A directed enolization strategy enables by-product-free construction of contiguous stereocentres en route to complex amino acids

nature chemistry Article https://doi.org/10.1038/s41557-024-01473-5 A directed enolization strategy enables by-product-free construction of contiguous stereocentres en route to complex amino acids Received: 11 September 2023 Fenglin Hong1, Timothy P. Aldhous , Paul D. Kemmitt 1,2 3 & John F. Bower 1 Accepted: 8 February 2024 Published online: xx xx xxxx Check for updates Homochiral α-amino acids are widely used in pharmaceutical design as key subunits in chiral catalyst synthesis or as building blocks in synthetic biology. Many synthetic methods have been developed to access rare or unnatural variants by controlling the installation of the α-stereocentre. By contrast, and despite their importance, α-amino acids possessing β-stereocentres are much harder to synthesize. Here we demonstrate an iridium-catalysed protocol that allows the direct upconversion of simple alkenes and glycine derivatives to give β-substituted α-amino acids with exceptional levels of regio- and stereocontrol. Our method exploits the native directing ability of a glycine-derived N–H unit to facilitate Ir-catalysed enolization of the adjacent carbonyl. The resulting stereodefined enolate cross-couples with a styrene or α-olefin to install two contiguous stereocentres. The process offers very high levels of regio- and stereocontrol and occurs with complete atom economy. In broader terms, our reaction design offers a unique directing-group-controlled strategy for the direct stereocontrolled α-alkylation of carbonyl compounds, and provides a powerful approach for the synthesis of challenging contiguous stereocentres. Amino acids are arguably the most valuable homochiral building blocks available to synthetic chemists. This has stimulated the development of a variety of methods to access rare or unnatural variants, focusing predominantly on control of the α-stereocentre1. Exemplar catalytic asymmetric methods include Strecker reactions2, phase-transfer-catalysed alkylations of glycine imines3, alkene hydrogenations4, cross-couplings5 and conjugate additions6,7. Although highly effective, these approaches are not generally suitable for accessing amino acids possessing β-stereocentres (Fig. 1a). Substitution at this position has important ramifications for the three-dimensional structure of a derived peptide8,9, for example, or the physiochemical properties of a downstream product. As testament to this, a variety of biosynthetic processes are known that allow the β-functionalization of canonical amino acids10. A handful of catalytic asymmetric methods have emerged that allow the synthesis of certain β-stereogenic α-amino acids. These include biocatalytic dynamic kinetic resolutions11, diastereoselective C–H arylations12, asymmetric hydrogenations13 and stereoretentive cross-couplings14. These important approaches each have their own limitations and are non-trivial, requiring, for example, a preassembled framework and/or pre-installed homochirality and/or pre-functionalized reaction partners. We questioned whether an alternative and more convergent approach could be achieved by the direct and stereocontrolled C–H Department of Chemistry, University of Liverpool, Liverpool, UK. 2School of Chemistry, University of Bristol, Bristol, UK. 3Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK. e-mail: 1 Nature Chemistry Article https://doi.org/10.1038/s41557-024-01473-5 a c O O R1 HO R O R2 HO NH2 O 1 O ? H d Chiral lithium amide R R NHR Via C–H addition across an alkene? O H R NHR Alkyl halide Cat. amine* and photoredox O H Aldehydes only [Ir] O NR R I NR II Geometrically defined O [Ir] R Non-polarized alkene H Enantioenriched One new stereocentre f O Important bioactive scaffolds and feedstocks O e R N-metallation triggers enolization? Low atom and step economy High skill level required Alkyl halide i-Pr Few synthetic methods b O Strong base N NH2 Many synthetic methods R O R DG DG = native functionality Metal catalyst Non-polarized alkene High atom and step economy Simple experimental set-up Two new stereocentres Fig. 1 | A directed enolization strategy for the hydroalkylative coupling of glycine derivatives and alkenes to give synthetically challenging β-substituted α-amino acids. a, β-stereogenic α-amino acids are relatively difficult to access. b, This work outlines an N-directed enolization method that enables the stereocontrolled and branch selective C–H addition of glycine-based units across alkenes. c,d, Conventional stereoselective carbonyl α-alkylation methods require pre-functionalization of one or both reactions partners17–19. e, Catalyst-controlled α-C–H additions across mono-substituted alkenes can be achieved in a linear selective manner24. The asterisk indicates chiral. f, This study provides a directing-group-controlled framework for achieving stereocontrolled, branch selective additions of α-C–H bonds across alkenes. alkylation of a glycine-based precursor (Fig. 1b). In particular, we targeted a process where the new C–C bond and the two stereocentres are established in a single operation. In essence, this requires the invention of a catalytic method that allows the enantio- and diastereoselective direct (that is, stoichiometric base-free) intermolecular α-alkylation of carbonyl compounds. For systems that lack additional strong acidifying groups3, this area has proven to be exceptionally challenging15,16, such that auxiliary-based approaches are still dominant in target-directed synthesis (Fig. 1c)17,18. Asymmetric ketone α-alkylation can be achieved from lithium enolates using catalytic quantities of a chiral amine ligand (Fig. 1d)19. Other catalytic enantioselective methods have emerged, but these are not usually direct, relying either on the pre-formation of an enolate or enolate equivalent20–22 or the pre-installation of sacrificial functionality23. In a key advance, a tricatalytic system was developed that promotes the direct linear selective α-alkylation of aldehydes (Fig. 1e)24. This process is also important because it harnesses readily available non-activated alkenes as alkylating agents for enantioselective α-functionalization reactions25. Also developed is an alternative Ir-catalysed C–H activation-based branch-selective process that offers promising levels of stereocontrol26. Although elegant, these methods are not applicable to the issue at hand, because they are reliant on a condensation event to generate an enamine. In this Article we outline an alternative approach that is predicated on using the glycine-based N–H unit as a directing group (I) to trigger metal-catalysed ‘soft’ enolization en route to geometrically defined homochiral enolates of type II (Fig. 1b)27–29. At the outset, this proposition was considered tentative because of the low acidity of I. Nevertheless, based on our earlier studies involving N-directed C–C bond activation30, we were drawn to diphosphine-m (...truncated)