Mechanism and conditions for highly enantioselective epoxidation of α,β-enones using charge-accelerated catalysis by a rigid quaternary ammonium salt

Article abstract of DOI:10.1021/ol990964z

(Matrix presented) Highly enantioselective (up to 130:1) epoxidation of a variety of α,β-enones to form α,β-epoxy ketones is described along with a rational analysis of the mechanistic basis for this strong absolute stereochemical control by the chiral ca

Full text of DOI:10.1021/ol990964z

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1287-1290
Mechanism and Conditions for Highly
Enantioselective Epoxidation of
r,â-Enones Using Charge-Accelerated
Catalysis by a Rigid Quaternary
Ammonium Salt
E. J. Corey* and Fu-Yao Zhang
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford
Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received August 19, 1999
ABSTRACT
Highly enantioselective (up to 130:1) epoxidation of a variety of r,â-enones to form r,â-epoxy ketones is described along with a rational
analysis of the mechanistic basis for this strong absolute stereochemical control by the chiral catalyst 2.
We have recently reported the development of the chiral
quaternary cinchonidinium cation 1 as a superior catalyst
for enantioselective alkylation1,2 and Michael,3 aldol,4 and
nitroaldol5 reactions. For example, with 1 as catalyst a wide
variety of chiral R-amino acids can be synthesized with
enantioselectivities as high as 400:1 by alkylation of the
benzophenone Schiff base of tert-butyl glycinate.1,6 The
mechanistic reasons for the extraordinarily high enantiose-
lectivities achieved with 1 have also been clarified. In brief,
these reactions are channeled through a specific three-
dimensional arrangement of a contact ion pair in which a
nucleophilic site of the substrate is proximate to the
quaternary cationic center in which there is optimum van
der Waals attractive interaction between the two. This
mechanistic insight is important to the design of new catalysts
and the discovery of other catalytic enantioselective reactions
that are subject to control by chiral quaternary ammonium
ions. For some time we have been studying the nucleophilic
epoxidation of R,â-enones to form R,â-epoxy ketones, a
reaction pioneered by Prof. Hans Wynberg7 (with ee’s on
the order of 25%) and subsequently investigated by several
other groups.8,9 In the most recent work9 enantioselectivities
averaging ca. 80% have been reported with benzalacetophe-
(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) Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett.
1999, 40, 3843.
(5) Corey, E. J.; Zhang, F.-Y. Angew. Chem. Intl. Ed. 1999, 38, 1931.
(6) For earlier work on the enantioselective alkylation of the benzophe-
none Schiff base of tert-butyl glycinate, see: (a) O’Donnell, M. J.; Bennett,
W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353. (b) O’Donnell, M. J.;
Wu, S.; Huffman, J. C. Tetrahedron 1994, 50, 4507. (c) Lipkowitz, K. B.;
Cavanaugh, M. W.; Baker, B.; O’Donnell, M. J. J. Org. Chem. 1991, 56,
5181.
(7) (a) Helder, R.; Hummelen, J. C.; Laane, R. W. P. M.; Wiering, J. S.;
Wynberg, H. Tetrahedron Lett. 1976, 1831. (b) Wynberg, H.; Greijdanus,
B. J. Chem. Soc., Chem. Commun. 1978, 427. (c) Hummelen, J. C.;
Wynberg, H. Tetrahedron Lett. 1978, 1089. (d) Wynberg, H.; Marsman,
B. J. Org. Chem. 1980, 45, 158. (e) Pluim, H.; Wynberg, H. J. Org. Chem.
1980, 45, 2498.
10.1021/ol990964z CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/18/1999

none type substrates using our N-9-anthracenylmethylcin-
chonidinium salt1,10 and N-benzylcinchoninium salts.11
Table 1. Enantioselective Epoxidation of (E)-Aroylethylenes
with a Chiral Quaternary Ammonium Catalyst
In this Letter we describe the achievement of truly useful
enantioselectivities for the nucleophilic epoxidation of vari-
ous R,â-enones (ranging from 92 to 98.5% ee for various
benzalacetophenones) and the use of this process for practical
syntheses of chiral R,â-epoxy esters, R-hydroxy esters,
â-hydroxy esters, and â-hydroxy ketones. These results
clearly demonstrate the scope and versatility of the enanti-
oselective epoxidation. Furthermore, because of the high
degree of enantioselection in the epoxidation process, the
analysis of the fundamental factors that are responsible for
enantiocontrol by the rigid chiral cation 1 is greatly
facilitated. Specifically, the data described herein lead to a
simple stereomechanistic rationale in which the chiral cation
assembles the oxidant (OCl-) and the R,â-enone in a specific
three-dimensional arrangement which channels the epoxi-
dation through an energetically and entropically favored
transition state assembly, as detailed below. This pathway
involves structured contact ion pairs, related to those
previously discussed,1,2,5 which allow charge-accelerated
face-selective conjugate addition of ion-paired hypochlorite
to an R,â-enone substrate that is held in proximity by
electrostatic and van der Waals forces.
(ee’s 95-98.5%). A 2,4-dibromophenoxyphenyl group at-
tached to carbonyl also leads to an excellent ee (98%). The
â-substituent on the E-R,â-double bond of the phenyl or
4-substituted phenyl ketone may be varied from aryl to
n-alkyl or cycloalkyl without a major effect on enantiose-
lection.
Of key mechanistic significance is the finding that when
the aromatic ring attached to the carbonyl group of the R,â-
enone is constrained to be coplanar with the carbonyl σ plane,
enantioselection drops precipitously. Thus the R,â-enones 3
and 4 are epoxidized under the standard conditions of Table
The results of our studies on the nucleophilic epoxidation
of 15 substrates are summarized in Table 1 for standardized
conditions as follows: 10 mol % of the dihydrocin-
chonidinium salt 2 as catalyst in toluene at -40 °C with 8
M aqueous potassium hypochlorite12 as the stoichiometric
oxidant. The presence of a phenyl substituent on the carbonyl
carbon is important for enantioselectivity.13 Further, the
4-fluorophenyl substituent is definitely better than phenyl
(8) (a) Mazaleyrat, J. P. Tetrahedron Lett. 1983, 24, 1243. (b) Shi, M.;
Kazuta, K.; Satoh, Y.; Masaki, Y. Chem. Pharm. Bull. 1994, 42, 2625. (c)
Shi, M.; Masaki, Y. J. Chem. Res. 1994, 250. (d) Baba, N.; Oda, J.;
Kawaguchi, M. Agric. Biol. Chem. 1986, 50, 3113.
(9) (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1998, 39, 1599.
(b) Lygo, B.; Wainwright, P. G. Tetrahedron 1999, 55, 6289.
(10) For the original publication on the use of the N-9-anthracenylmethyl
group as a rigidifying element with cinchonidinium derivatives, see: Corey,
E. J.; Noe, M. C.; Ting, A. Y. Tetrahedron Lett. 1996, 37, 1735.
(11) Arai, S.; Tsuge, H.; Shioiri, T. Tetrahedron Lett. 1998, 39, 7563.
(12) Potassium hypochlorite solution (8.0 M) was prepared by treatment
of 50% aqueous potassium hydroxide with chlorine and filtration of the
precipitate of KCl. The resulting cold light straw-colored solution must be
used promptly or stored at -20 °C since it is unstable above 0 °C. Potassium
hypochlorite is superior to sodium hypochlorite because it leads to more
rapid and more enantioselective epoxidation under phase transfer conditions
with 2.
1 to give products of only 76 and 61% ee, respectively. These
results argue that the highly enantioselective epoxidations
summarized in Table 1 probably proceed via transition states
in which the phenyl substituent and the carbonyl σ plane
are nonplanar, i.e., out of π-conjugation. An important feature
of this geometrical orthogonality is that it allows placement
of the R,â-enone structures listed in Table 1 in a binding
mode with quaternary ammonium 2 similar to that which
explains a number of other highly enantioselective reactions
(13) The epoxidation of a variety of R,â-enones with alkyl or other non-
phenyl groups attached to carbonyl under the standard conditions defined
herein leads to only modest enantioselection.
1288
Org. Lett., Vol. 1, No. 8, 1999

catalyzed by 1 or 2.1-5 The specific three-dimensional
arrangement of cation 2, benzal-4-fluoroacetophenone, and
hypochlorite ion which is consistent with previous results
and also with all the data reported herein for nucleophilic
epoxidation of R,â-enones by hypochlorite is shown in Figure
1. In this figure, two different views of the complex are
philic attack also favors reaction via the assembly shown in
Figure 1, along the lines previously discussed for enanti-
oselective nitroaldol reactions catalyzed by 1.5 Another
feature of this geometry is that it allows a smooth transition
of the resulting conjugate adduct to the R,â-epoxy ketone
and Cl- with the latter contact ion paired to cation 2. Most
importantly, the three-dimensional arrangement shown in
Figure 1 corresponds unambiguously to the enantiomeric
preference, i.e., absolute stereoselectivity, which has been
observed experimentally.14 We believe that these insights
(14) The beneficial effect of the 4-fluoro substituent in the examples of
Table 1 relative to hydrogen (X ) F or H) may be due to a stronger edge
interaction of 4-fluorophenyl as compared with phenyl with the contacting
quinoline ring, as shown in Figure 1.
(15) For a prior report of Baeyer-Villiger reactions of R,â-epoxy phenyl
ketones to form R,â-epoxy acid phenyl esters, see: Baures, P. W.; Eggleston,
D. S.; Flisak, J. R.; Gombatz, K.; Lantos, I.; Mendelson, W.; Remich, J. J.
Tetrahedron Lett. 1990, 45, 6501.
(16) Baeyer-Villiger products were prepared from a number of the R,â-
epoxy benzalacetophenones shown in Table 1 (X ) H) using m-
chloroperbenzoic acid (m-CPBA) in CH2Cl2 at reflux for 16 h in the
indicated yields: R ) C6H5 (81%); R ) cyclo-C6H11 (74%); R ) 4-Cl-
C6H4 (82%); R ) 4-NO2-C6H4 (84%); R ) â-naphthyl (87%); R ) 4-CH3-
C6H4 (73%).
(17) Representative Procedure for Epoxidation: 4′-Fluorochalcone.
A mixture of 4′-fluorochalcone (226 mg, 1.0 mmol), chiral quaternary
ammonium salt 2 (66 mg, 0.1 mmol), and toluene (10 mL) was cooled to
-40 °C and treated with an aqueous solution of potassium hypochlorite
(0.63 mL, 5.0 mmol, 8.0 M). After stirring at -40 °C for 12 h, the solvent
was removed under reduced pressure and the solid quaternary ammonium
salt was precipitated by addition of hexanes-ether (4:1) to give after
filtration 53 mg of the chiral catalyst for reuse (80% recovery). The filtrate
was washed with water and brine, concentrated, and chromatographed (silica
gel, 6:1 hexanes-ethyl acetate) to afford 225 mg of (2S,3R)-trans-2,3-epoxy-
3-phenyl-1-(4-fluorophenyl)propan-1-one (93% yield, 98% ee): mp 86-
87 °C; [R]23D ) +213.4 (c ) 2.0, CH2Cl2); IR (film) 1681.7, 1598.3, 1237.5,
1
1229.4, 1158.3, 885.2 cm-1; H NMR (400 MHz, CDCl3) 8.08-8.04 (m,
2H), 7.41-7.36 (m, 5H), 7.18-7.14 (m, 2H), 4.24 (d, J ) 1.8 Hz, 1H),
4.07 (d, J ) 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) 191.6, 166.3 (d, J
) 255.0 Hz), 135.4, 131.9 (d, J ) 3.1 Hz), 131.2 (d, J ) 9.1 Hz), 129.2,
128.9, 125.8, 116.2 (d, J ) 21.5 Hz), 61.1, 59.3 ppm; HRMS (EI+) calcd
for [C15H11FO2]+ 242.0743, found 242.0741. Enantioselectivity was
determined by HPLC analysis using a Chiralcel OB-H column and 5%
isopropyl alcohol in hexanes as eluent on 0.5 mL/min at 23 °C, 254 nm, tR
) 44.9 min (major), tR ) 59.9 min (minor).
(18) Baeyer-Villiger Oxidation of (2S,3R)-trans-2,3-Epoxy-1,3-diphe-
nylpropan-1-one. A solution of (2S,3R)-trans-2,3-epoxy-1,3-diphenylpro-
pan-1-one (202 mg, 0.9 mmol, 93% ee) and m-chloroperoxybenzoic acid
(650 mg, 2.7 mmol) in 5 mL of methylene chloride was heated at reflux
for 16 h. The mixture was stirred with saturated aqueous sodium bisulfite
at 23 °C for 2 h and then washed with a saturated sodium bicarbonate
solution and brine. After evaporating, the residue was purified by flash
chromatography (silica gel, 10:1 hexanes-ethyl acetate) to give 175 mg of
(2S,3R)-phenyl-trans-2,3-epoxy-3-phenyl propionate (81% yield, 93% ee):
mp 87-89 °C; [R]23D ) +169.6 (c ) 1.0, THF); IR (film) 1754.1, 1457.9,
Figure 1.
displayed which are related by a 180° rotation about the
vertical axis. The hypochlorite ion is contact ion-paired with
the sole accessible face of the charged nitrogen with the Cl
of ClO- and N+ as nearest neighbors. The R,â-enone in the
complex is situated so that the 4-fluorophenyl group is
wedged between the ethyl and quinoline substituents on the
quinuclidine ring and simultaneously the carbonyl oxygen
is placed as close to N+ as permitted by van der Waals forces.
In this arrangement the nucleophilic oxygen of ClO- is
proximate to the â-carbon of the R,â-enone, i.e., correctly
positional for nucleophilic epoxidation by conjugate addition.
In fact, as the nucleophilic attack occurs, the negative charge
which is developed at the carbonyl oxygen in the transition
state is electrostatically stabilized by the proximate N+ of
catalyst 2. Thus, cationic charge acceleration of the nucleo-
1
1263.6, 1204.5, 893.9 cm-1; H NMR (400 MHz, CDCl3) 7.43-7.16 (m,
10H), 4.26 (d, J ) 1.6 Hz, 1H), 3.74 (d, J ) 1.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) 166.7, 150.2, 134.6, 129.6, 129.2, 128.8, 126.3, 125.9, 121.2,
58.4, 56.7 ppm. Enantioselectivity was determined by HPLC analysis with
a Chiralcel OD column, 3% isopropyl alcohol in hexanes, 1.0 mL/min, 254
nm, tR ) 13.7 min (minor), tR ) 15.1 min (major).
(19) Preparation of (S)-Phenyl 2-Hydroxyl-3-phenylpropionate. A
mixture of (2S,3R)-phenyl-trans-2,3-epoxy-3-phenyl propionate (24 mg, 0.1
mmol), 5% Pd-C (10 mg), and THF (1 mL) was hydrogenated with 1 atm
of hydrogen at ambient temperature for 1 h. After filtering and evaporating,
23 mg of the desired product was obtained (95% yield, 92% ee): mp 80-
81 °C; [R]23D ) -15.7 (c ) 1.5, CH2Cl2); IR (KBr) 3457.6, 3425.0, 2930.3,
1751.0, 1494.3, 1486.3, 1401.9, 1213.9, 1196.5, 1170.9, 1155.2, 1093.2
cm-1 1H NMR (400 MHz, CDCl3) 7.41-7.26 (m, 8H), 7.04-7.01 (m,
;
2H), 4.73 (dt, J ) 6.3 and 4.7 Hz, 1H), 3.30 (dd, J ) 14.0 and 4.7 Hz,
1H), 3.19 (dd, J ) 14.0 and 6.3 Hz, 1H), 2.79 (d, J ) 6.5 Hz, 1H); 13C
NMR (100 MHz, CDCl3) 172.8, 150.3, 136.0, 129.7, 129.6, 128.6, 127.2,
126.3, 121.2, 71.4, 40.6 ppm; HRMS (CI+) calcd for [C15H14O3 + NH4]+
260.1287, found 260.1292. Enantioselectivity was determined by HPLC
analysis with a Chiralcel OD column, 10% isopropyl alcohol in hexanes,
1.0 mL/min, 254 nm, tR ) 13.4 min (minor), tR ) 15.0 min (major).
Org. Lett., Vol. 1, No. 8, 1999
1289

Finally, it should be noted that the highly enantioselective
epoxidations which are described herein afford access to a
wide variety of highly useful organic intermediates of
excellent enantiomeric purity, including R,â-epoxy esters15,16
and acids, R-hydroxy ketones or acids, and â-hydroxy
ketones or acids, as shown in Scheme 1.17-20
Scheme 1
Acknowledgment. This research was assisted financially
by grants from the National Science Foundation and the
National Institutes of Health.
OL990964Z
(20) Determination of Enantioselectivities for the Epoxidations Sum-
marized in Table 1. HPLC analysis of the epoxy ketones listed in Table
1 were carried out using commercially available chiral columns with
isopropyl alcohol-hexanes as eluent at 23 °C and detection at 254 nm.
For each product of Table 1, the corresponding enantiomers of a racemic
reference sample of epoxy ketone were cleanly separated under the
conditions used for analysis. The following chiral columns were used for
the products in Table 1: for entries 1, 6, 7, and 13, Whelk 01 column
(Regis Co.); for entries 2, 3, 11, and 14, OB-H column (Chiral Technologies
Inc.); for entries 4, 9, 10, 12, and 15, OD column (Chiral Technologies
Inc.); for entries 5 and 8, OJ column (Chiral Technologies Inc.).
unify all the highly enantioselective catalytic reactions of 1
and 2 which are now known and, at the same time, provide
a conceptual basis for the rational development of new
enantioselective processes under chiral cation control.
1290
Org. Lett., Vol. 1, No. 8, 1999