DOI: 10.1002/chem.201402485
Full Paper
& Asymmetric Synthesis
Diastereo- and Enantioselective Construction of a Bispirooxindole Scaffold Containing a Tetrahydro-b-carboline Moiety through an Organocatalytic Asymmetric Cascade Reaction Wei Dai, Han Lu, Xin Li, Feng Shi,* and Shu-Jiang Tu[a]
Abstract: The first catalytic asymmetric construction of a new class of bispirooxindole scaffold-containing tetrahydro-b-carboline moiety has been established through chiral phosphoric acid-catalyzed three-component cascade Michael/Pictet–Spengler reactions of isatin-derived 3-indolylmethanols, isatins, and amino-ester, which afforded structurally complex and diverse bispirooxindoles with one quaternary and one tetrasubstituted stereogenic centers in excellent stereoselectivities (all > 95:5 diastereomeric ratio (d.r.),
Introduction Spirooxindoles are privileged structural motifs that exist in a large family of natural products[1] and synthetic compounds[2] exhibiting versatile bioactivities such as antitumoral,[3] antiHIV,[4] antimalarial,[5] antidiabetic,[6] and as SIRT 1 inhibitors (Figure 1).[7] Especially, as exemplified by compounds I and II, bispirooxindoles fusing two spirooxindole cores into one molecule have shown potent antitubercular activity[8] and found to be cholinesterase inhibitors.[9] The significance of the spirooxindole architecture with regard to medicinal application has led to a great demand for efficient synthetic methods, particularly those producing enantiomerically pure products because the enantiomers may have higher or different bioactivity compared with the racemates in most cases.[5a, 10] Hence, elegant developments have been achieved in the catalytic asymmetric construction of chiral spirooxindole skeleton and many enantioselective approaches have been available [Eq. (1)].[2, 11] However, in sharp contrast, only a few catalytic enantioselective methods have been avail[a] W. Dai,+ H. Lu,+ X. Li, Prof. Dr. F. Shi, Prof. S.-J. Tu School of Chemistry and Chemical Engineering Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University Xuzhou, 221116 (P.R. China) Fax: (+ 86) 516-83500065 E-mail: [email protected] [+] These authors contributed equally to this work. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402485. Chem. Eur. J. 2014, 20, 11382 – 11389
up to 98:2 enantiomeric ratio (e.r.)). This intriguing class of chiral bispirooxindoles integrated the two important structures of tetrahydro-b-carboline and bispirooxindole, both of them possessing significant bioactivities. This approach also combined the merits of asymmetric organocatalysis and multicomponent tandem reaction, which provided a unique strategy for the preparation of structurally rigid bispiro-architectures with concomitant creation of multiple quaternary stereogenic centers.
able to construct optically pure bispirooxindole motif [Eq. (2)].[12] On one hand, bispirooxindoles incorporate two oxindole motifs with other heterocyclic moieties into a type of unique and complex bispiro-structures, which may exhibit combined or enhanced bioactivity of both oxindoles and other heterocy-
cles.[13] Besides, this type of complex structures with multiple substituents provides an easy access to structurally diverse bispirooxindoles, which should be useful in medicinal chemistry and diversity-oriented synthesis (DOS).[14] On the other hand, the stereoselective construction of bispirooxindole motif is very complicated and challenging because of its structurally rigid architecture with at least two quaternary stereogenic centers. Therefore, the diastereo- and enantioselective formation of bispirooxindole framework is highly desirable but challeng11382
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper
Figure 1. Some bioactive natural products and synthetic compounds containing the spirooxindole core.
ing, which requires synthetic design based on specific strategies. Until recently, some organocatalytic asymmetric cascade reactions were developed to construct diastereo- and enantioselective bispirooxindole skeletons III–VI, which contain cyclopentane (III),[12a–c] thiopyrrolidine (IV),[12d–g] dihydrofuran (V),[12h] and cyclopropane (VI)[12i] moieties, respectively (Figure 2). Despite these creative works, the catalytic asymmetric cascade reactions resulting in enantioenriched bispirooxindole motifs are still underdeveloped. Among various spirooxindolines, chiral spiro[oxindoline-tetrahydro-b-carbolines] as exemplified by compound VII have proven to be potent antimalarial drugs (Figure 3).[5] This intriguing class of compounds triggered us to envision that the integration of spiro[oxindole-tetrahydro-b-carboline] moiety with another spiro-oxindole skeleton into a new type of bispirooxindole structure (VIII) may result in improved or important bioactivities. Nevertheless, the chemistry related to the synthesis of this promising structure is still unknown. In recent years, the chiral phosphoric acid (CPA)-catalyzed asymmetric cascade reaction has proven to be a powerful tool to construct complex chiral scaffolds with several stereogenic centers in one step.[15] Besides, isatin-derived 3-indolylmethanols have emerged as efficient Michael acceptors to perform enantioselective substitutions,[16] and isatin-derived azomethine ylides as privileged 1,3-dipole to undergo enantioselective [3 + 2] cycloadditions [Eq. (3)].[17a–b] Encouraged by these achieve-
Figure 2. Limited examples for constructing chiral bispirooxindole skeletons. Chem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
ments and our previous work on CPA-catalyzed asymmetric cascade reactions,[17] we envisaged that this complex chiral bispirooxindole skeleton (VIII) could be constructed by cascade Michael/Pictet–Spengler reactions between these two classes of isatin-derived substrates in the presence of CPA (Figure 3). However, due to the relatively low reactivity inherent in both the isatins and the resultant azomethine ylides,[17] the construction of this type of structurally more rigid bispirooxindole scaffold is still a great challenge [Eq. (4)].
Nevertheless, the catalytic asymmetric syntheses of tetrahydro-b-carboline scaffolds have been well-established, which mainly include metal-catalyzed or combined metal/organocatalytic tandem reactions,[18a–d] CPA-catalyzed cascades,[18e–k] thiourea-catalyzed transformations,[18l, m] and domino reactions based on iminium/enamine activation.[18n–s] These elegant works will enlighten our investigation on the stereoselective construction of spirotetrahydro-b-carboline bioxindole scaffold. Herein, we report the first catalytic asymmetric construction of a new class of bispirooxindole scaffold incorporated with tetrahydro-b-carboline moiety through CPA-catalyzed threecomponent cascade Michael/ Pictet–Spengler reactions of isatin-derived 3-indolylmethanols, isatins, and amino-ester, which afforded structurally complex and diverse bispirooxindoles with one quaternary and one tetrasubstituted stereogenic center in excellent stereoselectivities (all > 95:5 diastereomeric ratio (d.r.), up to 98:2 enantiomeric ratio (e.r.)).
11383
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper alyst. The subsequent evaluation of solvents (entries 11–17, Table 1) revealed that 1,1,2,2-tetrachloroethane (1,1,2,2-TCE) had the highest capacity of delivering the bispiro-product 7 aaa with high stereoselectivity, albeit in moderate yield (entry 14, Table 1). It should be mentioned that neither DMF as a polar non-protonic solvent nor EtOH as a protonic solvent could deliver the desired product 7 aaa (entries 16 and 17, Table 1). Changing the molecular sieves (MS) from 3 to 4 could greatly improve the yield, but the stereoselectivity was decreased (entry 14 vs. 18, Table 1). Furthermore, a trace amount of the desired product was observed in the absence of MS (entry 19, Table 1), which indicated that MS played an important role in the reaction, mainly by scavenging the water molecules generated from the protonation of 2 a and the condensation of 1 a with 3 a. Elevating the reaction temperature to 65 8C was detrimental to Figure 3. The design of enantioselective cascade reaction leading to the bispirooxindole both yield and stereoselectivity (entry 14 vs. 20, structure. Table 1), but properly lowering the temperature to 25 8C was helpful to the reaction, which provided 7 aaa with the highest stereoselectivity (> 95:5 d.r., 96:4 e.r.) Results and Discussion and in a relatively high yield of 61 % (entry 21, Table 1). With the optimal reaction conditions in hand, we then perOur investigation commenced with a three-component reacformed the diastereo- and enantioselective synthesis of this tion of N-benzylisatin 1 a, N-methyl isatin-derived 3-indolylmenew class of bispirooxindoles 7 with one quaternary and one thanol 2 a, and diethyl 2-aminomalonate 3 a in chloroform at tetrasubstituted stereogenic center. The substrate scope of isa45 8C in the presence of CPA 4 a (10 mol %), which afforded the tins 1 was summarized in Table 2, which showed that this prodesired bispirooxindole 7 aaa but with low yield and poor stetocol was applicable to a variety of isatins, affording structuralreoselectivity (entry 1, Table 1). The screening of BINOL-derived ly diverse bispirooxindoles 7 in high enantioselectivities rangcatalysts 4 a–4 e disclosed that CPA 4 e with bulky 9-phenaning from 91:9 to 97:3 e.r. and good diastereoselectivities of all threnyl group at 3,3’-positions was better than others in terms > 95:5 d.r. of enantioselectivity and yield (entry 5 vs. entries 1–4, Table 1). Firstly, the effect of N-substituents of isatins 1 on the reacHowever, 3,3’-bis(2,4,6-triisopropylphenyl)-1,1’-binaphthyl-2,2’tion was studied (entries 1–11, Table 2). Generally, N-benzyldiylhydrogenphosphate (TRIP)-PA 4 f failed to catalyze the desubstituted isatins 1 a–1 j showed higher capability in enantiosired reaction (entry 6, Table 1) in spite of its excellent perselective control than N-alkyl-substituted ones as exemplified formance in enantioselective Pictet–Spengler reaction.[18e] Furby 1 k (entries 1–10 vs. 11, Table 2). For N-benzyl-substituted thermore, we examined the catalytic activity of commercially isatins, the variation on the substituents of benzyl moiety had available thiourea 5 a as hydrogen bond donor catalyst, belittle effect on the enantioselectivity regardless of their eleccause thiourea catalysts and their combination with HOAc tronic nature (entries 2–10, Table 2), which delivered the decould efficiently catalyze asymmetric transformations leading sired spiro-products in excellent enantioselectivities ranging to chiral tetrahydro-b-carbolines.[18l–m] Nevertheless, thiourea from 95:5 to 97:3 e.r. in most cases. An exception was para5 a could not catalyze our designed tandem reaction, even the bromo-substituted isatin 1 c, which was obviously inferior to condensation of 1 a with 3 a to generate the corresponding others in terms of enantioselectivity (entry 3, Table 2). Besides, imine (entry 7, Table 1). The combination of thiourea 5 a with ortho-methyl-substituted isatin 1 j offered a yield and an e.r. HOAc could catalyze the condensation of 1 a with 3 a to form value higher than its para- and meta-methyl-substituted counthe isatin-derived imine, but the reaction just stopped at this terparts 1 h and 1 i (entries 10 vs. 8 and 9, Table 2), indicating stage and no targeted product 7 aaa was produced (entry 8, Table 1). Moreover, the formation of the isatin-derived imine the position of the substituents linked to the benzyl moiety exmight be largely ascribed to the action of HOAc, since the conerted some influence on the reactivity and enantioselectivity. trol experiment brought out the same results in the absence Then, the impact of the substituents at the phenyl moiety of of thiourea 5 a (entry 9, Table 1). Then, in the presence of isatins 1 on the reaction was investigated. As indicated in BINOL-derived CPA 4 e, increasing the stoichiometry of 3-indoTable 2, entries 12–15, isatins 1 l–1 o with electronically differlylmethanol 2 a could efficiently improve the yield without the ent substituents at position C5, C6, and C7 of the phenyl sacrifice of the stereoselectivity (entry 10, Table 1). When using moiety could be utilized to the tandem reaction in excellent structurally more rigid H8-BINOL-based CPA 6 a as catalyst stereoselectivities. It seemed that the position of the substituents had no obvious effect on the enantioselectivity (entry 12 (entry 11, Table 1), a higher yield with parallel stereoselectivity vs. 14, entry 13 vs. 15, Table 2), but the electronic nature of the was obtained. So, CPA 6 a was chosen as the most suitable catChem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
11384
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper an important hint on the activating mode of CPA to the substrates. Next, the substrate scope of isatin-derived 3-indolylmethanols 2 was investigated. As illustrated in Table 3, this approach was amenable to a series of isatin-derived 3-indolylmethanols 2, providing chiral bispirooxindoles 7 with structural diversity in excellent stereoselectivities (94:6 to 98:2 e.r., all > 95:5 d.r.). Notably, by changing R, R1, and R2 groups at three positions of the substrates 2, this reaction offered significant opportunities for structural diversification of the bispiro-products. It is obvious that Nalkyl, -benzyl, or -phenyl-substituted isatin-derived 3Entry Cat. Solvent Yield d.r.[c] e.r.[d] indolylmethanols 2 a–2 c can smoothly participate in [b] [%] the tandem reaction, and the N-benzyl-substituted 1 4a CHCl3 28 54:46 60:40 one exhibited the highest capacity in enantioselec2 4b CHCl3 28 58:42 63:37 tive control (entry 2 vs. entries 1 and 3, Table 3). Be28 70:30 76:24 3 4c CHCl3 sides, various 3-indolylmethanols 2 d–2 h with differ25 87:13 86:14 4 4d CHCl3 5 4e CHCl3 44 83:17 91:9 ent substituents at either the C5, C6, or C7 position –[e] – – 6 4f CHCl3 of the isatin moiety could be employed to the reacno reaction – – 7 5a CHCl3 tion in generally high enantioselectivity varying from [e] – – – 8 5 a/HOAc CHCl3 95:5 to 98:2 e.r. (entries 4–8, Table 3). Moreover, as 9 HOAc CHCl3 –[e] – – 4e CHCl3 72 88:12 91:9 10[f] exemplified by 3-indolylmethanols 2 i–2 k, variation 6a CHCl3 78 88:12 91:9 11[f] of the substituents on the indole moiety had no ob[f] 6a DCE 28 62:38 84:16 12 vious effect on the stereoselectivity and reactivity, [f] 6a 1,1,2-TCE 75 81:19 92:8 13 leading to the desired bispirooxindoles with one qua6a 1,1,2,2-TCE 52 89:11 95:5 14[f] 6a toluene 26 53:47 75:25 15[f] ternary and one tetrasubstituted stereogenic centers 6a DMF –[e] – – 16[f] in uniformly high stereoselectivities and good yields [f] [e] 6a EtOH – – – 17 (entries 9–11, Table 3). In some examples with low [f,g] 6a 1,1,2,2-TCE 82 82:18 91:9 18 yields, utilizing chloroform as solvent instead of 6a 1,1,2,2-TCE Trace – – 19[f,h] 6a 1,1,2,2-TCE 49 86:14 93:7 20[f,i] 1,1,2,2-TCE efficiently improved the yields again, and 6a 1,1,2,2-TCE 61 > 95:5 96:4 21[f,j] the enantioselectivities were slightly reduced to an [a] Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in solacceptable extent (entries 3, 5, and 6, in parentheses, vent (1 mL) with 3 MS (100 mg) at 45 8C for 24 h, and the ratio of 1 a/2 a/3 a was Table 3). 1.2:1:1. [b] Total yields of two isolated diastereomers. [c] The diastereomeric ratio (d.r.) The absolute configuration of bispirooxindole was determined by HPLC of crude products after purification. [d] The enantiomeric 7 eaa was assigned to be (S,R) by the X-ray structure ratio (e.r.) referred to the major diastereomer 7 aaa and was determined by HPLC. [e] Only isatin-derived imine was generated by the condensation of 1 a with 3 a, but of compound 8 (> 99 % enantiomeric excess (ee) after no desired product 7 aaa was formed. [f] The ratio of 1 a/2 a/3 a was 1.2:1.5:1. [g] 4 recrystallization),[19] which was derived from benzoyMS (100 mg) were used. [h] In the absence of MS. [i] T = 65 8C. [j] T = 25 8C. lation of 7 eaa (Scheme 1). The configurations of other bispirooxindoles 7 were determined by analogy. Therefore, this catalytic asymmetric three-composubstituents affected the enantioselectivity, because 5- and 7nent tandem reaction provides an easy access to a new class methyl isatins delivered higher enantioselectivity than 5- and of chiral bispirooxindole scaffold. These enantioenriched bispir6-chloro isatins (entries 13 and 15 vs. entries 12 and 14, ooxindole products possess the significant structural features Table 2). of incorporating a tetrahydro-b-carboline moiety with a bispirTo further improve the yield, chloroform was employed as ooxindole framework, both of which are core structures of solvent to replace 1,1,2,2-TCE in the cases that resulted in unpharmaceutically important compounds. More importantly, the satisfactory yields (less than or equal to 50 %) such as comstructural diversity and complexity of these chiral bispirooxinpounds 7 caa, 7 gaa, 7 iaa, 7 maa, and 7 naa. In general, the doles will make promising candidates for chemical biology and yields of these compounds were remarkably increased albeit drug discovery. with some erosion of the enantioselectivity (entries 3, 7, 9, 13 Based on the experimental results, together with related and 14, in parentheses, Table 2). studies on CPA-catalyzed reactions,[16a, g, 17] we proposed a possiIt should be noted that when NH isatin 1 p was utilized to ble reaction pathway to explain the stereochemistry of bispirthe cascade reaction, only isatin-derived imine was generated ooxindoles 7 generated from this cascade reaction (Scheme 2). by the condensation of 1 p with 3 a, but no desired spiro-prodUnder the catalysis of CPA 6 a through hydrogen-bonding inuct 7 paa was formed (entry 16, Table 2), which may provide teractions, isatin-derived azomethine ylide 9 initially participated in the Michael addition with the vinyliminium intermediate Table 1. Screening of catalysts and optimization of the reaction conditions.[a]
Chem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
11385
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper Table 2. The substrate scope of isatin.[a]
Entry
7
R/R1
Yield [%][b]
d.r.[c]
e.r.[d]
1 2 3 4 5 6 7
7 aaa 7 baa 7 caa 7 daa 7 eaa 7 faa 7 gaa
Bn/H (1 a) p-FC6H4CH2/H (1 b) p-BrC6H4CH2/H (1 c) p-ClC6H4CH2/H (1 d) m-ClC6H4CH2/H (1 e) m,p-Cl2C6H3CH2/H (1 f) p-tBuC6H4CH2/H (1 g)
61 56 50 (78[e]) 61 57 60 44 (64[e])
> 95:5 > 95:5 > 95:5 (> 95:5[e]) > 95:5 > 95:5 > 95:5 > 95:5 (> 95:5[e])
96:4 95:5 91:9 (88:12[e]) 96:4 95:5 96:4 96:4 (89:11[e])
8 9 10 11 12 13 14 15 16
7 haa 7 iaa 7 jaa 7 kaa 7 laa 7 maa 7 naa 7 oaa 7 paa
p-MeC6H4CH2/H (1 h) m-MeC6H4CH2/H (1 i) o-MeC6H4CH2/H (1 j) Me/H (1 k) Bn/5-Cl (1 l) Bn/5-Me (1 m) Bn/6-Cl (1 n) Bn/7-Me (1 o) H/H (1 p)
52 50 (58[e]) 61 53 53 50 (60[e]) 47 (69[e]) 54 –[f]
> 95:5 > 95:5 (> 95:5[e]) > 95:5 > 95:5 > 95:5 > 95:5 (> 95:5[e]) > 95:5 (> 95:5[e]) > 95:5 –
96:4 96:4 (90:10[e]) 97:3 92:8 94:6 97:3 (94:6[e]) 93:7 (81:19[e]) 97:3 –
[a] Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale catalyzed by 6 a (10 mol %) in 1,1,2,2-TCE (1 mL) with 3 MS (100 mg) for 24 h, and the ratio of 1:2 a/3 a was 1.2:1.5:1. [b] Yields of the isolated products. [c] The diastereomeric ratio (d.r.) was determined by 1H NMR spectroscopy of the crude products after purification. [d] The enantiomeric ratio (e.r.) was determined by HPLC. [e] CHCl3 was used as solvent. [f] Only isatin-derived imine was generated by the condensation of 1 p with 3 a, but no desired product 7 paa was formed.
Table 3. The substrate scope of isatin-derived 3-indolylmethanols.[a]
Entry
7
R/R1/R2
Yield [%][b]
d.r.[c]
e.r.[d]
1 2 3 4 5 6 7[e] 8 9 10 11
7 aaa 7 aba 7 aca 7 ada 7 aea 7 afa 7 aga 7 aha 7 aia 7 aja 7 aka
Me/H/H (2 a) Bn/H/H (2 b) Ph/H/H (2 c) Bn/5-Me/H (2 d) Bn/6-Cl/H (2 e) Bn/6-Br/H (2 f) Bn/7-Me/H (2 g) Me/7-F/H (2 h) Me/H/5’-F (2 i) Me/H/5’-OMe (2 j) Me/H/6’-F (2 k)
61 61 48 (73[e]) 52 40 (91[e]) 47 (73[e]) 54 70 62 72 63
> 95:5 > 95:5 > 95:5 (> 95:5[e]) > 95:5 > 95:5 (> 95:5[e]) > 95:5 (> 95:5[e]) > 95:5 > 95:5 > 95:5 > 95:5 > 95:5
96:4 98:2 95:5 (92:8[e]) 97:3 97:3 (93:7[e]) 98:2 (91:9[e]) 95:5 96:4 94:6 95:5 95:5
[a] Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale catalyzed by 6 a (10 mol %) in 1,1,2,2-TCE (1 mL) with 3 MS (100 mg) for 24 h, and the ratio of 1:2 a/3 a was 1.2:1.5:1. [b] Yield of the isolated products. [c] The diastereomeric ratio (d.r.) was determined by 1H NMR spectroscopy of crude products after purification. [d] The enantiomeric ratio (e.r.) was determined by HPLC. [e] CHCl3 was used as the solvent.
Chem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
11386
10 generated from isatin-derived 3-indolylmethanols 2, affording a transient intermediate 11. Subsequently, this intermediate 11 underwent a Pictet–Spengler reaction facilitated by the same CPA 6 a, to afford the enantioenriched (SR)-bispirooxindoles 7. In our proposed reaction pathway, CPA 6 a simultaneously formed two hydrogen bonds with two types of isatin-derived substrates, which may have largely contributed to the excellent diastereo- and enantioselectivity observed in the formation of bispiro-products 7. To verify our suggested activation mode and gain some insight into the H-bonding interactions between the catalyst CPA 6 a and the two types of isatin-derived intermediates, some control experiments were carried out under the optimized reaction conditions. Firstly, ethanol was employed as a protonic solvent to replace non-protonic 1,1,2,2-TCE. In contrast to the model reaction proceeded in 1,1,2,2-TCE, which afforded the desired spiro-product 7 aaa, the same reaction in ethanol failed to deliver the product 7 aaa but just generated the isatin-derived imine. This result comes from the fact that ethanol as a hydrogen-bonding solvent is apt to create H-bonds with CPA and thereby prevents CPA forming H-bonding interactions with the substrates. This experiment demonstrated that the H-bonding interactions between the catalyst and the substrates played a crucial role in performing the cascade reaction. Secondly, N-methyl-protected 3-indolylmethanol 2 l was utilized as a substrate instead of N-unprotected 3-indolylmethanol 2 a to the reaction (Scheme 3). However, no desired product 7 ala was produced, and only isatin-derived imine was observed during the reaction process. In this case, the N-protected vinyliminium intermediate could not be deprotonated and create a hydrogen-bonding interaction with CPA because of the existence of the N-protective group in the indole moiety, which resulted in the failure of the desired cascade reaction. This phenomenon not only indicated that the N H group in the indole moiety of 3-indolylmethanol was essentially important for deprotonation of the vinyliminium intermediate to generate a H-bond with CPA, but also testified our proposed activation mode that CPA 6 a simultaneously formed two H-bonds with both of the isatin-derived intermediates so as to facilitate the tandem reaction. Finally, as mentioned in Table 2, entry 16, when N H isatin 1 p was used as a substrate to replace N-substituted isatins, no targeted spiro-product 7 paa was generated at all, albeit with the formation of isatinderived imine. This is mainly because N H isatin-derived imine could form two H-bonds with CPA, which would compete with and interrupt the H-bonding interaction between vinyliminium intermediate and CPA. So, this experimental outcome also supported our suggestion that the activating mode of double 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper Conclusion
Scheme 1. The benzoylation of 7 eaa and X-ray structure of compound 8.
Scheme 2. Proposed reaction pathway and activation mode.
H-bonds between CPA and two isatin-derived intermediates led to the observed reactivity and stereoselectivity of the tandem reaction.
We have established the first catalytic asymmetric construction of a new class of chiral bispirooxindole scaffold through CPA-catalyzed three-component cascade Michael/Pictet–Spengler reactions. This intriguing class of chiral bispirooxindoles not only contains one quaternary and one tetrasubstituted stereogenic centers with excellent diastereoand enantioselectivities (all > 95:5 d.r., up to 98:2 e.r.), but also integrated the two structures of tetrahydro-b-carboline and bispirooxindole, both of them possessing significant bioactivities. Besides, this approach combined the merits of asymmetric organocatalysis and multicomponent tandem reaction, which not only efficiently assembled three achiral reagents of isatin-derived 3indolylmethanols, isatins, and amino-ester in a single step to form three new bonds and two chiral centers, but also provided an easy access to a variety of enantioenriched multisubstituted bispirooxindoles with structural complexity and diversity. This new type of chiral bispirooxindoles may find their medicinal applications as new therapeutic agents based on the significant bioactivities of tetrahydro-b-carbolines,[5, 20] and this tandem synthetic methodology may provide a unique strategy for the preparation of structurally rigid bispiro-architectures with concomitant creation of multiple chiral centers.
Experimental Section Typical experimental procedure for the organocatalytic asymmetric synthesis
Scheme 3. Control experiment using N-protected 3-indolylmethanol 2 l as a substrate. Chem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
11387
Bispirooxindole 7 aaa: After a solution of isatin 1 a (0.12 mmol), amino-ester 3 a (0.1 mmol), the catalyst 6 a (0.01 mmol), and 3 molecular sieves (100 mg) in 1,1,2,2-TCE (0.5 mL) was stirred at 25 8C for 30 min, the solution of isatin-derived 3-indolylmethanols 2 a (0.15 mmol) in 1,1,2,2-TCE 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper (0.5 mL) was added. After being stirred at 25 8C for 24 h, the reaction mixture was filtered to remove molecular sieves and the solid powder was washed with ethyl acetate. The resultant solution was concentrated under the reduced pressure to give the residue, which was purified through flash column chromatography on silica gel or preparative thin layer chromatography to afford pure product 7 aaa. Flash column chromatography eluent, petroleum ether/ ethyl acetate = 5:1; Reaction time = 24 h; yield: 61 %; > 95:5 d.r.; yellow sticky oil; enantiomeric ratio: 96:4, determined by HPLC (Daicel Chirapak OD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL min 1, T = 30 8C, 254 nm): tR = 10.04 min (minor), tR = 1 17.44 min (major) [a]20 D = + 232.4 (c 0.25, CHCl3); H NMR (400 MHz, CDCl3): d = 8.27 (d, J = 7.7 Hz, 1 H), 8.16 (d, J = 7.5 Hz, 1 H), 7.54–7.43 (m, 4 H), 7.42–7.31 (m, 3 H), 7.22 (t, J = 7.7 Hz, 1 H), 7.15–7.06 (m, 2 H), 7.04–6.94 (m, 2 H), 6.87 (d, J = 7.8 Hz, 1 H), 6.77 (d, J = 7.6 Hz, 1 H), 6.17 (d, J = 8.1 Hz, 1 H), 5.18 (d, J = 15.2 Hz, 1 H), 4.64 (d, J = 15.3 Hz, 1 H), 4.49–4.39 (m, 1 H), 4.29–4.18 (m, 1 H), 4.03–3.93 (m, 1 H), 3.91–3.81 (m, 1 H), 3.23 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H), 0.87 ppm (t, J = 7.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3) d = 175.3, 175.0, 166.9, 165.9, 144.5, 143.0, 136.5, 136.2, 130.8, 130.4, 130.2, 128.9, 128.7, 128.1, 127.9, 126.5, 125.1, 123.9, 122.9, 122.3, 119.6, 119.5, 111.2, 109.6, 109.0, 107.4, 71.3, 61.9, 61.7, 61.0, 53.6, 44.2, 26.6, 13.8, 13.4 ppm; IR (KBr): n˜ = 3648 3628, 1844, 1792, 1771, 1647, 1557, 1541, 1521, 1456, 798 cm 1; ESI FTMS: m/z calcd for [C39H34N4O6 + Na] + : 677.2371; found: 677.2414.
Acknowledgements We are grateful for financial support from National Natural Science Foundation of China (21372002 and 21232007), Open Foundation of Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials (K201314), PAPD and QingLan Project of Jiangsu Province. Keywords: asymmetric synthesis · bispirooxindoles · enantioselectivity · multicomponent reactions · organocatalysis [1] a) C. V. Galliford, K. A. Scheidt, Angew. Chem. 2007, 119, 8902 – 8912; Angew. Chem. Int. Ed. 2007, 46, 8748 – 8758; b) A. Jossang, P. Jossang, H. A. Hadi, T. Sevenet, B. Bodo, J. Org. Chem. 1991, 56, 6527 – 6530; c) C. B. Cui, H. Kakeya, H. Osada, Tetrahedron 1996, 52, 12651 – 12666. [2] For a recent review, see: G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112, 6104 – 6155. [3] a) M. M.-C. Lo, C. S. Newmann, S. Nagayams, E. O. Perlstein, S. L. Schreiber, J. Am. Chem. Soc. 2005, 127, 10130 – 10131; b) R. Tripathy, A. Reiboldt, P. A. Messina, M. Iqbal, J. Singh, E. R. Bacon, T. S. Angeles, S. X. Yang, M. S. Albom, C. Robinson, H. Chang, B. A. Ruggeri, J. P. Mallamo, Bioorg. Med. Chem. Lett. 2006, 16, 2158 – 2162; c) V. V. Kouznetsov, D. R. M. Arenas, F. Arvelo, J. S. B. Forero, F. Sojo, A. MuÇoz, Lett. Drug Des. Discovery 2010, 7, 632 – 639. [4] G. Kumari, M. Nutan, M. Modi, S. K. Gupta, R. K. Singh, Eur. J. Med. Chem. 2011, 46, 1181 – 1188. [5] a) B. K. S. Yeung, B. Zou, M. Rottmann, S. B. Lakshminarayana, S. H. Ang, S. Y. Leong, J. Tan, J. Wong, S. Keller-Maerki, C. Fischli, A. Goh, E. K. Schmitt, P. Krastel, E. Francotte, K. Kuhen, D. Plouffe, K. Henson, T. Wagner, E. A. Winzeler, F. Petersen, R. Brun, V. Dartois, T. T. Diagana, T. H. Keller, J. Med. Chem. 2010, 53, 5155 – 5164; b) M. Rottmann, C. McNamara, B. K. S. Yeung, M. C. S. Lee, B. Zhou, B. Russell, P. Seitz, D. M. Plouffe, N. V. Dharia, J. Tan, S. B. Cohen, K. R. Spencer, G. E. GonzalezPaez, S. B. Lakshminarayana, A. Goh, R. Suwanarusk, T. Jegla, E. K. Schmitt, H.-P. Beck, R. Brun, F. Nosten, L. Renia, V. Dartois, T. H. Keller, D. A. Fidock, E. A. Winzeler, T. T. Diagana, Science 2010, 329, 1175 – 1180; c) B. Zou, P. Yap, L.-S. Sonntag, S. Y. Leong, B. K. S. Yeung, T. H. Keller, Molecules 2012, 17, 10131 – 10141. Chem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
[6] R. Murugan, S. Anbazhagan, S. S. Narayanan, Eur. J. Med. Chem. 2009, 44, 3272 – 3279. [7] D. Rambabu, G. Raja, B. Y. Sreenivas, G. P. K. Seerapu, K. L. Kumar, G. S. Deora, D. Haldar, M. V. B. Rao, M. Pal, Bioorg. Med. Chem. Lett. 2013, 23, 1351 – 1357. [8] P. Prasanna, K. Balamurugan, S. Perumal, P. Yogeeswari, D. Sriram, Eur. J. Med. Chem. 2010, 45, 5653 – 5661. [9] Y. Kia, H. Osman, R. S. Kumar, V. Murugaiyah, A. Basiri, S. Perumal, H. A. Wahab, C. S. Bing, Bioorg. Med. Chem. Lett. 2013, 21, 1696 – 1707. [10] G. M. Chinigo, M. Paige, S. Grindrod, E. Hamel, S. Dakshanamurthy, M. Chruszcz, W. Minor, M. L. Brown, J. Med. Chem. 2008, 51, 4620 – 4631. [11] For some reviews, see: a) K. Shen, X. Liu, L. Lin, X. Feng, Chem. Sci. 2012, 3, 327 – 334; b) F. Zhou, Y.-L. Liu, J. Zhou, Adv. Synth. Catal. 2010, 352, 1381 – 1470; c) J. E. M. N. Klein, R. J. K. Taylor, Eur. J. Org. Chem. 2011, 6821 – 6841; d) X. W. Dou, Y. X. Lu, Chem. Eur. J. 2012, 18, 8315 – 8319; e) R. Rios, Chem. Soc. Rev. 2012, 41, 1060 – 1074; f) L. Hong, R. Wang, Adv. Synth. Catal. 2013, 355, 1023 – 1052; g) D. Cheng, Y. Ishihara, B. Tan, C. F. Barbas, III, ACS Catal. 2014, 4, 743 – 762. [12] a) B. Tan, N. R. Candeias, C. F. Barbas III, Nat. Chem. 2011, 3, 473 – 477; b) W. Sun, G. Zhu, C. Wu, L. Hong, R. Wang, Chem. Eur. J. 2012, 18, 6737 – 6741; c) W. Sun, L. Hong, G. Zhu, Z. Wang, X. Wei, J. Ni, R. Wang, Org. Lett. 2014, 16, 544 – 547; d) Y.-M. Cao, F.-F. Shen, F.-T. Zhang, R. Wang, Chem. Eur. J. 2013, 19, 1184 – 1188; e) W.-Y. Han, S.-W. Li, Z.-J. Wu, X.-M. Zhang, W.-C. Yuan, Chem. Eur. J. 2013, 19, 5551 – 5556; f) H. Wu, L.L. Zhang, Z.-Q. Tian, Y.-D. Huang, Y.-M. Wang, Chem. Eur. J. 2013, 19, 1747 – 1753; g) F. Tan, H.-G. Cheng, B. Feng, Y.-Q. Zou, S.-W. Duan, J.-R. Chen, W.-J. Xiao, Eur. J. Org. Chem. 2013, 2071 – 2075; h) Y.-L. Liu, X. Wang, Y.-L. Zhao, F. Zhu, X.-P. Zeng, L. Chen, C.-H. Wang, X.-L. Zhao, J. Zhou, Angew. Chem. 2013, 125, 13980 – 13984; Angew. Chem. Int. Ed. 2013, 52, 13735 – 13739; i) A. Noole, M. Osˇeka, T. Pehk, M. eren, I. Jrving, M. R. J. Elsegood, A. V. Malkov, M. Lopp, T. Kanger, Adv. Synth. Catal. 2013, 355, 829 – 835. [13] a) S.-L. Zhu, S.-J. Ji, Z. Yong, Tetrahedron 2007, 63, 9365 – 9372; b) A. H. Abdel-Rahman, E. M. Keshk, M. A. Hanna, S. M. El-Bady, Bioorg. Med. Chem. 2004, 12, 2483 – 2488. [14] For some reviews, see: a) C. J. O’Connor, H. S. G. Beckmann, D. R. Spring, Chem. Soc. Rev. 2012, 41, 4444 – 4456; b) J. E. Biggs-Houck, A. Younai, J. T. Shaw, Curr. Opin. Chem. Biol. 2010, 14, 371 – 382; c) S. Dandapani, L. A. Marcaurelle, Curr. Opin. Chem. Biol. 2010, 14, 362 – 370; d) W. R. J. D. Galloway, A. Bender, M. Welch, D. R. Spring, Chem. Commun. 2009, 2446 – 2462. [15] For early examples: a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. 2004, 116, 1592 – 1594; Angew. Chem. Int. Ed. 2004, 43, 1566 – 1568; b) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356 – 5357; For reviews: c) T. Akiyama, Chem. Rev. 2007, 107, 5744 – 5758; d) M. Terada, Chem. Commun. 2008, 35, 4097 – 4112; e) M. Terada, Synthesis 2010, 1929 – 1982; f) J. Yu, F. Shi, L.-Z. Gong, Acc. Chem. Res. 2011, 44, 1156 – 1171. [16] For enantioselective substitutions of 3-indolylmethanols: a) Q.-X. Guo, Y.-G. Peng, J.-W. Zhang, L. Song, Z. Feng, L.-Z. Gong, Org. Lett. 2009, 11, 4620 – 4623; b) P. G. Cozzi, F. Benfatti, L. Zoli, Angew. Chem. 2009, 121, 1339 – 1342; Angew. Chem. Int. Ed. 2009, 48, 1313 – 1316; c) B. Han, Y.-C. Xiao, Y. Yao, Y.-C. Chen, Angew. Chem. 2010, 122, 10387 – 10389; Angew. Chem. Int. Ed. 2010, 49, 10189 – 10191; d) D.-S. Wang, J. Tang, Y.-G. Zhou, M.-W. Chen, C.-B. Yu, Y. Duan, G.-F. Jiang, Chem. Sci. 2011, 2, 803 – 806; e) J. Xiao, K. Zhao, T.-P. Loh, Chem. Asian J. 2011, 6, 2890 – 2894; f) J. Xiao, Org. Lett. 2012, 14, 1716 – 1719; g) L. Song, Q.-X. Guo, X.-C. Li, J. Tian, Y.-G. Peng, Angew. Chem. 2012, 124, 1935 – 1938; Angew. Chem. Int. Ed. 2012, 51, 1899 – 1902; h) C. Guo, J. Song, J.-Z. Huang, P.-H. Chen, S.W. Luo, L.-Z. Gong, Angew. Chem. 2012, 124, 1070 – 1074; Angew. Chem. Int. Ed. 2012, 51, 1046 – 1050; For enantioselective cyclizations of 3-indolylmethanols: i) B. Xu, Z.-L. Guo, W.-Y. Jin, Z.-P. Wang, Y.-G. Peng, Q.-X. Guo, Angew. Chem. 2012, 124, 1083 – 1086; Angew. Chem. Int. Ed. 2012, 51, 1059 – 1062; j) J. Huang, S. Luo, L. Gong, Acta Chim. Sin. (Engl. Ed.) 2013, 71, 879 – 883; k) F. Shi, R.-Y. Zhu, W. Dai, C.-S. Wang, S.-J. Tu, Chem. Eur. J. 2014, 20, 2597 – 2604. [17] a) F. Shi, Z.-L. Tao, S.-W. Luo, S.-J. Tu, L.-Z. Gong, Chem. Eur. J. 2012, 18, 6885 – 6894; b) F. Shi, R.-Y. Zhu, X. Liang, S.-J. Tu, Adv. Synth. Catal. 2013, 355, 2447 – 2458; c) F. Shi, G.-J. Xing, R.-Y. Zhu, W. Tan, S. Tu, Org. Lett. 2013, 15, 128 – 131; d) F. Shi, W. Tan, R.-Y. Zhu, G.-J. Xing, S.-J. Tu, Adv.
11388
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper Synth. Catal. 2013, 355, 1605 – 1622; e) F. Shi, W. Tan, H.-H. Zhang, M. Li, Q. Ye, G.-H. Ma, S.-J. Tu, G. Li, Adv. Synth. Catal. 2013, 355, 3715 – 3726. [18] For some representative works, see: a) G. Erre, S. Enthaler, K. Junge, D. Addis, M. Beller, Adv. Synth. Catal. 2009, 351, 1437 – 1441; b) C.-X. Zhuo, Q.-F. Wu, Q. Zhao, Q.-L. Xu, S.-L. You, J. Am. Chem. Soc. 2013, 135, 8169 – 8172; c) A. W. Gregory, P. Jakubec, P. Turner, D. J. Dixon, Org. Lett. 2013, 15, 4330 – 4333; d) Y. Liu, Q. Wang, Y. Zhang, J. Huang, L. Nie, J. Chen, W. Cao, X. Wu, J. Org. Chem. 2013, 78, 12009 – 12017; e) J. Seayad, A. M. Seayad, B. List, J. Am. Chem. Soc. 2006, 128, 1086 – 1087; f) N. V. Sewgobind, M. J. Wanner, S. Ingemann, R. de Gelder, J. H. van Maarseveen, H. Hiemstra, J. Org. Chem. 2008, 73, 6405 – 6408; g) M. E. Muratore, C. A. Holloway, A. W. Pilling, R. I. Storer, G. Trevitt, D. J. Dixon, J. Am. Chem. Soc. 2009, 131, 10796 – 10797; h) S. Duce, F. Pesciaioli, L. Gramigna, L. Bernardi, A. Mazzanti, A. Ricci, G. Bartoli, G. Bencivenni, Adv. Synth. Catal. 2011, 353, 860 – 864; i) J. J. Badillo, A. Silva-Garca, B. H. Shupe, J. C. Fettinger, A. K. Franz, Tetrahedron Lett. 2011, 52, 5550 – 5553; j) D. Huang, F. Xu, X. Lin, Y. Wang, Chem. Eur. J. 2012, 18, 3148 – 3152; k) Q. Yin, S.-G. Wang, S.-L. You, Org. Lett. 2013, 15, 2688 – 2691; l) N. S. Rajapaksa, M. A. McGowan, M. Rienzo, E. N. Jacobsen, Org. Lett. 2013, 15, 706 – 709; m) M. P. Lalonde, M. A. McGowan, N. S. Rajapaksa, E. N. Jacobsen, J. Am. Chem. Soc. 2013, 135, 1891 – 1894; n) C.-F. Li, H.
Chem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
Liu, J. Liao, Y.-J. Cao, X.-P. Liu, W.-J. Xiao, Org. Lett. 2007, 9, 1847 – 1850; o) J. Franzn, A. Fisher, Angew. Chem. 2009, 121, 801 – 805; Angew. Chem. Int. Ed. 2009, 48, 787 – 791; p) X.-Y. Wu, X.-Y. Dai, H.-H. Fang, L.-L. Nie, J. Chen, W.-G. Cao, G. Zhao, Chem. Eur. J. 2011, 17, 10510 – 10514; q) H.-L. Zhu, J.-B. Ling, P.-F. Xu, J. Org. Chem. 2012, 77, 7737 – 7743; r) A. Albrecht, F. Morana, A. Fraile, K. A. Jørgensen, Chem. Eur. J. 2012, 18, 10348 – 10354; s) B.-C. Hong, W.-K. Liao, N. S. Dange, J.-H. Liao, Org. Lett. 2013, 15, 468 – 471. [19] CCDC-988428 (7) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. [20] a) J. Garnier, J. Mahuteau, M. Plat, C. Merienne, Phytochemistry 1989, 28, 308 – 309; b) S. P. Hollinshead, M. L. Trudell, P. Skolnick, J. M. Cook, J. Med. Chem. 1990, 33, 1062 – 1069; c) A. Itoh, T. Tanahashi, N. Nagakura, T. Nishi, Phytochemistry 2003, 62, 359 – 369; d) K. W. Bentley, Nat. Prod. Rep. 2004, 21, 395 – 424.
Received: March 5, 2014 Published online on July 23, 2014
11389
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper
& Asymmetric Synthesis
Diastereo- and Enantioselective Construction of a Bispirooxindole Scaffold Containing a Tetrahydro-b-carboline Moiety through an Organocatalytic Asymmetric Cascade Reaction Wei Dai, Han Lu, Xin Li, Feng Shi,* and Shu-Jiang Tu[a]
Abstract: The first catalytic asymmetric construction of a new class of bispirooxindole scaffold-containing tetrahydro-b-carboline moiety has been established through chiral phosphoric acid-catalyzed three-component cascade Michael/Pictet–Spengler reactions of isatin-derived 3-indolylmethanols, isatins, and amino-ester, which afforded structurally complex and diverse bispirooxindoles with one quaternary and one tetrasubstituted stereogenic centers in excellent stereoselectivities (all > 95:5 diastereomeric ratio (d.r.),
Introduction Spirooxindoles are privileged structural motifs that exist in a large family of natural products[1] and synthetic compounds[2] exhibiting versatile bioactivities such as antitumoral,[3] antiHIV,[4] antimalarial,[5] antidiabetic,[6] and as SIRT 1 inhibitors (Figure 1).[7] Especially, as exemplified by compounds I and II, bispirooxindoles fusing two spirooxindole cores into one molecule have shown potent antitubercular activity[8] and found to be cholinesterase inhibitors.[9] The significance of the spirooxindole architecture with regard to medicinal application has led to a great demand for efficient synthetic methods, particularly those producing enantiomerically pure products because the enantiomers may have higher or different bioactivity compared with the racemates in most cases.[5a, 10] Hence, elegant developments have been achieved in the catalytic asymmetric construction of chiral spirooxindole skeleton and many enantioselective approaches have been available [Eq. (1)].[2, 11] However, in sharp contrast, only a few catalytic enantioselective methods have been avail[a] W. Dai,+ H. Lu,+ X. Li, Prof. Dr. F. Shi, Prof. S.-J. Tu School of Chemistry and Chemical Engineering Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University Xuzhou, 221116 (P.R. China) Fax: (+ 86) 516-83500065 E-mail: [email protected] [+] These authors contributed equally to this work. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402485. Chem. Eur. J. 2014, 20, 11382 – 11389
up to 98:2 enantiomeric ratio (e.r.)). This intriguing class of chiral bispirooxindoles integrated the two important structures of tetrahydro-b-carboline and bispirooxindole, both of them possessing significant bioactivities. This approach also combined the merits of asymmetric organocatalysis and multicomponent tandem reaction, which provided a unique strategy for the preparation of structurally rigid bispiro-architectures with concomitant creation of multiple quaternary stereogenic centers.
able to construct optically pure bispirooxindole motif [Eq. (2)].[12] On one hand, bispirooxindoles incorporate two oxindole motifs with other heterocyclic moieties into a type of unique and complex bispiro-structures, which may exhibit combined or enhanced bioactivity of both oxindoles and other heterocy-
cles.[13] Besides, this type of complex structures with multiple substituents provides an easy access to structurally diverse bispirooxindoles, which should be useful in medicinal chemistry and diversity-oriented synthesis (DOS).[14] On the other hand, the stereoselective construction of bispirooxindole motif is very complicated and challenging because of its structurally rigid architecture with at least two quaternary stereogenic centers. Therefore, the diastereo- and enantioselective formation of bispirooxindole framework is highly desirable but challeng11382
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper
Figure 1. Some bioactive natural products and synthetic compounds containing the spirooxindole core.
ing, which requires synthetic design based on specific strategies. Until recently, some organocatalytic asymmetric cascade reactions were developed to construct diastereo- and enantioselective bispirooxindole skeletons III–VI, which contain cyclopentane (III),[12a–c] thiopyrrolidine (IV),[12d–g] dihydrofuran (V),[12h] and cyclopropane (VI)[12i] moieties, respectively (Figure 2). Despite these creative works, the catalytic asymmetric cascade reactions resulting in enantioenriched bispirooxindole motifs are still underdeveloped. Among various spirooxindolines, chiral spiro[oxindoline-tetrahydro-b-carbolines] as exemplified by compound VII have proven to be potent antimalarial drugs (Figure 3).[5] This intriguing class of compounds triggered us to envision that the integration of spiro[oxindole-tetrahydro-b-carboline] moiety with another spiro-oxindole skeleton into a new type of bispirooxindole structure (VIII) may result in improved or important bioactivities. Nevertheless, the chemistry related to the synthesis of this promising structure is still unknown. In recent years, the chiral phosphoric acid (CPA)-catalyzed asymmetric cascade reaction has proven to be a powerful tool to construct complex chiral scaffolds with several stereogenic centers in one step.[15] Besides, isatin-derived 3-indolylmethanols have emerged as efficient Michael acceptors to perform enantioselective substitutions,[16] and isatin-derived azomethine ylides as privileged 1,3-dipole to undergo enantioselective [3 + 2] cycloadditions [Eq. (3)].[17a–b] Encouraged by these achieve-
Figure 2. Limited examples for constructing chiral bispirooxindole skeletons. Chem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
ments and our previous work on CPA-catalyzed asymmetric cascade reactions,[17] we envisaged that this complex chiral bispirooxindole skeleton (VIII) could be constructed by cascade Michael/Pictet–Spengler reactions between these two classes of isatin-derived substrates in the presence of CPA (Figure 3). However, due to the relatively low reactivity inherent in both the isatins and the resultant azomethine ylides,[17] the construction of this type of structurally more rigid bispirooxindole scaffold is still a great challenge [Eq. (4)].
Nevertheless, the catalytic asymmetric syntheses of tetrahydro-b-carboline scaffolds have been well-established, which mainly include metal-catalyzed or combined metal/organocatalytic tandem reactions,[18a–d] CPA-catalyzed cascades,[18e–k] thiourea-catalyzed transformations,[18l, m] and domino reactions based on iminium/enamine activation.[18n–s] These elegant works will enlighten our investigation on the stereoselective construction of spirotetrahydro-b-carboline bioxindole scaffold. Herein, we report the first catalytic asymmetric construction of a new class of bispirooxindole scaffold incorporated with tetrahydro-b-carboline moiety through CPA-catalyzed threecomponent cascade Michael/ Pictet–Spengler reactions of isatin-derived 3-indolylmethanols, isatins, and amino-ester, which afforded structurally complex and diverse bispirooxindoles with one quaternary and one tetrasubstituted stereogenic center in excellent stereoselectivities (all > 95:5 diastereomeric ratio (d.r.), up to 98:2 enantiomeric ratio (e.r.)).
11383
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper alyst. The subsequent evaluation of solvents (entries 11–17, Table 1) revealed that 1,1,2,2-tetrachloroethane (1,1,2,2-TCE) had the highest capacity of delivering the bispiro-product 7 aaa with high stereoselectivity, albeit in moderate yield (entry 14, Table 1). It should be mentioned that neither DMF as a polar non-protonic solvent nor EtOH as a protonic solvent could deliver the desired product 7 aaa (entries 16 and 17, Table 1). Changing the molecular sieves (MS) from 3 to 4 could greatly improve the yield, but the stereoselectivity was decreased (entry 14 vs. 18, Table 1). Furthermore, a trace amount of the desired product was observed in the absence of MS (entry 19, Table 1), which indicated that MS played an important role in the reaction, mainly by scavenging the water molecules generated from the protonation of 2 a and the condensation of 1 a with 3 a. Elevating the reaction temperature to 65 8C was detrimental to Figure 3. The design of enantioselective cascade reaction leading to the bispirooxindole both yield and stereoselectivity (entry 14 vs. 20, structure. Table 1), but properly lowering the temperature to 25 8C was helpful to the reaction, which provided 7 aaa with the highest stereoselectivity (> 95:5 d.r., 96:4 e.r.) Results and Discussion and in a relatively high yield of 61 % (entry 21, Table 1). With the optimal reaction conditions in hand, we then perOur investigation commenced with a three-component reacformed the diastereo- and enantioselective synthesis of this tion of N-benzylisatin 1 a, N-methyl isatin-derived 3-indolylmenew class of bispirooxindoles 7 with one quaternary and one thanol 2 a, and diethyl 2-aminomalonate 3 a in chloroform at tetrasubstituted stereogenic center. The substrate scope of isa45 8C in the presence of CPA 4 a (10 mol %), which afforded the tins 1 was summarized in Table 2, which showed that this prodesired bispirooxindole 7 aaa but with low yield and poor stetocol was applicable to a variety of isatins, affording structuralreoselectivity (entry 1, Table 1). The screening of BINOL-derived ly diverse bispirooxindoles 7 in high enantioselectivities rangcatalysts 4 a–4 e disclosed that CPA 4 e with bulky 9-phenaning from 91:9 to 97:3 e.r. and good diastereoselectivities of all threnyl group at 3,3’-positions was better than others in terms > 95:5 d.r. of enantioselectivity and yield (entry 5 vs. entries 1–4, Table 1). Firstly, the effect of N-substituents of isatins 1 on the reacHowever, 3,3’-bis(2,4,6-triisopropylphenyl)-1,1’-binaphthyl-2,2’tion was studied (entries 1–11, Table 2). Generally, N-benzyldiylhydrogenphosphate (TRIP)-PA 4 f failed to catalyze the desubstituted isatins 1 a–1 j showed higher capability in enantiosired reaction (entry 6, Table 1) in spite of its excellent perselective control than N-alkyl-substituted ones as exemplified formance in enantioselective Pictet–Spengler reaction.[18e] Furby 1 k (entries 1–10 vs. 11, Table 2). For N-benzyl-substituted thermore, we examined the catalytic activity of commercially isatins, the variation on the substituents of benzyl moiety had available thiourea 5 a as hydrogen bond donor catalyst, belittle effect on the enantioselectivity regardless of their eleccause thiourea catalysts and their combination with HOAc tronic nature (entries 2–10, Table 2), which delivered the decould efficiently catalyze asymmetric transformations leading sired spiro-products in excellent enantioselectivities ranging to chiral tetrahydro-b-carbolines.[18l–m] Nevertheless, thiourea from 95:5 to 97:3 e.r. in most cases. An exception was para5 a could not catalyze our designed tandem reaction, even the bromo-substituted isatin 1 c, which was obviously inferior to condensation of 1 a with 3 a to generate the corresponding others in terms of enantioselectivity (entry 3, Table 2). Besides, imine (entry 7, Table 1). The combination of thiourea 5 a with ortho-methyl-substituted isatin 1 j offered a yield and an e.r. HOAc could catalyze the condensation of 1 a with 3 a to form value higher than its para- and meta-methyl-substituted counthe isatin-derived imine, but the reaction just stopped at this terparts 1 h and 1 i (entries 10 vs. 8 and 9, Table 2), indicating stage and no targeted product 7 aaa was produced (entry 8, Table 1). Moreover, the formation of the isatin-derived imine the position of the substituents linked to the benzyl moiety exmight be largely ascribed to the action of HOAc, since the conerted some influence on the reactivity and enantioselectivity. trol experiment brought out the same results in the absence Then, the impact of the substituents at the phenyl moiety of of thiourea 5 a (entry 9, Table 1). Then, in the presence of isatins 1 on the reaction was investigated. As indicated in BINOL-derived CPA 4 e, increasing the stoichiometry of 3-indoTable 2, entries 12–15, isatins 1 l–1 o with electronically differlylmethanol 2 a could efficiently improve the yield without the ent substituents at position C5, C6, and C7 of the phenyl sacrifice of the stereoselectivity (entry 10, Table 1). When using moiety could be utilized to the tandem reaction in excellent structurally more rigid H8-BINOL-based CPA 6 a as catalyst stereoselectivities. It seemed that the position of the substituents had no obvious effect on the enantioselectivity (entry 12 (entry 11, Table 1), a higher yield with parallel stereoselectivity vs. 14, entry 13 vs. 15, Table 2), but the electronic nature of the was obtained. So, CPA 6 a was chosen as the most suitable catChem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
11384
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper an important hint on the activating mode of CPA to the substrates. Next, the substrate scope of isatin-derived 3-indolylmethanols 2 was investigated. As illustrated in Table 3, this approach was amenable to a series of isatin-derived 3-indolylmethanols 2, providing chiral bispirooxindoles 7 with structural diversity in excellent stereoselectivities (94:6 to 98:2 e.r., all > 95:5 d.r.). Notably, by changing R, R1, and R2 groups at three positions of the substrates 2, this reaction offered significant opportunities for structural diversification of the bispiro-products. It is obvious that Nalkyl, -benzyl, or -phenyl-substituted isatin-derived 3Entry Cat. Solvent Yield d.r.[c] e.r.[d] indolylmethanols 2 a–2 c can smoothly participate in [b] [%] the tandem reaction, and the N-benzyl-substituted 1 4a CHCl3 28 54:46 60:40 one exhibited the highest capacity in enantioselec2 4b CHCl3 28 58:42 63:37 tive control (entry 2 vs. entries 1 and 3, Table 3). Be28 70:30 76:24 3 4c CHCl3 sides, various 3-indolylmethanols 2 d–2 h with differ25 87:13 86:14 4 4d CHCl3 5 4e CHCl3 44 83:17 91:9 ent substituents at either the C5, C6, or C7 position –[e] – – 6 4f CHCl3 of the isatin moiety could be employed to the reacno reaction – – 7 5a CHCl3 tion in generally high enantioselectivity varying from [e] – – – 8 5 a/HOAc CHCl3 95:5 to 98:2 e.r. (entries 4–8, Table 3). Moreover, as 9 HOAc CHCl3 –[e] – – 4e CHCl3 72 88:12 91:9 10[f] exemplified by 3-indolylmethanols 2 i–2 k, variation 6a CHCl3 78 88:12 91:9 11[f] of the substituents on the indole moiety had no ob[f] 6a DCE 28 62:38 84:16 12 vious effect on the stereoselectivity and reactivity, [f] 6a 1,1,2-TCE 75 81:19 92:8 13 leading to the desired bispirooxindoles with one qua6a 1,1,2,2-TCE 52 89:11 95:5 14[f] 6a toluene 26 53:47 75:25 15[f] ternary and one tetrasubstituted stereogenic centers 6a DMF –[e] – – 16[f] in uniformly high stereoselectivities and good yields [f] [e] 6a EtOH – – – 17 (entries 9–11, Table 3). In some examples with low [f,g] 6a 1,1,2,2-TCE 82 82:18 91:9 18 yields, utilizing chloroform as solvent instead of 6a 1,1,2,2-TCE Trace – – 19[f,h] 6a 1,1,2,2-TCE 49 86:14 93:7 20[f,i] 1,1,2,2-TCE efficiently improved the yields again, and 6a 1,1,2,2-TCE 61 > 95:5 96:4 21[f,j] the enantioselectivities were slightly reduced to an [a] Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in solacceptable extent (entries 3, 5, and 6, in parentheses, vent (1 mL) with 3 MS (100 mg) at 45 8C for 24 h, and the ratio of 1 a/2 a/3 a was Table 3). 1.2:1:1. [b] Total yields of two isolated diastereomers. [c] The diastereomeric ratio (d.r.) The absolute configuration of bispirooxindole was determined by HPLC of crude products after purification. [d] The enantiomeric 7 eaa was assigned to be (S,R) by the X-ray structure ratio (e.r.) referred to the major diastereomer 7 aaa and was determined by HPLC. [e] Only isatin-derived imine was generated by the condensation of 1 a with 3 a, but of compound 8 (> 99 % enantiomeric excess (ee) after no desired product 7 aaa was formed. [f] The ratio of 1 a/2 a/3 a was 1.2:1.5:1. [g] 4 recrystallization),[19] which was derived from benzoyMS (100 mg) were used. [h] In the absence of MS. [i] T = 65 8C. [j] T = 25 8C. lation of 7 eaa (Scheme 1). The configurations of other bispirooxindoles 7 were determined by analogy. Therefore, this catalytic asymmetric three-composubstituents affected the enantioselectivity, because 5- and 7nent tandem reaction provides an easy access to a new class methyl isatins delivered higher enantioselectivity than 5- and of chiral bispirooxindole scaffold. These enantioenriched bispir6-chloro isatins (entries 13 and 15 vs. entries 12 and 14, ooxindole products possess the significant structural features Table 2). of incorporating a tetrahydro-b-carboline moiety with a bispirTo further improve the yield, chloroform was employed as ooxindole framework, both of which are core structures of solvent to replace 1,1,2,2-TCE in the cases that resulted in unpharmaceutically important compounds. More importantly, the satisfactory yields (less than or equal to 50 %) such as comstructural diversity and complexity of these chiral bispirooxinpounds 7 caa, 7 gaa, 7 iaa, 7 maa, and 7 naa. In general, the doles will make promising candidates for chemical biology and yields of these compounds were remarkably increased albeit drug discovery. with some erosion of the enantioselectivity (entries 3, 7, 9, 13 Based on the experimental results, together with related and 14, in parentheses, Table 2). studies on CPA-catalyzed reactions,[16a, g, 17] we proposed a possiIt should be noted that when NH isatin 1 p was utilized to ble reaction pathway to explain the stereochemistry of bispirthe cascade reaction, only isatin-derived imine was generated ooxindoles 7 generated from this cascade reaction (Scheme 2). by the condensation of 1 p with 3 a, but no desired spiro-prodUnder the catalysis of CPA 6 a through hydrogen-bonding inuct 7 paa was formed (entry 16, Table 2), which may provide teractions, isatin-derived azomethine ylide 9 initially participated in the Michael addition with the vinyliminium intermediate Table 1. Screening of catalysts and optimization of the reaction conditions.[a]
Chem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
11385
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper Table 2. The substrate scope of isatin.[a]
Entry
7
R/R1
Yield [%][b]
d.r.[c]
e.r.[d]
1 2 3 4 5 6 7
7 aaa 7 baa 7 caa 7 daa 7 eaa 7 faa 7 gaa
Bn/H (1 a) p-FC6H4CH2/H (1 b) p-BrC6H4CH2/H (1 c) p-ClC6H4CH2/H (1 d) m-ClC6H4CH2/H (1 e) m,p-Cl2C6H3CH2/H (1 f) p-tBuC6H4CH2/H (1 g)
61 56 50 (78[e]) 61 57 60 44 (64[e])
> 95:5 > 95:5 > 95:5 (> 95:5[e]) > 95:5 > 95:5 > 95:5 > 95:5 (> 95:5[e])
96:4 95:5 91:9 (88:12[e]) 96:4 95:5 96:4 96:4 (89:11[e])
8 9 10 11 12 13 14 15 16
7 haa 7 iaa 7 jaa 7 kaa 7 laa 7 maa 7 naa 7 oaa 7 paa
p-MeC6H4CH2/H (1 h) m-MeC6H4CH2/H (1 i) o-MeC6H4CH2/H (1 j) Me/H (1 k) Bn/5-Cl (1 l) Bn/5-Me (1 m) Bn/6-Cl (1 n) Bn/7-Me (1 o) H/H (1 p)
52 50 (58[e]) 61 53 53 50 (60[e]) 47 (69[e]) 54 –[f]
> 95:5 > 95:5 (> 95:5[e]) > 95:5 > 95:5 > 95:5 > 95:5 (> 95:5[e]) > 95:5 (> 95:5[e]) > 95:5 –
96:4 96:4 (90:10[e]) 97:3 92:8 94:6 97:3 (94:6[e]) 93:7 (81:19[e]) 97:3 –
[a] Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale catalyzed by 6 a (10 mol %) in 1,1,2,2-TCE (1 mL) with 3 MS (100 mg) for 24 h, and the ratio of 1:2 a/3 a was 1.2:1.5:1. [b] Yields of the isolated products. [c] The diastereomeric ratio (d.r.) was determined by 1H NMR spectroscopy of the crude products after purification. [d] The enantiomeric ratio (e.r.) was determined by HPLC. [e] CHCl3 was used as solvent. [f] Only isatin-derived imine was generated by the condensation of 1 p with 3 a, but no desired product 7 paa was formed.
Table 3. The substrate scope of isatin-derived 3-indolylmethanols.[a]
Entry
7
R/R1/R2
Yield [%][b]
d.r.[c]
e.r.[d]
1 2 3 4 5 6 7[e] 8 9 10 11
7 aaa 7 aba 7 aca 7 ada 7 aea 7 afa 7 aga 7 aha 7 aia 7 aja 7 aka
Me/H/H (2 a) Bn/H/H (2 b) Ph/H/H (2 c) Bn/5-Me/H (2 d) Bn/6-Cl/H (2 e) Bn/6-Br/H (2 f) Bn/7-Me/H (2 g) Me/7-F/H (2 h) Me/H/5’-F (2 i) Me/H/5’-OMe (2 j) Me/H/6’-F (2 k)
61 61 48 (73[e]) 52 40 (91[e]) 47 (73[e]) 54 70 62 72 63
> 95:5 > 95:5 > 95:5 (> 95:5[e]) > 95:5 > 95:5 (> 95:5[e]) > 95:5 (> 95:5[e]) > 95:5 > 95:5 > 95:5 > 95:5 > 95:5
96:4 98:2 95:5 (92:8[e]) 97:3 97:3 (93:7[e]) 98:2 (91:9[e]) 95:5 96:4 94:6 95:5 95:5
[a] Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale catalyzed by 6 a (10 mol %) in 1,1,2,2-TCE (1 mL) with 3 MS (100 mg) for 24 h, and the ratio of 1:2 a/3 a was 1.2:1.5:1. [b] Yield of the isolated products. [c] The diastereomeric ratio (d.r.) was determined by 1H NMR spectroscopy of crude products after purification. [d] The enantiomeric ratio (e.r.) was determined by HPLC. [e] CHCl3 was used as the solvent.
Chem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
11386
10 generated from isatin-derived 3-indolylmethanols 2, affording a transient intermediate 11. Subsequently, this intermediate 11 underwent a Pictet–Spengler reaction facilitated by the same CPA 6 a, to afford the enantioenriched (SR)-bispirooxindoles 7. In our proposed reaction pathway, CPA 6 a simultaneously formed two hydrogen bonds with two types of isatin-derived substrates, which may have largely contributed to the excellent diastereo- and enantioselectivity observed in the formation of bispiro-products 7. To verify our suggested activation mode and gain some insight into the H-bonding interactions between the catalyst CPA 6 a and the two types of isatin-derived intermediates, some control experiments were carried out under the optimized reaction conditions. Firstly, ethanol was employed as a protonic solvent to replace non-protonic 1,1,2,2-TCE. In contrast to the model reaction proceeded in 1,1,2,2-TCE, which afforded the desired spiro-product 7 aaa, the same reaction in ethanol failed to deliver the product 7 aaa but just generated the isatin-derived imine. This result comes from the fact that ethanol as a hydrogen-bonding solvent is apt to create H-bonds with CPA and thereby prevents CPA forming H-bonding interactions with the substrates. This experiment demonstrated that the H-bonding interactions between the catalyst and the substrates played a crucial role in performing the cascade reaction. Secondly, N-methyl-protected 3-indolylmethanol 2 l was utilized as a substrate instead of N-unprotected 3-indolylmethanol 2 a to the reaction (Scheme 3). However, no desired product 7 ala was produced, and only isatin-derived imine was observed during the reaction process. In this case, the N-protected vinyliminium intermediate could not be deprotonated and create a hydrogen-bonding interaction with CPA because of the existence of the N-protective group in the indole moiety, which resulted in the failure of the desired cascade reaction. This phenomenon not only indicated that the N H group in the indole moiety of 3-indolylmethanol was essentially important for deprotonation of the vinyliminium intermediate to generate a H-bond with CPA, but also testified our proposed activation mode that CPA 6 a simultaneously formed two H-bonds with both of the isatin-derived intermediates so as to facilitate the tandem reaction. Finally, as mentioned in Table 2, entry 16, when N H isatin 1 p was used as a substrate to replace N-substituted isatins, no targeted spiro-product 7 paa was generated at all, albeit with the formation of isatinderived imine. This is mainly because N H isatin-derived imine could form two H-bonds with CPA, which would compete with and interrupt the H-bonding interaction between vinyliminium intermediate and CPA. So, this experimental outcome also supported our suggestion that the activating mode of double 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper Conclusion
Scheme 1. The benzoylation of 7 eaa and X-ray structure of compound 8.
Scheme 2. Proposed reaction pathway and activation mode.
H-bonds between CPA and two isatin-derived intermediates led to the observed reactivity and stereoselectivity of the tandem reaction.
We have established the first catalytic asymmetric construction of a new class of chiral bispirooxindole scaffold through CPA-catalyzed three-component cascade Michael/Pictet–Spengler reactions. This intriguing class of chiral bispirooxindoles not only contains one quaternary and one tetrasubstituted stereogenic centers with excellent diastereoand enantioselectivities (all > 95:5 d.r., up to 98:2 e.r.), but also integrated the two structures of tetrahydro-b-carboline and bispirooxindole, both of them possessing significant bioactivities. Besides, this approach combined the merits of asymmetric organocatalysis and multicomponent tandem reaction, which not only efficiently assembled three achiral reagents of isatin-derived 3indolylmethanols, isatins, and amino-ester in a single step to form three new bonds and two chiral centers, but also provided an easy access to a variety of enantioenriched multisubstituted bispirooxindoles with structural complexity and diversity. This new type of chiral bispirooxindoles may find their medicinal applications as new therapeutic agents based on the significant bioactivities of tetrahydro-b-carbolines,[5, 20] and this tandem synthetic methodology may provide a unique strategy for the preparation of structurally rigid bispiro-architectures with concomitant creation of multiple chiral centers.
Experimental Section Typical experimental procedure for the organocatalytic asymmetric synthesis
Scheme 3. Control experiment using N-protected 3-indolylmethanol 2 l as a substrate. Chem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
11387
Bispirooxindole 7 aaa: After a solution of isatin 1 a (0.12 mmol), amino-ester 3 a (0.1 mmol), the catalyst 6 a (0.01 mmol), and 3 molecular sieves (100 mg) in 1,1,2,2-TCE (0.5 mL) was stirred at 25 8C for 30 min, the solution of isatin-derived 3-indolylmethanols 2 a (0.15 mmol) in 1,1,2,2-TCE 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper (0.5 mL) was added. After being stirred at 25 8C for 24 h, the reaction mixture was filtered to remove molecular sieves and the solid powder was washed with ethyl acetate. The resultant solution was concentrated under the reduced pressure to give the residue, which was purified through flash column chromatography on silica gel or preparative thin layer chromatography to afford pure product 7 aaa. Flash column chromatography eluent, petroleum ether/ ethyl acetate = 5:1; Reaction time = 24 h; yield: 61 %; > 95:5 d.r.; yellow sticky oil; enantiomeric ratio: 96:4, determined by HPLC (Daicel Chirapak OD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL min 1, T = 30 8C, 254 nm): tR = 10.04 min (minor), tR = 1 17.44 min (major) [a]20 D = + 232.4 (c 0.25, CHCl3); H NMR (400 MHz, CDCl3): d = 8.27 (d, J = 7.7 Hz, 1 H), 8.16 (d, J = 7.5 Hz, 1 H), 7.54–7.43 (m, 4 H), 7.42–7.31 (m, 3 H), 7.22 (t, J = 7.7 Hz, 1 H), 7.15–7.06 (m, 2 H), 7.04–6.94 (m, 2 H), 6.87 (d, J = 7.8 Hz, 1 H), 6.77 (d, J = 7.6 Hz, 1 H), 6.17 (d, J = 8.1 Hz, 1 H), 5.18 (d, J = 15.2 Hz, 1 H), 4.64 (d, J = 15.3 Hz, 1 H), 4.49–4.39 (m, 1 H), 4.29–4.18 (m, 1 H), 4.03–3.93 (m, 1 H), 3.91–3.81 (m, 1 H), 3.23 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H), 0.87 ppm (t, J = 7.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3) d = 175.3, 175.0, 166.9, 165.9, 144.5, 143.0, 136.5, 136.2, 130.8, 130.4, 130.2, 128.9, 128.7, 128.1, 127.9, 126.5, 125.1, 123.9, 122.9, 122.3, 119.6, 119.5, 111.2, 109.6, 109.0, 107.4, 71.3, 61.9, 61.7, 61.0, 53.6, 44.2, 26.6, 13.8, 13.4 ppm; IR (KBr): n˜ = 3648 3628, 1844, 1792, 1771, 1647, 1557, 1541, 1521, 1456, 798 cm 1; ESI FTMS: m/z calcd for [C39H34N4O6 + Na] + : 677.2371; found: 677.2414.
Acknowledgements We are grateful for financial support from National Natural Science Foundation of China (21372002 and 21232007), Open Foundation of Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials (K201314), PAPD and QingLan Project of Jiangsu Province. Keywords: asymmetric synthesis · bispirooxindoles · enantioselectivity · multicomponent reactions · organocatalysis [1] a) C. V. Galliford, K. A. Scheidt, Angew. Chem. 2007, 119, 8902 – 8912; Angew. Chem. Int. Ed. 2007, 46, 8748 – 8758; b) A. Jossang, P. Jossang, H. A. Hadi, T. Sevenet, B. Bodo, J. Org. Chem. 1991, 56, 6527 – 6530; c) C. B. Cui, H. Kakeya, H. Osada, Tetrahedron 1996, 52, 12651 – 12666. [2] For a recent review, see: G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112, 6104 – 6155. [3] a) M. M.-C. Lo, C. S. Newmann, S. Nagayams, E. O. Perlstein, S. L. Schreiber, J. Am. Chem. Soc. 2005, 127, 10130 – 10131; b) R. Tripathy, A. Reiboldt, P. A. Messina, M. Iqbal, J. Singh, E. R. Bacon, T. S. Angeles, S. X. Yang, M. S. Albom, C. Robinson, H. Chang, B. A. Ruggeri, J. P. Mallamo, Bioorg. Med. Chem. Lett. 2006, 16, 2158 – 2162; c) V. V. Kouznetsov, D. R. M. Arenas, F. Arvelo, J. S. B. Forero, F. Sojo, A. MuÇoz, Lett. Drug Des. Discovery 2010, 7, 632 – 639. [4] G. Kumari, M. Nutan, M. Modi, S. K. Gupta, R. K. Singh, Eur. J. Med. Chem. 2011, 46, 1181 – 1188. [5] a) B. K. S. Yeung, B. Zou, M. Rottmann, S. B. Lakshminarayana, S. H. Ang, S. Y. Leong, J. Tan, J. Wong, S. Keller-Maerki, C. Fischli, A. Goh, E. K. Schmitt, P. Krastel, E. Francotte, K. Kuhen, D. Plouffe, K. Henson, T. Wagner, E. A. Winzeler, F. Petersen, R. Brun, V. Dartois, T. T. Diagana, T. H. Keller, J. Med. Chem. 2010, 53, 5155 – 5164; b) M. Rottmann, C. McNamara, B. K. S. Yeung, M. C. S. Lee, B. Zhou, B. Russell, P. Seitz, D. M. Plouffe, N. V. Dharia, J. Tan, S. B. Cohen, K. R. Spencer, G. E. GonzalezPaez, S. B. Lakshminarayana, A. Goh, R. Suwanarusk, T. Jegla, E. K. Schmitt, H.-P. Beck, R. Brun, F. Nosten, L. Renia, V. Dartois, T. H. Keller, D. A. Fidock, E. A. Winzeler, T. T. Diagana, Science 2010, 329, 1175 – 1180; c) B. Zou, P. Yap, L.-S. Sonntag, S. Y. Leong, B. K. S. Yeung, T. H. Keller, Molecules 2012, 17, 10131 – 10141. Chem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
[6] R. Murugan, S. Anbazhagan, S. S. Narayanan, Eur. J. Med. Chem. 2009, 44, 3272 – 3279. [7] D. Rambabu, G. Raja, B. Y. Sreenivas, G. P. K. Seerapu, K. L. Kumar, G. S. Deora, D. Haldar, M. V. B. Rao, M. Pal, Bioorg. Med. Chem. Lett. 2013, 23, 1351 – 1357. [8] P. Prasanna, K. Balamurugan, S. Perumal, P. Yogeeswari, D. Sriram, Eur. J. Med. Chem. 2010, 45, 5653 – 5661. [9] Y. Kia, H. Osman, R. S. Kumar, V. Murugaiyah, A. Basiri, S. Perumal, H. A. Wahab, C. S. Bing, Bioorg. Med. Chem. Lett. 2013, 21, 1696 – 1707. [10] G. M. Chinigo, M. Paige, S. Grindrod, E. Hamel, S. Dakshanamurthy, M. Chruszcz, W. Minor, M. L. Brown, J. Med. Chem. 2008, 51, 4620 – 4631. [11] For some reviews, see: a) K. Shen, X. Liu, L. Lin, X. Feng, Chem. Sci. 2012, 3, 327 – 334; b) F. Zhou, Y.-L. Liu, J. Zhou, Adv. Synth. Catal. 2010, 352, 1381 – 1470; c) J. E. M. N. Klein, R. J. K. Taylor, Eur. J. Org. Chem. 2011, 6821 – 6841; d) X. W. Dou, Y. X. Lu, Chem. Eur. J. 2012, 18, 8315 – 8319; e) R. Rios, Chem. Soc. Rev. 2012, 41, 1060 – 1074; f) L. Hong, R. Wang, Adv. Synth. Catal. 2013, 355, 1023 – 1052; g) D. Cheng, Y. Ishihara, B. Tan, C. F. Barbas, III, ACS Catal. 2014, 4, 743 – 762. [12] a) B. Tan, N. R. Candeias, C. F. Barbas III, Nat. Chem. 2011, 3, 473 – 477; b) W. Sun, G. Zhu, C. Wu, L. Hong, R. Wang, Chem. Eur. J. 2012, 18, 6737 – 6741; c) W. Sun, L. Hong, G. Zhu, Z. Wang, X. Wei, J. Ni, R. Wang, Org. Lett. 2014, 16, 544 – 547; d) Y.-M. Cao, F.-F. Shen, F.-T. Zhang, R. Wang, Chem. Eur. J. 2013, 19, 1184 – 1188; e) W.-Y. Han, S.-W. Li, Z.-J. Wu, X.-M. Zhang, W.-C. Yuan, Chem. Eur. J. 2013, 19, 5551 – 5556; f) H. Wu, L.L. Zhang, Z.-Q. Tian, Y.-D. Huang, Y.-M. Wang, Chem. Eur. J. 2013, 19, 1747 – 1753; g) F. Tan, H.-G. Cheng, B. Feng, Y.-Q. Zou, S.-W. Duan, J.-R. Chen, W.-J. Xiao, Eur. J. Org. Chem. 2013, 2071 – 2075; h) Y.-L. Liu, X. Wang, Y.-L. Zhao, F. Zhu, X.-P. Zeng, L. Chen, C.-H. Wang, X.-L. Zhao, J. Zhou, Angew. Chem. 2013, 125, 13980 – 13984; Angew. Chem. Int. Ed. 2013, 52, 13735 – 13739; i) A. Noole, M. Osˇeka, T. Pehk, M. eren, I. Jrving, M. R. J. Elsegood, A. V. Malkov, M. Lopp, T. Kanger, Adv. Synth. Catal. 2013, 355, 829 – 835. [13] a) S.-L. Zhu, S.-J. Ji, Z. Yong, Tetrahedron 2007, 63, 9365 – 9372; b) A. H. Abdel-Rahman, E. M. Keshk, M. A. Hanna, S. M. El-Bady, Bioorg. Med. Chem. 2004, 12, 2483 – 2488. [14] For some reviews, see: a) C. J. O’Connor, H. S. G. Beckmann, D. R. Spring, Chem. Soc. Rev. 2012, 41, 4444 – 4456; b) J. E. Biggs-Houck, A. Younai, J. T. Shaw, Curr. Opin. Chem. Biol. 2010, 14, 371 – 382; c) S. Dandapani, L. A. Marcaurelle, Curr. Opin. Chem. Biol. 2010, 14, 362 – 370; d) W. R. J. D. Galloway, A. Bender, M. Welch, D. R. Spring, Chem. Commun. 2009, 2446 – 2462. [15] For early examples: a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. 2004, 116, 1592 – 1594; Angew. Chem. Int. Ed. 2004, 43, 1566 – 1568; b) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356 – 5357; For reviews: c) T. Akiyama, Chem. Rev. 2007, 107, 5744 – 5758; d) M. Terada, Chem. Commun. 2008, 35, 4097 – 4112; e) M. Terada, Synthesis 2010, 1929 – 1982; f) J. Yu, F. Shi, L.-Z. Gong, Acc. Chem. Res. 2011, 44, 1156 – 1171. [16] For enantioselective substitutions of 3-indolylmethanols: a) Q.-X. Guo, Y.-G. Peng, J.-W. Zhang, L. Song, Z. Feng, L.-Z. Gong, Org. Lett. 2009, 11, 4620 – 4623; b) P. G. Cozzi, F. Benfatti, L. Zoli, Angew. Chem. 2009, 121, 1339 – 1342; Angew. Chem. Int. Ed. 2009, 48, 1313 – 1316; c) B. Han, Y.-C. Xiao, Y. Yao, Y.-C. Chen, Angew. Chem. 2010, 122, 10387 – 10389; Angew. Chem. Int. Ed. 2010, 49, 10189 – 10191; d) D.-S. Wang, J. Tang, Y.-G. Zhou, M.-W. Chen, C.-B. Yu, Y. Duan, G.-F. Jiang, Chem. Sci. 2011, 2, 803 – 806; e) J. Xiao, K. Zhao, T.-P. Loh, Chem. Asian J. 2011, 6, 2890 – 2894; f) J. Xiao, Org. Lett. 2012, 14, 1716 – 1719; g) L. Song, Q.-X. Guo, X.-C. Li, J. Tian, Y.-G. Peng, Angew. Chem. 2012, 124, 1935 – 1938; Angew. Chem. Int. Ed. 2012, 51, 1899 – 1902; h) C. Guo, J. Song, J.-Z. Huang, P.-H. Chen, S.W. Luo, L.-Z. Gong, Angew. Chem. 2012, 124, 1070 – 1074; Angew. Chem. Int. Ed. 2012, 51, 1046 – 1050; For enantioselective cyclizations of 3-indolylmethanols: i) B. Xu, Z.-L. Guo, W.-Y. Jin, Z.-P. Wang, Y.-G. Peng, Q.-X. Guo, Angew. Chem. 2012, 124, 1083 – 1086; Angew. Chem. Int. Ed. 2012, 51, 1059 – 1062; j) J. Huang, S. Luo, L. Gong, Acta Chim. Sin. (Engl. Ed.) 2013, 71, 879 – 883; k) F. Shi, R.-Y. Zhu, W. Dai, C.-S. Wang, S.-J. Tu, Chem. Eur. J. 2014, 20, 2597 – 2604. [17] a) F. Shi, Z.-L. Tao, S.-W. Luo, S.-J. Tu, L.-Z. Gong, Chem. Eur. J. 2012, 18, 6885 – 6894; b) F. Shi, R.-Y. Zhu, X. Liang, S.-J. Tu, Adv. Synth. Catal. 2013, 355, 2447 – 2458; c) F. Shi, G.-J. Xing, R.-Y. Zhu, W. Tan, S. Tu, Org. Lett. 2013, 15, 128 – 131; d) F. Shi, W. Tan, R.-Y. Zhu, G.-J. Xing, S.-J. Tu, Adv.
11388
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper Synth. Catal. 2013, 355, 1605 – 1622; e) F. Shi, W. Tan, H.-H. Zhang, M. Li, Q. Ye, G.-H. Ma, S.-J. Tu, G. Li, Adv. Synth. Catal. 2013, 355, 3715 – 3726. [18] For some representative works, see: a) G. Erre, S. Enthaler, K. Junge, D. Addis, M. Beller, Adv. Synth. Catal. 2009, 351, 1437 – 1441; b) C.-X. Zhuo, Q.-F. Wu, Q. Zhao, Q.-L. Xu, S.-L. You, J. Am. Chem. Soc. 2013, 135, 8169 – 8172; c) A. W. Gregory, P. Jakubec, P. Turner, D. J. Dixon, Org. Lett. 2013, 15, 4330 – 4333; d) Y. Liu, Q. Wang, Y. Zhang, J. Huang, L. Nie, J. Chen, W. Cao, X. Wu, J. Org. Chem. 2013, 78, 12009 – 12017; e) J. Seayad, A. M. Seayad, B. List, J. Am. Chem. Soc. 2006, 128, 1086 – 1087; f) N. V. Sewgobind, M. J. Wanner, S. Ingemann, R. de Gelder, J. H. van Maarseveen, H. Hiemstra, J. Org. Chem. 2008, 73, 6405 – 6408; g) M. E. Muratore, C. A. Holloway, A. W. Pilling, R. I. Storer, G. Trevitt, D. J. Dixon, J. Am. Chem. Soc. 2009, 131, 10796 – 10797; h) S. Duce, F. Pesciaioli, L. Gramigna, L. Bernardi, A. Mazzanti, A. Ricci, G. Bartoli, G. Bencivenni, Adv. Synth. Catal. 2011, 353, 860 – 864; i) J. J. Badillo, A. Silva-Garca, B. H. Shupe, J. C. Fettinger, A. K. Franz, Tetrahedron Lett. 2011, 52, 5550 – 5553; j) D. Huang, F. Xu, X. Lin, Y. Wang, Chem. Eur. J. 2012, 18, 3148 – 3152; k) Q. Yin, S.-G. Wang, S.-L. You, Org. Lett. 2013, 15, 2688 – 2691; l) N. S. Rajapaksa, M. A. McGowan, M. Rienzo, E. N. Jacobsen, Org. Lett. 2013, 15, 706 – 709; m) M. P. Lalonde, M. A. McGowan, N. S. Rajapaksa, E. N. Jacobsen, J. Am. Chem. Soc. 2013, 135, 1891 – 1894; n) C.-F. Li, H.
Chem. Eur. J. 2014, 20, 11382 – 11389
www.chemeurj.org
Liu, J. Liao, Y.-J. Cao, X.-P. Liu, W.-J. Xiao, Org. Lett. 2007, 9, 1847 – 1850; o) J. Franzn, A. Fisher, Angew. Chem. 2009, 121, 801 – 805; Angew. Chem. Int. Ed. 2009, 48, 787 – 791; p) X.-Y. Wu, X.-Y. Dai, H.-H. Fang, L.-L. Nie, J. Chen, W.-G. Cao, G. Zhao, Chem. Eur. J. 2011, 17, 10510 – 10514; q) H.-L. Zhu, J.-B. Ling, P.-F. Xu, J. Org. Chem. 2012, 77, 7737 – 7743; r) A. Albrecht, F. Morana, A. Fraile, K. A. Jørgensen, Chem. Eur. J. 2012, 18, 10348 – 10354; s) B.-C. Hong, W.-K. Liao, N. S. Dange, J.-H. Liao, Org. Lett. 2013, 15, 468 – 471. [19] CCDC-988428 (7) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. [20] a) J. Garnier, J. Mahuteau, M. Plat, C. Merienne, Phytochemistry 1989, 28, 308 – 309; b) S. P. Hollinshead, M. L. Trudell, P. Skolnick, J. M. Cook, J. Med. Chem. 1990, 33, 1062 – 1069; c) A. Itoh, T. Tanahashi, N. Nagakura, T. Nishi, Phytochemistry 2003, 62, 359 – 369; d) K. W. Bentley, Nat. Prod. Rep. 2004, 21, 395 – 424.
Received: March 5, 2014 Published online on July 23, 2014
11389
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
