Synergistic Chemo/Biocatalytic Synthesis of Alkaloidal Tetrahydroquinolines

This is a repository copy of Synergistic Chemo/Biocatalytic Synthesis of Alkaloidal Tetrahydroquinolines. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/133028/ Version: Accepted Version Article: Cosgrove, SC, Hussain, S, Turner, NJ et al. (1 more author) (2018) Synergistic Chemo/Biocatalytic Synthesis of Alkaloidal Tetrahydroquinolines. ACS Catalysis, 8 (6). pp. 5570-5573. ISSN 2155-5435 https://doi.org/10.1021/acscatal.8b01220 (c) 2018, American Chemical Society. This is an author produced version of a paper published in ACS Catalysis. Uploaded in accordance with the publisher's self-archiving policy. Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Synergistic chemo/biocatalytic synthesis of alkaloidal tetrahydroquinolines Sebastian C. Cosgrove,1,2 Shahed Hussain,1 Nicholas J. Turner*1 and Stephen P. Marsden*2 1School of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manches- ter M1 7DN, United Kingdom 2Institute of Process Research and Development and School of Chemistry, University of Leeds, Leeds, LS2 9JT, United Kingdom ABSTRACT: The power of complementary chemo- and biocatalytic transformations is demonstrated in the asymmetric synthesis of 2-substituted tetrahydroquinolines. A series of racemic tetrahydroquinolines were synthesized through a conver- gent one-pot Rh(I)-catalysed addition/condensation sequence of alkyl vinyl ketones and aminophenylboronic acids. The re- sulting tetrahydroquinolines were thereafter shown to be substrates for the flavin-dependent enzyme cyclohexylamine oxidase, and preparative-scale deracemizations have been demonstrated on these high-value targets. KEYWORDS: rhodium catalysis, biocatalysis, amine oxidase, alkaloidal tetrahydroquinoline, enzymatic deracemization Introduction Amines are an important class of molecule that are pre- sent in many biologically-relevant compounds. A recent analysis of FDA registered pharmaceuticals revealed that 84% contained an amine moiety, with 59% of these being cyclic.1 Particularly relevant are chiral amines, which are Figure 1. Alkaloids isolated from Galipea officinalis subunits of ca. 40% of all pharmaceuticals.2 A variety of strategies have been developed for the preparation of enan- While many cyclic amines have been deracemised by AOx tiopure amines, from classical resolution through to asym- enzymes, studies on deracemization of THQs have been lim- metric chemocatalysis.3,4 ited.25 27 Lau engineered CHAO using iterative mutagenesis, Biocatalysis has found numerous applications in chiral producing a mutant which fully deracemized 2-methylTHQ amine synthesis5 and the toolbox of enzymes that can be on a preparative scale, but no activity was seen against 26 used to synthesise chiral amines includes transaminase,6 other THQ substrates. More recently this group demon- amino acid dehydrogenase,7 9 imine reductase,10,11 reduc- strated that the selectivity of CHAO could be reversed through a single point mutation of the wild-type, and tive aminase12 and phenylalanine ammonia-lyase.13 In addi- 28 tion, amine oxidase (AOx) has been applied by many groups showed an improved substrate scope of the enzyme. Deng in biocatalytic deracemization reactions.14,15 Several flavin- found that a novel AOx from Pseudomonas monteilii could dependent AOx enzymes have been used in the deracemiza- catalyse selective oxidation of THQ derivatives to the re- tion of racemic amines including the S-selective monoamine spective quinolines, and demonstrated mutants that could oxidase from Aspergillus niger (MAO-N)16,17 and cyclohexyl- be used for a traditional kinetic resolution of 2-methyl- THQs.29 amine oxidase (CHAO),18 and 6-hydroxy-D-nicotine oxidase (6-HDNO)19 which demonstrates complementary R-selec- For these deracemisation studies, the majority of the ra- tivity and has also been engineered to generate a more ac- cemic THQs were prepared by reduction of the correspond- tive mutant.20 22 ing quinolines and they are therefore contingent upon the Tetrahydroquinolines (THQs) are an important class of availability of these compounds. A more direct and modular biologically-active amines, found in a range of synthetic approach would be attractive. A powerful emerging syn- pharmaceuticals and naturally-occurring alkaloids.23 As thetic strategy is the union of chemo- and biocatalysis to 30 typical examples, a family of 2-substituted THQs 1-4 iso- achieve cascade or sequential transformations. This ap- lated from Galipea officinalis are shown in Figure 1, several proach is particularly powerful when harnessing metal-cat- of which have biological activity against certain malarial alysed C-C bond forming processes for which there are no strains (Figure 1).24 Methods for the asymmetric synthesis direct biocatalytic equivalents, hence greatly expanding the 31 37 of THQs are therefore of interest in medicinal chemistry. range of substrates for the biocatalytic transformation. Herein we show that the synergistic application of a chemocatalytic one-pot, two-component condensation and biocatalytic deracemisation enables the efficient asymmetric synthesis of THQ natural products. Results Previously, we have demonstrated a formal [4+2] approach to the assembly of nitrogen heterocycles through rhodium-catalysed conjugate addition/condensation of or- tho-aminophenylboronic acids with Michael acceptors.38 40 In the case of enone acceptors, the addition/condensation generates unstable dihydroquinoline intermediates which can be reduced in the same pot to give tetrahydroquinolines.40 Chemocatalytic asymmetric addition to beta-substituted enones (using a chiral phosphine/rhodium complex) followed by a diastereoselective syn-reduction allowed ac- cess to highly enantioenriched 2,4-disubstituted THQ products.40 However, many valuable products (including alkaloids 1-4) feature stereocentres only at the 2-position, which cannot be accessed asymmetrically through this approach. The approach to simple 2-substituted THQs requires the use of highly reactive unsubstituted vinyl ketones, and mod- ification of the previously disclosed conjugate addition conditions was required for good conversion. Specifically, we found that introduction of the phenylboronic acid as its HCl salt rather than the free base and operating at elevated (90 oC) rather than room temperature gave the optimal results. Scheme 2. Synthesis of 2-substituted tetrahydroquino- Initially, we examined the use of imine reductases to reduce lines aTBAF, THF, rt., 16h the prochiral dihydroquinoline intermediates 5; however exposure of the crude reaction mixture following filtration We then turned to the AOx-mediated deracemisation of to both (R) and (S)-IREDs failed to give any observable THQ the THQs 6a-f in order to complete formal asymmetric syn- product. The racemic 2-substituted THQ was therefore pro- theses of the alkaloids. The analytical scale biotransfor- duced in a one-pot process by addition of sodium tri(ace- mations were run using whole E. coli cells expressing three toxy)borohydride to the reaction mixture on completion of AOx enzymes described previously: MAO-N D9,15 the CHAO the conjugate addition. Under these conditions, the model variant described by Lau et al.,26 and 6-HDNO20 which was 2-(2-phenylethyl)THQ 6a could be assembled efficiently engineered previously in the Turner group. On an analytical (Scheme 1). scale almost full deracemization of 6a was observed with the CHAO variant, with an ee of 94% after 96 h. With MAO- N D9 only trace activity was observed, and 6-HDNO gave no activity towards this substrate. Pleasingly, CHAO also dis- played good activity towards the natural product substrates 6b-f, with cuspareine precursor 6c giving 90% ee, galipinine precursor 6c being converted to a lower ee of 70%, galipeine substrate 6e also giving an ee of 70% and the isomeric substrate 6f was fully deracemized in only 48h. In- terestingly, when the angustureine precursor 6b was sub- jected to deracemization by CHAO, an ee of only 47% was Scheme 1. Conditions for Rh(I)-catalysed 2-substituted- observed, but inspection of the HPLC trace showed a new tetrahydroquinoline synthesis peak not corresponding to either enantiomer which was We next used these optimized conditions to extend the subsequently shown to be the fully oxidised 2-pentylquino- substrate scope to encompass the 2-substituents found in line (see below). The THQ 6b was however a suitable sub- alkaloids 1-4 (Scheme 2). Pleasingly, incorporation of a sim- strate for the MAO-N D9 enzyme, giving an ee of 85% after ple pentyl substituent gave 6b in good yield, while (3,4-di- 96 h. Interestingly, it also showed limited activity towards methoxyphenyl)- and (3,4-methylenedioxyphenyl)ethyl 6-HDNO, with selectivity shown for the opposite enantio- substituents were also tolerated in 6c/d. Galipeine 4 fea- mer

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