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DOI: 10.1002/slct.201701047 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57

z Catalysis

An Efficient Ecofriendly Enantioselective Organocatalytic Ring-Closing Reaction of 2-Hydroxychalcone via Intramolecular Oxa-Michael Reaction Ashawani Kumar Singh+,[a] Shrawan Kumar Mangawa+,[a] Arvind Kumar,[a] A. K. Dixit,[b] and Satish Kumar Awasthi*[a] An organocatalyzed highly asymmetric cascade oxa-Michael addition reaction for the synthesis of flavanone from 2hydroxychalcone has been developed. This method works well with low catalyst loading and has broad range substrate scope, furnishing the desired product in excellent yield and displays an intrinsic enantioselectivity of upto 99.9 % ee. This method provides a straightforward entry into highly functionalized chiral flavanone derivatives.

Flavanones act as precursors in flavanoid biosynthesis, which is reversible cyclization of 2’-hydroxychalcones by the enzyme chalcone isomerase.[1,2] The synthesis of flavanone from 2’hydroxychalcone occurs via oxa-Michael type cyclization. Typically, the synthesis of flavanone from non-substituted 2hydroxychalcone takes place spontaneously in solution under ambient temperature and neutral conditions to give an equilibrium mixture of chalcones and flavanones.[3] In 1904, Kostanecki reported the synthesis of flavanone from 2-hydroxychalcone using mineral acid catalytic system.[4] Since then, a wide range of catalysts have been used for flavanone cyclization including alkali metal hydroxide,[5] sodium acetate,[6] potassium fluoride,[7] amine bases,[8] amino acids,[9] photoirradiation,[10] Co(III)-Salen complexes,[11] Lewis acids,[12] SiO2,[13] organoboronic acids,[14] electrochemical conditions,[15] aqueous buffers[16] at different pH, mineral acids,[17] ion-exchange resins[18] and acetic acids.[19] All the above methods give racemic mixtures. Yet, only a few stereoselective methods have been developed for generating enantio-enriched flavanoids via carbon-carbon and carbonheteroatom bond formation[20,21].Recently, biologically interesting asymmetric flavanones have been synthesized using

[a] A. K. Singh,+ Dr. S. K. Mangawa,+ A. Kumar, Prof. S. K. Awasthi Chemical Biology Laboratory, Department of Chemistry University of Delhi India-110007, India E-mail: [email protected] [b] Dr. A. K. Dixit Department of Chemistry VSSD College Kanpur, India [+] Both authors have equal contributions Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.201701047

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activated alkylidene b-ketoesters via a catalytic asymmetric intramolecular oxa-Michael reaction by using chiral N, N’Dioxide Nickel(II) Complex.[20] Scheidt and co-workers used asymmetric cinchona derived thiourea organocatalyst for cyclization of activated 2-hydroxy alkylidene b-ketoesters.[21a] (Figure 1)

Figure 1. Common Chiral catalyst used in synthesis of enantiopure flavonone. Catalyst 20 was used for enantioselective cyclization of 2-hydroxy chalcone. Catalyst 21–25 were used for enantioselective cyclization of activated 2-hydroxy alkylidene b-ketoesters 19.

Recently, highly enantioselective flavanones were synthesized with controlled stereochemistry at C2 position using advanced asymmetric methods. Recently Hinterman et al. reported cinchona alkaloid derived quaternary ammonium salt for enantioselective flavanone synthesis but the result showed lower enantioselectivity.[21b] Literature survey revealed that tert-butyl ester functional group of the chalcone substrate enhances the reactivity of conjugate acceptor, thus playing a crucial role in the cyclization reactions.[20,21] It also provides a subsequent basic position for potential interaction with catalyst which acts as bifunctional (Scheme 1). The specific asymmetric cyclization of inactive 2-hydroxychalcone has not been developed yet. The biomimetic approach requires the development of more reactive and selective catalysts for the highly stereo-selective synthesis of flavanone derivatives by using inactivated 2-hydroxychalcone.[22] Simple organic molecules as alternative to metal-

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Scheme 1. Effect of functional group on chiral catalyst.

Figure 2. Chiral catalyst (sTn) used in synthesis of chiral flavonone.

containing catalysts have been used as promising chiral organocatalysts in asymmetric transformations.[23–24] Among these, the catalysts containing guanidine and amidine group work efficiently as chiral catalysts in asymmetric conversion reactions,[25] like recently, guanidine and thiourea containing organocatalysts have displayed very impactful asymmetric catalytic performance in alkylation and cyclization reactions.[26] It has been proposed that guanidine group in a quaternary ammonium salt stabilizes the complex molecule through parallel interaction with substrate anions.[26] It is well known that s-triazine shows good catalytic performance in organic transformations, particularly in C C and C N bond formation and cyclization reactions.[27] Recently, our research group has explored diversified uses of s-triazine as a starting material for the synthesis of new quaternary ammonium organocatalysts for enantioselective alkylation.[28] Further, in search of other uses of s-triazine, we have designed and synthesized s-triazine based chiral organocatalyst (sTn) for asymmetric flavanone synthesis from 2-hydroxychalcone. The result was unsatisfactory due to lower yield (10-20 %), however, high enantioselectivity (99 % ee) was observed (Scheme 2 route

guanidine type functional group (Figure 2) can be easily prepared in two steps and are cost effective for the synthesis of enantio-enriched flavonones. Herein, we report the enantioselective cyclization of 2hydroxychalcone into asymmetric flavanone via intramolecular oxa-Micheal reaction using newer chiral ammonium quaternary salt (sTn). We have synthesized 2-hydroxychalcone (1 A-18 A) derivatives by Claisen Schmidt condensation reaction for studying asymmetric cyclization.[29] Briefly, 2-hydroxychalcone substrate was synthesized by reacting commercially available 2-hydroxyacetophenone with substituted aldehydes in the presence of a base, KOH. To optimize the enantioselective potential of synthesized quaternary salts in the asymmetric cyclizations, we performed cyclization with highly efficient and green approach[30] within 2 to 10 minutes (Scheme 2). Among the three synthesized catalysts viz. sT2, sT3 and sT4, sT2 was found to be the best for cyclization step with 95 % ee (Table 1, Entry 3). Briefly, the

Scheme 2. Optimization of Reaction condition.

c). Further, it was discovered that the use of piperidine as an additive in the reaction led to an overall increase in yield upto 100 % in some cases with 99 % ee (Scheme 2 route a). According to reported articles, after cyclization of 2-hydroxy alkylidene b-ketoesters, the 3-carboxy group was removed by treatment with acid for obtaining the desired product.[20,21] However, in route ‘a’, no such step is required (Scheme 2). These s-triazine based chiral organocatalysts (sTn) having ChemistrySelect 2017, 2, 11160 – 11163

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Table 1. Optimization of phase transefer organocatalyst according to the Scheme 2a.

Entry

Flavanone

Catalyst (sTn)

X Mol (%)

Yielda (%)

eeb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13

7 7 7 7 7 7 7 7 7 7 7 7 7

sT2 sT2 sT2 sT2 sT3 sT3 sT3 sT3 sT4 sT4 sT4 sT4 NC

5 10 15 20 5 10 15 20 5 10 15 20

91 93 97 88 85 87 89 80 90 92 94 80 98

90 93 95 88 79 76 83 80 78 81 89 78 Rac

a

Quantitative Yield; bDetermined by CHIRALCEL OD H using IPA: Hexane as eluent, c Room temperature. Reaction conditions: Piperidine (0.25 mmol), KOH (1mmol), sTn (5-20 mol %), rtc.

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synthesis procedure can be summarized as follows. To the stirred suspension of 2-hydroxychalcone in water at room temperature, aqueous solution of KOH, piperidine and s-triazine based chiral phase transfer catalyst (sT2) were added and stirred for 2–10 minutes.

Table 2. Substrate scope for enantioseletive flavanones using chiral organocatalyst sT2.

Experimental Yield, ee = enantiomeric excess (IPA: He)

Figure 3. Proposed transition state of catalyst with substrate.

Figure 4. Ortep ellipsoid drawn at 50 % probability of compound 7.


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Scheme 3. Derivatization of Chiral Dihydroflavanone.

The reaction was monitored by thin layer chromatography. The most important feature of this synthetic approach is that there is no need for column chromatography. Due to hydrophobic nature, the desired enantioselective flavanone compound gets precipitated, which can be collected by filtration and then further washed with water. To optimize the reaction conditions, three reaction strategies were planned, (a) in the presence of KOH, piperidine and sTn quaternary ammonium salts (b) in the presence of KOH and piperidine without asymmetric quaternary ammonium salts (c) in the presence of KOH and quaternary ammonium salts but without piperidine. The comparison of results based on yield and enantiomeric excess supported route ‘a’. (Scheme 2). To optimize the amount of enantioselective phase transfer catalyst sTn, a series of experiments were performed (Table 1). For all the three catalysts, 15 mol% catalyst loading was found to be most effective. However, the enantiomeric excess was found to be the highest in case of sT2 organocatalyst. To extend the scope of intramolecular Michael addition, different substituted substrates were subjected to the optimized reaction conditions (Table 2). Ortho & para-substituted arenes exhibited high reactivity and stereoselectivity. Similarly, efficient cyclization was observed in the case of metasubstituted arenes giving products (13-15) with 91–99 % yield and 82–92 % ee. The yield (58-64 %) and enantiomeric excess (44-77 % ee) for compounds 11, 12 & 16–18 was found to be lower. The proposed transition state is stabilized by hydrogen bonding (nitrogen of guanidine group is hydrogen-bonded to hydrogen atom of hydroxyl group of z-enolate) and p-p interaction between phenyl group of 2-hydroxychalcone and sT2 catalyst.[31] (Figure 3) Single-crystal X-ray analysis indicated that compound 7 has S absolute configuration (CCDC 1476221) (Figure 4). The results are synchronized with G level alerts check CIF reports showing stereochemistry S. The configurations of other cyclized products were summarized by analogy. The results are synchronized with G level alerts check CIF reports showing stereochemistry S. The configurations of other cyclized products were summarized by analogy. Further transformation of chiral dihydroflavanone was explored. We investigated the reaction of dihydroflavanone (S)7 with LiAlH4 and obtained tetrahydroflavanone (S)-7b in 70 % yield without the loss of optical purity.[32] (Scheme 3) In conclusion, we have designed and synthesized a new series of s-triazine based phase transfer catalysts (PTCs). These 11162


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PTCs have been effective in promoting enantioselective OxaMichael addition reaction of 2-hydroxychalcone to afford flavanones in good yield and high enantioselectivity. This simple and straightforward biomimetic cyclization approach requires mild reaction conditions. This study opens new avenues for second generation s-trazine based guanidine catalysts for enantiselective synthesis of diversified chiral organic molecules.

Supporting Information Summary Details of the experimental procedures and characterization data, copies of NMR (1H, 13C) spectra for all new compounds, HPLC traces of all compounds are available in the SI file.

Acknowledgements AKS and SKM are thankful to CSIR, India for providing fellowship. SKM also acknowledges IUPAC for travel grant to participate and present these results in IUPAC-2015 held in Busan, Korea. SKA acknowledges DU-DST purse grant, DST New Delhi, India and the University of Delhi, Delhi, India for financial support. Authors are thankful to USIC, University of Delhi for spectral data analysis.

Conflict of Interest The authors declare no conflict of interest. Keywords: Asymmetric Synthesis · Chiral flavanone Organocatalysis · Oxygen heterocycles · s-Triazine

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Submitted: May 16, 2017 Revised: August 29, 2017 Accepted: September 5, 2017

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