ARTICLE https://doi.org/10.1038/s41467-020-20205-0 OPEN Pyrinap ligands for enantioselective syntheses of amines ✉ Qi Liu1,2,4, Haibo Xu1,2,4, Yuling Li1, Yuan Yao3, Xue Zhang1, Yinlong Guo1 & Shengming Ma 1,3 Amines are a class of compounds of essential importance in organic synthesis, pharma- ceuticals 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 R R N R S N 1234567890():,; report the development of ( , a)- -Nap-Pyrinap and ( , a)- -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. 1 State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, 200032 Shanghai, People’s Republic of China. 2 University of Chinese Academy of Sciences, 100049 Beijing, People’s Republic of China. 3 Research Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, 220 Handan Road, 200433 Shanghai, People’s Republic of China. 4These ✉ authors contributed equally: Qi Liu, Haibo Xu. email: [email protected] NATURE COMMUNICATIONS | (2021) 12:19 | https://doi.org/10.1038/s41467-020-20205-0 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-20205-0 hiral amines have been not only used as resolving reagents, propargylic amines are a very important class of compounds Cchiral ligands, and versatile building blocks in organic commonly used as precursors for other amines and diversified synthesis but also demonstrated wide applications in organic motifs. Consequently, attention has been paid to the pharmaceuticals and agrochemicals (Fig. 1a)1–9. Thus, the synthesis of this type of compounds12–14. Enantioselective three- development of highly efficient and enantioselective methods for component coupling reaction of terminal alkynes, aldehydes, and syntheses of amines is of fundamental interest10,11. Due to the amines provides one of the most straightforward approaches to presence of a synthetically versatile carbon–carbon triple bond, propargylic amines due to the easy availability and diversity of the O O a MeO Cl MeO N (S) (S) (S) (S) O N N N N H MeO N (R) O N O (S)-(+)-coniine (S)-Nicotine (R)-(+)-crispine A (S)-metolachlor (S)-pefurazoate (ref. 1) (ref. 2) (ref. 3) N (ref. 4) (ref. 5) MeO OH (S) N MeO NHAc HN F3C 2 (R) Cl (S) NH MeO (S)-(+)-dysoxyline (ref. 8) O N O H Rasagiline DPC 961 O MeO (S)-(-)-N-acetylcolchinol (ref. 6) (ref. 7) (ref. 9) OMe b X Ph Ph Ph Ph Ph N O S N N N N N N NH HN NH PPh PPh 2 PPh 2 PPh2 2 CO H F5 F5 2 F3C CF3 X = O, NH Ligand-a QUINAP X-PINAP StackPhos UCD-PHIM/StackPhim Br Selected typical examples of challenging substrates: O Bn Bn Bn Bn Bn Bn N N N N N (E) (R) N Ph Ph (R) Ph (S) OH Cy (S) Ph TMS OH (S) (S) OH Ph Ph 96% yield 82% yield 90% yield 72% yield 49% yield 95% yield 82% ee 85% ee 84% ee 69% ee (d.r. = 1:1) 32% ee 68% ee (ref. 22) (ref. 25) (ref. 42) (ref. 28) (ref. 32) (ref. 30) c R3 R4 R3 R4 N R ++2 cat. CuBr/Pyrinap chiral amines R CHO N * H and allene R2 R Challenges: (1) Lack of a powerful catalytic system that could be applied to broad spectrum of substrate combinations. (2) Highly efficient catalytic systems. R6 3 R R5 d R2 4 R PPh2 PPh2 1 R PPh2 4 R PPh2 PPh2 PPh2 R5 R6 BINAP R1 = MeO, R2,R3 = H MeO-NAPhePHOS R4 = MeO, R5,R6 = H MeO-BIPHEP 1 2 3 R ,R ,R = Me TriMe-NAPhePHOS 4 5 6 R ,R = -OCH2O-, R = H SEGPHOS R4,R6 = MeO, R5 = H Garphos * * X Ph HN Ar HN Ph N N N N N N N PPh2 MeO PPh2 PPh2 PPh 2 X = O, NH Ar = Ph, N-Ph-Pyrinap L1 OMe QUINAP X-PINAP Ar = 1-Naphthyl, N-Nap-Pyrinap L2 Pyriphen L3 Fig. 1 Background and concept design. a Selected biologically active chiral amines. b Known ligands for catalytic enantioselective A3-coupling reactions. c The method developed in this study. d Conceptual advance: evolution of binaphthyl to phenyl-naphthyl to biphenyl bisphosphines and the design of Pyrinap and Pyriphen. 2 NATURE COMMUNICATIONS | (2021) 12:19 | https://doi.org/10.1038/s41467-020-20205-0 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-20205-0 ARTICLE a Synthesis of N-Ph-Pyrinap L1 and N-Nap-Pyrinap L2 H2N (R) or Cl HN Ar N Cl H N (R) N O O N 2 B (i) N N 1. (ii) + OMOM OMOM N OTf 2. (iii) 3. (iv) Cl (1.4 equiv) S4 Ar = Ph, S6 S2 S3 58% Ar = 1-Naphthyl, S8 C20 C21 C19 C22 HN Ph (R) HN (R) Ph C18 C23 C17 C15 C24 N N C14 N3 C7 C13 N2 C8 N N C12 C6 N1 C16 C9 C11 + C5 C10 C4 (S) C33 PPh2 PPh2 C1 C3 C32 C34 C31 C2 P1 C35 C25 C36 Ar = Ph C26 C30 C27 C29 (v) (R,Ra)-N-Ph-Pyrinap (R,Sa)-N-Ph-Pyrinap C28 (R,Ra)-L1 (R,Sa)-L1 30% 37% CCDC 1911487 C21 C23 C24 C20 C19 C22 C27 C25 Ar = 1-Naphthyl C26 C18 C28 HN (R) HN (R) C17 N3 C14 C15 N2 N N C13 N1 C7 C12 N N C8 C11 C6 C9 + C10 C16 C31 C30 C32 (S) C5 PPh2 PPh 2 C4 C1 P1 C33 C29 C34 C3 C2 C35 C40 C39 C36 (R,Ra)-N-Nap-Pyrinap (R,Sa)-N-Nap-Pyrinap C37 (R,Ra)-L2 (R,Sa)-L2 C38 27% 35% CCDC 1911488 b Determination of the rotation barrier of L2 HN (R) HN (R) ‡ Δ (N-Nap-Pyrinap) 30.8 kcal/mol G 100 °C N N 100 °C ‡ Δ G (Stackphos) 28.4 kcal/mol N N 75 °C Toluene Δ ‡ (S) G (O-PINAP) 27.6 kcal/mol PPh2 PPh2 ‡ Δ (Stackphim) 27.5 and 26.8 kcal/mol G 50 °C ‡ L2 Δ G (UCD-PHIM) 26.8 kcal/mol (R,Sa)- (R,Ra)-L2 80 °C ‡ Δ G = 30.8 kcal/mol 100 °C Fig. 2 Synthesis of Pyrinap ligands and determination of rotation barrier between (R,Sa)-L2 and (R,Ra)-L2. Reagents and conditions: (i) Pd(OAc)2 (5 mol%), PPh3 (20 mol%), Na2CO3 (2 equiv), DME/H2O = 3:1, reflux, (58%); (ii) (R)-1-phenylethyl amine or (R)-1-(1-naphthyl)ethyl amine (1.3 equiv), Pd (OAc)2 (5 mol%), rac-Binap (7.5 mol%), Cs2CO3 (1.4 equiv), toluene, reflux; (iii) HCl (3 M in MeOH/H2O), r.t.; (iv) PhNTf2 (1.0 equiv), Et3N (1.0 equiv), DMAP (10 mol%), DCM, r.t. (for Ar = Ph, 83% yield in step (ii) and 90% yield over 2 steps (iii and iv); for Ar = 1-naphthyl, 86% yield over 2 steps (ii and iii) and 90% yield in step (iv).) (v) NiCl2(dppe) (10 mol%), HPPh2 (2 equiv), DABCO (4 equiv), DMF, 120 °C, 12 h. DME 1,2-dimethoxyethane, DMAP 4-dimethylaminopyridine, DCM dichloromethane, DABCO triethylenediamine, DMF N,N-dimethylformamide. three starting materials. Chiral ligands listed in Fig. 1b have been (MeO-NAPhePHOS and TriMe-NAPhePHOS) and biphenyl developed or applied for this reaction by Brown15, Knochel16–23, ligands (MeO-BIPHEP, SEGPHOS, and Garphos), some of the Carreira24,25, Aponick26–28, Naeimi29, Seidel30, and Guiry31,32. challenges in enantioselective hydrogenation reactions have been However, challenges still remain: (1) Lack of a powerful catalytic properly addressed33–39. system that could be applied to broad spectrum of very challen- In this work, inspired by such backbone effect on catalytic ging combinations for three types of substrates of terminal activity and previous studies on axially chiral P,N ligands24,40,we alkynes, aldehydes, and amines. (2) More practical and efficient report the development of the ligands phenyl-naphthyl-type catalytic systems are highly desirable. Developing ligands should ligand N-Ph-Pyrinap L1, N-Nap-Pyrinap L2, and the diphenyl- be the solution. type ligand L3 to address the challenges with respect to the scope It is well known that for atropisomeric diphosphine ligands the of the combination of alkynes, aldehydes, and amines (Fig. 1d) backbone skeletons greatly affect their catalytic performance in terms of both reactivity and enantioselectivity. For example, when Results binaphthyl ligand BINAP (2,2′-bis(diphenylphosphino)-1,1′- Synthesis of Pyrinap ligands.Atfirst, we tried to synthesize binaphthyl) was replaced with the phenyl-naphthyl ligands Pyriphen L3. But the transformation from triflate S1 to L3 could NATURE COMMUNICATIONS | (2021) 12:19 | https://doi.org/10.1038/s41467-020-20205-0 | www.nature.com/naturecommunications 3 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-20205-0 Table 1 Optimization of the reaction conditions. CuBr (x mol%) Ligand (1.1x mol%) N 4 Å MS, Toluene ++PhCHO N OH 25 °C, 24 h Ph ()(S) H OH 0.2 mmol 1.05 equiv 1.05 equiv (S)-4aaa 1a 2a 3a Entry Ligand x (mol%) Yield of 4aaaa ee of 4aaa (%)b 1(R,Sa)-L1 568 −78 2(R,Sa)-L2 575 −84 3(R,Ra)-L2 58485 c 4 (R,Ra)-L2 57490 c,d 5 (R,Ra)-L2 57990 c,d,e f 6 (R,Ra)-L2 2.5 73 (70 )90 g 7 (S,S,Ra)-UCD-PHIM 1 84 −98 h 8 (S,S,Ra)-UCD-PHIM 1 86 −85 a 1 Determined by H NMR analysis with CH2Br2 as the internal standard.