Thiourea-Catalyzed Enantioselective Malonate Addition onto 3

Letter Cite This: Org. Lett. 2018, 20, 6327−6331

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Thiourea-Catalyzed Enantioselective Malonate Addition onto 3‑Sulfonyl-3′-indolyl-2-oxindoles: Formal Total Syntheses of (−)-Chimonanthine, (−)-Folicanthine, and (+)-Calycanthine K. Naresh Babu, Avishek Roy, Manvendra Singh, and Alakesh Bisai* Department of Chemistry, IISER Bhopal, Bhopal Bypass Road, Bhauri, Bhopal 462 066, Madhya Pradesh, India

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S Supporting Information *

ABSTRACT: A general approach to bispyrroloindolines via a key thiourea-catalyzed addition of malonates to 3-sulfonyl-3′indolyl-2-oxindoles is reported. The enantioselelective process is found to be highly effective (up to 94% ee), where a C−C bond formation leads to the synthesis of a number of 2-oxindoles with an all-carbon quaternary stereocenter.

D

a wide range of cyclotryptamine alkaloids. In this communication, we report thiourea-catalyzed enantioselective addition of malonate to 3-sulfonyl-3′-indolyl-2-oxindoles for a targetoriented synthesis of bistryptamine alkaloids. Our retrosynthetic strategy to synthesize the core structure of 1a,b is shown in Scheme 1. We envisioned that Overman

imeric cyclotryptamine alkaloids (1 and 2, Figure 1) sharing vicinal all-carbon quaternary stereocenters,1,2 with

Scheme 1. Retrosynthetic Analysis of 1 and Our Hypothesis Figure 1. Selected biscyclotryptamine alkaloids 1 and 2.

a labile C3a−C3a′ σ-bond (Figure 1), remain one of the most fascinating targets that continues to attract tremendous synthetic interest.3 Owing to their impressive biological activities4 in addition to intriguing architecture, a number of elegant total syntheses have been disclosed to date.5−9 Toward these targets, Overman’s elegant dialkylation5 and sequenatial Heck cyclizations for the bisaldehyde 3a intermediate6 and Movassaghi’s Co(I)-promoted reductive dimerization reactions7−9 have been explored to establish the vicinal all-carbon quaternary stereocenters. From 2012 onward, catalytic asymmetric approaches have been reported to address the synthesis of vicinal all-carbon quaternary stereocenters.10−15 These include Gong’s enecarbamate addition onto 3-hydroxy 2-oxindole,10a Zhang’s indole addition onto isatylidene-3-acetaldehyde,11a Kanai and Matsunaga’s Michael reaction of bisoxindole with nitroethylene,11b Pd-catalyzed decarboxylative allylations independently by Trost12 and our group,13 and a recent Cu(II)-catalyzed malonate addition by us.14 Despite these elegant reports, there is a strong need to develop a catalytic enantioselective method under “transition-metal-free” conditions, which allows access to © 2018 American Chemical Society

aldehyde 3a, which is an advanced intermediate for the total synthesis of 1a−c and 2, could be obtained from compound 4, which in turn could be accessed from a catalytic enantioselective malonate addition onto 3-(3′-indolyl)-3-sulfonyl-2-oxindole 5. It was envisioned that removal of sulfinate can be triggered by catalytic thiourea to generate indol-2-ones 6.15,16 With the above hypothesis, it was decided to use 3-indolyl-2oxindoles with 3′-functionalized with a leaving group such as 3hydroxy (7a), 3-methoxy (7b), and 3-sulfonyl (5a) groups. At the outset, we carried out the reaction using 1 equiv of 7a and 7b independently with dimethyl malonate 8a (3 equiv) in 1.5 mL of toluene at 25 °C in the presence of 10 mol % of thiourea17,18 L1 with 1.2 equiv of K2CO3, however, without any success (Table 1, entries 1 and 2). Interestingly, changing the substrate from 7a,b Received: July 24, 2018 Published: October 9, 2018 6327

DOI: 10.1021/acs.orglett.8b02327 Org. Lett. 2018, 20, 6327−6331

Letter

Organic Letters Table 1. Optimization of Enantioselective Malonate Addition

entrya

7a,b, 5a

8a−f

solvent

base

time (h)

yield %b (4a−f)

% ee (4a−f)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17e 18f 19g 20 21 22

7a 7b 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a

8a 8a 8a 8b 8c 8d 8e 8f 8d 8d 8d 8d 8d 8d 8d 8d 8d 8d 8d 8d 8d 8d

PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe 1,4-dioxan CH2Cl2 (CH2Cl)2 CHCl3 PhMe PhMe PhMe PhMe PhMe PhMe

K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 Na2CO3 Cs2CO3 DBU K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4

34 30 28 32 28 29 28 28 27 25 30 25 30 28 31 29 34 36 20 35 35 34

-- (4a) -- (4a) 64 (4a) 68 (4b) 67 (4c) 72 (4d) 73 (4e) 70 (4f) 78 (4d) 83 (4d) 54 (4d) 85 (4d) 60 (4d) 69 (4d) 60 (4d) 63 (4d) 54 (4d) 23 (4d) 67 (4d) 36 (4d) 59 (4d) 15 (4d)

NDd NDd 21 25 34 86 38 60 74 28 32 94 15 35 51 47 66 NDd 82 84 56 NDd

a

Reactions were carried out using 0.04 mmol of 5 or 7 (1 equiv) with 0.12 mmol of dialkylmalonate 8 (3 equiv) in 1.5 mL of toluene at room temperature under argon conditions. bIsolated yields after column chromatography. cEnantioselectivities were determined using chiral HPLC. d Enantioselectivity not determined. eAt 0 °C. fAt −10 °C. gAt 40 °C.

to 5a furnished product 4a in 64% yield with 21% ee in 28 h (entry 3).10b Among various malonates tested (8a−d), dibenzyl malonate afforded product 4d in 72% yield with 86% ee in 29 h (entry 6). The high enantioselectivity arises probably through a stabilizing π−π interaction between the aromatic ring-sharing electronwithdrawing group of the substrate with that of dibenzyl malonate in the transition state during the course of this reaction. On the other hand, a drop in enantioselectivity was also observed in the reaction of electronegative groups on the 4position of the phenyl ring of dibenzyl malonate, which can weaken the π−π interaction with the substrate (entries 7 and 8).18 Among various bases (entries 8−12), potassium phosphate was found to be superior, which afforded 4d in 85% yield (25 h) with 94% ee (entry 12). Among various solvents screened (entries 12−16), the reaction is efficient in toluene (entry 12) to afford a high yield of 4d with better enantioselectivity (94% ee). Further, decreasing the temperature of reaction affects the yields as well as enantioselectivity (entries 17 and 18). The same observation was made at higher temperature, as well (entry 19).

Among various catalysts, it was observed that the cinchoninederived thiourea L2 afforded product 4d in 68% yield (22 h) with 83% ee (Scheme 2). Cinchonidine-derived thiourea L3 afforded product 4d in 79% yield (26 h) with −82% ee, whereas quinine-derived thiourea L4 afforded product 4d in 81% yield (25 h) with −92% ee. Gratifyingly, we observed that 94% ee of (+)-4d could be achieved by performing the reaction using L1 (quinidine-derived thiourea) catalyst in toluene at rt (Scheme 2). It was also found that other catalysts (L5−L10) are not suitable for the malonate addition reaction. Under the optimized condition [0.04 mmol of 5 (1 equiv), 10 mol % of L1 (0.004 mmol), 1.1 equiv of K3PO4 (0.044 mmol), and 3.0 equiv of dibenzyl malonate (0.12 mmol) in toluene], we tested the substrate scope using various N-substituted electrophiles19 (Scheme 3) to afford 4d,g−k in good yield and enantiomeric excess. Further, we have utilized 3-(3′-indolyl)-3sulfonyl-2-oxindole substrates 5 having different functional groups on the aromatic ring of indole and 2-oxindoles. As shown in Scheme 3, our optimized conditions could be extended to a variety of 3-(3′-indolyl)-3-sulfonyl-2-oxindoles of type 5 with functionalization on both scaffolds, namely, 2-oxindole as well as 6328


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Organic Letters Scheme 2. Optimization of Malonate Addition onto 5aa,b

Scheme 3. Substrate Scope Using Various N-Substituted Electrophilesa,b

a

Reactions were carried out using 0.04 mmol of 5 (1 equiv) with 0.12 mmol of dialkylmalonate 8d (3 equiv) in 1.5 mL of toluene at room temperature under argon conditions. bIsolated yields after column chromatography.

the indole part of 5. As a result, a wide range of 3-(3′-indolyl)-3malonyl-2-oxindoles bearing all-carbon quaternary centers at the pseudobenzylic position are obtained in good to excellent enantioselectivities with high yields (4m−s; Scheme 3). Surprisingly, it was observed that reactivity and enantioselectivity decreased in case of N,N-unprotected 3-indolyl-3-sulfonyl-2oxindole 5g and N-methylindole substrate 5o with dibenzyl malonate addition under standard conditions (Scheme 4, 4l and 4t). A plausible rationale of organocatalyzed activation of 3sulfonyl-3′-indolyl-2-oxindole (5a) with malonate is shown in Figure 2. Thiourea catalyst can activate 5a in the presence of potassium phosphate base to form a planar intermediate 2-Hindol-2-one 6 by removal of 1 equiv of p-toluenesulfinate. There are two forms of intermediate 6, that is, 6a and 6b (6b stabilized by electron-rich indole at the 3-position of 2-oxindole). Malonate can be activated by thiourea catalyst via H-bonding.18a At the same time, intermediates 6a,b will be activated through H-bonding by a protonated quinuclidine moiety20,21 (Figure 2). Therefore, an organized transition state will emerge from these stabilizing interactions. At this stage, the enolate form of dibenzyl malonate can react with intermediates 6a,b from the above face, leading to the formation of (R)-4. After successful synthesis of various enantioenriched oxindoles, we proceeded to apply the method for enantioselective synthesis of dimeric cyclotryptamine alkaloids sharing vicinal all-carbon quaternary stereocenters. Thus, we began with 2-oxindole malonate adduct 4d (94% ee) and 4g (92% ee) (Scheme 5). Toward this end, we carried out Krapcho debenzylative decarboxylation of one of the benzyl esters’ functionality with LiCl at increased temperature to form 10a,b in 85−90% yields, which was alkylated using methyl iodide and benzyl bromide to 11a,b in 84−90% yields (Scheme 5). Later, the indole functionality of 11a was converted to 2-oxindole by reaction with DMSO (HCl) in AcOH at 50 °C to form 12a in

a

Reactions were carried out using 0.04 mmol of 5 (1 equiv) with 0.12 mmol of dialkylmalonate 4d (3 equiv) in 1.5 mL of toluene at room temperature under argon conditions. bIsolated yields after column chromatography.

Scheme 4. Malonate Addition on N,N-Unprotected and Protected 3-Indolyl-3-sulfonyl-2-oxindole

86% yield with ∼1.66:1 dr. However, a similar reaction with 11b was unsuccessful. Therefore, compound 11b was converted to 11c by trans-esterification using ethyl bromide in DMSO in the presence of NaH. Compounds 11a and 11c were reacted with DMSO (HCl) in AcOH at 50 °C to form 12a,b in 79−86% yield with ∼1.25:1 dr. At this stage, C-alkylation of 2-oxindoles of 12a,b with bromoethyl acetate afforded bisesters 13a,b in 78− 82% yields with >20:1 dr (Scheme 5). Later, bisesters 13a,b were reduced with LiBH4 to form C2symmetric diols 14a,b in 79−82% yields. As the total synthesis of 1b is known from C2-symmetric diol 14a, our effort culminated in the formal total synthesis of (−)-folicanthine 1b.13b The absolute configuration of the stereogenic center in compound 4d was determined to be R on the basis of optical 6329


Letter

Organic Letters

indolyl-2-oxindoles 5 followed by an enantioselective malonate addition. Utilizing the aforementioned methodology, we have shown the formal total syntheses of (−)-chimonanthine (1a), (−)-folicanthine (1b), and (+)-calycanthine (1c). Further investigation on synthetic applications of our method is currently underway.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02327. Experimental procedures, spectroscopic data for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

Figure 2. Stereochemistry rationale.

*E-mail: [email protected].

Scheme 5. Formal Total Synthesis of (−)-1a, (−)-1b, and (+)-1c

ORCID

Alakesh Bisai: 0000-0001-5295-9756 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the DST [EMR/2016/000214], CSIR [02(0295)/17/EMR-II], and MoES [09-DS/11/2018-PC-IV], Govt. of India, is gratefully acknowledged. K.N.B. thanks the CSIR for SRF. A.R. and M.S. thank IISER Bhopal for research fellowships.

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DEDICATION This work is dedicated to Professor Javed Iqbal, Chairman & Founder, Cosmic Discoveries Pvt. Ltd., Hyderabad, India. REFERENCES

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Thiourea-Catalyzed Enantioselective Malonate Addition onto 3

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