Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of Bridged Biaryl Atropisomers via Sequential Cu- and PdCatalyzed Asymmetric Ring Opening and Cyclization Xiaoping Xue and Zhenhua Gu* Department of Chemistry, Center for Excellence in Molecular Synthesis, and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China
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S Supporting Information *
ABSTRACT: Bridged biaryl atropisomers are important units in bioactive molecules. A synthesis of lactone-bridged biaryl atropisomers was realized by a Cu-catalyzed asymmetric ringopening/acyoxylation of cyclic diaryliodoniums, followed by a palladium-catalyzed diastereoselective cyclization. It was found that a catalytic amount of Cu(OTf)2 served as an additive to promote the palladium-catalyzed Heck cyclization.
B
Scheme 1. Synthesis of Seven-Membered Bridged Biaryl Atropisomers
iaryl structures bearing bridged seven-membered lactone or lactam are one class of unique and important units in bioactive natural products, such as Ulocladol and LY-411575. The strain of the bridged seven-membered rings results in the two aryl rings being twisted, which causes stable axial chirality in some cases (Figure 1).1 For example, spirombandakamines A1
Figure 1. Representative examples of seven-membered bridged biaryls in bioactive compounds.
and A2 bear both axial chirality of the biaryl structure and point chirality in the seven-membered ring, and they show strong antiprotozoal properties. Albeit the importance of biaryl atropisomers bridged with seven-membered lactones, the synthesis of these molecules is appealing, and yet still challenging. Bringmann and co-workers found that the racemic seven-membered biaryl lactone was efficiently resolved by the reductive cleavage of the lactone structure upon treatment with oxazaborolidine-activated borane to give optically active lactone in 96% ee (Scheme 1a).2 Cramer and co-workers described a palladium-catalyzed atroposelective C−H arylation reaction for facile access to axially chiral dibenzazepinones (Scheme 1b).3 Among various methods developed for asymmetric atropisomers syntheses,4 kinetic dynamic ring opening of six-membered lactone analogues is a very powerful and unique strategy.5 In 2002, Hayashi and coworkers described a synthesis of atropisomers via Ni-catalyzed ring cleavage reaction of dibenzo[b,d]thiophenes with Grignard reagents.6 Later, the same group pioneered a palladiumcatalyzed asymmetric ring-opening reaction of five-membered cyclic diaryliodonium, though only one example was presented © XXXX American Chemical Society
and 38% yield, 28% ee were achieved.7,8 Recently, our group realized Cu-catalyzed enantioselective ring-opening amination and thiolation reactions of cyclic diaryliodonium with very high atroposelectivity.9 The reaction afforded atropisomers bearing an Ar−I bond, which was supposed to be useful for divergent elaborations. In continuation of our research interests in atropisomer synthesis,10 we are keen to pursue the synthesis of bridged biaryl atropisomers from cyclic diaryliodoniums, which bear both axial and point chiralities. By taking advantage of the high reactivity of cyclic diaryliodoniums, it was reasoned that these diaryliodoniums salts were able to serve as double electrophiles to react with α,β-unsaturated carboxylic acids to give bridged biaryl lactones (Scheme 1c). Enantioselective oxygenative ring opening was supposed to be readily realized based on our previous achievements. The diastereoselective induction of the Received: March 26, 2019
A
DOI: 10.1021/acs.orglett.9b01062 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Substrate Scopea
axial chirality to the new stereocenter formed in palladiumcatalyzed seven-membered ring construction was highly appealing. Geometrically, the two reactive centers, being coplanar, experience difficulty in undergoing an insertion reaction due to steric repulsion of the ortho tetra-substituted biaryls. We started our investigation by the use of cyclic diaryliodonium 1a and carboxylicacid 2a as the model substrates. The reaction proceeded efficiently by the use of Bn-Pybox L1 or PhPybox L2 as the ligand, with the ee value being 84% and 91% (Table 1, entries 1 and 2). Pleasingly, the (Ph)-bis(oxazoline) Table 1. Reaction Condition Optimizationa
entry
[Cu] (mol %)
ligand (mol %)
conv (%)
ee of 3a (%)
1 2 3 4 5b 6b,c
Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2
L1 (20) L2 (20) L3 (10) L3 (10) L3 (12) L3 (6)
99 97 97 99 98 99
84 (R) 91 (R) 99 (S) 99 (S) 99 (S) 99 (S)
a
Unless stated otherwise, the reaction was conducted with 1a (0.075 mmol), 2a (0.09 mmol, 1.2 equiv), Cu catalyst (0.0075 mmol, 10 mol %), Ligand (1.2−2.0 equiv to Cu), Na2CO3 (3.0 equiv) in CH2Cl2 (1.5 mL) at rt for 24 h. bThe reaction was performed at 40 °C for 12 h. c5 mol % of Cu(OTf)2 was used.
a
The reaction was conducted with 1 (0.50 mmol), carboxylic acid 2 (0.60 mmol, 1.2 equiv), Cu(OTf)2 (0.025 mmol, 5.0 mol %), L3 (0.030 mmol, 6.0 mol %), Na2CO3 (1.50 mmol, 3.0 equiv) in dichloromethane (10 mL) at 40 °C for 12 h. bThe ee value was determined after the hydrolysis to the corresponding phenol. cThe reaction was performed on 0.20 mmol scale of 1.
ligand L3 improved the enantioselectivity to 99% (entry 3). The screening of copper sources indicated that the lower cost Cu(OTf)2 has the same efficacy as Cu(MeCN)4PF6 (entry 4). The reaction was accelerated by elevating the reaction temperature to 40 °C in a sealed Schlenk flask, while the same efficiency and enantiocontrol were observed even with 5 mol % of copper catalyst (entries 5 and 6). The reaction proceeded uneventfully (99% yield and 99% ee) at 2.0 mmol scale of 1a (see the Supporting Information). With the optimum conditions in hand, a series of oxygenated axially chiral biaryls were prepared (Scheme 2). In contrast to thioacetic acid, carboxylic acid can be directly used, where the former should be used in its potassium or sodium salt forms. Different substituted α,β-unsaturated carboxylic acids worked highly efficiently with excellent enantiocontrol (3a−3f), though 3-methyl-2-phenylbut-2-enoic acid resulted in slightly lower enantioselectivity (3g). Additionally, both saturated aliphatic and aromatic carboxylic acids were compatible for this asymmetric ring-opening reaction (3h−3k). 5,5′-Dimethyl, 5,5′-difluoro, and 4,4′-dimethyl substituted diaryliodoniums were further tested, and high enantioselectivity was achieved uneventfully (3l−3n). Likewise, diaryliodoniums with 3,3′bis(p-tosyloxy), 3,3′-dichloro substituents, as well as binaphthyl skeletons, successfully underwent the ring-opening reaction with minimal difference in reactivity or selectivity (3o−3q). Introducing a methyl group adjacent the C−I bond resulted in
a chemoselective ring opening of unsymmetric diaryliodonium, and the less sterically hindered C(sp2)−I bond was cleaved (3r). The construction of seven-membered rings via palladiumcatalyzed cyclization is a formidable task, particularly for those highly strained compounds.11,12 Unfortunately, the cyclization reaction for the construction of strained seven-membered lactone was far from trivial, and the yields were not reliable. These results urged us to search for potential factors for unreliable outcome. We surmised the copper source, which was used in the asymmetric ring-opening step, affected the Heck cyclization reaction. Pleasingly, in the presence of a catalytic amount of Cu(OTf)2, the reaction became cleaner and the yield of the product became reproducible. The reaction proceeded smoothly using Pd(acac)2/PPh3/Cu(OTf)2 as the catalyst to afford the lactone 4a in 86% NMR yield, along with a small amount of unidentified dimer 5a (Table 2, entries 1 and 2). Tentatively, the role of Cu(OTf)2 is unclear. However, the likely coordination of cationic Cu2+ to carbonyl group would activate the substrate and adjust the conformation for an easier double bond insertion into the C(sp2)−Pd bond. The reaction proceeded in high stereoselectivity, and only one diastereomer was detected by 1H NMR analysis of crude material. Increasing the concentration resulted an increased amount of unknown dimer 5a, thus deteriorating the yield of 4a (entry 3). The use of B
DOI: 10.1021/acs.orglett.9b01062 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 2. Reaction Condition Optimizationa
full conversion, which was possibly caused by the steric repulsion between palladium and the terminal methyl group (Scheme 3, bottom). The generality of this Heck cyclization reaction was further investigated (Scheme 4). For most cases, the reaction should be Scheme 4. Substrate Scopea
entry
conditions
4a (%)
5a (%)
3a (%)
1 2 3 4 5 6 7 8 9 10 11
standard conditions without Cu(OTf)2 0.05 M instead of 0.01 M CuTC instead of Cu(OTf)2 Cu(OTf)·PhH instead of Cu(OTf)2 Cu(acac)2 instead of Cu(OTf)2 CuO instead of Cu(OTf)2 NaOTf instead of Cu(OTf)2 dppe instead of PPh3 dppb instead of PPh3 TFP instead of PPh3
86b 68 42 14 29 16 10 12 77 47 64
7 8 23 − − − − − 8 4 9
− − − 51 45 60 74 78 − 17 −
a
Unless stated otherwise, the reaction was conducted with 3a (0.10 mmol), Cu(OTf)2 (5.0 mol %), Pd(acac)2 (10 mol %), PPh3 (22 mol %), Ag2CO3 (0.30 mmol, 3.0 equiv) in CH3CN (10 mL) at 100 °C for 12 h. Yields were calculated by crude 1H NMR with CH2Br2 as internal standard. bThe isolated yield was 77%.
other copper sources significantly decreased the efficacy of this Heck cyclization reaction (entries 4−7). The addition of NaOTf instead of Cu(OTf)2 also decreased the conversion (entry 8). Ultimately, the screening of different phosphines, including bidentate 1,2-bis(diphenylphosphino)ethane (dppe), 1,2-bis(diphenylphosphino)butane (dppb), and monodentate tri(2furyl)phosphine (TFP), indicated that PPh3 was optimal for this reaction (entries 9−11). Finally, the crude reaction mixture of the Cu-catalyzed alkoxylation was dried under reduced pressure and was treated with Pd(acac)2, PPh3, Ag2CO3, and CH3CN and heated to 100 °C. However, only a 60% NMR yield of 4a was achieved, along with 15% of 3a remaining, even when heated over 36 h (see the Supporting Information). The intramolecular Heck cyclization could be performed at 1.0 mmol scale of 3a with a slightly decreased yield (from 77% at 0.10 mmol to 67% at 1.0 mmol) (see the Supporting Information). The geometry of the CC double bond did not change the diastereochemistry of the cyclized products. However, it strongly influenced the efficacy of this cyclization reaction. For example, under the optimal conditions, 3a was smoothly converted to 4a in high yield (Scheme 3, top). However, the reaction with corresponding Z-isomer 3b has to be conducted in DMF at elevated temperature (150 °C) to achieve
a
The reaction was conducted with 3 (0.10 mmol), Cu(OTf)2 (5.0 mol %), Pd(acac)2 (0.01 mmol, 10 mol %), PPh3 (0.022 mmol, 22 mol %), Ag2CO3 (0.30 mmol, 3.0 equiv) in DMF (10 mL) at 150 °C for 12 h. bThe reaction was conducted in CH3CN (2 mL), and 26% of dimer was isolated. cIn CH3CN, 100 °C.
conducted in DMF to obtain high conversions. When 3c was used as the substrate, the yield of desired product 4c decreased to 21%, along with a significant amount of dimer being formed. Interestingly, the reaction of 3d proceeded much better than the one with 3c as the substrate. A pair of CC double bond position isomers 4d and 4d′ were obtained. Unfortunately, the reaction only afforded a complicated mixture other than the desired 4e and 4f. The substituents at the 4,4′-, 5,5′-positions of the biaryl skeleton did not obviously affect the outcome of this cyclization reaction (4l−4n). The absolute configuration, along with the diastereochemistry, was finally determined by singlecrystal X-ray diffraction analysis of 4n (CCDC 1902827). orthoHeteroatom substituted biaryls 4o and 4p were obtained in moderate yields with full chirality retention and diastereoinduction. The binaphthyl structure iodide 3q also proceeded uneventfully to afford 4q in 57% yield; however, the highly bulky substrate 4r was obtained in a trace amount via the analysis of 1H NMR spectroscopy, along with unidentified mixtures. In summary, we have developed a sequential asymmetric ringopening and diastereoselective cyclization reaction for the
Scheme 3. Geometry Effect
C
DOI: 10.1021/acs.orglett.9b01062 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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synthesis of lactone bridged biaryls bearing both axial and point chirality. The Cu/(Ph)-bis(oxazoline)-catalyzed ring-opening reaction afforded highly enantioenriched acyoxylated biaryls, and the palladium-catalyzed Heck cyclization gave the strained lactones in high diastereoselectivity. The biological studies of these biaryl lactones are underway in our laboratory.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01062. Experimental procedures, characterization of products, and spectroscopic data (PDF) Accession Codes
CCDC 1902827 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Zhenhua Gu: 0000-0001-8168-2012 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (21622206, 21871241), the ‘973’ project from the MOST of China (2015CB856600) and Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000), and the Fundamental Research Funds for the Central Universities (WK2060190086).
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REFERENCES
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DOI: 10.1021/acs.orglett.9b01062 Org. Lett. XXXX, XXX, XXX−XXX
