DOI: 10.1002/chem.201501655
Communication
& Asymmetric Catalysis
A New Strategy for Enantioselective Construction of Multisubstituted Five-Membered Oxygen Heterocycles via a Domino Michael/Hemiketalization Reaction Yuan-Zhao Hua, Meng-Meng Liu, Pei-Jin Huang, Xixi Song, Min-Can Wang,* and Jun-Biao Chang*[a] Abstract: A new highly enantioselective domino Michael/ hemiketalization reaction of a-hydroxyacetophenone with b,g-unsaturated a-keto esters for the synthesis of 2,2,4,5tetrasubstituted chiral tetrahydrofurans is reported. With 2 mol % intramolecular dinuclear zinc-AzePhenol complex prepared in situ from the reaction of multidentate semiazacrown ether ligand with ZnEt2, the corresponding antimultisubstituted tetrahydrofuran products were obtained in up to 90 % yields, and 98 % enantiomeric excess (ee) at 0 8C for 45 min. Moreover, the products were easily converted to 2,3,5-trisubstituted 2,3-dihydrofurans without any loss in optical activity.
Oxygen heterocycles, especially five-membered oxygen heterocycles like tetrahydrofurans (THFs) are important functionalized building blocks of natural and unnatural products with significant and various biological activities,[1] such as amphidinolide, chagosensine, fijianolide, and leiodelide.[2] Thus, considerable effort has been devoted toward the development of a number of strategies for their stereoselective synthesis.[3] A few examples for catalytic enantioselective construction of multisubstituted THF derivatives have been reported in the literature. These mainly include: 1) the ring expansion of oxetanes;[4] 2) catalytic oxa-Michael/Michael desymmetrization;[5] 3) cycloetherification strategy;[6] 4) Michael addition/lactonization.[7] Asymmetric synthesis of dihydrofurans[8] and trihydrofurans[9] has been extensively studied. Therefore, the development of a new asymmetric catalytic approach to chiral multisubstituted THFs remains a great challenge. Over the past few decades, great progress has been made in the catalytic asymmetric Michael addition reaction.[10] Due to this intense research effort, a wide variety of acceptors and
[a] Y.-Z. Hua,+ M.-M. Liu,+ P.-J. Huang, X. Song, Prof. Dr. M.-C. Wang, Prof. Dr. J.-B. Chang College of Chemistry and Molecular Engineering, Zhengzhou University 75, Daxue Street, Zhengzhou City, 450052 (China) E-mail: [email protected] [email protected]
[+] The first two authors contributed equally to this work. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201501655. Chem. Eur. J. 2015, 21, 11994 – 11998
donors can be employed and high enantioselectivity has been realized. However, compared with a,b-unsaturated ketones and nitroalkene, b,g-unsaturated a-keto esters as Michael acceptors are limited.[11] The asymmetric addition of 1,3-difunctional donors to b,g-unsaturated-a-ketoesters catalyzed by organocatalysts[11b–p] and chiral metal catalysts based on copper,[11r] nickel,[11s] yttrium,[11t] and zinc[11u] has received intense attention, because the reaction can follow a domino acetalization to construct a chiral six-membered oxygenated heterocycle. Retrosynthetically, a chiral five-membered oxygen heterocycle can be formed through the reaction of b,g-unsaturateda-ketoester with 1,2-difunctional compound such as a-hydroxyacetophenone, which has acted as donor in the Michael addition of a,b-unsaturated ketones or nitroalkenes.[12] In order to demonstrate our idea, we present a new catalytic asymmetric approach to multifunctionalized chiral five-membered oxygen heterocycle by virtue of the asymmetric domino Michael/hemiacetalization reaction of a-hydroxyacetophenone and b,g-unsaturated-a-ketoester (Scheme 1).
Scheme 1. New strategy for enantioselective construction of multisubstituted five-membered oxygen heterocycles.
Importantly, the features of the strategy include: 1) a novel use of dinuclear zinc-AzePhenol catalyst; 2) the first trial of addition of a-hydroxyacetophenone to b,g-unsaturated-a-ketoester; 3) completion of the transformation under mild conditions with good yields (59–90 %) and good to excellent enantioselectivities (75–98 % ee); 4) the addition products are easily converted to the corresponding dihydrofurans without any loss in optical activity, and contain molecular skeletons that are key subunits of various biologically active compounds as well as versatile intermediates for the construction of complex molecules.[13] We initially investigated a reaction model of a-hydroxyacetophenone 1 with b,g-unsaturated a-keto ester 2 a in the presence of 20 mol % ligands L1 and 20 mol % ZnEt2 in dichloromethane (DCM) at room temperature. After 30 min, the reaction afforded the anti-product in 63 % isolated yield (Table 1, entry 1).
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Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication was efficient in asymmetric co-polymerization of not only cyclohexene oxide (CHO) and carbon dioxide (CO2) but also cyclopentene oxide (CPO) and CO2 both with excellent enantioselectivity.[17b,c] Notably, much higher enantioselectivity was achieved by using this Zn2EtL system than that of Trost’s dinuclear zinc-ProPhenol catalyst in the same reaction of asymmetric co-polymerization of CHO and CO2.[17b] This was another example that among the same type of chiral b-amino alcohol moiety containing nitrogen heterocycles, four-membered heterocycle as a chiral ligand affords the best enantioselectivity in some catalytic asymmetric reactions.[18] Thus, the following question was asked: could the asymmetric induction be enhanced in the Michael addition of a-hydroxyacetophenone 1 to b,g-unsaturated a-keto ester 2 a if our Zn2EtL system was used instead of Trost’s dinuclear zinc catalyst? To provide an answer to the above question, we applied our Zn2EtL complex prepared in situ as a catalyst to the model reaction.
Table 1. Effect of chiral ligands on the Michael/hemiketalization reaction.[a]
Entry
Ligand[b]
t [min]
Yield [%][c]
d.r.[c] 3 (anti/syn)
ee [%][e]
1 2 3 4 5 6
(S)-L1 (S)-L2 (R,2S)-L3 (R,2R)-L4 (S,S)-L5 (S,S)-L6
30 30 30 30 15 15
63 61 60 59 50 60
1.8:1 1.7:1 1.8:1 1.5:1 1.0:1 1.7:1
4 8 2 0 85 49
[a] Unless otherwise noted, all reactions were conducted with 1 (0.25 mmol), 2 a (0.275 mmol), ligands and ZnEt2 (20 mol %) in DCM (1.5 mL) under N2 at 25 8C. [b] Ligands L1–L4 (20 mol %), ligand L5, L6 (10 mol %). [c] Isolated yield of anti-3 a. [d] Determined by 1H NMR spectroscopic analysis of the crude reaction product. [e] The ee value of anti3 a was determined by HPLC analysis. Scheme 2. Dinuclear zinc-AzePhenol complex Zn2EtL.
The 1H and 13C NMR spectra revealed that major product anti-3 a was obtained as an equilibrating mixture of anomers (about 2:1) caused by 2-OH and 2-COOCH3. These anomers equilibrated slowly enough so as to appear as separate compounds in 1H and 13C NMR spectra but quickly enough that they did not resolve by chromatography. The trace of the racemic anti-3 a on a chiral HPLC column showed only one pair of peaks for the two enantiomers.[11, 14] However, the minor synproduct was a rapid equilibrium between the cyclic hemiketal syn-3 a and the Michael-type product syn-3 a’.[15] A series of ligands were then examined and the results are summarized in Table 1. All the ligands L1–L6 could catalyze the reaction efficiently to give the product anti-3 a with low to high enantiomeric excess (ee) in 15–30 min at room temperature. Simple b-amino alcohol ligands were not efficient in enantioselectivity (Table 1, entries 1–4). Fortunately, Trost’s dinuclear zinc catalysts[16] generated from chiral semi-azacrown ether ligand (S,S)-L5 and ZnEt2 catalyzed the reaction to give anti-3 a with 50 % yield and 85 % ee (Table 1, entry 5). However, ligand (S,S)-L6 which was similar to that of Trost’s but contains a piperidine instead of a pyrrolidine gave anti-3 a with 60 % yield and 49 % ee (Table 1, entry 6). Recently, we reported a new dinuclear zinc-AzePhenol complex Zn2EtL (L = (S,S)-L7) generated in situ by treating the chiral ligand (S,S)-L7 with two equivalents of diethylzinc wherein a dynamic balance between the (Zn2EtL)n and Zn2EtL (Scheme 2) existed.[17] This Zn2EtL system showed excellent performance in the catalytic asymmetric Friedel–Crafts alkylation of unprotected pyrrole with a series of chalcones.[17a] In addition, this intramolecular dinuclear zinc catalytic system Chem. Eur. J. 2015, 21, 11994 – 11998
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Gratifyingly, our Zn2EtL system prepared in situ catalyzed the reaction with a much higher ee value of 93 % in DCM at room temperature (Table 2, entry 1). However, changing the metal reagents led to a reduction on both yields and ee values (Table 2, entries 2 and 3). Thus, the effective catalytic system Zn2EtL was used for further screening of solvents. The reactions proceeded well in most of the solvents examined, giving the desired product anti-3 a in different diastereoselectivity. The highest ee value of 93 % was obtained in DCM with 65 % yield (Table 2, entry 1). Dioxane was not chosen as a good solvent because the ee value of anti-3 a was only 85 % though the d.r.anti/syn value of 5.2:1 was the highest (Table 2, entry 9). A slight decrease in enantioselectivity was observed when the mixed solvents of DCM and dioxane in different proportions were used (Table 2, entries 10–12). Reaction temperature and the catalyst amounts were also examined (Table 3). Temperature proved to have a significant effect on diastereoselectivity (Table 3, entries 1–4). Conducting the reaction at 0 8C improved both the d.r.anti/syn value and the ee value of anti-3 a (Table 3, entry 2). However, no obvious improvement in enantioselectivity was observed when the reaction was conducted at ¢20 or ¢50 8C, except that prolonged reaction times were required (Table 3, entries 3 and 4), so we carried out the catalyst amount screening at 0 8C. Reducing the loading of the ligand (S,S)-L7 to 5.0, 2.0, 1.0 and 0.1 mol % (Table 3, entries 4–8), 2.0 mol % was found to be the most effective, and the reaction was complete after 45 min with d.r.anti/syn value of 10:1 affording anti-3 a in 90 % yield with
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Communication Table 3. Screening conditions for the Michael/hemiketalization reaction in the presence of (S,S)-L7.[a]
Table 2. Effect of new chiral ligand and solvents on the Michael/hemiketalization reaction.[a]
Entry
Metal
Solvent
Yield [%][b]
d.r.[c] 3 (anti/syn)
ee [%][d]
1 2 3 4 5 6 7 8 9 10 11 12
ZnEt2 ZnMe2 Mg(nBu)2 ZnEt2 ZnEt2 ZnEt2 ZnEt2 ZnEt2 ZnEt2 ZnEt2 ZnEt2 ZnEt2
DCM DCM DCM toluene THF dichloroethane CHCl3 CH3CN dioxane dioxane/DCM (1:1) dioxane/DCM (10:1) dioxane/DCM (1:10)
65 45 46 64 62 58 45 71 82 83 80 57
2.0:1 1.2:1 1.0:1 1.8:1 5.0:1 1.4:1 1.5:1 2.5:1 5.2:1 4.8:1 4.9:1 1.6:1
93 75 6 86 77 91 88 87 84 85 82 90
98 % ee (Table 3, entry 6). The derivatives with different substituents (R1) at the ester moiety of compounds 2 were also tested. Substrates 2 b–2 d all gave excellent results in enantioselectivities but lower diastereoselectivity (Table 3, entries 9– 11). Extensive screening showed that the optimal conditions were as follows: Zn2EtL complex (2 mol %), a-hydroxyacetophenone 1 (0.25 mmol) and b,g-unsaturated a-keto esters 2 a (0.275 mmol), in DCM (1.5 mL) at 0 8C. In order to explore the generality of this reaction, we subsequently examined the treatment of a-hydroxyacetophenone 1 with various b,g-unsaturated a-keto esters 2 under the optimal reaction conditions achieved above, and the results are summarized in Table 4. More importantly, the highly enantiomerically enriched Michael/hemiacetalization adducts anti-3 a obtained by this method can be easily converted to dihydrofuran anti-4 a by a simple one-step treatment without any loss in optical activity. The substituents on the aromatic ring of b,g-unsaturated aketo esters affected the results significantly. Good yields, good diastereoselectivities and excellent enantioselectivities were achieved with b,g-unsaturated a-keto esters 2 e–2 j bearing various substituents at the para position of the g-aromatic ring, irrespective of their electronic nature (Table 4, entries 2– 7). The substrates 2 k–2 n with substituent at the meta position of the g-aromatic ring provided the same good results but moderate d.r.anti/syn values (Table 4, entries 8–11). Interestingly, syn-products were obtained mainly with good yields but moderate ee values when the substrates 2 o and 2 p with Cl, Br groups at the ortho position of the g-aromatic ring were examined (Table 4, entries 12 and 13). The bigger steric hindrance effect of group at the ortho position of the g-aromatic ring www.chemeurj.org
L7 [mol %]
T [oC]
t [min]
R1
Yield [%][b]
d.r.[c] 3 (anti/syn)
ee [%][d]
1 2 3 4 5 6 7 8[e] 9 10 11
10 10 10 10 5 2 1 0.1 2 2 2
25 0 ¢20 ¢50 0 0 0 0 0 0 0
15 20 120 300 30 45 120 2 days 45 45 45
Me Me Me Me Me Me Me Me Et iPr tBu
65 86 84 82 88 90 79 < 10 66 70 67
2.0:1 7.0:1 6.8:1 6.8:1 8.3:1 10:1 6.8:1 – 2.2:1 3.0:1 2.1:1
93 96 97 97 97 98 97 93 97 96 97
[a] Unless otherwise noted, all reactions were conducted with 1 (0.25 mmol), 2 a (0.275 mmol), (S,S)-L7 and ZnEt2 in DCM (1.5 mL) under N2. [b] Isolated yield of anti-3. [c] Determined by 1H NMR spectroscopic analysis of the crude reaction product. [d] The ee value of anti-3 was determined by HPLC analysis. [e] Compound 1 (2.5 mmol), 2 a (2.75 mmol) and DCM (4.5 mL) were used.
[a] Unless otherwise noted, all reactions were conducted with 1 (0.25 mmol), 2 a (0.275 mmol), ligands (10 mol %) and ZnEt2 (20 mol %) in solvent (1.5 mL) under N2 at 25 8C for 15 min. [b] Isolated yield of anti3 a. [c] Determined by 1H NMR spectroscopic analysis of the crude reaction product. [d] The ee value of anti-3 a was determined by HPLC analysis.
Chem. Eur. J. 2015, 21, 11994 – 11998
Entry
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Table 4. Examination of the generality of the reaction with different b,gunsaturated a-keto ester 2 and 1.[a]
Entry
R2
d.r.[b] 3 (anti/syn)
Yield anti-3/4 [%][c]
ee 3/4 [%][d]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18[h]
Ph(2 a) 4-FC6H4(2 e) 4-ClC6H4(2 f) 4-BrC6H4(2 g) 4-NO2C6H4(2 h) 4-MeC6H4(2 i) 4-MeOC6H4(2 j) 3-ClC6H4(2 k) 3-BrC6H4(2 l) 3-MeOC6H4(2 m) 3-MeC6H4(2 n) 2-ClC6H4(2 o) 2-BrC6H4(2 p) 3-Br-4-ClC6H3(2 q) 3,4-OCH2OC6H3(2 r) 2-naphthyl(2 s) 2-thienyl(2 t) Ph(2 a)
10:1 4.7:1 6.0:1 4.3:1 3.6:1 5.1:1 4.4:1 2.0:1 2.3:1 2.0:1 1.7:1 1:5.4 1:9.5 2.2:1 3.6:1 2.5:1 2.3:1 9.8:1
90:80 81:75 85:69 78:72 76:55 81:62 85:21[e] 64:67 67:73 65:43 59:53 77[f]:62 83[g]:56 67:63 73:18[e] 70:23[e] 68:15[e] 88:–
98:98 95:95 96:96 95:95 90:90 97:97 98:98 94:94 94:94 93:92 96:96 78:77 75:76 93:92 97:97 94:95 96:97 98:–
[a] Unless otherwise noted, all reactions were conducted with 1 (0.25 mmol), 2 (0.275 mmol), (S,S)-L7 (2 mol %) and ZnEt2 (4 mol %) in DCM (1.5 mL) under N2 at 0 8C for 45 min. [b] Determined by 1H NMR spectroscopic analysis of the crude reaction product. [c] Isolated yield of anti-3/4. [d] The ee value was determined by HPLC analysis. [e] Mostly carbonized. [f] syn-3 o was obtained. [g] syn-3 p was obtained. [h] (R,R)-L7 was used. Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication might be a key element. The catalytic system was also suitable for disubstituted g-aromatic ring substrates, g-naphthyl ring substrates and g-heteroaromatic ring substrates 2 q–2 t, affording the desired products in moderate to good yields and excellent enantioselectivities (Table 4, entries 14–17). (R,R)-L7 was also applied to catalyze the reaction, and the anti-3 a was obtained in 88 % yield and 98 % ee with opposite optical activity compared with entry 1, Table 4 (Table 4, entry 18). A single crystal solid of 3 g was obtained from the minor product which was a mixture of cyclic hemiketal product and the Michael-type product.[15] It was determined to be syn-configuration by X-ray crystallographic analysis (Figure 1),[19] and the rest of the products were assigned by analogy. Unfortunately, the single crystal consisted of a pair of enantiomers because of the low ee value of syn-3 g. The absolute configuration of the product anti-3 g remains unknown.
2.0 mol %, a series of synthetically useful multisubstituted chiral tetrahydrofurans were obtained with moderate to good yields and up to 98 % ee. Further efforts will focus on determining the absolute configuration of products and the mechanistic studies of this domino Michael/hemiacetalization reaction, as well as the application of this dinuclear zinc-AzePhenol complex to other reactions.
Experimental Section General procedure for the catalytic reaction In a flame-dried Schlenk tube, a solution of diethylzinc (0.01 mL, 1.0 mol L¢1 in hexane, 0.01 mmol) was added to a solution of the chiral ligand (S,S)-L7 (3.1 mg, 0.005 mmol) in dry DCM (0.8 mL) under nitrogen at 0 8C. The mixture was stirred at room temperature for 30 min. Then a solution of 1 (34 mg, 0.25 mmol) and 2 a (0.275 mmol) in dry DCM (0.7 mL) was added to the mixture at 0 8C. The solution was stirred at 0 8C for the necessary reaction times, and then quenched with aqueous NH4Cl (5 mL), and extracted three times with DCM (3 Õ 10 mL). The combined organics was washed with brine before being dried by MgSO4, filtered and concentrated in vacuo. The crude product was separated by flash column chromatography.
Acknowledgements Figure 1. X-ray structure of compound syn-3 g.
To show the synthetic application of the current method, a large-scale synthesis of 3 a was examined. As shown in Scheme 3, domino Michael/hemiacetalization reaction of a-hydroxyacetophenone 1 with b,g-unsaturated a-keto esters 2 a was accomplished by using only 2 mol % of dinuclear zinc-AzePhenol complex leading to multiple-substituted tetrahydrofuran products with good results (85 % yield, 98 % ee). In conclusion, we have reported a new catalytic asymmetric domino Michael/hemiacetalization reaction of a-hydroxyacetophenone with b,g-unsaturated a-keto esters leading to multiple-substituted tetrahydrofuran products by using dinuclear zinc-AzePhenol complex. With a low catalyst loading of
Scheme 3. Catalytic asymmetric domino Michael/hemiacetalization reaction of a-hydroxyacetophenone 1 a with b,g-unsaturated a-keto esters 2 a on a 1.0 mmol scale. Chem. Eur. J. 2015, 21, 11994 – 11998
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We are grateful to the National Natural Sciences Foundation of China (NNSFC: 21272216, 81330075, 21302173), and the Department of Science and Technology of Henan Province for financial supports. Keywords: asymmetric catalysis · domino reactions · Michael/ hemiacetalization reactions · tetrahydrofuran · zinc [1] a) T. Eicher, S. Hauptmann, The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications, Wiley-VCH, Weinheim, 2003; b) E. J. Kang, E. Lee, Chem. Rev. 2005, 105, 4348; c) A. Lorente, J. LamarianoMerketegi, F. Albericio, M. Alvarez, Chem. Rev. 2013, 113, 4567. [2] a) S. Mahapatra, R. G. Carter, Angew. Chem. Int. Ed. 2012, 51, 7948; Angew. Chem. 2012, 124, 8072; b) T. Rezanka, L. O. Hanus, V. M. Dembitsky, Eur. J. Org. Chem. 2003, 4073; c) A. Gollner, J. Mulzer, Org. Lett. 2008, 10, 4701; d) Y. Chen, J. Jin, J. Wu, W. M. Dai, Synlett 2006, 1177; e) J. Jin, Y. Chen, Y. Li, J. Wu, W. M. Dai, Org. Lett. 2007, 9, 2585; f) W. M. Dai, Y. Chen, J. Jin, J. Wu, J. Lou, Q. He, Synlett 2008, 1737; g) J. S. Sandler, P. L. Colin, M. Kelly, W. Fenical, J. Org. Chem. 2006, 71, 7245; h) J. S. Sandler, P. L. Colin, M. Kelly, W. Fenical, J. Org. Chem. 2006, 71, 8684. [3] For reviews, see: a) L. F. Tietze, H. Ila, H. P. Bell, Chem. Rev. 2004, 104, 3453; b) J. P. Wolfe, M. B. Hay, Tetrahedron 2007, 63, 261; c) G. Jalce, X. Franck, B. Figadere, Tetrahedron: Asymmetry 2009, 20, 2537; d) K.-S. Yeung, X.-S. Peng, J. Wu, R. Fan, X.-L. Hou, in Progress in Heterocyclic Chemistry Vol. 25 (Eds.: G. W. Gribble, J. A. Joule), Elsevier, Oxford, 2013, p. 183.
11997
Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication [4] a) M. M. C. Lo, G. C. Fu, Tetrahedron 2001, 57, 2621; b) E. D. Butova, A. V. Barabash, A. A. Petrova, C. M. Kleiner, P. R. Schreiner, A. A. Fokin, J. Org. Chem. 2010, 75, 6229. [5] M. T. Corbett, J. S. Johnson, Chem. Sci. 2013, 4, 2828. [6] a) S. H. Kang, M. Kim, J. Am. Chem. Soc. 2003, 125, 4684; b) S. H. Kang, S. B. Lee, C. M. Park, J. Am. Chem. Soc. 2003, 125, 15748; c) U. Hennecke, C. H. Muller, R. Frohlich, Org. Lett. 2011, 13, 860; d) K. Asano, S. Matsubara, J. Am. Chem. Soc. 2011, 133, 16711; e) D. H. Miles, M. Veguillas, F. D. Toste, Chem. Sci. 2013, 4, 3427; f) Y. P. Lu, G. Zou, G. Zhao, ACS Catal. 2013, 3, 1356. [7] D. Belmessieri, A. Houpliere, E. D. D. Calder, J. E. Taylor, A. D. Smith, Chem. Eur. J. 2014, 20, 9762. [8] For selected examples for asymmetric synthesis of substituted dihydrofurans, see: a) H. M. L. Davies, G. Ahmed, R. L. Calvo, M. R. Churchill, D. G. Churchill, J. Org. Chem. 1998, 63, 2641; b) D. A. Evans, Z. K. Sweeney, T. Rovis, J. S. Tedrow, J. Am. Chem. Soc. 2001, 123, 12095; c) F. Garzino, A. M¦ou, P. Brun, Eur. J. Org. Chem. 2003, 1410; d) W. Xia, C. Yang, B. O. Patrick, J. R. Scheffer, C. Scott, J. Am. Chem. Soc. 2005, 127, 2725; e) M. A. Calter, R. M. Phillips, C. Flaschenriem, J. Am. Chem. Soc. 2005, 127, 14566; f) S. Son, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 1046; g) J.-C. Zheng, C.-Y. Zhu, X.-L. Sun, Y. Tang, L.-X. Dai, J. Org. Chem. 2008, 73, 6909; h) M. Rueping, A. Parra, U. Uria, F. Besselievre, E. Merino, Org. Lett. 2010, 12, 5680; i) X.-W. Dou, F.-R. Zhong, Y.-X. Lu, Chem. Eur. J. 2012, 18, 13945; j) M. A. Calter, A. Korotkov, Org. Lett. 2011, 13, 6328; k) J.-L. Zhou, L.-J. Wang, H. Xu, X.-L. Sun, Y. Tang, ACS Catal. 2013, 3, 685. [9] For reviews on asymmetric synthesis of substituted trihydrofurans, see: a) I. J. S. Fairlamb, Angew. Chem. Int. Ed. 2004, 43, 1048; Angew. Chem. 2004, 116, 1066; b) I. D. G. Watsona, F. D. Toste, Chem. Sci. 2012, 3, 2899; c) A. Marinetti, H. Jullien, A. Voituriez, Chem. Soc. Rev. 2012, 41, 4884. For selected examples for asymmetric synthesis of substituted trihydrofurans, see: d) S. R. Gilbertson, G. S. Hoge, D. G. Genov, J. Org. Chem. 1998, 63, 10077; e) P. Cao, X. Zhang, Angew. Chem. Int. Ed. 2000, 39, 4104; Angew. Chem. 2000, 112, 4270; f) M. Hatano, M. Terada, K. Mikami, Angew. Chem. Int. Ed. 2001, 40, 249; Angew. Chem. 2001, 113, 255; g) A. Lei, M. He, S. Wu, X. Zhang, Angew. Chem. Int. Ed. 2002, 41, 3457; Angew. Chem. 2002, 114, 3607; h) B. M. Trost, M. R. Machacek, Angew. Chem. Int. Ed. 2002, 41, 4693; Angew. Chem. 2002, 114, 4887; i) M. Hatano, M. Yamanaka, K. Mikami, Eur. J. Org. Chem. 2003, 2552; j) K. Mikami, S. Kataoka, Y. Yusa, K. Aikawa, Org. Lett. 2004, 6, 3699; k) P. A. Wender, L. O. Haustedt, J. Lim, J. A. Love, T. J. Williams, J.-Y. Yoon, J. Am. Chem. Soc. 2006, 128, 6302; l) T. Shibata, Y.-K. Tahara, J. Am. Chem. Soc. 2006, 128, 11766; m) K. Aikawa, S. Akutagawa, K. Mikami, J. Am. Chem. Soc. 2006, 128, 12648; n) B. M. Trost, M. R. Machacek, B. D. Faulk, J. Am. Chem. Soc. 2006, 128, 6745; o) R. Shintani, Y. Sannohe, T. Tsuji, T. Hayashi, Angew. Chem. Int. Ed. 2007, 46, 7277; Angew. Chem. 2007, 119, 7415; p) T. Shibata, H. Kurokawa, K. Kanda, J. Org. Chem. 2007, 72, 6521; q) R. Shintani, H. Nakatsu, K. Takatsu, T. Hayashi, Chem. Eur. J. 2009, 15, 8692; r) E. G. Corkum, M. J. Hass, A. D. Sullivan, S. H. Bergens, Org. Lett. 2011, 13, 3522; s) Y. Miyauchi, K. Noguchi, K. Tanaka, Org. Lett. 2012, 14, 5856. [10] For recent reviews on asymmetric Michael additions, see: a) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033; b) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org. Chem. 2002, 1877; c) J. Christoffers, A. Baro, Angew. Chem. Int. Ed. 2003, 42, 1688; Angew. Chem. 2003, 115, 1726; d) W. Notz, F. Tanaka, C. F. Barbas, Acc. Chem. Res. 2004, 37, 580; e) R. Ballini, G. Bosica, D. Fiorini, A. Palmieri, M. Petrini, Chem. Rev. 2005, 105, 933; f) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701; g) S. Sulzer-Moss¦, A. Alexakis, Chem. Commun. 2007, 3123; h) D. Almasi, D. A. Alonso, C. Najera, Tetrahedron: Asymmetry 2007, 18, 299; i) X.-H. Liu, L.-L. Lin, X.-M. Feng, Acc. Chem. Res. 2011, 44, 574; j) G. Desimoni, G. Faita, P. Quadrelli, Chem. Rev. 2013, 113, 5924. [11] a) R. P. Herrera, D. Monge, E. Martin-Zamora, R. Ferandez, J. M. Lassaletta, Org. Lett. 2007, 9, 3303; b) S.-L. Zhao, C.-W. Zheng, H.-F. Wang, G.
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[12]
[13]
[14]
[15] [16] [17]
[18]
[19]
Zhao, Adv. Synth. Catal. 2009, 351, 2811; c) S.-L. Zhao, C.-W. Zheng, G. Zhao, Tetrahedron: Asymmetry 2009, 20, 1046; d) M. A. Calter, J. Wang, Org. Lett. 2009, 11, 2205; e) Y.-F. Wang, W. Zhang, S.-P. Luo, G.-C. Zhang, A.-B. Xia, X.-S. Xu, D.-Q. Xu, Eur. J. Org. Chem. 2010, 4981; f) Y. Gao, Q. Ren, L. Wang, J. Wang, Chem. Eur. J. 2010, 16, 13068; g) J.-J. Wang, J.-H. Lao, Z.-P. Hu, R.-J. Lu, S.-Z. Nie, Q.-S. Du, M. Yan, ARKIVOC 2010, 229; h) X.-K. Chen, C.-W. Zheng, S.-L. Zhao, Z. Chai, Y.-Q. Yang, G. Zhao, W.-G. Cao, Adv. Synth. Catal. 2010, 352, 1648; i) D.-Q. Xu, Y.-F. Wang, W. Zhang, S.-P. Luo, A.-G. Zhong, A.-B. Xia, Z.-Y. Xu, Chem. Eur. J. 2010, 16, 4177; j) Y. Gao, Q. Ren, S.-M. Ang, J. Wang, Org. Biomol. Chem. 2011, 9, 3691; k) J.-J. Wang, Z.-P. Hu, C.-L. Lou, J.-L. Liu, X.-M. Li, M. Yan, Tetrahedron 2011, 67, 4578; l) Q. Ren, Y. Gao, J. Wang, Org. Biomol. Chem. 2011, 9, 5297; m) Y.-F. Wang, K. Wang, W. Zhang, B.-B. Zhang, C.-X. Zhang, D.-Q. Xu, Eur. J. Org. Chem. 2012, 3691; n) J.-H. Feng, X. Fu, Z.-L. Chen, L.-L. Lin, X.-H. Liu, X.-M. Feng, Org. Lett. 2013, 15, 2640; o) N. Halland, T. Velgaard, K. A. Jørgensen, J. Org. Chem. 2003, 68, 5067; p) Z.-H. Dong, J.-H. Feng, X.-A. Fu, X.-H. Liu, L.-L. Lin, X.-M. Feng, Chem. Eur. J. 2011, 17, 1118; q) B. Yang, F. Xie, H. Yu, K.-J. Shen, Z.-N. Ma, W.-B. Zhang, Tetrahedron 2011, 67, 6197; r) L. Gremaud, A. Alexakis, Angew. Chem. Int. Ed. 2012, 51, 794; Angew. Chem. 2012, 124, 818; s) Z.-H. Dong, J.-H. Feng, W.-D. Cao, X.-H. Liu, L.-L. Lin, X.-M. Feng, Tetrahedron Lett. 2011, 52, 3433; t) L. Zhou, L.-L. Lin, W. Wang, J. Ji, X.-H. Liu, X.-M. Feng, Chem. Commun. 2010, 46, 3601; u) X. Song, J. Liu, M.-M. Liu, X. Wang, Z.-F. Zhang, M.-C. Wang, J. Chang, Tetrahedron 2014, 70, 5468. a) N. Kumagai, S. Matsunaga, M. Shibasaki, Org. Lett. 2001, 3, 4251; b) S. Harada, N. Kumagai, T. Kinoshita, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2003, 125, 2582; c) S. Matsunaga, T. Kinoshita, S. Okada, S. Harada, M. Shibasaki, J. Am. Chem. Soc. 2004, 126, 7559; d) B. M. Trost, S. Hisaindee, Org. Lett. 2006, 8, 6003. a) B. H. Lipshutz, Chem. Rev. 1986, 86, 795; b) O. R. Gottlied, New Natural Products and Plant Drugs with Pharmacological, Biological, or Therapeutical Activity, Springer, Heidelberg, 1987, p. 227; c) B. M. Fraga, Nat. Prod. Rep. 1992, 9, 217; d) A. T. Merritt, S. B. Ley, Nat. Prod. Rep. 1992, 9, 243; e) M. M. Faul, B. E. Huff, Chem. Rev. 2000, 100, 2407; f) T. G. Kilroy, T. P. O’Sullivan, P. J. Guiry, Eur. J. Org. Chem. 2005, 4929; g) J. D. Pettigrew, P. D. Wilson, Org. Lett. 2006, 8, 1427; h) A. R. Gallimore, Nat. Prod. Rep. 2009, 26, 266. See the Supporting Information. For studies on similar equilibriums of related compounds, see: a) W. R. Porter, W. F. Trager, J. Heterocycl. Chem. 1982, 19, 475; b) L. D. Heimark, W. F. Trager, J. Med. Chem. 1984, 27, 1092; c) Y.-B. Liu, X.-H. Liu, M. Wang, P. He, L.-L. Lin, X.-M. Feng, J. Org. Chem. 2012, 77, 4136. See the Supporting Information. a) B. M. Trost, H. Ito, J. Am. Chem. Soc. 2000, 122, 12003; b) B. M. Trost, V. S. C. Yeh, H. Ito, N. Bremeyer, Org. Lett. 2002, 4, 2621. a) Y.-Z. Hua, X.-W. Han, X.-C. Yang, X. Song, M.-C. Wang, J.-B. Chang, J. Org. Chem. 2014, 79, 11690; b) Y.-Z. Hua, L.-J. Lu, P.-J. Huang, D.-H. Wei, M.-S. Tang, M.-C. Wang, J.-B. Chang, Chem. Eur. J. 2014, 20, 12394; c) Y.Z. Hua, X.-C. Yang, M.-M. Liu, X. Song, M.-C. Wang, J.-B. Chang, Macromolecules 2015, 48, 1651. a) M.-C. Wang, Q.-J. Zhang, W.-X. Zhao, X.-D. Wang, X. Ding, T.-T. Jing, M.-P. Song, J. Org. Chem. 2008, 73, 168; other work comparing the same type of nitrogen heterocycles : b) X.-H. Liu, L.-L. Lin, X.-M. Feng, Org. Chem. Front. 2014, 1, 298. For 3 g, formula: C19H17BrO5 ; CCDC 988337 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.
Received: April 28, 2015 Published online on July 14, 2015
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& Asymmetric Catalysis
A New Strategy for Enantioselective Construction of Multisubstituted Five-Membered Oxygen Heterocycles via a Domino Michael/Hemiketalization Reaction Yuan-Zhao Hua, Meng-Meng Liu, Pei-Jin Huang, Xixi Song, Min-Can Wang,* and Jun-Biao Chang*[a] Abstract: A new highly enantioselective domino Michael/ hemiketalization reaction of a-hydroxyacetophenone with b,g-unsaturated a-keto esters for the synthesis of 2,2,4,5tetrasubstituted chiral tetrahydrofurans is reported. With 2 mol % intramolecular dinuclear zinc-AzePhenol complex prepared in situ from the reaction of multidentate semiazacrown ether ligand with ZnEt2, the corresponding antimultisubstituted tetrahydrofuran products were obtained in up to 90 % yields, and 98 % enantiomeric excess (ee) at 0 8C for 45 min. Moreover, the products were easily converted to 2,3,5-trisubstituted 2,3-dihydrofurans without any loss in optical activity.
Oxygen heterocycles, especially five-membered oxygen heterocycles like tetrahydrofurans (THFs) are important functionalized building blocks of natural and unnatural products with significant and various biological activities,[1] such as amphidinolide, chagosensine, fijianolide, and leiodelide.[2] Thus, considerable effort has been devoted toward the development of a number of strategies for their stereoselective synthesis.[3] A few examples for catalytic enantioselective construction of multisubstituted THF derivatives have been reported in the literature. These mainly include: 1) the ring expansion of oxetanes;[4] 2) catalytic oxa-Michael/Michael desymmetrization;[5] 3) cycloetherification strategy;[6] 4) Michael addition/lactonization.[7] Asymmetric synthesis of dihydrofurans[8] and trihydrofurans[9] has been extensively studied. Therefore, the development of a new asymmetric catalytic approach to chiral multisubstituted THFs remains a great challenge. Over the past few decades, great progress has been made in the catalytic asymmetric Michael addition reaction.[10] Due to this intense research effort, a wide variety of acceptors and
[a] Y.-Z. Hua,+ M.-M. Liu,+ P.-J. Huang, X. Song, Prof. Dr. M.-C. Wang, Prof. Dr. J.-B. Chang College of Chemistry and Molecular Engineering, Zhengzhou University 75, Daxue Street, Zhengzhou City, 450052 (China) E-mail: [email protected] [email protected]
[+] The first two authors contributed equally to this work. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201501655. Chem. Eur. J. 2015, 21, 11994 – 11998
donors can be employed and high enantioselectivity has been realized. However, compared with a,b-unsaturated ketones and nitroalkene, b,g-unsaturated a-keto esters as Michael acceptors are limited.[11] The asymmetric addition of 1,3-difunctional donors to b,g-unsaturated-a-ketoesters catalyzed by organocatalysts[11b–p] and chiral metal catalysts based on copper,[11r] nickel,[11s] yttrium,[11t] and zinc[11u] has received intense attention, because the reaction can follow a domino acetalization to construct a chiral six-membered oxygenated heterocycle. Retrosynthetically, a chiral five-membered oxygen heterocycle can be formed through the reaction of b,g-unsaturateda-ketoester with 1,2-difunctional compound such as a-hydroxyacetophenone, which has acted as donor in the Michael addition of a,b-unsaturated ketones or nitroalkenes.[12] In order to demonstrate our idea, we present a new catalytic asymmetric approach to multifunctionalized chiral five-membered oxygen heterocycle by virtue of the asymmetric domino Michael/hemiacetalization reaction of a-hydroxyacetophenone and b,g-unsaturated-a-ketoester (Scheme 1).
Scheme 1. New strategy for enantioselective construction of multisubstituted five-membered oxygen heterocycles.
Importantly, the features of the strategy include: 1) a novel use of dinuclear zinc-AzePhenol catalyst; 2) the first trial of addition of a-hydroxyacetophenone to b,g-unsaturated-a-ketoester; 3) completion of the transformation under mild conditions with good yields (59–90 %) and good to excellent enantioselectivities (75–98 % ee); 4) the addition products are easily converted to the corresponding dihydrofurans without any loss in optical activity, and contain molecular skeletons that are key subunits of various biologically active compounds as well as versatile intermediates for the construction of complex molecules.[13] We initially investigated a reaction model of a-hydroxyacetophenone 1 with b,g-unsaturated a-keto ester 2 a in the presence of 20 mol % ligands L1 and 20 mol % ZnEt2 in dichloromethane (DCM) at room temperature. After 30 min, the reaction afforded the anti-product in 63 % isolated yield (Table 1, entry 1).
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Communication was efficient in asymmetric co-polymerization of not only cyclohexene oxide (CHO) and carbon dioxide (CO2) but also cyclopentene oxide (CPO) and CO2 both with excellent enantioselectivity.[17b,c] Notably, much higher enantioselectivity was achieved by using this Zn2EtL system than that of Trost’s dinuclear zinc-ProPhenol catalyst in the same reaction of asymmetric co-polymerization of CHO and CO2.[17b] This was another example that among the same type of chiral b-amino alcohol moiety containing nitrogen heterocycles, four-membered heterocycle as a chiral ligand affords the best enantioselectivity in some catalytic asymmetric reactions.[18] Thus, the following question was asked: could the asymmetric induction be enhanced in the Michael addition of a-hydroxyacetophenone 1 to b,g-unsaturated a-keto ester 2 a if our Zn2EtL system was used instead of Trost’s dinuclear zinc catalyst? To provide an answer to the above question, we applied our Zn2EtL complex prepared in situ as a catalyst to the model reaction.
Table 1. Effect of chiral ligands on the Michael/hemiketalization reaction.[a]
Entry
Ligand[b]
t [min]
Yield [%][c]
d.r.[c] 3 (anti/syn)
ee [%][e]
1 2 3 4 5 6
(S)-L1 (S)-L2 (R,2S)-L3 (R,2R)-L4 (S,S)-L5 (S,S)-L6
30 30 30 30 15 15
63 61 60 59 50 60
1.8:1 1.7:1 1.8:1 1.5:1 1.0:1 1.7:1
4 8 2 0 85 49
[a] Unless otherwise noted, all reactions were conducted with 1 (0.25 mmol), 2 a (0.275 mmol), ligands and ZnEt2 (20 mol %) in DCM (1.5 mL) under N2 at 25 8C. [b] Ligands L1–L4 (20 mol %), ligand L5, L6 (10 mol %). [c] Isolated yield of anti-3 a. [d] Determined by 1H NMR spectroscopic analysis of the crude reaction product. [e] The ee value of anti3 a was determined by HPLC analysis. Scheme 2. Dinuclear zinc-AzePhenol complex Zn2EtL.
The 1H and 13C NMR spectra revealed that major product anti-3 a was obtained as an equilibrating mixture of anomers (about 2:1) caused by 2-OH and 2-COOCH3. These anomers equilibrated slowly enough so as to appear as separate compounds in 1H and 13C NMR spectra but quickly enough that they did not resolve by chromatography. The trace of the racemic anti-3 a on a chiral HPLC column showed only one pair of peaks for the two enantiomers.[11, 14] However, the minor synproduct was a rapid equilibrium between the cyclic hemiketal syn-3 a and the Michael-type product syn-3 a’.[15] A series of ligands were then examined and the results are summarized in Table 1. All the ligands L1–L6 could catalyze the reaction efficiently to give the product anti-3 a with low to high enantiomeric excess (ee) in 15–30 min at room temperature. Simple b-amino alcohol ligands were not efficient in enantioselectivity (Table 1, entries 1–4). Fortunately, Trost’s dinuclear zinc catalysts[16] generated from chiral semi-azacrown ether ligand (S,S)-L5 and ZnEt2 catalyzed the reaction to give anti-3 a with 50 % yield and 85 % ee (Table 1, entry 5). However, ligand (S,S)-L6 which was similar to that of Trost’s but contains a piperidine instead of a pyrrolidine gave anti-3 a with 60 % yield and 49 % ee (Table 1, entry 6). Recently, we reported a new dinuclear zinc-AzePhenol complex Zn2EtL (L = (S,S)-L7) generated in situ by treating the chiral ligand (S,S)-L7 with two equivalents of diethylzinc wherein a dynamic balance between the (Zn2EtL)n and Zn2EtL (Scheme 2) existed.[17] This Zn2EtL system showed excellent performance in the catalytic asymmetric Friedel–Crafts alkylation of unprotected pyrrole with a series of chalcones.[17a] In addition, this intramolecular dinuclear zinc catalytic system Chem. Eur. J. 2015, 21, 11994 – 11998
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Gratifyingly, our Zn2EtL system prepared in situ catalyzed the reaction with a much higher ee value of 93 % in DCM at room temperature (Table 2, entry 1). However, changing the metal reagents led to a reduction on both yields and ee values (Table 2, entries 2 and 3). Thus, the effective catalytic system Zn2EtL was used for further screening of solvents. The reactions proceeded well in most of the solvents examined, giving the desired product anti-3 a in different diastereoselectivity. The highest ee value of 93 % was obtained in DCM with 65 % yield (Table 2, entry 1). Dioxane was not chosen as a good solvent because the ee value of anti-3 a was only 85 % though the d.r.anti/syn value of 5.2:1 was the highest (Table 2, entry 9). A slight decrease in enantioselectivity was observed when the mixed solvents of DCM and dioxane in different proportions were used (Table 2, entries 10–12). Reaction temperature and the catalyst amounts were also examined (Table 3). Temperature proved to have a significant effect on diastereoselectivity (Table 3, entries 1–4). Conducting the reaction at 0 8C improved both the d.r.anti/syn value and the ee value of anti-3 a (Table 3, entry 2). However, no obvious improvement in enantioselectivity was observed when the reaction was conducted at ¢20 or ¢50 8C, except that prolonged reaction times were required (Table 3, entries 3 and 4), so we carried out the catalyst amount screening at 0 8C. Reducing the loading of the ligand (S,S)-L7 to 5.0, 2.0, 1.0 and 0.1 mol % (Table 3, entries 4–8), 2.0 mol % was found to be the most effective, and the reaction was complete after 45 min with d.r.anti/syn value of 10:1 affording anti-3 a in 90 % yield with
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Communication Table 3. Screening conditions for the Michael/hemiketalization reaction in the presence of (S,S)-L7.[a]
Table 2. Effect of new chiral ligand and solvents on the Michael/hemiketalization reaction.[a]
Entry
Metal
Solvent
Yield [%][b]
d.r.[c] 3 (anti/syn)
ee [%][d]
1 2 3 4 5 6 7 8 9 10 11 12
ZnEt2 ZnMe2 Mg(nBu)2 ZnEt2 ZnEt2 ZnEt2 ZnEt2 ZnEt2 ZnEt2 ZnEt2 ZnEt2 ZnEt2
DCM DCM DCM toluene THF dichloroethane CHCl3 CH3CN dioxane dioxane/DCM (1:1) dioxane/DCM (10:1) dioxane/DCM (1:10)
65 45 46 64 62 58 45 71 82 83 80 57
2.0:1 1.2:1 1.0:1 1.8:1 5.0:1 1.4:1 1.5:1 2.5:1 5.2:1 4.8:1 4.9:1 1.6:1
93 75 6 86 77 91 88 87 84 85 82 90
98 % ee (Table 3, entry 6). The derivatives with different substituents (R1) at the ester moiety of compounds 2 were also tested. Substrates 2 b–2 d all gave excellent results in enantioselectivities but lower diastereoselectivity (Table 3, entries 9– 11). Extensive screening showed that the optimal conditions were as follows: Zn2EtL complex (2 mol %), a-hydroxyacetophenone 1 (0.25 mmol) and b,g-unsaturated a-keto esters 2 a (0.275 mmol), in DCM (1.5 mL) at 0 8C. In order to explore the generality of this reaction, we subsequently examined the treatment of a-hydroxyacetophenone 1 with various b,g-unsaturated a-keto esters 2 under the optimal reaction conditions achieved above, and the results are summarized in Table 4. More importantly, the highly enantiomerically enriched Michael/hemiacetalization adducts anti-3 a obtained by this method can be easily converted to dihydrofuran anti-4 a by a simple one-step treatment without any loss in optical activity. The substituents on the aromatic ring of b,g-unsaturated aketo esters affected the results significantly. Good yields, good diastereoselectivities and excellent enantioselectivities were achieved with b,g-unsaturated a-keto esters 2 e–2 j bearing various substituents at the para position of the g-aromatic ring, irrespective of their electronic nature (Table 4, entries 2– 7). The substrates 2 k–2 n with substituent at the meta position of the g-aromatic ring provided the same good results but moderate d.r.anti/syn values (Table 4, entries 8–11). Interestingly, syn-products were obtained mainly with good yields but moderate ee values when the substrates 2 o and 2 p with Cl, Br groups at the ortho position of the g-aromatic ring were examined (Table 4, entries 12 and 13). The bigger steric hindrance effect of group at the ortho position of the g-aromatic ring www.chemeurj.org
L7 [mol %]
T [oC]
t [min]
R1
Yield [%][b]
d.r.[c] 3 (anti/syn)
ee [%][d]
1 2 3 4 5 6 7 8[e] 9 10 11
10 10 10 10 5 2 1 0.1 2 2 2
25 0 ¢20 ¢50 0 0 0 0 0 0 0
15 20 120 300 30 45 120 2 days 45 45 45
Me Me Me Me Me Me Me Me Et iPr tBu
65 86 84 82 88 90 79 < 10 66 70 67
2.0:1 7.0:1 6.8:1 6.8:1 8.3:1 10:1 6.8:1 – 2.2:1 3.0:1 2.1:1
93 96 97 97 97 98 97 93 97 96 97
[a] Unless otherwise noted, all reactions were conducted with 1 (0.25 mmol), 2 a (0.275 mmol), (S,S)-L7 and ZnEt2 in DCM (1.5 mL) under N2. [b] Isolated yield of anti-3. [c] Determined by 1H NMR spectroscopic analysis of the crude reaction product. [d] The ee value of anti-3 was determined by HPLC analysis. [e] Compound 1 (2.5 mmol), 2 a (2.75 mmol) and DCM (4.5 mL) were used.
[a] Unless otherwise noted, all reactions were conducted with 1 (0.25 mmol), 2 a (0.275 mmol), ligands (10 mol %) and ZnEt2 (20 mol %) in solvent (1.5 mL) under N2 at 25 8C for 15 min. [b] Isolated yield of anti3 a. [c] Determined by 1H NMR spectroscopic analysis of the crude reaction product. [d] The ee value of anti-3 a was determined by HPLC analysis.
Chem. Eur. J. 2015, 21, 11994 – 11998
Entry
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Table 4. Examination of the generality of the reaction with different b,gunsaturated a-keto ester 2 and 1.[a]
Entry
R2
d.r.[b] 3 (anti/syn)
Yield anti-3/4 [%][c]
ee 3/4 [%][d]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18[h]
Ph(2 a) 4-FC6H4(2 e) 4-ClC6H4(2 f) 4-BrC6H4(2 g) 4-NO2C6H4(2 h) 4-MeC6H4(2 i) 4-MeOC6H4(2 j) 3-ClC6H4(2 k) 3-BrC6H4(2 l) 3-MeOC6H4(2 m) 3-MeC6H4(2 n) 2-ClC6H4(2 o) 2-BrC6H4(2 p) 3-Br-4-ClC6H3(2 q) 3,4-OCH2OC6H3(2 r) 2-naphthyl(2 s) 2-thienyl(2 t) Ph(2 a)
10:1 4.7:1 6.0:1 4.3:1 3.6:1 5.1:1 4.4:1 2.0:1 2.3:1 2.0:1 1.7:1 1:5.4 1:9.5 2.2:1 3.6:1 2.5:1 2.3:1 9.8:1
90:80 81:75 85:69 78:72 76:55 81:62 85:21[e] 64:67 67:73 65:43 59:53 77[f]:62 83[g]:56 67:63 73:18[e] 70:23[e] 68:15[e] 88:–
98:98 95:95 96:96 95:95 90:90 97:97 98:98 94:94 94:94 93:92 96:96 78:77 75:76 93:92 97:97 94:95 96:97 98:–
[a] Unless otherwise noted, all reactions were conducted with 1 (0.25 mmol), 2 (0.275 mmol), (S,S)-L7 (2 mol %) and ZnEt2 (4 mol %) in DCM (1.5 mL) under N2 at 0 8C for 45 min. [b] Determined by 1H NMR spectroscopic analysis of the crude reaction product. [c] Isolated yield of anti-3/4. [d] The ee value was determined by HPLC analysis. [e] Mostly carbonized. [f] syn-3 o was obtained. [g] syn-3 p was obtained. [h] (R,R)-L7 was used. Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication might be a key element. The catalytic system was also suitable for disubstituted g-aromatic ring substrates, g-naphthyl ring substrates and g-heteroaromatic ring substrates 2 q–2 t, affording the desired products in moderate to good yields and excellent enantioselectivities (Table 4, entries 14–17). (R,R)-L7 was also applied to catalyze the reaction, and the anti-3 a was obtained in 88 % yield and 98 % ee with opposite optical activity compared with entry 1, Table 4 (Table 4, entry 18). A single crystal solid of 3 g was obtained from the minor product which was a mixture of cyclic hemiketal product and the Michael-type product.[15] It was determined to be syn-configuration by X-ray crystallographic analysis (Figure 1),[19] and the rest of the products were assigned by analogy. Unfortunately, the single crystal consisted of a pair of enantiomers because of the low ee value of syn-3 g. The absolute configuration of the product anti-3 g remains unknown.
2.0 mol %, a series of synthetically useful multisubstituted chiral tetrahydrofurans were obtained with moderate to good yields and up to 98 % ee. Further efforts will focus on determining the absolute configuration of products and the mechanistic studies of this domino Michael/hemiacetalization reaction, as well as the application of this dinuclear zinc-AzePhenol complex to other reactions.
Experimental Section General procedure for the catalytic reaction In a flame-dried Schlenk tube, a solution of diethylzinc (0.01 mL, 1.0 mol L¢1 in hexane, 0.01 mmol) was added to a solution of the chiral ligand (S,S)-L7 (3.1 mg, 0.005 mmol) in dry DCM (0.8 mL) under nitrogen at 0 8C. The mixture was stirred at room temperature for 30 min. Then a solution of 1 (34 mg, 0.25 mmol) and 2 a (0.275 mmol) in dry DCM (0.7 mL) was added to the mixture at 0 8C. The solution was stirred at 0 8C for the necessary reaction times, and then quenched with aqueous NH4Cl (5 mL), and extracted three times with DCM (3 Õ 10 mL). The combined organics was washed with brine before being dried by MgSO4, filtered and concentrated in vacuo. The crude product was separated by flash column chromatography.
Acknowledgements Figure 1. X-ray structure of compound syn-3 g.
To show the synthetic application of the current method, a large-scale synthesis of 3 a was examined. As shown in Scheme 3, domino Michael/hemiacetalization reaction of a-hydroxyacetophenone 1 with b,g-unsaturated a-keto esters 2 a was accomplished by using only 2 mol % of dinuclear zinc-AzePhenol complex leading to multiple-substituted tetrahydrofuran products with good results (85 % yield, 98 % ee). In conclusion, we have reported a new catalytic asymmetric domino Michael/hemiacetalization reaction of a-hydroxyacetophenone with b,g-unsaturated a-keto esters leading to multiple-substituted tetrahydrofuran products by using dinuclear zinc-AzePhenol complex. With a low catalyst loading of
Scheme 3. Catalytic asymmetric domino Michael/hemiacetalization reaction of a-hydroxyacetophenone 1 a with b,g-unsaturated a-keto esters 2 a on a 1.0 mmol scale. Chem. Eur. J. 2015, 21, 11994 – 11998
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We are grateful to the National Natural Sciences Foundation of China (NNSFC: 21272216, 81330075, 21302173), and the Department of Science and Technology of Henan Province for financial supports. Keywords: asymmetric catalysis · domino reactions · Michael/ hemiacetalization reactions · tetrahydrofuran · zinc [1] a) T. Eicher, S. Hauptmann, The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications, Wiley-VCH, Weinheim, 2003; b) E. J. Kang, E. Lee, Chem. Rev. 2005, 105, 4348; c) A. Lorente, J. LamarianoMerketegi, F. Albericio, M. Alvarez, Chem. Rev. 2013, 113, 4567. [2] a) S. Mahapatra, R. G. Carter, Angew. Chem. Int. Ed. 2012, 51, 7948; Angew. Chem. 2012, 124, 8072; b) T. Rezanka, L. O. Hanus, V. M. Dembitsky, Eur. J. Org. Chem. 2003, 4073; c) A. Gollner, J. Mulzer, Org. Lett. 2008, 10, 4701; d) Y. Chen, J. Jin, J. Wu, W. M. Dai, Synlett 2006, 1177; e) J. Jin, Y. Chen, Y. Li, J. Wu, W. M. Dai, Org. Lett. 2007, 9, 2585; f) W. M. Dai, Y. Chen, J. Jin, J. Wu, J. Lou, Q. He, Synlett 2008, 1737; g) J. S. Sandler, P. L. Colin, M. Kelly, W. Fenical, J. Org. Chem. 2006, 71, 7245; h) J. S. Sandler, P. L. Colin, M. Kelly, W. Fenical, J. Org. Chem. 2006, 71, 8684. [3] For reviews, see: a) L. F. Tietze, H. Ila, H. P. Bell, Chem. Rev. 2004, 104, 3453; b) J. P. Wolfe, M. B. Hay, Tetrahedron 2007, 63, 261; c) G. Jalce, X. Franck, B. Figadere, Tetrahedron: Asymmetry 2009, 20, 2537; d) K.-S. Yeung, X.-S. Peng, J. Wu, R. Fan, X.-L. Hou, in Progress in Heterocyclic Chemistry Vol. 25 (Eds.: G. W. Gribble, J. A. Joule), Elsevier, Oxford, 2013, p. 183.
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Communication [4] a) M. M. C. Lo, G. C. Fu, Tetrahedron 2001, 57, 2621; b) E. D. Butova, A. V. Barabash, A. A. Petrova, C. M. Kleiner, P. R. Schreiner, A. A. Fokin, J. Org. Chem. 2010, 75, 6229. [5] M. T. Corbett, J. S. Johnson, Chem. Sci. 2013, 4, 2828. [6] a) S. H. Kang, M. Kim, J. Am. Chem. Soc. 2003, 125, 4684; b) S. H. Kang, S. B. Lee, C. M. Park, J. Am. Chem. Soc. 2003, 125, 15748; c) U. Hennecke, C. H. Muller, R. Frohlich, Org. Lett. 2011, 13, 860; d) K. Asano, S. Matsubara, J. Am. Chem. Soc. 2011, 133, 16711; e) D. H. Miles, M. Veguillas, F. D. Toste, Chem. Sci. 2013, 4, 3427; f) Y. P. Lu, G. Zou, G. Zhao, ACS Catal. 2013, 3, 1356. [7] D. Belmessieri, A. Houpliere, E. D. D. Calder, J. E. Taylor, A. D. Smith, Chem. Eur. J. 2014, 20, 9762. [8] For selected examples for asymmetric synthesis of substituted dihydrofurans, see: a) H. M. L. Davies, G. Ahmed, R. L. Calvo, M. R. Churchill, D. G. Churchill, J. Org. Chem. 1998, 63, 2641; b) D. A. Evans, Z. K. Sweeney, T. Rovis, J. S. Tedrow, J. Am. Chem. Soc. 2001, 123, 12095; c) F. Garzino, A. M¦ou, P. Brun, Eur. J. Org. Chem. 2003, 1410; d) W. Xia, C. Yang, B. O. Patrick, J. R. Scheffer, C. Scott, J. Am. Chem. Soc. 2005, 127, 2725; e) M. A. Calter, R. M. Phillips, C. Flaschenriem, J. Am. Chem. Soc. 2005, 127, 14566; f) S. Son, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 1046; g) J.-C. Zheng, C.-Y. Zhu, X.-L. Sun, Y. Tang, L.-X. Dai, J. Org. Chem. 2008, 73, 6909; h) M. Rueping, A. Parra, U. Uria, F. Besselievre, E. Merino, Org. Lett. 2010, 12, 5680; i) X.-W. Dou, F.-R. Zhong, Y.-X. Lu, Chem. Eur. J. 2012, 18, 13945; j) M. A. Calter, A. Korotkov, Org. Lett. 2011, 13, 6328; k) J.-L. Zhou, L.-J. Wang, H. Xu, X.-L. Sun, Y. Tang, ACS Catal. 2013, 3, 685. [9] For reviews on asymmetric synthesis of substituted trihydrofurans, see: a) I. J. S. Fairlamb, Angew. Chem. Int. Ed. 2004, 43, 1048; Angew. Chem. 2004, 116, 1066; b) I. D. G. Watsona, F. D. Toste, Chem. Sci. 2012, 3, 2899; c) A. Marinetti, H. Jullien, A. Voituriez, Chem. Soc. Rev. 2012, 41, 4884. For selected examples for asymmetric synthesis of substituted trihydrofurans, see: d) S. R. Gilbertson, G. S. Hoge, D. G. Genov, J. Org. Chem. 1998, 63, 10077; e) P. Cao, X. Zhang, Angew. Chem. Int. Ed. 2000, 39, 4104; Angew. Chem. 2000, 112, 4270; f) M. Hatano, M. Terada, K. Mikami, Angew. Chem. Int. Ed. 2001, 40, 249; Angew. Chem. 2001, 113, 255; g) A. Lei, M. He, S. Wu, X. Zhang, Angew. Chem. Int. Ed. 2002, 41, 3457; Angew. Chem. 2002, 114, 3607; h) B. M. Trost, M. R. Machacek, Angew. Chem. Int. Ed. 2002, 41, 4693; Angew. Chem. 2002, 114, 4887; i) M. Hatano, M. Yamanaka, K. Mikami, Eur. J. Org. Chem. 2003, 2552; j) K. Mikami, S. Kataoka, Y. Yusa, K. Aikawa, Org. Lett. 2004, 6, 3699; k) P. A. Wender, L. O. Haustedt, J. Lim, J. A. Love, T. J. Williams, J.-Y. Yoon, J. Am. Chem. Soc. 2006, 128, 6302; l) T. Shibata, Y.-K. Tahara, J. Am. Chem. Soc. 2006, 128, 11766; m) K. Aikawa, S. Akutagawa, K. Mikami, J. Am. Chem. Soc. 2006, 128, 12648; n) B. M. Trost, M. R. Machacek, B. D. Faulk, J. Am. Chem. Soc. 2006, 128, 6745; o) R. Shintani, Y. Sannohe, T. Tsuji, T. Hayashi, Angew. Chem. Int. Ed. 2007, 46, 7277; Angew. Chem. 2007, 119, 7415; p) T. Shibata, H. Kurokawa, K. Kanda, J. Org. Chem. 2007, 72, 6521; q) R. Shintani, H. Nakatsu, K. Takatsu, T. Hayashi, Chem. Eur. J. 2009, 15, 8692; r) E. G. Corkum, M. J. Hass, A. D. Sullivan, S. H. Bergens, Org. Lett. 2011, 13, 3522; s) Y. Miyauchi, K. Noguchi, K. Tanaka, Org. Lett. 2012, 14, 5856. [10] For recent reviews on asymmetric Michael additions, see: a) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033; b) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org. Chem. 2002, 1877; c) J. Christoffers, A. Baro, Angew. Chem. Int. Ed. 2003, 42, 1688; Angew. Chem. 2003, 115, 1726; d) W. Notz, F. Tanaka, C. F. Barbas, Acc. Chem. Res. 2004, 37, 580; e) R. Ballini, G. Bosica, D. Fiorini, A. Palmieri, M. Petrini, Chem. Rev. 2005, 105, 933; f) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701; g) S. Sulzer-Moss¦, A. Alexakis, Chem. Commun. 2007, 3123; h) D. Almasi, D. A. Alonso, C. Najera, Tetrahedron: Asymmetry 2007, 18, 299; i) X.-H. Liu, L.-L. Lin, X.-M. Feng, Acc. Chem. Res. 2011, 44, 574; j) G. Desimoni, G. Faita, P. Quadrelli, Chem. Rev. 2013, 113, 5924. [11] a) R. P. Herrera, D. Monge, E. Martin-Zamora, R. Ferandez, J. M. Lassaletta, Org. Lett. 2007, 9, 3303; b) S.-L. Zhao, C.-W. Zheng, H.-F. Wang, G.
Chem. Eur. J. 2015, 21, 11994 – 11998
www.chemeurj.org
[12]
[13]
[14]
[15] [16] [17]
[18]
[19]
Zhao, Adv. Synth. Catal. 2009, 351, 2811; c) S.-L. Zhao, C.-W. Zheng, G. Zhao, Tetrahedron: Asymmetry 2009, 20, 1046; d) M. A. Calter, J. Wang, Org. Lett. 2009, 11, 2205; e) Y.-F. Wang, W. Zhang, S.-P. Luo, G.-C. Zhang, A.-B. Xia, X.-S. Xu, D.-Q. Xu, Eur. J. Org. Chem. 2010, 4981; f) Y. Gao, Q. Ren, L. Wang, J. Wang, Chem. Eur. J. 2010, 16, 13068; g) J.-J. Wang, J.-H. Lao, Z.-P. Hu, R.-J. Lu, S.-Z. Nie, Q.-S. Du, M. Yan, ARKIVOC 2010, 229; h) X.-K. Chen, C.-W. Zheng, S.-L. Zhao, Z. Chai, Y.-Q. Yang, G. Zhao, W.-G. Cao, Adv. Synth. Catal. 2010, 352, 1648; i) D.-Q. Xu, Y.-F. Wang, W. Zhang, S.-P. Luo, A.-G. Zhong, A.-B. Xia, Z.-Y. Xu, Chem. Eur. J. 2010, 16, 4177; j) Y. Gao, Q. Ren, S.-M. Ang, J. Wang, Org. Biomol. Chem. 2011, 9, 3691; k) J.-J. Wang, Z.-P. Hu, C.-L. Lou, J.-L. Liu, X.-M. Li, M. Yan, Tetrahedron 2011, 67, 4578; l) Q. Ren, Y. Gao, J. Wang, Org. Biomol. Chem. 2011, 9, 5297; m) Y.-F. Wang, K. Wang, W. Zhang, B.-B. Zhang, C.-X. Zhang, D.-Q. Xu, Eur. J. Org. Chem. 2012, 3691; n) J.-H. Feng, X. Fu, Z.-L. Chen, L.-L. Lin, X.-H. Liu, X.-M. Feng, Org. Lett. 2013, 15, 2640; o) N. Halland, T. Velgaard, K. A. Jørgensen, J. Org. Chem. 2003, 68, 5067; p) Z.-H. Dong, J.-H. Feng, X.-A. Fu, X.-H. Liu, L.-L. Lin, X.-M. Feng, Chem. Eur. J. 2011, 17, 1118; q) B. Yang, F. Xie, H. Yu, K.-J. Shen, Z.-N. Ma, W.-B. Zhang, Tetrahedron 2011, 67, 6197; r) L. Gremaud, A. Alexakis, Angew. Chem. Int. Ed. 2012, 51, 794; Angew. Chem. 2012, 124, 818; s) Z.-H. Dong, J.-H. Feng, W.-D. Cao, X.-H. Liu, L.-L. Lin, X.-M. Feng, Tetrahedron Lett. 2011, 52, 3433; t) L. Zhou, L.-L. Lin, W. Wang, J. Ji, X.-H. Liu, X.-M. Feng, Chem. Commun. 2010, 46, 3601; u) X. Song, J. Liu, M.-M. Liu, X. Wang, Z.-F. Zhang, M.-C. Wang, J. Chang, Tetrahedron 2014, 70, 5468. a) N. Kumagai, S. Matsunaga, M. Shibasaki, Org. Lett. 2001, 3, 4251; b) S. Harada, N. Kumagai, T. Kinoshita, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2003, 125, 2582; c) S. Matsunaga, T. Kinoshita, S. Okada, S. Harada, M. Shibasaki, J. Am. Chem. Soc. 2004, 126, 7559; d) B. M. Trost, S. Hisaindee, Org. Lett. 2006, 8, 6003. a) B. H. Lipshutz, Chem. Rev. 1986, 86, 795; b) O. R. Gottlied, New Natural Products and Plant Drugs with Pharmacological, Biological, or Therapeutical Activity, Springer, Heidelberg, 1987, p. 227; c) B. M. Fraga, Nat. Prod. Rep. 1992, 9, 217; d) A. T. Merritt, S. B. Ley, Nat. Prod. Rep. 1992, 9, 243; e) M. M. Faul, B. E. Huff, Chem. Rev. 2000, 100, 2407; f) T. G. Kilroy, T. P. O’Sullivan, P. J. Guiry, Eur. J. Org. Chem. 2005, 4929; g) J. D. Pettigrew, P. D. Wilson, Org. Lett. 2006, 8, 1427; h) A. R. Gallimore, Nat. Prod. Rep. 2009, 26, 266. See the Supporting Information. For studies on similar equilibriums of related compounds, see: a) W. R. Porter, W. F. Trager, J. Heterocycl. Chem. 1982, 19, 475; b) L. D. Heimark, W. F. Trager, J. Med. Chem. 1984, 27, 1092; c) Y.-B. Liu, X.-H. Liu, M. Wang, P. He, L.-L. Lin, X.-M. Feng, J. Org. Chem. 2012, 77, 4136. See the Supporting Information. a) B. M. Trost, H. Ito, J. Am. Chem. Soc. 2000, 122, 12003; b) B. M. Trost, V. S. C. Yeh, H. Ito, N. Bremeyer, Org. Lett. 2002, 4, 2621. a) Y.-Z. Hua, X.-W. Han, X.-C. Yang, X. Song, M.-C. Wang, J.-B. Chang, J. Org. Chem. 2014, 79, 11690; b) Y.-Z. Hua, L.-J. Lu, P.-J. Huang, D.-H. Wei, M.-S. Tang, M.-C. Wang, J.-B. Chang, Chem. Eur. J. 2014, 20, 12394; c) Y.Z. Hua, X.-C. Yang, M.-M. Liu, X. Song, M.-C. Wang, J.-B. Chang, Macromolecules 2015, 48, 1651. a) M.-C. Wang, Q.-J. Zhang, W.-X. Zhao, X.-D. Wang, X. Ding, T.-T. Jing, M.-P. Song, J. Org. Chem. 2008, 73, 168; other work comparing the same type of nitrogen heterocycles : b) X.-H. Liu, L.-L. Lin, X.-M. Feng, Org. Chem. Front. 2014, 1, 298. For 3 g, formula: C19H17BrO5 ; CCDC 988337 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.
Received: April 28, 2015 Published online on July 14, 2015
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