Highly enantioselective conjugate addition-cyclization cascade reaction of malonates with o-hydroxycinnamaldehydes: Asymmetric synthesis of 4-substituted chromanols

Article abstract of DOI:10.1002/adsc.201100324

The asymmetric organocatalytic conjugate addition-cyclization reaction of malonates with o-hydroxycinnamaldehydes, which affords 4-substituted chroman-2-ols, has been established using a diphenylprolinol trimethylsilyl (TMS) ether as organocatalyst. The d

Full text of DOI:10.1002/adsc.201100324

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DOI: 10.1002/adsc.201100324
Highly Enantioselective Conjugate Addition–Cyclization
Cascade Reaction of Malonates with o-Hydroxycinnamaldehydes:
Asymmetric Synthesis of 4-Substituted Chromanols
Yongcheon Lee,a Seung Woo Seo,a and Sung-Gon Kima,*
a
Department of Chemistry, Kyonggi University, San 94-6, Iui-dong, Yeongtong-gu, Suwon 443-760, Republic of Korea
Fax : (+82)-31-249-9639; phone: (+82)-31-249-9631; e-mail: sgkim123@kgu.ac.kr
Received: April 27, 2011; Revised: June 22, 2011; Published online: October 6, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100324.
Abstract: The asymmetric organocatalytic conju-
gate addition–cyclization reaction of malonates with
o-hydroxycinnamaldehydes, which affords 4-substi-
tuted chroman-2-ols, has been established using a
diphenylprolinol trimethylsilyl (TMS) ether as orga-
nocatalyst. The desired products were obtained
with good to excellent yields and high enantioselec-
tivities (up to >99% ee). Synthetically useful chro-
man derivatives were formed after subsequent reac-
tions.
Scheme 1. Asymmetric organocatalytic reactions of organo-
boronic acids with o-hydroxycinnamaldehydes.
Keywords: asymmetric synthesis; chromans; conju-
gate addition; malonates; organocatalysts
lectivities in this organocatalytic reaction, arylboronic
acids appeared to work with low enantioselectivities.
With the aim of development of these findings, we
considered the use of other nucleophiles instead of or-
ganoboronic acids for the highly enantioselective cat-
alytic production of chroman derivatives. The reaction
The chroman structural unit is common to many of malonates as nucleophiles with o-hydroxycinnamal-
drugs and biologically active natural products.[1] Mole- dehydes under the action of an appropriate organoca-
cules containing chroman scaffolds exhibit a broad talyst was assumed to form 4-substituted chroman-2-
range of bioactivities, such as antiviral,[2] antitumor,[3] ols in high enantioselectivity.[12]
antimicrobial,[4] sex pheromone,[5] and central nervous
During this process, the malonate reacts through
system activities.[6] They can also be used as biode- conjugate addition with an o-hydroxycinnamaldehyde
gradable agrochemicals.[7] Their importance has to give a chiral b-substituted aldehyde, which can be
driven the development of numerous synthetic meth- hemiacetalized to a chiral 4-substituted chroman-2-
ods for chromans with recent research particularly fo- ol,[13] if the malonate serves as a nucleophile rather
cused on enantioselective approaches.[8,9] Consequent- than the OH group of the o-hydroxycinnamaldehyde
ly, the development of an efficient enantioselective for the conjugate addition (Scheme 2).[14]
synthetic method to obtain chroman scaffolds has at-
The conjugate addition of dimethyl malonate 2a
tracted our attention. Herein, we disclose the first cat- with o-hydroxycinnamaldehyde 1a[9c,15] was selected as
alytic asymmetric addition–cyclization reaction of a model reaction, and optimizations of catalysts and
malonates with o-hydroxycinnamaldehydes using an solvent were carried out, the representative results of
organocatalyst that enables a facile access to enan- which are shown in Table 1. The MacMillan imidazoli-
tioenriched 4-substituted chroman derivatives.
dinone catalyst I[16] was initially tested in this reac-
We recently reported the asymmetric synthesis of tion: the reaction did not produced the corresponding
chromans from o-hydroxycinnamaldehydes and orga- chroman-2-ol 3a and the starting material was almost
noboronic acids using an organocatalyst derived from completely recovered after 24 h (entry 1). When di-
imidazolidinone (Scheme 1).[10,11] Although arylvinyl- phenylprolinol TMS ether II as catalyst[17] and
boronic acids showed good yields with high enantiose- NaOAc as additive were used, 77% yield and 92% ee
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Table 2. Catalyst II promoted conjugate addition–cyclization
reaction of malonates (2) with o-hydroxycinnamaldehyde
(1a).[a]
Scheme 2. Organocatalytic conjugate addition–cyclization
cascade reactions of malonates with o-hydroxycinnamalde-
hydes.
[a]
Unless otherwise specified, the reaction was carried out
Table 1. Asymmetric conjugate addition–cyclization reaction
of dimethyl malonate (2a) to o-hydroxycinnamaldehyde
(1a) by organocatalyst.[a]
in CHCl3 (0.3M) with 1.2 equiv. of malonates 2 relative
to the o-hydroxycinnamaldehyde 1a in the presence of
20 mol% catalyst.
[b]
Isolated yield after chromatographic purification.
[c]
Determined by HPLC analysis after reduction.
[d]
1
Determined by H NMR analysis.
ty than those using additives (entry 5 vs. entries 2 and
4). Examination of solvent effects revealed that
CH2Cl2, CHCl3, toluene and methanol were all good
solvents for this conjugate addition reaction (en-
tries 5–8). Low catalyst loadings (10 mol% catalyst)
diminished the efficiency of the reaction, though
slightly increasing the enantioselectivity (entry 9).
Having established the optimal reaction conditions,
the scope of this reaction of various malonates 2 to o-
hydroxycinnamaldehyde 1a was explored (Table 2).
Various malonates including dimethyl, diethyl, diiso-
propyl and dibenzyl esters showed high reactivity and
excellent enantioselectivity. The benzyl ester per-
formed particularly well: the 4-substituted chroman-2-
ol 3d was obtained with 85% yield with 97% ee
(Table 2, entry 4).[18]
The generality of this asymmetric catalytic reaction
with dimethyl malonate 2a to various o-hydroxycin-
AHCTUNGTREGUNnNN amaldehydes 1 was next studied (Table 3). A broad
range of o-hydroxycinnamaldehydes was tolerated
under the tested reaction conditions. A variety of 4-
substituted chroman-2-ols 4a–h was obtained in good
yields and with excellent enantioselectivities, up to >
[a]
Unless otherwise specified, the reaction was carried out
in solvent (0.3M) with 1.2 equiv. of dimethyl malonate 2a
relative to the o-hydroxycinnamaldehyde 1a in the pres-
ence of 20 mol% catalyst and additive.
Isolated yield after chromatographic purification.
Determined by HPLC analysis after reduction.
[b]
[c]
[d]
Not determined.
10 mol% catalyst was added.
[e]
were achieved (entry 2). However, trifluoromethyl- 99% ee (Table 3, entries 4 and 8). Variation of the
substituted diarylprolinol silyl ether III afforded low substituent on the phenyl group is allowed in this re-
reactivity (13% yield, entry 3). More interestingly, al- action without significant loss of enantioselectivity,
though acid and base additives can increase reactivity which remained high, independent of the nature of
and enantioselectivity in other organocatalytic conju- the substituent, irrespective of whether electron-with-
gate addition reactions, including the reaction of mal- drawing (entries 1–5) or electron-donating (entries 6–
onates to a,b-unsaturated aldehydes, no advantage 8) groups were included. The reaction was also found
was observed in this reaction. The reaction without to be unaffected by steric hindrance (entries 3, 4 and
additive showed better reactivity and enantioselectivi- 8).
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Highly Enantioselective Conjugate Addition–Cyclization Cascade Reaction of Malonates
Table 3. Organocatalytic asymmetric conjugate addition–cy-
cinnamaldehyde 1a as an a,b-unsaturated aldehyde by
catalyst II forming the iminium ion 5. This then reacts
with dimethyl malonate 2a in a 1,4-addition via the
formation of enamine 6 to produce intermediate 7.
Subsequent hydrolysis and cyclization provide the
chroman-2-ol 3a and regenerate catalyst II. Wang and
co-workers reported that the aminal 8, which was gen-
erated from iminium ion 5 through the isomerization
of the C=C bond and subsequent cyclization, was a
key intermediate functioning as active nucleophile in
the Michael reaction with nitroolefins.[9c] However,
we exclude this intermediate aminal 8 in our pro-
posed mechanism due to its reduced electrophilicity
compared to intermediate imminium ion 5.[19]
ACHTUNGTRENNUNGclization reaction of dimethyl malonate (2a) to o-hydroxy-
cinnamaldehydes (1).[a]
[a]
Unless otherwise specified, the reaction was carried out
in CHCl3 (0.3M) with 1.2 equiv. of dimethyl malonate 2a
relative to the o-hydroxycinnamaldehydes 1 in the pres-
ence of 20 mol% catalyst.
[b]
Isolated yield after chromatographic purification.
[c]
Determined by HPLC analysis after reduction.
[d]
1
Determined by H NMR analysis.
The proposed mechanism of this organocatalytic
conjugate addition–cyclization cascade reaction of o-
hydroxycinnamaldehyde 1a with dimethyl malonate
2a by catalyst II is depicted in Scheme 3. The reaction
sequence starts with the activation of the o-hydroxy-
Scheme 4. Various transformations of 4-substituted chro-
man-2-ols.
Scheme 3. Proposed mechanism of the organocatalytic conjugate addition–cyclization reaction of dimethyl malonate (2a) to
o-hydroxycinnamaldehyde (1a).
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Scheme 5. Determination of the absolute configuration.
Scheme 4 outlines some transformations of the 4- J=7.6 Hz, 0.6H), 3.64–3.87 (m, 1H), 3.76 (s, 1.2H), 3.73 (s,
1.8H), 3.71 (s, 1.8H), 3.69 (s, 1.2H), 3.64 (brs, 0.4H), 3.48
(brs, 0.6H), 2.27–2.38 (m, 1H), 2.01–2.19 (m, 1H); 13C NMR
(100 MHz, CDCl3): d=169.5 (minor), 168.8 (minor), 168.7
(major), 168.3 (major), 152.1 (major), 152.0 (minor), 128.8
(minor), 128.5 (major), 128.4 (minor), 127.1 (major), 122.3
(major), 121.5 (minor), 121.0 (major), 120.9 (minor), 117.5
(major), 117.4 (minor), 92.6 (minor), 91.4 (major), 55.8
(minor), 54.5 (major), 52.7 (major), 52.6 (minor), 52.5
(minor), 52.3 (major), 32.5 (minor), 31.3 (major), 30.5
(major), 30.0 (minor); HR-MS: m/z=280.0945, [M+]: calcd.
substituted chroman-2-ols. Chiral 4-substituted chro-
man-2-on 9, 4-substituted chroman 10 and 2-hydroxy-
phenyl compound 11 could be made in good yields
through the respective oxidation, reduction and
Wittig reactions of compound 3a.
Finally, the absolute configuration of the chroman-
2-ols 3 and 4 was determined as follows: methylation
of alcoholic compound 12 afforded the methyl ether
compound 13, which is in good agreement having the
same (À)-sign for its optical rotation, as determined for C14H16O6 [M+]: 280.0947.
by polarimeter anlaysis, with an authentic sample pre-
pared from the known compound 14[20] (Scheme 5).
In conclusion, an asymmetric organocatalytic conju-
gate addition–cyclization cascade reaction of malo-
Acknowledgements
This research was supported by Basic Science Research Pro-
nates with o-hydroxycinnamaldehydes was developed
to produce chiral 4-substituted chroman-2-ols in good
to excellent yields with up to >99% ee. The resulting
products could readily form chiral chroman deriva-
tives through oxidation, reduction and Wittig reac-
tion. Thus the present approach provides a useful ap-
proach for the synthesis of chiral chroman derivatives
under mild reaction conditions.
gram through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (2010-0004139).
References
[1] a) G. P. Ellis, I. M. Lockhart, in: The Chemistry of Het-
erocyclic Compounds, Chromenes, Chromanones, and
Chromones, (Ed.: G. P. Ellis), Wiley-VCH, New York,
2007, Vol. 31, pp 1–1196; b) G. R. Geen, J. M. Evans,
A. K. Vong, in: Comprehensive Heterocyclic Chemistry
II: Pyrans and their Benzo Derivatives: Applications,
(Ed.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven),
Pergamon Press, Oxford, UK, 1996, Vol. 5, pp 469–500;
c) D. A. Horton, G. T. Boume, M. L. Smythe, Chem.
Rev. 2003, 103, 893.
[2] a) C. Conti, N. Desideri, Bioorg. Med. Chem. 2009, 17,
3720; b) G. A. Kraus, J. Mengwasser, W. Maury, C. Oh,
Bioorg. Med. Chem. Lett. 2011, 21, 1399.
[3] a) Y. Dong, K. Nakagawa-Goto, C.-Y. Lai, S. L. Morris-
Natschke, K. F. Bastow, K.-H. Lee, Bioorg. Med. Chem.
Lett. 2010, 20, 4085; b) T. Hahn, L. Szabo, M. Gold, L.
Ramanathapuram, L. H. Hurley, E. T. Akporiaye,
Cancer Res. 2006, 66, 9374.
[4] a) N. Hoettecke, S. Rotzoll, U. Albrecht, M. Lalk, C.
Fischer, P. Langer, Bioorg. Med. Chem. 2008, 16,
10319; b) M. Cacic, M. Trkovnik, F. Cacic, E. Has-
Schon, Molecules 2006, 11, 134; c) B. S. Basappa Priya,
S. N. Swamy, K. S. Rangappa, Bioorg. Med. Chem.
2005, 13, 2623.
[5] G. Bianchi, A. Tava, Agric. Biol. Chem. 1987, 51, 2001.
[6] M. Koufaki, C. Kiziridi, X. Alexi, M. N. Alexi, Bioorg.
Med. Chem. 2009, 17, 6432.
Experimental Section
Typical Procedure (Table 2, entry 1)
An amber 2-dram vial equipped with a magnetic stir bar,
containing catalyst II (16 mg, 0.05 mmol) and o-hydroxycin-
namaldehyde 1a (37 mg, 0.25 mmol) was charged with
chloroform (0.8 mL) at room temperature. The solution was
stirred for 5 min before the addition of dimethyl malonate
2a (34 mL, 0.30 mmol). The resulting mixture was stirred at
constant temperature until complete consumption of o-hy-
droxycinnamaldehyde 1a was observed as determined by
TLC. The resulting mixture was directly purified by silica
gel chromatography (20% EtOAc/hexanes) to afford the de-
sired compound 3a as a colorless gum; yield: 62 mg (89%
yield, 96% ee). The enantioselectivity was determined by
HPLC analysis of the chroman 9, which was prepared by
subsequent reduction (Et3SiH/BF3·Et2O, CH2Cl2), using a
Chiralcel AD-H column and AD-H guard column (5%
EtOH:hexanes, 1.0 mLminÀ1 flow, l=220 nm); minor-
isomer tr =12.6 min and major-isomer tr =26.9 min; [a]2D2:
1
À58.8 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): d=7.03–
7.20 (m, 2H), 6.83–6.92 (m, 2H), 5.69 (dd, J=3.2, 5.2 Hz,
0.6H), 5.64 (brs, 0.4H), 4.37 (d, J=9.6 Hz, 0.4H), 4.02 (d,
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Highly Enantioselective Conjugate Addition–Cyclization Cascade Reaction of Malonates
[7] K. M. Meepagala, K. K. Schradert, C. L. Burandt, D. E.
Wedge, O. D. Stephen, J. Agric. Food Chem. 2010, 58,
9476.
Chem. 2007, 119, 8583; Angew. Chem. Int. Ed. 2007, 46,
8431; e) S. Brandau, A. Landa, J. Franzꢃn, M. Marigo,
K. A. Jørgensen, Angew. Chem. 2006, 118, 4411;
Angew. Chem. Int. Ed. 2006, 45, 4305.
[8] For the synthesis of achiral chroman derivatives, see:
a) X. Meng, Y. Huang, H. Zhao, P. Xie, J. Ma, R. Chen,
Org. Lett. 2009, 11, 991; b) Y. Yamamoto, K. Itonaga,
Org. Lett. 2009, 11, 717; c) F. Ulgheri, M. Marchetti, O.
Piccolo, J. Org. Chem. 2007, 72, 6056; d) A. Jagdale,
R. A. Sudalai, Tetrahedron Lett. 2007, 48, 4895; e) K.
Li, K. Vanka, W. H. Thompson, J. A. Tunge, Org. Lett.
2006, 8, 4711; f) C. Hedberg, P. G. Andersson, Adv.
Synth. Catal. 2005, 347, 662; g) Z. Shi, C. He. J. Am.
Chem. Soc. 2004, 126, 13596.
[9] For the asymmetric synthesis of chroman derivatives,
see: a) H.-H. Lu, H. Liu, W. Wu, X.-F. Wang, L.-Q. Lu,
W.-J. Xiao, Chem. Eur. J. 2009, 15, 2742; b) M. Yoshida,
M. Higuchi, K. Shishido, Org. Lett. 2009, 11, 4752; c) L.
Zu, S. Zhang, H. Xie, W. Wang, Org. Lett. 2009, 11,
1627; d) L. Hong, L. Wang, W. Sun, K. Wong, R. Wang,
J. Org. Chem. 2009, 74, 6881; e) M. Rueping, E. Sugio-
no, E. Merino, Chem. Eur. J. 2008, 14, 6329; f) P. T.
Franke, B. Richter, K. A. Jørgensen, Chem. Eur. J.
2008, 14, 6317.
[10] a) K.-S. Choi, S.-G. Kim, Tetrahedron Lett. 2010, 51,
5203; b) K.-S. Choi, S.-G. Kim, Synthesis 2010, 3999.
[11] For selected recent organocatalysis reviews, see: a) S.
Bertelsen, K. A. Jørgensen, Chem. Soc. Rev. 2009, 38,
2178; b) A. Dondoni, A. Massi, Angew. Chem. 2008,
120, 4716; Angew. Chem. Int. Ed. 2008, 47, 4638; c) H.
Pellisier, Tetrahedron 2007, 63, 9267; d) S. Mukherjee,
J. W. Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107,
5471; e) A. Erkkilꢁ, I. Majander, P. M. Pihko, Chem.
Rev. 2007, 107, 5416.
[13] For recent examples having the similar strategy on or-
ganocatalytic conjugate addition–cyclization cascade re-
action, see: a) M. Rueping, E. Merino, E. Sugiono,
Adv. Synth. Catal. 2008, 350, 2127; b) M. Rueping, E.
Sugiono, E. Merino, Angew. Chem. 2008, 120, 3089;
Angew. Chem. Int. Ed. 2008, 47, 3046; c) Ref.[9e]
[14] For examples of the phenol OH group which has
served as nucleophile, see: a) M. Rueping, M.-Y. Lin,
Chem. Eur. J. 2010, 16, 4169; b) K. Liu, A. Chougnet,
W.-D. Woggon, Angew. Chem. 2008, 120, 5911; Angew.
Chem. Int. Ed. 2008, 47, 5827; c) M. M. Biddle, M. Lin,
K. A. Scheidt, J. Am. Chem. Soc. 2007, 129, 3830; d) H.
Sundꢃn, I. Ibrahem, G. L. Zhao, L. Eriksson, A. Cꢄrdo-
va, Chem. Eur. J. 2007, 13, 574; e) H. Li, J. Wang, T. E-
Nunu, L. Zu, W. Jiang, S. Wei, W. Wang, Chem.
Commun. 2007, 507.
[15] a) K. Zeiter, C. A. Rose, J. Org. Chem. 2009, 74, 1759;
b) J. H. Kim, S. Lee, M.-G. Kwon, Y. S. Park, S.-K.
Choi, B.-M. Kwon, Synth. Commun. 2004, 34, 1223.
[16] For a review on MacMillan’s imidazolidinone catalyst,
see: G. Lelais, D. W. C. MacMillan, Aldrichimica Acta
2006, 39, 79.
[17] For a review of diarylprolinol silyl ether as catalyst,
see: A. Mielgo, C. Palomo, Chem. Asian J. 2008, 3, 922.
[18] In order to expand reaction scope, malonitrile has been
used in this reaction as nuleophile, but the reaction was
complicated and the corresponding chroman-2-ol prod-
uct was only obtained in 23% yield.
[19] For more precise reaction mechanism, the reaction of
dimethyl malonate 2a and aminal 8 was performed
under the above mentioned reaction conditions. How-
ever, we could not obtain the desired compound 3a in
this reaction.
[12] For organocatalytic conjugate addition of malonates to
a,b-unsaturated aldehydes, see: a) I. Fleischer, A.
Pfaltz, Chem. Eur. J. 2010, 16, 95; b) O. V. Maltsev,
A. S. Kucherenko, S. G. Zlotin, Eur. J. Org. Chem.
2009, 5134; c) Y. Wang, P. Li, X. Liang, J. Ye, Adv.
Synth. Catal. 2008, 350, 1383; d) C. Palomo, A. Landa,
A. Mielgo, M. Oiarbide, ꢂ. Puente, S. Vera, Angew.
[20] H. Sato, F. Nagashima, T. Oriyama, Chem. Lett. 2010,
39, 379.
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