Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enantioselective and Regioselective Hydroetherification of Alkynes by Gold-Catalyzed Desymmetrization of Prochiral Phenols with P‑Stereogenic Centers Yin Zheng, Linna Guo, and Weiwei Zi* State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
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ABSTRACT: The gold(I)-catalyzed enantioselective hydroetherification of alkynes was achieved via desymmetrization of prochiral bisphenols bearing P-stereogenic centers. (S)-DTBMSegphos(AuCl)2/AgNTf2 proved to be a highly efficient catalyst system for this transformation, affording P-chiral cyclic phosphine oxides in good yields with high enantioselectivities (with up to 99% ee). The same catalyst system allowed for the enantioselective desymmetrization of dialkynes. Synthetic transformations of the cyclization products afforded other P-chiral molecules with high enantiospecificity.
ince the first successful application of P-chiral phosphine ligand DiPAMP in Rh-catalyzed asymmetric hydrogenation reactions by Knowles in 1970s,1 chiral phosphorus compounds with P-stereogenic centers have been widely utilized in transition-metal catalysis2 as well as organo-catalysis.3 Traditionally, access to enantioenriched P-chiral phosphorus compounds is achieved through the use of chiral reagents- or auxiliary-assisted transformations.4 Recently, considerable progress has been made for the introduction of P-chirality via catalytic asymmetric processes.2c Most prominently, enantioselective synthesis of P-stereogenic phosphines have been accomplished through dynamic kinetic resolution of racemic secondary phosphines and their derivatives catalyzed by transition metals,5 such as palladium,5a−d platinum,5e ruthenium,5f,g and copper.5h The preparation of P-stereogenic centers via the catalytic desymmetrization of prochiral phosphorus compounds presents an attractive alternative.6 Examples include Rh-catalyzed [2 + 2 + 2] cycloaddition,6a Mo-catalyzed asymmetric ring-closing (ARC) reaction,6b and Pd or Rh-catalyzed asymmetric C−H activation reactions.6c−f Organo-catalysts, such as Brønsted acids7a and N-heterocyclic carbenes,7b have also been employed. Despite those achievements, the developments of efficient methods to prepare Pstereogenic phosphorus compounds containing novel architectures remains highly desirable.8 During the past decade, asymmetric gold catalysis has attracted intensive studies, leading to successful applications of gold catalysis in the enantioselective formation of C−O, C−N, and C−C bonds.9 Enantioselective reactions based on hydrofunctionalization of allenes and alkenes are among the most successful achievements in this area;10 however, in sharp
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contrast, gold-catalyzed enantioselective hydrofunctionalization reactions of alkynes remain rare.11 This paucity partially derives from the fact that alkynes are not prochiral; therefore, stereocenters cannot be directly formed during the formation of Csp2−O or Csp2−N bonds in hydroetherification or hydroamination reactions of alkynes. However, prochiral carbon-based nucleophiles have been employed in enantioselective C−C bond formation through gold-catalyzed hydrofunctionalization of alkynes; however, only poor enantioselectivities have been obtained thus far using gold catalysis.12 Czekelius and co-workers first developed a desymmetrization strategy to establish a quaternary carbon stereocenter in the gold-catalyzed enantioselective hydroamination of alkynes.11e More recently, Toste and co-workers have reported a gold(I)catalyzed desymmetrization of 1,3-diols for the preparation of quaternary carbon centers.13a Considering the important application of cyclic phosphines with P-chirality in transitionmetal catalysis,2,14 we envisioned developing a desymmetrization strategy to construct the phosphorus-based stereocenters (Scheme 1). Herein, we disclose the first gold(I)-catalyzed enantioselective hydroetherification reaction of alkynes, featuring intramolecular desymmetrization of bisphenols or dialkynes, which provides a highly efficient method to prepare chiral cyclic phosphine oxides with P-chirality.15 We began our investigation employing bisphenol 1a as the model substrate. On the basis of previous works,13a a chiral counteranion strategy was investigated as a means to achieve the Received: September 18, 2018
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DOI: 10.1021/acs.orglett.8b02982 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Gold(I)-Catalyzed Asymmetric Desymmetrization To Construct Quaternary Centers
entry
L
AgX
solvent
1 2 3 4 5 6 7 8 9 10 11 12 13e
Ph3P L1 L2 L3 L4 L5 L3 L3 L3 L3 L3 L3 L3
(S)-AgTrip AgNTf2 AgNTf2 AgNTf2 AgNTf2 AgNTf2 AgOTf AgOTs AgBF4 AgSbF6 AgNTf2 AgNTf2 AgNTf2
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene o-xylene toluene
time (h) yield (%)b 24 1 1 1 1 1 1 20 3 1 1 1 24
86 90 86 85 84 84 93 >95 80 81 92 94 >95
ee (%)c 50 75 80 85 80 66 73 21 76 71 91 89 96
a
Reaction conditions: 5 mol % gold catalyst, 10 mol % AgX, 0.10 mmol substrate, 1 mL of solvent, room temperature. bYields were determined by 1H NMR spectroscopic analysis using CH2Br2 as the internal standard. cEnantiomeric excess values were determined by chiral HPLC analysis. d5 mol % Ph3PAuCl, 5 mol % (S)-TripAg. e0.2 mmol scale; reaction was conducted at −20 °C.
desired asymmetric desymmetrization reaction using homogeneous gold catalysis. Catalyzed by a combination of Ph3PAuCl and (S)-AgTrip, the reaction proceeded smoothly in dichloromethane to deliver the desired cyclization product 2a in 86% yield after 24 h. Although the enantioselectivity was moderate (50% ee, Table 1, entry 1), high regioselectivity was obtained with only the 6-endo-dig cyclization product being detected.16 Moreover, despite the noted tendency for N-oxides and sulfoxides to undergo redox reactions under gold catalysis, such a reaction of the phosphine oxide was not observed.17 Further optimization of the enantioselectivity by structural tuning of the chiral phosphates was met with failure, which prompted us to evaluate other catalyst systems. In Toste’s recent work on gold(I)-catalyzed asymmetric tandem alkoxylation/ Claisen rearrangement reaction, sterically demanding bisphosphine ligands provided excellent results in the asymmetric desymmetrization of 1,4-dialkenes.13b In contrast, Czekelius and co-workers reported that bisphosphine-type ligands gave no enantioselectivity in the desymmetrization of 1,4-dialkynes via a 5-exo-dig hydroamination reaction.11e In our system, we anticipated that the 6-endo-dig pathway would allow the prochiral phosphorus center to be much closer to the chiral environment of the chiral ligand, resulting in increased enantioinduction in the cyclization event.9e With this hypothesis, we turned our attention to the use of prevalent chiral bisphosphine ligands for the gold-catalyzed desymmetrization reaction (Table 1). When (S)-DTBMBiphep(AuCl)2/AgNTf2 was employed as catalyst, the reaction was completed within 1 h, with 2a being isolated in 75% ee. Commercially available bisphosphines with different backbones were then surveyed. Changing the ligand from (S)-DTBMBiphep (L1) to (S)-DTBM-Segphos (L3) increased the observed enantioselectivity to 85% ee. Bisphosphines with
much bulkier groups at 3,5 positions on Ar (L4 vs L3) or with smaller dihedral angles18 (L1 vs L3 vs L5) gave better enantioselectivities. Efforts to improve the ee by changing AgNTf2 to other silver salts (AgOTs, AgOTf, AgBF4, or AgSbF6) exclusively failed.19 A brief survey of solvents revealed that a nonpolar solvent, such as toluene, resulted in significantly improved enantioinduction (91% ee) with a modest improvement in yield (entry 11). Finally, optimal results were obtained by lowering the reaction temperature to −20 °C, which afforded the desired cyclic chiral phosphine oxide 2a in 95% yield with 96% ee, albeit prolonging the reaction time to 24 h (entry 13). With these optimized conditions in hand, the reaction scope was examined (Scheme 2). The reaction shows excellent scope with regard to aryl alkynes. For example, the aryl rings substituted with an electron-withdrawing (Cl, F) or electrondonating (MeO, Me, t-Bu) group at the para-position was welltolerated (entries 2−6). Substituents on the meta-position gave satisfactory results as well (entry 7−9); however, substrates with sterically demanding groups (e.g., MeO) at the ortho-position gave diminished enantioselectivity (96% yield, 87% ee) (entry 10). A substrate with a thiophene ring was also examined under the standard conditions, providing the desired compound 2l in 94% yield with 93% ee. In most cases, excellent enantioselectivities and yields were obtained for substrates with different substituents on the phenol (entries 13 to 16). Only the parabromophenol-derived substrate gave slightly decreased ee (entry 17). Finally, substrate with two methyl groups on the phenol ring maintained reactivity (entry 18). To determine the absolute stereochemistry of the substrate, 2a (96% ee) was B
DOI: 10.1021/acs.orglett.8b02982 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Scope of Bisphenols Substratesa,b,c
however, with extremely low conversion under the standard conditions even after prolonged reaction times (
