C O M M U N I C A T I O N S
Table 2. Scope of Cyclization/Decarboxylationa
Acknowledgment. Financial support for this work has been
provided by Northwestern (Summer Research Fellowship to M.L.),
Abbott Laboratories, Amgen, 3M, and Boehringer Ingelheim.
M.M.B. acknowledges NIH for a postdoctoral training fellowship
(T32 AG00260) directed by the Northwestern University Center
for Drug Discovery and Chemical Biology. We thank FMCLithium
and BASF for reagent support and Troy Reynolds (NU) for
assistance with X-ray crystallography.
entry
R
R1
R2
product
ee (%)b,c
yield (%)d
1
2
3
4
5
6
7
8
9
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
7
8
9
10
11
12
13
14
15
16
94
92
91
90
88
91e
89
90
89
80
92
65
89
83
67
94
71
97
78
65
4-BrPh
2-naphthyl
4-CH3-Ph
2-Cl-Ph
4-OMe-Ph
Ph
Supporting Information Available: Complete ref 2b, experimental
procedures, and spectral data for all new compounds (PDF). This
OMe
Me
-(CH)4-
H
References
Ph
Ph
(1) (a) Harborne, J. B., Ed. The FlaVonoids. AdVances in Research Since 1980;
Chapman and Hall: New York, 1988. (b) Harborne, J. B.; Williams, C.
A. Nat. Prod. Rep. 1995, 12, 639-657. (c) Chang, L. C.; Kinghorn, A.
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Ltd.: London, 2001; Chapter 5. (d) FlaVonoids: Chemistry, Biochemistry
and Applications; Andersen, Ø. M., Markham, K. R., Eds.; Taylor &
Francis Ltd.: London, 2006.
10
cyclohexyl
H
a Reaction conditions: 0.1 M of ester. b Determined by HPLC analysis
(Chiralcel OD-H). c Absolute configuration determined by comparison of
optical rotation to literature values.7 d Yield after chromatography. e De-
termined prior to decarboxylation; see ref 12.
(2) (a) Chen, H. Y.; Dykstra, K. D.; Birzin, E. T.; Frisch, K.; Chan, W.; Yang,
Y. T.; Mosley, R. T.; DiNinno, F.; Rohrer, S. P.; Schaeffer, J. M.;
Hammond, M. L. Bioorg. Med. Chem. Lett. 2004, 14, 1417-1421. (b)
Tan, Q.; et al. Bioorg. Med. Chem. Lett. 2005, 15, 1675-1681.
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Lett. 1970, 26, 2305-2308.
excellent yield. Different phenol moieties can also be accommodated
in the reaction, including electron-rich (entry 7) and extended
aromatic substrates (entry 9). The cyclohexyl-substituted alkylidene
also undergoes cyclization to afford chromanone 16 in good
enantioselectivity (80% ee, entry 10).13
Alkyl-substituted alkenes (R ) alkyl) are challenging to purify
due to minor amounts of nonselective cyclization. Since the
Knoevenagel and conjugate addition reactions are both performed
in toluene, these reactions can be merged in a tandem procedure
(eq 4). The combination of 18, hydrocinnamaldehyde (19), acetic
acid, piperidine, and I14 in the presence of molecular sieves in
toluene at room temperature affords the natural product flindersi-
achromanone15 (20) in 80% ee and 77% overall yield after
decarboxylation with p-TsOH.
(4) (a) Noda, Y.; Wantanabe, M. HelV. Chim. Acta 2002, 85, 3473-3477.
(b) Hodgetts, K. J. Tetrahedron 2005, 61, 6860-6870.
(5) Brown, M. K.; Degrado, S. J.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2005, 44, 5306-5310.
(6) Kabbe, H. J.; Widdig, A. Angew. Chem., Int. Ed. 1982, 21, 247-256.
(7) See Supporting Information for details.
(8) For reviews of thiourea catalysis, see: (a) Takemoto, Y. Org. Biomol.
Chem. 2005, 3, 4299-4306. (b) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2006, 45, 1520-1543. (c) Connon, S. J. Chem.sEur. J.
2006, 12, 5418-5427.
(9) For developments and applications of cinchona-derived thioureas, see:
(a) Vakulya, B.; Varga, S.; Csampai, A.; Soo´s, T. Org. Lett. 2005, 7,
1967-1969. (b) Mccooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed.
2005, 44, 6367-6370. (c) Ye, J. X.; Dixon, D. J.; Hynes, P. S. Chem.
Commun. 2005, 4481-4483. (d) Bernardi, L.; Fini, F.; Herrera, R. P.;
Ricci, A.; Sgarzani, V. Tetrahedron 2006, 62, 375-380. (e) Tillman, A.
L.; Ye, J. X.; Dixon, D. J. Chem. Commun. 2006, 1191-1193. (f) Mattson,
A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc.
2006, 128, 4932-4933. (g) Song, J.; Wang, Y.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 6048-6049. (h) Wang, J.; Li, H.; Zu, L. S.; Jiang, W.;
Xie, H. X.; Duan, W. H.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652-
12653.
(10) For developments and applications of chiral cyclohexylamine-derived
thiourea catalysis, see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y.
Tetrahedron Lett. 2003, 44, 2817-2821. (b) Taylor, M. S.; Jacobsen, E.
N. J. Am. Chem. Soc. 2004, 126, 10558-10559. (c) Berkessel, A.;
Cleemann, F.; Mukherjee, S.; Muller, T. N.; Lex, J. Angew. Chem., Int.
Ed. 2005, 44, 807-811. (d) Yoon, T. P.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2005, 44, 466-468. (e) Okino, T.; Hoashi, Y.; Furukawa, T.;
Xu, X. N.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119-125. (f)
Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964-8965.
(g) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed. 2005,
44, 4032-4035. (h) Tsogoeva, S. B.; Yalalov, D. A.; Hately, M. J.;
Weckbecker, C.; Huthmacher, K. Eur. J. Org. Chem. 2005, 4995-5000.
(i) Berkessel, A.; Cleemann, F.; Mukherjee, S. Angew. Chem., Int. Ed.
2005, 44, 7466-7469. (j) Li, H.; Zu, L. S.; Wang, J.; Wang, W.
Tetrahedron Lett. 2006, 47, 3145-3148.
(11) (a) Ref 9a. (b) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J.
H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 929-931. (c) Li, H.;
Wang, J.; Zu, L. S.; Wang, W. Tetrahedron Lett. 2006, 47, 2485-2589.
(12) The 4′-methoxyphenyl substrate (12, R ) 4-OMe-Ph) affords racemic
product under p-TsOH conditions. The decarboxylation using MgBr2‚OEt2
affords the 4′methoxy flavanone in 78% ee.
Our preliminary understanding of this reaction invokes hydrogen
bonding between the â-ketoester substrate and chiral thiourea. The
interaction between the quinuclidine nitrogen and phenol then
promotes the selective intramolecular conjugate addition. Impor-
tantly, tertiary amine and thiourea functional groups together in a
single catalyst deliver high selectivity. For example, quinine as a
catalyst for the reaction (20 mol %) results in low enantioselectivity
(17% ee), and the bis(3,5-CF3phenyl)thiourea alone does not
promote cyclization when combined with 5 in toluene. Additionally,
the combination of 20 mol % each of quinine and bis(3,5-CF3-
phenyl)thiourea affords only 23% ee of 6.
In summary, we have developed an enantioselective method for
the synthesis of flavanones and chromanones. This is a novel
example of a bifunctional quinine-derived thiourea catalyst activat-
ing a â-ketoester alkylidene substrate and promoting a conjugate
addition of a phenol to deliver enantioenriched flavanones and
chromanones. Mechanistic investigations of the reaction and its
application toward biologically active molecules are currently in
progress.
(13) The Z-isomer alkylidenes have not been synthesized yet. However, no
equilibration of the E-isomers has been observed under the reaction
conditions (1H NMR spectroscopy).
(14) The use of catalyst III instead of I affords lower enantioselectivity at
23 °C, the temperature required for the Knoevenagel reaction.
(15) Picker, K.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1976, 29, 2023-2036.
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