Cu-catalyzed asymmetric regiodivergent electrosynthesis and its application in the enantioselective total synthesis of (-)-fumimycin

Quaternary amino acids are one of the essential building blocks and precursors of medicinally important compounds. Various synthetic strategies towards their synthesis have been reported. On the other hand, developing core-structure-oriented cross-dehydrogenative coupling (CDC) reactions, is a largely unsolved problem. Herein, we describe a copper-catalyzed regiodivergent electrochemical CDC reaction of Schiff bases and commercially available hydroquinones to obtain three classes of chiral quaternary amino acid derivatives for the efficient assembly of complex scaffolds with excellent stereocontrol. The electrochemical anodic oxidation process with slow releasing of quinones serves as an internal syringe pump and provides high levels of reaction efficiency and enantiomeric control. The utility of this strategy is highlighted through the synthetic utility in the asymmetric total synthesis of (-)-fumimycin.

Stereochemically rigid α,α-disubstituted amino acids are a prevalent structural feature in a wide range of biologically active compounds, fueling the ongoing development of a powerful and efficient tool for dramatically increasing the complexity of organic molecules.Fumimycin, which was originally isolated from Aspergillus fumisynnematus, has been shown to exhibit antibacterial and against peptide deformylase inhibitory activity (Fig. 1a) 1 .Elegant contributions from the groups of Bräse 2-4 , Zhou 5 , Roche 6 , Piersanti 7 , and Watanabe 8 have been dedicated to the development of powerful synthetic strategies for the efficient synthesis of fumimycin.Despite significant progress, the assembly of quaternary carbon stereocenters for asymmetric catalytic synthesis of fumimycin in a highly stereoselective manner is still challenging, most likely due to the congested nature of such scaffolds and a lack of reliable synthetic routes for the appropriate installation of the hydroquinone moiety.In this context, the development of crossdehydrogenative coupling (CDC) methods 9,10 in a catalytic asymmetric fashion would significantly simplify synthetic access to α-quaternary amino acids, which would be invaluable in delivering compound libraries to benefit chemical space in drug design and screening 11 .
The retrosynthetic analysis of (-)-fumimycin, which focuses on directly assembling quaternary carbon stereocenters, allows the design of the synthetic strategy that utilizes the enantioselective coupling of Schiff bases with electrochemically generated quinones, and would offer mechanistically diverse transformations to access valuable chiral α-tertiary amino ester derivatives rationally and predictably (Fig. 1b).Furthermore, well-established N-metallated azomethine ylides, serving as a binding cavity, reveal distinct reactivity patterns and enable the diversity-oriented synthesis of unnatural αamino acids with consistently high enantioselectivity 58,59 .In this work, we describe the chiral copper-catalyzed, highly enantioselective, regiodivergent, electrochemical CDC reactions of Schiff bases with hydroquinone derivatives, providing diverse synthetic routes toward chiral quaternary amino esters with multiple substituent patterns via anodic oxidation and Lewis acid catalysis (Fig. 1c).Notably, the efficiency of this approach is demonstrated by its application to the enantioselective total synthesis of (-)-fumimycin.

Results and discussion
We initiated the study by investigating the electrochemical reaction between racemic ketimine ester 1a and 2,3-dimethylhydroquinone 2a in tetrahydrofuran (THF) (Table 1).The use of chiral box ligand (S,S)-L1 afforded the 1,4-addition product 3a with poor stereocontrol (68% yield, 38% e.e., entry 1).We next evaluated a variety of chiral ligands for this asymmetric electrochemical CDC reaction (entries 2-5), and the product 3a was obtained in 71% yield and 92% e.e. with the use of Phosferrox ligand (S,S p )-L5 (entry 5).Interestingly, when the reaction was carried out at −10 °C, a switchable reaction pathway that results in kinetic resolution (KR, entry 6) over dynamic kinetic asymmetric transformation (DyKAT, entry 5) of racemic ketimine ester 1a successfully afforded 3a in 57% yield and 92% e.e., as well as the recovery of (S)-1a in 30% yield with 98% e.e. (entry 6).Further studies focused on the evaluation of different ester moieties of ketimine esters 1 (entries 7-9), and the hydroquinone adduct 4a, which can be applied in the analog synthesis of (-)-fumimycin, could be obtained via an initial 1,4-addition and a subsequent intramolecular cyclization.To our surprise, the use of 1-naphthyl ester 1d instead of methyl ester 1a resulted in a successful switchable production of the desired hydroquinone product 4a over 3a, albeit with 81% e.e. (entry 9).Under the electrolytic conditions, the stereoselectivity was further improved with the use of Phosferrox ligand (S,S p )-L4, leading to the desired product 4a in 80% yield with 95% e.e. (entry 10).Further studies showed that the hydroquinone backbone was also susceptible to the reaction.We successfully switched the α-arylated process to the aryloxylation reaction using bulky 2,6-dimethylhydroquinone 2b under otherwise identical reaction conditions, producing 5a in the majority (entry 11, 78% yield, 92% e.e.).
As shown in Fig. 2c, the 1 H NMR spectrum for the reaction progress of 1d and 2a was monitored under standard conditions (Table 1, entry 10).The full conversion of the starting materials was achieved within 5 h, delivering dehydrogenation adduct 4a smoothly with its e.e. value remaining stable at 95% during the reaction progress.The quinone intermediate 2a′ was not detected until the reaction was nearly complete, which suggested a slow release of quinone intermediate from dimethylhydroquinone 2a.We further investigated the potential pathway arising from the electrochemical-free process with quinone 2a′ (Fig. 2d).Surprisingly, exposing quinone 2a′ with 1d in one portion resulted in the formation of 4a in essentially the same yield, albeit with significantly lower e.e. (Fig. 2d, t = 0 h, 48% e.e.).We speculated that the concentration of quinone would play a key role in this reaction.Thus, the enantiomeric excess of product 4a was measured as a function of the addition time of quinone 2a′.Using a syringe pump, 2a′ was lowly added over 4.5 h, and the results of product 4a (95% e.e.) perfectly matched with the standard electricity-driven protocol (Table 1, entry 10).On this basis, we hypothesized that high levels of reaction efficiency and enantiocontrol can be achieved through an internal syringe pump protocol wherein the controlled release of reactive quinones from the in situ anodic oxidation process of hydroquinones is accomplished.
Taking into account the combined results of mechanistic studies, a proposed mechanism for the Cu-catalyzed regiodivergent CDC reactions is outlined in Fig. 2e.The catalytic cycles begin with the coordination of the copper catalyst to Schiff base 1 to generate the nucleophilic metallated azomethine ylide I.Meanwhile, hydroquinone 2 is electrochemically oxidized at the anode to produce quinone species 2′.Remarkably, mechanistic studies show that an anodic oxidation process exhibiting as the internal syringe pump to the controllable release of quinone species is essential to the stereoselective transformation.The structure of the hydroquinones employed in the reaction defined the initial selectivity between the competing 1,4-addition and 1,6-addition pathways with Cu-coordinated azomethine ylide I.We investigated the generality of this reaction with different substituted Schiff bases after optimizing the reaction conditions for the synthesis of quinone adduct 3 (Fig. 3).As shown in Fig. 3a, a broad range of racemic ketimine esters 1 gave products with high yields and enantioselectivities. Substrates bearing electron-withdrawing or -donating groups on the aromatic rings participated in the transformation, resulting in excellent enantioselectivities (3a-3i).Furthermore, 2-naphthyl and heteroaromatic ketimine esters smoothly underwent this catalytic transformation with high enantioselectivities (3j and 3k).The absolute configuration of adduct 3j was unambiguously assigned by X-ray analysis.Furthermore, methyl 2-thiazoline-4-carboxylate and aldimine ester were effectively converted into the corresponding products (3l and 3m).The generality of the electrochemical CDC reaction in terms of hydroquinone substituents was also explored, and the corresponding products were obtained with satisfactory results (3n and 3o).By lowering the reaction temperature, we were able to expand the purview of this catalytic KR reaction for various racemic Schiff bases 1 (Fig. 3b).The KR of Schiff base 1 with different benzene ring substituents proceeded smoothly, with nearly 50% conversion and with excellent KR results in all instances.Methyl 2-phenyl-2-oxazoline-4-carboxylate 1ap also worked well to deliver quinone product 3p with high levels of stereoselectivity, while unreacted enantiomeric Schiff base (S)-1ap was recovered with 83% e.e.
Next, we explored the scope of the tandem annulation reactions of 1-naphthyl ester 1, for which lactone products 4 are specifically available (Fig. 4).A wide variety of Schiff bases and hydroquinones were investigated under optimized reaction conditions (Table 1, entry 10).Aromatic and heteroaromatic Schiff bases were transformed catalytically with good enantioselectivities (4a-4j).Notably, the opposite enantiomer of 4a can be obtained by using ligand (R,R p )-L4 under otherwise identical conditions, and the absolute configuration of ent-4a was assigned by single-crystal X-ray diffraction analysis.Further exploration showed that naphthalen-1-yl 2-phenyl-4,5-dihydrothiazole-4-carboxylate was also an appropriate substrate (4k).We then attempted to assess the applicability of this methodology to other types of hydroquinones.The reaction with different substituents on the hydroquinone ring went smoothly, obtaining moderate yields and good enantioselectivities (4l-4o).
In comparison to the prevalence of reactions involving α-arylated reactivity, asymmetric α-aryloxylation for C-O bond formation has received far less attention.A wide range of Schiff bases 1 was investigated with 2,6-disubstituted hydroquinones (Fig. 5a).Substitutions on the benzene ring of Schiff bases had little effect on the reaction (5a-5f).The absolute configuration of 5b was assigned by single-crystal X-ray diffraction analysis.Furthermore, variations in the different substituted groups of hydroquinones 2 had no discernible effect on the reaction outcomes, giving the corresponding α-aryloxylation products in good yields and enantioselectivities (5g-5i).To test the synthetic utility of the electrochemical CDC reactions, optically active α-aryloxylation product 5a can be readily elaborated (Fig. 5b).Under basic conditions, the treatment of compound 5a with different thiols 6 furnished a variety of valuable quaternary thioethers 7 in high yields with maintaining e.e. (7a-7d).
The utility of the current method is further demonstrated by the enantioselective total synthesis of (-)-fumimycin with high stereochemical purity (Fig. 6).Accordingly, 4o was treated with allyl bromide and potassium carbonate to produce allyl ether 8 in 80% yield and 93% e.e.Acidic hydrolysis of the imine group, followed by the treatment with tert-butyl protected acid chloride, generates the corresponding amide 9 without affecting the enantioselectivity.The thermal Claisen rearrangement was performed to afford 10 in DMF at 180 °C2, 3 .Subsequent isomerization of the terminal double bond was accomplished under rhodium catalysis, and the desired product 11 was afforded without loss of enantioselectivity.Finally, the methyl group and the tert-butyl ester were cleaved to yield (-)-fumimycin successfully.All the spectroscopic data for our synthetic product are in agreement with those reported in the literature 4,7 .Notably, the absolute configuration of (-)-fumimycin is consistent with the X-ray diffraction analysis of 9.
We have developed a Cu-catalyzed asymmetric electrochemical regiodivergent CDC reaction of Schiff bases and hydroquinones.This methodology enables efficient and economic access to a regiodivergent and enantioselective synthesis of valuable amino esters bearing quaternary stereocenters with high functional group tolerance.The regioselectivity could be switched by using the appropriate substrates, and the electrochemical process acts as an internal syringe pump to boost the stereoselectivity, offering an effective platform for future efforts to create complex and value-added quaternary amino acids.The synthetic utility of this asymmetric electrochemical methodology is demonstrated by its application to the total synthesis of (-)-fumimycin.

Methods
General procedure for the synthesis of chiral products 3   6 | Asymmetric total synthesis of (-)-fumimycin.The current methodology could allow for the enantioselective product of (-)-fumimycin.The absolute structure of (-)-fumimycin agrees with the X-ray diffraction investigation of 9.

Fig. 2 |
Fig. 2 | Mechanistic studies.a Control experiments.b Racemization profile of (S)-1a and (S)-1d.c Kinetic profile of the reaction of 1d and 2a.d Effect of addition time of quinone 2a′ on the e.e. values of 4a. e Proposed catalytic cycles for the copper-catalyzed enantioselective electrochemical regiodivergent CDC reactions.