Letter Cite This: Org. Lett. 2017, 19, 6626−6629
pubs.acs.org/OrgLett
Organo-Catalyzed Asymmetric Michael−Hemiketalization−OxaPictet−Spengler Cyclization for Bridged and Spiro Heterocyclic Skeletons: Oxocarbenium Ion as a Key Intermediate Wei-Tai Fan,† Nai-Kai Li,† Lumei Xu,‡ Chunhua Qiao,*,‡ and Xing-Wang Wang*,† †
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, and College of Pharmaceutical Science, Soochow University, Suzhou 215123, People’s Republic of China
‡
S Supporting Information *
ABSTRACT: A Michael−hemiketalization−oxa-Pictet−Spengler cyclization has been developed for the construction of chiral bridged and spiro heterocyclic skeletons with one spiro stereogenic carbon center and two bridgehead carbon centers, utilizing cooperative catalysts of a Takemoto thiourea catalyst and a triflimide. In particular, an oxocarbenium ion acts as a key intermediate for this cyclization reaction. Additionally, biological evaluation of this type of novel structure has revealed obvious antiproliferative activity against some cancer cell lines.
P
bear one tetrasubstituted spiro stereogenic carbon center and two bridgehead carbon centers from 3-pyrrolyloxindoles and (E)-2-hydroxyaryl-2-oxobut-3-enoates, which is performed well by a multicatalyst directed tandem reaction process.13 Oxocarbenium ions are the key intermediates in various synthetically important transformations. Among the relevant reports, isomerization of enol ethers,14 metal-mediated cyclization of alkynols or alkynylaryl ketones,15 oxidation of cyclic or acyclic benzyl ethers,16 and dehydration or dealkyloxylation of hemiacetals and acetals17 constituted the most widely used strategies for the generation of oxocarbenium ions. In view of these reports, rationally designed, desired molecules containing electron-rich arenes and precursors of oxocarbenium ions might undergo inter- or intramolecular oxa-Pictet−Spengler reactions.18 3-Pyrrolyloxindoles, directly containing pyrrolyl at the C-3 position of the oxindole motif, have been successfully used as Michael donors reacting with diverse electrophiles.19 We envision that (E)-2-hydroxyaryl-2-oxobut-3-enoates20 could probably react with 3-pyrrolyloxindoles via organocatalytic asymmetric Michael addition to produce a chiral Michael adduct bearing pyrrolyl, phenolic hydroxyl, and ketone ester groups. Subsequently, followed by sequential formation of the hemiketal and the oxocarbenium ion under Brønsted acid catalysis, facile oxa-Pictet−Spengler cyclization reaction18a could be practically carried out to furnish enantiomerically enriched multifunctionally poly-heterocyclic compounds with bridged and spiro heterocyclic skeletons.21
oly-heterocyclic compounds have occupied a central role in the annals of alkaloids, steroids, terpenoids, pesticides, pharmaceuticals, fine chemicals, as well as ligands or organocatalysts, which display a diverse set of biological activities and functionalizations (Figure 1).1 Some of the most therapeutically
Figure 1. Representative poly-heterocyclic compounds.
useful drugs are, in fact, N,O-heterocycles with intricate polycyclic frameworks.2 Thus, new synthetic methods are important for the construction of highly substituted polyheterocyclic compounds with a defined configuration, selectivity as well as efficiency.3 Among them, the synthesis of bridged or spiro heterocycles that possess all quaternary carbon centers is always a challenging research area.4 It has been primarily addressed by nucleophilic addition,5 photoinduced electron transfer,6 intramolecular Baylis−Hillman reaction,7 Diels−Alder reaction,8 cycloadditions and condensations,9 rearrangement,10 dearomatization,11 as well as multicomponent and domino reactions.12 Despite the myriad approaches afforded by these reactions, few synthetic methods that produce bridged and spiro heterocycles structures were developed by using acyclic precursors. Herein, we report the organo-catalyzed enantioselective synthesis of bridged and spiro heterocyclic skeletons that © 2017 American Chemical Society
Received: October 26, 2017 Published: December 1, 2017 6626
DOI: 10.1021/acs.orglett.7b03341 Org. Lett. 2017, 19, 6626−6629
Letter
Organic Letters The feasibility of this proposed reaction was valuated between salicylaldehyde-derived (E)-2-hydroxyaryl-2-oxobut-3-enoate 1a and 3-pyrrolyloxindole 2a by the use of a series of bifunctional organocatalysts I−IX and chiral guanidine catalyst X in TBME. After the first step, the isolated intermediates were directly treated with 20 mol % of triflimide (Tf2NH) in toluene for sequential transformations. As shown in Table 1, with Takemoto thiourea VI as the catalyst,22 the reaction proceeded smoothly and gave the desired Michael−oxa-Pictet−Spengler reaction product 3aa in 65% yield with 97% ee and >20:1 dr, which were optimal catalytic results in comparison with other catalysts (entry 6 vs entries 1−5 and 7−10). Then this reaction was investigated
by the use of VI and Tf2NH as successive catalysts in several other reaction media. All reactions proceeded smoothly, affording the desired product 3aa with similar catalytic results in EtOAc, Et2O, and THF (entries 11−13 vs entry 6). In comparison, relatively lower yields were obtained with dichloromethane, CH3CN, EtOH, and aromatic reaction media (entries 14−19). When the catalyst loading was decreased to 5 mol %, the desired product 3aa was obtained in 65% yield with >20:1 dr and 94% ee (entry 20 vs entry 6). Finally, several Brønsted acids including p-TsOH, PhCOOH, and CF3COOH were tested, but no improved results were observed (entry 21). With the optimal reaction conditions in hand (Table 1, entry 6), we proceeded to investigate the utility of this reaction, and the results are summarized in Scheme 1. First, the substrates 1b−e
Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Substrate Scope of 1a
entry
cat.
solvent
yieldb (%)
drc
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20e 21f
I II III IV V VI VII VIII IX X VI VI VI VI VI VI VI VI VI VI VI
TBME TBME TBME TBME TBME TBME TBME TBME TBME TBME Et2O THF EtOAc CH2Cl2 CH3CN EtOH toluene PhF PhCF3 TBME TBME
32 51 62 59 60 65 40 trace 47 NR 64 58 60 20 36 41 16 42 46 65 trace
>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1
55 78d 65 65 62d 97 56
>20:1 ->20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1
77d = 94 89 90 88 86 86 89 89 83 94
a
Unless otherwise noted, reaction conditions as for entry 6 in Table 1.
without any substituents or bearing a methyl or methoxyl group at the C-3 or C-4 position on the benzene ring were tested. The corresponding products 3ab−ae were isolated in moderate yields (52−67%) with good enantioselectivities (73−89%) under the optimal conditions. Then, substrates 1f−h containing an electron-donating (−Me, −tBu) or electron-withdrawing group (−NO2, −Br) at the C-3 or C-5 position on the benzene ring were also investigated, and the desired products 3af−ai were obtained in 61−76% yields with 84−96% ee. Furthermore, no desired product was detected for the substrate 1j bearing a 3,5-ditert-butyl group. Finally, methyl (E)-4-(5-chloro-2-hydroxyphenyl)-2-oxobut-3-enoate 1k was employed for this transformation under the identical reaction conditions, giving the desired product 3ak in 78% yield with 93% ee. To further test the substrate scope, we investigated the reactions of substrates 3-pyrrolyloxindoles 2 bearing various substituents with 1a, and the catalytic results are summarized in Scheme 2. The corresponding N-protected or N-unprotected substrates 2b−d (−H, −Allyl, −MOM) all gave the desired products 3ba−da in high yields with good to excellent stereoselectivities. We next investigated the substrates 2e−o bearing various substituents (−Me, −OMe, −F, −Cl, −-Br, or −I) at the 4-, 5-, 6-, or 7-positions of the oxindolyl rings, and the substrates showed good tolerance and gave the desired products 3ea−oa in 36−75% yields with >20:1 dr and 81−99% ee.
a
Unless otherwise noted, reactions were carried out with 1a (0.15 mmol), 2a (0.1 mmol), and cat. (10 mol %) in corresponding solvents (1 mL) at 25 °C for 12 h. After the first reaction step, the intermediate was isolated by flash chromatography on silica gel and then treated with Tf2NH (20 mol %) in toluene (1 mL) at 25 °C for 12 h. bIsolated yield. cDetermined by chiral HPLC. dent-3aa was obtained. eVI (5 mol %) was used. fScreening other Brønsted acids: including p-TsOH, PhCOOH, and CF3COOH. 6627
DOI: 10.1021/acs.orglett.7b03341 Org. Lett. 2017, 19, 6626−6629
Letter
Organic Letters Scheme 2. Substrate Scope of 2a
Scheme 4. Proposed Mechanistic Pathway
(Scheme 5). Then, treating the product 3aa with methylamine in ethanol yielded the aminolysis product 4aa in 95% yield with Scheme 5. Scale up and Further Transformations
a
Unless otherwise noted, reaction conditions as for entry 6 in Table 1.
Additionally, we also investigated the substrates of 2p−r bearing monosubstituents (−F, −Cl, −CF3) at the 7-positions of the oxindolyl rings. The desired products 3pa−ra were obtained in high yields with moderate to good enantioselectivities. Finally, we were fortunate to obtain single crystals of compound 3aa from EtOAc, which unambiguously confirmed that the absolute configuration of this compound was (3S,6′R,12′R) by X-ray crystallographic analysis (Scheme 2). With regard to the mechanism, the pure hemiketal IIad was carefully isolated, which was determined by spectroscopic analysis (Scheme 3). Thus, we propose that both 1 and 2 are
retained stereoselectivity (Scheme 5). Additionally, monobromination of 3aa was successfully performed, and the desided product 5aa was obtained in 85% yield (Scheme 5). In summary, we have developed an asymmetric Michael− hemiketalization−oxa-Pictet−Spengler cyclization reaction of 3pyrrolyloxindoles and (E)-2-hydroxyaryl-2-oxobut-3-enoates. A series of optically active bridged and spiro heterocyclic skeletons that bear one tetrasubstituted spiro stereogenic carbon center and two bridgehead carbon centers were obtained in high yields with excellent diastereoselectivities and enantioselectivities. In addition, biological evaluation of this type of novel structure has revealed obvious antiproliferative activity against some cancer cell lines. Salient features of the present protocol include high stereoselectivity, cheap and readily available substrate and catalyst, mild reaction conditions, simple manipulation, and facile chemical transformations.
Scheme 3. Verification of the Reaction Intermediates
activated by a bifunctional tertiary amine-thiourea organocatalyst to control the stereoselectivity. (E)-2-Hydroxyaryl-2-oxobut-3enoates 1 are first attacked by nucleophilically deprotonted 3pyrrolyloxindoles, leading to Michael adduct I. The phenolic hydroxyl subsequently undertakes intramolecular nucleophilic attack on the keto-carbonyl group to give hemiketal intermediate II. Under Brønsted acid assistance, oxocarbenium ion is produced via dehydration of the hemiketal, followed by the nucleophilic C-2 attack of pyrrolyl to give oxa-Pictet−Spengler cyclic product 3 (Scheme 4). To demonstrate the potential of this method for preparative purposes, we investigated the reaction of 3-pyrrolyloxindole 2a and (E)-2-hydroxyaryl-2-oxobut-3-enoates 1a on a gram scale
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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.7b03341. Experimental details, compound characterization, and Xray crystallographic data for 3aa (PDF) 6628
DOI: 10.1021/acs.orglett.7b03341 Org. Lett. 2017, 19, 6626−6629
Letter
Organic Letters Accession Codes
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CCDC 1539271 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Xing-Wang Wang: 0000-0002-6004-8458 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (21572150) and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
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DOI: 10.1021/acs.orglett.7b03341 Org. Lett. 2017, 19, 6626−6629
