fact that the a-H amino acid product VI is produced in the presence of H2O as a cosolvent (regardless of H/D labeling of HEH). Conversely, when D2O is used as a cosolvent, complete deuterium incorporation is obtained at the a-position. As illustrated in Table 1, we identied conditions that efficiently unite 2-bromo-5-hydroxypyridine with the indicated dehydroalanine derivative (readily accessed on 35 g scale from Boc-Ser-OMe) to give the protected azatyrosine 1 in 98% NMR yield (entry 1). These conditions employ 1 mol% of the photosensitizer [Ir(ppy)2(dtbbpy)]PF6 (excited by irradiation with a commercial blue LED) and Hantzsch ester (1.5 equiv.) as a stoichiometric reductant in aqueous DMSO. Control experiments indicated that all of these components are necessary for the reaction (entries 2–4, 0% yield), and that use of the prototypical Ru(bpy)32+ chromophore results (...truncated)