Chiral Phosphoric Acid-Cocatalyzed Enantioselective Synthesis

Letter Cite This: Org. Lett. 2018, 20, 4531−4535

pubs.acs.org/OrgLett

Rh(II)/Chiral Phosphoric Acid-Cocatalyzed Enantioselective Synthesis of Spirooxindole-Fused Thiaindans Guolan Xiao,† Tiantian Chen,† Chaoqun Ma,† Dong Xing,*,† and Wenhao Hu*,†,‡ †

Shanghai Engineering Research Centre of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China ‡ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China

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S Supporting Information *

ABSTRACT: An asymmetric strategy for the construction of chiral sulfur-containing spirooxindole-fused heterocycles was achieved via a rhodium(II)/chiral phosphoric acid-cocatalyzed reaction between 2-mercaptophenyl ketones and 3diazooxindoles. With this method, a series of spirooxindolethiaindan derivatives bearing two contiguous quaternary carbon stereogenic centers were obtained in high yields with high diastereoselectivities and high-to-excellent enantioselectivities. Michael/Michael cascade reaction between α,β-unsaturated ester-tethered oxindole and cinnamaldehyde to give spirooxindole-fused tetrahydrothiopyrans, which showed novel p53MDM2 inhibiting abilities.5c The same group later developed catalytic asymmetric Michael/Henry and Michael/aldol cascade approaches for the construction of similar spirooxindole-fused sulfur-containing six-membered heterocycles.6f,5d Arai and co-workers reported a PyBidine-Ni(II)-catalyzed asymmetric tandem Michael/aldol reaction of methyleneindolinones with thiosalicylaldehydes to obtain spirooxindole-fused thiochromanes.6g In light of the high potential of chiral spirooxindole-fused sulfur-containing heterocycles in drug discovery, efficient catalytic asymmetric approaches for the rapid construction of such heterocycles with different structural patterns are still in great demand. Our research group has been devoted to the development of metal carbene-involved asymmetric multicomponent reactions (MCRs) via electrophilic trapping of in situ-generated active ylide intermediates, which constituted a powerful protocol for the rapid construction of complex molecular architectures.9−11 Recently, we reported a catalytic asymmetric MCR based on a Mannich-type trapping of in situ-generated sulfonium ylides with imines to synthesize polyfunctional sulfur-containing compounds.12 As part of our continuous research efforts in developing stereoselective MCRs to produce complicated heterocycles with potential biological activities, we devised a strategy starting from 3-diazooxindole and another single substrate possessing both a sulfonium ylide precursor and a suitable electrophilic trapping unit. We envisioned that an intramolecular electrophilic trapping of the sulfonium ylide intermediate generated from 3-diazooxindole under Rh(II) catalysis would result in the formation of spirooxindole-fused

S

ulfur is an important element in a variety of biological systems.1 Owing to its ubiquitous incorporating ability with proteins and other biomolecules, sulfur-containing organic compounds have been widely used in medicinal chemistry and drug design.2 For example, more than one-fifth of the top 200 most-prescribed drugs in 2011 were sulfurcontaining compounds.3 On the other hand, spirooxindole scaffolds belong to a large family of biologically active natural and unnatural compounds, which show significant biological activities.4 As a consequence, spirooxindole-fused sulfurcontaining hetereocycles, which possess both the sulfur element and spirooxindole skeleton, have been a highly promising structural motif pursued from both the medicinal and synthetic communities.5,6 Among a large number of organo- and organometallic catalytic asymmetric approaches for the stereoselective construction of spirooxindole-fused heterocycles,7,8 successful asymmetric syntheses of such sulfur-containing molecules are relatively limited. For the construction of chiral spirooxindolefused sulfur-containing 5-membered heterocycles, Xiao’s group first reported a Michael/aldol cascade reaction between 1,4dithiane-2,5-diol and 3-alkenyloxindoles to synthesize spirooxindole-fused tetrahydrothiophenes using an organo-Cinchonabased squaramide catalyst.6a Feng and co-workers further applied a chiral N,N′-dioxide-nickel(II) catalytic system to the same transformation.6b Zhao and co-workers developed an organocatalyzed thia-Michael/Michael tandem sequence for the asymmetric synthesis of spirooxindole-fused tetrahydrothiophenes.6d Li and co-workers developed an organocatalyzed [3 + 2] approach between 1,3-dithiane-2,5-diol and isatinederived ketimines to construct chiral spirooxindole-fused 4thiazolidinones.6e A number of catalytic asymmetric approaches for the synthesis of spirrooxindole-fused sulfurcontaining six-membered heterocycles have also been developed. Sheng and co-workers reported an organocatalyzed © 2018 American Chemical Society

Received: June 12, 2018 Published: July 25, 2018 4531

DOI: 10.1021/acs.orglett.8b01833 Org. Lett. 2018, 20, 4531−4535

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opportunity for catalytic asymmetric control. A set of substituted chiral PPAs were utilized as the cooperative catalysts for this transformation.13 Among them, (R)-3,3′bis(triphenylsilyl)-BINOL phosphoric acid (R)-4e was optimal, producing the desired product 3a in 93% yield with 93:7 dr and 86% ee (Table 1, entries 3−6). By choosing (R)-4e as the chiral catalyst, further optimizations were conducted. Reducing the reaction temperature to 0 °C improved both the yield and enantioselectivity of desired product 3a (95% yield; 92:8 dr; 96% ee) (Table 1, entry 7). Changing the solvent from CH2Cl2 to other halogenated solvents such as 1,2dichloroethane (DCE) or CHCl3 caused slightly decreased yields and diastereoselectivities of the desired product (Table 1, entries 8 and 9). Using toluene as the solvent resulted in a very low yield of the desired product, and no product formation was observed when THF was used as the solvent (Table 1, entries 10 and 11). With the optimized conditions in hand (Table 1, entry 7), the substrate scope of this transformation was investigated. A series of substituted N-benzyl 3-diazooxindoles were first evaluated. N-Benzyl 3-diazooxindoles bearing either electrondonating or -withdrawing groups at the 5-position of the aromatic ring all worked well, generating the corresponding cyclization products in high yields with good stereoselectivities (Scheme 2, 3a−f). Substrate 2g bearing the Cl atom at the 7position gave the corresponding cyclization product 3g in good yield and stereoselectivity. N-Methyl-substituted 3-diazooxindole also proved to be efficient, producing the desired product in high yield with good diastereoselectivity and enantioselectivity (Scheme 2, 3h). Different substituted 2-mercaptophenyl ketones were then tested. It appeared that both electron-deficient and -donating substituents on the aryl ring could be tolerated, producing corresponding spirooxindole-fused thiaindans in high yields and good stereoselectivities (Scheme 2, 3i−l). When 1-(2mercaptophenyl)pentan-1-one 2m was used as the substrate, the desired cyclization product 3m was obtained in high yield and excellent stereoselectivity. When 2-mercaptobenzaldehyde 2n instead of the ketone substrate was used, the corresponding aldol-type cyclization product was still obtained in excellent yield, however, with a relatively poor diastereoselectivity (60:40 dr with 86 and 92% ee, respectively). Finally, the absolute configuration of the main diastereomer of product 3a was determined by X-ray crystallography analysis as (2S, 3R).When (2-mercaptophenyl)(phenyl)methanone 1o bearing a phenyl group was used as the substrate, the desired cyclization product 3o was obtained in 91% yield with excellent diastereoselectivity (eq 1).14 However, no enantioselectivity was observed for this reaction when subjecting the isolated pure product to chiral HPLC analysis.15

sulfur-containing heterocycles. By introducing suitable chiral cooperative catalysts, an asymmetric version of this transformation can be achieved, thus establishing an efficient and stereoselective approach for the synthesis spirooxindole-fused sulfur-containing heterocycles (Scheme 1). Herein, we report Scheme 1. Proposed Transformation via an Intramolecular Electrophilic Trapping of the Sulfonium Ylide Intermediate

the development of a Rh(II)/chiral phosphoric acid (PPA) cooperatively catalyzed reaction of 3-diazooxindoles and 2mercaptophenyl ketones for the stereoselective construction of chiral spirooxindole-fused thiaindanes. 1-(2-Mercaptophenyl)ethan-1-one 1a was chosen as the substrate for its easy preparation and good aldol-accepting feature of the tethered acetophenone group. In the presence of 2 mol % of Rh2(OAc)4, 1a reacted with 1-benzyl-3diazoindolin-2-one 2a readily to yield the desired cyclization product 3a in 93% yield with 95:5 dr (Table 1, entry 1). This reaction also proceeded smoothly in the presence of 10 mol % racemic BINOL-type phosphoric acid (PPA) rac-4a (93% yield and 90:10 dr) (Table 1, entry 2), thus offering a good Table 1. Catalyst Screening and Optimization of Reaction Conditionsa

entry

solvent

temp (°C)

1 2 3 4 5 6 7 8 9 10 11

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 DCE CHCl3 toluene THF

rt rt rt rt rt rt 0 0 0 0 0

4 rac-4a (R)-4b (R)-4c (R)-4d (R)-4e (R)-4e (R)-4e (R)-4e (R)-4e (R)-4e

time 20 20 20 20 20 20 6 6 6 24 24

min min min min min min h h h h h

yieldb (%) 93 93 89 93 88 93 95 88 80 23 trace

drc (anti/ syn)

eed (%)

95:5 90:10 73:27 80:20 80:20 93:7 92:8 90:10 88:12 95:5

51 65 86 86 96 96 96 94

3-Mercapto-1-phenylpropan-1-one 1p possessing an aliphatic linkage was then used as the substrate to react with 2a (Scheme 3). Compared with 2-mercaptophenyl ketones bearing an aromatic backbone, the reaction between 1p and 2a went much slower. Longer reaction time and higher reaction

a 1a/2a = 1.0:1.2. bIsolated yield. cThe dr (diastereoselective ratio) was determined by 1H NMR spectroscopy of the crude reaction mixture. dDetermined by chiral HPLC.

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philic trapping process. When the crude reaction mixture from 1p and 2a was treated with 1 equiv of TsOH·H2O, part of the S−H insertion product 5p could be transferred to cyclization product 3p (Scheme 3), indicating that an intramolecular aldol reaction of 5p could be achieved under acidic conditions. A putative mechanism for this Rh(II)/chiral PPAcocatalyzed transformation is shown in Scheme 4. Rhodium Scheme 4. Proposed Mechanism

carbene derived from 2a first reacted with 1 to generate the sulfonium ylide intermediate A. The enolized sulfonium ylide intermediate A′ may undergo protonation to generate the enol form B as assisted by the coordinated CPA through hydrogen bonding with the ketone carbonyl group.16 Enol B then undergoes an intramolecular aldol-type trapping to afford cyclization product 3 (path a). Upon 1,3-proton transfer, the enol form B might be isomerized into the corresponding S−H insertion product 5 (path b). However, for the reactions between 2-mercaptophenyl ketones and 3-diazooxindoles, the corresponding S−H insertion products were never observed, indicating that either a very fast enolization of the corresponding S−H insertion product (path b) or a rapid aldol-type cyclization is involved in this transformation (path c). For the reaction between 1p and 2a, the alkyl sulfur atom may poison the rhodium catalyst by a stronger coordination and therefore cause relatively slow formation of the sulfonium ylide intermediate, which opts to undergo 1,3-proton transfer to afford S−H insertion product 5p as the major product.12 Chiral PPA is responsible for asymmetric induction via hydrogen bonding between the ketone carbonyl group. For the stereoselective outcome of this transformation to be explained, an interaction model is proposed (Figure 1). Chiral PPA (R)-

a 1a/2a = 1.0:1.2. bIsolated yield. cThe dr was determined by 1H NMR spectrum of the crude reaction mixture. dDetermined by chiral HPLC. eReaction was conducted on a 1 mmol scale. fReaction was conducted in an ice−water bath for 12 h instead of at 0 °C. gThe ee of the minor product.

Scheme 3. Reaction between 3-Mercapto-1-phenylpropan-1one and 3-Diazooxindole

Figure 1. Proposed transition state.

4e first coordinates with the ketone carbonyl group via hydrogen bonding. The si face attack of the TS instead of the re face would be because of the steric repulsion between the aryl backbone of the ketone and the 3,3′-triphenylsilyl group. The aryl moiety of the ketone as well as the N-benzyl substituent are oriented toward the empty pocket of the PPA catalyst. Meanwhile, weak hydrogen bonding between the

temperature were required for full conversion. After the reaction was completed, the S−H insertion product 5p was observed as the major product (78% yield) along with the formation of the desired cyclization product 3p in 18% yield with 80:20 dr and no enantioselectivity observed. This indicates that the aromatic backbone of the 2-mercaptophenyl ketone substrates was quite essential for the in situ electro4533

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(3) Bartholow, M. Top 200 drugs of 2011. http://www. pharmacytimes.com/publications/issue/2012/July2012/Top-200Drugs-of-2011 (accessed Jun 08, 2018). (4) For representative examples, see: (a) Kitajima, M.; Nakamura, T.; Kogure, N.; Ogawa, M.; Mitsuno, Y.; Ono, K.; Yano, S.; Aimi, N.; Takayama, H. J. Nat. Prod. 2006, 69, 715. (b) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36. (c) Zhou, X.; Xiao, T.; Iwama, Y.; Qin, Y. Angew. Chem., Int. Ed. 2012, 51, 4909. (5) (a) Vintonyak, V. V.; Warburg, K.; Kruse, H.; Grimme, S.; Hübel, K.; Rauh, D.; Waldmann, H. Angew. Chem., Int. Ed. 2010, 49, 5902. (b) Vintonyak, V. V.; Warburg, K.; Over, B.; Hübel, K.; Rauh, D.; Waldmann, H. Tetrahedron 2011, 67, 6713. (c) Wang, S.; Jiang, Y.; Wu, S.; Dong, G.; Miao, Z.; Zhang, W.; Sheng, C. Org. Lett. 2016, 18, 1028. (d) Wang, S.; Chen, S.; Guo, Z.; He, S.; Zhang, F.; Liu, X.; Chen, W.; Zhang, S.; Sheng, C. Org. Biomol. Chem. 2018, 16, 625. (e) Ji, C.; Wang, S.; Chen, S.; He, S.; Jiang, Y.; Miao, Z.; Li, J.; Sheng, C. Bioorg. Med. Chem. 2017, 25, 5268. (6) (a) Duan, S.-W.; Li, Y.; Liu, Y.-Y.; Zou, Y.-Q.; Shi, D.-Q.; Xiao, W.-J. Chem. Commun. 2012, 48, 5160. (b) Zhou, P.; Cai, Y.; Lin, L.; Lian, X.; Xia, Y.; Liu, X.; Feng, X. Adv. Synth. Catal. 2015, 357, 695. (c) Gui, Y.-Y.; Yang, J.; Qi, L.-W.; Wang, X.; Tian, F.; Li, X.-N.; Peng, L.; Wang, L.-X. Org. Biomol. Chem. 2015, 13, 6371. (d) Huang, Y.-M.; Zheng, C.-W.; Chai, Z.; Zhao, G. Adv. Synth. Catal. 2014, 356, 579. (e) Cheng, P.; Guo, W.; Chen, P.; Liu, Y.; Du, X.; Li, C. Chem. Commun. 2016, 52, 3418. (f) Wang, S.; Guo, Z.; Chen, S.; Jiang, Y.; Zhang, F.; Liu, X.; Chen, W.; Sheng, C. Chem. - Eur. J. 2018, 24, 62. (g) Arai, T.; Miyazaki, T.; Ogawa, H.; Masu, H. Org. Lett. 2016, 18, 5824. (7) For reviews, see: (a) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247. (b) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org. Biomol. Chem. 2012, 10, 5165. (c) Hong, L.; Wang, R. Adv. Synth. Catal. 2013, 355, 1023. (d) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C. F., III ACS Catal. 2014, 4, 743. (e) Santos, M. M. M. Tetrahedron 2014, 70, 9735. (8) (a) Zhang, J.-X.; Wang, H.-Y.; Jin, Q.-W.; Zheng, C.-W.; Zhao, G.; Shang, Y.-J. Org. Lett. 2016, 18, 4774. (b) Han, X.; Chan, W.-L.; Yao, W.; Wang, Y.; Lu, Y. Angew. Chem., Int. Ed. 2016, 55, 6492. (c) Sankar, M. G.; Garcia-Castro, M.; Golz, C.; Strohmann, C.; Kumar, K. Angew. Chem., Int. Ed. 2016, 55, 9709. (d) Huang, Y.; Zheng, C.; Zhao, G. RSC Adv. 2013, 3, 16999. (e) Zhao, K.; Zhi, Y.; Shu, T.; Valkonen, A.; Rissanen, K.; Enders, D. Angew. Chem., Int. Ed. 2016, 55, 12104. (f) Jia, Z.; Jiang, H.; Li, J.; Gschwend, B.; Li, Q.; Yin, X.; Grouleff, J.; Chen, Y.; Jørgensen, K. A. J. Am. Chem. Soc. 2011, 133, 5053. (g) Tan, B.; Hernández-Torres, G.; Barbas, C. F., III J. Am. Chem. Soc. 2011, 133, 12354. (h) Li, G.; Liang, T.; Wojtas, L.; Antilla, J. C. Angew. Chem., Int. Ed. 2013, 52, 4628. (9) For selected MCRs via the trapping of oxonium ylides developed by our group, see: (a) Huang, H.-X.; Guo, X.; Hu, W.-H. Angew. Chem., Int. Ed. 2007, 46, 1337. (b) Hu, W.-H.; Xu, X.-F.; Zhou, J.; Liu, W.-J.; Huang, H.-X.; Hu, J.; Yang, L.-P.; Gong, L.-Z. J. Am. Chem. Soc. 2008, 130, 7782. (c) Tang, M.; Xing, D.; Huang, H.-X.; Hu, W.H. Chem. Commun. 2015, 51, 10612. (10) For selected MCRs via the trapping of ammonium ylides developed by our group, see: (a) Jiang, J.; Xu, H.-D.; Xi, J.-B.; Ren, B.Y.; Lv, F.-P.; Guo, X.; Jiang, L.-Q.; Zhang, Z.-Y.; Hu, W.-H. J. Am. Chem. Soc. 2011, 133, 8428. (b) Jiang, J.; Ma, X.-C.; Liu, S.-Y.; Qian, Y.; Lv, F.-P.; Qiu, L.; Wu, X.; Hu, W.-H. Chem. Commun. 2013, 49, 4238. (c) Ma, X.-C.; Jiang, J.; Lv, S.-Y.; Yao, W.-F.; Yang, Y.; Liu, S.Y.; Xia, F.; Hu, W.-H. Angew. Chem., Int. Ed. 2014, 53, 13136. (11) For selected MCRs via the trapping of the zwitterionic intermediate developed by our group, see: (a) Qiu, H.; Li, M.; Jiang, L.-Q.; Lv, F.-P; Zan, L.; Zhai, C.-W.; Doyle, M. P.; Hu, W.-H. Nat. Chem. 2012, 4, 733. (b) Zhang, D.; Qiu, H.; Jiang, L.-Q.; Lv, F.-P.; Ma, C. Q.; Hu, W.-H. Angew. Chem., Int. Ed. 2013, 52, 13356. (c) Zhang, D.; Zhou, J.; Xia, F.; Kang, Z.-H; Hu, W.-H. Nat. Commun. 2015, 6, 5801. (12) Xiao, G.; Ma, C.; Xing, D.; Hu, W. Org. Lett. 2016, 18, 6086. (13) For chiral phosphoric acid-catalyzed asymmetric transformations of ketones, see: (a) Nie, J.; Zhang, G.-W.; Wang, L.; Fu,

Lewis basic phosphoryl oxygen atom and the acidic O−H proton of the enol intermediate through the sterically favored configuration is formed (N-benzyl substituent is away from the phenyl group of the ketone, see Figure 1, TS). Followed with this dual hydrogen bonding activation mode, the desired product is formed with an efficient asymmetric control. In summary, we have developed a highly effective strategy for the construction of sulfur-containing spirooxindole-fused heterocycles via a Rh(II)/chiral phosphoric acid-cocatalyzed reaction between 2-mercaptophenyl ketones and 3-diazooxindoles. With this method, a series of spirooxindole-thiaindan derivatives bearing two contiguous quaternary carbon stereogenic centers were obtained in high yields with high diastereoselectivities and high-to-excellent enantioselectivities.

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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.8b01833. Experimental procedures and full spectroscopic data for all new products (PDF) Accession Codes

CCDC 1829185−1829186 contain 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 [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

Dong Xing: 0000-0003-3718-4539 Wenhao Hu: 0000-0002-1461-3671 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from National Science Foundation of China (Grant No. 21332003 and 21772043) is greatly acknowledged. We also acknowledge financial support from the Program for Guangdong Introducing Innovative and Entrepreneurial Teams (No. 2016ZT06Y337). Dr. A.G.K. Reddy is thanked for proofreading this manuscript.

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REFERENCES

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