Pyrinap ligands for enantioselective syntheses of amines

Amines are a class of compounds of essential importance in organic synthesis, pharmaceuticals and agrochemicals. Due to the importance of chirality in many practical applications of amines, enantioselective syntheses of amines are of high current interest. Here, we wish to report the development of (R,Ra)-N-Nap-Pyrinap and (R,Sa)-N-Nap-Pyrinap ligands working with CuBr to catalyze the enantioselective A3-coupling of terminal alkynes, aldehydes, and amines affording optically active propargylic amines, which are platform molecules for the effective derivatization to different chiral amines. With a catalyst loading as low as 0.1 mol% even in gram scale reactions, this protocol is applied to the late stage modification of some drug molecules with highly sensitive functionalities and the asymmetric synthesis of the tubulin polymerization inhibitor (S)-(-)-N-acetylcolchinol in four steps. Mechanistic studies reveal that, unlike reported catalysts, a monomeric copper(I) complex bearing a single chiral ligand is involved in the enantioselectivity-determining step. Chiral amines find use as chiral ligands, resolving reagents and versatile building blocks as well as in pharmaceuticals and agrochemicals. Here, the authors developed Pyrinap ligands for the copper-catalyzed enantioselective A3-coupling of terminal alkynes, aldehydes, and amines affording optically active propargylic amines.

C hiral amines have been not only used as resolving reagents, chiral ligands, and versatile building blocks in organic synthesis but also demonstrated wide applications in pharmaceuticals and agrochemicals (Fig. 1a) [1][2][3][4][5][6][7][8][9] . Thus, the development of highly efficient and enantioselective methods for syntheses of amines is of fundamental interest 10,11 . Due to the presence of a synthetically versatile carbon-carbon triple bond, propargylic amines are a very important class of compounds commonly used as precursors for other amines and diversified organic motifs. Consequently, attention has been paid to the synthesis of this type of compounds [12][13][14] . Enantioselective threecomponent coupling reaction of terminal alkynes, aldehydes, and amines provides one of the most straightforward approaches to propargylic amines due to the easy availability and diversity of the ( (1) Lack of a powerful catalytic system that could be applied to broad spectrum of substrate combinations.
In this work, inspired by such backbone effect on catalytic activity and previous studies on axially chiral P,N ligands 24,40 , we report the development of the ligands phenyl-naphthyl-type ligand N-Ph-Pyrinap L1, N-Nap-Pyrinap L2, and the diphenyltype ligand L3 to address the challenges with respect to the scope of the combination of alkynes, aldehydes, and amines ( Fig. 1d)
not be realized by the Ni-catalyzed phosphorylation reaction. The reaction gave only a complex mixture (see Supplementary information for the details). Subsequently, we turned our attention to synthesize N-Ph-Pyrinap L1 or N-Nap-Pyrinap L2. The synthesis of Pyrinap was successfully realized as shown in Fig. 2b: the Suzuki coupling reaction of 3,6-dichloro-4,5-dimethylpyridazine S2 with boronate S3 produced biaryl compound S4 in 58% yield. Subsequent amination reaction with (R)-1-phenylethyl amine or (R)-1-(1-naphthyl)ethyl amine, deprotection, and triflation afforded corresponding triflates S6 or S8, respectively. Finally, Ni-catalyzed coupling of S6 or S8 with HPPh 2 provided a mixture of diastereomers of L1 or L2, respectively, which may be separated easily via column chromatography separation on silica gel. The absolute configurations of (R,S a )-L1 and (R,S a )-L2 were firmly established by X-ray single-crystal analysis, respectively. (S, R a )-L2 and (S,S a )-L2 could also be easily prepared by the same synthetic procedure with (S)-1-(1-naphthyl)ethyl amine (see the Supplementary Fig. 3 for the details). In order to understand the nature of these ligands, we first determined the rotational barrier between (R,S a )-L2 and (R,R a )-L2 in toluene at 100°C to be 30.8 kcal/mol, which is higher than those for O-PINAP (27.6 kcal/mol) 41 , at 75°C for Stackphos (28.4 kcal/mol) 26 , at 50°C for StackPhim (26.8 and 27.5 kcal/mol) 28 , and at 80°C for UCD-PHIM (26.8 kcal/mol) 31 (Fig. 2b). Thus, the ligand L2 is configurationally more stable under ambient conditions.
Optimization of reaction conditions. With these two ligands in hand, we tried the enantioselective A 3 -coupling of the most challenging propargyl alcohol 1a with a much smaller steric hindrance, benzaldehyde 2a, and pyrrolidine 3a. After some screenings, it was observed that (R,R a )-L2 ligand gave the highest yield (84%) and enantiomeric excess (ee) (85%) at room temperature (r.t.) ( Following the same conditions reported in ref. 32 (Table 1, entry  7), (S,S,R a )-UCD-PHIM provided the product in 86% yield with −85% ee ( Table 1, entry 8).
Encouraged by the above results, we turned to explore the scope of amines (Fig. 3c) 30 : a range of amines with different types of aldehydes and alkynes were tested (Fig. 3c). The ring size of 6to 8-membered cyclic amines had no obvious effect on the enantiocontrol of the reaction (products (S)-4fab, (S)-4dab, (S)-4aqb, (S)-4gac, and (S)-4had). For 4-piperidone 3e, which was used as an ammonia equivalent 25 , chiral (S)-4dte was obtained in 76% yield and 90% ee under a further modified conditions. Morpholine 3f could also furnish the product (S)-4iaf in 85% yield with 94% ee by using dimethyl carbonate instead of toluene as the solvent. Meanwhile, the reaction could be extended to acyclic amines with good yields and excellent ee for products (S)-4jag and (S)-4kah. As we know that dibenzyl amine 3i is an   32 . h Data produced in this laboratory using (S,S,R a )-UCD-PHIM prepared in this laboratory.
important amine due to the potential of debenzylation for further possible functionalization of the nitrogen atom. It should be noted that the known ligands for the reactions with dibenzyl amine 3i afforded (S)-4eai and (S,E)-4lvi in 49% yield with an ee of merely 32% and 96% yield with 82% ee, respectively 22,32 . Thus, the scope of this transformation with dibenzyl amine 3i was investigated: both aromatic and aliphatic aldehydes could achieve excellent yields and ee with tertiary propargylic alcohol 1e (products (S)-4eai and (S)-4eui). Even an alk-2-enal or 2-alkynal, which may readily undergo conjugate addition with the amine, worked with an excellent selectivity: cinnamaldehyde E-2v smoothly yielded the corresponding product (S,E)-4lvi in 80% yield and 99% ee; the reaction of 3-phenylpropiolaldehyde 2w under standard conditions was very sluggish in toluene, producing (S)-4lwi in merely 6% nuclear magnetic resonance (NMR) yield. However, 88% yield and 94% ee of (S)-4lwi could be obtained by using dichloromethane (DCM) as solvent with 1.5 equiv of trimethylsilylacetylene 1l 27 . Importantly, all four different stereoisomers of 4oti may be obtained in excellent yields, ee, and diastereomeric excess (d.e.) by starting from optically active propargylic alcohol (R)-1o 43 or (S)-1o 43 and chiral ligand (R,R a )-L2 or (R,S a )-L2, respectively.   Having illustrated the broad substrate scope and efficient enantiocontrol ability of this catalytic system, late-stage modification of biologically active or drug molecules were further performed (Fig. 3d): alkynes derivatives of carbohydrate Dfructose 1p and amino acid L-phenylalanine (S)-1q 44 provided the corresponding products (R)-4poa and (S,S)-4qaa smoothly in high yields and d.e.; the terminal alkyne groups in commercial drugs, ethisterone 1r, mestranol 1s, and Boc-protected Rasagiline (R)-1t 45 , may be readily converted to corresponding chiral propargylic amines (S)-4raa, (S)-4saa, (S)-4sxa, and (S,R)-4tba, without affecting other functionalities. For ethisterone 1r, cases of match and mismatch between the substrate chirality and the ligand chirality were observed: the reaction with (R,R a )-L2 or (S, R a )-L2 yielded (S)-4raa in 93% yield with 97% d.e. or 82% yield with 98% d.e., respectively. As a comparison, with (R,S a )-L2 or (S, S a )-L2, the same product was produced in 50% yield with 75% d. e. or 83% yield with 67% d.e., respectively. The reaction of the terminal alkyne derivative of dihydroartemisinin, indole carboaldehyde, and piperidine afforded (R)-4unb and (S)-4unb successfully via the current protocol: even the fragile bridged peroxide group in the dihydroartemisinin, which plays an important role in antimalarial activity 46 , was tolerated. In this case, the absolute configuration of the newly formed propargylic chiral center was completely controlled by the axial chirality of the chiral ligand, regardless of the substrate chirality or the central chirality of the chiral ligand. This may be explained by the fact that the chirality in dihydroartemisinin is far away from the terminal sp carbon atom. Moreover, amine-containing drug molecules, trimetazine (3j), duloretine ((S)-3k), and paroxetine ((S,R)-3l), could be used directly in this reaction to deliver products (S)-4daj, (S,S)-4dak, and (S,S,R)-4dal in high enantioselectivity under slightly modified conditions (Fig. 3d).
Synthetic applications. The colchicine degradation product (S)-(−)-N-acetylcolchinol (S)-6 is the tubulin polymerization inhibitor [47][48][49] . Previously reported enantioselective synthesis of (S)-6 suffered from using stoichiometric amounts of chiral reagents and step-economy 9,50-58 . We reasoned that our methodology could be applied to the highly efficient enantioselective synthesis of (S)-6 as outlined in Fig. 4a. The key step would be the enantioselective A 3 reaction with the abovementioned challenging dibenzyl amine 3i (Fig. 4b): at first, the enantioselective A 3 -coupling reaction of alkyne 1v, aromatic aldehyde 2y, and dibenzyl amine 3i under standard conditions at r.t. was very sluggish, affording the desired propargylic amine (R)-4vyi in 81% yield and 96% ee with 19% of 1v being recovered even after 7 days. Fortunately, this targeted transformation could be efficiently achieved at r.t. with 1.0 mol% of CuBr and 1.1 mol% of (R,S a )-L2 in dimethyl carbonate 1.1 equiv 2y

equiv 3i
CuBr (1 mol%  As stated in the introduction, the unique structure of chiral propargylic amine offers opportunities for further synthetic elaboration for the asymmetric syntheses of different amines (Fig. 4c): partial reduction of the C≡C triple bond in (S)-4aaa using "P-2 nickel" in the presence of ethylenediamine or LiAlH 4 provided highly selectively (R,Z)-7 and (R,E)-7 in excellent yields and ee 59,60 ; the Mitsunobu reaction 61 of (S)-4aaa with phthalimide afforded 1,4-butynyl diamine (S)-8 in 74% yield and 91% ee; primary α-allenols (R)-9 may also be prepared with 75% yield and Mechanistic studies. It has been reported that Quinap demonstrated a strong positive nonlinear effect 16 , while a weak positive nonlinear effect was observed for StackPhos (see the Supplementary information file of ref. 27 ). Interestingly, a perfect linear effect was observed between the enantiopurity of (R,R a )-L2 and product (S)-4aqa for the current reaction shown in Fig. 5a, which indicated that the catalytically active species most likely involves a monomeric copper(I) complex bearing a single chiral ligand. In order to acquire more information of the catalyst species in this reaction, we tried to isolate the Cu(I)-(R,R a )-L2 complex 64 (Fig. 5c, see Supplementary information, pp 87-92 for the detailed information of computational methods). The calculated results showed that Int_N,P was more stable than Int_N by 1.5 kcal/mol. Solvent-assisted electrospray ionization mass spectrometric experiment (SAESI-MS) was further applied to unveil the nature of catalytically active species in this reaction 66 . First, a solution of CuBr (6.25 μmol), (R,R a )-L2 (6.88 μmol), and alkyne 1d (0.25 mmol) in toluene (1 mL) was stirred at r.t. under Ar atmosphere. After 10 min, a signal with m/z of 650, which matched the m/z of mono-ligated species [Cu((R,R a )-L2)] + (MS-Int. I, Fig. 5c(i), calcd for C 40 H 34 63 CuN 3 P + : 650.2) was observed. Meanwhile, an alkyne-coordinated intermediate MS-Int. II was confirmed by a SAESI-MS/MS experiment (Fig. 5c(ii)). Then, aldehyde 2a (0.3 mmol) and pyrroline 3a (0.3 mmol) were added. The signal m/z of 928.7 and 990.7 were attributed to mono-ligated intermediates MS-Int. V (Fig. 5c(iii), calcd for C 59 H 55 63 CuN 4 OP + : 929.3) and MS-Int. VI (Fig. 5c(iv), calcd for C 59 [7][8][9][10][11][12][13][14].
Based on these experimental data, we proposed a mechanism shown in Fig. 6: the mono-ligated Int. I would interact with the terminal alkyne 1d to generate Int. II, in which the chiral amine in the ligand may act as a proton shuttle. The reaction of amine with aldehyde generated Int. III, which would coordinate with the Cu atom in Int. II to form Int. IV. H + -mediated elimination of water formed the iminium species in Int. V. Enantioselective 1,2-addition would afford Int. VI (Re face attack is more favored), which underwent disassociation to release the productpropargylic amine (S)-4daa and regenerate the catalytically active Int. I to finish the catalytic cycle.
In conclusion, we have developed axially chiral P,N-ligands Pyrinap for the highly efficient catalytic enantioselective A 3coupling reaction of readily available alkynes, aldehydes, and amines to provide a variety of chiral amine-synthesis platform molecules, chiral propargylic amines, in high yields and enantioselectivity. Compared to known ligands, the salient features of this work are: (a) a general catalytic system that could be applied to a variety of challenging substrate combinations with high enantioselectivity; (b) monomeric copper(I) complex bearing a single chiral ligand has been identified as the catalytically active species; (c) the reaction has been successfully applied to the late-stage modification of some drug molecules with the sensitive

Data availability
All data that support the findings of this study are available in the online version of this paper in the accompanying Supplementary information (including experimental procedures, compound characterization data, and spectra).
The X-ray crystallographic coordinates for structures of (R,S a )-N-Ph-Pyrinap and (R,