Brønsted Acid Co-Catalysis Enabling Decarboxylative

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Photoredox/Brønsted Acid Co-Catalysis Enabling Decarboxylative Coupling of Amino Acid and Peptide Redox-Active Esters with N-Heteroarenes Wan-Min Cheng, Rui Shang, and Yao Fu ACS Catal., Just Accepted Manuscript • Publication Date (Web): 23 Dec 2016 Downloaded from http://pubs.acs.org on December 24, 2016

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Photoredox/Brønsted Acid Co-Catalysis Enabling Decarboxylative Coupling of Amino Acid and Peptide Redox-Active Esters with N-Heteroarenes Wan-Min Cheng, Rui Shang,*§ and Yao Fu* Hefei National Laboratory for Physical Sciences at the Microscale, iChEM, CAS Key Laboratory of Urban Pollutant Conversion, Anhui Province Key Laboratory of Biomass Clean Energy, Department of Chemistry, University of Science and Technology of China, Hefei 230026, China.

Supporting Information Placeholder ABSTRACT: An iridium photoredox catalyst in combination with a phosphoric acid catalyzes the decarboxylative α-aminoalkylation of natural and unnatural α-amino acid-derived redox-active esters (N-hydroxyphthalimide esters) with a broad substrate scope of Nheteroarenes at room temperature under irradiation. Dipeptide- and tripeptide-derived redox-active esters are also amenable substrates to achieve decarboxylative insertion of a N-heterocycle at the C-terminal of peptides, yielding molecules that have potential medicinal applications. The key factors for the success of this reaction are the following: use of a photoredox catalyst of suitable redox potential to controllably generate α-aminoalkyl radicals, without overoxidation, and an acid co-catalyst to increase the electron deficiency of Nheteroarenes. KEYWORDS: Photoredox catalysis, N-heteroarenes, decarboxylation, α-aminoalkylation, N-(acyloxy)phthalimide

Regioselective alkylation of N-heteroarenes, a transformation often required in medicinal chemistry and pharmaceutical industry,1 is achieved by the established Minisci reaction, in which an oxidatively generated alkyl radical homolytically attacks a protonated N-heteroarene to afford alkylated products upon oxidation.2 However, this method is inefficient when α-aminoalkylation is required due to the ease of overoxidation of an α-aminoalkyl radical to the iminium cation, removing its nucleophilicity.3 Thus, a general strategy for α-aminoalkylation of N-heteroarenes using αamino acids and peptides is still lacking. Considering the prevalence of α-amino acids and N-heteroarenes in biological systems and as common structure motifs in bioactive molecules,4 a general method to decarboxylatively cross-couple α-amino acids with coordinative N-heteroarenes may offer new opportunities in drug discovery and biochemistry applications. However, due to the inherent problem of overoxidation of α-aminoalkyl radicals in the presence of an excess amount of oxidants,5 a method that uses αamino acids to alkylate N-heteroarenes suffers from extremely limited scope and only highly electrophilic N-heteroarenes are suitable.6 Furthermore, oxidative elimination of an α-amino group via Strecker degradation/decarbonylation can take place to yield alkylation products.7 We consider that the recently rejuvenated synthetic application of N-(acyloxy)phthalimide,8 in combination with photodredox9 and Brønsted catalysis,10 may offer an opportunity to solve the abovementioned synthetic problems. We hypothesized that a photoredox catalyst (Mn) with suitable redox potential can interact with N-(acyloxy)phthalimide (A) to afford α-amino carboxylate radical (C) and to further generate αaminoalkyl radical (D) after decarboxylation. The photoredox catalyst may not further oxidize the α-aminoalkyl radical to form an iminium cation. The α-aminoalkyl radical that is generated is able to attack a N-heteroarene activated by an acid co-catalyst to

form a radical cation (E). The radical cation may be further oxidized by an excited photoredox catalyst (*Mn+1) and then be deprotonated by a counteranion to afford the α-aminoalkylation product, with regeneration of the photoredox catalyst. Figure 1 illustrates our working hypothesis. The key to achieve this hypothesized transformation is the choice of a photoredox catalyst of suitable redox potential and an acid catalyst that enhances the electrophilicity of N-heteroarenes.

Figure 1. Working Hypothesis

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Guided by this hypothesis, we discovered that an iridium photoredox catalyst (Ir[dF(CF3)ppy]2(dtbbpy)PF6)11 in combination with a phosphoric acid co-catalyst12 served well to catalyze the αaminoalkylation of a broad scope of N-heteroarenes with either natural or unnatural α-amino acid-derived redox-active esters. The reaction proceeds smoothly at room temperature under mild conditions, under the irradiation of blue LEDs. The almost neutral reaction conditions make it feasible to use a peptide-derived redox-active ester to connect a N-heteroarene at the C-terminal of a peptide that tolerates commonly used protecting groups in peptide synthesis.13 The reaction reported here offers the first general methodology for α-aminoalkylate N-heteroarenes using a broad scope of amino acids and peptides.

Table 1. Optimization of Decarboxylative αAminoalkylation of Phenylalanine Derivatives with 4Phenylquinoline

entry 1 2 3 4 5 6 7 8 9 10 11 12 13

variations of conditionsa None Ru(bpy)3(PF6)2 instead of Ir-cat. fac-Ir(ppy)3 instead of Ir-cat. Mes-Acr instead of Ir-cat. Without photocatalyst 100 mol % TFA instead of PA-1 Al(OTf)3 instead of PA-1 PA-2 instead of PA-1 PA-3 instead of PA-1 H3PO4 instead of PA-1 Without PA-1 Without light Using 1 mol % Ir-cat.

yieldb 85% < 5% 17% < 5% N.D. 68% 62% 60% 27% 23% 15% < 5% 84%

a Reactions were performed on a 0.2 mmol scale using photocatalyst (2 mol %) and acid catalyst (10 mol %) in DMA (2.0 mL) under irradiation of 36 W blue LEDs for 3 h under Ar. bYields reported are isolated yields.

After extensive experimentation, we found the optimized reaction condition given in Table 1, entry 1. A transparent Schlenk tube charged with Ir[dF(CF3)ppy]2(dtbbpy)PF6 (Ir-cat.) (2 mol %), (±)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (PA-1) (10 mol %), 4-phenylquinoline (0.2 mmol), and N-(tertbutoxycarbonyl)-L-phenylalanine-derived redox-active ester (Boc-Phe-ONPhth) (150 mol %) in DMA solvent was exposed under irradiation of 36 W blue LEDs at room temperature. After irradiation for 3 h and aqueous work-up, α-aminoalkylated product (1) was isolated in 85% yield. Important factors controlling the reaction are given in Table 1 (see Supporting Information for more details). The redox potential of the photoredox catalyst plays a crucial role in dictating the reaction outcome. With the redox potential reported for N-(acyloxy)phthalimide (−1.26 to −1.37 V vs SCE),14 the observed efficiency of catalysts can be rationalized

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by redox potentials. For the optimal catalyst, Ir[dF(CF3)ppy]2(dtbbpy)PF6 (E1/2*III/II = 1.21 V, E1/2III/II= –1.37; E1/2IV/*III = –0.89 V, E1/2IV/III = +1.69 V),9a it is reasonable that N(acyloxy)phthalimide (E1/2 = −1.26 to −1.37 V) can oxidize Ir(II) to Ir(III). The long-lived triplet *Ir(III) can oxidize the radical cation (E) in preference to the α-aminoalkyl radical (D) (E1/2 = −1.03 V)3c, due to rearomatization, to afford the α-aminoalkylated product (F). Considering the weak oxidation ability of N(acyloxy)phthalimide, it is less possible that an Ir(IV) species can be generated under this condition (E1/2IV/*III = –0.89 V). Thus, in contrast to previous photoredox catalyzed Minisci-type reactions that proceed via an IrIII/IrIV photoredox cycle,15 an IrIII/IrII mechanism is likely to proceed for this α-aminoalkylation reaction. The failure of other photoredox catalysts may be due to either the weak reducing ability to reduce N-(acyloxy)phthalimide [Ru(bpy)3(PF6)2, E1/2III/*II = –0.81 V, E1/2III/II = +1.29 V. Eosin Y E1/2red = –1.06 V, E1/2ox = +0.79 V. Mes-Acr E1/2red = -0.57 V, E1/2ox = +2.06 V]9a,16 or to the weak oxidation ability of its excited triplet state (Table 1, entries 2–4) [Ir(ppy)3 E1/2III/II = –2.91 V, E1/2*III/II = +0.31 V].9a The reaction did not proceed without photoredox catalyst under irradiation (entry 5). An acid catalyst is also crucial as described in the working hypothesis. The desired product was detected in only 15% yield in the absence of acid cocatalyst. Using a stoichiometric amount of strong acid such as trifluoroacetic acid (TFA) as additive can improve the yield to 68%, but a stoichiometric amount of strong acid is not preferred due to the sensitivity of protected amino acids and peptides toward strong acids. Using Al(OTf)3 as acid catalyst afforded the desired product in moderate yield (See SI for more details). We found that BINOL-derived phosphoric acid served as an optimal acid co-catalyst. Other phosphates such as diphenylphosphate and dibutylphosphate are much less effective (entries 8 and 9). Phosphoric acid is ineffective as a co-catalyst (entry 10). These experimental results revealed that the acidity and steric structure of acid catalyst are both crucial for the performance of the acid catalyst. The efficacy of BINOL-derived phosphoric acid may be ascribed to its facile tune-over (F to G) caused by steric bulkiness of the counteranion. A control experiment showed that the reaction cannot proceed without irradiation. Reducing the loading of Ir-cat. to 1 mol % did not reduce the yield. With the optimized reaction in hand, we first studied the scope of the reaction with respect to the amino acid coupling partners. Various natural and unnatural amino acid-derived redox-active esters are suitable substrates. The amenable amino acids include phenylalanine (1), glycine (4), alanine (5), proline (6), homophenylalanine (7), isoleucine (9), lysine (10), tryptophan (11), aspartic acid (12), glutamic acid (13), methionine (14), tyrosine (15), glutamine (16), and serine (17). Typical N-protecting group in peptide chemistry, such as the tert-butyloxycarbonyl (-Boc) and benzyloxycarbonyl (-Cbz) groups serve as suitable protecting groups for the amino groups. Since the reaction proceeds at room temperature without any strong acid and oxidant, the reaction exhibits excellent functional group compatibility, as shown in Scheme 1, amide (3, 16), ester (12, 13), ether (15, 17), N–H free indole (11), iodide (8), and sulfide (14) are all tolerable. The sulfide structure in methionine, which is incompatible in the Minisci reaction, was well tolerated in this reaction. This demonstrated the advantage of photoredox catalysis to controllably generate radicals while avoiding the use of stoichiometric oxidant.17 Aryl iodide (8), bromide (18), and chloride (19), which are useful for further modification, are all well compatible. This reaction is easy to upscale to gram scale with no decrease in the yield (11).

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a

a

Reaction conditions: heteroarene (0.2 mmol), redox-active ester (150 mol %), Ir-cat. (1 mol %), PA-1 (10 mol %), in DMA (2 mL), irradiated by 36 W blue LEDs for 3 h under Ar. bReaction time 6 h.

Scheme 1. Scope Investigation Focused on Various Amino Acid Estersa Next, we investigated the scope of the reaction with respect to N-heteroarenes (see Scheme 2). A broad scope of N-heteroarenes is amenable despite their inherent differences in electrophilicity. Isoquinoline (18), quinoline (19), quinoxaline (21), phthalazine (22), phenanthridine (24), pyrimidine (25), quinazoline (26), 1,10phenanthroline (27), and purine (30) can all be smoothly aminoalkylated in moderate to good yields (50–90%). Reactions selectively took place on the most electrophilic position, which can be predicted by a radical nucleophilic attack mechanism.18 For substrates possessing more than one reactive site, use of an excess amount of N-heteroarene results in predominantly the formation of monoalkyaltion products. This monoselectivity may be attributed to the reduced electrophilicity of the α-aminoalkylated heteroarenes, slowing down the second α-aminoalkylation (22, 25, 27). It is interesting to observe that when quinoline was used in excess, the reaction selectively took place on the C4 position, and a small amount of C2-alkylation was observed (23). The selective monoaminoalkylation of 3,4,7,8-tetramethyl-1,10-phenanthroline may find further application in ligand synthesis. The applicability of this reaction in medicinal chemistry was demonstrated by successful late-stage functionalization of three drug molecules, fasudil hydrochloride (28), caffeine (29), and famciclovir (30). Considering the prevalence of amine structures derived from natural amino acids in bioactive molecules, the new linkage may offer new opportunities in drug discoveries.

Reaction conditions: heteroarene (0.2 mmol), redox-active ester (150 mol %), Ir-cat. (1 mol %), PA-1 (10 mol %), in DMA (2 mL), irradiated by 36 W blue LEDs for 3 h under Ar. b0.2 mmol ester and 0.4 mmol heteroarene, yield based on ester. cIr-cat. (2 mol %), PA-1 (20 mol %) dialkylation product was observed in 10% yield. dUsing fasudil hydrochloride salt, DMA/H2O (10:1) as solvent. eRedox-active ester (0.2 mmol) and famciclovir (0.3 mmol), yield based on ester.

Scheme 2. Scope Investigation Focused on Various NHeteroarenesa

Scheme 3. Decarboxylative N-Heteroarylation of Dipeptide and Tripeptide The mild reaction conditions and the broad substrate scope encouraged us to test further the feasibility of using this reaction to functionalize the C-terminal of peptides.19 To our knowledge, there is no method yet available for directly installing a Nheteroarene on the C-terminal of a peptide via C–H coupling. We have demonstrated (Scheme 3) that dipeptide- and tripeptidederived redox-active esters can be successfully used in the decarboxylative α-aminoalkylation reaction, generating desired products in good yields. We believe that this reaction will be of use in peptide functionalization for pharmaceutical and biomedical applications.20 In summary, enabled by merging iridium photoredox catalyst with a phosphate acid catalyst, we solved the synthetic problem of the α-aminoalkylation of N-heteroarenes using amino acids. Such

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a reaction is unsuccessful under Minisci reaction conditions. Heteroarenes can be α-aminoalkylated using various natural and unnatural amino acid-derived redox active esters. Furthermore, peptides can also be decarboxylatively functionalized at the Ctermianl to connect with a N-heterocycle. This reaction offers a new method for the coupling of two structure motifs of medicinal importance. We hope that it will find future application in chemical biology research.

ASSOCIATED CONTENT Supporting Information This material is available free of charge via the Internet at http://pubs.acs.org. Experimental details and characterization data for all products (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected], [email protected]

Present Addresses R.S.: Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113- 0033, Japan.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the 973 Program (2012CB215305), NSFC (21325208, 21402181, 21572212), IPDFHCPST (2014FXCX006), CAS (KFJ-EW-STS-051, YZ201563), FRFCU and PCSIRT.

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