Dual catalysis for enantioselective convergent synthesis of enantiopure vicinal amino alcohols

Enantiopure vicinal amino alcohols and derivatives are essential structural motifs in natural products and pharmaceutically active molecules, and serve as main chiral sources in asymmetric synthesis. Currently known asymmetric catalytic protocols for this class of compounds are still rare and often suffer from limited scope of substrates, relatively low regio- or stereoselectivities, thus prompting the development of more effective methodologies. Herein we report a dual catalytic strategy for the convergent enantioselective synthesis of vicinal amino alcohols. The method features a radical-type Zimmerman–Traxler transition state formed from a rare earth metal with a nitrone and an aromatic ketyl radical in the presence of chiral N,N′-dioxide ligands. In addition to high level of enantio- and diastereoselectivities, our synthetic protocol affords advantages of simple operation, mild conditions, high-yielding, and a broad scope of substrates. Furthermore, this protocol has been successfully applied to the concise synthesis of pharmaceutically valuable compounds (e.g., ephedrine and selegiline).

We recently envisioned that an efficient and flexible strategy for enantiopure vicinal amino alcohols might be realized by aptly combining merits of the aforementioned SmI 2 -mediated [12][13][14][15] and photocatalytic 23-28 protocols from nitrones and aldehydes. That is, a photocatalytic protocol featuring with intermolecular singleelectron-transfer (SET) can be used to reduce selectively the substrate of higher electron affinity (i.e., higher reduction potential) 26,30 and an oxophilic Lewis acid co-catalyst (e.g., rare earth metal cation) can be introduced to bind simultaneously both substrates 31,32 , and, more importantly, an appropriate chiral ligand to form precursor complex I and to induce desired enantioselectivity likely through a radical-type M(OTf) 3 35,36 coordinated rare earth ion and Ru-photocatalyst for enantioselective radical convergent synthesis of enantiopure vicinal hydroxyamino alcohols from nitrones and aromatic aldehydes, together with a mechanism deciphering catalytic cycle and stereoselectivity of this reaction.

Results
Optimization of the reaction conditions. Our investigation into this dual catalysis protocol began by studying the model reaction of nitrone 1a with 4-fluorobenzaldehyde under various conditions (Table 1). Initial experiments revealed the synergistic catalytic effect of Lewis acid and photocatalyst, which led to desired vicinal hydroxyamino alcohol (±)− 2a-1. Among several chiral ligand classes examined (see Supplementary Table 1), Feng's chiral N,N′-dioxides (such as L1-a and L1-b), which are wellknown privileged chiral catalysts 37 , provided enantioselective results for this reductive coupling reaction (see Supplementary  Tables 2 and 3), despite that this class of ligands has not proved to be effective for asymmetric radical reaction before 35,36 . Meanwhile, we noted that chiral N,N′-dioxides were potentially reduced by this dual-catalyst system owing to the oxidation ability of tertiary amine oxides (see Supplementary Note 1 for details). Fortunately, by optimization of Lewis acids we found that rare earth ions coordinated N,N′-dioxides were stable enough under our conditions to give optically enriched product. PyBOX ligands, which are originally utilized by Yoon and colleagues 38 for photocatalyst/chiral Lewis acid dual-activation catalysis, also provided enantioselectivity but only with low ee (such as L2-a and L2-b). Other optimization studies involving chiral ligands, Lewis acids, co-reductants, temperature and solvents were performed.
Enantioselective reductive cross-coupling of nitrones with aldehydes. With these optimized conditions in hand, we next examined the scope of nitrones. As illustrated in Table 2, symmetrical ketonitrones 1b to 1d gave the desired vicinal hydroxyamino alcohols with single chiral centers, respectively, in moderate to good yields with excellent enantioselectivity ( Table 2, entries 2-6). The absolute configuration of 2b-3 was determined to be (S) by derivatization 39 and single-crystal X-ray diffraction analysis (see Supplementary Fig. 2). Notably, as for these symmetrical ketonitrones, dichloromethane (DCM) was better than DCE. Next, we turned our attention to the scope of aldonitrones. Compared with nitrone 1a, more or less steric hindrance of substituents R 3 (R 2 = H) of nitrones diminished the reaction yields and stereoselectivity ( Table 2, entry 1 vs. entries 7-10). The influences of N-alkyl substituent groups of nitrones were also investigated and N-benzyl nitrone 1a provided a better result than N-methyl nitrone 1i and N-isopropyl nitrone 1j ( Table 2, entry 1 vs. entries 11 and 12).
We also explored the scope of aldehydes and found aromatic aldehydes to be excellent partners with nitrone 1a; aliphatic aldehydes, which were compatible with previous SmI 2 -mediated conditions 12 , are unavailable for this reaction. As for parasubstituted aromatic aldehydes, the more electron-deficient one   gave the higher stereoselectivity ( Furthermore, by using L1-a as chiral ligand and N,Ndiisopropylethylamine (DIPEA) instead of TEEDA (see Methods, modified method 1), cyclic nitrone (2k to 2m) also can be crosscoupled with aromatic aldehydes in moderate to excellent yields with high enantioselectivity but low diastereoselectivity ( Table 2, entries 23-27; 58-94% combined yields, 92-97% ee, 1/1.9-1/9.9 dr). It is noteworthy that, by using a complex of La(OTf) 3 with PyBOX ligand L2-b as the chiral Lewis acid (see Methods, modified method 2), reductive cross-coupling of nitrone 1k with aromatic aldehydes can also offer the desired products in goodto-excellent yields with high stereoselectivity ( Table 2, entries 23-25; 76-94% combined yield, 87-92% ee, dr <1/20). Nevertheless, this modified condition was not quite compatible with nitrones 1l and 1m. The absolute configuration of vicinal hydroxyamino alcohols 2a-9 and 2k-3 were both determined to be (S,S) by single-crystal X-ray diffraction analysis (see Supplementary Fig. 2). Notably, aromatic ketones can also cross-couple with nitrones smoothly under racemic photocatalytic conditions to produce the desired vicinal hydroxyamino alcohols. However, following the general method or modified methods mentioned in Table 2, only traces of desired products were observed. In addition, aromatic nitrones, such as N-benzylbenzylidene amine oxide (1o, see Supplementary Fig. 3), always provided complex results in this reaction.

Mechanistic investigations.
A series of experiments were carried out to get a deep insight into this reaction (see Supplementary  Discussion). Control experiments showed no product was formed in the absence of photocatalyst, Lewis acid, amine reductant or light source, thus established that the reaction is synergistically catalyzed by Lewis acid and photocatalyst through a light-driven reductive process. Moreover, a radical mechanism is consistent with the phenomenon that photoreaction was entirely inhibited when 1 equivalent TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) was added to the reaction mixture. We postulated that this photocatalytic reaction, unlike the previous SmI 2 -mediated reactions, is initiated by the visible light excited SET reduction of aldehydes to ketyl radicals. To verify our hypothesis, radical clock reactions of nitrone 1f under the racemic photocatalytic condition were carried out (Fig. 2). Considering the ring opening of αcyclopropylbenzyl radical is not a thermodynamic feasible process 40 (e.g., with 4-fluorophenyl ketone 3, vicinal hydroxyamino alcohol 2f-2 was obtained in 27% yield as a 1/1.6 (minor/major) mixture of inseparable diastereomers, along with 72% of recovered ketone 3), we designed and synthesized cyclopropylcontaining ketone 4 as a radical clock precursor 41 . Cyclopropyl opening of ketone 4 followed by cross-coupling with nitrone 1f provided δ-hydroxyamino ketone 5 in 53% yield as a 1/2.0 (minor/major) mixture of diastereomers, along with 46% of recovered ketone 4. Thus, the radical clock reactions proved that our photocatalytic reaction of nitrones with aldehydes is initiated by the SET reduction of aldehydes.
The hypothesis was supported by the cyclic voltammetry studies and density functional theory (DFT) calculations (see Supplementary Fig. 4~6 and 8~11). The coordination of 4-fluorobenzaldehyde with Sc(OTf) 3 in CH 3 CN resulted in a significant reduction in the aldehyde's half-wave potential which shifted from − 1.86 V to − 0.62 V [vs. saturated calomel electrode (SCE)]. With the fact that nitrone has a higher affinity with Lewis acid (see Supplementary Fig. 7, the reactants' solubility studies), a complex A of nitrone, aldehyde and Lewis acid was supposed to be a plausible starting point of the reaction, which leads to the proposed mechanism shown in Fig. 3. Photoexcitation and reductive quenching of Ru(bpy) 3 2+ by DIPEA affords [iPr 2 (Et)N·] + and Ru(bpy) 3 + (E 1/2 II/I = − 1.33 V vs. SCE in MeCN 42,43 ), which is sufficient to reduce complex A by intermolecular SET (onset potential E op > −0.5 V vs. SCE) and generate the radical complex B. Indeed, DFT calculations confirmed that the electron affinity of A is much higher (~63.0 kcal mol −1 in free energy) than that of nitrone 1a (~23.4 kcal mol −1 ) and 4-fluorobenzaldehyde (~45.1 kcal mol −1 ) in solvent, and the as-generated cross-coupling precursor B has spin density localized predominantly on the aldehyde moiety. Subsequently, N-radical intermediate C (or C′ of anti-configuration) is formed through an analogous 6-endotrig radical annulation and the transition state TS B leading to a syn-configuration is predicted to be by 1.9 kcal mol −1 favored over the anti-configuration transition state TS B′ . C upon hydrogen abstraction from [iPr 2 (Et)N·] + affords regioselectively intermediate D (via TS C ) other than D′ (via TS C′ ). Finally, protonation of D gives the desired vicinal hydroxyamino alcohol 2a-1 as a major diastereomer. Moreover, DFT calculations also showed that the formation of cross-coupling precursor B is overwhelmingly favored over the formation of homocoupling  precursors, accounting well for the reaction specificity towards cross-coupling rather than homocoupling. On the basis of this mechanism, the diastereoselectivity of vicinal hydroxyamino alcohols, such as 2a-1, can be illustrated through comparing the energy of six-member ring transition state TS B with that of TS B′ . The enantioselectivity is revealed by chiral scandium complex I 36 involving a Re-to-Re-facial attack of the ketyl radical to nitrone 1a.
Concise synthesis of (+)-ephedrine and (−)-selegiline. With the dual aim of taking further insight into this reaction and demonstrating the utility of this enantioselective radical protocol, we undertook the synthesis of ephedrine and selegiline (Fig. 4). Following the modified method 1, asymmetric reductive coupling of nitrone 1n with benzaldehyde gave product 2n as the major diastereomer (85% combined yield, 11/1 dr) with 94% ee 44 . After the indium-mediated reduction 39 Table 2, this diastereoselectivity is supported by the DFT calculations that revealed the involvement of six-member ring transition state (see Supplementary Fig. 10). Furthermore, dehydroxylation of vicinal hydroxyamino alcohol 2n was carried out in an aqueous solution of HCl under a mild Pd/Ccatalyzed hydrogenolysis condition to provide methamphetamine hydrochloride 7. N-propargylation of crude 7 in acetonitrile with K 2 CO 3 afforded (−)-selegiline (8)

Discussion
In summary, we demonstrated a photocatalytic enantioselective reductive cross-coupling reaction of nitrones with aromatic aldehydes via the synergistic catalysis of Ru-photocatalyst and chiral N,N′-dioxide ligand-coordinated rare earth ion. In this protocol, chiral Lewis acid represents an indispensable template for assembling to the key intermediate and triggers the asymmetric radical process to afford enantiopure vicinal hydroxyamino alcohols in moderate to excellent yields with high stereoselectivity. Taking advantage of this catalytic mechanism, unavoidable pinacol-type homocoupling side reactions in previous SmI 2 -mediated system were entirely inhibited. Notably, chiral N,N′-dioxide ligands were used in a radical-mediated system to account for a high level of stereoselectivity. Furthermore, this reaction is operationally simple with a wide array of readily available substrates under mild condition, allowing for the stepeconomy synthesis of highly valuable enantiopure vicinal amino alcohols (e.g., (1S,2R)-(+)-ephedrine) and amphetamine derivatives (e.g., (R)-(−)-selegiline) rivaling those of industrial biosynthetic procedures 48 . Based on a deep insight of this reaction, we believed that a foundation has been established for further research and application of these related reactions. Modified method 1. An oven-dried 25 ml Schlenk tube equipped with a magnetic stir bar was added nitrone (0.30 mmol, 1.0 eq), L1-a (37.9 mg, 0.054 mmol, 18 mol %), Ru(bpy) 3 (PF 6 ) 2 (5.2 mg, 0.006 mmol, 2.0 mol%), and Sc(OTf) 3 (22.1 mg, 0.045 mmol, 15 mol%) in the glove box. When the tube was sealed and removed from the glove box, DCM (6.0 ml) was added, followed by the aldehyde (0.45 mmol, 1.5 eq), and DIPEA (0.21 ml, 1.2 mmol, 4.0 eq). The tube was placed approximately 10 cm away from a 65 W CFL and the reaction mixture was stirred at − 5°C under an argon atmosphere for 48 h to afford desired products 2k to 2m.
Data availability. The crystallographic data have been deposited at the Cambridge Crystallographic Data Centre (CCDC) as CCDC 1537335 (6a-9•HCl), 1537337 (6b-3•HCl), and 1537338 (6k-3•HCl), and can be obtained free of charge from www.ccdc.cam.ac.uk/structures. Any further relevant data are available from the authors upon reasonable request.