Letter Cite This: Org. Lett. 2019, 21, 5438−5442
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Chiral Imidodiphosphoric Acid-Catalyzed Highly Diastereo- and Enantioselective Synthesis of Poly-Substituted 3,4Dihydro‑2H‑pyrans: [4 + 2] Cycloadditions of β,γ-Unsaturated α‑Ketoesters and 3‑Vinylindoles Xu-Kai Guan, Guo-Feng Liu, Dong An, Heng Zhang, and Suo-Qin Zhang*
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College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China S Supporting Information *
ABSTRACT: Imidodiphosphoric acids were employed to catalyze inverse-electron-demand hetero-Diels−Alder reaction of β,γ-unsaturated α-ketoesters and 3-vinylindoles. A series of optically active 3,4-dihydro-2H-pyran derivatives with three contiguous stereogenic centers was synthesized in excellent yields (70−99%), diastereoselectivities (>20:1), and enantioselectivities (73−99%). The resulting indole containing 3,4-dihydro-2H-pyran could be converted to tetrahydropyran derivatives, which appear in several biological active compounds by simple hydrogenation reduction.
O
ver the past 20 years, asymmetric inverse-electrondemand hetero-Diels−Alder reactions (IED hetero-DA) involving β,γ-unsaturated α-ketoesters have received considerable attention due to the high efficiency for synthesis of chiral six-membered heterocyclic compounds.1 With this method, numerous biologically active molecules have been synthesized, which include carbohydrate derivatives,2 3,4-dihydro-2Hpyranol,3 3,4-dihydro-2H-pyranone,4 3,4-dihydro-2H-pyranamine,5 spiroketals, spiroaminals,6 and bicyclic N,O acetals,7 in excellent yields and enantioselectivities. However, indole containing 3,4-dihydro-2H-pyran derivatives have not been synthesized using this method. This type of molecules could be converted to tetrahydropyran derivatives, which exist in many pharmaceutical active compounds. For example, C-indolylxylosides serve as sodium-dependent glucose cotransporter 2 inhibitors against type 2 diabetes mellitus.8 The C-glycosidic attachment of a hexopyranosyl residue to the indole ring was discovered in tryptophan residue 7 of human RNase Us (Figure 1).9 By contrast, 3-vinylindoles, which have commonly been used as conjugated dienes in DA reaction,10 rarely participate in IED hetero-DA reaction as dienophiles with the exceptions of chiral phosphoric acid catalyzed Povarov reactions11 and chiral tertiary amine thiourea-catalyzed IED hetero-DA reaction of chromone heterodienes.12 Furthermore, accessing optically pure indole containing 3,4-dihydro-2H-pyran with three contiguous stereogenic centers is more challenging. Thus, a method to realize this version of IED hereo-DA reaction is desirable. We envisioned that imidodiphosphoric acids, which feature a good stereocontrol capability in many asymmetric transformations,13 could © 2019 American Chemical Society
Figure 1. Biologically active molecules of indole-containing tetrahydropyran derivatives.
provide an efficient IED hetero-DA reaction. Herein, we disclose our efforts on IED hetero-DA reaction of β,γ-unsaturated αketoesters using 3-vinylindoles as dienophiles by employing imidodiphosphoric acids. Initially, 3-vinylindole 1a was selected as dienophile to react with β,γ-unsaturated α-ketoester 2a in toluene at 0 °C. Imidodiphosphoric acid 3a (with 3,5-bis(trifluoromethyl)phenyl groups at 3,3′-position) was used as catalyst. However, the reaction did not provide any product (Table 1, entry 1). We then selected 3-vinylindole 1b, containing a phenyl group at the terminal alkene, as dienophile to react with 2a in the same condition. To our delight, the IED hetero-DA reaction proceeded well and the corresponding product 5a was obtained in excellent diastereo- and enantioselectivity (92% ee, >20:1 d.r.) albeit with 42% yield (Table 1, entry 2). Generally, the Received: May 13, 2019 Published: July 3, 2019 5438
DOI: 10.1021/acs.orglett.9b01675 Org. Lett. 2019, 21, 5438−5442
Letter
Organic Letters Table 1. Catalysts Screeninga
entry 1 2 3 4 5 6 7 8 9 10 11
substrate 1a 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b
cat.
t (h)
3a 3a 3b 3c 3d 3e 4a 4b 4c 4d 4e
− 48 48 48 48 − 48 48 48 48 −
yieldb (%) n.r. 42 48 40 42 n.r. 45 20 78 56 n.r.
e
eec (%)
d.r.d (%)
− 92 78 57 40 − 53 45 60 40 −
− >20:1 >20:1 >20:1 >20:1 − >20:1 >20:1 >20:1 >20:1 −
temperature to −10 or −20 °C did not affect the yield, but the ee was increased to 96%, whereas the reaction time was longer (96 h, Entries 7 and 8). In order to reduce the reaction time, we added additives in the reaction. Thus, addition of 3 Å molecular sieves largely reduced the reaction time and increased both the yield and ee to 99% (Entry 9). Finally, we examined the catalyst loading, when the catalyst loading was decreased to 2 mol %, the yield and enantioselectivity remained similar (98% yield, 98.5% ee; Entry 10) at the expense of 20 h reaction time. Further decreasing the catalyst loading to 1 mol % affected the reaction significantly (30% yield, 95% ee; Entry 11). Thus, the optimal reaction condition was established as catalyst 3a (5 mol %), 1b (0.10 mmol), 2a (0.15 mmol), and 3 Å molecular sieves (15 mg) in CCl4 (1 mL) at −20 °C. With the optimized conditions in hand, the substrate scope of β,γ-unsaturated α-ketoesters was evaluated (Table 2). SubTable 2. Optimization of the Reaction Conditionsa
entry 1 2 3 4 5 6 7 8 9 10 11
a
Reactions were performed with 0.1 mmol of 1b, 0.15 mmol of 2a, 5 mol % catalyst in 1 mL of toluene. bYield of the isolated product based on 3-vinylindole 1b. cDetermined by HPLC analysis on Chiralcel OD-H columns. dDetermined by 1H NMR spectrum. en.r. = no reaction.
introduction of a phenyl group at the terminal alkene of 3vinylindole will lead to decreased electron density of the terminal alkene and reduced reactivity. It probably has more important influence than the influence of electronic effect, such as the π−π conjugate between the aromatic ring of catalyst and 3-vinylindole. We screened a few imidodiphosphoric acids 3b−e for the model reaction, the results of which were shown in Table 1. Catalyst 3b with phenyl groups at the 3,3′-position provided product 5a with 42% yield and 78% ee (Entry 3). Other two catalysts 3c and 3d did not afford better results (Entries 4 and 5). When catalyst 3e with TRIP groups at the 3,3′-position was employed, no reaction occurred (Entry 6). Phosphoric acids 4a−e, which contained the same groups at 3,3′-position as catalysts 3a−e were also examined, the best result (78% yield, 60% ee) was accomplished with the catalyst 4c bearing 1naphthyl groups at the 3,3′-position (Entry 9). When phosphoric acid 4e bearing TRIP groups at the 3,3′-position was employed, there was no reaction. Next, we screened a range of solvents and found that the solvent polarity had a crucial influence on the reaction. The use of chlorinated alkanes brought excellent enantioselectivities and increased yields (Entries 1−3). Among them, dichloromethane and chloroform provided high ee values with low yields, and tetrachloromethane exhibited a superior performance in this reaction and provided product 5a in 96% yield and 94% ee. Aromatic solvents such as toluene and m-xylene did not provide better results (Entry 4). In comparison, solvents such as tetrahydrofuran and 1,4-dioxane could not furnish product (Entries 5 and 6). So we selected tetrachloromethane as the optimal solvent. Lowering the
solvents CH2Cl2 CHCl3 CCl4 m-xylene THF 1,4-dioxane CCl4 CCl4 CCl4f CCl4g CCl4h
T (°C) 0 0 0 0 0 0 −10 −20 −20 −20 −20
t (h) 48 48 48 48 − − 72 96 10 20 40
yieldb (%) e
40 60 96 30 n.r.e n.r. 90 92 99 98 30
eec (%)
d.r.d (%)
93 95 94 91 − − 95 96 99 98 95
>20:1 >20:1 >20:1 >20:1 − − >20:1 >20:1 >20:1 >20:1 >20:1
a
Reactions were performed with 0.1 mmol of 1b, 0.15 mmol of 2a, 5 mol % catalyst in 1 mL of solvent. bYield of the isolated product based on 3-vinylindole 1b. cDetermined by HPLC analysis on Chiralcel OD-H columns. dDetermined by 1H NMR spectrum. en.r. = no reaction. f30 mg of 3 Å MS was added. gCatalyst loading was 2 mol %. h Catalyst loading was 1 mol %
strates 2a bearing electron-donating group (4-CH3) gave the corresponding product 5a in 99% yield and 99% ee; however, the substrate 2b bearing strong electron-donating group (4OCH3) could not afford the corresponding product with good result (5a, 5b; Scheme 1). Substrates containing halogen on benzene ring participate well in the reaction, excellent yields (95%−99%), enantioselectivities (99% ee), and diastereoselectivities (>20:1 d.r.) were obtained (5c−k, Scheme 1). When substrates with ortho-position substituents on benzene ring were examined, the enantioselectivity was decreased to 84−85% (5l, 5m, Scheme 1). Longer reaction time (50 h) was needed when substrates with electron-withdrawing groups (4-NO2, 4CN, 4-CF3) reacted with 1b. However, the yields and enantioselectivities were excellently maintained (80−96% yields, 97−99% ee; 5n−p, Scheme 1). When the methyl ester group of β,γ-unsaturated α-ketoester was replaced by ethyl and benzyl ester groups, good yields and enantioselectivities were also obtained (80−84% yields, 95−96% ee; 5q, 5r, Scheme 1). Subsequently, the reaction scope with respect to 3-vinylindole was tested. The electron-donating substituents (5-OCH3, 55439
DOI: 10.1021/acs.orglett.9b01675 Org. Lett. 2019, 21, 5438−5442
Letter
Organic Letters Scheme 1. Substrate Scope of β,γ-Unsaturated α-Ketoestera
Scheme 2. Substrate Scope of 3-Vinylindolea
a
Reactions were performed with 0.1 mmol of 1c−r, 0.15 mmol of 2b, 5 mol % catalyst 3a in 1 mL of CCl4. Yield of the isolated product based on 3-vinylindole 1c−r, ee determined by HPLC analysis on Chiralcel AD-H or OD-H columns, and d.r. determined by 1H NMR spectrum. a Reactions were performed with 0.1 mmol of 1b, 0.15 mmol of 2a− 2r, 5 mol % catalyst 3a in 1 mL of CCl4. Yield of the isolated product based on 3-vinylindole 1b, ee determined by HPLC analysis on Chiralcel AD-H or OD-H columns, and d.r. determined by 1H NMR spectrum. bReactions were run at 10 °C.
Substrate 1o containing 2-FC6H5 group at the terminal alkene provided the product 6m in 99% yield and in 96% ee (Scheme 2). Substrates 1p containing 2-ClC6H5 group at the terminal alkene provided product 6n in 95% yield and 90% ee (Scheme 2). When the substrate 1q containing methyl at C2-position of indole was examined, the product 6o was obtained in a low yield and enantioselectivity (70% yield, 73% ee; Scheme 2). The substrate 1r containing electron-withdrawing group could not participate in the reaction (Scheme 2). The gram-scale reaction of 1b and 2j also gave excellent yield and enantioselectivity (99% yield, 98% ee; Scheme 3); the product 5j could be easily converted to tetrahedropyran derivative in good yield by hydrogenation. The absolute configuration of product 5a was determined to be (2S, 3R, 4R) by single-crystal X-ray diffraction analysis (see Supporting Information). In order to confirm the crucial adjective function of double H-bond catalyst in this reaction, N-methyl 3-vinylindole 1s reacted with β,γ-unsaturated α-ketoester 2a (Scheme 4). The ee was sharply decreased to 19%, suggesting that the stereoselectivity control is largely dependent on the formation of double H-bond between catalyst and the two reactants. On the basis of the result of control experiment, previous work,12 and the absolute configuration of product 5a detected by single-crystal X-ray diffraction analysis, the proposed transitionstate was revealed. As shown in Scheme 5, the catalyst 3a grasped two reactants by the formation of double H-bond first.
CH3) on indole could largely accelerate the reaction. Substrates 1c and 1d could react completely within 1 and 4 h, respectively. The products 6a and 6b were obtained in high yields and enantioselectivities (98%, 92% yields; 91%, 92% ee; Scheme 2). Substrates 1e−h (5-Br, 5-F, 5-Cl, 6-Cl) also provided the corresponding products 6c−f with high yields and enantioselectivities (97−99% yields, 94−99% ee; Scheme 2). Substrates 1j and 1k containing 3-CH3−C6H6 and 4-CH3−C6H6 groups at the terminal alkene provided the products 6h and 6i with 99% yield, 97% ee and 99% yield, 99% ee respectively, while substrate 1i containing 2-CH3−C6H6 group at the terminal alkene provided product 6g with 99% yield and 91% ee. Substrate 1l containing 4-FC6H6 group at the terminal alkene provided product 6j with 99% yield and 99% ee. Substrates containing 4BrC6H6 and 4-ClC6H6 could not be consumed completely even when the reaction time extended to 7 d. Increasing the acidity of the catalyst 3a by acidifying with 6 N hydrochloric acid provided better results (99% yield, 99% ee, 99% yield, 92% ee; 6k, 6l, Scheme 2), and the reaction time was shortened to 18 h. 5440
DOI: 10.1021/acs.orglett.9b01675 Org. Lett. 2019, 21, 5438−5442
Organic Letters
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Scheme 3. Gram-Scale Reaction of 1b and 2i and the Subsequent Hydrogenation of Product 5j
Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Suo-Qin Zhang: 0000-0002-0524-0797 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21202059), the China Postdoctoral Science Foundation (2013M541287), and the Jilin Province Science & Technology Development Program (20100538, 20110436, 201215033) for financial support.
Scheme 4. Control Experiment
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Scheme 5. Proposed Transition State
In the meantime, 3,5-bis(trifluoromethyl)-phenyl groups at 3,3′position of catalyst 3a shields the Si face of the β,γ-unsaturated α-ketoester 2. Therefore, a predominant Re face attack of 3vinylindole 1 provides the product 5 through a synergistic process. In conclusion, we have developed an imidodiphosphoric acidcatalyzed IED hetero-DA reaction between β,γ-unsaturated αketoesters and 3-vinylindoles. A series of 3,4-dihydro-2H-pyran derivatives with three contiguous stereogenic centers was synthesized in excellent yields (70−99%), diastereoselectivities (>20:1), and enantioselectivities (73−99%). Formation of a double H-bond between catalyst and two reactants was essential for an excellent outcome.
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REFERENCES
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01675. Experimental procedures and characterization data for all new compounds (PDF) Accession Codes
CCDC 1911545 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. 5441
DOI: 10.1021/acs.orglett.9b01675 Org. Lett. 2019, 21, 5438−5442
Letter
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DOI: 10.1021/acs.orglett.9b01675 Org. Lett. 2019, 21, 5438−5442
