Direct Access of the Chiral Quinolinyl Core of Cinchona Alkaloids via a

Letter Cite This: Org. Lett. 2018, 20, 1195−1199

pubs.acs.org/OrgLett

Direct Access of the Chiral Quinolinyl Core of Cinchona Alkaloids via a Brønsted Acid and Chiral Amine Co-catalyzed Chemo- and Enantioselective α‑Alkylation of Quinolinylmethanols with Enals Mengchao Tong,†,§ Sinan Wang,†,§ Jinchen Zhuang,† Cong Qin,† Hao Li,*,† and Wei Wang*,†,‡ †

State Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New Drug Design, and School of Pharmacy, East China University of Science and Technology, 130 Mei-long Road, Shanghai 200237, China ‡ Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131-0001, United States S Supporting Information *

ABSTRACT: A strategy for the facile construction of the chiral quinolinylmethanolic structure, a core featured in cinchona alkaloids, is reported. A new reactivity is harnessed by TfOH-promoted chemoselective activation of α-C−H over O−H bond in quinolinylmethanols. The new reactivity is successfully engineered with an iminium catalysis in a synergistic manner to create a powerful conjugate addition−cyclization cascade process for synthesis of chiral quinoline derived γ-butyrolactones in good yields and with good to excellent enantioselectivities. The method enables the first total synthesis of natural product broussonetine in three steps.

C

asymmetric conjugate addition reaction of quinolinylmethanols with enals. Chiral quinoline-derived γ-butyrolactones after in situ oxidation of the hemiacetal products are efficiently synthesized in good yields and good to excellent enantioselectivities. Under optimized reaction conditions, a broad array of quinolinylmethanols and structurally diverse enals can efficiently engage in the process. The synthetic utility is demonstrated in a three-step synthesis of natural product broussonetine for the first time. It is noted that, in sharp contrast, a structurally relevant natural product broussonetine featuring two quinoline units and an interesting chiral γbutyrolactone isolated in 1984 has received little attention despite its fascinating structure along with its undetermined biological functions (Scheme 1).10 To the best of our knowledge, this compound has not been totally synthesized. We envisioned that the disconnection of C−C bond in quinine could provide a new and efficient approach to the quinolinylmethanolic core (Scheme 1, eq 2). In this case, simple and readily available quinolinylmethanols could be used. However, the realization of the proposed process faces a critically challenging chemoselectivity between C−H and O−H bonds (eq 3). In general, the OH group is employed as a

inchona alkaloids such as quinine and quinidine occupy a unique position in natural products and medicinal and organic chemistry due to their interesting structures, important biological properties,1 and “privileged” ligands widely used in catalysis and synthesis (Scheme 1, eq 1).2 Their broad utilities make them long-sought targets in organic synthesis over 150 years.3 Furthermore, importantly, despite their relatively simple structures, they serve as a model to test newly developed synthetic technologies and strategies. In particular, the quinine synthesis is considered a landmark in organic chemistry with rich history. It serves as the target for testing of new synthetic strategies, reactions, and strategies.4−9 Inspired by the exciting stories behind quinine synthesis and the beautiful chemistries and the demand for more efficient synthetic strategies and methods to further advance the field, we recently initiated a program aimed at developing a new approach to the chiral quinolinylmethanolic molecular architecture, a core structure featured in these natural products (Scheme 1, eq 2). We devised a distinct C−C bond connection approach for the assembly of the core structure. The process employs readily accessible quinolinylmethanols as one of the reacting substances. A new reactivity, harnessed by TfOHpromoted chemoselective activation of the α-C−H over the O−H bond in the alcohols as a nucleophile, is achieved for the first time. The new activation mode equips synergistically with a chiral iminium catalysis to create an unprecedented © 2018 American Chemical Society

Received: January 10, 2018 Published: February 7, 2018 1195

DOI: 10.1021/acs.orglett.8b00118 Org. Lett. 2018, 20, 1195−1199

Letter

Organic Letters Table 1. Optimization of Reaction Conditions.a

Scheme 1. Quinoline Alkaloids Featuring a Quinolinyl Methanolic Core and Strategies for Constructing the Framework

nucleophile in C−O bond forming reactions11 owning to the easy ionization of the O−H bond. It is inherently difficult to activate an alcoholic α-C−H bond as a nucleophilic partner by virtue of its high bond dissociation energy.12 Therefore, a new strategy is needed to chemoselectively activate the inert C−H bond while keeping the OH group untouched. As far as we are aware, only photocatalytic radical processes for direct functionalization of α-carbon in alcohols have been reported.13 Nonetheless, achieving an asymmetric version with the radical engaged pathway is difficult. Recently, we have developed a chiral amine-catalyzed direct enantioselective addition of unfunctionalized arylmethanes as nucleophiles to enals and a series of reactions associated with the chemistry.14 Furthermore, related works have been reported by Lam,15 Huang,16 Rios,17 Jørgensen,18 and You.19 It should be noted that although a similar approach using Lewis acid InCl3 and PhCO2H as additive for the activation of simple unfunctionalized 4-methyl moiety of quinoline has been reported by Jørgensen,18 we aim to explore a metal-free catalytic system. Furthermore, toward our goal of pursuing an efficient strategy for the facile assembly of the chiral quinolinylmethanolic structure, a core featured in cinchona alkaloids, the incorporation of an additional hydroxy group is needed. To test our working hypothesis, we carried out a model reaction between quinolin-4-ylmethanol 1a (0.5 mmol) and trans-cinnamaldehyde 2a (0.75 mmol) in the presence of diphenylprolinol trimethylsilyl ether (I) (10 mol %) and TfOH (0.5 equiv) in 0.5 mL of DMF for 96 h at rt for initial evaluation (Table 1). We were pleased that the desired product 3a was obtained in 72% yield. As the hemiacetal product has three chiral centers and complicates their characterization, the crude product was directly oxidized to lactone 4a by NMO and TPAP for the NMR characterization and the determination of enantioselectivities. Diastereomeric cis and trans γ-butyrolactones 4a were obtained in good yield (70% yield) but with moderate enantioselectivities and 1.4:1 dr (entry 1). Screening of various chiral amine catalysts was conducted aimed at

entry

cat.

additive

1e 2e 3e 4e 5e 6f 7 8g,h 9g,h 10g,h 11g,h 12g,h 13g,h,i

I II III IV V V V V V V V V V

TfOH TfOH TfOH TfOH TfOH TfOH TfOH TfOH AcOH HCl HNO3 TfOH

3a, yieldb (%)

dr 4ac (cis/ trans)

ee 4ad (%) (cis/ trans)

72 55 24 70 75 50 63 75 0 0 70 71 82

1.4:1 nd 1.1:1 1.5:1 1.5:1 1.5:1 1.5:1 1.5:1

63/65 7/7 15/40 66/68 71/71 84/83 73/78 72/78

1.5:1 1.5:1 1.6:1

71/71 70/70 92/93

a

Unless otherwise specified, a mixture of 1a (0.5 mmol), 2a (0.75 mmol), amine catalyst, and additive (0.5 equiv) in DMF (0.5 mL) was stirred for 96 h at 10 °C. bIsolated yields. cDetermined by 1H NMR of crude mixture. dDetermined by chiral HPLC analysis. eThe reaction was run at rt. fThe reaction was run at 0 °C. g0.2 mL of DMF used. h 15 mol % of V was used. i0.2 equiv of TfOH was used. nd = not determined. NMO = 4-methylmorpholine N-oxide. TPAP = tetrapropylammonium perruthenate.

improving these parameters (entries 2−5). (S)-Proline (II) and (S)-pyrrolidine sulfonamide (III) afforded the product in moderate to low yields and with lower enantioselectivities (entries 2 and 3). When the more hindered prolinol diphenyl silyl ethers IV and V were used, the reaction yields and enantioselectivities were increased slightly (entries 4 and 5). Catalyst V gave better results and was selected for further optimization of reaction conditions. The enantioselectivities were improved by lowering the reaction temperature, while the reaction yield was decreased (entries 6−7). Solvent screening revealed DMF as the choice.20 To enhance the reaction yield, higher V loading and higher concentration were employed, capable of delivering the product in 75% yield without loss of enantioselectivities and dr (entry 8). As demonstrated, acids indeed played an essential role in copromoting the process. No reaction took place without acid or with a weaker acid (AcOH) (entries 9 and 10). Stronger acids such as HCl and HNO3 could provide similar results (entries 11 and 12). Further optimization of the reaction conditions revealed that the acid catalyst loading was critical for the enantioselectivities. When the acid was decreased to 20 mol %, both reaction yield and enantioselectivity improved dramatically (entry 13). We also tried to improve diastereoselectivity. Although after various attempts the best dr of 1.6:1 was obtained, both can be separated by chromatography with high enantioselectivity (92% and 93% ee, respectively, entry 13). With the optimal conditions in hand, we then probed the scope of the reactions between quinolin-4-ylmethanol 1a and various α, β-unsaturated aldehydes (Table 2). Good to 1196

DOI: 10.1021/acs.orglett.8b00118 Org. Lett. 2018, 20, 1195−1199

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Organic Letters Table 2. Scope of α,β-Unsaturated Aldehydes.a

entry

R

1 2e 3 4 5 6 7f 8 9f 10f 11f 12

Ph 4-NO2C6H4 4-ClC6H4 4-BrC6H4 3-FC6H4 2-NO2C6H4 4-CH3C6H4 4-quinolinyl 2-furyl C2H5 n-C3H7 CO2Et

3, yieldb (%) 82 91 85 87 78 90 65 90 63 58 55 72

(3a) (3b) (3c) (3d) (3e) (3f) (3g) (3h) (3i) (3j) (3k) (3l)

Scheme 2. Scope of Quinolinylmethanolsa

4, drc (cis/ trans)

4, eed (%) (cis/ trans)

1.6:1 1:1.5 1.4:1 1.5:1 1.5:1 1:1 1.5:1 1.3:1 1:1 1:1.6 1:1.6 1.3:1

92/92 83/97 90/91 90/92 91/91 96/93 88/90 97/96 77/80 87/57 96/71 79/80

a

See the Supporting Information for the experimental protocol. Isolated yields. cDetermined by 1H NMR of crude mixture. d Determined by chiral HPLC analysis. eDMF (0.6 mL) was used. f The reaction was stirred for 120 h.

a

See the Supporting Information for the experimental protocol; all reactions were stirred for 120 h. Isolated yields. The dr was determined by the 1H NMR of crude mixtures. The ee was determined by chiral HPLC analysis.

b

excellent yields and enantioselectivities were obtained with the aryl rings bearing electron-withdrawing NO2, F, Cl, and Br (entries 2−6) and -donating (entry 7) groups. Furthermore, heterocyclic α, β-unsaturated aldehydes including electrondeficient 4-quinolinyl and electron-rich 2-furyl were tolerated by the protocol (entries 8 and 9). In addition to aromatic enals, aliphatic structures proceeded smoothly as well to give the desired products 3j and 3k in moderate yields but with good enantioselectivities for major diastereomers (entries 10 and 11). Finally, the method was applicable for an enal containing an ester moiety (entry 12). The ester handle could be conveniently transformed into new functionalities. The absolute and relative cis and trans configurations of the products were determined by single-crystal X-ray diffraction analysis of cis-4d and trans-4d (Figure S1). Further investigations of the conjugate addition−cyclization process were carried out to probe the generality of the nucleophilic component quinolinylmethanols (Scheme 2). The results show that the process serves as a general approach to the structurally diverse quinolinyl lactones. The quinolinyl ring structures bearing electron-donating OMe and -withdrawing Cl gave the desired products 3m and 3n in 52% and 62% yields, respectively. It appeared that the electronic effects have an impact on yield and enantioselectivity. In addition to quinolin4-ylmethanols, quinolin-2-ylmethanols could engage in the synergistic catalytic process. Under the same reaction conditions, the processes proceeded with good yields and excellent enantioselectivities regardless of the aromatic rings of the cinnamaldehydes carrying substituents with electronneutral, -donating, and -withdrawing groups (4o−q). Moreover, the diastereoselectivities were improved, probably owning to the steric hindrance effect. To our delight, this reaction can extend beyond quinolines. Isoquinolines can also participate in the processes by affording the products 4r,s in high yields and with excellent enantioselectivities. The power of the new synthetic methodology is demonstrated as a key step in the three-step synthesis of natural

product broussonetine (Scheme 3). The hemiacetal product 3u was obtained in 85% yield under the standard reaction conditions. Then the resulting product 3u was oxidized to cis-4u and trans-4u in 60% yield. Demethylation of the desired major isomer cis-4u by treating with 48% HBr in H2O at 110 °C afforded target broussonetine in 63% yield. Acylation of the free phenol groups in broussonetine by reacting with Ac2O and Scheme 3. Total Synthesis of Broussonetine and DeuteriumExchange Experiments and Proposed Activation Mode

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Organic Letters

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pyridine to give diacetyled form 5 in 75% yield, which enables us to determine its enantioselectivity (91% ee). During the synthesis, the enantioselectivity is affected marginally. It should be noted that this study represents the first total synthesis of the natural product broussonetine. To understand why the reaction proceeds at the α-C rather than often observed “O”, deuterium-exchange experiments with quinolin-4-ylmethanol 1a in DMF/D2O were performed (Scheme 3). Without TfOH, no D/H exchange 1a-d was observed by 1H NMR at 10 °C (eq 1). However, when 20 mol % of TfOH was added into the mixture, the deuterated 1a could be obtained at 20% deuterium incorporation at the arylic position after 96 h (eq 2). The experimental results indicated that the acid plays a key role in the activation of arylic C(sp3) of quinolin-4-ylmethanol 1a via an enol intermediate A (eq 3). It has been shown that the OH group of an alcohol with a hydrogen-bond acceptor (eg, H + ) can enhance n−s* delocalization of the oxygen lone pair, rendering the a α-C− H bond more polarized and thus weakening the C−H bond.21 Furthermore, it is believed that the protonation of the pyridine ring of quinolinylmethanols 1 enhances the deprotonation of the alcohol O−H group, which therefore decreases the strength of the C−H bond upon deprotonation via the “oxy anionic substituent effect”.22 These effects may account for the selective activation of the α−C-H bond as a new type of nucleophiles for unprecedented C−C bond connection in hydroxyl compound synthesis. In summary, driven by the privileged status of cinchona alkaloids in organic and medicinal chemistry, while the relevant biologically intriguing natural product broussonetine has not been synthesized, we have developed a novel synergistic catalytic strategy for the enantioselective synthesis of the chiral quinolinylmethanolic core of these natural products. A new reactivity harnessed by TfOH-promoted chemoselective activation of the α-C−H over the O−H bond in the alcohols is successfully engineered into a chiral amine-catalyzed enantioselective conjugate addition reaction with α,β-unsaturated aldehydes. A powerful conjugate addition−cyclization cascade process is created for efficient synthesis of chiral quinoline derived γ-butyrolactones in good yields and with good to excellent enantioselectivities despite relatively poor dr. The protocol displays a broad substrate scope for both substrates of quinolinylmethanols and enals. As demonstrated, the process serves as the key step in the efficient three-step synthesis of broussonetine. Further application of the reaction in synthesis of cinchona alkaloids and the biological study of broussonetine are being pursued in our laboratories.

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Letter

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Wei Wang: 0000-0001-6043-0860 Author Contributions §

M.T. and S.W. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21738002, 21572054, and 21572055), the program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, the Fundamental Research Funds for the Central Universities, and the China 111 Project (Grant B07023).

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00118. Experimental details and spectroscopic data (PDF) Accession Codes

CCDC 1564751−1564752 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. 1198

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