Enantioselective Decarboxylative Alkylation of β-Keto Acids to ortho-Quinone Methides as Reactive Intermediates: Asymmetric Synthesis of 2,4-Diaryl-1-benzopyrans

Article abstract of DOI:10.1021/acs.orglett.8b00993

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-1-benzopyran derivatives with a wide range of functional group tolerance.

Full text of DOI:10.1021/acs.orglett.8b00993

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Decarboxylative Alkylation of β‑Keto Acids to ortho-
Quinone 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 deriv-
atives 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-1-
benzopyran derivatives with a wide range of functional group tolerance.
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
Scheme 1. Strategy for the Synthesis of 2,4-Diaryl-1-
benzopyrans
Figure 1. Examples of bioactive compounds containing 2,4-diaryl-1-
benzopyran 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 demon-
strated another catalytic enantioselective synthesis of chiral 2,4-
diaryl-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-1-
benzopyrans is highly desired.
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
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-
Received: March 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00993
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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 intermedi-
ates using chiral phosphoric acids,11 followed by sequential
cyclization and dehydration.
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 test this concept, we started with the reaction between β-
keto 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
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 o-
hydroxy 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 electron-
withdrawing 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).
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
cat.
additive
solvent
yield (%)
ee (%)
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
1
4a
4a
4b
4c
4d
4e
4f
−
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
trace
35
45
51
47
40
35
79
60
60
23
55
68
51
45
52
56
75
−
2
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
32
45
27
21
71
50
89
71
81
80
91
74
44
36
27
73
91
3
4
5
6
7
8
4g
4h
4g
4g
4g
4g
4g
4g
4g
4g
4g
9
10
11
12
13
14
15
16
17
TCE
CH2Br2
CCl4
PhMe
d
18
CHCl3
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.
Isolated yield. Enantiopurity was determined by HPLC analysis
using Chiralpak AD-H column. Reaction was carried out at 60 °C at
second step.
b
c
d
B
DOI: 10.1021/acs.orglett.8b00993
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a−c
Scheme 2. Substrate Scope with β-Keto Acids 2
Scheme 4. Gram Scale Synthesis of (R)-2,4-Diphenyl-4H-1-
benzopyran (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 enantio-
selective decarboxyaltive alkylation of β-keto acids to o-QM
intermediates, followed by sequential cyclization and dehy-
dration. 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
b
c
°C. Isolated yield. Enantiopurity was determined by HPLC analysis
using Chiralpak AD-H column.
Scheme 3. Substrate Scope with o-Hydroxy Benzylic
Alcohols 1
a−c
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00993.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dyoung@sch.ac.kr.
ORCID
Dae Young Kim: 0000-0002-6337-7505
Notes
a
The authors declare no competing financial interest.
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
ACKNOWLEDGMENTS
■
b
c
°C. Isolated yield. Enantiopurity was determined by HPLC analysis
using Chiralpak AD-H column.
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

Organic Letters
Letter
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 (NRF-
2016R1D1A1B03933723).
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.; Proenca
̧ , 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.; Proenca
̧ , 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