Enantioselective Decarboxylative Alkylation of β-Keto Acids to ortho

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Enantioselective Decarboxylative Alkylation of β‑Keto Acids to orthoQuinone Methides as Reactive Intermediates: Asymmetric Synthesis of 2,4-Diaryl-1-benzopyrans Hyun Jung Jeong and Dae Young Kim* Department of Chemistry, Soonchunhyang University, Asan, Chungnam 31538, Republic of Korea S Supporting Information *

ABSTRACT: A novel and efficient asymmetric synthesis of 2,4-diaryl-1-benzopyrans via enantioselective decarboxylative alkylation of β-keto acids to o-QM intermediates, followed by sequential cyclization and dehydration, has been developed. The synthetically useful chiral 2,4-diaryl-1-benzopyran derivatives were obtained in moderate to high yields and high enantioselectivities through a one-pot, two-step sequence. This approach offers a facile way to prepare chiral 2,4-diaryl-1benzopyran derivatives with a wide range of functional group tolerance.

Scheme 1. Strategy for the Synthesis of 2,4-Diaryl-1benzopyrans

4H-1-Benzopyrans are a privileged class of structural motifs found in many pharmaceuticals and bioactive natural products.1 In particular, 2,4-diaryl-1-benzopyrans bearing a stereogenic center at the C4-position have been reported to be biologically active against a variety of targets (Figure 1).2 Consequently, the

Figure 1. Examples of bioactive compounds containing 2,4-diaryl-1benzopyran core.

asymmetric synthesis of 2,4-diaryl-1-benzopyran derivatives has received significant attention as a research area in organic chemistry over the past decades. In 2013, the groups of Terada and Rueping reported asymmetric ion-pair catalysis for performing an enantioselective 1,4-reduction of the pyrylium ions (Scheme 1a).3 Recently, Toste and co-workers demonstrated another catalytic enantioselective synthesis of chiral 2,4diaryl-1-benzopyran derivatives by the addition of phenol nucleophiles to benzopyrylium salts through a chiral anion phase-transfer strategy (Scheme 1b).4 Although these are to some extent satisfied as a synthetic process, a new and efficient synthetic route for the synthesis of chiral 2,4-diaryl-1benzopyrans is highly desired. ortho-Quinone methides (o-QMs) are versatile intermediates in organic synthesis and biological processes as well as materials science.5 Much progress has been made in the addition of a various types of nucleophiles to o-QMs under transition-metal catalysis6 or organocatalysis.7 Recently, o-QMs have success© XXXX American Chemical Society

fully been applied to catalytic enantioselective reactions with various nucleophiles. However, the asymmetric alkylation reaction between o-QMs and β-keto acids has not been Received: March 28, 2018

A

DOI: 10.1021/acs.orglett.8b00993 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters described. The decarboxylative reactions of β-keto acids as ketone enolate equivalents have received much attention due to their higher reactivity and regioselectivity.8 We therefore envisioned that in situ generated o-QMs A could probably react with β-keto acids via enantioselective decarboxylative alkylation to produce chiral Michael adduct B, followed by sequential formation of the hemiketals C and dehydration to give chiral 2,4-diaryl-1-benzopyrans (Scheme 1c). In connection with the ongoing research program on the development of synthetic methods for the enantioselective construction of stereogenic carbon centers,9 we recently reported catalytic enantioselective C−C bond formations of active methylenes and methines.10 Herein, we report a new and facile asymmetric synthesis of 2,4-diarylbenzopyranes via decarboxylative alkylation of β-keto acids to o-QM intermediates using chiral phosphoric acids,11 followed by sequential cyclization and dehydration. To test this concept, we started with the reaction between βketo acids and in situ generated o-QMs. The initial investigation was performed with o-hydroxy benzylic alcohol 1a and benzoylacetic acid (2a) in the presence of phosphoric acid 4a at rt. The desired product 3a was obtained with a trace amount (Table 1, entry 1). To improve the yield, a one-pot, two-step

process involving decarboxyaltive alkylation of benzoylacetic acid (2a) with 10 mol % of phosphoric acid 4a at rt for 12 h, followed by sequential cyclization and dehydration sequences by addition of Sc(OTf)3 (50 mol %) as an additive at 40 °C for 12 h, was examined. The reaction gave a moderate yield (35%) of 3a with moderate enantioselectivity (32% ee) (Table 1, entry 2). We examined the evaluation of the catalyst structure of phosphoric acids 4a−4h on reactivity and selectivity (Table1, entries 2−9). 9-Anthryl substituted phosphoric acid 4g was selected as the best catalyst. Among the additives proved, the best result was achieved when the reaction was carried out in Sc(OTf)3 (Table 1, entries 8 and 10−11). In order to improve the enantioselectivity, different solvents were then tested in the presence of 10 mol % of catalyst 4g together with benzoylacetic acid (2a) and o-hydroxy benzylic alcohol 1a. The commonly used solvents, such as dichloromethane, 1,2-dichloroethanes, 1,1,2-trichloroethane, dibromomethane, carbon tetrachloride, and toluene, were tolerated well in this reaction with a slightly significant decrease in enantioselectivities (27−91% ee, Table 1, entries 8 and 12−17). Among the solvents probed, the best results (55% yield and 91% ee) were achieved when the reaction was carried out in chloroform (Table 1, entry 12). At high temperature (60 °C), the yield can be elevated to 71%, without compromising enantioselectivity (entry 18). To examine the generality of the catalytic enantioselective decarboxylative alkylation reaction of the β-keto acid derivatives 2 to o-hydroxy benzylic alcohol 1a, we studied the decarboxylative alkylation of various β-keto acids 2 with ohydroxy benzylic alcohol 1a in the presence of 10 mol % of catalyst 4g, followed by sequential cyclization and dehydration sequences by addition of Sc(OTf)3 (50 mol %) as an additive at 60 °C for 4 h. A range of electron-donating and electronwithdrawing substituents on the β-aryl group of the β-keto acids 2 gave out the desired products in high yields (70−80%) and with high enantioselectivities (76−92% ee, Scheme 2, for 3a−3g). The heteroaryl- and naphthyl-substituted β-keto acids 2 provided the products with high selectivity (80−91% ee, Scheme 2, for 3i−3j). The research on the possibility of decarboxylative alkylation using a wide range of o-hydroxy benzylic alcohols 1 with benzoylacetic acid (2a) under optimized conditions was carried out (Scheme 3). A range of substitutions on the benzylic aryl group of o-hydroxy benzylic alcohols 1 provided the corresponding products in high yields (57−81%) and with excellent enantioselectivities (85−94% ee, Scheme 3, 3j−3o). The absolute configuration of the adducts 3 was determined for some derivatives by comparison of their optical and HPLC properties with the literature values.3,4 The present method is operationally simple and efficient and, thus, may be valuable for practical chemical synthesis. As shown in Scheme 4, when 2-(hydroxy(phenyl)methyl)phenol (1a) was added to benzoylacetic acid (2a) under the optimal reaction conditions, the reaction proceeded smoothly to afford the desired (R)-2,4-diphenyl-4H-chromene (3a) at the gram scale with a 78% yield and 91% ee (Scheme 4). Based on the experimental results, a plausible reaction pathway and activation mode were proposed (Scheme 5). The o-QM intermediate A was generated in situ from o-hydroxy benzyl alcohol 1 under the catalysis of a chiral Brønsted acid. Then, catalyst 4g simultaneously generated two hydrogen bonds with both the o-QM intermediate A and enol intermediate derived from β-keto acids 2, which facilitated an enantioselective alkylation. The attack from enol to the re-face

Table 1. Optimization of the Reaction Conditionsa

entry

cat.

additive

solvent

yieldb (%)

eec (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18d

4a 4a 4b 4c 4d 4e 4f 4g 4h 4g 4g 4g 4g 4g 4g 4g 4g 4g

− Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Yb(OTf)3 Mg(OTf)2 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 DCE TCE CH2Br2 CCl4 PhMe CHCl3

trace 35 45 51 47 40 35 79 60 60 23 55 68 51 45 52 56 75

− 32 45 27 21 71 50 89 71 81 80 91 74 44 36 27 73 91

a Reactions were carried out with 1a (0.1 mmol), 2a (0.3 mmol), and catalyst 4 (0.01 mmol) in solvent (2 mL) at rt for 12 h, and then additive (50 mol %) was added, followed by stirring for 12 h at 40 °C. b Isolated yield. cEnantiopurity was determined by HPLC analysis using Chiralpak AD-H column. dReaction was carried out at 60 °C at second step.

B

DOI: 10.1021/acs.orglett.8b00993 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Substrate Scope with β-Keto Acids 2a−c

Scheme 4. Gram Scale Synthesis of (R)-2,4-Diphenyl-4H-1benzopyran (3a)

Scheme 5. Proposed Reaction Pathway and Stereochemical Mode

a

of the o-QM intermediate A gives chiral Michael products B, followed by sequential formation of the hemiketals C and dehydration to give chiral 2,4-diaryl benzopyrans 3 with the observed absolute configurations. In conclusion, we have presented a new and efficient asymmetric synthesis of 2,4-diaryl-1-benzopyrans via enantioselective decarboxyaltive alkylation of β-keto acids to o-QM intermediates, followed by sequential cyclization and dehydration. The synthetically useful chiral 2,4-diaryl-1-benzopyran derivatives were obtained in moderate to high yields and high enantioselectivities through a one-pot, two-step sequence. Current studies are aimed at developing a catalytic enenatioselective alkylation of β-keto acids for the efficient buildup of complex natural products.

Reactions were carried out with 1a (0.1 mmol), 2 (0.3 mmol), and catalyst 4g (0.01 mmol) in CHCl3 (2 mL) at rt for 12 h, and then Sc(OTf)3 (50 mol %) was added, followed by stirring for 12 h at 60 °C. bIsolated yield. cEnantiopurity was determined by HPLC analysis using Chiralpak AD-H column.

Scheme 3. Substrate Scope with o-Hydroxy Benzylic Alcohols 1a−c

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00993. Experimental procedures and characterization data (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Dae Young Kim: 0000-0002-6337-7505 Notes

The authors declare no competing financial interest.

■

a

Reactions were carried out with 1 (0.1 mmol), 2a (0.3 mmol), and catalyst 4g (0.01 mmol) in CHCl3 (2 mL) at rt for 12 h, and then Sc(OTf)3 (50 mol %) was added, followed by stirring for 12 h for 60 °C. bIsolated yield. cEnantiopurity was determined by HPLC analysis using Chiralpak AD-H column.

ACKNOWLEDGMENTS This research was supported by the Soonchunhyang University Research Fund and Basic Science Research Program through C

DOI: 10.1021/acs.orglett.8b00993 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Kim, D. Y. Bull. Korean Chem. Soc. 2015, 36, 1512. (e) Jeong, H. J.; Kwon, S. J.; Kim, D. Y. Bull. Korean Chem. Soc. 2015, 36, 1516. (f) Jang, H. S.; Kim, Y.; Kim, D. Y. Beilstein J. Org. Chem. 2016, 12, 1551. (g) Suh, C. W.; Kwon, S. J.; Kim, D. Y. Org. Lett. 2017, 19, 1334. (10) For a selection of our recent work on synthetic methods for the formation of enantioselective C−C bond formations of active methylenes and methines, see: (a) Woo, S. B.; Suh, C. W.; Koh, K. O.; Kim, D. Y. Tetrahedron Lett. 2013, 54, 3359. (b) Sung, H. J.; Mang, J. Y.; Kim, D. Y. J. Fluorine Chem. 2015, 178, 40. (c) Kwon, S. J.; Kim, D. Y. J. Fluorine Chem. 2015, 180, 201. (d) Kim, K. Y.; Kim, D. Y. Bull. Korean Chem. Soc. 2016, 37, 5. (e) Kim, Y.; Kim, Y. J.; Jeong, H. I.; Kim, D. Y. J. Fluorine Chem. 2017, 201, 43. (f) Kim, Y. H.; Yoon, J. H.; Lee, M. Y.; Kim, D. Y. Bull. Korean Chem. Soc. 2017, 38, 1242. (11) For selected reviews for chiral phosphoric acid catalysis, see: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744. Terada, M. Synthesis 2010, 2010, 1929. (c) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047. (d) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2017, 117, 10608.

the National Research Foundation of Korea (NRF2016R1D1A1B03933723).

■

REFERENCES

(1) For selected reviews, see: (a) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406. (b) Pratap, R.; Ram, V. J. Chem. Rev. 2014, 114, 10476. (c) Costa, M.; Dias, T. A.; Brito, A.; Proença, F. Eur. J. Med. Chem. 2016, 123, 487. (2) For selected examples, see: (a) Wu, Y. C.; Liu, L.; Liu, Y. L.; Wang, D.; Chen, Y. J. J. Org. Chem. 2007, 72, 9383. (b) Lu, Z.; Lin, Z.; Wang, W.; Du, L.; Zhu, T.; Fang, Y.; Gu, Q.; Zhu, W. J. Nat. Prod. 2008, 71, 543. (c) Jeso, V.; Nicolaou, K. C. Tetrahedron Lett. 2009, 50, 1161. (d) Kamdar, N.; Haveliwala, D.; Mistry, P.; Patel, S. Eur. J. Med. Chem. 2010, 45, 5056. (e) Das, S.; Srinivasan, B.; Hermanson, D.; Bleeker, N.; Doshi, J.; Tang, R.; Beck, W.; Xing, C. J. Med. Chem. 2011, 54, 5937. (f) Yao, C.; Jiang, B.; Li, T.; Qin, B.; Feng, X.; Zhang, H.; Wang, C.; Tu, S. Bioorg. Med. Chem. Lett. 2011, 21, 599. (g) Makawana, J.; Mungra, D.; Patel, M.; Patel, R. Bioorg. Med. Chem. Lett. 2011, 21, 6166. (h) Li, S.; Li, F. Z.; Gong, J. X.; Yang, Z. Org. Lett. 2015, 17, 1240. (i) Costa, M.; Dias, T. A.; Brito, A.; Proença, F. Eur. J. Med. Chem. 2016, 123, 487. (3) (a) Hsiao, C. C.; Liao, H. H.; Sugiono, E.; Atodiresei, I.; Rueping, M. Chem. - Eur. J. 2013, 19, 9775. (b) Terada, M.; Yamanaka, T.; Toda, Y. Chem. - Eur. J. 2013, 19, 13658. (4) Yang, Z.; He, Y.; Toste, F. D. J. Am. Chem. Soc. 2016, 138, 9775. (5) For selected reviews, see: (a) Amouri, H.; Le Bras, J. Acc. Chem. Res. 2002, 35, 501. (b) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367. (c) Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. Rev. 2005, 105, 4757. (d) Rokita, S. E. Quinone Methides; Wiley: New York, 2009. (e) Bai, W.-J.; David, J. G.; Feng, Z.G.; Weaver, M. G.; Wu, K.-L.; Pettus, T. R. R. Acc. Chem. Res. 2014, 47, 3655. (f) Wang, Z.; Sun, J. Synthesis 2015, 47, 3629. (g) Caruana, L.; Fochi, M.; Bernardi, L. Molecules 2015, 20, 11733. (h) Jaworski, A. A.; Scheidt, K. A. J. Org. Chem. 2016, 81, 10145. (6) (a) Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 3076. (b) Jensen, K. H.; Pathak, T. P.; Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2009, 131, 17074. (c) Pathak, T. P.; Gligorich, K. M.; Welm, B. E.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132, 7870. (d) Jensen, K. H.; Webb, J. D.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132, 17471. (e) Jana, R.; Pathak, T. P.; Jensen, K. H.; Sigman, M. S. Org. Lett. 2012, 14, 4074. (f) Huang, Y.; Hayashi, T. J. Am. Chem. Soc. 2015, 137, 7556. (g) Zheng, J.; Lin, L.; Dai, L.; Yuan, X.; Liu, X.; Feng, X. Chem. - Eur. J. 2016, 22, 18254. (7) For selected recent examples, see: (a) El-Sepelgy, O.; Haseloff, S.; Alamsetti, S. K.; Schneider, C. Angew. Chem., Int. Ed. 2014, 53, 7923. (b) Hsiao, C.-C.; Liao, H.-H.; Rueping, M. Angew. Chem., Int. Ed. 2014, 53, 13258. (c) Hsiao, C.-C.; Raja, S.; Liao, H.-H.; Atodiresei, L.; Rueping, M. Angew. Chem., Int. Ed. 2015, 54, 5762. (d) Zhao, W.; Wang, Z.; Chu, B.; Sun, J. Angew. Chem., Int. Ed. 2015, 54, 1910. (e) Saha, S.; Alamsetti, S. K.; Schneider, C. Chem. Commun. 2015, 51, 1461. (f) Lai, Z.; Wang, Z.; Sun, J. Org. Lett. 2015, 17, 6058. (g) Xu, M.-M.; Wang, H.-Q.; Wan, Y.; He, G.; Yan, J.; Zhang, S.; Wang, S.-L.; Shi, F. Org. Chem. Front. 2017, 4, 358. (8) For selected examples, see: (a) Zhang, H.-X.; Nie, J.; Cai, H.; Ma, J.-A. Org. Lett. 2014, 16, 2542. (b) Tang, X.-D.; Li, S.; Guo, R.; Nie, J.; Ma, J.-A. Org. Lett. 2015, 17, 1389. (c) Wei, A.-J.; Nie, J.; Zheng, Y.; Ma, J.-A. J. Org. Chem. 2015, 80, 3766. (d) Wei, Y.; Guo, R.; Dang, Y.; Nie, J.; Ma, J.-A. Adv. Synth. Catal. 2016, 358, 2721. (e) Moon, H. W.; Kim, D. Y. Tetrahedron Lett. 2012, 53, 6569. (f) Kang, Y. K.; Lee, H. J.; Moon, H. W.; Kim, D. Y. RSC Adv. 2013, 3, 1332. (g) Suh, C. W.; Chang, C. W.; Choi, K. W.; Lim, Y. J.; Kim, D. Y. Tetrahedron Lett. 2013, 54, 3651. (h) Kim, Y. H.; Gil, M. K.; Kim, D. Y. Bull. Korean Chem. Soc. 2017, 38, 1499. (i) Kwon, S. J.; Gil, M. K.; Kim, D. Y. Tetrahedron Lett. 2017, 58, 1592. (j) Jeong, H. J.; Kim, Y. H. Kim D. Y. Bull. Korean Chem. Soc. 2018, 39, 12. (9) For a selection of our recent work on asymmetric catalysis, see: (a) Kang, Y. K.; Kim, D. Y. Chem. Commun. 2014, 50, 222. (b) Suh, C. W.; Woo, S. B.; Kim, D. Y. Asian J. Org. Chem. 2014, 3, 399. (c) Suh, C. W.; Kim, D. Y. Org. Lett. 2014, 16, 5374. (d) Kim, Y. S.; Kwon, S. J.; D

DOI: 10.1021/acs.orglett.8b00993 Org. Lett. XXXX, XXX, XXX−XXX