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Pyrrolidines and Piperidines Bearing Chiral Tertiary Alcohols by Nickel-Catalyzed Enantioselective Reductive Cyclization of N-Alkynones

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Pyrrolidines and Piperidines Bearing Chiral Tertiary Alcohols by Nickel-Catalyzed Enantioselective Reductive Cyclization of N-Alkynones ARTICLE DOI: 10.1038/s42004-018-0092-1 OPEN Pyrrolidines and piperidines bearing chiral tertiary alcohols by nickel-catalyzed enantioselective reductive cyclization of N-alkynones Guodu Liu 1,2, Wenzhen Fu1, Xingye Mu1, Ting Wu1, Ming Nie1, Kaidi Li1, Xiaodong Xu1 & Wenjun Tang1 1234567890():,; Pyrrolidines and piperidines are important building blocks in organic synthesis. Numerous methods exist for constructing substituted pyrrolidines and piperidines. However, efficient syntheses of pyrrolidines and piperidines bearing chiral tertiary alcohols are limited. Here we report an efficient enantioselective nickel-catalyzed intramolecular reductive cyclization of N- alkynones. A P-chiral bisphosphorus ligand DI-BIDIME is designed and applied in the synthesis of tertiary allylic siloxanes bearing pyrrolidine and piperidine rings in high yields and excellent enantioselectivities, with triethylsilane as reducing reagent. The highest turn over number achieved is 1000 (0.1 mol% catalyst loading) with > 99:1 er. This reaction provides a practical way to synthesize pyrrolidine and piperidine derivatives with chiral tertiary alcohols from easily accessible starting materials under mild conditions. The products can be scaled up and transformed to various useful chiral intermediates. The P-chiral bisphosphorus ligand developed in this study represents one of the few ligands for highly enantioselective cycli- zation of alkynones. 1 State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai 200032, China. 2 Department of Chemistry and Chemical Engineering, Inner Mongolia University, 235 Da Xue West Road, Hohhot 010021, China. Correspondence and requests for materials should be addressed to W.T. (email: [email protected]) COMMUNICATIONS CHEMISTRY | (2018) 1:90 | DOI: 10.1038/s42004-018-0092-1 | www.nature.com/commschem 1 ARTICLE COMMUNICATIONS CHEMISTRY | DOI: 10.1038/s42004-018-0092-1 ransition metal-catalyzed coupling of alkynals/alkynones could be achieved by the development of our privileged ligand has become a powerful method for efficient construction of BIDIME31–34. We intuitively designed DI-BIDIME in hope to T 1–3 allylic alcohol derivatives in current organic chemistry . develop a more efficient enantioselective nickel-catalyzed reaction Recent development by employing various transition metal cat- (Fig. 1a). Our design in DI-BIDIME are in two strategies: (1) DI- alysts such as Ti4,Ni5–18,Rh19–24,Ir25,Ru26–28, and Pd29,30 in BIDIME is free of H7, not only avoiding the potential C–H combination with a variety of coupling components and redu- functionalization at H7 position35–37 but also making the adja- cing/alkylative agents has greatly expanded its scope and appli- cent C–O bond more hindered and resistant to cleave in the cations. Among them, the nickel-catalyzed coupling of π systems presence of a nickel metal38,39; (2) both phosphorus atoms in DI- pioneered by Mori5,8, Montgomery6,7,10, and Jamison9,15,is BIDIME should function independently with a reduced ligand particularly attractive and offers a broad substrate scope and good entropy by half. This could be helpful for increasing the longevity functional group compatibility. However, the enantioselective of nickel catalyst. We herein report the development of DI- cyclization of these substrates, especially for constructing chiral BIDIME (L4) by using this strategy. tertiary alcohols is limited16. The chiral tertiary alcohols con- struction is synthetically more difficult as the asymmetric addi- Reaction discovery. Multi-substituted pyrrolidines and piper- tion to ketones (tetrasubstituted carbon synthesis) is generally more challenging than addition to aldehydes. Furthermore, the idines are widely present in the structures of bioactive natural products and drugs40–43 (Fig. 1b). In general, their optical active nickel-catalyzed reactions usually demonstrated in considerably version led to enhanced bio-activities44,45. However, methods for high catalytic loadings (5 to 30 mol% of Ni catalyst), which is not fi “ ” ef cient construction of chiral substituted pyrrolidines and green enough for the practicality of nickel-catalyzed synthesis. 46 Thus, the development of efficient enantioselective nickel- piperidines were limited . In the past two decades, many metal- catalyzed cyclizations were developed for constructing functio- catalyzed reactions remains a major challenge for synthetic – chemists. nalized pyrrolidines and piperidines (Fig. 1c h). From 2000s, Montgomery group have first studied Ni-catalyzed regioselective Herein, we report an efficient regiospecific and enantioselective nickel-catalyzed intramolecular reductive cyclization of N-alky- cyclization of tethered N-alkynals without investigated their enantioselectivity6,7,11 (Fig. 1c). Krische and Tanaka then devel- nones with up to 1000 TON (0.1 mol% catalyst loading) and > 99:1 er under mild conditions. oped the rhodium-catalyzed enantioselective cyclizations of N- alkynals to form pyrrolidines with chiral secondary alcohols/ ethers20,22,23 (Fig. 1d). In 2007, Zhou and colleagues21 first Results reported one enantioselective rhodium-catalyzed hydrosilylation/ Ligand design. Despite the recent progress in nickel-catalyzed cyclization of 1,6-enynes (Fig. 1e) and followed by a enantiose- reactions, few reports are available on ligand engineering in lective Ni-catalyzed intramolecular hydroalkenylation of N-1,6- seeking for a more robust and active nickel catalyst. Based on our dienes to synthesize chiral functionalized pyrrolidines and previous experience on ligand design, we proposed this objective piperidines18 (Fig. 1f). In 2013, the first regioselective cyclization a H 7 O OMe MeO P 1) Enhance ligand efficiency tBu MeO OMe 2) Reduce ligand entropy OMe POO P MeO tBu tBu (S)-BI-DIME (S,S)-DI-BIDIME (L4) b F Me HO Me OH N N Et OMe COOH O O O Me O N O N O H N COOH O O N H O N Me N Me O Me Prodine Kainic acid H (–)-Paroxetine O2N (+)-Femoxetine Homocrepidine B (analgesic) (neuroexcitatory) (anti-depressants) Nifeviroc (anti-HIV) (anti-depressants) (anti-inflammatory) c Montgomery d Tanaka, Krische e Zhouf Zhou 1 R R1 1 1 1 R1 R R1 R R R1 Rh, 2 Rh, R2 Ni, 2 O R SiR R Ni N O ligand ligand 3 ligand N TsN TsN ∗ R2M TsN n n TsN 2 TsN R3SiH TsN OH n R H n OR2 Aldehyde, Ni, no enantioselectivity Aldehyde, Rh, low TON Alkene, Rh, no chiral alcohol Alkene, Ni, low TON, no chiral alcohol 1 1 g Luh Xui This work R Ni(cod) (0.1 mol%) R R1 1 R1 1 2 R R L4 (0.05 mol%) Rh, O H TsN O Pd H O Ar Et3SiH (3 equiv) R OSiEt TsN Ligand TsN TsN 3 TsN OH OH R2 dioxane, 12 h n 2 2 TsN 2 n R n R n 2 n R ArB(OH)2 n R2 R First asymmetric Ni- catalyzed cyclization of N-alkynones Ketone, Pd, no enantioselectivity Ketone, Rh, low TON, with coupling reagents Excellent enantioselectivity and yields, highest TON (1000) Fig. 1 Ligand design and reaction discovery of nickel-catalyzed regiospecific asymmetric reductive cyclization of N-alkynones. a Design of a more robust ligand for Ni-catalyzed reductive coupling. b Several therapeutic agents and bioactive molecules bearing a multi-substituted pyrrolidine/piperidine moiety. c–h Previous work of constructing functionalized multi-substituted pyrrolidines/piperidines via metal-catalyzed cyclizations. i This work: efficient nickel- catalyzed regiospecific asymmetric reductive cyclization of N-alkynones to synthesize pyrrolidines/piperidines with chiral tertiary alcohol sillyl ether 2 COMMUNICATIONS CHEMISTRY | (2018) 1:90 | DOI: 10.1038/s42004-018-0092-1 | www.nature.com/commschem COMMUNICATIONS CHEMISTRY | DOI: 10.1038/s42004-018-0092-1 ARTICLE C10 C9 O2 C11 Ph Ni(cod) (X mol%), Ph Ph C8 C6 2 S1 C4 C7 C19 C3 C5 Ligand (Y mol%) C18 N1 H TBAF H C20 O3 O C1 C2 TsN C23 R TsN R O1 Et SiH (3 equiv), OSiEt3 OH C21 C13 3 C22 TsN THF C12 C24 Ph dioxane, 12 h Ph C14 Ph C17 C15 1a 2a 3a C16 3a Me O O OMe MeO Me Me P P tBu tBu O MeO OMe MeO OMe OMe MeO Fe POO P PPh2 tBu tBu L1 L2 [(S)-Me-BIDIME] L3 [(S)-BIDIME] L4 [(S,S)-DI-BIDIME] Fig. 2 Reaction optimization. Nickel-catalyzed regiospecific asymmetric reductive cyclization of N-alkynones (1a) applying different ligands. Full screening conditions are reported in Table 1 30 of N-alkynones was reported by Lu and colleagues , which is Table 1 Ligand effects and catalyst loading optimization of catalyzed by a Pd precursor to construct a series of pyrrolidines N 24 nickel-catalyzed intramolecular reductive coupling of - with tertiary alcohols (Fig. 1g). Then Li and Xu reported an alkynone (1a) asymmetric rhodium-catalyzed cyclization for chiral tertiary allylic alcohols (Fig. 1h). To the best of our knowledge, there is no a fi Entries Ligand X Y T Solvent Yield er ef cient Ni-catalyzed cyclization with high TONs (> 100), which (mol (mol (oC) (%)b (%)c can provide pyrrolidines and piperidines with chiral tertiary %) %) fi alcohols. We herein describe a highly ef cient and practical 1 PPh 10 10 25 Dioxane 98 0 nickel-catalyzed intramolecular reductive cyclization of N-alky- 3 fi 2 PCy3 10 10 25 Dioxane 82 0 nones for the rst time with the nickel loading as low as 0.1 mol 3 Ru-Phos 10 10 25 Dioxane 95 0 %, by employing the newly developed chiral bisphosphorus ligand 4 S-Phos 10 10 25 Dioxane 98 0 DI-BIDIME through ligand engineering. A variety of pyrrolidine/ 5 X-Phos 10 10 25 Dioxane 85 0 piperidine derivatives bearing a chiral tertiary alcohol silyl ether 6 (R)- 10 10 25 Dioxane 0 ND moiety are prepared in high yields and excellent enantioselec- MONOPHOS tivities (Fig. 1i). Further transformations of the silyl ether to 7 (R)-BINAP 10 5 25 Dioxane < 5 ND R S alcohol and related derivatives were demonstrated. The applica- 8 ( )-( )- 10 5 25 Dioxane < 5 ND tions of this method to the synthesis of key intermediates of JosiPhos – 9 (R)-Me- 10 5 25 Dioxane 0 ND prodine and ( )-peroxetine were also accomplished.
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