Mark D. Greenhalgh

Aryloxide-Facilitated Catalyst Turnover in Enantioselective α,β-Unsaturated Acyl Ammonium Catalysis

A new general concept for a,b-unsaturated acyl ammonium catalysis is reported that uses p-nitrophenoxide release from an a,b-unsaturated p-nitrophenyl ester substrate to facilitate catalyst turnover. This method was used for the enantioselective isothiourea-catalyzed Michael addition of nitroalkanes to a,b-unsaturated p-nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples, up to 79% yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylation by the a,bunsaturated p-nitrophenyl ester, and a recently reported variable-time normalization kinetic analysis method was used to delineate the complex reaction kinetics. Lewis base organocatalysis is a widely studied field due to the diverse range of molecular frameworks that can be produced with high levels of regio-, chemoand stereocontrol. At the carboxylic acid oxidation level a variety of ammonium intermediates with differing reactivity can be accessed from readily available substrates using tertiary amine Lewis bases (Scheme 1a). Acyl ammonium and ammonium enolate intermediates have been extensively studied and applied in enantioselective acyl transfer processes and formal cycloadditions, respectively. 3] A less studied but equally powerful reactivity mode is that of a,b-unsaturated acyl ammonium intermediates. These species contain electrophilic centres at the C1 and C3 positions, and a latent nucleophilic centre at C2, providing new opportunities for reaction design to target previously inaccessible product architectures. Seminal work by Fu first demonstrated the feasibility of this concept in a formal [3+2] cycloaddition using a,bunsaturated acyl fluorides as the a,b-unsaturated acyl ammonium precursor (Scheme 1b). Recent studies from ourselves, Romo, and Matsubara, has built on this precedent to achieve highly enantioselective Michael addition-annulation, formal cycloaddition and complex cascade methodologies. These examples used a,b-unsaturated acid anhydrides or halides as the a,b-unsaturated acyl ammonium precursors. In addition, these methodologies require the reactive partner to contain two distinct nucleophilic functionalities to 1) undergo conjugate addition to the a,b-unsaturated acyl ammonium intermediate, and 2) enable turnover of the Lewis base catalyst (Scheme 1b). This requirement inherently limits a,b-unsaturated acyl ammonium catalysis and must be overcome to allow more diverse processes. In addition only preliminary experimental mechanistic work has been undertaken, with no kinetic analysis reported to date. Here we report the development of a new general concept for a,b-unsaturated acyl ammonium catalysis. Catalyst turnover is not facilitated by the nucleophilic reaction partner, but by an aryloxide counterion released in situ during the reaction by using an a,b-unsaturated aryl ester as the a,b-unsaturated acyl ammonium precursor (Scheme 1c). This allows the use of simple nucleophiles as reaction partners, providing enhanced potential for further advancement of the field. Mechanistic work including kinetic analysis, catalyst labeling and crossover studies are also reported to deliver a fundamental understanding of this process. Scheme 1. Nomenclature, reactivity and applications of ammonium intermediates in catalysis. [*] A. Matviitsuk, Dr. M. D. Greenhalgh, D.-J. B. Antfflnez, Prof. A. M. Z. Slawin, Prof. A. D. Smith EaStCHEM, School of Chemistry, University of St Andrews North Haugh, St Andrews, Fife, KY16 9ST (UK) E-mail: ads10@st-andrews.ac.uk Homepage: http://ch-www.st-andrews.ac.uk/staff/ads/group/ The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/anie.201706402. 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Angewandte Chemie Communications 1 Angew. Chem. Int. Ed. 2017, 56, 1 – 7 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! As initial proof of concept, the Michael addition of nitroalkanes to a,b-unsaturated aryl esters using a Lewis basic isothiourea catalyst was investigated. Although the organocatalytic enantioselective Michael addition of nitroalkanes to enones or enals is well precedented, Lewis base catalysis of this process has not been demonstrated at the carboxylic acid oxidation level. Initial investigations focused on the reaction of a range of a,b-unsaturated aryl esters 1–4, bearing different aryl groups, with excess nitromethane using HyperBTM 5 as catalyst (Table 1, entries 1–4). The Michael addition products 6–9 were formed in each case in moderate to excellent yield (48– 81%) but with uniformly high enantioselectivity (up to 96:4 er) and with complete regioselectivity. The highest yields were obtained using p-nitrophenyl (PNP) and 3,5bis(trifluoromethyl)phenyl esters 1 and 4, with PNP ester 1 chosen for further studies due to the higher enantioselectivity obtained. Mixed solvent systems proved ineffective, with lower yields obtained in the presence of both THF and MeCN (entries 5 and 6). The addition of a base (2,6-lutidine) did not prove beneficial (entry 7), whilst heating the reaction at 70 8C resulted in complete decomposition (entry 8). Alternative isothiourea catalysts did not provide improved results, and lower catalyst loadings resulted in incomplete conversion, which complicated product isolation. The scope and limitations of the method was then investigated. Given the moderate isolated yields of PNP ester products, the addition of a suitable nucleophile at the end of the reaction was used to give a range of readily isolable functionalized products (Table 2). The use of primary and secondary amines gave secondary and tertiary amides 10–14 in good yield, whilst addition of methanol gave methyl ester 15. All amide and ester products were obtained with high enantioselectivity indicating no significant loss in enantiopurity during the derivatization process. The scope of bsubstituted a,b-unsaturated aryl esters amenable to the process was then investigated. Methyl-, isopropyland benzyl esters gave the addition products 16–18 in good yield and with excellent enantioselectivity. The incorporation of amides at the b-position was also well tolerated, giving unsymmetrical succinamide derivatives 19 and 20 in equally high yield and levels of enantiocontrol. The absolute configuration of 19 was confirmed by single crystal X-ray analysis, with all other examples assigned by analogy. Limitations of this methodology include incompatibility of substrates such as g-keto ester derivative 22, which gave a complex mixture of products, and cinnamic acid derivative 23, which was completely unreactive. A derivative bearing b-alkyl substitution however gave product 21 with excellent enantiocontrol, albeit in low yield. The synthesis of a quaternary stereogenic carbon centre was also attempted, however application of b,bdisubstituted derivative 24 failed to give the desired Michael addition product. The effect of olefin configuration was investigated using maleate PNP ester derivative 25 (Scheme 2). Interestingly, Table 1: Reaction optimization. Entry Subst. Solvent Additive (equiv) Yield [%] er 1 1 neat – 81 (55) 96:4 2 2 neat – 54 (41) 94:6 3 3 neat – 48 (33) 95:5 4 4 neat – 78 (45) 93:7 5 1 MeNO2:THF (1:1) – 50 ND [c] 6 1 MeNO2:MeCN (1:1) – 43 ND [c] 7 1 neat 2,6-lutidine (0.2) 63 ND 8 1 neat – 0 – [a] Determined by H NMR spectroscopic analysis using 1,4-dinitrobenzene as internal standard (isolated yields given in parentheses). [b] Determined by chiral HPLC analysis. [c] ND= not determined. [d] Reaction performed at 70 8C. Table 2: Reaction scope: Variation of a,b-unsaturated p-nitrophenyl ester and nucleophilic quench. [a] Isolated yields given; er determined by chiral HPLC analysis. [b] Excess MeOH and DMAP (20 mol%) used in step ii). Angewandte Chemie Communications 2 www.angewandte.org 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2017, 56, 1 – 7 These are not the final page numbers! the Michael addition product 12 was obtained in the same enantiomeric form (93:7 er) as when using the isomeric fumarate PNP ester 1 (95:5 er). Monitoring reaction progress by H NMR spectroscopy revealed rapid isomerization of maleate 25 to fumarate PNP ester 1 on a faster timescale than formation of product, with control reactions in [D6]DMSO indicating reversible aryloxide conjugate addition as a possible mechanism for this isomerization process. Attention was next turned to the use of alternative nitroalkanes and subsequent derivatization of the products. Nitroethane and nitropropane were suitable nucleophiles giving addition products 26 and 27 in good yield. Although only minimal diastereocontrol was observed, both diastereoisomers were obtained with excellent enantioselectivity (99:1 er, Table 3). Pleasingly, the use of 2-nitropropane and nitrocyclopentane was also successful, giving amide and ester products 28–31 in moderate yield but with excellent enantiocontrol. Reduction of g-nitro methyl esters 15, 29 and 31 and subsequent cyclization was achieved with no loss in enantiopurity to give pyrrolidinone derivatives 32–34 in excellent yield and highly enantioenriched form (Table 4). The biological importance of pyrrolidinones, and g-aminobutryric acid (GABA) derivatives in general, is well precedented. To provide greater insight into this methodology, the reaction mechanism and kinetics were investigated to identify reaction intermediates and determine the reaction order with respect to each component. Quantitative reaction monitoring was achieved by in situ F{H} NMR spectroscopy using Flabeled PNP ester 35 and (2R,3S)-8F-HyperBTM 36 in MeNO2 using PhF as internal standard and a C6D6

A C=O⋅⋅⋅Isothiouronium Interaction Dictates Enantiodiscrimination in Acylative Kinetic Resolutions of Tertiary Heterocyclic Alcohols

A combination of experimental and computational studies have identified a C=O⋅⋅⋅isothiouronium interaction as key to efficient enantiodiscrimination in the kinetic resolution of tertiary heterocyclic alcohols bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. This discrimination was exploited in the isothiourea-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols (38 examples, s factors up to >200). The reaction proceeds at low catalyst loadings (generally 1 mol %) with either isobutyric or acetic anhydride as the acylating agent under mild conditions.

Evaluating polymer-supported isothiourea catalysis in industrially-preferable solvents for the acylative kinetic resolution of secondary and tertiary heterocyclic alcohols in batch and flow

Polymer-supported Lewis base catalysts, based on the homogeneous isothioureas HyperBTM and BTM, have been synthesised and applied for the acylative kinetic resolution of secondary and tertiary heterocyclic alcohols. In batch, the use of industrially-preferable solvents was investigated, with dimethyl carbonate proving to be most generally-applicable. Significantly, the HyperBTM-derived immobilised catalysts were readily recycled, with no loss in either activity or selectivity. In addition to the kinetic resolution of secondary benzylic, propargylic, allylic and cycloalkanol derivatives, a range of 22 tertiary heterocyclic alcohols, based on privileged 3-hydroxyoxindole and 3-hydroxypyrrolidinone substructures, were resolved with up to excellent selectivity (s = 7–190). Finally, the immobilised isothiourea catalysts were applied in a packed bed reactor to demonstrate the first example of the kinetic resolution of tertiary heterocyclic alcohols in a continuous flow process. High selectivities were obtained for the resolution of 3-hydroxyoxindole derivatives in ethyl acetate (s up to 70); and for 3-hydroxypyrrolidinones derivatives in toluene (s up to 42).

Chiral Au(I)- and Au(III)-Isothiourea Complexes: Synthesis, Characterization and Application

During an investigation into the potential union of Lewis basic isothiourea organocatalysis and gold catalysis, the formation of gold-isothiourea complexes was observed. These novel gold complexes were formed in high yield and were found to be air- and moisture stable. A series of neutral and cationic chiral gold(I) and gold(III) complexes bearing enantiopure isothiourea ligands was therefore synthesized and fully characterized. The steric and electronic properties of the isothiourea ligands was assessed through calculation of their percent buried volume and the synthesis and analysis of novel iridium(I)-isothiourea carbonyl complexes. The novel gold(I)- and gold(III)-isothiourea complexes have been applied in preliminary catalytic and biological studies, and display promising preliminary levels of catalytic activity and potency towards cancerous cell lines and clinically relevant enzymes.

Iron-Catalysed Hydrosilylation of Alkenes and Alkynes

The hydrosilylation of alkenes represents one of the largest applications of homogeneous catalysis on an industrial scale, and currently uses precious transition-metal catalysts such as platinum. This chapter deals with the development of an iron-catalysed methodology for the hydrosilylation of alkenes and alkynes using a bench-stable iron(II) pre-catalyst, which could be activated in situ. The reaction scope and limitations are presented along with preliminary mechanistic studies, which lead to a discussion of possible reaction mechanisms and future work required to investigate this method further.

Iron-Catalysed Hydromagnesiation of Styrene Derivatives

Grignard reagents are highly versatile organometallic reagents, and can be used for the formation of a range of carbon-carbon and carbon-heteroatom bonds, through reaction with electrophiles, or by cross-coupling methodologies. The hydromagnesiation of alkenes, dienes and alkynes provides an alternative method for the synthesis of alkyl-, allyl and vinyl Grignard reagents which may be challenging to prepare by conventional methods. This chapter deals with the development of an iron-catalysed methodology for the hydromagnesiation of styrene derivatives to give benzylic Grignard reagents. The reaction scope and limitations are presented along with a discussion of possible reaction mechanisms based on in-depth mechanistic studies.

Iron-Catalysed Hydroboration of Alkenes and Alkynes

Boronic acid derivatives have become ubiquitous in chemical synthesis, and can be conveniently synthesised by transition-metal-catalysed hydroboration of alkenes and alkynes, with rhodium and iridium catalysts most commonly used. This chapter deals with the development of an iron-catalysed methodology for the hydroboration of alkenes and alkynes using a bench-stable iron(II) pre-catalyst, which could be activated in situ. The reaction scope and limitations were investigated and a discussion of possible reaction mechanisms is presented.