Highly enantioselective dimerization of α,β-enones catalyzed by a rigid quaternary ammonium salt

Article abstract of DOI:10.1021/ol048583v

(Chemical Equation Presented) The chiral quaternary ammonium salt 1 served as a phase-transfer catalyst for the enantioselective dimerization of α,β-enones, providing a route for the asymmetric syntheses of chiral 1,5-dicarbonyl compounds and α-alkylated

Full text of DOI:10.1021/ol048583v

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3397-3399
Highly Enantioselective Dimerization of
r,â-Enones Catalyzed by a Rigid
Quaternary Ammonium Salt
Fu-Yao Zhang† and E. J. Corey*
Department of Chemistry and Chemical Biology HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received July 21, 2004
ABSTRACT
The chiral quaternary ammonium salt 1 served as a phase-transfer catalyst for the enantioselective dimerization of r,â-enones, providing a
route for the asymmetric syntheses of chiral 1,5-dicarbonyl compounds and r-alkylated γ-keto acids.
Enantioselective phase-transfer catalysis by chiral quaternary
ammonium salts is an attractive and important approach for
organic synthesis in both academia and industry because of
the advantages of mild conditions, simple reaction proce-
dures, safe and inexpensive reagents and solvents, and metal-
free conditions. Among all developed chiral phase-transfer
catalysts, chiral quaternary N-(9-anthracenylmethyl)cin-
chonidium cations 1 and 2 have been shown to be especially
useful and versatile catalysts for a variety of enantioselective
reactions, for example, alkylation,1-3 Michael,4 aldol,5 and
epoxidation6 processes. With these catalysts, enantioselec-
tivities of >20:1 have frequently been observed in the above
reactions. In addition, these chiral catalysts have been applied
to control diastereoselectivity in nitro aldol reactions of
aldehydes with nitromethane.7 These methodologies have
been demonstrated for the syntheses of several different types
of compounds including chiral R-amino acids, γ-amino acids,
R-hydroxy ketones, and â-hydroxy ketones as well as a
highly efficient and practical synthesis of the HIV protease
inhibitor amprenavir. We have recently described the enan-
tioselective Michael addition of acetophenone to chalcones
catalyzed by a chiral quaternary N-(9-anthracenylmethyl)-
cinchonidium cation 1 to form the Michael adduct with 80%
ee.8 The enantioselectivity of this Michael addition has
further been improved to 95% ee using trimethylsilyl enol
ethers as reactants.9 The utility of this transformation was
illustrated by syntheses of chiral δ-keto acids and chiral
2-cyclohexenones. In continuing this work, we found that
R,â-enones with a γ-proton can be dimerized under chiral
phase-transfer conditions to provide chiral 1,5-dicarbonyl
compounds in high yield and high enantioselectivity through
an enantioselective Michael reaction-double-bond transposi-
tion sequence. This process with the chiral quaternary
ammonium salt 1 as catalyst and its application to the
syntheses of chiral γ-keto acids are described herein.
† Current address: Lilly Research Laboratories, A Division of Eli Lilly
and Company, Chemical Product Research and Development Division,
Indianapolis, IN 46285.
(1) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.
(2) Corey, E. J.; Bo, Y.; Busch-Petersen, J. J. Am. Chem. Soc. 1998,
120, 13000.
(3) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347.
(4) Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257.
(5) Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett.
1999, 40, 3843.
(6) Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287.
(7) Corey, E. J.; Zhang, F.-Y. Angew. Chem., Int. Ed. 1999, 38, 1931.
10.1021/ol048583v CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/14/2004

Treatment of 1-phenyl-2-buten-1-one (3) with 5 mol %
of catalyst 1 in toluene and 50% aq KOH led to the formation
of a chiral coupling product in 87% yield and with 89%
enantiomeric purity (ee) as determined by HPLC analysis
using a chiral column. The structure of this compound was
The data in Table 1 reveal some noteworthy features of
the dimerization reaction: (1) in general, good yields (80-
90% range) and high enantioselectivities (86-98% ee) were
achieved at -40 °C under the standard conditions using a
simple and reproducible procedure; (2) R,â-enones with an
electron-withdrawing substituent on the phenyl ring provided
higher enantioselectivities than those with an electron-
donating substituent (entries 3 and 4 vs 5), which is consistent
with the previous experience in Michael and epoxidation
reactions with catalyst 2;6,9 (3) higher enantioselectivity was
observed for R,â-enones having a bulkier substituent than
methyl at C(â) of the R,â double bond (entries 6 and 7 vs 1
and 2), although the dimerization reaction was relatively
slower; (4) as usual, higher enantioselectivity was observed
at lower reaction temperatures (entry 2 vs 1).
1
shown to be 4 by H NMR, 13C NMR, NOE, and MS
analysis. This dimerization of 1-phenyl-2-buten-1-one clearly
occurs via an enantioselective Michael reaction to form 5,
followed by base-catalyzed â,γ-R,â-double bond transposi-
tion (Scheme 1). None of the isomeric dimer 6 could be
detected.
Scheme 1
The absolute configurations for the chiral products (4 and
7a-e) were verified to be as predicted by the previously
described mechanistic model6,8 by comparison of the optical
rotation with literature data after conversion of the products
4 and 7d to the γ-keto acids 910 and 10.11 The face selectivity
of the dimerization is in agreement with the results previously
(8) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097.
(9) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2001, 3, 639.
(10) Hoffman, R. V.; Kim, H. O. J. Org. Chem. 1995, 60, 5107.
(11) Cregge, R. J.; Durham, S. L.; Farr, R. A.; Gallion, S. L.; Hare, C.
M.; Hoffman, R. V.; Janusz, M. J.; Kim, H. O.; Koehl, J. R.; Mehdi, S.;
Metz, W. A.; Peet, N. P.; Pelton, J. T.; Schreuder, H. A.; Sunder, S.; Tardif,
C. J. Med. Chem. 1998, 41, 2461.
(12) McEvoy, F. J.; Lai, F. M.; Albright, J. D. J. Med. Chem. 1983, 26,
381.
(13) Nakamura, E.; Sekiya, K.; Kuwajima, I. Tetrahedron Lett. 1987,
28, 337.
(14) Hoffman, R. V.; Kim, H. O. Tetrahedron Lett. 1993, 34, 2051.
(15) Noguchi, T.; Onodera, A.; Tomisawa, K.; Yamashita, M.; Takeshita,
K.; Yokomori, S. Bioorg. Med. Chem. 2002, 10, 2713.
Various other R,â-enones possessing a γ-C-H subunit were
also tested as substrates for this dimerization. Table 1
(16) Preparation of 4. To a cold (-40 °C) mixture of 1-phenyl-2-buten-
1-one (3) (67.0 mg, 0.5 mmol) and chiral quaternary salt 1 (14.4 mg, 0.025
mmol) in toluene (2.5 mL) was added 0.5 mL of 50% KOH aqueous
solution. After being stirred at -40 °C for 12 h, the reaction mixture was
treated with 10 mL of diethyl ether and 5.0 mL of water. The organic phase
was separated, concentrated, and purified by flash chromatography (silica
gel, 9:1 hexanes-ethyl acetate) to afford 4 (58.3 mg, 87% yield, 89% ee)
as a thick oil. Found for 4: [R]23D ) -6.2 (c ) 2.0, CH2Cl2); FTIR (film)
2928.5, 1685.2, 1645.5, 1597.8, 1271.7 cm-1; 1H NMR (400 MHz, CDCl3)
7.97-7.35 (m, 10H), 6.18 (q, J ) 7.0 Hz, 1H), 3.60 (m, 2H), 3.34 (m,
1H), 1.94 (d, J ) 7.0 Hz, 3H), 1.33 (d, J ) 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 200.1, 199.5, 144.5, 139.9, 139.5, 137.3, 132.9, 131.7,
129.6, 128.5, 128.1, 128.0, 43.4, 29.7, 29.2, 19.4, 14.1 ppm; HRMS (CI+)
calcd [C20H20O2 + H]+ 293.1540, found 293.1541. The ee of product 4
was determined by HPLC analysis with a Chiralcel OB-H column, 1%
isopropyl alcohol in hexanes, 1.0 mL per min, λ ) 254 nm, retention times
of the enantiomers of 4: 12.4 min (minor), 23.5 min (major).
(17) Conversion of 4 to 9. A cold (-78 °C) solution of 4 (58.4 mg, 0.2
mmol) in ethyl acetate was treated with a stream of ozone until a blue
color appeared (ca. 3 min). The excess of ozone was removed by sparging
with nitrogen, and 0.5 mL of 30% hydrogen peroxide and 0.5 mL of glacial
acetic acid were added at -78 °C. This mixture was warmed to ambient
temperature and was stirred at this temperature for 22 h. The reaction mixture
was extracted with ethyl acetate (10 mL) and then washed with brine. After
evaporation of solvent, the residue was purified by preparative TLC (silica
gel, 9:1 CH2Cl2-MeOH) to give 34.6 mg of 9 as a colorless solid (90%
yield). Found for 9: [R]23D ) +28.4 (c ) 1.0, CHCl3); FTIR (film) 1706.8,
Table 1. Enantioselective Dimerization of R,â-Enones
Catalyzed by 1
T (°C),
yielda ee (%),b
entry
X
R
prod time (h)
(%)
config
1
2
3
4
5
6
7
H
H
F
CH3
CH3
CH3
CH3
4
4
23, 0.5
-40, 12
-40, 12
-40, 12
-40, 48
-40, 36
-40, 48
92
87
89
97
80
81
79
83, R
89, R
90, R
88, R
86, R
98, S
97, S
7a
7b
7c
7d
7e
Cl
OMe CH3
H
H
Isopropyl
Cyclohexyl
a Isolated yield after chromatography. b ee was determined by HPLC
analysis using chiral columns (Chiralcel OB-H and OJ).
1681.1, 1216.9 cm-1 1H NMR (500 MHz, CDCl3) 7.97-7.44 (m, 5H),
;
3.47 (dd, J ) 17.5, 7.5 Hz, 1H), 3.17 (m, 1H), 3.07 (d, J ) 17.5 Hz, 1H),
1.32 (d, J ) 6.5 Hz, 3H). The configuration of 9 was assigned by comparison
of the optical rotation with literature data.10 The γ-keto acid 10 was prepared
similarly. Data for 10: [R]23 ) +31.8 (c ) 1.0, MeOH); FTIR (film)
summarizes the results of experiments with these R,â-enones
under the standard chiral phase-transfer conditions with 1
(5 mol %) as catalyst, toluene as the organic phase, and 50%
aqueous KOH as base.
D
2990.2, 1706.9, 1689.5, 1224.8 cm-1; 1H NMR (400 MHz, CDCl3) 7.97-
7.46 (m, 5H), 3.47 (dd, J ) 17.2, 7.2 Hz, 1H), 3.30 (m, 2H), 0.98 (d, J )
7.6 Hz, 6H). The configuration of 10 was assigned by comparison of the
optical rotation with literature data.11
3398
Org. Lett., Vol. 6, No. 19, 2004

observed for other types of Michael reactions of R,â-enones,
for which a clear mechanistic rationale has been provided.
The products of this dimerization are useful intermediates
for the syntheses of chiral γ-keto acids, important chiral
backbones for the preparation of peptide mimetics (peptide
isosteres) in drug discovery, such as, human neutrophile
elastase inhibitors11 and angiotensin converting enzyme
inhibitors.12 Preparation of chiral γ-keto acids was previously
problematic.13-15 To our knowledge, no catalytic asymmetric
route to these compounds has been reported previously. The
chiral γ-keto acids 9 and 10 were easily synthesized by
ozonolysis of 4 and 7d at -78 °C in ethyl acetate, followed
by oxidation with hydrogen peroxide at ambient temperature
in 90% yield (Scheme 2).
Scheme 2
acids, which are important intermediates for preparation of
peptide isosteres. The following procedures are illustra-
tive.16,17
In summary, we have developed a novel catalytic asym-
metric dimerization of R,â-enones having a proton at C(γ)
involving an enantioselective Michael reaction with an initial
N-(9-anthracenylmethyl)cinchonidium hydroxide as a chiral
catalyst. Using this methodology, we have demonstrated a
simple and practical pathway to chiral R-alkylated γ-keto
Supporting Information Available: Physical data are
given for compounds 7a-e. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL048583V
Org. Lett., Vol. 6, No. 19, 2004
3399