Phosphine-Catalyzed Formal Oxa-[4 + 2] Annulation Employing

Letter Cite This: Org. Lett. 2018, 20, 5515−5518

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Phosphine-Catalyzed Formal Oxa-[4 + 2] Annulation Employing Nitroethylene and Enones: Enantioselective Synthesis of Dihydropyrans Zhichao Jin,†,§ Huanzhen Ni,† Bo Zhou,† Wenrui Zheng,†,‡ and Yixin Lu*,†,‡ †

Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore National University of Singapore (Suzhou) Research Institute, 377 Lin Quan Street, Suzhou Industrial Park, Suzhou, Jiangsu 215123, PR China

Org. Lett. 2018.20:5515-5518. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 09/08/18. For personal use only.

‡

S Supporting Information *

ABSTRACT: The first phosphine-catalyzed enantioselective formal oxa-[4 + 2] reaction between nitroethylene and α-cyanoα,β-unsaturated ketones has been developed. In the presence of a dipeptide-based phosphine catalyst and achiral Brønsted acid additives, highly functionalized 3,4-dihydro-2H-pyrans were obtained with excellent enantio- and diastereoselectivities.

A

drawn considerable attention from the synthetic community in recent years.8 To devise an asymmetric approach to rapidly access the dihydropyran core, we reasoned that oxa-[4 + 2] annulation of enones would be ideal. Enones are readily available substrates, yet their utilization in RC reaction-induced cyclization has not been explored. For the selection of the C2 reaction partner, we were interested in examining suitability of nitroalkenes (Scheme 1, eq c). It was somewhat surprising to note that even though nitroalkenes are one of the most common substrates in a myriad of asymmetric reactions catalyzed by chiral amines, their employment in asymmetric phosphine catalysis is unknown.9 Herein, we document an enantioselective formal oxa-[4 + 2] annulation process between nitroethylene and enones, for the creation of highly functionalized dihydropyrans, under the catalytic action of amino acid-derived multifunctional phosphines and achiral Brønsted acid additives. Our investigation started with examination of the model reaction between nitroethylene 1a and α,β-unsaturated ketone 2a in the presence of various amino acid derived phosphine catalysts (Table 1). The reaction was performed at 0 °C in order to minimize polymerization of highly reactive nitroethylene 1a upon phosphine addition. Monoamino acid derived phosphines were ineffective; desired annulation products were obtained in very low yields and with poor stereoselectivities (entries 1 and 2). Dipeptide-based phosphine catalysts led to the formation of the product in much

symmetric phosphine catalysis has progressed remarkably in the past decade.1 Among a wide range of asymmetric transformations developed to date, phosphine-catalyzed annulation reactions making use of various forms of allenes have become the most widely explored reaction type (Scheme 1, eq a).2 As part of our continued interest in asymmetric phosphine catalysis,3 we were interested in developing a novel mode of cycloaddition reactions to access important molecular architectures, especially with the employment of readily available starting materials. Activated alkenes are the most common building blocks in organic synthesis; thus, ringforming reactions utilizing alkene substrates are highly desirable. Surprisingly, examples of phosphine-mediated annulation using activated alkenes as a nucleophilic reaction partner are very limited (Scheme 1, eq b). Loh, Zhong and coworkers first reported a catalytic asymmetric [4 + 2] annulation initiated by an aza-Rauhut−Currier (RC) reaction for the construction of functionalized tetrahydropyridines.4 Almost at the same time, Chi and co-workers developed an intramolecular [4 + 2] annulation of acrylates and imines, which was also induced by a RC reaction.5 Shortly after, the Shi group disclosed an intermolecular RC reaction-induced [4 + 2] annulation between vinyl ketones and isatin-derived α,βunsaturated imines.6 It is highly desirable to develop novel cyclization method to prepare important molecular structures from readily available common alkene precursors. Dihydropyran skeletons are frequently found in natural products and bioactive molecules,7 and they are also useful synthetic intermediates in organic chemistry. Therefore, effective construction of chiral dihyropyran structures has © 2018 American Chemical Society

Received: August 7, 2018 Published: August 22, 2018 5515

DOI: 10.1021/acs.orglett.8b02519 Org. Lett. 2018, 20, 5515−5518

Letter

Organic Letters Table 1. Reaction Screeninga

Scheme 1. Phosphine-Catalyzed Cycloadditions

enhanced chemical yield10 (entry 3), and the installation of a thiourea moiety at the second amino acid unit in the phosphine catalyst dramatically enhanced stereoselectivities (entry 4). To further improve both enantio- and diastereoselectivities of the reaction, we then introduced an achiral Brønsted acid additive.11 To our delight, the addition of a stoichiometric amount of benzoic acid led to substantial improvement; 72% ee and a 10:1 dr ratio were attainable (entry 5). Further screening of other thiourea-containing dipeptide phosphine catalysts was followed. When a TBS group was installed as a threonine OH protection, both ee and dr values were improved, but the chemical yield remained less satisfactory (entry 6). Introducing phenyalanine as the second amino acid residue in the dipeptide catalyst led to enhanced chemical yield, with slightly decreased stereoselectivities (entry 8). Notably, D-Thr-L-Phe-based phosphines were shown to be more effective than phosphine catalyst with an L,L-configuration (entry 7 versus entry 9). Screening of Brønsted acid additives revealed that the electron-rich 2-methoxylbenzoic acid best facilitated the reaction (entries 10 and 11). Under the optimal conditions, the desired annulation product 3a was obtained in 66% yield with 92% enantiomeric excess and >19:1 diastereomeric ratio (entry 12). With the established optimized reaction conditions in hand, we next explored the reaction scope, and the results are summarized in Scheme 2. The vinylic moieties (R1) in αcyano-α,β-unsaturated ketones 2 were well tolerated; meta- or para-substituted aryls with different halogen atoms and of different electronic nature were all found to be suitable (3b− m). 2-Naphthyl-containing substrate could also be used (3n). However, an ortho-substituted aryl was less ideal, and the enantioselectivity of the reaction dropped dramatically (3o). The ketone substituents (R2) could also be varied; while the presence of 2-thiophene led to slightly decreased enantioselectivity (3p), various other aromatic substituents were shown to be suitable (3q to 3t). It should be noted that our current

entry

cat.

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

4 5 6 7a 7a 7b 7c 7d 7e 7d 7d 7d

additive

yieldb (%)

eec

drd

PhCO2H PhCO2H PhCO2H PhCO2H PhCO2H Ar1CO2He Ar2CO2Hf Ar1CO2He

14 9 39 24 51 51 48 67 13 66 37 66h

5 20 −12 54 72 82 75 77 14 80 75 92

1:1 4:1 1:1 8:1 10:1 >19:1 10:1 11:1 2:1 11:1 15:1 >19:1

a

Reaction conditions: 1a (0.10 mmol), 2a (0.05 mmol), catalyst (0.01 mmol), acid additive (0.05 mmol), toluene (1.0 mL), 0 °C, 24 h, unless otherwise specified. bYield was determined by 1H NMR analysis using 1,3,5-trimethoxylbenzene as the internal standard. cThe ee values were determined by HPLC analysis on a chiral stationary phase. dThe dr values were determined by 1H NMR analysis of the crude reaction mixture. eAr1 = 2-CH3OC6H4. fAr2 = 2-CH3C(O)C6H4. gConditions: 1a (0.40 mmol), 2a (0.10 mmol), 7d (0.02 mmol), 2-MeOC6H4COOH (0.10 mmol), toluene (6.0 mL), −20 °C, 96 h. hIsolated yield.

reaction system is not applicable to substrates containing an alkyl group at either the R1 or R2 position; only less than 10% of the desired products could be isolated when those substrates were used. Moreover, our reaction could not be extended to substituted nitroalkene substrates, as only poor results were attainable.12 The [4 + 2] annulation products are rich in functionality; thus, they can be easily converted to various optically enriched dihydropyrans. For instance, reduction of 3a yielded chiral primary amine 8 and subsequently formed the corresponding sulfonamide 10, with virtually retained optical purity.13 The cyano group could also be easily manipulated; hydrolysis of 3a afforded amide 9. The absolute configurations of the annulation products were assigned on the basis of X-ray crystallographic analysis of compound 10 (Scheme 3). The proposed reaction mechanism is outlined in Scheme 4. Phosphine attack on nitroalkene 1a generates zwitterionic intermediate A, which adds on to enone 2a to form advanced intermediate B. Subsequent cyclization then affords the [4 + 2] annulation product and regenerates the catalyst at the same 5516

DOI: 10.1021/acs.orglett.8b02519 Org. Lett. 2018, 20, 5515−5518

Letter

Organic Letters Scheme 2. Reaction Scopea

network induced by the Brønsted acid is crucial for enhanced enantio- and diasteroselectivities, and our theoretical investigations are ongoing to elucidate the origin of observed stereoselectivities. In summary, we have developed the first phosphinecatalyzed enantioselective formal oxa-[4 + 2] annulation between nitroethylene and enones. Notably, this is the first example of employing a nitroalkene in a phosphine-catalyzed cyclization reaction. Under the catalytic action of a chiral phosphine and an achiral Brønsted acid additive, highly functionalized 3,4-dihydro-2H-pyrans were obtained in moderate yields, and with excellent enantio- and diastereoselectivities. Currently, we are extending the concept of this oxa-[4 + 2] annulation to access a broader range of oxygen-containing ring structures.

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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.8b02519. Experimental procedures and spectral data for all new compounds (PDF) Accession Codes

a

Reaction conditions were the same as those stated in Table 1, entry 12.

CCDC 1527120 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Scheme 3. Synthetic Transformations of 3a

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yixin Lu: 0000-0002-5730-166X Present Address §

(Z.J.) Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, PR China.

Scheme 4. Proposed Mechanism

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Y.L. thanks the Singapore National Research Foundation, Prime Minister’s Office, for the NRF Investigatorship Award (R-143-000-A15-281). Financial support from the National University of Singapore (R-143-000-695-114) is also gratefully acknowledged.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b02519 Org. Lett. 2018, 20, 5515−5518