Metal-template effect in the asymmetric Weitz-Scheffer epoxidation of α,β-enones by an optically active hydroperoxide [10]

Full text of DOI:10.1021/ja9945008

5654
J. Am. Chem. Soc. 2000, 122, 5654-5655
Table 1. Enantioselective Weitz-Scheffer Epoxidation of
R,â-Enones 2 by S-(-)-(1-Phenyl)ethyl Hydroperoxide (1)a
Metal-Template Effect in the Asymmetric
Weitz-Scheffer Epoxidation of r,â-Enones by an
Optically Active Hydroperoxide
Waldemar Adam,* Paraselli Bheema Rao,
Hans-Georg Degen, and Chantu R. Saha-Mo¨ller
Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg
D-97074 Wu¨rzburg, Germany
ReceiVed December 30, 1999
Recently we have reported the synthesis of optically active
hydroperoxides by enzymatic kinetic resolution1 and utilized these
hydroperoxides in the Ti(IV)-catalyzed asymmetric oxidation of
sulfides and allylic alcohols.2 To date, such optically active
hydroperoxides have not been employed for the asymmetric
epoxidation of electron-deficient olefins, for example, in the
Weitz-Scheffer epoxidation of R,â-enones. After the seminal
work of Wynberg and co-workers,3 this preparatively valuable
oxidation of R,â-enones under basic conditions has received much
attention during the past few years. For this purpose, a variety of
asymmetric methods has been developed, which include the use
of molecular oxygen and diethylzinc in the presence of (R,R)-
N-methylpseudoephedrine4 or optically active polybinaphthyl
derivatives.5 Good enantioselectivities have also been achieved
with hydrogen peroxide in the presence of polypeptides6 or chiral
platinum(II) complexes.7 Achiral alkyl peroxides in conjunction
with optically active lanthanide-binaphthol complexes8 or with
diethyl (+)-tartrate9 as chiral auxiliaries have provided as well
high enantioselectivities. Lately, Wynberg’s approach of using
optically active quarternary ammonium salts as phase-transfer
catalysts for such epoxidations has been significantly extended.10
Herein we report our preliminary results on the first application
of the optically active S-(-)-(1-phenyl)ethyl hydroperoxide (1)
for the enantioselective Weitz-Scheffer epoxidation of R,â-
enones, in which we demonstrate that enantioselectivities up to
90% ee may be achieved, if the appropriate substrates and
a Epoxidations were carried out on 0.1-0.5 mmol of the enone 2,
1.0 equiv of hydroperoxide 1 and 2-3 equiv of base; quantitative
consumption of both the enone 2 and hydroperoxide 1 was observed.
bYield of isolated epoxide 3; no cis-epoxide was observed. cDetermined
by HPLC analysis on chiral columns with 2-propanol-hexane as eluent
and detection at 260 nm; for entries 1-3 and 8-12 an OD column
and for entries 4-6 and 13 an OB-H column were used, error e3%
of the stated values. dConfiguration of the major enantiomer was
determined by comparison with literature data; for refs see Supporting
Information. eThe epoxidation was carried out at ∼20 °C; RR,âS-3a is
the major enantiomer.
conditions are utilized. These results are summarized in Table 1,
which are rationalized mechanistically in terms of steric effects
between the â substituent in the enone substrate and the groups
on the chirality center of the hydroperoxide oxygen donor in the
potassium-coordinated template.
* Corresponding author. Fax: (+)49-931-888 4756; E-mail: adam@
chemie.uni-wuerzburg.de. Internet: http://www-organik.chemie.uni-wuerzburg.de.
(1) (a) Adam, W.; Hoch, U.; Lazarus, M.; Saha-Mo¨ller, C. R.; Schreier, P.
J. Am. Chem. Soc. 1995, 117, 11898-11901. (b) Adam, W.; Fell, R. T.; Hoch,
U.; Saha-Mo¨ller, C. R.; Schreier, P. Tetrahedron: Asymmetry 1995, 6, 1047-
1050.
(2) (a) Adam, W.; Korb, M. N.; Roschmann, K. J.; Saha-Mo¨ller, C. R. J.
Org. Chem. 1998, 63, 3423-3428. (b) Adam, W.; Korb, M. N. Tetrahedron:
Asymmetry 1997, 8, 1131-1142.
(3) (a) Helder, R.; Hummelen, J. C.; Laane, R. W. P. M.; Wiering, J. S.;
Wynberg, H. Tetrahedron Lett. 1976, 17, 1831-1834. (b) Wynberg, H.;
Greijdanus, B. J. Chem. Soc., Chem. Commun. 1978, 427-428. (c) Wynberg,
H.; Marsman, B. J. Org. Chem. 1980, 45, 158-161. (d) Plium, H.; Wynberg,
H. J. Org. Chem. 1980, 45, 2498-2502.
(4) Enders, D.; Zhu, J.; Kramps, L. Liebigs Ann./Recl. 1997, 1101-1113.
(5) Yu, H.-B.; Zheng, X.-F.; Lin, Z.-M.; Hu, Q.-S.; Huang, W.-S.; Pu, L.
J. Org. Chem. 1999, 64, 8149-8155.
After screening diverse inorganic bases and solvents under a
variety of experimental conditions, we found that the asymmetric
epoxidation of enone 2a by the hydroperoxide S-(-)-1 proceeded
smoothly with KOH as a base in CH3CN. At -40 °C, within
10-20 min the epoxide 3a is obtained quantitatively with an ee
value of 51% and preference for the (+)-enantiomer (entry 1,
Table 1). Comparison of the sign of the optical rotation with the
literature data11 revealed that the (+)-enantiomer of the epoxy
ketone 3a possesses the RS,âR configuration. Thus, the observed
enantioselectivity derives from the preferential attack of the chiral
hydroperoxide on the Re face of the S-cis conformation of the E
enone 2a to afford the (RS,âR)-3a epoxide as major enantiomer,
whereas the attack at the Si face leads to the (RR,âS)-epoxy ketone
3a (Scheme 1). Substitution on the aromatic ring of the enone
carbonyl function by p-Me, p-OMe, p-Br groups (entries 4-6)
does not change the enantioselectivity, the ee values are within
the experimental error. In contrast, a definite trend to higher ee
values is displayed by para substituents on the â-phenyl group in
the order p-OMe > p-Me > p-NO2 (entries 7-9). Thus, electron-
donating â-aryl groups enhance the enantioselectivity, but to a
minor extent. Also the â-methyl substituent in the enone 2h (entry
(6) (a) Julia, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. Engl. 1980,
19, 929-931. (b) Kroutil, W.; Lasterra-Sanchez, M. E.; Maddrell, S. J.; Mayon,
P.; Morgan, P.; Roberts, S. M.; Thornton, S. R.; Todd, C. J.; Tu¨ter, M. J.
Chem. Soc., Perkin Trans. 1 1996, 2837-2844. (c) Itsuno, S.; Sakakura, M.;
Ito, K. J. Org. Chem. 1990, 55, 6047-6049. (d) Pu, L. Tetrahedron:
Asymmetry 1998, 9, 1457-1477. (e) Ebrahim, S.; Wills, M. Tetrahedron:
Asymmetry 1997, 8, 3163-3173. (f) Porter, M. J.; Roberts, S. M.; Skidmore,
J. Bioorg. Med. Chem. 1999, 7, 2145-2156.
(7) Baccin, C.; Gusso, A.; Pinna, F.; Strukul, G. Organometallics 1995,
14, 1161-1167.
(8) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am.
Chem. Soc. 1997, 119, 2329-2330.
(9) Elston, C. L.; Jackson, R. F. W.; MacDonald, S. J. F.; Murray, P. J.
Angew. Chem., Int. Ed. Engl. 1997, 36, 410-412.
(10) (a) Lygo, B.; Wainwright, P. G. Tetrahedron 1999, 55, 6289-6300.
(b) MacDonald, G.; Alcaraz, L.; Lewis, N. J.; Taylor, R. J. K. Tetrahedron
Lett. 1998, 39, 5433-5436. (c) Arai, S.; Tsuge, H.; Shioiri, T. Tetrahedron
Lett. 1998, 39, 7563-7566. (d) Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1,
1287-1290.
(11) Marsman, B.; Wynberg, H. J. Org. Chem. 1979, 44, 2312-2314.
10.1021/ja9945008 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/27/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 23, 2000 5655
Scheme 1. Enatioselectivity for the Epoxidation of Enone 2a
oxygen-atom transfer from the K+-coordinated peroxide anion
to the â carbon atom of the K+-ligated enone substrate, the latter
must assume a S-cis conformation. But this does not suffice,
because an additional structural requirement is that during the
oxygen-atom transfer the energetically favored 90-120° dihedral
angle of the peroxide bond should be fulfilled,12 as exhibited in
the transition structures of Scheme 2. The pertinent steric inter-
actions that ensue in these geometrical arrangements are between
the substituents of the hydroperoxide chirality center and the
â-tert-butyl group of the enone 2i substrate in the K+-coordinated
template. The sterically largest group, namely the phenyl one,
needs to point away (outward of the paper plane), which brings
either the hydrogen atom (Re-face attack) or the methyl group
(Si-face attack) in close proximity of the tert-butyl group at the
reaction center (the â carbon atom of the enone substrate).
Evidently, oxygen transfer from the Re face is energetically
preferred and the RS,âR-epoxide enantiomer formed predomi-
nantly, as is observed experimentally (Table 1). Complexation
of the K+ ion by the crown ether (entries 2 and 12) destroys the
template effect, and enantio-control breaks down. Alternatively,
for the organic base DBU (entry 3), a template is not possible
and again low enantionselectivity results.
Scheme 2. Metal Template Effect for the Epoxidation of
Enone 2i
One structural feature in the transition state in Scheme 2 may
be controlled at will, namely the S-cis conformation of the enone,
by selecting a substrate in which this arrangement is rigidly fixed.
For this purpose, the cyclic derivative 2j (entry 13) with an
exomethylene substituent was chosen. Gratifyingly, an ee value
as high as 90% was achieved for the (RS,âR)-epoxide 3i (Re-
face attack). This is the highest enantioselectivity ever obtained
in the asymmetric oxyfunctionalization with optically active
hydroperoxides.2,13 The high enantioselectivity that has been
achieved for the rationally designed substrate 2i validates the
mechanistic construct offered in Scheme 2.
In summary, in this novel asymmetric Weitz-Scheffer epoxi-
dation mode, the attack of the optically active hydroperoxide
S-(-)-1 on the Re face of the S-cis conformation of enone 2 has
been rationalized in terms of minimized steric repulsions between
the substituents at the hydroperoxide chirality center and the enone
â-substituent. Responsible for the good enantioselectivity is the
simultaneous coordination of the metal ion to the R,â-enone 2
and hydroperoxide S-(-)-1 (template effect). This unprecedented
methodology, that is, the direct use of an optically active oxidant,
offers attractive opportunities in asymmetric synthesis.
10) leads to ee values similar to those by the â-phenyl one in the
enone 2a (entry 1); but more significantly, the same sense in the
enantioselectivity is observed, namely Re face attack, to afford
the RS,âR-enantiomer. For the sterically more demanding â-tert-
butyl group in the substrate 2i (entry 11), an ee value as high as
75% has been achieved, which represents a substantial improve-
ment in the Re-face stereocontrol.
When the epoxidation of substrate 2a was carried out with DBU
as organic base (entry 3), compared to the inorganic base KOH
(entry 1), the ee value is reduced from 51 to 9%, and even the
opposite enantiomer is favored. Evidently, the potassium metal
ion is important for the high enantio-control, and to substantiate
this, the reaction with KOH was performed in the presence of
18-crown-6 ether as chelating agent under otherwise identical
reaction conditions. It is mechanistically noteworthy that in the
epoxidation of the â-phenyl enone 2a (entry 2), and even more
so, the tert-butyl one 2i (entry 12), the enantioselectivity was
almost negligible in the presence of 18-crown-6 ether. As antic-
ipated, the potassium ion is playing a pivotal role in generating
preferentially the (RS,âR)-epoxides 3, that is, the potassium ion
steers the Re-face attack on the enone (Scheme 2). The â-tert-
butyl-substituted enone 2i has been chosen as the substrate in
Scheme 2 because it displays the highest ee value of the
derivatives in Table 1 discussed as far and, thus, the pertinent
steric interactions are most pronounced, which facilitates their
illustration.
Acknowledgment. We are grateful to the DFG (SFB-347 “Selektive
Reaktionen Metall-aktivierter Moleku¨le) and the Fonds der Chemischen
Industrie (Doctoral Fellowship 1998-2000 for H.-G.D.) for generous
financial support. P.B.R. thanks the Alexander-von-Humboldt Foundation
for a Postdoctoral Fellowship (1999-2000).
Supporting Information Available: Experimental procedure for the
asymmetric epoxidation and conditions for the chiral HPLC analysis of
the epoxides 3 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
What is the electronic and structural nature of this metal-ion
steering effect? It is the simultaneous coordination (template
effect) of the metal ion to the lone pair of the carbonyl oxygen
atom in the enone 2a and the distal oxygen atom of the peroxide
functionality of the S-(-)-1 hydroperoxide, which presumably
governs the π-facial differentiation. For effective nucleophilic
JA9945008
(12) Kalinowski, H. O.In Methods of Organic Chemistry (Houben Weyl),
4th ed.; Kropf, H., Ed; G. Thieme: Stuttgart, New York, 1995; Vol. E 13, pp
5-24.
(13) Hamann, H.-J.; Hoeft, E.; Mostowicz, D.; Mishnev, A.; Urbanzyk-
Lipkowska, Z.; Chmielewski, M. Tetrahedron 1997, 53, 185-192.